- Email: [email protected]
The UK Cancer Drugs Fund Experiment and the US Cancer Drug Cost Problem
COMMENTARY
The UK Cancer Drugs Fund Experiment and the US Cancer Drug Cost Problem: Bearing the Cost of Cancer Drugs Until It Is Unbearable Vinay Prasad, MD, MPH, and Sham Mailankody, MB, BS
E
arlier this year, under increasing budgetary pressure, the United Kingdom through its Cancer Drugs Fund (CDF) declined to pay for 45 cancer indications. This decision is estimated to affect more than 5000 patients.1 Then, on April 1, 2016, the entire UK CDF underwent an overhaul with plans to integrate with the existing National Institute for Health and Clinical Excellence (NICE) appraisal program.2 Although critics of the government’s policy argue that this action will limit patients’ access to important drugs, defenders point out that these choices are inevitable as we continue to witness the rapidly escalating cost of cancer treatments in a world of finite budgets.1 The reasons for and implications of the United Kingdom’s action provide important lessons regarding the price of cancer drugs. The CDF The CDF was created in 2010 as a mechanism to bypass the United Kingdom’s strict standards of demonstrated cost-effectiveness of new therapies. Through the CDF, drugs that had been denied by the United Kingdom’s NICE as low value could still receive funding, and patients who receive these drugs would bear no additional copay. However, because the CDF inherently subverts the guiding principle of the UK systemddo the most good with the money you havedcritics alleged from the outset that the CDF “undermines the entire concept of a rational and evidence-based approach to the allocation of finite health-care resources” and is “already intellectually bankrupt.”3,389 Unlike the situation in the United States, the UK CDF negotiates the price of drugs with the pharmaceutical industry. The magnitude of discount is not revealed and is protected by confidentiality agreements. However, in some cases, negotiations have stalled
because companies were unwilling to reach an agreement with the United Kingdom on what some call “realistic prices,”4 making rejection necessary. Earlier this year, before restructuring, to protect the solvency of the CDF, 45 indications were cut from the fund (Table). Many excluded drugs offer real, albeit marginal, benefits, and the US Food and Drug Administration (FDA) has approved all of the 45 drug indications. Seventeen excluded drug indications (38%) improve overall survival, a standard that exceeds the percentage of new FDA drug approvals that meet this mark (19 of 63, 30%).5 Other denied drugs, such as ibrutinib and brentuximab, are able to achieve responses in patients refractory to all other therapies, serving as a bridge to potentially beneficial treatment, such as stem cell transplant. In short, if cost were not an issue, we believe that most oncologists would not hesitate to prescribe many of these drugs in the appropriate setting. Yet, in each of these cases, cost is the deciding factor. It is instructive to highlight the ocean of difference between the discussion of cost in the United Kingdom versus the United States. Take, for example, brentuximab, a monoclonal antibody to CD30, which is overexpressed in several forms of lymphoma. One month of brentuximab therapy costs approximately £9000 in the United Kingdom (equivalent of approximately $13,000 in the United States). The CDF has stated that it is unable to pay for brentuximab for patients with relapsed Hodgkin and anaplastic large cell lymphoma. In the United States, brentuximab was approved for this purpose in 2011, and it has been universally embraced by oncologists. However, with median progression-free survival in pivotal trials of approximately 6 months, a rough estimate of total cost per patient in the United States
Mayo Clin Proc. n June 2016;91(6):707-712 n http://dx.doi.org/10.1016/j.mayocp.2016.04.028 www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research
From the Division of Hematology Oncology/Knight Cancer Institute and the Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland (V.P.); and Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (S.M.).
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TABLE. Cancer Drug Indications That Were Removed From the UK Cancer Drugs Fund in 2015a Median OS-(mo) Drug Drugs With a Proven Survival Benefit Ibrutinib Relapsed CLL
Pemetrexed Pemetrexed Bevacizumab Bevacizumab
Second line for nonsquamous NSCLC Maintenance therapy for nonsquamous NSCLC Second/third line for metastatic colon cancer First line for metastatic colon cancer with irinotecan-based chemotherapy Cabazitaxel Refractory metastatic prostate cancer Nabpaclitaxel First line for metastatic pancreas cancer Eribulin Third line for breast cancer Nintedanib Metastatic adenocarcinoma of the lung after first line Radium-223 Metastatic prostate cancer Bevacizumab Advanced cervical cancer Abiraterone Chemotherapy-naive metastatic prostate cancer Aflibercept Second line for metastatic colon cancer Pomalidomide R/R MM (beyond third line) Pazopanib Previously treated soft-tissue sarcoma Trastuzumab Emtansine Further treatment of Her2þ MBC Lenalidomide Second line for MM Drugs With Unknown Effects on Survival Bendamustine Relapsed mantle cell lymphoma Bendamustine Relapsed CLL Bendamustine Refractory indolent non-Hodgkin lymphoma Bosutinib AP-CML Bosutinib Blast phase CML Bosutinib CP-CML refractory to nilotinib/dasatinib Dasatinib Blast phase CML Brentuximab Relapsed ALCL Brentuximab Relapsed Hodgkin lymphoma Dasatinib Phþ ALL Ibrutinib Relapsed MCL Pepide receptor GEP NET radionucleotide Liposomal doxorubin Angiosarcoma Liposomal doxorubicin Fibromatosis Liposomal doxorubin Primary sarcomas of the heart and great vessels Bortezomib Relapsed WM Bortezomib Relapsed mantle cell lymphoma Bortezomib Retreatment in relapsed myeloma Ofatumumab Relapsed/refractory CLL Drugs for Which Best Evidence Suggests No Improvement in OS Bevacizumab TNMBC Bevacizumab First line for metastatic colon cancer with oxaliplatin-based chemotherapy Bevacizumab First line for metastatic colon cancer with single-agent fluoropyrimidine Bevacizumab With combination chemotherapy in recurrent platinum-sensitive ovarian cancer Everolimus ER-positive breast cancer
Change in OS (mo)
£b
$b
5151
7512
1.3 2.9 2.1 4.7
1728 1728 1109 1109
2520 2520 1617 1617
15.1 8.7 13.2 10.9
2.4 2.1 2.7 3.0
4435 2657 2365 2581
6462 3871 3446 3761
11.3 13.3 30.3 13.5 8.1 10.7 25.1 31.6
14.9 17.0 34.7 12.1 13.1 12.5 30.9 38.0
3.6 3.7 4.4 1.4 5.0 1.8 5.8 6.4
4848 3328 3282 1064 10,661 2511 5908 5242
7064 4849 4782 1550 15,534 3659 8608 7638
NA NA NA NA NA NA NA NA NA NA NA NA
NA NA NA NA NA NA NA NA NA NA NA NA
NA NA NA NA NA NA NA NA NA NA NA NA
1162 829 1491 4124 4124 4124 2806 9000 9000 2806 6868 67,200
