Enhanced quadrivalent influenza vaccines that include an adjuvant (aQIV) or a high dose of antigen (QIV-HD), which stimulate a stronger immune response in older adults than the standard vaccine (QIVe), are now approved. The objective of this research is to compare available vaccines and determine the cost-effectiveness of immunizing persons aged 65 years and above with aQIV compared to QIVe and QIV-HD in Germany. A compartmental transmission model calibrated to outpatient visits for influenza in Germany was used to predict the number of medically attended infections using the three vaccines. The rates of hospitalizations, deaths, and other economic consequences were estimated with a decision tree using German data where available. Based on meta-analysis, the rVE of −2.5% to 8.9% for aQIV versus QIV-HD, the vaccines are similar clinically, but aQIV is cost saving compared to QIV-HD (unit cost of EUR 40.55). All results were most sensitive to changes in vaccine effectiveness. aQIV may be cost-effective compared to QIVe depending on the willingness to pay for additional benefits in Germany. As aQIV and QIV-HD are similar in terms of effectiveness, aQIV is cost saving compared to QIV-HD at current unit prices.

Indirect treatment comparisons (ITCs) are essential in the context of joint clinical assessments (JCAs) under Regulation (European Union [EU]) 2021/2282, bridging evidence gaps where head-to-head data are lacking and enabling assessment across diverse national patient, intervention, comparator, and outcome (PICO) requirements. This paper critically reviews the EU Health Technology Assessment Coordination Group’s (HTACG) guidelines on direct and indirect comparisons, with particular focus on ITCs. While the guidelines promote transparency and rigorous evaluation of assumptions, they adopt a restrictive stance on assumption violations, the use of unanchored comparisons, and population-adjusted methods such as matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC). The guidance shows limited support for Bayesian methods and undervalues meta-regression in favor of subgroup analyses. Operational implications for health technology developers (HTDs) are substantial, including new requirements for dual systematic reviews, multiple network structures, and shifted null hypothesis testing. Moreover, the exclusion of non-randomized comparisons in rare or rapidly evolving indications may inadvertently hinder access to effective treatments. Emerging practices such as external control arms (ECA) or target trial emulation are underdeveloped. Notably, there is no indication that the guidelines are grounded in systematic methodological validation studies. As JCAs evolve, greater methodological flexibility, empirical grounding, and clear operational guidance will be essential. Refining the guidelines along these principles would enhance their practical utility, mitigate intrinsic assessment variability, support consistent assessments across Member States (MS), and ultimately improve patient access to innovative therapies.

Background: The objective of this work was to support the implementation of the European Health Technology Assessment Regulation (EU HTAR) and optimize performance of the evolving EU HTA system. Therefore, an inclusive multi-stakeholder framework of key performance indicators (KPI) for success measurement was developed. Methods: A modified Delphi-procedure was applied as follows: (1) development of a generic KPI pool at the Fall Convention 2024 of the European Access Academy (EAA); (2) review of initial pool and identification of additional KPIs; (3) development of prioritized KPIs covering patient, clinician, Health Technology Developer (HTD), and System/Member State (MS) perspectives, and (4) consolidation of the stakeholder-centric KPIs after EAA’s Spring Convention 2025. Results: Steps 1 and 2 of the Delphi procedure revealed 14 generic KPI domains. Steps 3 and 4 resulted in four prioritized KPIs for patients (patient input; utilization of patient-centric outcome measures; time to access; equity); six for clinicians (population/intervention/comparator/outcomes (PICO); addressing uncertainty; clinician involvement; transparency; equity and time to access); four for HTDs (PICO; joint scientific consultation (JSC) process; joint clinical assessment (JCA) process; time to national decision making); five from a system/MS perspective (PICO; learning and training the health system; reducing duplication; equity and time to access). The scope of, e.g., the PICO-related KPI, differed between stakeholder groups. Also, several KPIs intentionally reached beyond the remit of EU HTA as they are also dependent on MS-specific factors including national health systems and budgets. Discussion and Conclusions: The KPI framework developed here presents a step towards the generation of systematic multi-stakeholder evidence to support a successful implementation of the EU HTAR. The relevance of the identified stakeholder-centric KPIs is confirmed by their alignment with the Health System Goals suggested in the context of “Performance measurement for health improvement” by the World Health Organisation. Implementation of the framework, i.e., measurement of KPIs, is envisioned to provide evidence to inform the 2028 revision of the EU HTAR.

Indirect treatment comparisons (ITCs) are essential in the context of joint clinical assessments (JCAs) under Regulation (European Union [EU]) 2021/2282, bridging evidence gaps where head-to-head data are lacking and enabling assessment across diverse national patient, intervention, comparator, and outcome (PICO) requirements. This paper critically reviews the EU Health Technology Assessment Coordination Group’s (HTACG) guidelines on direct and indirect comparisons, with particular focus on ITCs. While the guidelines promote transparency and rigorous evaluation of assumptions, they adopt a restrictive stance on assumption violations, the use of unanchored comparisons, and population-adjusted methods such as matching-adjusted indirect comparisons (MAIC) and simulated treatment comparisons (STC). The guidance shows limited support for Bayesian methods and undervalues meta-regression in favor of subgroup analyses. Operational implications for health technology developers (HTDs) are substantial, including new requirements for dual systematic reviews, multiple network structures, and shifted null hypothesis testing. Moreover, the guidelines effectively dissuade the use of non-randomized comparisons in rare or rapidly evolving indications and may inadvertently hinder access to effective treatments. Emerging practices such as external control arms (ECA) or target trial emulation are underdeveloped. Notably, there is no indication that the guidelines are grounded in systematic methodological validation studies. As JCAs evolve, greater methodological flexibility, empirical grounding, and clear operational guidance will be essential. Refining the guidelines along these principles would enhance their practical utility, mitigate intrinsic assessment variability, support consistent assessments across Member States (MS), and ultimately improve patient access to innovative therapies.

The practice of Health Technology Assessment (HTA) inherently involves moral, epistemological, and ontological commitments, which shape how assessments are conducted, interpreted, and used for decision-making

The Joint Clinical Assessment (JCA) report on tovorafenib (Ojemda), the first assessment of an orphan oncology medicinal product completed under Regulation (EU) 2021/2282 [1], conformed closely to predictions made across our earlier work. This Perspective argues that the outcome was foreseeable from the framework’s design rather than from any feature of the product. We characterise the JCA as an audit that confronts developer-submitted evidence against a corpus of EUnetHTA methodological guidance whose scientific validity and development process have been widely contested. Four structural features explain the result: the referential cannot function as a settled gold standard; the assessment omits the interpretive, context-dependent judgment that gives evidence meaning, on the assumption — specific to one national tradition — that assessment can be separated from appraisal and conducted free of judgment; products supported only by single-arm trials are predictably assessed negatively, as Ojemda illustrates; and the framework departs from the tripod of evidence-based medicine by marginalising clinicians and patients. By multiplying PICOs, subgroups and outcomes and then criticising the resulting analyses as post hoc, the JCA generates its own limitations and ultimately cannot state a degree of certainty of relative effectiveness. We conclude that single-arm-supported products should fall outside the JCA’s remit and that the framework requires a transparent route from documented uncertainty to a stated certainty.