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THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ JULY/AUGUST 2010

VOLUME 3, NUMBER 4

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

REGULATORY

Accountable Care Organizations in the Era of Healthcare Reform Interview with Mark B. McClellan, MD, PhD

BUSINESS

Expect the Unexpected: A Role for Behavioral Economics in Understanding the Impact of Cost-Sharing on Emergency Department Utilization Albert Tzeel, MD, MHSA; Jack Brown, BA

Stakeholder Perspective by Alberto M. Colombi, MD, MPH ™

Comparing Medical Cost of Care for Patients with Metastatic Breast Cancer Receiving Taxane Therapy: Claims Analysis Rex W. Force, PharmD; Brooke A. Pugmire, PharmD; Vaughn L. Culbertson, PharmD

Stakeholder Perspective by Atheer A. Kaddis, PharmD CLINICAL

Effectiveness of Anti-Tumor Necrosis Factor Agents in the Treatment of Rheumatoid Arthritis: Observational Study Anna D’Souza, PhD; Brian L. Meissner, PharmD, PhD; Boxiong Tang, MD, PhD; R. Scott McKenzie, MD; Catherine T. Piech, MBA

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA HEALTHCARE REFORM

The New Accountable Care Organizations and Medicare Gain-Sharing Program Kip Piper, MA, FACHE

The Impact of Healthcare Reform on Payers’ Products, Provider Reimbursement, and Member Engagement Sam Muppalla; Robert Capoblanco

Generic Drug Trends

Industry Trends

©2009 Engage Healthcare Communications, LLC ©2010 www.AHDBonline.com


Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

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EDITORIAL BOARD

CLINICAL EDITOR

Nirav R. Shah, MD, MPH Assistant Professor of Medicine NYU School of Medicine, NYC Senior Investigator, Geisinger Health System, Danville, PA

Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA GOVERNMENT EDITOR

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Sr. Counselor, Fleishman-Hillard Washington, DC

HEALTH INFORMATION TECHNOLOGY

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson Co.

ACTUARY

David Williams Milliman Health Consultant Windsor, CT CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University President, ACCC Past Chair, Board of Directors, NCCN

HEALTH OUTCOMES RESEARCH

Gordon M. Cummins, MS Director, IntegriChain Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

CARDIOLOGY RESEARCH

Michael A. Weber, MD Professor of Medicine Department of Medicine (Cardiology) State University of New York

MANAGED CARE & GOVERNMENT AFFAIRS

ENDOCRINOLOGY RESEARCH

MANAGED MARKETS

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ

Jeffrey A. Bourret, MS, RPh, FASHP Senior Director, Customer Marketing & Innovation, US Specialty Customers Pfizer Specialty Business Unit, PA

EMPLOYERS

Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim, CT

Sharad Mansukani, MD Chief Strategic Officer, Nations Health Senior Advisor, Texas Pacific Group, FL

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

William E. Fassett, BSPharm, MBA, PhD Professor of Pharmacy Law & Ethics Vice Chair, Dept. of Pharmacotherapy College of Pharmacy, Washington State University, Spokane, WA

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL

William J. Cardarelli, PharmD Director of Pharmacy Atrius Health Harvard Vanguard Medical Associates Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta Paul Anthony Polansky, BSPharm, MBA Former Executive VP and Chief Pharmacy Officer, Sanovia Corp., Philadelphia, PA Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality and biomedical research consultancy J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago REIMBURSEMENT POLICY

Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account, Amgen, CA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental Pharmacology and Therapeutics, HarvardMIT Division of Health Sciences and Technology, Cambridge, MA

PERSONALIZED MEDICINE

F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA Senior Fellow, Jefferson School of Population Health

Wayne A. Rosenkrans, Jr, PhD Chairman and President, Personalized Medicine Coalition, Distinguished Fellow, MIT Center for Biomedical Innovation PHARMACOECONOMICS

Jeff Jianfei Guo, BPharm, MS, PhD Associate Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Vice President, Strategic Research CVS Caremark, Hunt Valley, MD

American Health & Drug Benefits

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

RESEARCH & DEVELOPMENT PATIENT ADVOCACY

Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE

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SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care, Wellesley, MA