1693 1208 2173 6009 6009 6009 4089 13,114 13,114 4089 10,007 97,914
NA NA NA NA NA NA NA
NA NA NA NA NA NA NA
NS NA NA NA NA NA NA
1710 1710 1710 3659 3659 3659 4368
2492 2492 2492 5331 5331 5331 6364
25.2 19.9
26.7 21.3
NS NS
2219 1109
3233 1616
12.9
16.6
NS
1692
2465
33.7
33.4
NS
3328
4849
26.6
31.0
NS
3326
4846
Control
Experimental
81% (1-y survival, median not reached) 8.0 11.0 10.8 15.6
90% (1-y survival, median not reached) 9.3 13.9 12.9 20.3
12.7 6.6 10.5 7.9
Indication
Cost per cycle
9%
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LESSONS FROM THE UK CANCER DRUGS FUND
TABLE. Continued Median OS-(mo) Drug
Indication
Control
Experimental
Change in OS (mo)
14.5 16.2 37.7 17.4
15.9 18.8 44.0 17.4
NS NS NS NS
Drugs for Which Best Evidence Suggests No Improvement in OS, continued Eribulin Third line for metastatic breast cancer Lapatinib Her-2þ breast cancer Everolimus PNET moderately differentiated Regorafenib Previously treated GIST
Cost per cycle £b
$b
2599 1448 3326 4493
3787 2110 4846 6547
ALCL ¼ anaplastic large cell lymphoma; ALL ¼ acute lymphoblastic leukemia; AP-CML ¼ acute-phase chronic myelocytic leukemia; CLL ¼ chronic lymphocytic leukemia; CP-CML ¼ chronic-phase chronic myelocytic leukemia; ER ¼ estrogen receptor; GEP NET ¼ gastroenteropancreatic neuroendocrine tumor; GIST ¼ gastrointestinal stromal tumor; MBC ¼ metastatic breast cancer; MCL ¼ myeloid cell leukemia; MM ¼ multiple myeloma; NA ¼ not applicable; NS ¼ not significant; NSCLC ¼ non-small cell lung cancer; OS ¼ overall survival; PNET ¼ pancreatic neuroendocrine tumors; R/R ¼ relapsed/refractory; TNMBC ¼ triple negative metastatic breast cancer; WM ¼ Waldenstrom’s macroglobulinemia. b Cost per cycle of treatment was obtained from the NHS England website at http://www.england.nhs.uk/ourwork/pe/cdf/cdf-drug-sum. Full data are also available at this website. a
would be $100,000. Note that this is not the cost per life-year added; in fact, one cannot calculate the cost-effectiveness ratio of brentuximab for this or any other indication because no randomized trial has found a survival benefit.6 However, the use of brentuximab in this salvage context, when all else has failed, is believed to be a valuable indication by most US oncologists. The story of brentuximab does not end here. The difference between the United States and the United Kingdom is even wider with brentuxumab used as salvage therapy. In 2015, brentuximab received a second approval in the United States as consolidation therapy after autologous stem cell transplant for Hodgkin disease, where it is prescribed for 16 cycles, costing approximately $250,000. In this setting, a randomized phase 3 trial found that the drug improves progression-free survival, but it has not reported overall survival benefits. Overall survival curves remain superimposable,7 suggesting that maintenance brentuximab therapy may not offer additional benefits over salvage brentuximab therapy. However, the overall point here is that although the United Kingdom struggles to pay for a costly indication with marginal to unclear benefits, in the United States, we accept this eagerly and go further, paying for an even more costly indication with smaller, unclear, or no benefit. Why Are These Drugs Prohibitively Costly? It is easy to think that the United Kingdom’s inability to pay for the drugs in the Table is due to lack of motivation or desire to raise the necessary funds, but it is a much harder Mayo Clin Proc. n June 2016;91(6):707-712 www.mayoclinicproceedings.org
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reality to accept the fact that the drug prices are simply too high, especially given the number of patients requesting and using these drugs in the United Kingdom. In fact, during the past few years, the United Kingdom increased the CDF budget from an initial cap of £200 million to £340 million. Projections called for the CDF to increase to £410 million next year, a trend that could not be sustained. The CDF itself exists to pay for therapies that fall outside conventional thresholds of costeffectiveness. Historically, this threshold was considered to be $50,000 per quality-adjusted life-year gained, although recently some have argued for higher thresholds.8 There may be some legitimate debate about the appropriate threshold of willingness to pay, but we should not forget two facts. First, $50,000 continues to approximate the annual median household income in the United States, and, second, a threshold of $50,000 per quality-adjusted lifeyear includes many high-value medical interventions.9 Thus, the $50,000 mark is achievable by many interventions. Empirical analyses show that the novelty of cancer drugs, their basis of regulatory approval, and their relative improvement in overall or progression-free survival cannot explain the price of drugs.5 Common arguments that high prices are justified based on research and development (R&D) costs, or that market forces already achieve fair prices, or that any price controls will be catastrophic have been dismantled.10-12 Even commentators generally supportive of the market and the pharmaceutical industry have argued that justifying
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high drug prices based on R&D inefficiencies is misguided,13 and critics of the industry argue that commonly accepted figures for the cost of developing a new drug are nontransparent and likely inflated.14 In short, in an era of doubledigit profit margins of the industry,15 the only explanation for the high price of drugs is that payers are unwilling or unable to say nodexcept of course, when they can no longer say yes. Proponents argue that high prices are needed to sustain high levels of innovation, but innovation in this context is often used interchangeably with the number of new drug approvals. However, drug approvals are an inadequate, and potentially inaccurate, measure of innovation because many approved drugs offer marginal benefits with formidable toxicity in highly selected patient populations, raising the question of whether they truly do more good than harm as they are used in real-world practice. Evidence of marginal approvals is noted in the simple fact that the median improvement in overall survival among 71 consecutive drugs for solid tumor from 2002 through 2012 is 2.1 months,16 and evidence of unrepresentative trial populations comes from data showing that the average age of patients with cancer is often a decade older than those enrolled in trials.17 In short, one wonders whether the fact that companies can charge so much and get marginal compounds approved so readily is driving an epidemic of pseudoinnovationdwhere new, costly, and heavily promoted drugs come to market but offer little real benefit for patients. Lessons for the United States What are the lessons that the UK CDF holds for the United States? Before tackling this question, we must acknowledge that the nature of this comparison is inherently speculative. The United States is a much bigger player in the global pharmaceutical market, and, thus, simple comparisons may be inadequate. Nevertheless, the United Kingdom’s dilemma points to several universal challenges. First, the price of cancer drugs is now so high that even wealthy nationsdthe United Kingdom is the world’s fifth largest economydcannot pay for all the drugs that improve overall survival. Drug cost is so outrageous that we cannot even equip our toolbox with all the tools that work. Second, the cost of cancer drugs places a large burden on patients with cancer in the 710
