A team of participants in Work Package 5 created a quantitative model of rosiglitazone in combination with metformin, to quantify the benefit-risk balance of that combination as compared to metformin alone. A model based on statistical summaries of the evidence showed a better benefit-risk balance for metformin alone, a finding that did not change over a wide range of differences in judgements about clinical benefits.

A further modification of the model incorporated uncertainties associated with the statistical summaries. The subsequent Monte-Carlo analysis generated a probability of 0.998 that the benefit-risk balance of metformin alone is better than that of the rosiglitazone-metformin combination.

The team concluded that despite the complexity of the problem, it was possible to create a quantitative model that helped the team to draw conclusions about the current status of rosiglitazone used in combination with metformin. The support of the quantitative model lay in its ability to accommodate and make explicit both evidence and clinical judgements about the evidence. Graphical displays of the results further deepened understanding.


Rosiglitazone received marketing authorisation in 1999 in the United States and in 2000 in the European Union. New data subsequently emerged about possible heart problems associated with rosiglitazone, confirmed by a meta-analysis in 2007 (Nissen & Wolski, 2007), which resulted in a European suspension late in 2010. This suspension included its use as a fixed dose combination with metformin or glimepiride, which had been approved in 2003 for metformin and 2006 for glimepiride. The drug remains available in the United States, but only under a restricted-access program.

It is the chequered history of this drug that led to its choice for modelling as one of six drugs explored in Work Package 5. Twelve PROTECT participants from the pharmaceutical industry and academia gathered on 28 June and 24 July 2012 in a facilitated workshop to develop and explore the quantitative model. Participants took the role of regulators in a hypothetical European country, in 2012, considering all publicly-available data from clinical trials and from available post-authorisation information.


The purpose of Work Package 5 is “to develop methods for use in benefit-risk assessment, including both the underpinning modelling and the presentation of the results, with a particular emphasis on graphical methods.” The rosiglitazone case study contributed to these objectives by exploring how a qualitative framework, PrOACT-URL, could be applied in creating a quantitative model of the benefit-risk balance, and how multi-criteria decision analysis (MCDA) could provide a methodology for quantifying the balance.