Economic evaluation of cancer drugs : using clinical trial and real-world data
Author(s)
Bibliographic Information
Economic evaluation of cancer drugs : using clinical trial and real-world data
（Chapman & Hall/CRC biostatistics series）（A Chapman & Hall book）
CRC Press, c2020
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National Graduate Institute for Policy Studies Library (GRIPS Library)
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Includes bibliographical references (p. 361-400) and index
Description and Table of Contents
Description
Cancer is a major healthcare burden across the world and impacts not only the people diagnosed with various cancers but also their families, carers, and healthcare systems. With advances in the diagnosis and treatment, more people are diagnosed early and receive treatments for a disease where few treatments options were previously available. As a result, the survival of patients with cancer has steadily improved and, in most cases, patients who are not cured may receive multiple lines of treatment, often with financial consequences for the patients, insurers and healthcare systems. Although many books exist that address economic evaluation, Economic Evaluation of Cancer Drugs using Clinical Trial and Real World Data is the first unified text that specifically addresses the economic evaluation of cancer drugs.
The authors discuss how to perform cost-effectiveness analyses while emphasising the strategic importance of designing cost-effectiveness into cancer trials and building robust economic evaluation models that have a higher chance of reimbursement if truly cost-effective. They cover the use of real-world data using cancer registries and discuss how such data can support or complement clinical trials with limited follow up. Lessons learned from failed reimbursement attempts, factors predictive of successful reimbursement and the different payer requirements across major countries including US, Australia, Canada, UK, Germany, France and Italy are also discussed. The book includes many detailed practical examples, case studies and thought-provoking exercises for use in classroom and seminar discussions.
Iftekhar Khan is a medical statistician and health economist and a lead statistician at Oxford Unviersity's Center for Statistics in Medicine. Professor Khan is also a Senior Research Fellow in Health Economics at University of Warwick and is a Senior Statistical Assessor within the Licensing Division of the UK Medicine and Health Regulation Agency.
Ralph Crott is a former professor in Pharmacoeconomics at the University of Montreal in Quebec, Canada and former head of the EORTC Health Economics Unit and former senior health economist at the Belgian HTA organization.
Zahid Bashir has over twelve years experience working in the pharmaceutical industry in medical affairs and oncology drug development where he is involved in the design and execution of oncology clinical trials and development of reimbursement dossiers for HTA submission.
Table of Contents
Contents
Preface......................................................................................................................xv
Acknowledgments.............................................................................................. xvii
Acronyms and Abbreviations............................................................................ xix
1 Introduction to Cancer....................................................................................1
1.1 Cancer......................................................................................................1
1.2 Epidemiology of Cancer........................................................................1
1.2.1 Cancer Trends............................................................................2
1.3 Prognostic Factors Associated with Cancer Outcomes ...................5
1.4 Economic Burden of Cancer.................................................................6
1.4.1 Health Expenditure..................................................................6
1.4.2 Healthcare Expenditure on Drugs.........................................7
1.5 Treatments for Cancer......................................................................... 10
1.6 Important Economic Concepts for Cost-Effectiveness of
Cancer Interventions......................................................... 12
1.6.1 Economics, Health Economics, Economic Evaluation,
and Pharmacoeconomics .................................................. 12
1.6.1.1 Value ......................................................................... 13
1.6.1.2 Allocative Efficiency............................................... 14
1.6.1.3 Technical Efficiency................................................ 15
1.6.1.4 Opportunity Cost.................................................... 16
1.6.1.5 Discounting.............................................................. 17
1.6.1.6 The Incremental Cost-Effectiveness Ratio .......... 18
1.6.1.7 The Cost-Effectiveness Plane................................. 19
1.6.1.8 Quality-Adjusted Life-Years (QALY) ...................22
1.7 Health Economic Evaluation and Cancer Drug
Development in Practice .........................................................................23
1.7.1 The Modern Paradigm................................................................... 24
1.8 Efficacy versus Effectiveness .............................................................26
1.9 Real-World Data ..................................................................................27
1.10 Economic versus Clinical Hypotheses .............................................29
1.11 Summary............................................................................................... 32
1.12 Exercises for Chapter 1........................................................................33
2 Important Outcomes for Economic Evaluation in Cancer Studies......35
2.1 Introduction .........................................................................................35
2.2 Important Common, Surrogate, and Novel Cancer Endpoints............... 36
2.2.1 Overall Survival......................................................................36
2.2.1.1 OS and Economic Evaluation ............................... 41
2.2.2 Surrogate Endpoints...............................................................46
2.3 HTAs with Surrogate Endpoints.......................................................53
2.4 Emerging Tumor-Centered Endpoints.............................................55
2.5 Demonstrating Value from Other Cancer Endpoints..................... 57
2.6 Summary...............................................................................................58
2.7 Exercises for Chapter 2........................................................................58
3 Health-Related Quality of Life for Cost-Effectiveness.......................... 59
