title: Benefit-risk assessment in a post-market setting: a case study integrating real-life experience into benefit-risk methodology.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: School of Public Health, Imperial College London, London, UK.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Hallgreen
authors.forename: Hendrika A
authors.initials: HA
authors.lastname: van den Ham
authors.forename: Shahrul
authors.initials: S
authors.lastname: Mt-Isa
authors.forename: Simon
authors.initials: S
authors.lastname: Ashworth
authors.forename: Richard
authors.initials: R
authors.lastname: Hermann
authors.forename: Steve
authors.initials: S
authors.lastname: Hobbiger
authors.forename: Davide
authors.initials: D
authors.lastname: Luciani
authors.forename: Alain
authors.initials: A
authors.lastname: Micaleff
authors.forename: Andrew
authors.initials: A
authors.lastname: Thomson
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.forename: Tjeerd P
authors.initials: TP
authors.lastname: van Staa
authors.forename: Gerald
authors.initials: G
authors.lastname: Downey
authors.forename: Ian
authors.initials: I
authors.lastname: Hirsch
authors.forename: Kimberley
authors.initials: K
authors.lastname: Hockley
authors.forename: Juhaeri
authors.initials: J
authors.lastname: Juhaeri
authors.forename: Marilyn
authors.initials: M
authors.lastname: Metcalf
authors.forename: Jeremiah
authors.initials: J
authors.lastname: Mwangi
authors.forename: Richard
authors.initials: R
authors.lastname: Nixon
authors.forename: Ruth
authors.initials: R
authors.lastname: Peters
authors.forename: Isabelle
authors.initials: I
authors.lastname: Stoeckert
authors.forename: Ed
authors.initials: E
authors.lastname: Waddingham
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tzoulaki
authors.forename: Deborah
authors.initials: D
authors.lastname: Ashby
authors.forename: Lesley
authors.initials: L
authors.lastname: Wise
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000009:adverse effects / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000150:complications / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D015233:Models, Statistical; D011322:Primary Prevention / Q000379:methods; D011336:Probability; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment / Q000379:methods; D020521:Stroke / Q000209:etiology / Q000517:prevention & control*; D014859:Warfarin / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000925:Anticoagulants; D014859:Warfarin
keywords: benefit-risk; decision making; medicines; pharmacoepidemiology; qualitative; quantitative; warfarin