The EU HTA Regulation: Evidence Planning When Regulators and Payers Converge

The regulatory architecture for health technologies in Europe is undergoing a structural shift that moves beyond traditional market access boundaries. For decades, the European Union has harmonized the requirements for placing a medical product on the internal market through the centralized procedure for drugs and the conformity assessment frameworks for devices. However, the determination of whether a health system will actually pay for—and provide access to—these technologies has remained firmly within the domain of individual Member States. This separation between regulatory authorization (safety and efficacy) and reimbursement decision-making (value and cost-effectiveness) has created a fragmented landscape where a technology approved by the European Medicines Agency (EMA) might be readily available in one country but inaccessible in another due to divergent Health Technology Assessment (HTA) methodologies and requirements. The Regulation (EU) 2021/2282 on health technology assessment, commonly known as the EU HTA Regulation, seeks to bridge this divide by introducing a mandatory, cooperative procedure for the joint clinical assessment of certain health technologies. This legislation represents a pivotal moment for the life sciences industry, fundamentally altering the timeline and substance of evidence generation. It compels developers to integrate reimbursement expectations into their clinical development strategies much earlier in the product lifecycle, effectively converging the distinct worlds of regulatory science and health economics.

The Legal Architecture and Scope of the Regulation

At its core, the EU HTA Regulation establishes a framework for cooperation among Member States to conduct joint clinical assessments (JCAs) of the relative clinical effectiveness and safety of health technologies. It is crucial to understand that this Regulation does not replace national decision-making. Member States retain full sovereignty over pricing and reimbursement decisions. Instead, the Regulation creates a common evidence base—a “joint clinical assessment report”—that Member States are required to use as a reference point within their own procedures. The goal is to reduce duplication of effort, prevent manufacturers from having to answer varying evidentiary questions across different jurisdictions, and ultimately facilitate faster patient access to innovative technologies.

The scope of the Regulation is defined precisely, though it is being phased in. Initially, the mandatory JCA procedure applies to new medicines that receive central marketing authorization and fall into specific categories: advanced therapy medicinal products (ATMPs), medicinal products designated as orphan drugs, or medicinal products intended for the treatment or prevention of a rare disease. It also covers medicinal products that contain a new active substance and are intended for the treatment of a serious condition for which there is currently no satisfactory treatment method available in the Union, or which offer a significant therapeutic advantage.

For medical devices and in vitro diagnostic medical devices, the Regulation establishes a voluntary cooperation mechanism initially, with the possibility of moving to mandatory assessments in the future once the necessary implementing acts are in place. This distinction is vital for biotech and medtech companies; while drugs face immediate mandatory JCAs, device manufacturers should prepare for a similar shift in the evidentiary landscape, as the methodology for joint assessment will likely influence national payers’ expectations even before it becomes mandatory.

Joint Clinical Assessment (JCA) vs. Joint Scientific Consultation (JSC)

The Regulation introduces two primary mechanisms that operate at different stages of the product lifecycle: the Joint Scientific Consultation (JSC) and the Joint Clinical Assessment (JCA).

The Joint Scientific Consultation (JSC) is a voluntary mechanism that allows developers to seek coordinated advice from a group of Member States regarding their proposed clinical investigation plans or evidence generation strategies. This is akin to a parallel scientific advice procedure but involves multiple HTA bodies and regulators simultaneously. The key value proposition of the JSC is that it provides developers with an opportunity to align their clinical development programs with the evidentiary requirements of payers and HTA bodies across Europe before significant resources are committed to late-stage trials. It addresses questions regarding the suitability of proposed comparators, the relevance of endpoints, and the feasibility of the trial design from a reimbursement perspective.

The Joint Clinical Assessment (JCA), conversely, is mandatory for in-scope medicines at the time of or shortly after marketing authorization. This assessment focuses strictly on the relative clinical effectiveness and safety of the technology compared to available alternatives. It does not include economic evaluations (cost-effectiveness) or broader social/ethical considerations; these remain the responsibility of the Member States. The JCA produces a structured report that answers specific key questions about the technology, which Member States then utilize in their national appraisal processes.

