Presentation (CTI)

OBJECTIVES: The recently published EU HTA guidance on outcomes for joint clinical assessments specifies that the applicant can include surrogates of the outcome of interest in the dossier, if the latter is not available or data are immature at the time of the assessment. Surrogate outcomes can be biomarkers or intermediate outcomes. Furthermore, the guidance specifies evidence needs for the validation of surrogate outcomes and three levels of evidence are defined. We assess the guidance document in terms of evidence needs for successful surrogate outcome validations.
METHODS: To understand differences in evidence needs it is crucial to highlight the differences between level 1 and level 2. Whereas level 2 requires evidence demonstrating a consistent association between surrogate outcome and final patient-centred outcome (can be obtained from several data sources including observational data), level 1 requires evidence demonstrating that treatment effects (i.e., intervention specific effects) on the surrogate outcome correspond to effects on the patient-centred outcome. Such evidence would typically only be available from randomized controlled trials. The guidance states that validations would comprise a meta-analysis of several randomised controlled trials in the respective disease stage and sufficiently restricted to the interventions investigated.
RESULTS: Based on experiences from HTA in Germany where similar requirements have been formulated in IQWiG General Methods, we provide practical considerations around feasibility assessments and conduct of surrogate endpoint validations corresponding to level 1 as well as an overview of previous surrogate endpoint validations conducted within the German HTA framework.
CONCLUSIONS: Recommendations regarding evidence planning for pivotal clinical trials are provided.