Weighing false hope in population anticancer drug decision making
Authors: C. Chamberlain, R. Sullivan
Journal: Annals of Oncology (2018)

The prices of anticancer pharmaceuticals, as well as many other cancer technologies, have dramatically increased over the last decade [1.Mailankody S. Prasad V. Comparative effectiveness questions in oncology.N Engl J Med. 2014; 370: 1478-1481Crossref PubMed Scopus (34) Google Scholar]. While there are those that would argue the costs of anticancer drugs have escalated out of proportion to the benefit they provide [2.Mailankody P. Prasad V. Five years of cancer drug approvals: innovation, efficacy, and costs.JAMA Oncol. 2015; 1: 539-540Crossref PubMed Scopus (223) Google Scholar], there are others who justify these prices as the cost of innovation [3.DiMasi J.A. Grabowski H.G. Hansen RW. Innovation in the pharmaceutical industry: New estimates of R&D costs.J Health Econ. 2016; 47: 20-33Crossref PubMed Scopus (1624) Google Scholar]. Despite numerous supply and demand side policy approaches to address the growing gap between higher prices and equitable, affordable access [4.Wait S. Han D. Muthu V. et al.Towards sustainable cancer care: reducing inefficiencies, improving outcomes-A policy report from the All.Can initiative.J Cancer Policy. 2017; 13: 47-64Crossref Scopus (30) Google Scholar, 5.Sullivan R. Peppercorn J. Sikora K. et al.Delivering affordable cancer care in high-income countries.Lancet Oncol. 2011; 12: 933-980Abstract Full Text Full Text PDF PubMed Scopus (532) Google Scholar], there is no clear international consensus on how to frame this. The threshold of evidence required for anticancer drugs marketing authorization is lower than in other disease types [6.Davis C. Naci H. Gurpinar E. et al.Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13.BMJ. 2017; 359: j4530Crossref PubMed Scopus (354) Google Scholar, 7.Kim C. Prasad V. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: an analysis of 5 years of US Food and Drug Administration approvals.JAMA Intern Med. 2015; 175: 1992-1994Crossref PubMed Scopus (237) Google Scholar]. This therefore has the potential to not only allow drugs with less evidence of benefit or harm to the market, but also may risk the future generation of data to support or refute their benefit [8.Fojo T. Mailankody S. Lo A. Unintended consequences of expensive cancer therapeutics-the pursuit of marginal indications and a me-too mentality that stifles innovation and creativity: the John Conley Lecture.JAMA Otolaryngol Head Neck Surg. 2014; 140: 1225-1236Crossref PubMed Scopus (227) Google Scholar]. What then is the ethical and moral responsibility of clinicians and policy makers to define the context and level of uncertainty of evidence that is acceptable that ensures good clinical practice and does not expose patients either to real harm from toxicity and/or false hope? In an area rife with disagreement about the fundamental costs and benefits of anticancer drugs to individuals and society, Lipworth et al. [9.Lipworth W. Kerridge I. Ghinea N. Zalcberg J. Clearing the air: towards agreement about access to high cost cancer medicines.Ann Oncol. 2019; 30: 143-146Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar] present a conceptual framework to address this contentious area. Their framework summarizes six steps in the prioritization of anticancer drugs debate: Step 1: Define the clinical context (benefits, risks, alternatives, cost-effectiveness). Step 2: Categorize the drug according to these findings (types 1–3). Tabled 1CategorizationCost-effectiveSafeEffectiveType 1✓✓✓Type 2×✓✓Type 3UncertainUncertainUncertain Open table in a new tab Step 3: Identify points of agreement. Step 4: Systematically debate/clarify disagreements. Step 5: Weight criteria ('moderating factors'). Step 6: Define whose values and who decides? Employing the framework is likely to generate more questions than answers in its first application. However, the merit of the framework is in uncovering assumptions; transparently and systematically embedding a process that articulates values and priorities in anticancer drug funding decisions—decisions that are essential in both publicly funded and non-publicly funded systems beyond traditional health technology assessment methods. The Lipworth framework approach, much like accountability for reasonableness [10.Daniels N. Accountability for reasonableness.BMJ. 2000; 321: 1300-1301Crossref PubMed Scopus (463) Google Scholar] which informs general UK prioritization decision making, does not aim to have a single 'answer', which would be inappropriate to transfer across settings and countries, but instead a systematic, transparent means to articulate a process of consideration. Critics of accountability for reasonableness (and the authors themselves) acknowledge that in this approach the focus on fair process in decision making is incomplete in how to quantify what is a substantive value or a 'relevant' criteria for prioritization [11.Rid A. Justice and procedure: how does "accountability for reasonableness" result in fair limit-setting decisions?.J Med Ethics. 2009; 35: 12-16Crossref PubMed Scopus (52) Google Scholar, 12.Daniels N. Sabin JE. Accountability for reasonableness: an update.BMJ. 2008; 337: a1850.Crossref PubMed Scopus (147) Google Scholar]. Lipworth et al. attempt to address both process and substantive questions in their work by outlining agreed principles and values, including highlighting the need for harmonization of processes for type 1 category drugs, as well as defining those areas that remain for debate. The Lipworth framework comes with certain advantages, for example, being specific for anticancer drugs, but it is not without risks. There is a clear need for some type of reconciliation in decision making to mitigate the risk of over-prioritizing anticancer drugs above other interventions which aim to improve cancer mortality and morbidity, such as interventions to improve early cancer diagnosis. Rather than a framework that focuses entirely