Strategic Implications for Evidence Planning

The convergence of regulatory and reimbursement expectations under the EU HTA Regulation necessitates a paradigm shift in evidence planning. Historically, many companies adopted a linear approach: secure regulatory approval first, then gather health economic data for reimbursement submissions. This “regulatory-first” mindset is no longer viable for in-scope technologies. The JCA requires robust clinical evidence at the time of marketing authorization application (MAA), meaning the evidence generation strategy must be designed to satisfy both regulatory efficacy standards and HTA requirements for comparative effectiveness.

Early Alignment and the Value Proposition

The most significant change is the need for early alignment. The JSC mechanism is the primary tool for this, but even companies that choose not to utilize JSC must now anticipate HTA questions during the clinical development phase. This involves making critical decisions about trial design much earlier.

For instance, the choice of comparator is a central point of friction between regulators and HTA bodies. A regulatory trial might use a placebo if the condition is serious and no standard of care exists. However, an HTA body will almost certainly require a comparison against the current standard of care (SoC) to determine relative effectiveness. If a developer proceeds with a placebo-controlled trial without having secured buy-in from HTA bodies, they risk generating a dataset that is insufficient for a JCA, leading to delays in reimbursement and market access. Through the JSC, developers can negotiate the acceptability of non-inferiority designs or the feasibility of indirect comparisons if head-to-head data is not available.

Effective evidence planning now requires a “payer mindset” during Phase II trials. The design of pivotal studies must account for the need to demonstrate not just statistical significance against a control, but clinical meaningfulness against the relevant standard of care in a way that aligns with the diverse requirements of European health systems.

Endpoints and Patient-Reported Outcomes

HTA bodies place a high value on endpoints that reflect patient benefit in real-world settings. While regulators may accept surrogate endpoints for accelerated approval, HTA bodies generally require data on clinical outcomes that matter to patients and health systems (e.g., hospitalizations, quality of life, survival). The EU HTA Regulation emphasizes the need for evidence that is relevant to the decision-making context of Member States.

This places a premium on including patient-reported outcomes (PROs) and health-related quality of life (HRQoL) measures in clinical trials. Furthermore, the JCA process looks at the technology across its entire lifecycle. Therefore, evidence plans should include provisions for collecting real-world evidence (RWE) to support long-term effectiveness and safety claims. The Regulation acknowledges the potential of RWE, and developers should be prepared to discuss how RWE will be generated and used to complement clinical trial data, particularly for rare diseases where long-term follow-up is essential.

Operationalizing the JCA Process

Understanding the mechanics of the JCA is essential for operational teams. The process is managed by the Health Technology Assessment Coordination Group (HTACG), which comprises representatives from Member States. The manufacturer submits a dossier containing the necessary clinical data, and the HTACG selects a group of Member States (the “assessment cooperation group”) to perform the assessment.

The Assessment Cooperation Group

The selection of Member States is not random. It is based on the specific technology and the therapeutic area. The group typically includes countries that have a high volume of patients for that condition or possess specific expertise. This is a critical detail for companies: the assessment will be conducted by a diverse group of payers and HTA experts who may have different methodological preferences. For example, the German Institute for Quality and Efficiency in Health Care (IQWiG) has a very specific methodology for assessing benefits, often differing from the approach taken by the National Institute for Health and Care Excellence (NICE) in the UK or the Haute Autorité de Santé (HAS) in France.

While the JCA aims to harmonize the output, the process involves negotiation among these diverse stakeholders. The final JCA report represents a consensus view. However, companies must be aware that the “consensus” may result in a report that highlights uncertainties or gaps in evidence that individual countries might probe further during their national pricing and reimbursement (APR) processes.

