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Balancing benefit and risk of medicines: a systematic review and classification of available methodologies


  • Statement about prior postings and presentations: The contents of this paper have previously been presented at various scientific conferences, and a preliminary full report of this review has also been published online on the sponsor's website.

  • Christine E. Hallgreen and Sinan B. Sarac were previously employed by Novo Nordisk A/S, Søborg, Denmark, when this work started. Nan Wang was previously employed at Imperial College London (ICL) when this work was carried out and is publishing as an ICL's former employee. Lawrence D. Phillips was a consultant at the European Medicines Agency (EMA) when this work was carried out and is publishing as an EMA's former employee.

  • IMI-PROTECT Benefit–Risk participants: Billy Amzal, Deborah Ashby, Simon Ashworth, Alex Asiimwe, Johan Bring, Torbjorn Callreus, Edmond Kakit Chan, Christoph Dierig, Gerald Downey, David Gelb, Georgy Genov, Alesia Goginsky, Christine Hallgreen, Richard Hermann, Ian Hirsch, Steve Hobbiger, Kimberley Hockley, Diana Hughes, Juhaeri Juhaeri, Silvia Kuhls, Alfons Lieftucht, Davide Luciani, Marilyn Metcalf, Alain Micaleff, Shahrul Mt-Isa, Jeremiah Mwangi, Richard Nixon, Rebecca Noel, John Pears, Ruth Peters, Lawrence Phillips, George Quartey, Sinan B. Sarac, Susan Shepherd, Isabelle Stoeckert, Elizabeth J. Swain, Andrew Thomson, Laurence Titeux, Ioanna Tzoulaki, Rianne van den Ham, Tjeerd van Staa, Edward Waddingham, Nan Wang and Lesley Wise.



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.


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.


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.


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. Copyright © 2014 John Wiley & Sons, Ltd.