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Comparative-Effectiveness Research: Does It Matter?
Clinical Therapeutics/Volume 35, Number 4, 2013 · POHP Update
Contemporary Issues
Comparative-Effectiveness Research: Does It Matter? Joshua P. Cohen, PhD Center for the Study of Drug Development, Tufts University, Boston, Massachusetts ABSTRACT Background: For several years there has been a vigorous policy debate on comparative effectiveness research (CER). This debate has focused on whether more evidence should be gathered, and who should be doing the funding and developing of evidence. There has been less emphasis on implementation of CER findings, and examining whether CER has or will have an impact on prescribing patterns, reimbursement, health outcomes, and health care spending. Objective: This paper addresses both empirical and normative aspects of CER in terms of its impact on prescribing, reimbursement, cost-containment, and health outcomes. Results: A significant gap persists between the best available evidence on therapeutic effectiveness and tolerability and typical patterns of prescribing care, as well as patient choices. Consequently, there is room for building a more systematic evidence base in the United States, so that policymakers are better equipped to understand variation in clinical outcomes while promoting appropriate prescribing and reimbursement patterns. Methods: The author carried out a non-systematic literature review of both empirical and normative aspects pertaining to CER and its policy implications. Keywords for the Medline search were “comparative effectiveness research” and “policy implications.” Conclusion: CER has a modest impact on prescribing, reimbursement, cost-containment, and health outcomes. This impact will likely intensify as funding increases and novel models to steer prescribing and reimbursement choices incorporate comparative-effectiveness evidence. (Clin Ther. 2013;35:371–379) © 2013 Elsevier HS Journals, Inc. All rights reserved. Key words: clinical effectiveness research, decision making, policymaking.
compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or improve the delivery of care.”1,2 As such, CER uses a variety of data sources and methods to conduct studies and disseminate results to health care providers, patients, and payers. Comparative effectiveness researchers can perform systematic reviews of existing evidence, or retrospective analysis of existing observational data—in other words, examine all of the available evidence regarding the benefits and harms (which may include costs) of alternative choices of treatment for different groups of patients from completed clinical trials and studies.3,4 Alternatively, researchers can conduct prospective pragmatic clinical trials that generate new evidence on the comparative effectiveness of a test, treatment, or medical procedure, as used in actual clinical practice. The latter kinds of studies are much more expensive to conduct than the former. Broadly, CER comprises the rigorous evaluation of the impact of different options available for treating a given medical condition for a defined population. CER is invariably evidence based. However, it should not be conflated with cost-effectiveness analysis. We can distinguish between 3 types of evidencebased analysis that are not mutually exclusive: (1) effectiveness analysis, which is not comparative in a head-to-head sense and does not include costs; (2) comparative effectiveness analysis, which is comparative in a head-to-head sense (eg, drug vs another drug or a nonpharmaceutical therapy) and may include costs, but does not have to; and (3) cost-effectiveness analysis, which is comparative and includes costs. CER focused on drugs and drug-related products (eg, companion diagnostics) is designed to inform prescribing, reimbursement, and pricing decisions. Invest-
INTRODUCTION
Accepted for publication January 4, 2012. http://dx.doi.org/10.1016/j.clinthera.2012.12.018 0149-2918/$ - see front matter
Comparative effectiveness research (CER) is defined broadly as the “generation and synthesis of evidence that
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© 2013 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics ing in CER may help address the current gap in publicly available, evidence-based information on the comparative effectiveness of medical technologies. As a result, findings from CER could lead to a reduction in unwarranted variation in practice patterns and resource allocation, better health outcomes, and a possible “bending of the cost curve.”1–3 The objective of this review article was to address empirical and normative aspects related to CER (empirical: How has CER evolved over time?; Have past (international) efforts at investing in, carrying out, and implementing actionable findings from CER had clinical or economic impact?; and Will CER in its present form with more funding and wider dissemination have clinical or economic impact?; and normative: To what extent should CER findings impact prescribing and reimbursement decisions?; and Should the United States learn from international experience with CER?).
EMERGENCE OF CER IN THE UNITED STATES Unlike many members of the Organization for Economic Cooperation and Development, the United States has not systematically implemented CER findings with a view to altering prescribing patterns to diminish variation in health outcomes and control the growth of health expenditures.5,6 Yet, even the world’s largest market for biopharmaceuticals has not been bypassed by use of CER evidence to inform prescribing and reimbursement decisions (ie, as a “fourth hurdle”), in addition to the traditional regulatory hurdles of efficacy, tolerability, and quality of manufacturing practices. Although considered a laggard compared to other nations, a de facto fourth hurdle has been instituted by virtually all payers.6 Approval of a drug by the US Food and Drug Administration (FDA) does not guarantee its reimbursement. When new medical technologies are launched, health care providers and patients decide on their use, while insurers decide on reimbursement. For these purposes, decision makers may use evidence from CER. There is nothing new per se about CER or its use. For several decades, public and private payers as well as health care providers have used many sources to inform their prescribing and reimbursement decisions, including findings from CER.7–9 Providers of CER data have included public agencies such as the Agency for Healthcare Research and Quality (AHRQ), founded in 1989, and also influential private organizations such as Blue Cross/Blue Shield’s Technology
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Evaluation Center, established in 1985. Public–private partnerships have also been formed, including the Drug Effectiveness Review Project (DERP) in 2003. DERP is an Oregon-based collaboration of public and private entities, including 15 states (state Medicaid agencies) that have joined together to provide systematic evidence-based reviews of the comparative effectiveness and tolerability of drugs in many widely used drug classes, and to apply the findings to inform public policy decisions.7,10,11 Among watershed events in the past 10 years, perhaps the least publicized yet most influential we have witnessed is the issuance in 2000 (and subsequent updates) of Academy of Managed Care Pharmacy (AMCP) guidelines specifying clinical and cost-effectiveness parameters to be included by drug sponsors in the formulary dossiers that they submit to payers for the purpose of reimbursement of newly marketed pharmaceuticals. Presently, over 50 payers and pharmacy benefit managers adhere to AMCP formulary dossier guidelines.12 In the early 2000s, the Institute of Medicine (IOM) convened a series of meetings of health care stakeholders to discuss challenges facing clinical research. At the meetings, stakeholders criticized the inadequacy of public and private investment in clinical research to produce enough quality information to support appropriate prescribing and policy decisions.1 Specifically, payers and physicians pointed to the dearth of unbiased evidence on which to base prescribing and reimbursement decisions.13 Around the same time as the IOM meetings, the Medicare prescription drug benefit legislation sparked renewed interest in having better information available on the relative effectiveness of alternative therapies.3 In 2003, the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) directed the Centers for Medicare and Medicaid Services (CMS) to work with AHRQ on conducting comparative effectiveness studies of prescription drugs, medical devices, and diagnostics. CMS has since commissioned dozens of studies. In early 2009, the American Recovery and Reinvestment Act allocated $1.1 billion to increase the number of CER studies.14 And, with enactment of the Affordable Care Act (ACA) in 2010, CER received a further funding boost at the federal level, along with calls for more systematic implementation of research findings.15 Furthermore, ACA has revitalized the discussion regarding the locus of CER as a potential way of
