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Sara Cueva

How should pharmaceutical companies prepare for the upcoming joint EU HTA?

The Health Technology Assessment landscape is changing in the EU – soon a single standardised assessment will be used across all member states.

January 2022 marked the beginning of the transition towards a new pan-EU Health Technology Assessment (HTA) for drugs and medical devices. It will first be applied to oncology drugs and advanced therapy medicinal products (ATMPs) in 2025, followed by orphan drugs in 2028 and all other centrally approved drugs and certain medical devices by 2030. The intention is to harmonise relative effectiveness assessments across the EU by
having a joint clinical assessment (JCA) conducted by a group of representatives from member states. These JCAs should inform national value assessments and price negotiations, reducing the need for submitting multiple individual dossiers.

What will the joint EU HTA look like and what can be expected to be brought by it?

For member states, the regulation could mean those typically regarded as less attractive markets – i.e., due to smaller populations or budgets – will gain negotiating power by partnering with more attractive markets (e.g., EU4). Ideally, this would result in increased and more rapid access to health technologies across all EU countries.

Importantly, while some functions in the market access pathway will be performed at the EU-level, many activities will remain at the national level. The EU-wide collaboration will only involve clinical assessments, not health economic or cost-effectiveness evaluations. Within this clinical assessment, the Coordination Group (overseeing JCA reports) will choose appropriate comparators. While all countries will have to reach JCA conclusions together and consider them when making national decisions, member states will be able to conduct their own additional analyses, and pricing and reimbursement (P&R) negotiations will remain at the national level. As for JCA reports themselves, they will have two parts: one with a consolidated (not unanimous) EU-level assessment and another with national conclusions, including further recommendations and requirements for individual countries.

The regulation could result in either:

an all-or-nothing way of reaching P&R agreements – the same clinical assessment will be considered for every country-level decision; or
more resources being used on assessments overall across Europe – countries deciding to still conduct their own HTAs because JCA conclusions do not fit their context well enough

Assessment of clinical added benefit can differ by country

The high heterogeneity that exists among EU countries creates an important question around the usefulness of joint HTA decisions/recommendations for individual member states. To assess this heterogeneity, we compared HTA decisions made in 2021 by the French HAS (Haute Autorité de Santé) and the German G-BA (Gemeinsamer Bundesausschuss). This comparison is possible given the similarities between the ‘added benefit’ rating system used in Germany and the ASMR system used in France.

HTA outcomes were standardised on a single scale to allow comparison, with ratings for individual drugs compared and classified as ‘equivalent’ (same rating), ‘minor difference’ (one rating apart) or ‘major difference’ (two+ ratings apart) (Table 1). As ASMR ratings from HAS and the added benefit rating from the G-BA are not always directly equivalent, drugs were separated into the minor and major difference groups.

From the 35 identified drugs, 10 (29%) showed different decisions by HAS and G-BA, and only 2 (6%) showed a major difference between outcomes (Table 2). The remaining majority (71%) of drugs displayed similar decisions by both HTA bodies.

A clear pattern for one HTA body tending to constantly grant higher or lower ratings was not found. Nonetheless, we suggest that some tendencies support the existence of different priorities and requirements by the different countries.

In the case of Rukobia, the submission of a placebo-controlled pivotal study alongside indirect comparisons to alternative comparator treatments was deemed unsuitable by the G-BA, leading to a no added benefit outcome. However, this was not the case in France, where this clinical evidence alongside the high unmet need in the specific population was sufficient to drive a positive HTA outcome. While these findings support that most drugs (71%) are rated similarly between France and Germany, almost 1/3^rd of cases had divergent outcomes. These differences could pose significant challenges to manufacturers once the joint HTA process is implemented for many products in development.

If a future joint HTA requires pharmaceutical companies to meet the requirements of all individual counties, then this could lead to greater scrutiny of the clinical evidence package as a whole. Many factors are likely to significantly differ between countries in their HTA decision-making, including the choice of comparator and the weighting of different primary endpoints. There are also country-specific instances to be considered, such as the automatic added benefit for orphan drugs in Germany, or France’s unwillingness to accept non-traditional study designs. The JCA process could pose significant challenges to manufacturers if there is disagreement between countries before the first assessments are made.

This analysis only considers two EU countries that are relatively similar in many aspects of their profiles (e.g. demographics and wealth). When considering all 27 countries in the EU, there is likely to be even greater divergence in assessment priorities and outcomes, adding to the difficulty of aligning HTA processes.

What does the regulation mean for the pharma industry?

It is crucial for pharmaceutical companies to understand the implications of these changes to the overall landscape and factor them into their future planning. There are a number of key considerations for manufacturers:

1. Work as an industry to ensure the final process is fair and straightforward – there are many outstanding issues that must be solved before the new joint HTA system is implemented. Working with industry groups such as EUCOPE and EFPIA can allow manufacturers to convey what is important to them and any concerns that exist, as well as understand how the EU-wide and national assessments will fit together.

2. Build a strong rationale for trial design – Consolidating the requirements of all EU HTA bodies may lead to more scrutiny of trial designs. Sub-optimal trial designs are necessary in certain instances, such as many rare diseases. If surrogate endpoints or patient-reported outcomes are used, manufacturers should build robust justification for their use and translate the evidence into patient benefit, potentially including validation studies and real-world evidence development.

3. Prioritize early scientific advice as key part of strategy – consolidating the needs/wants of all HTA bodies in the EU might lead to greater scrutiny when assessing clinical evidence and more stringency when granting products with added benefit status. Thus, traditional ‘market access’ planning will be more important than ever. Manufacturers should consider joint scientific advice as a necessity for products that will undergo the new process to minimize the risk of extremely impactful surprise negative outcomes.

EU HTA in the future: Only time will tell

Whilst many of the
potential benefits and challenges the joint HTA will bring have been identified, important unknowns still exist regarding the new regulation. Although the
rationale behind the joint EU HTA seems sound and could theoretically lead to improved access across the EU, there is not yet much clarity around how the regulation will circumvent the key issue of heterogeneity between EU countries. There is a long road to implementation ahead and only time will tell whether this joint EU HTA will effectively achieve what it was designed to do.