WHAT TO DO IN ABSENCE OF HEAD TO HEAD CLINICAL TRIAL DATA. Lead the economic evaluation group at CHERE, University of Technology, Sydney

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1 WHAT TO DO IN ABSENCE OF HEAD TO HEAD CLINICAL TRIAL DATA MIXED TREATMENT COMPARISON (MTC) Stephen Goodall, Associate Professor of Health Economics Centre for Health Economics Research and Evaluation, UTS Disclosures Lead the economic evaluation group at CHERE, University of Technology, Sydney Conduct independent reviews of submissions to the Pharmaceutical Benefits Advisory Committee (PBAC) Conduct independent reviews and complete submissions for the Medical Services Advisory Committee (MSAC) Do not consult or receive income from Industry 1

2 Motivation for MTC Pragmatic, randomised, naturalistics, head-to-head trial Gold standard for comparative effectiveness Maximase internal and external validity Limitations Long-time to complete (delayed reimbursement) May be unethical (allocation to harmful treatment) Infeasible (rare disease) Regulatory trials Selective inclusion criteria compromised external validity Often compared to placebo or BSC No commercial incentive to compare to active control Role of Mixed Treatment Comparison Decisions need to be made Incorrect decisions health foregone! Delayed decisions health foregone! Decision-makers need to trade-off these two risks Potential role for MTC In the absence of head-to-head trials for all treatment comparisons, Combines direct and indirect evidence for pairwise comparisons Advantage of traditional meta-analysis synthesises more data 2

3 MTC example Ribeiro et al 2011 Study aim Compare statin doses 47 trials (11 direct comparisons) High dose Intermediate dose MTC Results (strokes only) High doses (v low) reduces stroke Low dose Placebo Direct comparison Mixed treatment comparison N RR 95%CI N RR 95%CI High v Low , High v Int 35, , Int v Low , MTC - validity issues Identifying all studies in the network publication bias? The quality of the individual RCTs Questionable randomisation, imbalanced groups, allocation concealment, unblinded outcomes Confounding due to; Lack of similarity and consistency between studies pt characteristics, length of follow-up, loss to follow-up, prior treatment, and protocol differences Any treatment effect modifiers not balanced between trials will bias the indirect comparison Important explicit reporting!!! 3

4 Australia - PBAC Role of MTC in Australia has been limited Predominately single drug submissions, against 1 or 2 comparators. In general, Direct RCT data superiority ITC to support non-inferiority Non-randomised studies rare diseases Currently the motivation for MTC is limited MTC in Australia Statin review In 2005, PBAC changed listing of atorvastatin to costeffective (relative to simvastatin, previously cost-min) In 2006, rosuvastatin cost-min with atorvastatin This led to formation of 2 therapeutic groups Statins therapeutic group (simva and prava) Statins-higher potency TG (atorva and rosuva) Nov 2010 request made in Senate for; Advice from the PBAC on any new evidence on whether or not, rosuvastatin and atorvastatin should be included in the existing statins therapeutic group 4

5 Statin review External consultant engaged with DOHA 36 head-to-head RCT comparing combinations of the 4 statins MTC undertaken for each outcome measure (CHDD, non-fatal MI, stroke, CR) Regression analysis performed using WinBUGS Relevant comparisons LP statins v PBO HP statins v PBO HP v LP Low-medium dose v PBO High-dose v low-medium dose PBAC conclusions PBAC noted; Inconsistent (counterintuitive) results produced by MTC across the various statins and their doses e.g. Simva 40mg fewer QALYs gained than simva 20mg Substantial heterogeneity Patient populations (age, prior CHD, diabetes, baseline LDL-C) Trial characteristics (design, duration, year, place) Random variation Small number of cardiovascular events statistically imprecise estimates of treatment effect Comparison of ICERs between statins needs to be done with caution 5

6 PBAC recommendations PBAC re-affirmed previous recommendations Atorvastatin and rosuvastatin more effective than simvastatin Atorvastatin and rosuvastatin interchangeable Maintain the price differential (12.5%) Only basis for a relative price increase Incremental CEA based on major cardiovascular events measured directly in randomised trials rather than based on predictions modelled from surrogates Should we use MTC for HTA reimbursement 6

7 THANK YOU Stephen Goodall, Associate Professor of Health Economics Centre for Health Economics Research and Evaluation, UTS 7