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VOLUME 3, NUMBER 4

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS Publisher Nicholas Englezos nick@engagehc.com 732-992-1884

REGULATORY

242 Accountable Care Organizations in the Era of Healthcare Reform Interview with Mark B. McClellan, MD, PhD BUSINESS

248 Expect the Unexpected: A Role for Behavioral Economics in Understanding the Impact of Cost-Sharing on Emergency Department Utilization Albert Tzeel, MD, MHSA; Jack Brown, BA

255 Stakeholder Perspective by Alberto M. Colombi, MD, MPH

Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Lara J. Reiman lara@engagehc.com 732-992-1892 Editorial Assistant Jessica A. Smith

276 Comparing Medical Cost of Care for Patients with Metastatic Breast Cancer Receiving Taxane Therapy: Claims Analysis Rex W. Force, PharmD; Brooke A. Pugmire, PharmD; Vaughn L. Culbertson, PharmD

284 Stakeholder Perspective by Atheer A. Kaddis, PharmD

Senior Production Manager Lynn Hamilton Business Manager Blanche Marchitto Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

CLINICAL

266 Effectiveness of Anti-Tumor Necrosis Factor Agents in the Treatment of Rheumatoid Arthritis: Observational Study Anna D’Souza, PhD; Brian L. Meissner, PharmD, PhD; Boxiong Tang, MD, PhD; R. Scott McKenzie, MD; Catherine T. Piech, MBA 273 Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

Continued on page 240

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare. This publication further provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory

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Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1892 F: 732-992-1881

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We focus on the human in human health care

At Eisai (a•zi), caring for people is our work Satisfying unmet medical needs and increasing benefits to patients, their families, and caregivers is Eisai’s human health care (hhc) mission. This includes the development of innovative medicines– notably the discovery of the world’s most widely used treatment for Alzheimer’s disease. Eisai is recognized for our business and patient advocacy partnerships, as well as our commitment to working with healthcare professionals to achieve improved patient care worldwide. That is our quest. That is our promise. That is what makes us Eisai.

Ingenuity that Drives Innovation in Neurology, GI Disorders, and Oncology/Critical Care

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JULY/AUGUST 2010

VOLUME 3, NUMBER 4

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

HEALTHCARE REFORM

261 The New Accountable Care Organizations and Medicare Gain-Sharing Program Kip Piper, MA, FACHE 289 The Impact of Healthcare Reform on Payers’ Products, Provider Reimbursement, and Member Engagement Sam Muppalla; Robert Capoblanco

DEPARTMENTS

American Health & Drug Benefits, ISSN 19422962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2010 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

274 GENERIC DRUG TRENDS Enhanced Generic Utilization Saved US Healthcare $139.6 Billion in 2009 Dalia Buffery, MA, ABD

Address all editorial correspondence to: editorial@AHDBonline.com. Telephone: 732-992-1892. Fax: 732-992-1881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

292 INDUSTRY TRENDS

Permission requests to reprint all or part of any article published in this journal should be addressed to PERMISSIONS DEPARTMENT. Fax: 732-992-1881.

The Current State of Bundled Payments Jim Evans CAPTION CONTEST

The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

WEB EXCLUSIVE www.AHDBonline.com

GI Drugs in Late Development: DDW 2010 By Alice Goodman

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

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exploring

DIABETES inspired to make a

DIFFERENCE

Copyright Š2010, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

(06/10)

DI77201MHC-A


REGULATORY

Accountable Care Organizations in the Era of Healthcare Reform Interview with Mark B. McClellan, MD, PhD See also Primer on ACOs, page 261

Under the Patient Protection and Affordable Care Act (PPACA) of 2010, Medicare providers, including physician groups and hospitals, will soon have the option to form accountable care organizations (ACOs) to improve quality and efficiency. ACO participants may share financial gains generated from improved clinical and economic performance, provided that quality goals and patient safeguards are met. Through future regulations, the Centers for Medicare & Medicaid Services (CMS) must implement the ACO option no later than January 1, 2012. In this interview, Dr Mark B. McClellan, former CMS Administrator and US Food and Drug Administration Commissioner, discusses the extraordinary implications of the new ACO option for improving patient care and reducing unnecessary costs. Kip Piper, MA, FACHE: You and your colleagues were influential in developing the ACO concept1 and successfully persuading Congress to make ACOs an option in Medicare. Are you surprised by the tremendous interest in ACOs since enactment of the PPACA this year?

er to add up to getting better value, getting higher quality, and avoiding unnecessary costs. That’s contributing to the interest in ACOs. It is a confluence of factors, and in retrospect I should not be so surprised by the intense interest in the ACO model.