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J.P. Cohen improving the health care system’s “added value,” measured in terms of health outcomes and cost-containment in relation to resources spent.16 The law established the Patient-Centered Outcomes Research Institute (PCORI), whose stated mission is to “carry out research that provides quality, relevant evidence on how diseases and health conditions can effectively be prevented, diagnosed, treated, monitored, and managed.” PCORI has provisionally been appropriated $300 million in annual funding.15
INTERNATIONAL EXPERIENCE: LESSONS FOR THE UNITED STATES? Across European health care systems, CER findings are generally intended to be more than solely informative. Accordingly, CER is assuming an increased role in prescribing, reimbursement, and, in some cases, pricing decisions. Several jurisdictions in Europe, among which are the United Kingdom and the Netherlands, employ cost-effectiveness thresholds. A threshold represents the amount of money society or a payer is willing to pay for an additional unit of health outcome (eg, an additional quality-adjusted life-year [QALY]) produced by a new technology. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) is responsible for conducting appraisals of new technologies—systematic reviews—for select new products. NICE appraisals include calculations of cost-per-QALY estimates, which compare the incremental cost-effectiveness ratio of a new technology with that of an older technology or another new product. Based on these estimates, NICE may recommend a drug’s routine use for all licensed indications, recommend only for specific indications, or not recommend for use at all. Cost-perQALY estimates are intended to be compared within and across therapeutic indications. Also, NICE aims to have guidance that applies universally across hundreds of primary and acute care National Health Service (NHS) trusts.17 In this respect, the cost-per-QALY threshold delineates an arbitrary cutoff between technologies the NHS can afford for all, as opposed to those it will fund for no one.18 NICE has been criticized on numerous grounds, among which is that it imposes a “one-size-fits-all” population-based view of medicine. Further, besides Australia, Canada, and the Netherlands, no other technology assessment authority employs the cost-per-QALY method as extensively as NICE.19,20
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The German Ministry of Health has explicitly rejected the cost-per-QALY approach to determine reimbursement, on the basis that it is “discriminatory.” That is, it is deemed to imply that patients are less worthy of treatment if they have diminished life expectancy.21 In contrast to NICE’s charge, the mandate of Germany’s Institute for Quality and Efficiency in Health Care (IQWiG) is to address benefits relative to costs for a given therapeutic indication, not to set funding priorities across indications. Accordingly, IQWiG has developed an alternative approach based on an “efficiency-frontier model.”22 The efficiency frontier depicts the relationship between value and cost for drugs within a therapeutic class, or for a particular patient subgroup. Here, the policymaker’s focus is to calculate an efficiency (cardinal) ranking of drugs, given a specific indication.23 All available compounds within a therapeutic class are compared in terms of value and cost. Patient preferences are incorporated, that is, end points such as a patient’s experience or perception of physical, mental, and social functioning as a result of use of the new drug. New compounds must show comparable efficiency, relative to the cost– benefit ratio of the most efficient available alternative, or the average cost– benefit ratio within the specific indication. Hence, this model narrows the focus of each evaluation to a single therapeutic area, that is, compares the cost-effectiveness of newer treatments with that of existing ones targeting patients with the same disease or condition, thus comparing like with like. In this respect, IQWiG’s approach is more patientcentric and therefore similar to DERP’s method of analyzing each therapeutic class individually, incorporating patient-relevant end points per indication. CER in Europe and elsewhere has been used primarily to influence prescribing patterns and inform reimbursement. This is changing with the emergence of value-based pricing, in which the maximum reimbursement level of a drug is linked to the value that the drug adds over and above existing care. Value-based pricing is being launched in 2 of Europe’s largest pharmaceutical markets: the United Kingdom and Germany. Effective January 2012, Germany’s new rules require pharmaceutical companies to negotiate valuebased prices for all newly licensed drugs. New products enter the market at a price set by the company sponsor. Subsequently, within 3 months, regulators assess the product’s value based on a 6-point scale.24 Prices will then be a function of the assessment of a drug’s bene-
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Clinical Therapeutics fits, based mostly on randomized controlled clinical trial (RCT) data. If the new treatment is deemed to have no additional therapeutic benefit relative to existing care, prices will be set at a level no greater than that of the comparable medicine already on the market (ie, a “reference price”). “Premium prices” of varying levels relative to reference prices set per therapeutic class will be awarded to drugs deemed to have at least “slightly added benefit” compared to a benchmark drug. Presumably, the higher the added benefit, the higher the price will be. The United Kingdom will introduce mandatory, value-based pricing on all newly licensed drugs starting in 2014. In contrast to Germany, value-based pricing in the United Kingdom will be based on a cost-per-QALY evaluation at launch. As such, it is not an intraclass determination of relative benefit. Cost-effectiveness will not be the only criterion, as factors such as burden of disease in terms of unmet need or severity of illness may trump cost-effectiveness, allowing for premium prices to be set despite relatively poor cost-effectiveness numbers. International CER bodies have also been experimenting with various forms of conditional coverage, enabling patient access to newly approved therapeutics while comparative-effectiveness evidence is being gathered in prospective studies. One such conditional coverage scheme is risk-sharing. Here, contracts are drawn up in which payers cover a drug (patients therefore have access) but hold the manufacturers at some level of risk for the cost of providing the drug if expectations regarding its effectiveness are not met.25 Prospective, postmarketing trial studies are carried out to measure a drug’s performance over time. These risk-sharing agreements that also fall under the rubric of “pay-forperformance” have become a systematic feature of some CER entities, including NICE and the Italian reimbursement authority. Examples of drugs that have been subject to risksharing agreements include: (1) drugs that provide a benefit, but with substantial safety concerns inadequately described in the available clinical literature (eg, natalizumab)26; (2) drugs for which available clinical studies have not adequately described the risks and benefits in specific patient subgroups (eg, gefitinib)27; and (3) drugs for which the risks and benefits of offlabel uses have not been adequately addressed in the available clinical literature (eg, Medicare’s coverage of off-label uses of oxaliplatin, irinotecan, cetuximab, and bevacizumab in colorectal cancer patients, pro-
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vided patients enroll in studies examining the drugs’ comparative effectiveness).28 Medicare has coined this policy, which has been extended to other drugs and devices, “coverage with evidence development.”29 The growing use of CER overseas highlights opportunities and challenges for the United States. There is consensus among virtually all stakeholders that it is sensible to make decisions about the use of newly approved drugs on a data-driven basis. PCORI may lead the way, following the path AHRQ has laid out over the past 2 decades. PCORI will be the first national CER body to primarily produce prospective research, which includes conducting postmarketing clinical trials to examine effectiveness and tolerability.29 Significant qualitative differences exist between CER entities across jurisdictions. The table highlights similarities and differences between CER entities. International CER entities primarily serve payer needs. On the other hand, PCORI is a research producer, not user, and is intended primarily to serve clinical decision-making needs. In this regard, PCORI’s mission statement stands in stark contrast with those of other CER entities. Also, PCORI prioritizes research areas differently, has no preferred method of analysis, and is merely informative without stated positions on what should or should not be prescribed or reimbursed. In the US context, CER is invariably intended to inform, and not recommend policy.30 In other words, CER is not meant to directly influence prescribing behavior or reimbursement. US-based CER entities tend to address strictly clinically oriented research questions. To illustrate, they may ask what the comparative effectiveness of drugs is within a drug class for treatment of specific indications in certain subpopulations. Alternatively, they may address whether comparative effectiveness varies by patient subgroups defined by biomarkers, demographics (age, race, sex), socioeconomic status, use of other medications, or presence of comorbidities. In the United States, policymakers can and should learn from international approaches to conducting and implementing CER. However, the author would caution against wholesale importation of solutions from other health care systems, given the importance of the context of each health care system within which CER is to operate. Should policymakers continue to exclude cost and cost-per-QALY as CER considerations, this would make the NICE experience much less relevant. On the other hand, should policymakers emphasize
