Clinical and regulatory acceptability of hierarchical composite endpoints in infectious disease clinical trials.

OBJECTIVES: Hierarchical composite endpoints (HCEs) combine different clinical attributes in a single endpoint and establish a ranking of these components based on clinical importance. We studied the acceptance of HCEs in infectious disease clinical trials for clinical and regulatory decision-making. METHODS: We conducted four online focus groups in November 2025 with decision makers involved in funding, trial assessment, guideline development, medicine registration, or reimbursement. Transcripts were analyzed following thematic analysis. Additionally, European Public Assessment Reports of medicines through 2024 and current international infectious disease society guidelines as of October 2025 were reviewed. RESULTS: Focus group findings were structured into three themes: HCE context of use, HCE development, and HCE assessment. Respondents indicated that HCEs could be considered when conventional endpoints are infeasible. When constructing an HCE, clinically relevant components, based on rigorous consensus-building activities, should be included. There was a divergence of views regarding the integration of both efficacy and safety components, and the choice of tiebreaking components that may unfairly advantage one intervention group. Complexity may impede the interpretation of trial results, which should be reported transparently. We did not identify a pivotal trial with an HCE supporting the registration of an anti-infective medicine. Across 67 clinical guidelines reviewed, only three guidelines cited a study (one randomized controlled trial cited two times and an observational study) with an HCE. CONCLUSIONS: HCEs have been used to a limited extent to support decision-making and their use as primary endpoints in trials should be well-reasoned and aligned with the trial objective.