Timelines and Interactions

The Regulation sets out strict timelines for the JCA process. The assessment must be completed within a specific period following the submission of the dossier. This predictability is intended to help companies plan their market access activities. However, the interaction between the JCA and the national APR process is complex.

Once the JCA report is finalized, it is published and made available to all Member States. The national authorities are obliged to take the report into account. In practice, this means that the JCA report will form the technical backbone of the national appraisal. In some countries, the national body will essentially “adopt” the JCA findings regarding clinical effectiveness and focus their own resources on the economic evaluation. In others, the national body may re-analyze the data or ask additional questions, although they must justify why they are deviating from the JCA findings.

Timeline Consideration: The mandatory JCA applies to medicines authorized after 1 January 2025. For technologies in development, this means that clinical trials designed to read out after this date must be JCA-ready. Companies currently in Phase II need to finalize their Phase III protocols with the JCA requirements in mind.

Distinguishing EU-Level Harmonization from National Implementation

It is a common misconception that the EU HTA Regulation creates a “European price” or a centralized reimbursement authority. This is not the case. The distinction between the EU-level assessment and national implementation is the defining feature of the Regulation.

The Role of the Joint Clinical Assessment Report

The JCA report answers specific questions regarding the relative clinical effectiveness and safety of the technology. It provides a common set of facts. However, the translation of these facts into a funding decision involves variables that remain national competence:

• Budget Impact: The financial impact on the national health budget.
• Cost-Effectiveness Thresholds: The specific willingness-to-pay thresholds (e.g., £20,000 per QALY in the UK context, though this varies).
• Equity and Ethical Considerations: Societal values regarding the prioritization of certain patient groups.
• Legal Status: The specific legal framework for reimbursement (e.g., the difference between the German “AMNOG” system and the French “LEEM” negotiation).

Therefore, a “positive” JCA report does not guarantee a positive reimbursement decision in every country. Conversely, a negative JCA report makes a positive national decision extremely difficult, as the national body would have to justify overturning the consensus view of multiple European experts.

Comparative Analysis of National Approaches

While the JCA provides a common evidence base, the national adaptation varies significantly. We can observe three broad archetypes of implementation across Europe:

The “Evidence-Heavy” Systems (e.g., Germany, France)

In countries like Germany, the JCA report will likely be integrated directly into the early benefit assessment (Early Benefit Assessment under AMNOG). The German system is highly methodological and relies heavily on the “G-BA” (Federal Joint Committee) determining the added benefit. Here, the JCA report serves as a critical input, but the G-BA retains the power to interpret the data. If the JCA report identifies significant uncertainty, the German system tends to default to “no proven added benefit,” leading to price erosion. Companies must ensure their JCA dossier addresses the specific methodological standards expected by IQWiG to survive the national transition.

The “Negotiation-Heavy” Systems (e.g., Italy, Spain)

In Southern European countries, the process is often less rigidly methodological and more focused on budget impact and confidential discounts. The JCA report provides the technical justification for the negotiation, but the actual price is determined through bilateral discussions between the manufacturer and the regional or national health authorities. In these systems, the JCA helps standardize the technical dialogue, reducing the need for local evidence generation, but the commercial strategy remains paramount.

The “Integrated” Systems (e.g., Benelux, Nordics)

Countries like the Netherlands or Sweden often use HTA bodies (such as Zorginstituut Nederland or TLV) that balance clinical effectiveness with cost-effectiveness in a transparent process. The JCA report fits neatly into these systems as the source of clinical evidence, allowing the national body to focus on the economic modeling. The risk here is that if the clinical evidence from the JCA is not robust enough to support a specific economic model, the technology may fail to reach the necessary cost-effectiveness ratio.

For a biotech company, this means that while the JCA reduces the burden of generating country-specific clinical evidence, it does not eliminate the need for a sophisticated country-specific market access strategy. The JCA creates a level playing field regarding the *facts*, but the *interpretation* of those facts remains a national sport.