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Table. Key similarities and differences between entities of clinical effectiveness research (CER). PCORI & AHRQ (United States)
NICE (England and Wales)
Stated mission
Sponsor and carry out research that provides relevant evidence on how diseases and health conditions can effectively be prevented, diagnosed, treated, monitored, and managed
Offer authoritative guidance on the clinical and costeffectiveness of new and existing technologies
Prioritization
Prioritization to be based on Institute of Medicine report which identified 100 “highpriority” research topics
Types of research
Systematic reviews and prospective primary research as well as observational studies; no specific source cited or required
Function of CER
Informative (no direct link to reimbursement or pricing)
Selection based on policy priorities, potential budgetary impact, potential to improve health outcomes, variation in outcomes and practice patterns, availability of relevant evidence Randomized controlled clinical trial data preferred; source: meta-analyses and systematic reviews, as well as observational studies and expert opinion Reimbursement and clinical practice guidelines
Preferred method of analysis
None; by law, analyses will not include costeffectiveness metrics
Cost-effectiveness analysis
IQWIG (Germany)
HAS (France)
PBAC (Australia)
CVZ (Netherlands)
Evaluate the feasibility and value of therapeutic and diagnostic services, and disseminate findings to health care providers, patients, and the general public Drugs, devices, and diagnostics referred by the Federal Joint Commission; with potentially significant health or cost impact; with inconclusive or controversial evidence
Provide evidence-based information to decision-makers and support for the pricing and reimbursement processes
Conduct quality, safety, efficacy, and costeffectiveness reviews of new drugs and devices to inform government benefit coverage decision-makers
Develop the conditions and requirements for the health care insurance system
Committee considers all submissions
Committee considers all submissions
Committee considers all drugs that cannot be classified under reference pricing system (do not have therapeutic equivalents)
Randomized controlled clinical trial data preferred; source: systematic reviews and analysis of clinical and economic studies
Randomized controlled clinical trial data preferred; source: evidence from drugmanufacturer dossier
Randomized controlled clinical trial data preferred; source: evidence from drugmanufacturer dossier
Randomized controlled clinical trial data preferred; source: evidence from drug manufacturer dossier
Reimbursement, pricing, and prescribing information Efficiency frontier analysis
Reimbursement, pricing, and prescribing information Clinical effectiveness and budget-impact analyses
Reimbursement
Reimbursement and pricing
Costeffectiveness analysis
Cost-effectiveness and budget-impact analyses
AHRQ ⫽ Agency for Healthcare Research and Quality; CVZ ⫽ College voor Zorgverzekeringen; HAS ⫽ Haute Autorité de Santé; IQWiG ⫽ Institute for Quality and Efficiency in Health Care; NICE ⫽ National Institute for Health and Clinical Excellence; PBAC (Australia) ⫽ Pharmaceutical Benefits Advisory Committee; PCORI and Patient-Centered Outcomes Research Institute.
more patient-centric methods of value determination, this would make the IQWiG approach more relevant.
POLICY IMPLICATIONS Ideally, CER information should be used judiciously to inform prescribing and reimbursement decisions, thereby facilitating access to and public and private investment in the most beneficial technologies. In turn, CER can create incentives for higher-quality technologies, thereby encouraging the development of innovative products.
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Thus far, however, CER has had limited impact in the United States. In part, this has to do with the incentive structure of the US health care system, which still largely encourages utilization of services with less regard for clinical and cost-effectiveness.31 Presently, many reimbursement decisions in the United States resemble a black box, in some cases arbitrary and often devoid of an evidence base. Drugs with favorable data from a cost-effectiveness standpoint are often placed on unfavorable formulary tiers. And, drugs with unfavorable cost-effectiveness numbers often receive favor-
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Clinical Therapeutics able tier placement.31 In other words, patient cost sharing is often not a reflection of evidence-based value, instead being a function of a drug’s acquisition cost or the negotiating power of a health plan in securing rebates from a drug manufacturer. There are, however, examples in which CER already has an impact, including: (1) prescribing decisions (eg, through universal implementation of rigorously developed clinical practice guidelines [for example, in 2008, HIV treatment guidelines were revised based on extensive CER findings to incorporate HLA-B*5701 screening into routine care for patients before initiating abacavir treatment])32; and (2) reimbursement decisions (eg, through value-based insurance design, in which the levels of therapeutic benefit correspond to different levels of cost-sharing borne by the patient; payers promote the use of health care technologies when the cost– benefit ratio is favorable, and discourage the use when the ratio is unfavorable [in the United States, the insurer Humana is pursuing value-based reimbursement of drugs in a limited number of cardiovascular and antidiabetic therapeutic classes]).33 In the United States, CER will not affect pricing directly, as it will in the United Kingdom and Germany. However, payers, such as Humana, that implement value-based insurance design will be introducing a de facto system of value-based pricing in which reimbursement limits are set per therapeutic class. So, for example, because patients will have to pay a surcharge or hefty copayment for drugs deemed to have less value than others in the same class, manufacturers may be forced to lower prices of less cost-effective drugs. Value-based pricing, which relates price to cost-effectiveness, may in turn furnish important market signals to the industry as to what type and level of innovation is most useful and will be rewarded. Clinical trials of new drugs are designed primarily to meet the requirements of licensing authorities, not payers, providers, or patients. Surrogate end points used for licensing decisions can be predictive of clinical benefits, such as overall survival or time to disease progression, yet end points such as tumor shrinkage and progression-free survival may not be as relevant if they do not affect patients’ quality of life or actual life expectancy— outcomes that patients, providers, and payers care about. Therefore, it is imperative that quality-of-life indicators and survival estimates be integrated into clinical therapeutic development planning, as they will affect prescribing and reimbursement decisions. Such end points are be-
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ing employed earlier in the drug-development process (prior to Phase 3). In some cases, this has led to data sharing between payers (or their proxies) and drug manufacturers. For example, in 2011 The sanofi-aventis Group and the pharmacy benefits manager Medco announced an agreement that provided sanofi-aventis access to Medco’s comparative data to help shape its drug-development strategy.34 In other instances, the integration of value end points has caused early termination decisions.35 It is in this respect that CER is seen as reaching back to impact drug development in Phases 1, 2, and 3. Added value over comparable treatment options will be the basis for a premium price and lower copayment. To illustrate, in a risk-share arrangement, Merck agreed in 2009 to peg what the insurer Cigna paid for sitagliptin and the sitagliptin/metformin combination to how well individuals with type 2 diabetes were able to control their blood sugar. Cigna beneficiaries paid little or no copayments for either sitagliptin or the sitagliptin/metformin combination.36 Following the commercial payer model, Pearson and Bach37,38 proposed a tiered payment system for Medicare in which health services, including prescription drugs, with evidence to suggest superior health benefits would obtain cost-based reimbursement, but services offering benefits only comparable to an existing alternative would receive a “reference price” equal to the reimbursement rate for that alternative.39 – 41 This model explicitly incorporates the principles underlying CER into Medicare decision making. Accordingly, it ties the reimbursement of a new technology to its comparative effectiveness relative to an existing product by encouraging providers and patients to use more cost-effective drugs that are in tiers with lower copayments. Critics raise the specter of one-size-fits-all, “cookbook” medicine that is merely focused on cost-containment and restricting access. Has this really occurred? No. Indeed, it is possibly a red herring as there is little evidence that actual prescribing and reimbursement decisions have changed as a result of prospective studies such as ALLHAT.42 Using a different study to illustrate this issue, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was conducted to compare the effectiveness of different classes of antipsychotic medications.43 For years, clinicians had debated in the psychiatric literature about whether newer antipsychotics were more effective than the older anti-