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United States. Out-of-pocket expenses can rise to several thousand dollars per month, and a diagnosis of cancer remains a major cause of personal bankruptcy.18 Efforts are ongoing to reduce these expenses, and some fall under the “oral parity” laws. But the United Kingdom’s experience suggests that the costs are always borne by someone. Shifting payment is not a substitute for reducing it. A society can only bear so much. Third, the UK CDF makes explicit something that is hidden in the US system: paying for cancer drugs inherently means not paying for something else. Increased spending on lowvalue, poor cost-effectiveness ratio cancer care inherently means that money is diverted from more beneficial health care services, something critics have called “onco-exceptionalism.”2 For example, large spending on marginal cancer drugs inherently means loss of high-value operations such as coronary artery bypass surgery in appropriate patients, early palliative care, and social services such as better social and nursing support. At the same time, many cancer therapies prescribed near the end of life are not associated with improvement in quality of life.19 With fixed budgets, it is indisputable that there are better ways to spend health care dollars than on costly cancer drugs with marginal or disputed benefits. The United Kingdom confronts this choice directly, whereas in the US system this choice is hidden from view. It is hard to avoid the overarching conclusion that the high price of cancer drugs represents a desire to maximize profits in a fractured system unable to exert downward pressure on price and that is itself a product of decades of careful political lobbying by the pharmaceutical industry. The current system mandates that the Centers for Medicare and Medicaid Services (CMS) pay for any drug approved by the FDA as well as any drug recommended in one of a half dozen compendia, and the agency must do this without any negotiation. Such a policy violates all known market principles and creates a system in which there is no limit to the rising price of cancer drugs. What Are Potential Solutions to the High Price of Cancer Drugs? First, large payers such as the CMS must be allowed to deny coverage of drugs that have
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failed to show clear and convincing evidence of benefit in the elderly population that composes Medicare.20 The CMS has a responsibility to pay for only what is reasonable and necessary, and one may question marginal drugs that improve only surrogate metrics in patient populations that are, by virtue of age or comorbidity, markedly different from the CMS’ beneficiaries. Second, the CMS must be empowered to negotiate the price of drugs. Although the United Kingdom failed to reach sustainable prices despite negotiation, the CMS has a market share far larger than the United Kingdom and may be capable of exerting meaningful downward pressure. At a minimum, prohibiting negotiation violates basic market principles. Third, the United States should allow the importation of foreign drugs, which are overwhelmingly of similar standards and efficacy and will create a global marketplace able to drive down cost.11 Fourth, drug price “transparency” legislation has the potential to resolve some major unanswered questions. Such bills would mandate honest disclosure of the true cost of industry-wide R&D efforts, manufacturing, and marketing. Several such bills are working their way through state legislators but are facing heavy criticism from pharmaceutical lobbying groups.21 Many believe that transparency is a prerequisite to effective negotiation. Fifth, the CMS has proposed several measures aimed at bending the cost curve, including changing rates of physician reimbursement, varying payment based on the indication that a drug is used for, altering payment based on real-world efficacy, paying only the cost of the cheapest equipotent alternative in a class or set of drugs, and reducing cost sharing.22 Elsewhere, we consider the potential of each of these measures and highlight the most important part of the CMS proposal, namely, that each initiative will be tested prospectively, in some cases with ZIP codeelevel variation.23 Health policy, prone to unintended consequences, should be validated with careful empirical study, similar to any medical intervention. The overarching lesson of the UK CDF experience is that the status quo cannot continue. Any solution to high drug prices must include a rational drug pricing strategy Mayo Clin Proc. n June 2016;91(6):707-712 www.mayoclinicproceedings.org
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that balances the legitimate business interests of the pharmaceutical industry while also accounting for the proven efficacy of drugs, which remains, in many cases, frankly, marginal. Recent cost-effectiveness analyses for new drugs, such as pertuzumab in metastatic breast cancer24 and regorafenib in relapsed colorectal cancer,25 now report cost-effectiveness ratios nearing $1 million per quality-adjusted lifeyear. For other drugs, such as second-line ramucirumab for colorectal cancer, some argue that cost-effectiveness ratios do not need to be calculated because the drug has a higher price and no increased benefit over alternatives, so the cost-effectiveness ratio is too high to quantify.26 Conclusion If cancer drugs were a cure, these ratios would improve, and the prices would be justified. However, they are often not a cure, and for society to justify their continued use, their prices must fall. The price of cancer drugs is bearable until it is not. It seems that we have reached that point. Abbreviations and Acronyms: CDF = Cancer Drugs Fund; CMS = Centers for Medicare and Medicaid Services; FDA = Food and Drug Administration; R&D = research and development Correspondence: Address to Sham Mailankody, MB, BS, Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1233 York Ave, New York, NY 10065 (mailanks@ mskcc.org).
