Biostatistics GH Health Technology oo ep The term health technology refers to drugs, devices, and programs that can improve rk ei n and extend quality of life. As decision-makers struggle to find ways to reduce costs e s Assessment while improving health care delivery, health technology assessments (HTA) provide the evidence required to make better-informed decisions. This is the first book that focuses on the statistical options of HTAs to fully capture the value of health improvements along with their associated economic consequences. After Using Biostatistics to Break H reading the book, readers will better understand why some health technologies receive the Barriers of Adopting New Medicines regulatory or reimbursement approval while others do not, what can be done to improve e the chances of approval, as well as common shortcomings of submissions for drug and a device reimbursement. l t h The book begins by contrasting the differences between regulatory approval and reimbursement approval. Next, it reviews the principles and steps for conducting an HTA, T including the reasons why different agencies will have a different focus for their scope in e the HTA. c h Supplying an accessible introduction to the various statistical options for different methods n in an HTA, the book identifies the links to regulatory and reimbursement decisions for o each option. It highlights many of the methodological advances that have occurred since l HTA research began to provide researchers and decision-makers with a cutting-edge o framework. It also details the logical basis for the methods along with simple instructions g on how to conduct the various techniques. y Both authors have considerable experience in generating evidence for submissions and A reviewing submissions to decision-makers for funding. One of the authors has also s received a nationally recognized lifetime achievement award in this area. s e s s m e n t K23491 6000 Broken Sound Parkway, NW ISBN: 978-1-4822-4452-6 Suite 300, Boca Raton, FL 33487 90000 711 Third Avenue Robert B. Hopkins, MA, MBA, PhD New York, NY 10017 an informa business 2 Park Square, Milton Park www.crcpress.com Abingdon, Oxon OX14 4RN, UK 9 781482 244526 Ron Goeree, MA www.productivitypress.com K23491 cvr mech.indd 1 2/23/15 10:07 AM Health Technology Assessment Using Biostatistics to Break the Barriers of Adopting New Medicines Health Technology Assessment Using Biostatistics to Break the Barriers of Adopting New Medicines Robert B. Hopkins, MA, MBA, PhD PATH Research Institute, St. Joseph’s Healthcare Hamilton, Department of Clinical Epidemiology & Biostatistics, Faculty of Health Sciences, McMaster University Ron Goeree, MA PATH Research Institute, St. Joseph’s Healthcare Hamilton, Department of Clinical Epidemiology & Biostatistics, Faculty of Health Sciences, McMaster University CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2015 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20150217 International Standard Book Number-13: 978-1-4822-4453-3 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the valid- ity of all materials or the consequences of their use. 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Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Contents Authors ..............................................................................................xi Preface .............................................................................................xiii 1 Regulation, Reimbursement and Health Technology Assessment ..................................................................................1 Introduction .................................................................................................1 Regulatory Approval ............................................................................2 Regulatory Approval for Prescription Drugs ...............................3 Regulatory Approval for Devices ..............................................10 Regulatory Approval for Public Health and Other Non- Drug, Non-Device Approvals ............................................12 Reimbursement Approval for Drugs .................................................13 Initiation of Drug Review for Reimbursement .........................14 Further Clinical Evidence for Drug Reimbursement ................14 Consideration of Cost in Drug Reimbursement Decisions .......15 Drug Price Negotiations ............................................................15 Reimbursement Approval for Devices ..............................................16 Health Technology Assessment ........................................................17 Step 1: Identify the Topic for Assessment .................................20 Step 2: Clear Specification of the Problem ...............................22 Step 3: Gathering the Evidence .................................................24 Step 4: Aggregation and Appraisal of the Evidence .................25 Step 5: Synthesize and Consolidate Evidence ..........................27 Step 6: Collection of Primary Data (Field Evaluation) ..............28 Step 7: Economic Evaluation, Budget and Health Systems Impact Analysis ..........................................................................29 Step 8: Assessment of Social, Ethical and Legal Considerations ...........................................................................30 v vi ◾ Contents Step 9: Formulation of Findings and Recommendations .........30 Step 10: Dissemination of Findings and Recommendations ....32 Step 11: Monitoring the Impact of Assessment Reports ...........32 Summary ...................................................................................................33 References .................................................................................................33 2 Requirements and Sources of Data to Complete an HTA ..........37 Data Requirements to Complete an HTA .................................................37 Cost-Effectiveness ......................................................................................37 Introduction to Health-Related Quality of Life ........................................41 Introduction to Resource Utilization and Costs .......................................44 Need for Modelling ...................................................................................46 Decision Analytic Model ...................................................................47 Markov Model ....................................................................................48 Start with the Trials: Safety and Efficacy ..................................................49 Secondary Data Requirements .................................................................50 Rare Diseases ....................................................................................52 Effectiveness versus Efficacy .............................................................53 Long-Term Outcomes ........................................................................54 Health-Related Quality of Life ..........................................................55 Resource Utilization and Costs .........................................................56 Epidemiology .....................................................................................59 Summary ...................................................................................................60 References .................................................................................................60 3 Meta-Analysis .............................................................................65 Overview of Meta-Analysis .......................................................................65 Initial Steps before a Meta-Analysis .........................................................67 A Comment on Frequentist and Bayesian Approaches ...........................68 Steps in a