Table 3.

Methodological recommendations to ensure transferability of future EU JCAs for the German benefit assessment process

Domain	Recommendation
Population	- Within the therapeutic indication the definition of subpopulations with different therapeutic situations should be based on current European evidence-based guidelines
Study Intervention	- Evidence from pivotal studies should be applicable for the assessment and used preferably. Decisions on the acceptability of possible deviations of the study interventions from the approved administration should be clarified in consultation with the regulatory authority. In case of minor deviations, a pragmatic approach is recommended
Comparator	- For comparator selection, medicines with marketing authorisation for the therapeutic indication should be given priority, off-label therapies with demonstrated clinical efficacy for the therapeutic indication should be considered. Selection should be made according to available clinical evidence and European guidelines - The PICO Survey amongst EUnetHTA partners should enable a transparent, timely and consistent process to establish a consensus on Standard of care selection amongst EU Member States and, therefore, should replace the national selection. Any decisions within the subsequent national appraisal process must remain separately, i.e., the PICO Survey national comparator must remain basis of the national appraisal process
Endpoints	- Assessment methods for endpoints should be harmonised - Prespecified clinical trial test hierarchies are not recommended in an HTA because of the different scopes of HTA and drug approval. For HTA, an evaluation is intended across multiple endpoint categories - In line with the scope of the HTA, the inclusion of surrogate endpoints accepted in the marketing authorisation as well as the consideration of patient-reported symptoms, HRQoL and adverse events is advocated to enable a patient-centered assessment in all four endpoint categories (mortality, morbidity, HRQoL and adverse events) - Differences in observation times between study arms should be accounted for in the assessment of endpoints via an adequate methodology
Subgroup Analysis	- Subgroup analyses should be considered very cautiously due to their possible exploratory character. Conclusions about differential effects in subgroups should only be drawn based on adequate statistical interaction tests and only with sufficient credibility through biological plausibility (with clinical, pharmacological, or mechanistic rationale) and replication (in multiple data sources)

EU European Union, HTA health technology assessment, HRQoL health-related quality of life, JCA joint clinical assessment, PICO population, intervention, comparator, outcome