3.1 Health-Related Quality of Life (HRQoL) in Cancer Patients......... 59
3.1.1 Limitations of Anti-Cancer Treatments...............................59
3.1.2 Why Collect HRQoL Data?....................................................60
3.1.3 Challenges with HRQoL in Cancer Studies........................ 61
3.2 Measuring Health-Related Quality of Life Outcomes for
Common Cancer Types .................................................................62
3.2.1 Condition-Specific Measures of HRQoL ............................ 62
3.2.2 Common General Condition-Specific Measures of
HRQoL in Cancer......................................................................................63
3.3 Measuring HRQoL for Economic Evaluation ................................. 67
3.3.1 EuroQol EQ-5D-3L and 5L....................................................68
3.3.2 EuroQol EQ-5D-5L................................................................. 69
3.4 Constructing Utilities.......................................................................... 70
3.5 Quality-Adjusted Life-Years (QALYs)................................................72
3.5.1 QALY Calculation in Cancer Trials......................................73
3.6 Economic Evaluation in the Absence of Utility Data:
Mapping and Utility Studies ................................................................. 74
3.7 Sensitivity and Responsiveness of EQ-5D versus QLQ-C30
HRQoL for Detecting Improvement in Cancer Patients ...................... 76
3.8 Measuring Post-Progression (PP) Utility: Some Approaches .......77
Why Is Estimation of Utility between Disease Progression
and Death Relevant?............................................................... 78
The Behavior of Utility in Cancer Patients between
Progression and Death?.........................................................79
3.8.1 Plausible Post-Progression Utility Behavior ......................80
3.8.2 Non-Linear Models.................................................................82
3.9 HRQoL issues in Health Technology Appraisals of Cancer
Drugs .........................................................................................................87
3.10 Summary...............................................................................................89
3.11 Exercises for Chapter 3........................................................................89
4 Introductory Statistical Methods for Economic Evaluation in
Cancer............................................................................................................... 91
4.1 Introduction.......................................................................................... 91
4.2 Uncertainty and Variability................................................................ 91
4.2.1 Uncertainty..............................................................................92
4.2.2 Variability.................................................................................92
4.2.2.1 Hypothesis Testing.................................................93
4.3 Distributions: Cost, Utility, and Survival Data ...............................93
4.4 Important Measures Used in Cancer Trials.....................................95
4.4.1 Time-to-Event Endpoints.......................................................95
4.4.2 Median Survival.....................................................................96
4.4.3 Hazard Rate and Hazard Ratio............................................98
4.4.4 Hazard Ratio............................................................................99
4.4.5 Survival Rates and Proportions.......................................... 101
4.4.6 Relationship between Hazard Rate and Survival Rate......102
4.4.7 Transition Probability and Matrix...................................... 103
4.4.8 Relation between Transition Probability and
Survival Rates .............................................................................. 104
4.4.9 Proportional Hazards.......................................................... 106
4.4.10 Mean Survival and Restricted Mean ................................ 106
4.5 Simulation: Bootstrapping and Monte-Carlo Simulation............ 109
4.5.1 Simulating Using Monte-Carlo Sampling......................... 111
4.6 Analyzing Data from Cancer Trials................................................ 111
4.6.1 Semi-Parametric Methods: The Cox PH Model............... 111
4.6.1.1 Adjusting for Covariates with the Cox Model......112
4.6.1.2 Using Hazard Ratios to Predict Survival Rates.....113
4.6.2 Parametric Methods: Modeling Survival Data for
Extrapolation ........................................................................... 114
4.6.3 Advanced Modeling Techniques for Survival Data ....... 118
4.6.3.1 Flexible Parametric Survival Models................. 118
4.6.3.2 Applications in Cancer Surveillance ................. 119
4.7 Issues in Fitting Models....................................................................122
4.8 Handling Crossover, Treatment Switching, and
Subsequent Anti-Cancer Therapy ............................................. 123
4.8.1 Introduction to Treatment Switching................................. 123
4.8.2 Types of Switching ............................................................... 124
4.8.3 Implications of Switching.................................................... 124
4.8.4 Handling Switching in Statistical Analyses .................... 126
4.8.4.1 Intent-to-Treat (ITT)............................................... 127
4.8.4.2 Per Protocol Analysis............................................ 128
4.8.4.3 IPCW....................................................................... 128
4.8.4.4 RPFSTM.................................................................. 129
4.8.4.5 Two-Stage Adjustment Model ............................ 131
4.8.4.6 Other Approaches: Structural
Nested Mean Models (SNNM) ............................................................. 131
4.9 Data Synthesis and Network Meta-Analyses................................ 132
4.9.1 Mixed Treatment Comparisons ......................................... 132
4.9.1.1 Direct Comparison................................................ 133
4.9.1.2 Indirect Treatment Comparison (ITC) .............. 133
4.9.1.3 Meta-Analysis ....................................................... 134
4.9.1.4 Network of Evidence ........................................... 134
4.9.2 Assumptions for Carrying Out MTCs .............................. 134
4.10 Summary............................................................................................. 138
4.11 Exercises for Chapter 4...................................................................... 140
5 Collecting and Analysis of Costs from Cancer Studies...................... 141
5.1 Types of Costs Typical of Cancer Trials.......................................... 141