on improved access to cancer drugs, the aim should be access to the most appropriate care for every patient, irrespective of the modality. It is important not to lose sight of the fact that for some patients, the most appropriate treatment may not be anticancer drugs, but better palliative care. Many high-cost anticancer therapies are introduced in the incurable cancer setting and will not cure the cancer but aim to prolong life and improve quality of life. As Lipworth et al. write in their broad areas of agreement, there is a 'need to be compassionate which, depending on the context, might be achieved through access to medicine, or through the provision of alternative forms of care'. So how do we define what is medically futile when it comes to cancer drugs? The promissory nature of the 'right to try' (the United States) and the Medical Innovation Bill (UK) legislation sent a powerful message that for those with 'nothing more to lose', access to even the most experimental anticancer drugs was a 'right'. However, where the balance of 'right to try' has tipped too far, the potential for harm to the individual is false hope and harm, which can lead to patients forgoing a good death and the lost opportunity to make their peace. It may even shorten life expectancy. There is also the question of societal cost—the right to try, some would argue, adds to the evidence base around these medications and their potential for use to extend life or for use in other earlier disease contexts (as adjuvant/neoadjuvant treatment) and therefore they may justify their cost to society and the individual. On the other hand, the costs to society may be too high in absolute financial terms, when considering the opportunity cost of money diverted from evidence-based therapies, as well as generating concern the promised evidence may not materialize due to real-world bias, rather than real-world data [13.Lewis J. Kerridge I. Lipworth W. Use of real-world data for research, development, and evaluation of oncology precision medicines.JCO Precis Oncol. 2017; : 1-11Google Scholar, 14.Skovlund E. Leufkens H.G.M. Smyth JF. The use of real-world data in cancer drug development.Eur J Cancer. 2018; 101: 69-76Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar]. By making greater use of clinically meaningful benefit scales developed by the American Society of Clinical Oncology (ASCO Value Framework) [15.Schnipper L.E. Davidson N.E. Wollins D.S. et al.American Society of Clinical Oncology Statement: a conceptual framework to assess the value of cancer treatment options.J Clin Oncol. 2015; 33: 2563-2577Crossref PubMed Scopus (681) Google Scholar] and the European Society of Medical Oncology (Magnitude of Clinical Benefit Scale) [16.Chernt N.I. Dafni U. Bogaerts J. et al.ESMO-Magnitude of Clinical Benefit Scale, version 1.1.Ann Oncol. 2017; 28: 2340-2366Abstract Full Text Full Text PDF PubMed Scopus (325) Google Scholar], can we more fairly define false hope at a population level? Although Lipworth et al. do not comment on these clinically meaningful scales, there is the potential to complement their framework approach by including a transparent, measured assessment of clinically meaningful benefit and financial toxicity, in the case of the ASCO scale. Universally validated clinical scales are not the same as locally sensitive frameworks for policy decisions that can reflect the nuances of culture, society and economics specific for that population. These societal values can be openly debated within the Lipworth framework. Although the Lipworth framework aims to provide flexibility across settings so that individual countries can decide on the importance of social justice (e.g. universal health care utilitarianism and prioritarianism) or whether libertarianism is the priority, the model still requires a substantial number of assumptions. For instance, the framework suggests that there is an agreed tenant that there is a 'need to promote equity and address existing inequities by attempting to fund medicines for patients who are already disadvantaged because of their disease (e.g. those with rare cancers) or their financial situation'. This assumption may not hold true for all health systems. Similarly, by virtue of the tool forcing decision makers to evaluate safety, efficacy and cost-effectiveness, the framework implies that these are 'essential criteria' for drug decisions and therefore cost-effectiveness is embedded even for non-publicly funded health systems. Again this does not reflect the ground reality. If there is an 'answer' in the anticancer drug decision making debate, it lies in clarity of information sharing both at the individual and population levels. Health professionals have a duty of non-maleficence and beneficence. All treatments of uncertain benefit also have uncertain harms and unintended consequences at a population level due to opportunity costs and distorted incentives. Balancing patient advocacy with stewardship of scarce resources, as the authors describe, is challenging, but exposing assumptions and finding areas of common ground will improve accountability and provide an opportunity to reflect society values in our choices for cancer care. Outstanding questions in cancer drug decision making include how can we make clinical drug outcome uncertainty more measured, meaningful, fair and sustainable in order to support population decision making: the Lipworth framework is a useful tool in the armory. The views expressed in this article are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care. National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care West (NIHR CLAHRC West). CC is funded by the University of Bristol, working in collaboration with the CLAHRC West as an NIHR academic clinical lecturer in palliative medicine and Dan Hill equity fellow. RS is funded by King's College London, Comprehensive Cancer Centre, Institute of Cancer Policy, School of Cancer and Pharmaceutical Sciences, Guy's Hospital, Great Maze Pond, London (no grant numbers apply).