REFERENCES 1. Ward A. Cancer drugs cut as UK budget clampdown bites. Financial Times website. http://www.ft.com/intl/cms/s/0/ 01ac9236-5327-11e5-b029-b9d50a74fd14.html. Published September 4, 2015. Accessed March 21, 2016. 2. McCabe C, Paul A, Fell G, Paulden M. Cancer Drugs Fund 2.0: a missed opportunity? Pharmacoeconomics. Mar 22, 2016 [Epub ahead of print]. 3. New £50 million cancer fund already intellectually bankrupt [editorial]. Lancet. 2010;376(9739):389. 4. Spencer B. Thousands of cancer patients to be denied lifeextending drugs due to NHS funding cuts. Secondary Thousands of cancer patients to be denied life-extending drugs due to NHS funding cuts. Daily Mail website. http://www.dailymail.co.uk/health/ article-3222588/Thousands-cancer-patients-denied-life-extendingdrugs-NHS-funding-cuts.html. Accessed March 21, 2016. 5. Mailankody S, Prasad V. Five years of cancer drug approvals: innovation, efficacy, and costs. JAMA Oncol. 2015;1(4):539-540. 6. 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(12):1992-1994.
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7. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet. 2015; 385(9980):1853-1862. 8. Neumann PJ, Cohen JT, Weinstein MC. Updating costeffectiveness: the curious resilience of the $50,000-per-QALY threshold. N Engl J Med. 2014;371(9):796-797. 9. Moran AE, Odden MC, Thanataveerat A, et al. Costeffectiveness of hypertension therapy according to 2014 guidelines. N Engl J Med. 2015;372(5):447-455. 10. Kantarjian H, Steensma D, Rius Sanjuan J, Elshaug A, Light D. High cancer drug prices in the United States: reasons and proposed solutions. J Oncol Pract. 2014;10(4): e208-e211. 11. Kantarjian H, Rajkumar SV. Why are cancer drugs so expensive in the United States, and what are the solutions? Mayo Clin Proc. 2015;90(4):500-504. 12. Tefferi A, Kantarjian H, Rajkumar SV, et al. In support of a patient-driven initiative and petition to lower the high price of cancer drugs. Mayo Clin Proc. 2015;90(8):996-1000. 13. Herper M. The truly staggering cost of inventing new drugs. Forbes website. http://www.forbes.com/sites/matthewherper/ 2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/ #4903ff994477. Accessed May 5, 2016. 14. Avorn J. The $2.6 billion pill: methodologic and policy considerations. N Engl J Med. 2015;372(20):1877-1879. 15. Anderson R. Pharmaceutical industry gets high on fat profits. BBC News website. http://www.bbc.com/news/business28212223. Accessed May 5, 2016. 16. 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(12):1225-1236.
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17. Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004; 22(22):4626-4631. 18. Ramsey SD, Bansal A, Fedorenko CR, et al. Financial insolvency as a risk factor for early mortality among patients with cancer. J Clin Oncol. 2016;34(9):980-986. 19. Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol. 2015;1(6):778-784. 20. Dhruva SS, Prasad V. Application of Medicare’s new technology add-on payment program for blinatumomab. JAMA Oncol. 2016;2(2):165-166. 21. Weisman R. Bill to rein in drug costs spurs controversy. Boston Globe website. https://www.bostonglobe.com/ business/2016/04/11/drug-price-control-bill-gets-mass-hearing/ Brd6HGfbhIUDFvnFxpMxaP/story.html. Accessed May 5, 2016. 22. CMS proposes to test new Medicare Part B prescription drug models to improve quality of care and deliver better value for Medicare beneficiaries. Centers for Medicare & Medicaid Services website. https://www.cms.gov/Newsroom/ MediaReleaseDatabase/Press-releases/2016-Press-releases-items/ 2016-03-08.html. Accessed May 5, 2016. 23. Mailankody S, Prasad V. Implications of proposed Medicare reforms to counteract high cancer drug prices. JAMA May 5, 2016 [Epub ahead of print]. 24. Durkee BY, Qian Y, Pollom EL, et al. Cost-effectiveness of pertuzumab in human epidermal growth factor receptor 2epositive metastatic breast cancer. J Clin Oncol. 2016;34(9): 902-909. 25. Goldstein DA, Ahmad BB, Chen Q, et al. Cost-effectiveness analysis of regorafenib for metastatic colorectal cancer. J Clin Oncol. 2015;33(32):3727-3732. 26. Goldstein DA, El-Rayes BF. Considering efficacy and cost, where does ramucirumab fit in the management of metastatic colorectal cancer? Oncologist. 2015;20(9):981-982.
