Benefit–risk assessment in a post‐market setting: a case study integrating real‐life experience into benefit–risk methodology

Abstract

Purpose Difficulties may be encountered when undertaking a benefit–risk assessment for an older product with well‐established use but with a benefit–risk balance that may have changed over time. This case study investigates this specific situation by applying a formal benefit–risk framework to assess the benefit–risk balance of warfarin for primary prevention of patients with atrial fibrillation. Methods We used the qualitative framework BRAT as the starting point of the benefit–risk analysis, bringing together the relevant available evidence. We explored the use of a quantitative method (stochastic multi‐criteria acceptability analysis) to demonstrate how uncertainties and preferences on multiple criteria can be integrated into a single measure to reduce cognitive burden and increase transparency in decision making. Results Our benefit–risk model found that warfarin is favourable compared with placebo for the primary prevention of stroke in patients with atrial fibrillation. This favourable benefit–risk balance is fairly robust to differences in preferences. The probability of a favourable benefit–risk for warfarin against placebo is high (0.99) in our model despite the high uncertainty of randomised clinical trial data. In this case study, we identified major challenges related to the identification of relevant benefit–risk criteria and taking into account the diversity and quality of evidence available to inform the benefit–risk assessment. Conclusion The main challenges in applying formal methods for medical benefit–risk assessment for a marketed drug are related to outcome definitions and data availability. Data exist from many different sources (both randomised clinical trials and observational studies), and the variability in the studies is large. Copyright © 2014 John Wiley & Sons, Ltd.

Benefit–risk assessment of paliperidone oral extended-release tablet versus monthly injectable for maintenance treatment of schizophrenia

“…The BRAT framework is a structured approach to pharmaceutical benefit–risk assessment that facilitates the selection, organization, summarization, and communication of evidence relevant to benefit–risk decisions ( Coplan et al , 2011 ; Levitan et al , 2011 ; Noel et al , 2012 ). It was chosen for the current analysis because the complexity and number of endpoints considered for this assessment required more focus on assessment setup, data selection, and endpoint definitions than on quantitative modeling ( Hallgreen et al , 2014 ; Hughes et al , 2015 ). The approach and endpoints used here are similar to that of a recent application of the BRAT framework to LAI antipsychotics ( Detke et al , 2014 ).…”

Number needed to harm in the post‐marketing safety evaluation: results for rosiglitazone and pioglitazone

“…However, the establishment of structured frameworks for benefit–risk assessment, which comprises qualitative and quantitative approaches, can contribute to improve transparency and traceability of regulatory decisions . Quantitative methodologies, in particular, allow that sensitivity analyses can be carried out to assess the impact of different assumptions on the benefit–risk ratio conclusions . When a drug is being evaluated, some quantitative approach for assessing benefits and risks may be of increased value and help inform regulatory decisions .…”

“…Quantitative methodologies, in particular, allow that sensitivity analyses can be carried out to assess the impact of different assumptions on the benefit–risk ratio conclusions . When a drug is being evaluated, some quantitative approach for assessing benefits and risks may be of increased value and help inform regulatory decisions . NNT/NNH methodology and derived concepts, such as the weighted net clinical benefit, are well known in medical literature, are easy to understand and communicate, and have proven to be valuable in quantifying benefits and risks of drugs .…”

Advancing regulatory science, advancing regulatory practice

“…Work done on quantitative methods for benefit–risk assessment of medicines represents a third example. From a large number of methodologies for benefit–risk assessment reviewed, classified and appraised, 13 were recommended for future use and tested in eight case studies . As there was a lack of consensus on which visual representations were most suitable to display benefit–risk profiles, PROTECT also reviewed, described and illustrated 16 ways in which benefits and risk may be communicated to different target groups in different situations with an evaluation of their strengths and weaknesses .…”