Meta-Analysis ...........................................................................69 Step 1: Identify the Type of Data for Each Outcome ..............................70 Step 2: Select an Appropriate Outcome Measure ....................................72 Outcomes for Continuous Data ........................................................74 Step 3: Conduct the Preliminary Analysis with an Assessment of Heterogeneity ........................................................................................75 Weighting of Each Study ...................................................................75 Random or Fixed Effects ...................................................................76 Testing for Heterogeneity ..................................................................77 Step 4: Adjustment for Heterogeneity .......................................................78 Step 5: Assess Publication Bias .................................................................80 Contents ◾ vii Step 6: Assess the Overall Strength of Evidence .....................................81 An Example of Meta-Analysis ...................................................................82 Outliers ..............................................................................................86 Risk-Adjusted or Unadjusted Analysis ..............................................87 Publication Bias .................................................................................89 Meta-Analysis of Diagnostic Accuracy Studies .........................................90 Example of Meta-Analysis for Diagnostic Accuracy ................................95 Hierarchical Summary Receiver Operator Curve .............................99 Summary .................................................................................................101 References ...............................................................................................101 Appendix I: Diagnostic Accuracy Measures ..........................................103 Appendix II: Estimation of Cohen’s Kappa Score..................................104 4 Network Meta-Analysis ............................................................105 Introduction .............................................................................................105 Head-to-Head and Placebo-Controlled Trials.................................105 Step 1: Establish Potential Network Diagram of Linking Studies ..........110 Step 2: Check for Consistency in Outcomes for Common Linking Arms ...........................................................................................112 Step 3: Conduct Meta-Analysis and Assess Heterogeneity within Common Comparators ............................................................................114 Step 4: Conduct Indirect Meta-Analysis across the Comparators ..........116 Network Meta-Analysis Software ....................................................116 Step 5: Conduct Subgroup and Sensitivity Analyses ..............................120 Step 6: Report Network Meta-Analysis Results ......................................121 Bayesian Mixed Treatment Comparisons ...............................................122 Network Meta-Analysis Example ............................................................122 Assessing Robustness: Homogeneity and Consistency of Evidence ......................................................................................123 Adjustment for Difference in Baseline Characteristics ...................123 Network Meta-Analysis of Diagnostic Accuracy ....................................124 References ...............................................................................................125 5 Bayesian Methods ....................................................................127 Introduction .............................................................................................127 Study Power for Trials of Rare Diseases .........................................128 Interpretation of Bayesian Results ..................................................129 Bayesian Theorem ..................................................................................130 Step 1: Specify the Model .......................................................................131 Step 2: Assign the Prior(s) .......................................................................134 viii ◾ Contents Step 3: Conduct the Simulation ..............................................................135 Step 4: Assess Convergence ....................................................................137 Step 5: Report the Findings ....................................................................142 Advanced Bayesian Models ....................................................................143 Advanced Example 1: Combining RCTs and Observational Data ...144 Advanced Example 2: Covariate Adjustment ..................................144 Advanced Example 3: Hierarchical Outcomes ...............................145 Summary .................................................................................................146 References ...............................................................................................147 6 Survival Analysis .....................................................................149 Introduction .............................................................................................149 Kaplan–Meier Analysis ............................................................................150 Exponential, Gompertz and Weibull Models .........................................156 Establishing and Using Risk Equations ..................................................162 Diabetes Modelling..........................................................................168 Acceptability of Surrogates .....................................................................169 Survival Adjustment for Crossover Bias..................................................170 Building a Life Table from Cross-Sectional Data ...................................173 Summary .................................................................................................175 References ...............................................................................................175 7 Costs and Cost of Illness Studies .............................................179 From Clinical Events to Resource Utilization to Costs ...........................180 Measurement of Resource Utilization .............................................181 Attribution and Adjustment for Comorbidities .......................................182 Strategies to Isolate the Cost of an Event .......................................184 Regression Methods.........................................................................186 Other Strategies to Estimate Costs ..................................................186 Unit Costs Valuation for Resources .................................................188 Perspective and Types of Costs ..............................................................189 Burden of Illness Study ..........................................................................191 Budget Impact Analysis ..........................................................................193 Statistical Issues with Cost Data .....................................................194 Summary .................................................................................................195 References ...............................................................................................196 8 Health-Related Quality of Life .................................................199 Why QOL? ...............................................................................................200 Good Properties of Scales ......................................................................202