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69th meeting of EWG-MCDA, Brussels Multi-criteria decision analysis in drug benefit-risk assessment T. Tervonen(1), D. Postmus(2), H.L. Hillege(3) 1 Faculty of Economics and Business, RUG.nl 2 Department of Epidemiology, UMCG.nl 3 Department of Cardiology/Epidemiology, UMCG.nl 69th meeting of EWG-MCDA, Brussels >Introduction Drug Benefit-Risk (BR) analysis aims to systemically compare the benefits and risks of drugs within a therapeutic group Regulatory Logic BR analysis has multiple possible applications - Support prescription decisions - One criterion for drug marketing authorization decision (in Europe, FDA in USA doesn’t give incorporate BR analysis in clinical assessment) Data and evidence Benefit-risk assessment 69th meeting of EWG-MCDA, Brussels >Two ways to approach BR analysis >Universal model Becomes too general Explicitly requires qualitative measurements Hard for MD’s to accept Doesn’t show the potential of MCDA >Therapeutic group specific model Allows to take into account quantitative clinical data The model can be discussed with leading experts of the therapeutic area Separates qualitative judgments from clinical data 69th meeting of EWG-MCDA, Brussels >Clinical data Therapeutic group Drug 1 Study 1 Endpoint A Drug 2 Study 2 Endpoint b Drug 3 Study 3 Endpoint c Study 4 69th meeting of EWG-MCDA, Brussels > SMAA approach to BR analysis Step 1: Analyze without preference information to characterize the drugs Step 2: Analyze through common scenarios including ordinal preferences obtained from expert MD’s > Justification for SMAA: 1. Allows missing/incomplete preferences 2. Gaussian distributed criteria values 3. is based on MAUT 69th meeting of EWG-MCDA, Brussels >Example Therapeutic group: Second-generation antidepressants Drugs: - Fluoxetine (Prozac) - Paroxetine (Seroxat) - Sertraline (Zoloft) - Venlafaxine (Effexor) Purpose: Analyze trade-offs based on clinical data to support prescription decision for two scenarios: - Mild depression - Severe depression 69th meeting of EWG-MCDA, Brussels > 1 benefit criterion (efficacy), a primary endpoint in studies of the 4 drugs > 5 risk criteria corresponding to the 5 most frequent adverse drug events > Measurements from meta-analysis that pooled results of compatible studies Name Measurements Pref. dir. Scale Relative value compared with Fluoxetine ↑ [0.97, 1.23] Diarrhea ADE’s Absolute % ↓ [1, 20.6] Dizziness ADE’s Absolute % ↓ [2.9, 24.4] Headache ADE’s Absolute % ↓ [8, 31.3] Insomnia ADE’s Absolute % ↓ [3.4, 21.3] Nausea ADE’s Absolute % ↓ [22.1, 34] Efficacy 69th meeting of EWG-MCDA, Brussels >Measurements (mean, stdev) Drug Efficacy Diarrhea Dizziness Headache Insomnia Nausea Fluoxetine 1, 0 11.7, 2.5 7.2, 1.45 16.6, 3.27 13.7, 1.89 18.6, 1.79 Paroxetine 1.09, 0.06 9.2, 1.86 10.6, 1.58 21.2, 5.15 14.3, 2.93 18.3, 3.7 Sertraline 1.1, 0.05 15.4, 2.65 7.5, 1.48 20.2, 3.78 15, 3.21 19.5, 2.6 Venlafaxine 1.12, 0.05 5.5, 2.32 15.7, 4.44 12.8, 2.45 11.2, 3.98 31, 1.68 69th meeting of EWG-MCDA, Brussels >Measurements (mean, stdev) Drug Efficacy Diarrhea Dizziness Headache Insomnia Nausea Fluoxetine 1, 0 11.7, 2.5 7.2, 1.45 16.6, 3.27 13.7, 1.89 18.6, 1.79 Paroxetine 1.09, 0.06 9.2, 1.86 10.6, 1.58 21.2, 5.15 14.3, 2.93 18.3, 3.7 15, 3.21 19.5, 2.6 11.2, 3.98 31, 1.68 Sertraline 1.1, 0.05 15.4, 2.65 Not a significant 7.5, 1.48difference! 20.2, 3.78 Venlafaxine 1.12, 0.05 5.5, 2.32 15.7, 4.44 12.8, 2.45 69th meeting of EWG-MCDA, Brussels > SMAA analysis without preferences: central weights and confidence factors CF 25 46% 20 53% 15 % Fluoxetine Paroxetine 34% Sertraline 10 Venlafaxine 68% 5 0 Efficacy Diarrhea Dizziness Headache Insomnia Nausea > Can be used in describing the most preferred drug taking into account the patient history 69th meeting of EWG-MCDA, Brussels >Ordinal preferences Expert in the field of anti-depressants could understand the model and rank the criteria swings during a short teleconference (30min) Two rankings for the two scenarios: - Mild depression: Diarrhea > Nausea > Dizziness > Insomnia > Headache > Efficacy - Severe depression: Similar ranking, except efficacy the most important criterion Ranking took into account swings, and was justified through clinical practice 69th meeting of EWG-MCDA, Brussels >SMAA analyses with preferences: rank acceptabilities Mild depression Severe depression >Can be used for scenario-based prescription 69th meeting of EWG-MCDA, Brussels >Conclusions We constructed a therapeutic group specific SMAA model for benefit-risk assessment of second-generation anti-depressants Separation of clinical data from preferences gives “credibility” to the model The problem statement is not “choice” or “ranking”, but “risk assessment” Merci !