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J.P. Cohen psychotics. CATIE was designed to answer that question. The trials revealed than older antipsychotics were as effective as the newer drugs. However, CATIE has had little or no effect on the sales of older antipsychotics and put no dent on the sales of the newer ones.44 More recently, a National Institutes of Health study comparing ranibizumab and bevacizumab in the treatment of age-related macular degeneration sparked controversy as it concluded that the 2 drugs were equivalent in terms of effectiveness.45 Ranibizumab costs up to 50 times the bevacizumab dose needed to treat macular degeneration. According to experts, this study is unlikely to impact practice patterns.46 Moreover, in the United Kingdom, ⬎10 years of institutionalization of CER by way of systematic reviews across many therapeutic classes has failed to decrease the growth rate of drug spending following its implementation.47 Most reviewed drugs have been given positive recommendations for reimbursement, with or without restrictions. Positive recommendations by NICE have implied increased costs for the NHS because they result in a mandate for funding new treatments.48 CER will likely intensify as federal funding increases and novel models to steer prescribing and reimbursement choices incorporate comparative-effectiveness evidence. Ultimately, any net effect on health care (eg, pharmaceutical) spending will depend on how CER evidence is used to change clinical practice and on whether such use is effective in producing change. The translation to actual clinical practice that implements CER findings is slow and fragmented, even when there is evidence that points unambiguously in a certain direction.49 Dissemination planning should therefore become a part of CER. Here, CER faces the central challenge of relevance, that is, producing information that diverse stakeholders can readily apply (ie, tangible information on survival, disability, or quality-of-life indices, and patient preferences). Strategies that attempt to influence medical practice using CER fall along a spectrum ranging from dissemination of information to financial penalties for choosing less effective options. Decreased spending could occur through reduced utilization of health care technologies that are shown to be either ineffective or more expensive and equally or less effective than treatment alternatives. The ways in which policies aimed at reducing utilization of services are implemented determine the extent
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to which spending is affected. Here, the key questions include: Will information on costs be included, or merely evidence on comparative clinical effectiveness?; How strong will the financial incentives be to alter prescribing behavior?; and Will incentives be directed at providers, patients, or both? The impact of CER will be shaped by the policy choices facing federal agencies and payers as they seek to implement its findings. In turn, these choices will be circumscribed by political limits, specifically with respect to Medicare’s use of CER. Section 6301(d) (8)(A)(iv) of the ACA explicitly states that PCORI shall ensure that CER findings not be construed as clinical practice guidelines, coverage, payment, or policy recommendations. Section 6301(j)(1)(A) goes further by stating that PCORI may not mandate coverage, reimbursement, or other policies for any public or private payer, and that findings cannot be used in ways that treat extending the life of an elderly, disabled, or terminally ill individual as of lower value. And finally, PCORI shall not develop or use cost-effectiveness thresholds. These political limits will likely mitigate CER’s impact. A significant gap persists between the best available evidence on therapeutic effectiveness and tolerability and typical patterns of prescribing care, as well as patient choices. Consequently, there is room for building a more systematic evidence base in the United States, so that policymakers are better equipped to understand variation in clinical outcomes while promoting appropriate prescribing and reimbursement patterns. We can and should learn from international approaches to developing an evidence base and implementing CER findings. Payers, physicians, and patients have a vested interest in knowing whether and on what dimensions a drug works, how well it works in comparison with alternatives, and its cost. Accordingly, comparativeeffectiveness evidence could help to close the gap between what we know and what we do in health care.
ACKNOWLEDGMENT Dr. Cohen was solely responsible for the literature search, data interpretation, and writing of the manuscript.
CONFLICTS ON INTEREST The author has indicated that he has no conflicts of interest with regard to the content of this article.
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21. Caro J. Method of economic evaluation for the German statutory health care system. Pharmacoeconomics. 2009; 27:263–264. 22. Bridges J, Cohen J, Grist P, Muhlbacher A. International experience with comparative effectiveness research: case studies from England/ Wales and Germany. Adv Health Econ Health Serv Res. 2010;22:29 –50. 23. Caro JJ. Methods for Assessment of the Relation of Benefits to Costs in the German Statutory Health Care System. Presented at: IQWiG Symposium, February 26, 2008, Berlin, Germany. https://www.iqwig.de/download/ Caro_Methodological_foundation_ of_the_Efficiency_Frontier_concept. pdf. Accessed October 1, 2012. 24. German Federal Ministry of Health. http://www.bmg.bund.de/kranken versicherung/arzneimittelversorgung/ arzneimittelmarktneuordnungsgesetzamnog.html. Accessed October 1, 2012. 25. Carlson J, Sullivan S, Garrison L, et al. Linking payment to health outcomes: a taxonomy and examination of performance-based reimbursement schemes between healthcare payers and manufacturers. Health Policy. 2010;96:179 –190. 26. Dorsey E, Thompson J, Noyes K, et al. Quantifying the risks and benefits of natalizumab in relapsing multiple sclerosis. Neurology. 2007;68:1524 – 1528. 27. US Dept Health and Human Services, Food and Drug Administration. Alert for Healthcare Professionals: Gefitinib (Marketed as Iressa). http://www.fda.gov/downloads/Drugs/ DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/ ucm126182.pdf. Accessed September 19, 2012. 28. Carino T, Williams R, Colbert A, Bridger P. Medicare’s coverage of colorectal cancer drugs: a case study in evidence development and policy. Health Aff. 2006;25:1231–1239. 29. Pearson S, Bach P. How Medicare could use comparative effectiveness
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research in deciding on new coverage and reimbursement. Health Aff. 2010;29:1796 –1804. Patient-Centered Outcomes Research Institute. Mission and Vision. http://www.pcori.org/about/missionand-vision/. Accessed October 1, 2012. Neumann P, Greenberg D. Is the United States ready for QALYs? Health Aff. 2009;28:1366 –1371. Neumann P, Sullivan S. Economic evaluation in the US: what is the missing link? Pharmacoeconomics. 2006;24:1163–1168. Aberg J, Kaplan J, Libman H. Primary care guidelines for the management of persons infected with human immunodeficiency virus: 2009 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2009; 49:651– 681. Chernew M, Shah M, Wegh A, et al. Impact of decreasing co-payments on medication adherence within a disease management environment. Health Aff. 2008;27:103–112. Levine D. Drug developers feel pressure from payers. The Burrill Report. 2012;2:1–3. Chuang-Stein C, Kirby S, French J, et al. A quantitative approach for making go/no-go decisions in drug development. Drug Inf J. 2011;45:187– 202. New England Healthcare Institute. Paying for Value: Exploring Innovative Pricing Arrangements for Biopharmaceuticals. NEHI Issue Brief. March 2012. Denny C, Emanuel E, Pearson S. Why well-insured patients should demand value-based insurance benefits. JAMA. 2007;297:2515–2518. Kanavos P, Saka O. How should functionally equivalent drugs be reimbursed? A retrospective analysis of reimbursement for epoetin-alfa and darbepoeitin-alfa in 20012003 and the cost implications for CMS. Dis Manag Health Outcome. 2005;13: 359 –370.
