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.nl2 Department of Epidemiology, UMCG.nl3 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

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)

Benefit-risk assessment

Data and evidence

Regulatory Logic

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

Drug 1 Drug 2 Drug 3

Therapeuticgroup

Endpoint A Endpoint b

Study 1 Study 2 Study 3 Study 4

Endpoint c

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 preferences2. Gaussian distributed criteria values3. is based on MAUT

69th meeting of EWG-MCDA, Brussels

>Example Therapeutic group: Second-generation anti-

depressants 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

EfficacyRelative 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]

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

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

Not asignificantdifference!

69th meeting of EWG-MCDA, Brussels

> SMAA analysis without preferences: central weights and confidence factors

> Can be used in describing the most preferred drug taking into account the patient history

0

5

10

15

20

25

Efficacy Diarrhea Dizziness Headache Insomnia Nausea

%

Fluoxetine

Paroxetine

Sertraline

Venlafaxine

CF

46%

53%

34%

68%

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

>Can be used for scenario-based prescription

Mild depression

Severe depression

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 !