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The UK Cancer Drugs Fund Experiment and the US Cancer Drug Cost Problem: Bearing the Cost of Cancer Drugs Until It Is Unbearable Vinay Prasad, MD, MPH, and Sham Mailankody, MB, BS
E
arlier this year, under increasing budgetary pressure, the United Kingdom through its Cancer Drugs Fund (CDF) declined to pay for 45 cancer indications. This decision is estimated to affect more than 5000 patients.1 Then, on April 1, 2016, the entire UK CDF underwent an overhaul with plans to integrate with the existing National Institute for Health and Clinical Excellence (NICE) appraisal program.2 Although critics of the government’s policy argue that this action will limit patients’ access to important drugs, defenders point out that these choices are inevitable as we continue to witness the rapidly escalating cost of cancer treatments in a world of finite budgets.1 The reasons for and implications of the United Kingdom’s action provide important lessons regarding the price of cancer drugs. The CDF The CDF was created in 2010 as a mechanism to bypass the United Kingdom’s strict standards of demonstrated cost-effectiveness of new therapies. Through the CDF, drugs that had been denied by the United Kingdom’s NICE as low value could still receive funding, and patients who receive these drugs would bear no additional copay. However, because the CDF inherently subverts the guiding principle of the UK systemddo the most good with the money you havedcritics alleged from the outset that the CDF “undermines the entire concept of a rational and evidence-based approach to the allocation of finite health-care resources” and is “already intellectually bankrupt.”3,389 Unlike the situation in the United States, the UK CDF negotiates the price of drugs with the pharmaceutical industry. The magnitude of discount is not revealed and is protected by confidentiality agreements. However, in some cases, negotiations have stalled
because companies were unwilling to reach an agreement with the United Kingdom on what some call “realistic prices,”4 making rejection necessary. Earlier this year, before restructuring, to protect the solvency of the CDF, 45 indications were cut from the fund (Table). Many excluded drugs offer real, albeit marginal, benefits, and the US Food and Drug Administration (FDA) has approved all of the 45 drug indications. Seventeen excluded drug indications (38%) improve overall survival, a standard that exceeds the percentage of new FDA drug approvals that meet this mark (19 of 63, 30%).5 Other denied drugs, such as ibrutinib and brentuximab, are able to achieve responses in patients refractory to all other therapies, serving as a bridge to potentially beneficial treatment, such as stem cell transplant. In short, if cost were not an issue, we believe that most oncologists would not hesitate to prescribe many of these drugs in the appropriate setting. Yet, in each of these cases, cost is the deciding factor. It is instructive to highlight the ocean of difference between the discussion of cost in the United Kingdom versus the United States. Take, for example, brentuximab, a monoclonal antibody to CD30, which is overexpressed in several forms of lymphoma. One month of brentuximab therapy costs approximately £9000 in the United Kingdom (equivalent of approximately $13,000 in the United States). The CDF has stated that it is unable to pay for brentuximab for patients with relapsed Hodgkin and anaplastic large cell lymphoma. In the United States, brentuximab was approved for this purpose in 2011, and it has been universally embraced by oncologists. However, with median progression-free survival in pivotal trials of approximately 6 months, a rough estimate of total cost per patient in the United States
Mayo Clin Proc. n June 2016;91(6):707-712 n http://dx.doi.org/10.1016/j.mayocp.2016.04.028 www.mayoclinicproceedings.org n ª 2016 Mayo Foundation for Medical Education and Research
From the Division of Hematology Oncology/Knight Cancer Institute and the Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland (V.P.); and Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (S.M.).
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TABLE. Cancer Drug Indications That Were Removed From the UK Cancer Drugs Fund in 2015a Median OS-(mo) Drug Drugs With a Proven Survival Benefit Ibrutinib Relapsed CLL
Pemetrexed Pemetrexed Bevacizumab Bevacizumab
Second line for nonsquamous NSCLC Maintenance therapy for nonsquamous NSCLC Second/third line for metastatic colon cancer First line for metastatic colon cancer with irinotecan-based chemotherapy Cabazitaxel Refractory metastatic prostate cancer Nabpaclitaxel First line for metastatic pancreas cancer Eribulin Third line for breast cancer Nintedanib Metastatic adenocarcinoma of the lung after first line Radium-223 Metastatic prostate cancer Bevacizumab Advanced cervical cancer Abiraterone Chemotherapy-naive metastatic prostate cancer Aflibercept Second line for metastatic colon cancer Pomalidomide R/R MM (beyond third line) Pazopanib Previously treated soft-tissue sarcoma Trastuzumab Emtansine Further treatment of Her2þ MBC Lenalidomide Second line for MM Drugs With Unknown Effects on Survival Bendamustine Relapsed mantle cell lymphoma Bendamustine Relapsed CLL Bendamustine Refractory indolent non-Hodgkin lymphoma Bosutinib AP-CML Bosutinib Blast phase CML Bosutinib CP-CML refractory to nilotinib/dasatinib Dasatinib Blast phase CML Brentuximab Relapsed ALCL Brentuximab Relapsed Hodgkin lymphoma Dasatinib Phþ ALL Ibrutinib Relapsed MCL Pepide receptor GEP NET radionucleotide Liposomal doxorubin Angiosarcoma Liposomal doxorubicin Fibromatosis Liposomal doxorubin Primary sarcomas of the heart and great vessels Bortezomib Relapsed WM Bortezomib Relapsed mantle cell lymphoma Bortezomib Retreatment in relapsed myeloma Ofatumumab Relapsed/refractory CLL Drugs for Which Best Evidence Suggests No Improvement in OS Bevacizumab TNMBC Bevacizumab First line for metastatic colon cancer with oxaliplatin-based chemotherapy Bevacizumab First line for metastatic colon cancer with single-agent fluoropyrimidine Bevacizumab With combination chemotherapy in recurrent platinum-sensitive ovarian cancer Everolimus ER-positive breast cancer
