Guidance on the validity of clinical studies for joint clinical assessment

Document adopted on 19 September 2024 by the HTA CG pursuant to Article 3(7), point (d), of Regulation (EU) 2021/2282 on Health Technology Assessment

The Commission has published a guidance document on the validity of clinical studies for joint clinical assessments under the EU Health Technology Assessment Regulation, adopted by the Member State Coordination Group. This guidance helps to define, classify, and assess the certainty of clinical study results in an objective, reproducible and transparent way. It covers the analysis of data from different types of single clinical studies. 

This guidance complements the guidance documents previously adopted by the Member State Coordination Group on outcomes for joint clinical assessments, on quantitative evidence synthesis for direct and indirect comparisons and on reporting requirements for multiplicity issues and subgroup, sensitivity and post hoc analyses in joint clinical assessments. -

The Member State Coordination Group on Health Technology Assessment adopted the new guidance document at its 10th meeting on 19 September 2024, pursuant to Article 3(7), point (d), of Regulation (EU) 2021/2282 on Health Technology Assessment. Set to take effect on January 12, 2025, the new guidance supports the EU Health Technology Assessment Regulation (HTAR) by providing practical guidelines to ensure that clinical studies used in JCAs meet rigorous standards for internal and external validity, as well as statistical precision. 

Guidance on the validity of clinical studies for joint clinical assessments

The 44-page guidance focuses on single clinical studies, providing a clear framework for interpreting results and determining the reliability and applicability of data in assessing relative effectiveness. It builds upon previous guidance documents adopted by the Member State Coordination Group for joint clinical assessment (JCA), including the published guidance discussing the methodological and practical approaches to quantitative evidence synthesis for direct and indirect comparisons, and reporting requirements for issues such as multiplicity, subgroup analysis, and sensitivity analysis. These criteria are crucial for evaluating the relative effectiveness of health interventions compared to their alternatives – a key consideration in decision-making processes across EU member states.

As the guidance notes “… valid scientific principles are still required, not only to guide the development of JCAs at the European level, but also to support the understandability and usability of these results for national decision-making ”, the guidance provides detailed recommendations on the classification and labelling of study design for use in JCA.

Clinical studies are categorized as either interventional or observational, with specific reporting requirements outlined for various designs. These include randomized controlled trials (RCTs), considered the ‘gold standard,’ as well as single-arm trials, cohort studies, and case-control studies. The guidance highlights the strengths and limitations of each design, offering a structured approach to assessing their applicability to the specific research question. It also emphasizes the use of standard, study design-specific tools to assess the risk of bias.

Additionally, the guidance addresses studies that fall outside traditional trial design frameworks but are increasingly relevant for HTA. These include studies utilizing master protocols, such as platform, basket, and umbrella trials, as well as clinical registries. Real-world data (RWD) and the generation of real-world evidence (RWE) are also discussed in this context. For studies that rely on RWD, the guidance emphasizes the importance of assessing the validity and reliability of the data, particularly when using proxy variables, mitigating attrition bias, and ensuring adequate measurement of outcomes.