Real-World Evidence for Health Technology Assessment of Pharmaceuticals: Opportunities and Challenges

REAL-WORLD EVIDENCE FOR HEALTH TECHNOLOGY ASSESSMENT OF PHARMACEUTICALS: OPPORTUNITIES AND CHALLENGES Amr Ahmed Mahmoud Abdelkader Makady ISBN: 978-94-6182-886-6 Cover Image: Off Page, Amsterdam Layout and print production: Off Page, Amsterdam Chapter 2: © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved. Chapter 3: © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved. Chapter 4: © The Author(s) 2017. Open Access. This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made REAL-WORLD EVIDENCE FOR HEALTH TECHNOLOGY ASSESSMENT OF PHARMACEUTICALS: OPPORTUNITIES AND CHALLENGES Real-World Evidence voor Health Technology Assessment van Geneesmiddelen: Kansen en Uitdagingen (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G. J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op woensdag 9 mei 2018 des middags te 4.15 uur door Amr Ahmed Mahmoud Abdelkader Makady geboren op 5 januari 1990 te Adan, Koeweit Promotoren: Prof.dr. A. de Boer Prof.dr. J. L. Hillege Prof.dr. O.H. Klungel Copromotor: Dr. W.G. Goettsch TABLE OF CONTENTS Chapter 1 Introduction 9 Health, Health Systems & the Role of HTA 11 Evidence-Based Medicine & the Efficacy-Effectiveness Gap: 13 Why is this an issue? Real-World Evidence: Potential complement to RCTs? Growing need & 14 the IMI-GetReal project. 14 Statement of Research Gap & Thesis Objective 15 Outline of Thesis 15 Reference List 17 Chapter 2 What is Real-World Data? A review of definitions based on literature and 23 stakeholder interviews Abstract 24 Introduction 25 Methods 26 Analysis 29 Results 29 Discussion 33 Conclusion 38 Reference List 39 Chapter 3 Policies for Use of Real-World Data in Health Technology 45 Assessment (HTA): A comparative study of 6 HTA agencies Abstract 46 Introduction 47 Methods 48 Results 50 Discussion 65 Conclusion 67 Reference List 69 Chapter 4 Using Real-World Data in Health Technology Assessment (HTA) Practice: 75 A comparative study of 5 HTA agencies Abstract 76 Introduction 77 Methods 78 Analysis 79 Results 80 Discussion 84 Conclusions 88 Reference List 89 Chapter 5 Implementing Managed Entry Agreements in Practice: 93 The Dutch reality check Abstract 94 Introduction 95 Methods 96 Results 99 Discussion 103 Conclusion 109 Reference List 110 Chapter 6 Conditional Financing of Drugs in the Netherlands: 113 Past, Present and Future. Results from Stakeholder Interviews Abstract 114 Introduction 115 Methods 116 Results 118 Discussion 126 Conclusion 129 Reference List 130 Chapter 7 Practical Implications of Using Real-World Evidence in 135 Comparative Effectiveness Research: Learnings from IMI-GetReal Abstract 136 Why is real-world evidence (RWE) relevant for comparative effectiveness research (CER)? 137 Why is individual patient-level data (IPD) important when using 137 RWE in CER? What were IMI-GetReal’s experiences in 138 accessing IPD throughout case studies? What are the consequences of inaccessibility to IPD from 140 RWE repositories on its potential use for decision-making in healthcare? What are potential solutions to addressing issues faced with access to 141 IPD from RWE repositories in the future? Reference List 143 Chapter 8 Use of Social Media in the Assessment of Relative Effectiveness: 149 An explorative review with examples from oncology. Hopeful or hopeless? Abstract 150 Introduction 151 Methods 152 Results 153 Discussion 160 Conclusion 162 Reference List 163 Chapter 9 Social Media as a Tool for Assessing Patient Perspectives on Quality of 167 Life in Metastatic Melanoma: a feasibility study Abstract 168 Introduction 169 Methods 170 Analysis 171 Results 171 Discussion 178 Conclusions 186 Reference List 187 Chapter 10 Real-World Evidence for Health Technology Assessment of 193 Pharmaceuticals: Perspectives on the status quo and the future Re-statement of Research Question 195 Main Findings & Implications 195 Ongoing Initiatives on RWE & Relevance to Main Findings 201 Limitations of Research 205 Which steps can be taken towards more optimal use of RWE in 206 HTA decision making? Recommendations based on findings Conclusion 208 Reference List 209 Chapter 11 Appendices 215 Chapter 2 217 Chapter 3 230 Chapter 4 232 Chapter 5 248 Chapter 6 258 Chapter 9 287 Chapter 12 Summary 301 Samenvatting in het Nederlands 304 Acknowledgements 307 List of publications 309 About the author 311 CHAPTER Introduction 1 HEALTH, HEALTH SYSTEMS & THE ROLE OF HTA Shortly after the end of the Second World War and the