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40. Lichtenberg F. Did CMS’ functional equivalence decision result in equitable payments? J Pharmaceut Finance Econ Pol. 2006;15:7–20. 41. Fox D. Evidence of evidence-based policy: the politics of systematic reviews coverage decisions. Health Aff. 2005;24:114 –122. 42. Maio V, Gagne J. Impact of ALLHAT publication on antihypertensive prescribing patterns in Regione EmiliaRomagna, Italy. J Clin Pharm Ther. 2010;35:55– 61. 43. Meltzer D, Basu A, Meltzer H. Comparative effectiveness research for antipsychotic medications: how much is enough? Health Aff. 2009; 28:794 – 808. 44. Friedman R. A Call for Caution on Antipsychotic Drugs. http://www. nytimes.com/2012/09/25/health/acall-for-caution-in-the-use-of-antipsychotic-drugs.html?_r⫽0. Accessed November 21, 2012.
45. CATT Research Group. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364: 1897–1908. 46. Celia F. The Consequences of CATT: Will It Change Your Practice? http://www.retinalphysician.com/ articleviewer.aspx?articleid⫽105766. Accessed October 26, 2012. 47. Chalkidou K, Tunis S, Lopert R. Comparative effectiveness research and evidence-based health policy: experience from four countries. Milb Quart. 2009;87:339 –367. 48. Oberlander J, White J. System-wide cost control–the missing link in health care reform. N Engl J Med. 2009;17;361:1131–1133. 49. Avorn J, Fischer M. “Bench to behavior:” Translating comparative effectiveness research into improved clinical practice. Health Aff. 2010;29: 1891–1900.
Address correspondence to: Joshua P. Cohen, PhD, Center for the Study of Drug Development, Tufts University, 75 Kneeland Street, Suite 1100, Boston, MA 02111. E-mail: [email protected]
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Contemporary Issues
Comparative-Effectiveness Research: Does It Matter? Joshua P. Cohen, PhD Center for the Study of Drug Development, Tufts University, Boston, Massachusetts ABSTRACT Background: For several years there has been a vigorous policy debate on comparative effectiveness research (CER). This debate has focused on whether more evidence should be gathered, and who should be doing the funding and developing of evidence. There has been less emphasis on implementation of CER findings, and examining whether CER has or will have an impact on prescribing patterns, reimbursement, health outcomes, and health care spending. Objective: This paper addresses both empirical and normative aspects of CER in terms of its impact on prescribing, reimbursement, cost-containment, and health outcomes. Results: A significant gap persists between the best available evidence on therapeutic effectiveness and tolerability and typical patterns of prescribing care, as well as patient choices. Consequently, there is room for building a more systematic evidence base in the United States, so that policymakers are better equipped to understand variation in clinical outcomes while promoting appropriate prescribing and reimbursement patterns. Methods: The author carried out a non-systematic literature review of both empirical and normative aspects pertaining to CER and its policy implications. Keywords for the Medline search were “comparative effectiveness research” and “policy implications.” Conclusion: CER has a modest impact on prescribing, reimbursement, cost-containment, and health outcomes. This impact will likely intensify as funding increases and novel models to steer prescribing and reimbursement choices incorporate comparative-effectiveness evidence. (Clin Ther. 2013;35:371–379) © 2013 Elsevier HS Journals, Inc. All rights reserved. Key words: clinical effectiveness research, decision making, policymaking.
compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor a clinical condition or improve the delivery of care.”1,2 As such, CER uses a variety of data sources and methods to conduct studies and disseminate results to health care providers, patients, and payers. Comparative effectiveness researchers can perform systematic reviews of existing evidence, or retrospective analysis of existing observational data—in other words, examine all of the available evidence regarding the benefits and harms (which may include costs) of alternative choices of treatment for different groups of patients from completed clinical trials and studies.3,4 Alternatively, researchers can conduct prospective pragmatic clinical trials that generate new evidence on the comparative effectiveness of a test, treatment, or medical procedure, as used in actual clinical practice. The latter kinds of studies are much more expensive to conduct than the former. Broadly, CER comprises the rigorous evaluation of the impact of different options available for treating a given medical condition for a defined population. CER is invariably evidence based. However, it should not be conflated with cost-effectiveness analysis. We can distinguish between 3 types of evidencebased analysis that are not mutually exclusive: (1) effectiveness analysis, which is not comparative in a head-to-head sense and does not include costs; (2) comparative effectiveness analysis, which is comparative in a head-to-head sense (eg, drug vs another drug or a nonpharmaceutical therapy) and may include costs, but does not have to; and (3) cost-effectiveness analysis, which is comparative and includes costs. CER focused on drugs and drug-related products (eg, companion diagnostics) is designed to inform prescribing, reimbursement, and pricing decisions. Invest-
INTRODUCTION
Accepted for publication January 4, 2012. http://dx.doi.org/10.1016/j.clinthera.2012.12.018 0149-2918/$ - see front matter
Comparative effectiveness research (CER) is defined broadly as the “generation and synthesis of evidence that
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© 2013 Elsevier HS Journals, Inc. All rights reserved.
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Clinical Therapeutics ing in CER may help address the current gap in publicly available, evidence-based information on the comparative effectiveness of medical technologies. As a result, findings from CER could lead to a reduction in unwarranted variation in practice patterns and resource allocation, better health outcomes, and a possible “bending of the cost curve.”1–3 The objective of this review article was to address empirical and normative aspects related to CER (empirical: How has CER evolved over time?; Have past (international) efforts at investing in, carrying out, and implementing actionable findings from CER had clinical or economic impact?; and Will CER in its present form with more funding and wider dissemination have clinical or economic impact?; and normative: To what extent should CER findings impact prescribing and reimbursement decisions?; and Should the United States learn from international experience with CER?).
