Sandro Gsteiger, Mairead Kearney, and Ali Azough on behalf of the EFPIA HTA Methods Working Group.

Application of the European HTA Regulation is around the corner - in only a few months from now, the first products will go through the new European Joint Clinical Assessment (JCA) framework. This significant milestone in European collaboration consolidates previously separate and sometimes redundant local clinical assessments of new medicines under a single umbrella. Major changes often bring excitement and new opportunities, however, they can also stir a sense of anxiety as we navigate unknown territory. The JCA is no different and much is at stake for patients in Europe.

As always, the devil is in the details. For example, the consistent production of high quality and practically useful JCA reports requires clarity in terms of HTA methods. Which approaches are deemed appropriate for a specific evidence setup, what are the assumptions associated with a given method and how can those assumptions be assessed, how should analyses be reported to ensure downstream stakeholders have what they need? The Methodological and Practical Guidelines for Quantitative Evidence Synthesis: Direct and Indirect Comparisons from the Member State Coordination Group on HTA provide such direction [1,2]. They belong to a broader set of European methodological guideline documents, the development of which we warmly welcome.

The practical and methodological guidelines on evidence synthesis attempt at providing an up-to-date summary of the array of evidence synthesis approaches that may be used in the compilation of the EU JCA dossier. In the past, some EU Member States rarely used indirect treatment comparisons (ITC) to inform local decision-making, while (few) other Member States experimented with the most recent and progressive methods [3]. The guidelines put forward a rich set of approaches spanning for example the classical Bucher ITC, the well-established Bayesian and frequentist Network Meta-Analysis, as well as more recent approaches such as multi-level network meta-regression and evidence synthesis for disconnected evidence networks.

The broad toolkit put forward by the HTA Coordination Group is timely. From current knowledge, the pan-EU JCA PICO scoping process will likely lead to research questions that cannot be answered by the pivotal trial data alone. ITCs will be needed in many cases and may, at times, even constitute the majority of requested comparative evidence as suggested by PICO pilots [4,5].

In order to achieve workable and impactful JCA reports, a pragmatic application and interpretation of the guidelines as well as the willingness to adopt a European lens will be key (both at the PICO consolidation and at the JCA production stage). Pragmatic application and interpretation means, for example, that contextual factors are considered as part of the evidence validity assessments. The level and types of evidence that can be reasonably expected is context driven. For example, ATMPs and highly innovative therapeutic approaches may not allow the generation of long-term and/or comparative evidence at the point of marketing authorisation or within reasonable timeframes (meaning not causing disproportionate access delays). Algorithmic rules to judge whether an evidence base is appropriate or not appropriate risks to not set the JCA up for success in supporting Member State local value assessments.

The importance of a European lens has been noted by several authors [6,7] and should be kept in mind all the way from defining the JCA scope up to the interpretation of results in the JCA report. For example, definition of the EU level scope will need to strike the balance between inclusiveness (wish to cover all Member States’ needs) and evidentiary requirements (wish for highest level evidence for all comparisons). A larger set of comparators will lead to a larger evidence network, and with growing number of trials, the heterogeneity of an evidence network typically increases. If concerns for “poor quality” ITCs are strong, then the HTA Coordination Group should restrict the pan-EU PICO to comparators that allow the conduct of anchored ITCs.

The practical guideline does not always achieve a truly European perspective, which is concerning. Particularly worrying is the recommendation that JCAs should generally report both results from ‘population-level’ as well as ‘comparator-level’ networks ([2] page 9). So if multiple treatments are of interest for a specific population, one would not only run a joint analysis covering all comparators of interest (population-level), but also repeat the analysis for each subnetwork declared of interest by a single Member State? This approach results in unnecessary duplication (contradicting the objectives of the EU HTA Regulation) and is not in line with best practices of evidence based medicine. Focusing on the population-level network will ensure that the same set of consistent estimates are being used for decision-making across EU Member States and should therefore be preferred. Comparator-level networks should not be requested. The Methodological and Procedural Guidelines (MPG) Subgroup itself seems not fully at ease with its current recommendation, as the corresponding paragraph in the guideline concludes with the assurance that “further guidance on how multiple comparators should be handled in the context of JCA will be developed” ([2] page 9).

Finally, the Member States should rely on the expertise of the assessor/co-assessor and make full use of the scientific assessment provided in the JCA. The two evidence synthesis guidelines repeatedly emphasize the independence of Member States in making their own judgments, which reflects the spirit of the regulation when it comes to evidence appraisal and decision making. However, it risks undermining the scientific evaluation provided by the assessor/co-assessor when transferred also to the assessment stage. The scientific evaluation should happen in the JCA report, which includes judging the scientific validity of the evidence provided by the manufacturer.

Converging to an optimal set of recommendations for evidence synthesis in the context of EU JCA will be an exciting journey. We should leverage the expertise of all stakeholders and be open to constructive dialogue in order to move faster. Several members from the EFPIA HTA Methods Working Group will be at ISPOR EU 2024, and we look forward to discussing these issues with the full HEOR community.

1. Member State Coordination Group on Health Technology Assessment (HTA CG) (2024) Methodological Guideline for Quantitative Evidence Synthesis: Direct and Indirect Comparisons.
   
   
2. Member State Coordination Group on Health Technology Assessment (HTA CG) (2024) Practical Guideline for Quantitative Evidence Synthesis: Direct and Indirect Comparisons.
   
   
3. Tanaka S, Igarashi A, Moor RD, et al. (2024) A Targeted Review of Worldwide Indirect Treatment Comparison Guidelines and Best Practices. Value in Health 27: 1179–1190.
   
   
4. van Engen A, Kruger R, Ryan J, et al. (2022) HTA97 Impact of Additive PICOs in a European Joint Health Technology Assessment. a Hypothetical Case Study in Lung Cancer. Value in Health 25: S315.
   
   
5. Ryan J (2023) The EU JCA scoping process: a health technology developer perspective.
   
   
6. Julian E, Gianfrate F, Sola-Morales O, et al. (2022) How can a joint European health technology assessment provide an ‘additional benefit’ over the current standard of national assessments? Health Economics Review 12: 30.
   
   
7. Kanavos P, Angelis A, Drummond M (2019) An EU-wide approach to HTA: An irrelevant development or an opportunity not to be missed? Eur J Health Econ 1–4.