Jörg Ruof

This methodological commentary examines the Joint Clinical Assessment (JCA) report of lurbinectedin combined with atezolizumab as maintenance therapy for extensive-stage small-cell lung cancer, based on the phase 3 IMforte trial. The JCA's evaluation rests on two overall survival data cuts: a confirmatory, hypothesis testing, statistically significant interim cut (hazard ratio 0.73, p=0.0174) and a mature, hypothesis generation, non-significant cut (hazard ratio 0.81). We identify two main critical methodological issues in the JCA's handling of these results. First, the JCA prefers the mature cut under a treatment-policy strategy that embeds subsequent crossover to lurbinectedin in the control arm, which is unavailable in routine European practice and dilutes the estimated treatment effect. The report lacks a decision-relevant, hypothetical-strategy analysis adjusting for this treatment switching. Second, the JCA discounts the positive interim result by assigning an "Unclear" risk-of-bias rating based on a late alpha-spending protocol amendment. This suspicion was left unresolved despite available data, the power to seek developer clarification, and regulatory findings from the European Medicines Agency (EMA) clearing the amendment as operational. Instead of a reasoned synthesis, the JCA performs a silent substitution of the mature cut for the interim. The report ignores the information both cut bring and questionably assesses the second cut as low risk of bias. To address these concerns, we recommend: complementing treatment-policy estimates with hypothetical-strategy analyses when trial crossover differs from European practice; resolving risk-of-bias concerns rather than leaving them "unclear"; engaging with prior regulatory evaluations; and providing graded certainty statements to reconcile divergent clinical results.

Background:The EU Health Technology Assessment Regulation (2021/2282) mandates Joint Clinical Assessment (JCA) for new oncology drugs and advanced therapy medicinal products (ATMPs) from January 2025. Central to JCA is the PICO (Population, Intervention, Comparator, Outcome) framework. In 2024, pilot PICO exercises were conducted, including one for etranacogene dezaparvovec (ED), a haemophilia B gene therapy. Objectives:This study aims to systematically evaluate the feasibility of JCA-formulated PICOs by analysing the 2024 pilot exercise for ED.Methods:We analysed seven PICOs from the MP05 pilot ED exercise, mapping the pivotal HOPE-B trial against PICO requirements. We searched ClinicalTrials.gov and PubMed for comparator trials, and evaluated the feasibility of direct and indirect treatment comparisons (ITCs) across 25 subgroups derived from the primary PICOs.Results:No PICO could be addressed using direct comparative evidence. Five of seven PICOs were infeasible due to a lack of controlled trial data and the inability to conduct valid ITCs. Two PICOs were potentially addressable using before-after mirror studies if adequately powered, but evidence gaps remain. Unanchored ITCs were potentially feasible, but are considered methodologically inappropriate by JCA. Ultimately, zero PICOs were addressable under the current framework.Conclusions:The current JCA framework is not suited to ATMPs and orphan products developed through single-arm trials. Reforms are needed: mandatory evidence feasibility screening before PICO finalisation, early HTD consultation, revised ITC guidelines, a tiered evidence framework with uncertainty characterisation, and integration of PICO development with methodological guidance. Without these, JCA risks documenting evidence absence rather than informing reimbursement decisions, increasing Member States assessment burden.

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.

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 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: We examined four potential challenges for the implementation of the European Union (EU) Regulation 2021/2282 on Health Technology Assessment (EU HTAR): interaction with the European Medicines Agency (EMA), expert input, the interface of European health technology assessment (EU HTA) joint procedures with those within Member States, and the management of conflict of interest. This research aims to explore how to address these challenges in a balanced manner and prioritise key actions for effective collaboration in the context of the EU HTA. Methods: The methodology included a pre-convention survey among relevant stakeholders as well as working groups and the plenary ranking of discussion outcomes at the European Access Academy (EAA) Spring Convention 2024. Results: In the survey, 65.5% of respondents indicated that experts are currently not sufficiently included in the upcoming joint scientific consultations and clinical assessments; only 37.9% suggested that the EU HTA joint procedures would accelerate national appraisal decision-making, and 58.6% believed that the principles of ‘transparency’ and ‘competency’ are balanced in the EU HTA position on conflict of interest. The top priority action points identified in the working groups were the involvement of the best available expertise, the early and inclusive involvement of experts, strengthened early scientific dialogue, and the fostering of the political willingness/financial support of EU Member States to increase capacities. Conclusions: The key topics identified were an approach to conflict of interest that balances transparency obligations and the need for expertise, strengthens the involvement of clinical and patient experts, intensifies early interaction between the EMA and EU HTA, and increases the involvement of the EU Member States.