1. Network meta-analysis modelling in benefit- risk assessment Gert van Valkenhoef

2. Benefit-risk assessment Regulatory BR “does not require a new drug to be assessed against other available treatments” 1 Payers becoming more important for market access –Relative Efficacy / Relative Effectiveness –Better than placebo is not enough Non-inferiority trials – difficult in current framework –Assay sensitivity –Drift into failure Other decision makers (e.g. prescriber, patient) –Assess all available options 1. H-G Eichler et al., Nat Rev Drug Discov. 2010; 9(4):277-291 (doi:10.1038/nrd3079)10.1038/nrd3079

3. Network meta-analysis “In the absence of direct head-to-head trails, a next best approach … is … common reference indirect comparison” 1 Network meta-analysis 2,3,4 : –Extension of normal meta-analysis –Compare ≥ 2 alternative treatments –Using an evidence network of trials –Combination of direct + indirect evidence –Assessment of consistency in network –Incorporates all available evidence 1. H-G Eichler et al., Nat Rev Drug Discov. 2010; 9(4):277-291 (doi:10.1038/nrd3079)10.1038/nrd3079 2. T Lumley, Stat in Med. 2002; 21(16):2313–2324 (doi:10.1002/sim.1201)10.1002/sim.1201 3. G Lu & AE Ades, J Am Stat Assoc. 2006; 101(474):447-459 (doi:10.1198/016214505000001302)10.1198/016214505000001302 4. G Salanti et al., Stat Methods Med Res. 2008; 17(3):279-301 (doi:10.1177/0962280207080643)10.1177/0962280207080643

4. Our proposal BR assessment on basis of updating network meta-analysis Indirect comparisons: assess all relevant options –e.g. indirect comparison to placebo Interpretation of non-inferiority trials –Incorporate in network of trials –“Drift into failure” detectable –RE, not the chosen margin, is central Network meta-analysis is (meta-)observational –There may be unknown confounding

5. Example: anti-depressants Fluoxetine Paroxetine Placebo Sertraline Venlafaxine HAM-D response

6. Example: anti-depressants HAM-D response

7. Example: anti-depressants ADR: Diarrhea

8. Example: anti-depressants ORRiskNNTNNH HAM-D.49 - 1.8.36 -.673.2 Diarrhea.35 - 2.1.04 -.216.1 Dizziness.42 - 4.5.03 -.254.5 Headache.36 - 2.0.08 -.334.0 Insomnia.29 - 2.0.04 -.245.1 Nausea.46 - 2.4.10 -.373.7 Fluoxetine0.09 Paroxetine0.61 Placebo0.94 Sertraline0.29 Venlafaxine0.42 Confidence factors (preference free) Measurement scales

9. Conclusions Network meta-analysis useful in BR assessment –When placebo trials are not available –To detect “drift into failure” –To use all available evidence –Give insight for > 2 alternatives Network meta-analysis + multi-criteria model –Makes trade-offs explicit –Takes into account full uncertainty –Some options are bad, regardless of preference

10. Estimated densities (HAM-D)

11. No preferences: Rank Acceptabilities

12. No preferences: central weights

13. With preferences - efficacy

15. With preferences - safety