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The London School of Economics and Political Science Cancer Medicines The London School of Economics and Political Science Cancer medicines: clinical impact, economics, and value Sebastian Salas-Vega A thesis submitted to the Department of Social Policy at the London School of Economics and Political Science for the degree of Doctor of Philosophy, London, April 2017 Declaration I certify that’s the thesis I have presented for examination fully MPhil/PhD degree at the London School of Economics and Political Science is solely my own work other than where I have clearly indicated that the work of others (in which case the extent of any work carried out jointly by me and any other persons clearly identified in it – see ‘Statement of Conjoint Work’). The copyright of this thesis rests with the author. Quotation from it is permitted, provided that full acknowledgement is made. This thesis may not be reproduced without the prior written consent of the author. I warrant that this authorization does not, to the best of my belief, infringe the rights of any third party. I declare that my thesis consists of 63,084 words (excluding bibliography and appendix). ii Statement of Conjoint Work The work that is presented in Chapter 2, and part of the work that is presented in Chapter 4, has been published.1 My co-authors on these publications include: Dr Elias Mossialos of the London School of Economics and Political Science (London, UK) and Dr Othon Iliopoulos of the Harvard Medical School and Massachusetts General Hospital (Boston, MA, US), who provided guidance on research methodologies and clinical input. Mr Rayden Llano of the London School of Economics and Political Science (London, UK) could not be named as co-author in one of these publications due to policies on publishing by federal employees. His contributions are nevertheless acknowledged: he assisted with data collection by serving as a second, independent reviewer of cancer drug appraisals in Chapter 2. For the same chapter, Dr Mossialos was asked to serve as a third reviewer if consensus with Mr Llano could not be reached. This consensus-based approach was used to minimize the introduction of investigator bias during the review of HTA appraisals. All major work related to Chapter 2, including analysis and interpretation of data, was conducted by me. Copyeditor Sarah Moncrieff assisted with designing Figure 5. For the published aspects of this thesis (Chapters 2, 4), I conceived and designed studies, acquired, analyzed, and interpreted data, and drafted manuscripts. Dr Mossialos offered feedback on the published aspects of this thesis, as well as all remaining chapters. Journal reviewers provided feedback, and suggested secondary analyses, that have been incorporated into this thesis. Additional publications are being 1 Salas-Vega S, Mossialos E. Cancer Drugs Provide Positive Value In Nine Countries, But The United States Lags In Health Gains Per Dollar Spent. Health Aff (Millwood). 2016;35(5):813–23. Salas-Vega S, Iliopoulos O, Mossialos E. Assessment of Overall Survival, Quality of Life, and Safety Benefits Associated With New Cancer Medicines. JAMA Oncol. 2016;116(14):3493–504. iii prepared from the work that is presented in the remaining chapters of this thesis. Other than where I have cited the relevant contributions of others, I confirm that I am responsible for the entirety of the work presented in this doctoral thesis. iv Abstract Background and Importance: There has been much debate recently over rapidly growing drug expenditures. Cancer medicines, in particular, have driven new brand spending over recent years, and US oncological expenditures have risen faster than for many other disease areas, in part because of rapidly growing drug prices, as well as increased rates of use. Objective: In the face of ongoing debates on how to reasonably control growth in pharmaceutical spending, while also providing patients with the best possible care, this thesis sets out to help address the question of whether growing pharmaceutical expenditures are providing value-for-money to patients and society. Novelty and Empirical Contributions: This thesis is based in part on a systematic review with narrative synthesis of English-language HTA appraisals of the comparative clinical risks and benefits of new cancer medicines, as well as on the novel use of (b) (4) methods to generate comparative evidence on their use and cost. Adapting established methods, these data are then used to examine existing questions over whether growing expenditures are worth the cost to patients and society. This thesis makes five major contributions to the literature on value-based spending on cancer medicines: 1) approximately one in three newly licensed cancer medicines provide no known overall survival benefit, while one in five