EMERGENCE OF CER IN THE UNITED STATES Unlike many members of the Organization for Economic Cooperation and Development, the United States has not systematically implemented CER findings with a view to altering prescribing patterns to diminish variation in health outcomes and control the growth of health expenditures.5,6 Yet, even the world’s largest market for biopharmaceuticals has not been bypassed by use of CER evidence to inform prescribing and reimbursement decisions (ie, as a “fourth hurdle”), in addition to the traditional regulatory hurdles of efficacy, tolerability, and quality of manufacturing practices. Although considered a laggard compared to other nations, a de facto fourth hurdle has been instituted by virtually all payers.6 Approval of a drug by the US Food and Drug Administration (FDA) does not guarantee its reimbursement. When new medical technologies are launched, health care providers and patients decide on their use, while insurers decide on reimbursement. For these purposes, decision makers may use evidence from CER. There is nothing new per se about CER or its use. For several decades, public and private payers as well as health care providers have used many sources to inform their prescribing and reimbursement decisions, including findings from CER.7–9 Providers of CER data have included public agencies such as the Agency for Healthcare Research and Quality (AHRQ), founded in 1989, and also influential private organizations such as Blue Cross/Blue Shield’s Technology
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Evaluation Center, established in 1985. Public–private partnerships have also been formed, including the Drug Effectiveness Review Project (DERP) in 2003. DERP is an Oregon-based collaboration of public and private entities, including 15 states (state Medicaid agencies) that have joined together to provide systematic evidence-based reviews of the comparative effectiveness and tolerability of drugs in many widely used drug classes, and to apply the findings to inform public policy decisions.7,10,11 Among watershed events in the past 10 years, perhaps the least publicized yet most influential we have witnessed is the issuance in 2000 (and subsequent updates) of Academy of Managed Care Pharmacy (AMCP) guidelines specifying clinical and cost-effectiveness parameters to be included by drug sponsors in the formulary dossiers that they submit to payers for the purpose of reimbursement of newly marketed pharmaceuticals. Presently, over 50 payers and pharmacy benefit managers adhere to AMCP formulary dossier guidelines.12 In the early 2000s, the Institute of Medicine (IOM) convened a series of meetings of health care stakeholders to discuss challenges facing clinical research. At the meetings, stakeholders criticized the inadequacy of public and private investment in clinical research to produce enough quality information to support appropriate prescribing and policy decisions.1 Specifically, payers and physicians pointed to the dearth of unbiased evidence on which to base prescribing and reimbursement decisions.13 Around the same time as the IOM meetings, the Medicare prescription drug benefit legislation sparked renewed interest in having better information available on the relative effectiveness of alternative therapies.3 In 2003, the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) directed the Centers for Medicare and Medicaid Services (CMS) to work with AHRQ on conducting comparative effectiveness studies of prescription drugs, medical devices, and diagnostics. CMS has since commissioned dozens of studies. In early 2009, the American Recovery and Reinvestment Act allocated $1.1 billion to increase the number of CER studies.14 And, with enactment of the Affordable Care Act (ACA) in 2010, CER received a further funding boost at the federal level, along with calls for more systematic implementation of research findings.15 Furthermore, ACA has revitalized the discussion regarding the locus of CER as a potential way of
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J.P. Cohen improving the health care system’s “added value,” measured in terms of health outcomes and cost-containment in relation to resources spent.16 The law established the Patient-Centered Outcomes Research Institute (PCORI), whose stated mission is to “carry out research that provides quality, relevant evidence on how diseases and health conditions can effectively be prevented, diagnosed, treated, monitored, and managed.” PCORI has provisionally been appropriated $300 million in annual funding.15
INTERNATIONAL EXPERIENCE: LESSONS FOR THE UNITED STATES? Across European health care systems, CER findings are generally intended to be more than solely informative. Accordingly, CER is assuming an increased role in prescribing, reimbursement, and, in some cases, pricing decisions. Several jurisdictions in Europe, among which are the United Kingdom and the Netherlands, employ cost-effectiveness thresholds. A threshold represents the amount of money society or a payer is willing to pay for an additional unit of health outcome (eg, an additional quality-adjusted life-year [QALY]) produced by a new technology. In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) is responsible for conducting appraisals of new technologies—systematic reviews—for select new products. NICE appraisals include calculations of cost-per-QALY estimates, which compare the incremental cost-effectiveness ratio of a new technology with that of an older technology or another new product. Based on these estimates, NICE may recommend a drug’s routine use for all licensed indications, recommend only for specific indications, or not recommend for use at all. Cost-perQALY estimates are intended to be compared within and across therapeutic indications. Also, NICE aims to have guidance that applies universally across hundreds of primary and acute care National Health Service (NHS) trusts.17 In this respect, the cost-per-QALY threshold delineates an arbitrary cutoff between technologies the NHS can afford for all, as opposed to those it will fund for no one.18 NICE has been criticized on numerous grounds, among which is that it imposes a “one-size-fits-all” population-based view of medicine. Further, besides Australia, Canada, and the Netherlands, no other technology assessment authority employs the cost-per-QALY method as extensively as NICE.19,20
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The German Ministry of Health has explicitly rejected the cost-per-QALY approach to determine reimbursement, on the basis that it is “discriminatory.” That is, it is deemed to imply that patients are less worthy of treatment if they have diminished life expectancy.21 In contrast to NICE’s charge, the mandate of Germany’s Institute for Quality and Efficiency in Health Care (IQWiG) is to address benefits relative to costs for a given therapeutic indication, not to set funding priorities across indications. Accordingly, IQWiG has developed an alternative approach based on an “efficiency-frontier model.”22 The efficiency frontier depicts the relationship between value and cost for drugs within a therapeutic class, or for a particular patient subgroup. Here, the policymaker’s focus is to calculate an efficiency (cardinal) ranking of drugs, given a specific indication.23 All available compounds within a therapeutic class are compared in terms of value and cost. Patient preferences are incorporated, that is, end points such as a patient’s experience or perception of physical, mental, and social functioning as a result of use of the new drug. New compounds must show comparable efficiency, relative to the cost– benefit ratio of the most efficient available alternative, or the average cost– benefit ratio within the specific indication. Hence, this model narrows the focus of each evaluation to a single therapeutic area, that is, compares the cost-effectiveness of newer treatments with that of existing ones targeting patients with the same disease or condition, thus comparing like with like. In this respect, IQWiG’s approach is more patientcentric and therefore similar to DERP’s method of analyzing each therapeutic class individually, incorporating patient-relevant end points per indication. CER in Europe and elsewhere has been used primarily to influence prescribing patterns and inform reimbursement. This is changing with the emergence of value-based pricing, in which the maximum reimbursement level of a drug is linked to the value that the drug adds over and above existing care. Value-based pricing is being launched in 2 of Europe’s largest pharmaceutical markets: the United Kingdom and Germany. Effective January 2012, Germany’s new rules require pharmaceutical companies to negotiate valuebased prices for all newly licensed drugs. New products enter the market at a price set by the company sponsor. Subsequently, within 3 months, regulators assess the product’s value based on a 6-point scale.24 Prices will then be a function of the assessment of a drug’s bene-
