OBJECTIVES: Surrogate endpoints (SE) are increasingly used in clinical trials to predict clinical benefit. Limited information is available regarding validated SEs and the impact of their use on HTA outcomes. We sought to assess published HTA methodological guidelines on SEs and their impact on CADTH, G-BA, HAS and NICE recommendations.

METHODS: HTA websites were searched to identify guidelines for the application of SEs. In addition, appraisals were screened to identify technologies that used a SE as the sole primary outcome (PO) and to extract their HTA outcomes.

RESULTS: CADTH, G-BA, HAS and NICE have published guidelines specifically referencing the use of SEs and their acceptance; however, the guidance is currently not very prescriptive, illustrating the need for more definitive guidance for sponsors. From the 65 interventions that NICE reviewed in 2021/2022, only 20 included a SE as the sole PO (outcomes: 15 recommended, 4 restricted, 1 not recommended). When cross-referencing the medicines that included a SE as the sole PO versus other HTA agencies, CADTH evaluated 11 (outcomes: 8 recommended with restrictions, 3 not recommended). HAS assessed 15 technologies and provided the following scores: ASMR III: 3; IV: 4; V: 7; and 1 NA; SMR important: 10; moderate: 3; insignificant: 2. G-BA reviewed 17 interventions and provided: considerable benefit: 1; minor added benefit: 4; unquantifiable benefit: 1; and no added benefit: 11. Although G-BA required a strong SE correlation with final outcome for the results to be included in the assessment, other HTA agencies were less strict. Most interventions that were recommended by HTA bodies included overall survival as a secondary endpoint. Our analyses were limited to HTA agencies’ clear documentation on SE acceptability.

CONCLUSIONS: Many products that included validated SE data were recommended. However, submissions including SEs should include additional evidence to decrease uncertainty.