BACKGROUND: The need for formal and structured approaches for benefit-risk assessment of medicines is increasing, as is the complexity of the scientific questions addressed before making decisions on the benefit-risk balance of medicines. We systematically collected, appraised and classified available benefit-risk methodologies to facilitate and inform their future use.

METHODS: A systematic review of publications identified benefit-risk assessment methodologies. Methodologies were appraised on their fundamental principles, features, graphical representations, assessability and accessibility. We created a taxonomy of methodologies to facilitate understanding and choice.

RESULTS: We identified 49 methodologies, critically appraised and classified them into four categories: frameworks, metrics, estimation techniques and utility survey techniques. Eight frameworks describe qualitative steps in benefit-risk assessment and eight quantify benefit-risk balance. Nine metric indices include threshold indices to measure either benefit or risk; health indices measure quality-of-life over time; and trade-off indices integrate benefits and risks. Six estimation techniques support benefit-risk modelling and evidence synthesis. Four utility survey techniques elicit robust value preferences from relevant stakeholders to the benefit-risk decisions.

CONCLUSIONS: Methodologies to help benefit-risk assessments of medicines are diverse and each is associated with different limitations and strengths. There is not a 'one-size-fits-all' method, and a combination of methods may be needed for each benefit-risk assessment. The taxonomy introduced herein may guide choice of adequate methodologies. Finally, we recommend 13 of 49 methodologies for further appraisal for use in the real-life benefit-risk assessment of medicines.