Change in OS (mo)
£b
$b
5151
7512
1.3 2.9 2.1 4.7
1728 1728 1109 1109
2520 2520 1617 1617
15.1 8.7 13.2 10.9
2.4 2.1 2.7 3.0
4435 2657 2365 2581
6462 3871 3446 3761
11.3 13.3 30.3 13.5 8.1 10.7 25.1 31.6
14.9 17.0 34.7 12.1 13.1 12.5 30.9 38.0
3.6 3.7 4.4 1.4 5.0 1.8 5.8 6.4
4848 3328 3282 1064 10,661 2511 5908 5242
7064 4849 4782 1550 15,534 3659 8608 7638
NA NA NA NA NA NA NA NA NA NA NA NA
NA NA NA NA NA NA NA NA NA NA NA NA
NA NA NA NA NA NA NA NA NA NA NA NA
1162 829 1491 4124 4124 4124 2806 9000 9000 2806 6868 67,200
1693 1208 2173 6009 6009 6009 4089 13,114 13,114 4089 10,007 97,914
NA NA NA NA NA NA NA
NA NA NA NA NA NA NA
NS NA NA NA NA NA NA
1710 1710 1710 3659 3659 3659 4368
2492 2492 2492 5331 5331 5331 6364
25.2 19.9
26.7 21.3
NS NS
2219 1109
3233 1616
12.9
16.6
NS
1692
2465
33.7
33.4
NS
3328
4849
26.6
31.0
NS
3326
4846
Control
Experimental
81% (1-y survival, median not reached) 8.0 11.0 10.8 15.6
90% (1-y survival, median not reached) 9.3 13.9 12.9 20.3
12.7 6.6 10.5 7.9
Indication
Cost per cycle
9%
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TABLE. Continued Median OS-(mo) Drug
Indication
Control
Experimental
Change in OS (mo)
14.5 16.2 37.7 17.4
15.9 18.8 44.0 17.4
NS NS NS NS
Drugs for Which Best Evidence Suggests No Improvement in OS, continued Eribulin Third line for metastatic breast cancer Lapatinib Her-2þ breast cancer Everolimus PNET moderately differentiated Regorafenib Previously treated GIST
Cost per cycle £b
$b
2599 1448 3326 4493
3787 2110 4846 6547
ALCL ¼ anaplastic large cell lymphoma; ALL ¼ acute lymphoblastic leukemia; AP-CML ¼ acute-phase chronic myelocytic leukemia; CLL ¼ chronic lymphocytic leukemia; CP-CML ¼ chronic-phase chronic myelocytic leukemia; ER ¼ estrogen receptor; GEP NET ¼ gastroenteropancreatic neuroendocrine tumor; GIST ¼ gastrointestinal stromal tumor; MBC ¼ metastatic breast cancer; MCL ¼ myeloid cell leukemia; MM ¼ multiple myeloma; NA ¼ not applicable; NS ¼ not significant; NSCLC ¼ non-small cell lung cancer; OS ¼ overall survival; PNET ¼ pancreatic neuroendocrine tumors; R/R ¼ relapsed/refractory; TNMBC ¼ triple negative metastatic breast cancer; WM ¼ Waldenstrom’s macroglobulinemia. b Cost per cycle of treatment was obtained from the NHS England website at http://www.england.nhs.uk/ourwork/pe/cdf/cdf-drug-sum. Full data are also available at this website. a
would be $100,000. Note that this is not the cost per life-year added; in fact, one cannot calculate the cost-effectiveness ratio of brentuximab for this or any other indication because no randomized trial has found a survival benefit.6 However, the use of brentuximab in this salvage context, when all else has failed, is believed to be a valuable indication by most US oncologists. The story of brentuximab does not end here. The difference between the United States and the United Kingdom is even wider with brentuxumab used as salvage therapy. In 2015, brentuximab received a second approval in the United States as consolidation therapy after autologous stem cell transplant for Hodgkin disease, where it is prescribed for 16 cycles, costing approximately $250,000. In this setting, a randomized phase 3 trial found that the drug improves progression-free survival, but it has not reported overall survival benefits. Overall survival curves remain superimposable,7 suggesting that maintenance brentuximab therapy may not offer additional benefits over salvage brentuximab therapy. However, the overall point here is that although the United Kingdom struggles to pay for a costly indication with marginal to unclear benefits, in the United States, we accept this eagerly and go further, paying for an even more costly indication with smaller, unclear, or no benefit. Why Are These Drugs Prohibitively Costly? It is easy to think that the United Kingdom’s inability to pay for the drugs in the Table is due to lack of motivation or desire to raise the necessary funds, but it is a much harder Mayo Clin Proc. n June 2016;91(6):707-712 www.mayoclinicproceedings.org
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reality to accept the fact that the drug prices are simply too high, especially given the number of patients requesting and using these drugs in the United Kingdom. In fact, during the past few years, the United Kingdom increased the CDF budget from an initial cap of £200 million to £340 million. Projections called for the CDF to increase to £410 million next year, a trend that could not be sustained. The CDF itself exists to pay for therapies that fall outside conventional thresholds of costeffectiveness. Historically, this threshold was considered to be $50,000 per quality-adjusted life-year gained, although recently some have argued for higher thresholds.8 There may be some legitimate debate about the appropriate threshold of willingness to pay, but we should not forget two facts. First, $50,000 continues to approximate the annual median household income in the United States, and, second, a threshold of $50,000 per quality-adjusted lifeyear includes many high-value medical interventions.9 Thus, the $50,000 mark is achievable by many interventions. Empirical analyses show that the novelty of cancer drugs, their basis of regulatory approval, and their relative improvement in overall or progression-free survival cannot explain the price of drugs.5 Common arguments that high prices are justified based on research and development (R&D) costs, or that market forces already achieve fair prices, or that any price controls will be catastrophic have been dismantled.10-12 Even commentators generally supportive of the market and the pharmaceutical industry have argued that justifying