Impact on Biotech and Small-to-Medium Enterprises (SMEs)

The EU HTA Regulation poses specific challenges for SMEs and biotech companies. The resources required to prepare a JCA dossier and participate in JSCs are substantial. The level of detail required in the evidence submission is higher than what is typically required for a standard regulatory submission.

However, the Regulation also offers opportunities. The JSC mechanism allows SMEs to obtain high-level, coordinated advice that can prevent costly mistakes in clinical development. For a small company with a novel therapy, knowing early on that a specific comparator is required by European payers can save years of development time and millions of euros.

The key for SMEs is to view the JCA not as a regulatory hurdle, but as a strategic planning tool. By engaging with the JSC early, SMEs can:

1. Validate their Clinical Strategy: Ensure that the trial design will generate evidence acceptable to payers across Europe.
2. Identify Unmet Needs: Use the consultation to refine the value proposition based on the specific questions Member States ask.
3. Prepare for the Dossier: Understand exactly what data needs to be collected and how it should be structured for the JCA submission.

Furthermore, the Regulation includes support mechanisms for SMEs, including simplified procedures and guidance documents. It is imperative for SMEs to leverage these resources and seek expert counsel to navigate the procedural complexities.

Practical Steps for Evidence Planning

For professionals working in clinical development, regulatory affairs, and market access, the EU HTA Regulation requires a cross-functional approach. The silos between clinical development and market access must be dismantled.

Integrating HTA into Clinical Development Plans (CDP)

The Clinical Development Plan is no longer solely a regulatory document. It must now explicitly address HTA requirements. This involves:

• Comparator Selection: Justifying the choice of comparator not just on scientific grounds, but on grounds of clinical relevance to European health systems.
• Endpoint Strategy: Including endpoints that are recognized by HTA bodies (e.g., EQ-5D for QALYs) alongside regulatory endpoints.
• Subgroup Analysis: Planning for subgroup analyses that address the heterogeneity of patient populations across different European countries.
• Data Quality: Ensuring that data collection is rigorous enough to withstand the scrutiny of a JCA, where every data point may be questioned by multiple assessors.

The Role of Real-World Evidence (RWE)

The Regulation explicitly mentions the use of RWE. In the context of the JCA, RWE can be used to:

• Support extrapolation of trial results to broader populations.
• Provide long-term safety and effectiveness data where clinical trial follow-up is limited.
• Compare the technology against standard of care in a real-world setting if head-to-head randomized controlled trial (RCT) data is not available.

However, the quality of RWE is paramount. The JCA assessors will require robust methodologies for generating and analyzing RWE (e.g., appropriate study designs like propensity score matching, control for confounding). Developers should consider how RWE generation will be integrated into their post-authorization safety studies (PASS) or other regulatory commitments, ensuring these studies are designed to answer HTA questions as well.

Managing Risks and Uncertainties

Despite the harmonization goals, the JCA process introduces new types of risk. One major risk is the timing misalignment. The JCA process runs in parallel with the regulatory assessment. If there are delays in the regulatory assessment, the JCA timeline may be impacted, or the JCA may proceed based on data that is not yet fully validated. Companies must ensure their regulatory and HTA teams are perfectly synchronized.

Another risk is the consensus failure. While the process aims for consensus, it is possible for the assessment cooperation group to fail to reach an agreement. In such cases, the Regulation provides fallback mechanisms, but this can lead to delays and uncertainty. To mitigate this, companies must engage proactively during the assessment period to clarify any ambiguities in their submission dossier.

Finally, there is the risk of information overload. The JCA dossier is extensive. Submitting irrelevant data or poorly structured evidence can obscure the key messages. The role of the medical writer and the data scientist becomes critical in curating a dossier that is clear, concise, and directly answers the key questions posed by the HTACG.

Conclusion: The Convergence of Evidence and Value

The EU HTA Regulation is not merely a procedural change; it is a cultural shift in how Europe evaluates health technology. It signals the end of the era where regulatory approval and reimbursement could be treated as sequential,