5.1.1 Categorization of Health Resource Use............................. 142
5.1.2 Resource Use Monitoring.................................................... 142
5.1.3 Baseline Characteristics and Health Resource Use......... 143
5.1.4 Costs Determined by a Study Protocol.............................. 144
5.2 Perspective of Analysis and Costs Collection................................ 145
5.3 Collecting Health Resource Use across the Treatment
Pathway ....................................................................................... 146
5.3.1 Time Horizon ....................................................................... 148
5.4 Costing Methods: Micro versus Macro Approach........................ 150
5.4.1 Average versus Marginal and Incremental Cost.............. 151
5.4.2 Inflation.................................................................................. 152
5.4.3 Time Preference and Discounting...................................... 153
5.5 Charges................................................................................................ 154
5.5.1 Cost-to-Charge Ratios.......................................................... 155
5.5.2 Other Non-Medical Costs (e.g. Societal Costs)................. 155
5.6 Distribution of Costs.......................................................................... 155
5.6.1 Transforming Cost Data....................................................... 157
5.7 Handling Censored and Missing Costs ........................................ 158
5.7.1 Strategies for Avoiding Missing Resource Data .............. 160
5.7.2 Strategies for Analyzing Cost Data
When Data Are Missing or Censored ..................................... 160
5.7.3 Imputation Methods............................................................. 161
5.8 Handling Future Costs...................................................................... 162
5.9 Case Report Forms and Health Resource Use............................... 164
5.10 Statistical Analyses of Costs ............................................................ 165
5.11 Summary............................................................................................. 172
5.12 Exercises for Chapter 5...................................................................... 173
6 Designing Cost-Effectiveness into Cancer Trials................................. 175
6.1 Introduction and Reasons for Collecting Economic
Data in a Clinical Trial ........................................................................... 175
6.2 Clinical Trial Designs for Cancer Studies...................................... 178
6.2.1 Clinical Trial Designs........................................................... 178
6.2.2 Interim Analyses and Data Monitoring Committees
(DMC)..................................................................................... 188
6.3 Planning a Health Economic Evaluation in a Clinical Trial ....... 191
6.3.1 Important Considerations When Designing
a Cancer Study for Economic Evaluation ............................................... 191
6.3.2 Integrating Economic Evaluation in a Clinical Trial:
Considerations .......................................................................... 194
6.3.3 Endpoints and Outcomes.................................................... 196
6.3.3.1 Timing of Measurements..................................... 198
6.3.3.2 Trial Design............................................................ 198
6.3.3.3 CRF Design............................................................ 199
6.3.3.4 Sample Size Methods for Cost-Effectiveness....... 199
6.3.3.5 Sample Size Formulae for
Cost-Effectiveness: Examples .................................................... 201
6.3.4 Treatment Pathways.............................................................204
6.3.5 Time of Generic/Competition Entry..................................204
6.3.6 Treatment Compliance.........................................................205
6.3.7 Identify Subgroups/Heterogeneity....................................206
6.3.8 Early ICER/INMB.................................................................206
6.3.9 Multicenter Trials.................................................................. 207
6.4 Case Study of Economic Evaluation of Cancer Trials................... 210
6.4.1 TA516 Cabozanitib + Vandetanib....................................... 210
6.5 Summary............................................................................................. 210
6.6 Exercises for Chapter 6...................................................................... 213
7 Models for Economic Evaluation of Cancer........................................... 215
7.1 Types of Health Economic Models.................................................. 215
7.2 Decision Tree Models........................................................................ 215
7.2.1 Further Possible Improvements to the
Decision Model ......................................................................................224
7.3 Markov Models..................................................................................226
7.4 Continuous Time Markov Models...................................................230
7.5 The Partitioned Survival Model...................................................... 231
7.5.1 Developing an Economic Model Using Patient-Level
Data Using a Partitioned Survival Model Approach ......................... 231
7.5.1.1 Modeling the Efficacy Data (Survival Data)............................ 231
7.5.2 Case Study of an Economic Model Using Patient-
Level Data: A Partitioned Survival Model..................................................... 232
7.5.3 Crossover...............................................................................236
7.6 Summary of Cost-Effectiveness Models for Cancer
Used in HTA Submissions ....................................................................239
7.7 Summary............................................................................................. 243
7.8 Exercises for Chapter 7...................................................................... 243
8 Real-World Data in Cost-Effectiveness
Studies on Cancer ....................................................................................... 249
8.1 Introduction to Real-World Data..................................................... 249
8.2 Using RWD to Support Cost-Effectiveness Analysis ................... 251
8.3 Strengths and Limitations of Using RWD to Support
Cost-Effectiveness Analysis .....................................................253
8.3.1 Limitations.............................................................................255
8.3.2 Internal Validity versus Generalizability..........................256
8.4 Sources for RWD Generation........................................................... 257
