Iftekhar Khan, Ralph Crott, Zahid Bashir

Economic Evaluation of Cancer Drugs (eBook, ePUB)

Using Clinical Trial and Real-World Data

• Format: ePub

Produktbeschreibung

The first book on the design and analysis of not only clinical trials but also how observational non-interventional data using clinical data is applied to economic evaluation and re-imbursement in the context of Cancer. This book is a non technical exposition of economic evaluation and no knowledge of advanced statistical methods is assumed.

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Produktdetails

• Verlag: Taylor & Francis
• Seitenzahl: 352
• Erscheinungstermin: 19. Juni 2019
• Englisch
• ISBN-13: 9780429531842
• Artikelnr.: 57006516

Autorenporträt

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.

Inhaltsangabe

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