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high drug prices based on R&D inefficiencies is misguided,13 and critics of the industry argue that commonly accepted figures for the cost of developing a new drug are nontransparent and likely inflated.14 In short, in an era of doubledigit profit margins of the industry,15 the only explanation for the high price of drugs is that payers are unwilling or unable to say nodexcept of course, when they can no longer say yes. Proponents argue that high prices are needed to sustain high levels of innovation, but innovation in this context is often used interchangeably with the number of new drug approvals. However, drug approvals are an inadequate, and potentially inaccurate, measure of innovation because many approved drugs offer marginal benefits with formidable toxicity in highly selected patient populations, raising the question of whether they truly do more good than harm as they are used in real-world practice. Evidence of marginal approvals is noted in the simple fact that the median improvement in overall survival among 71 consecutive drugs for solid tumor from 2002 through 2012 is 2.1 months,16 and evidence of unrepresentative trial populations comes from data showing that the average age of patients with cancer is often a decade older than those enrolled in trials.17 In short, one wonders whether the fact that companies can charge so much and get marginal compounds approved so readily is driving an epidemic of pseudoinnovationdwhere new, costly, and heavily promoted drugs come to market but offer little real benefit for patients. Lessons for the United States What are the lessons that the UK CDF holds for the United States? Before tackling this question, we must acknowledge that the nature of this comparison is inherently speculative. The United States is a much bigger player in the global pharmaceutical market, and, thus, simple comparisons may be inadequate. Nevertheless, the United Kingdom’s dilemma points to several universal challenges. First, the price of cancer drugs is now so high that even wealthy nationsdthe United Kingdom is the world’s fifth largest economydcannot pay for all the drugs that improve overall survival. Drug cost is so outrageous that we cannot even equip our toolbox with all the tools that work. Second, the cost of cancer drugs places a large burden on patients with cancer in the 710
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United States. Out-of-pocket expenses can rise to several thousand dollars per month, and a diagnosis of cancer remains a major cause of personal bankruptcy.18 Efforts are ongoing to reduce these expenses, and some fall under the “oral parity” laws. But the United Kingdom’s experience suggests that the costs are always borne by someone. Shifting payment is not a substitute for reducing it. A society can only bear so much. Third, the UK CDF makes explicit something that is hidden in the US system: paying for cancer drugs inherently means not paying for something else. Increased spending on lowvalue, poor cost-effectiveness ratio cancer care inherently means that money is diverted from more beneficial health care services, something critics have called “onco-exceptionalism.”2 For example, large spending on marginal cancer drugs inherently means loss of high-value operations such as coronary artery bypass surgery in appropriate patients, early palliative care, and social services such as better social and nursing support. At the same time, many cancer therapies prescribed near the end of life are not associated with improvement in quality of life.19 With fixed budgets, it is indisputable that there are better ways to spend health care dollars than on costly cancer drugs with marginal or disputed benefits. The United Kingdom confronts this choice directly, whereas in the US system this choice is hidden from view. It is hard to avoid the overarching conclusion that the high price of cancer drugs represents a desire to maximize profits in a fractured system unable to exert downward pressure on price and that is itself a product of decades of careful political lobbying by the pharmaceutical industry. The current system mandates that the Centers for Medicare and Medicaid Services (CMS) pay for any drug approved by the FDA as well as any drug recommended in one of a half dozen compendia, and the agency must do this without any negotiation. Such a policy violates all known market principles and creates a system in which there is no limit to the rising price of cancer drugs. What Are Potential Solutions to the High Price of Cancer Drugs? First, large payers such as the CMS must be allowed to deny coverage of drugs that have
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failed to show clear and convincing evidence of benefit in the elderly population that composes Medicare.20 The CMS has a responsibility to pay for only what is reasonable and necessary, and one may question marginal drugs that improve only surrogate metrics in patient populations that are, by virtue of age or comorbidity, markedly different from the CMS’ beneficiaries. Second, the CMS must be empowered to negotiate the price of drugs. Although the United Kingdom failed to reach sustainable prices despite negotiation, the CMS has a market share far larger than the United Kingdom and may be capable of exerting meaningful downward pressure. At a minimum, prohibiting negotiation violates basic market principles. Third, the United States should allow the importation of foreign drugs, which are overwhelmingly of similar standards and efficacy and will create a global marketplace able to drive down cost.11 Fourth, drug price “transparency” legislation has the potential to resolve some major unanswered questions. Such bills would mandate honest disclosure of the true cost of industry-wide R&D efforts, manufacturing, and marketing. Several such bills are working their way through state legislators but are facing heavy criticism from pharmaceutical lobbying groups.21 Many believe that transparency is a prerequisite to effective negotiation. Fifth, the CMS has proposed