8.4.1 Registries ...............................................................................260
8.4.2 Audits .................................................................................... 261
8.4.3 Primary Care Databases: CPRD, THIN, QResearch........ 262
8.4.4 Insurance Claims Databases...............................................263
8.4.5 Digital Data Sources, Social Media and Applications....... 263
8.4.6 Commercial Data Sources...................................................264
8.4.7 Pragmatic Clinical Trials.....................................................264
8.4.8 Prospective Observational Research Studies...................265
8.4.9 Case Control Studies............................................................265
8.5 Using Cancer Registries....................................................................265
8.5.1 Examples of Registries in the UK for RWE ...................... 267
8.6 Statistical Analyses of RWD: Addressing Selection Bias.............268
8.6.1 Propensity Score Modeling.................................................268
8.6.2 Instrumental Variable Methods.......................................... 274
Results..................................................................................................277
8.7 Summary and Conclusion................................................................ 279
8.8 Exercises for Chapter 8...................................................................... 281
9 Reporting and Interpreting Results of Cost-Effectiveness
Analyses from Cancer Trials.....................................................................283
9.1 Interpreting Incremental Costs and QALYs...................................283
9.1.1 Informative Censoring.........................................................284
9.2 Interpreting Incremental QALYs..................................................... 287
9.3 Relationship between Costs and QALYs........................................290
9.4 Interpreting the ICER and the Cost-Effectiveness Plane.............. 292
9.4.1 Uncertainty............................................................................ 292
9.5 Presenting and Interpreting Results from Uncertainty
Analysis ....................................................................................................296
9.6 Bayesian Sensitivity Analysis...........................................................306
9.6.1 Limitations of the ICER and Using the INMB..................307
9.7 Presenting and Interpreting Results from Value of
Information Analyses .............................................................................308
9.8 Challenges of VOI Analysis in Healthcare Decisions................... 316
9.9 Summary ............................................................................................ 317
9.10 Exercises for Chapter 9...................................................................... 317
Technical Appendix for Chapter 9.............................................................. 318
A9.1 Simulation.............................................................................. 318
A9.2 Bayesian PSA......................................................................... 319
A9.3 Value of Information............................................................ 320
Before Any Data Is Observed........................................................... 321
After Data Have Been Observed...................................................... 321
10 Factors Predictive of HTA Success and the Global Landscape.......... 323
10.1 Introduction........................................................................................ 323
10.2 Cancer Drugs Rejected by NICE...................................................... 323
10.3 Summary of Criticisms of Economic Models of Cancer.............. 324
10.4 Factors Predictive of Successful HTAs in Cancer..........................335
10.5 The Changing Pace of the Reimbursement Environment .......... 341
10.6 Reimbursement and Payer Evidence Requirements
Across Different Countries ...........................................................344
10.6.1 Canada....................................................................................345
10.6.2 France......................................................................................345
10.6.3 Germany.................................................................................346
10.6.4 Italy.........................................................................................347
10.6.5 Spain.......................................................................................347
10.6.6 Australia.................................................................................348
10.6.7 United Kingdom...................................................................349
10.7 Pricing and Reimbursement Environment in the
United States.......................................................................................349
10.8 Value-Based Pricing (VBP) for Cancer Drugs................................350
10.9 Risk-Sharing Scheme ........................................................................ 352
10.10 The Future of Cost-Effectiveness of Cancer Treatments..............356
10.10.1 Future Research: Methodology..........................................356
10.10.2 Future Reimbursement Landscape....................................358
Budget Impact Threshold................................................... 359
10.10.2.1 Automatic Funding for Highly Specialized
Drugs for Rare Diseases.....................................................359
10.10.2.2 Fast-Track Appraisals......................................... 359
10.11 Summary.............................................................................................360
10.12 Exercises for Chapter 10....................................................................360
References............................................................................................................ 361
Additional Bibliography.............................................................................. 394
Chapter 1............................................................................................. 394
Chapter 3............................................................................................. 395
Chapter 4............................................................................................. 395
Chapter 5............................................................................................. 399
Chapter 7............................................................................................. 399
Chapter 9............................................................................................. 399
Index...................................................................................................................... 401
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