provide no known overall survival, quality of life, or safety benefit; 2) novel use of methodologies to model treatment course and duration reveals that cancer drug use and costs vary greatly between individual medicines, and across Australia, France, the UK, and the US; 3) the monetized value of survival gains attributable to cancer drug innovation, net of growth in cancer drug v spending, varies across individual medicines, and, at a country-level, remains unambiguously positive in Australia, France, and the UK, but negative in the US; 4) spending on new cancer medicines is often only weakly associated with their clinical benefits; and 5) the strength of this association nevertheless varies across countries, with the UK demonstrating the strongest evidence of value-based spending on new cancer medicines. Clinical and Policy Implications: Findings from this thesis provide a resource for value- based clinical decision-making by patients and physicians. Moreover, growing expenditures on cancer medicines may only weakly be associated with meaningful clinical benefits, though the extent to which this is true differs across countries. These findings highlight the important role that health policy can have in encouraging value- based cancer drug spending. In particular, it is argued that managed access schemes promoting access and evidence development, as well as the use of value-based spending policies, can help expedite access to new treatments, incentivize the development of clinically meaningful medicines, and rationalize growing cancer drug expenditures. Future Research Directions: The comparative clinical risks and benefits from new cancer medicines using real-world data, and how they compare with trial-based results; how evidence on the comparative impact from new treatments is measured, weighted, and rewarded in decision-making by regulators and payers; and how it is effectively linked through policy and regulation to cancer drug spending. vi Acknowledgments I would like to express my deepest gratitude to all who have offered their guidance and expertise throughout my PhD. In particular, I would like to sincerely thank my doctoral supervisors, Prof Elias Mossialos (1°) and Prof Alistair McGuire (2°), for their mentorship, patience, and, when most needed, encouragement. I am grateful to Mr Rayden Llano of the London School of Economics (London, UK) for assisting with the review of HTA appraisals, and to Dr Irini Moustaki, Dr Zlatko Nikoloski, Dr Anwen Zhang, and Dr Jon Cylus of the London School of Economics (London, UK) for offering feedback on regression and statistical methods. I would also like to thank Dr Othon Iliopoulos of the Harvard Medical School and Massachusetts General Hospital (Boston, MA, USA) and experts from the Food and Drug Administration (Silver Spring, MD, USA) for offering clinical and regulatory feedback on some of the research findings that are presented in this thesis. I must acknowledge the organizations offering the publicly available data that was used in this work: the Australian Bureau of Statistics, European Medicines Agency, Haute Autorité de Santé, Institute for Health Metrics and Evaluation, National Institute for Health and Care Excellence, NHS Digital, Organisation for Economic Co-operation and Development, Pharmaceutical Benefits Advisory Committee, Therapeutic Goods Administration, US Centers for Disease Control and Prevention, US Food and Drug Administration, World Bank, and World Health Organization. Their investments in the public disclosure of information are a testament of their commitment to research and public health. vii I would also like to thank the many individuals who offered insights that contributed to this research: Dr Caroline Rudisill (LSE), Dr Walter Holland (LSE), Aris Angelis (LSE), Sahan Jayawardana (LSE), Felix Cornehl (LSE), Dr Victoria Simpkin (LSE), Emmy Shearer (Stanford University), Ilias Kyriopoulos (LSE), Dr Jia Hu (University of Toronto), Dr José- Luis Fernández (LSE), Dr Bo Hu (LSE), Dr Rebecca Roylance (University College London), Dr David Dodwell (Public Health England), Dr Mauricio Avendano (King’s College London), Dr Isabelle Soerjomataram (WHO), Alex Carter (Imperial College London), Dr Wei Yang (University of Kent), (b) (4) Dr Alexandre Barna (OECD), (b) (4) Thomas Wilkinson (NICE), Dr Josep Figueras (WHO), Kai Schulze (University of Cambridge), Dr Lawrence Brown (Columbia University), Dr Guillaume Dedet (WHO), and Adria Haimann (Health Navigator). I would also like to acknowledge librarians Ellen Wilkinson and Alex Taylor (LSE) for their support. I am thankful to Dr Panos Kanavos and Dr Joachim Marti for their helpful feedback during my doctoral defense. Their comments have helped me strengthen the work that is presented here. I would like to thank QuintilesIMS and Imperial
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