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Integrating Value Assessment Into Discussions About the Price of Cancer Drugs

      Price is what you pay; value is what you get.Warren Buffet
      The cost of cancer drugs is becoming untenable, both for patients and for society. More than 60% of personal bankruptcies in the United States in 2007 were attributable to health care costs, and cancer was the highest-cost diagnosis for those claiming bankruptcy for medical reasons.
      • Himmelstein D.U.
      • Thorne D.
      • Warren E.
      • Woolhandler S.
      Medical bankruptcy in the United States, 2007: results of a national study.
      One-third of insured patients with cancer use up all or most of their savings or have difficulty paying their cancer bills. Among patients with cancer who were ever uninsured, one-quarter delayed or decided to forego cancer care due to cost.
      • Henry J.
      • et al.
      Kaiser Family Foundation
      Toplines: national survey of households affected by cancer.
      Given that a cancer diagnosis can increase the cost of health insurance and interfere with employability (and, therefore, employer-sponsored insurance coverage), the risk of becoming uninsured, even temporarily, is increased. With 16% of the US population currently uninsured, the implications of these statistics are alarming.
      The societal financial burden of health care is obvious when one considers the implications of new standard-of-care regimens to treat patients with metastatic colorectal cancer at a cost of $200,000 per year of life saved or that more than 90% of all anticancer drugs approved by the Food and Drug Administration (FDA) during the past several years cost more than $20,000 for a 12-week course of treatment. Moreover, cancer chemotherapy agents are frequently used in combination with other agents, and most patients with metastatic cancer will continue to receive multiple, subsequent lines of therapy until they succumb to their disease.
      • Wong Y.
      • Meropol N.J.
      • Sargent D.
      • Goldberg R.
      • Beck J.R.
      Direct cost-survival analysis of therapies for metastatic colorectal cancer [abstract 3515].
      These escalating health care costs must ultimately be financed by increasing costs of goods and services, which decrease US competitiveness in the global market. Indeed, the cost of cancer drugs carries serious implications for everyone.
      In this issue of Mayo Clinic Proceedings, Siddiqui and Rajkumar
      • Siddiqui M.
      • Rajkumar S.V.
      The high cost of cancer drugs and what we can do about it.
      articulate many of the reasons that cancer drugs are so expensive and posit possible interventions to control costs, some realistic and others less so, at least in the current political environment. Among the reasons cited are the high cost of cancer drug development, the “monopoly” that cancer drugs enjoy once approved, the higher prices patients and society seem willing to pay (even for marginal improvements in outcome), and the failure to take economic considerations into account in the drug approval and pricing processes. Also in this issue of Mayo Clinic Proceedings, Wittich et al
      • Wittich C.M.
      • Burkle C.M.
      • Lanier W.L.
      Ten common questions (and their answers) about off-label drug use.
      summarize off-label drug use (OLDU), its benefits, and its drawbacks. This article segues nicely with the concepts introduced by Siddiqui and Rajkumar,
      • Siddiqui M.
      • Rajkumar S.V.
      The high cost of cancer drugs and what we can do about it.
      given the frequency with which OLDU is used in cancer treatment. Wittich et al
      • Wittich C.M.
      • Burkle C.M.
      • Lanier W.L.
      Ten common questions (and their answers) about off-label drug use.
      note that OLDU is a common practice that can benefit patients by expanding access to useful agents approved for other indications, but OLDU also can be overused, often with limited supporting data. These characteristics apply with respect to OLDU of cancer drugs. Unfortunately, when OLDU occurs outside of clinical research trials, the most common off-label application of cancer drugs, it does not generate data that could help determine a cancer drug's utility for the unapproved application. In addition, OLDU increases the aggregate cost of cancer drugs by encouraging their use for unapproved indications. With many new cancer drugs typically costing $100,000 per year and frequently being used in combination with other agents, payers are becoming more restrictive about allowing the use of these agents for indications not approved by the FDA.
