OBJECTIVES: To identify, categorise, and rank the importance of the various types of uncertainties in estimating the broader value of antibiotics using the STEDI (Spectrum, Transmission, Enablement, Diversity and Insurance) value framework.

METHODS: We applied a mixed methods approach. First, we extracted all mentions of uncertainty from the official HTA reports by NICE describing the attempt to estimate the full STEDI value of two antibiotics in England. We then classified these by the root cause of their uncertainty, including conceptual, scientific, evidentiary, or methodological uncertainty. Finally, an interdisciplinary group of eight experts (two microbiologists, two health economists from industry, two health economists from academia/non-profit, and one health economist specialising in advanced modelling) refined, face validated and ranked the uncertainties according to their importance to more comprehensively and accurately estimate STEDI value.

RESULTS: Conceptual uncertainty results from different definitions and conceptualisation of the framework and is the most important uncertainty source for enablement value and highly relevant for spectrum and insurance value. Uncertainty due to suboptimal scientific understanding of microbiological, physiological and epidemiological phenomena, or clinical contexts is most relevant to transmission and diversity value. Evidentiary uncertainty stems from a lack of robust, relevant, and standardised evidence or data. It ranks first for spectrum and diversity value, second for transmission value and third for enablement and insurance value. Methodological uncertainty is most relevant for estimating insurance and enablement value.

CONCLUSIONS: Quantifying the broader value of antibiotics is crucial in appropriately incentivising antibiotic innovation. However, they are difficult to characterise and capture precisely and today's usage of the STEDI framework fails to achieve this task. It needs to be conceptually refined, underpinned by better methodological guidance and based on solid evidence.