Background: Selecting clinically meaningful and measurable efficacy endpoints for trials of outbreak-prone infections presents multiple challenges, including poor clinical characterisation, heterogeneity in disease presentation, and the absence of standardised methodologies to evaluate patient outcomes. Methods: This thesis addresses these issues through three case studies: Lassa fever, mpox, and bubonic plague. A mixed-methods approach was used, including systematic reviews to examine outcome selection challenges, validity and reliability studies to evaluate measurement tools, and a retrospective cohort study. In the absence of sufficient data to inform endpoint selection for Lassa fever, stakeholder consultations were conducted. Additionally, data from an ongoing randomised controlled trial were used to assess the risks of including problematic components in endpoint definitions. Results: Two primary challenges were identified: (1) limited robust evidence in the literature characterising disease outcomes and key patient events, and (2) the widespread use of unvalidated or inadequate measurement tools in current trials. These issues undermine the ability to evaluate interventions effectively in the context of outbreak-prone infections.