several measures aimed at bending the cost curve, including changing rates of physician reimbursement, varying payment based on the indication that a drug is used for, altering payment based on real-world efficacy, paying only the cost of the cheapest equipotent alternative in a class or set of drugs, and reducing cost sharing.22 Elsewhere, we consider the potential of each of these measures and highlight the most important part of the CMS proposal, namely, that each initiative will be tested prospectively, in some cases with ZIP codeelevel variation.23 Health policy, prone to unintended consequences, should be validated with careful empirical study, similar to any medical intervention. The overarching lesson of the UK CDF experience is that the status quo cannot continue. Any solution to high drug prices must include a rational drug pricing strategy Mayo Clin Proc. n June 2016;91(6):707-712 www.mayoclinicproceedings.org
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that balances the legitimate business interests of the pharmaceutical industry while also accounting for the proven efficacy of drugs, which remains, in many cases, frankly, marginal. Recent cost-effectiveness analyses for new drugs, such as pertuzumab in metastatic breast cancer24 and regorafenib in relapsed colorectal cancer,25 now report cost-effectiveness ratios nearing $1 million per quality-adjusted lifeyear. For other drugs, such as second-line ramucirumab for colorectal cancer, some argue that cost-effectiveness ratios do not need to be calculated because the drug has a higher price and no increased benefit over alternatives, so the cost-effectiveness ratio is too high to quantify.26 Conclusion If cancer drugs were a cure, these ratios would improve, and the prices would be justified. However, they are often not a cure, and for society to justify their continued use, their prices must fall. The price of cancer drugs is bearable until it is not. It seems that we have reached that point. Abbreviations and Acronyms: CDF = Cancer Drugs Fund; CMS = Centers for Medicare and Medicaid Services; FDA = Food and Drug Administration; R&D = research and development Correspondence: Address to Sham Mailankody, MB, BS, Myeloma Service, Division of Hematologic Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1233 York Ave, New York, NY 10065 (mailanks@ mskcc.org).
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7. Moskowitz CH, Nademanee A, Masszi T, et al. Brentuximab vedotin as consolidation therapy after autologous stem-cell transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression (AETHERA): a randomised, doubleblind, placebo-controlled, phase 3 trial. Lancet. 2015; 385(9980):1853-1862. 8. Neumann PJ, Cohen JT, Weinstein MC. Updating costeffectiveness: the curious resilience of the $50,000-per-QALY threshold. N Engl J Med. 2014;371(9):796-797. 9. Moran AE, Odden MC, Thanataveerat A, et al. Costeffectiveness of hypertension therapy according to 2014 guidelines. N Engl J Med. 2015;372(5):447-455. 10. Kantarjian H, Steensma D, Rius Sanjuan J, Elshaug A, Light D. High cancer drug prices in the United States: reasons and proposed solutions. J Oncol Pract. 2014;10(4): e208-e211. 11. Kantarjian H, Rajkumar SV. Why are cancer drugs so expensive in the United States, and what are the solutions? Mayo Clin Proc. 2015;90(4):500-504. 12. Tefferi A, Kantarjian H, Rajkumar SV, et al. In support of a patient-driven initiative and petition to lower the high price of cancer drugs. Mayo Clin Proc. 2015;90(8):996-1000. 13. Herper M. The truly staggering cost of inventing new drugs. Forbes website. http://www.forbes.com/sites/matthewherper/ 2012/02/10/the-truly-staggering-cost-of-inventing-new-drugs/ #4903ff994477. Accessed May 5, 2016. 14. Avorn J. The $2.6 billion pill: methodologic and policy considerations. N Engl J Med. 2015;372(20):1877-1879. 15. Anderson R. Pharmaceutical industry gets high on fat profits. BBC News website. http://www.bbc.com/news/business28212223. Accessed May 5, 2016. 16. 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(12):1225-1236.
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17. Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: a 7-year experience by the US Food and Drug Administration. J Clin Oncol. 2004; 22(22):4626-4631. 18. Ramsey SD, Bansal A, Fedorenko CR, et al. Financial insolvency as a risk factor for early mortality among patients with cancer. J Clin Oncol. 2016;34(9):980-986. 19. Prigerson HG, Bao Y, Shah MA, et al. Chemotherapy use, performance status, and quality of life at the end of life. JAMA Oncol. 2015;1(6):778-784. 20. Dhruva SS, Prasad V. Application of Medicare’s new technology add-on payment program for blinatumomab. JAMA Oncol. 2016;2(2):165-166. 21. Weisman R. Bill to rein in drug costs spurs controversy. Boston Globe website. https://www.bostonglobe.com/ business/2016/04/11/drug-price-control-bill-gets-mass-hearing/ Brd6HGfbhIUDFvnFxpMxaP/story.html. Accessed May 5, 2016. 22. CMS proposes to test new Medicare Part B prescription drug models to improve quality of care and deliver better value for Medicare beneficiaries. Centers for Medicare & Medicaid Services website. https://www.cms.gov/Newsroom/ MediaReleaseDatabase/Press-releases/2016-Press-releases-items/ 2016-03-08.html. Accessed May 5, 2016. 23. Mailankody S, Prasad V. Implications of proposed Medicare reforms to counteract high cancer drug prices. JAMA May 5, 2016 [Epub ahead of print]. 24. Durkee BY, Qian Y, Pollom EL, et al. Cost-effectiveness of pertuzumab in human epidermal growth factor receptor 2epositive metastatic breast cancer. J Clin Oncol. 2016;34(9): 902-909. 25. Goldstein DA, Ahmad BB, Chen Q, et al. Cost-effectiveness analysis of regorafenib for metastatic colorectal cancer. J Clin Oncol. 2015;33(32):3727-3732. 26. Goldstein DA, El-Rayes BF. Considering efficacy and cost, where does ramucirumab fit in the management of metastatic colorectal cancer? Oncologist. 2015;20(9):981-982.
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