      Several factors, including discovery costs, research and development costs, manufacturing costs, complexity of investigational protocols (eg, pharmacokinetics, frequent imaging, repeated biopsies, and pharmacogenetics), and number of patients tested per indication, contribute to the cost of drug development.
      • DiMasi J.A.
      • Grabowski H.G.
      Economics of new oncology drug development.
      Although data are limited, using commercial business intelligence data, it has been estimated that the cost of bringing a cancer drug to market is 20% higher than the average for all drugs.
      • Adams C.P.
      • Brantner V.V.
      Estimating the cost of new drug development: is it really 802 million dollars?.
      However, 70% of approved oncology drugs receive priority reviews by the FDA, in contrast to 40% of other drugs, and nearly half benefit from an orphan drug indication (a concept discussed by Wittich et al
      • Wittich C.M.
      • Burkle C.M.
      • Lanier W.L.
      Ten common questions (and their answers) about off-label drug use.
      ), as opposed to 13% for other new drugs.
      • DiMasi J.A.
      • Grabowski H.G.
      Economics of new oncology drug development.
      Orphan drug status facilitates drug approval, creates a 50% tax credit for clinical trial expenditures, and grants 7-year marketing exclusivity apart from any patent protection. So, despite some increased development costs, cancer drugs are more likely to receive favorable treatment in the development process than are other agents. The argument that development cost is the driver of drug cost is further weakened by the lack of a drug price change when the indications for an approved drug are expanded.
      The premise of Siddiqui and Rajkumar
      • Siddiqui M.
      • Rajkumar S.V.
      The high cost of cancer drugs and what we can do about it.
      that cancer drugs enjoy a “monopoly” because the constantly evolving drug resistance by cancer cells results in each drug's eventual use is novel. Essentially, the authors propose that oncologists do not choose whether to use a drug, they simply choose the timing. Here, care pathways, as opposed to the current use of treatment guidelines, may help. Clinical guidelines, such as those published by the American Society of Clinical Oncology and the National Comprehensive Cancer Network, offer multiple, evidence-based treatment options for different stages of each cancer, without consideration of cost-effectiveness analysis (CEA). Pathways, in contrast, recommend the specific treatment that maximizes effectiveness but also accounts for cost by choosing the least expensive, equally effective treatment option, if one exists. Level 1 pathway treatment has been demonstrated to reduce chemotherapy cost, cost per case, duration of treatment, and chemotherapy-related hospital admissions.
      • Hoverman J.R.
      • Cartwright T.H.
      • Patt D.A.
      • et al.
      Pathways, outcomes, and costs in colon cancer: retrospective evaluations in two distinct databases.
      Pathways can mitigate the monopoly effect because cancers tend to respond to subsequent-line therapies for progressively shorter durations. Therefore, competition for earlier-line therapies will increase, prompting the search for better agents and increasing price competition among agents of similar efficacy. Pathways also promote discontinuation of therapy when there is no demonstrable clinical benefit, thereby decreasing the number of therapies administered and further increasing competition for a place in the recommended pathway.
      The current use of published guidelines, with multiple-choice treatment options, promotes variability of treatment among patients, without evidence of a rationale for this variance, and prevents data collection or comparative effectiveness research to evaluate the effectiveness of alternative approaches to treatment. Pathways, in contrast, limit unwarranted variability and promote standardization, thereby improving efficiency and allowing for the conduct of comparative effectiveness research.
      “Coverage with evidence development” policies that provide for conditional coverage for promising treatments, but only for patients who are included in a study, would allow for broad access to promising therapies while creating an incentive for patients to participate in trials that will yield answers about “real-world” benefits or harm of a therapy.
      • Mullins C.D.
      • Montgomery R.
      • Tunis S.
      Uncertainty in assessing value of oncology treatments.