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Clinical Therapeutics fits, based mostly on randomized controlled clinical trial (RCT) data. If the new treatment is deemed to have no additional therapeutic benefit relative to existing care, prices will be set at a level no greater than that of the comparable medicine already on the market (ie, a “reference price”). “Premium prices” of varying levels relative to reference prices set per therapeutic class will be awarded to drugs deemed to have at least “slightly added benefit” compared to a benchmark drug. Presumably, the higher the added benefit, the higher the price will be. The United Kingdom will introduce mandatory, value-based pricing on all newly licensed drugs starting in 2014. In contrast to Germany, value-based pricing in the United Kingdom will be based on a cost-per-QALY evaluation at launch. As such, it is not an intraclass determination of relative benefit. Cost-effectiveness will not be the only criterion, as factors such as burden of disease in terms of unmet need or severity of illness may trump cost-effectiveness, allowing for premium prices to be set despite relatively poor cost-effectiveness numbers. International CER bodies have also been experimenting with various forms of conditional coverage, enabling patient access to newly approved therapeutics while comparative-effectiveness evidence is being gathered in prospective studies. One such conditional coverage scheme is risk-sharing. Here, contracts are drawn up in which payers cover a drug (patients therefore have access) but hold the manufacturers at some level of risk for the cost of providing the drug if expectations regarding its effectiveness are not met.25 Prospective, postmarketing trial studies are carried out to measure a drug’s performance over time. These risk-sharing agreements that also fall under the rubric of “pay-forperformance” have become a systematic feature of some CER entities, including NICE and the Italian reimbursement authority. Examples of drugs that have been subject to risksharing agreements include: (1) drugs that provide a benefit, but with substantial safety concerns inadequately described in the available clinical literature (eg, natalizumab)26; (2) drugs for which available clinical studies have not adequately described the risks and benefits in specific patient subgroups (eg, gefitinib)27; and (3) drugs for which the risks and benefits of offlabel uses have not been adequately addressed in the available clinical literature (eg, Medicare’s coverage of off-label uses of oxaliplatin, irinotecan, cetuximab, and bevacizumab in colorectal cancer patients, pro-
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vided patients enroll in studies examining the drugs’ comparative effectiveness).28 Medicare has coined this policy, which has been extended to other drugs and devices, “coverage with evidence development.”29 The growing use of CER overseas highlights opportunities and challenges for the United States. There is consensus among virtually all stakeholders that it is sensible to make decisions about the use of newly approved drugs on a data-driven basis. PCORI may lead the way, following the path AHRQ has laid out over the past 2 decades. PCORI will be the first national CER body to primarily produce prospective research, which includes conducting postmarketing clinical trials to examine effectiveness and tolerability.29 Significant qualitative differences exist between CER entities across jurisdictions. The table highlights similarities and differences between CER entities. International CER entities primarily serve payer needs. On the other hand, PCORI is a research producer, not user, and is intended primarily to serve clinical decision-making needs. In this regard, PCORI’s mission statement stands in stark contrast with those of other CER entities. Also, PCORI prioritizes research areas differently, has no preferred method of analysis, and is merely informative without stated positions on what should or should not be prescribed or reimbursed. In the US context, CER is invariably intended to inform, and not recommend policy.30 In other words, CER is not meant to directly influence prescribing behavior or reimbursement. US-based CER entities tend to address strictly clinically oriented research questions. To illustrate, they may ask what the comparative effectiveness of drugs is within a drug class for treatment of specific indications in certain subpopulations. Alternatively, they may address whether comparative effectiveness varies by patient subgroups defined by biomarkers, demographics (age, race, sex), socioeconomic status, use of other medications, or presence of comorbidities. In the United States, policymakers can and should learn from international approaches to conducting and implementing CER. However, the author would caution against wholesale importation of solutions from other health care systems, given the importance of the context of each health care system within which CER is to operate. Should policymakers continue to exclude cost and cost-per-QALY as CER considerations, this would make the NICE experience much less relevant. On the other hand, should policymakers emphasize
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Table. Key similarities and differences between entities of clinical effectiveness research (CER). PCORI & AHRQ (United States)
NICE (England and Wales)
Stated mission
Sponsor and carry out research that provides relevant evidence on how diseases and health conditions can effectively be prevented, diagnosed, treated, monitored, and managed
Offer authoritative guidance on the clinical and costeffectiveness of new and existing technologies
Prioritization
Prioritization to be based on Institute of Medicine report which identified 100 “highpriority” research topics
Types of research
Systematic reviews and prospective primary research as well as observational studies; no specific source cited or required
Function of CER
Informative (no direct link to reimbursement or pricing)
Selection based on policy priorities, potential budgetary impact, potential to improve health outcomes, variation in outcomes and practice patterns, availability of relevant evidence Randomized controlled clinical trial data preferred; source: meta-analyses and systematic reviews, as well as observational studies and expert opinion Reimbursement and clinical practice guidelines
Preferred method of analysis
None; by law, analyses will not include costeffectiveness metrics
Cost-effectiveness analysis
IQWIG (Germany)
HAS (France)
PBAC (Australia)
CVZ (Netherlands)
Evaluate the feasibility and value of therapeutic and diagnostic services, and disseminate findings to health care providers, patients, and the general public Drugs, devices, and diagnostics referred by the Federal Joint Commission; with potentially significant health or cost impact; with inconclusive or controversial evidence
Provide evidence-based information to decision-makers and support for the pricing and reimbursement processes
Conduct quality, safety, efficacy, and costeffectiveness reviews of new drugs and devices to inform government benefit coverage decision-makers
Develop the conditions and requirements for the health care insurance system
Committee considers all submissions
Committee considers all submissions
Committee considers all drugs that cannot be classified under reference pricing system (do not have therapeutic equivalents)
Randomized controlled clinical trial data preferred; source: systematic reviews and analysis of clinical and economic studies
Randomized controlled clinical trial data preferred; source: evidence from drugmanufacturer dossier
Randomized controlled clinical trial data preferred; source: evidence from drugmanufacturer dossier
Randomized controlled clinical trial data preferred; source: evidence from drug manufacturer dossier
Reimbursement, pricing, and prescribing information Efficiency frontier analysis
Reimbursement, pricing, and prescribing information Clinical effectiveness and budget-impact analyses
Reimbursement
Reimbursement and pricing
Costeffectiveness analysis
Cost-effectiveness and budget-impact analyses
AHRQ ⫽ Agency for Healthcare Research and Quality; CVZ ⫽ College voor Zorgverzekeringen; HAS ⫽ Haute Autorité de Santé; IQWiG ⫽ Institute for Quality and Efficiency in Health Care; NICE ⫽ National Institute for Health and Clinical Excellence; PBAC (Australia) ⫽ Pharmaceutical Benefits Advisory Committee; PCORI and Patient-Centered Outcomes Research Institute.
more patient-centric methods of value determination, this would make the IQWiG approach more relevant.
POLICY IMPLICATIONS Ideally, CER information should be used judiciously to inform prescribing and reimbursement decisions, thereby facilitating access to and public and private investment in the most beneficial technologies. In turn, CER can create incentives for higher-quality technologies, thereby encouraging the development of innovative products.