establishment of the World Health 1 Organization (WHO) as a subsidiary of the United Nations, representatives from 61 member Introduction states convened to develop the first Constitution ofthe WHO (1). In this constitution, the WHO ventured to lay the fundamental principles of the organization and its aims. This constituted devising a definition for “health”; a complicated concept which may know different meanings across cultures. Eventuallya holistic definition was devised, encompassing a state of complete well-being which extends to the physical, mental and social well-being of an individual (i.e., not merely the absence of ailment). Moreover, the constitution stipulated that health, encompassing such a state of complete well-being is a fundamental human right. By ratifying this constitution, member states of the WHO thus commit to the provision of health to all their citizens. However, the achievement of good health on population level is a herculean task, requiring the development of healthcare systems that guarantee the delivery of a plethora of interventions, such as curative therapy for acute or chronic diseases and public health programs to raise awareness on preventive measures for diseases. In order to provide the reader with more context on the aims and properties of healthcare systems, we take note of the following excerpt from Garrido et al. (2) in Box 1. Bearing in mind the aims of healthcare systems to provide good health to their respective populations, it may not come as a surprise that the financial resources needed to strive towards these aims are colossal. The Global Healthcare Expenditure Database (GHED) of the WHO states that member states dedicated $6.5 trillion U.S. dollars to healthcare systems in 2010 alone (3). To draw on a national example, the Dutch Ministry of Finance published a report in 2015 which estimated national healthcare expenditures in 2016 to reach €75 billion Euros, making them the government’s second-largest annual financial expenditure (4). However, despite the fact that such figures may imply that immense resources are available to establish healthcare systems worldwide, one must bear in mind that these resources are not infinite. Tothe contrary, such resources have very tangible limits. To make “A health system consists of all the people and actions whose primary purpose is to improve health. This definition coversa variety of professions and institutions and a broad range of activities dedicated to the promotion, restoration and protection of health. Health systems encompass both individual and population services, in addition to activities aimed at influencing the policies and actions of other sectors, in an effort to addressthe social, environmental, and economic determinants of health … modern health systems generally pursue the fundamental goals of improving the health of a population, responding to the wishes and expectations of individuals, and providing financial protection against the costs of ill-health.” Box 1 - Hallmarks of health systems. 11 matters more complex, healthcare expenditures over the past decade have been increasing 1 beyond the annual rate of gross domestic product (GDP) growth of the majority of countries (5). Introduction As a consequence of rising healthcare costs and finite budgets, governments are constantly faced with challenging questions on how to allocate resources to achieve the greatest health gains for their citizens. In an attempt to provide a transparent and accountable approach to decision making related to healthcare policy on resource allocation, governments increasingly turn to Health Technology Assessment (HTA). Briefly defined, HTA pertains tothe systematic evaluation of the properties and effects of health technologies (whether drugs, medical devices, surgical procedures or organizational aspects of health systems (6)), addressing their direct and intended effects, as well as their indirect and unintended consequences with the aim of informing decision making (7). In general, HTA is a policy analysis process including two components; firstly, an assessment of all available evidence relevant to the policy question at hand and secondly, an appraisal of the findings fromthe evidence to reach a decision (8). The prior of these components (i.e. assessment) is conventionally a scientific, robust process (8). From an organizational perspective, the conduct of HTA to inform decision making for healthcare systems is often delegated

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