      Such policies could substitute for OLDU and accelerated new drug approvals while concomitantly expanding access to therapies. In contrast, the continuation of existing OLDU practices, which typically do not systematically collect data from the treatment of patients (eg, because the patients are not treated in a clinical trial), miss an opportunity to evaluate a drug's potential value.
      Unshackling the Centers for Medicare and Medicaid Services from restrictions imposed by the Medicare Prescription Drug Improvement and Modernization Act of 2003, which prohibits price negotiation, would actually restore some free-market mechanisms to control costs. The current Act prevents the largest payer for health care in the United States from participating as a buyer in the market. Government payers in other countries are all price negotiators.
      • Drummond M.F.
      • Mason A.R.
      European perspective on the costs and cost-effectiveness of cancer therapies.
      FDA drug approval is based on evidence of clinical benefit and safety. The FDA frequently experiences criticism for approving cancer drugs with relatively low apparent value in patients with metastatic disease. The true value of a drug, however, may not be evident until years later, when its efficacy is demonstrated in the adjuvant setting.
      • Meropol N.J.
      • Schulman K.A.
      Cost of cancer care: issues and implications.
      Approval for modest activity, therefore, may not be unreasonable, but the lack of, indeed the prohibition from, using CEA to determine coverage or reimbursement is. As noted, the Patient Protection and Affordable Care Act created the Patient-Centered Outcomes Research Institute to inform clinical decision making using CEA but prohibited its use to affect coverage or negotiate price. Virtually every other Western country uses CEA to negotiate prices that reflect a drug's value to the patient. Indeed, these analyses can be used in novel ways, rather than simply setting price controls. In Great Britain, the National Institute for Health and Clinical Excellence recommended against approval for bortezomib in 2006 for patients with multiple myeloma in first relapse because of the drug’s cost. In response, the company proposed a cost-reduction scheme in which the National Health Service funded patients with multiple myeloma at first relapse who achieved a response to bortezomib and the company provided replacement stock for patients who did not respond. This scheme brought the effective cost of bortezomib to the National Health Service into the cost-effective range (approximately £30,000 per quality-adjusted life-year) established by the National Institute for Health and Clinical Excellence.
      The future will continue to bring improved understanding of the science of cancer and, with it, a stream of high-cost, novel anticancer therapeutics. We should welcome this. To be sustainable, however, we must ensure that our clinical decisions are evidence-based. We must attempt to determine the value of the new therapies. And we must integrate our judgments of value with our clinical guidelines.
      • Meropol N.J.
      • Schrag D.
      • Smith T.J.
      • et al.
      American Society of Clinical Oncology guidance statement: the cost of cancer care.

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      Linked Article

      • The High Cost of Cancer Drugs and What We Can Do About It
        Mayo Clinic ProceedingsVol. 87Issue 10
        • Preview
          Last year, ipilimumab (Yervoy; Bristol-Myers Squibb, New York, NY) was approved by the Food and Drug Administration (FDA) for the treatment of metastatic melanoma. The benefit in survival over and above standard treatment arms was 3.7 months in previously treated patients and 2.1 months in previously untreated patients.1,2 The cost: $120,000 for 4 doses. As staggering a figure as that is, the drug is hardly alone in its lofty price. We believe that the immense cost of contemporary cancer drugs signals even greater costs for future drugs (Table).
        • Full-Text
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      • Ten Common Questions (and Their Answers) About Off-label Drug Use
        Mayo Clinic ProceedingsVol. 87Issue 10
        • Preview
          The term off-label drug use (OLDU) is used extensively in the medical literature, continuing medical education exercises, and the media. Yet, we propose that many health care professionals have an underappreciation of its definition, prevalence, and implications. This article introduces and answers 10 questions regarding OLDU in an effort to clarify the practice's meaning, breadth of application, acceptance, and liabilities. Off-label drug use involves prescribing medications for indications, or using a dosage or dosage form, that have not been approved by the US Food and Drug Administration.
        • Full-Text
        • PDF