Opportunities for CER Methods in Drug Discovery, Development and Commercialization

Lei Zhu, PhD, MBA GlaxoSmithKline

Health Care Value Chain

Burns, L.R., et.al., The Wharton School Study of the Health Care Value Chain

Financial Intermediaries

Distributional Intermediaries

The Trend of Evidence for Market Access

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Adapted from Keiron Sparrowhawk’s seminar on “How payers value innovation and what are the implications for GSK R&D?”

Market Access Economic

Wei

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f Evi

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Market Dynamics Clinical

US

France

UK Canada

Some plans are increasing their use of comparative effectiveness in the US

Potential use of economic evaluation in France

•  Safety –  Side effects acceptable?

•  Efficacy –  Can it work? Net benefit optimal conditions

•  Effectiveness –  Does it work? Net benefit average conditions

•  Efficiency –  Is there sufficient value

Evaluation Methods

•  Evidence-Based Medicine (EBA) •  Health Technology Assessment (HTA) •  Comparative Effectiveness Research (CER)

Relationships of Evidence Processes: EBM, CER, and HTA

Interna'onalWorkingGroupforHTAAdvancement.LuceBR,DrummondMF,JonssonB,NeumannPJ,SchwartzJS,SiebertU,SullivanSD.EBM,HTA,andCER:ClearingtheConfusion.MilbankMemorialFundQuarterly.Inpress.

Implications for Pharmaceutical Industry •  Transform from regulatory driven indication

development to patient-centric product development –  CER makes a difference throughout the

drug development life cycle –  Develop new strategies for R&D and

commercial to deliver products of value to patients and payers

•  Incremental efficacy or safety improvement

•  QoL improvement •  Improved compliance

Payers’ Assessment of Value

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Avastin Sutent Glivec

Anti-TNFs

•  Morbidity/mortality benefit •  Targeted at a patient population with unmet need •  Reduces the burden on the healthcare system

• New MoA; similar effectiveness • Sometimes indirect cost reduction

Level of Reimbursement

Rasilez

Aclasta/Reclast Prostap 3

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Keiron Sparrowhawk, “How payers value innovation and what are the implications for GSK R&D?”

Demonstrate Value through Evidence Generation and Synthesis

•  Randomized Clinical Trials/Pragmatic Trials

•  Observational Studies

•  Systematic Reviews

CER Study Design

•  Relevant comparators •  Clinically relevant outcomes •  Best available data •  Well defined, rigorous, analytical methods

Explicitly characterize uncertainty Address issues of generalizability and transferability Adapted from Schwartz, S., “Comparative Effectiveness Research, Scope of the Problem”, http://www.cceb.upenn.edu/biostat/conferences/ClinTrials10/ Adapted from Drummond MD, Schwartz JS, Jonsson B, Luce B, Neumann PN, Siebert U, Sullivan SD. International Journal of Technology Assessment in Health Care. 2008;24:244-58; discussion 362–368.

A Sample of CER Analysis Methods

•  Indirect Comparison •  Control for confounding in Observational Study •  Subgroup Analysis

Indirect Comparison •  Well-validated statistical techniques from Canadian

Agency for Drugs and Technologies in Health (CADTH)(Wells et al., 2009) –  The Bucher method of indirect comparisons –  Network meta-analysis –  Mixed treatment comparisons using Bayesian analysis

•  Selection bias of the clinical trials and statistical methods

Control for Confounding in Observational Study

•  Stratified Analysis • Marginal Structural Model •  Propensity Score •  Instrumental Variable

Subgroup Analysis •  Multivariate Methods

–  PCA, PLS, PLS-DA, Cluster Analysis, etc. •  Data Mining Methods

–  Recursive Partitioning, Bayesian Network, Support Vector Machine, etc.

•  Prediction Modeling

•  Identifiers for subgroup need to be easy to measure

Patient Subgroup Analysis of Lipid Profiles Change from baseline at Week 24

Prediction of Risk Potential risk factors associated with fluid retention by survival recursive partitioning

Pharmacogenetics and Genomics 2007, Vol 17 No 12

Pharmacogenomics Approach to Personalized Medicine

Design of Targeted Clinical Trial based on Predictive Biomarkers

•  Imperfect predictive biomarker

•  How the performance affect the trial efficiency – sample size?

•  Early phase trial is an important CER tool

Reward for Personalized Medicine

•  “Without major changes in how we conceive, design, conduct, and analyze RCTs, the nation risks spending large sums of money inefficiently to answer the wrong questions -- or the right questions too late.”

Luce BR, Kramer JM, Goodman SN, Connor JT, Tunis S, Whicher D, Schwartz JS. Rethinking randomized clinical trials for comparative effectiveness research: The need for transformational change. Annals of Internal Medicine. 2009;151:206-209.

Summary •  Statistical community can make significant contribution

to the design and analysis of CER studies –  Design of large pragmatic trials; Bayesian adaptive

design –  Methods for indirect comparisons, subgroup

analysis, and controlling confounding in observational studies

It is better to be approximately right than precisely wrong

Acknowledgement • Kwan Lee • Alan Menius • Amit Bhattacharyya • Patrick Ryan • Xiwu Lin • Daniel Park • Jie Cheng