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Thus far, however, CER has had limited impact in the United States. In part, this has to do with the incentive structure of the US health care system, which still largely encourages utilization of services with less regard for clinical and cost-effectiveness.31 Presently, many reimbursement decisions in the United States resemble a black box, in some cases arbitrary and often devoid of an evidence base. Drugs with favorable data from a cost-effectiveness standpoint are often placed on unfavorable formulary tiers. And, drugs with unfavorable cost-effectiveness numbers often receive favor-
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Clinical Therapeutics able tier placement.31 In other words, patient cost sharing is often not a reflection of evidence-based value, instead being a function of a drug’s acquisition cost or the negotiating power of a health plan in securing rebates from a drug manufacturer. There are, however, examples in which CER already has an impact, including: (1) prescribing decisions (eg, through universal implementation of rigorously developed clinical practice guidelines [for example, in 2008, HIV treatment guidelines were revised based on extensive CER findings to incorporate HLA-B*5701 screening into routine care for patients before initiating abacavir treatment])32; and (2) reimbursement decisions (eg, through value-based insurance design, in which the levels of therapeutic benefit correspond to different levels of cost-sharing borne by the patient; payers promote the use of health care technologies when the cost– benefit ratio is favorable, and discourage the use when the ratio is unfavorable [in the United States, the insurer Humana is pursuing value-based reimbursement of drugs in a limited number of cardiovascular and antidiabetic therapeutic classes]).33 In the United States, CER will not affect pricing directly, as it will in the United Kingdom and Germany. However, payers, such as Humana, that implement value-based insurance design will be introducing a de facto system of value-based pricing in which reimbursement limits are set per therapeutic class. So, for example, because patients will have to pay a surcharge or hefty copayment for drugs deemed to have less value than others in the same class, manufacturers may be forced to lower prices of less cost-effective drugs. Value-based pricing, which relates price to cost-effectiveness, may in turn furnish important market signals to the industry as to what type and level of innovation is most useful and will be rewarded. Clinical trials of new drugs are designed primarily to meet the requirements of licensing authorities, not payers, providers, or patients. Surrogate end points used for licensing decisions can be predictive of clinical benefits, such as overall survival or time to disease progression, yet end points such as tumor shrinkage and progression-free survival may not be as relevant if they do not affect patients’ quality of life or actual life expectancy— outcomes that patients, providers, and payers care about. Therefore, it is imperative that quality-of-life indicators and survival estimates be integrated into clinical therapeutic development planning, as they will affect prescribing and reimbursement decisions. Such end points are be-
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ing employed earlier in the drug-development process (prior to Phase 3). In some cases, this has led to data sharing between payers (or their proxies) and drug manufacturers. For example, in 2011 The sanofi-aventis Group and the pharmacy benefits manager Medco announced an agreement that provided sanofi-aventis access to Medco’s comparative data to help shape its drug-development strategy.34 In other instances, the integration of value end points has caused early termination decisions.35 It is in this respect that CER is seen as reaching back to impact drug development in Phases 1, 2, and 3. Added value over comparable treatment options will be the basis for a premium price and lower copayment. To illustrate, in a risk-share arrangement, Merck agreed in 2009 to peg what the insurer Cigna paid for sitagliptin and the sitagliptin/metformin combination to how well individuals with type 2 diabetes were able to control their blood sugar. Cigna beneficiaries paid little or no copayments for either sitagliptin or the sitagliptin/metformin combination.36 Following the commercial payer model, Pearson and Bach37,38 proposed a tiered payment system for Medicare in which health services, including prescription drugs, with evidence to suggest superior health benefits would obtain cost-based reimbursement, but services offering benefits only comparable to an existing alternative would receive a “reference price” equal to the reimbursement rate for that alternative.39 – 41 This model explicitly incorporates the principles underlying CER into Medicare decision making. Accordingly, it ties the reimbursement of a new technology to its comparative effectiveness relative to an existing product by encouraging providers and patients to use more cost-effective drugs that are in tiers with lower copayments. Critics raise the specter of one-size-fits-all, “cookbook” medicine that is merely focused on cost-containment and restricting access. Has this really occurred? No. Indeed, it is possibly a red herring as there is little evidence that actual prescribing and reimbursement decisions have changed as a result of prospective studies such as ALLHAT.42 Using a different study to illustrate this issue, the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was conducted to compare the effectiveness of different classes of antipsychotic medications.43 For years, clinicians had debated in the psychiatric literature about whether newer antipsychotics were more effective than the older anti-
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J.P. Cohen psychotics. CATIE was designed to answer that question. The trials revealed than older antipsychotics were as effective as the newer drugs. However, CATIE has had little or no effect on the sales of older antipsychotics and put no dent on the sales of the newer ones.44 More recently, a National Institutes of Health study comparing ranibizumab and bevacizumab in the treatment of age-related macular degeneration sparked controversy as it concluded that the 2 drugs were equivalent in terms of effectiveness.45 Ranibizumab costs up to 50 times the bevacizumab dose needed to treat macular degeneration. According to experts, this study is unlikely to impact practice patterns.46 Moreover, in the United Kingdom, ⬎10 years of institutionalization of CER by way of systematic reviews across many therapeutic classes has failed to decrease the growth rate of drug spending following its implementation.47 Most reviewed drugs have been given positive recommendations for reimbursement, with or without restrictions. Positive recommendations by NICE have implied increased costs for the NHS because they result in a mandate for funding new treatments.48 CER will likely intensify as federal funding increases and novel models to steer prescribing and reimbursement choices incorporate comparative-effectiveness evidence. Ultimately, any net effect on health care (eg, pharmaceutical) spending will depend on how CER evidence is used to change clinical practice and on whether such use is effective in producing change. The translation to actual clinical practice that implements CER findings is slow and fragmented, even when there is evidence that points unambiguously in a certain direction.49 Dissemination planning should therefore become a part of CER. Here, CER faces the central challenge of relevance, that is, producing information that diverse stakeholders can readily apply (ie, tangible information on survival, disability, or quality-of-life indices, and patient preferences). Strategies that attempt to influence medical practice using CER fall along a spectrum ranging from dissemination of information to financial penalties for choosing less effective options. Decreased spending could occur through reduced utilization of health care technologies that are shown to be either ineffective or more expensive and equally or less effective than treatment alternatives. The ways in which policies aimed at reducing utilization of services are implemented determine the extent
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to which spending is affected. Here, the key questions include: Will information on costs be included, or merely evidence on comparative clinical effectiveness?; How strong will the financial incentives be to alter prescribing behavior?; and Will incentives be directed at providers, patients, or both? The impact of CER will be shaped by the policy choices facing federal agencies and payers as they seek to implement its findings. In turn, these choices will be circumscribed by political limits, specifically with respect to Medicare’s use of CER. Section 6301(d) (8)(A)(iv) of the ACA explicitly states that PCORI shall ensure that CER findings not be construed as clinical practice guidelines, coverage, payment, or policy recommendations. Section 6301(j)(1)(A) goes further by stating that PCORI may not mandate coverage, reimbursement, or other policies for any public or private payer, and that findings cannot be used in ways that treat extending the life of an elderly, disabled, or terminally ill individual as of lower value. And finally, PCORI shall not develop or use cost-effectiveness thresholds. These political limits will likely mitigate CER’s impact. A significant gap persists between the best available evidence on therapeutic effectiveness and tolerability and typical patterns of prescribing care, as well as patient choices. Consequently, there is room for building a more systematic evidence base in the United States, so that policymakers are better equipped to understand variation in clinical outcomes while promoting appropriate prescribing and reimbursement patterns. We can and should learn from international approaches to developing an evidence base and implementing CER findings. Payers, physicians, and patients have a vested interest in knowing whether and on what dimensions a drug works, how well it works in comparison with alternatives, and its cost. Accordingly, comparativeeffectiveness evidence could help to close the gap between what we know and what we do in health care.
ACKNOWLEDGMENT Dr. Cohen was solely responsible for the literature search, data interpretation, and writing of the manuscript.
CONFLICTS ON INTEREST The author has indicated that he has no conflicts of interest with regard to the content of this article.
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Address correspondence to: Joshua P. Cohen, PhD, Center for the Study of Drug Development, Tufts University, 75 Kneeland Street, Suite 1100, Boston, MA 02111. E-mail: [email protected]
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