Mark B. McClellan, MD, PhD: There has been a real expansion of interest in ACOs recently, and some of that is not surprising. The key ideas behind accountable care have been around for a while. CMS has implemented some Medicare demonstration programs previously that potentially use ACO concepts, and a number of private payers and providers have been working on ACO implementation as well. I have been a bit surprised by the breadth of interest. It is a reflection of how seriously providers and payers are taking the healthcare reform law. However, unlike many of the other provisions on payment reform, ACOs will be a real part of Medicare as of 2012, if not earlier; not a pilot, not a demo, but a part of the Medicare program. That may be contributing to the interest too. And finally, there is growing interest in making sure that payment policies fit togeth-

Piper: What are some of the factors critical to successfully implementing an ACO?

Dr McClellan directs the Engelberg Center for Health Care Reform at the Brookings Institution, Washington, DC (www. brookings.edu/health). He is former Commissioner of the US Food and Drug Administration and Administrator of the Centers for Medicare & Medicaid Services. Mr Piper is a Senior Advisor to TogoRun, Sellers Dorsey, and Fleishman-Hillard, and is Health Policy Editor of American Health & Drug Benefits.

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McClellan: One is a critical mass of providers who are willing and able to meaningfully take accountability for the well-being of a population of patients. This includes a primary care network and other types of healthcare providers, maybe even some providers who are involved in things that are not traditionally thought of as healthcare, such as wellness programs and population health management. But the key thing is that there is a critical mass of providers who are willing to work together and are able to take meaningful steps to get to better health for those beneficiaries. Second, there also is a need for a critical mass of payers. There needs to be enough reform in the way payments work so that steps that traditionally do not make much financial sense—such as promoting better coordination of care, taking steps to reduce complications and readmissions, and exchanging information effectively— make more financial sense. And that takes enough of the payer community to get behind the effort as well. Having both providers and payers simultaneously jump together is a challenge, but there is certainly a growing number of examples of ways to do it successful-

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ACOs in the Era of Healthcare Reform

ly. In the end, the success of ACOs is going to depend on actually reforming care so that costs are lower and results are better. It’s not just a matter of getting the critical mass (of providers and payers), but actually having meaningful steps that can be taken. These steps can take a little time, and certainly some effort, to reform the way healthcare works, which requires a commitment of time, effort, and expertise to meaningfully redesign care. Piper: How does the ACO model fit in context with other major reforms, most notably bundled payment, global and episode-based payment reforms, and the medical home model? McClellan: There is a tendency now to look at what is in the healthcare reform legislation and what is being tried in the private sector and states around the country as basically throwing a lot of spaghetti against the wall and seeing what sticks. That is the wrong way to look at these reforms. They all have a common goal of improving care delivery, making it better so that patients are healthier, and making it more efficient so that costs are lower. The best strategy for an organization is to view these as part of an overall approach to getting that result. So, for example, it can actually be easier to implement an ACO successfully by pairing it with a medical home reform. We are seeing many examples of this around the country, where the providers get the support they need for coordinating care and spending more time on patient management by the upfront investment needed to support a meaningful medical home. Payers get some accountability that, by taking these steps (or as they take these steps upfront to support reforms and care delivery), they are going to be able to see what the ultimate consequences are for health and for costs on the back end. That is what an ACO provides. So these reforms can truly reinforce each other. The best way to approach payment reform is as pieces that add up to a more comprehensive and effective whole. Piper: Long-term, which form of payment do you expect will work most effectively with the ACO model— shared fee-for-service savings, partial capitation, or some other form of global payment? McClellan: What we have seen in some early adopters is movement toward having less payment depend on fee for service. But that is not necessarily going to be the outcome. I can imagine some longerterm arrangements where ACOs are operating at a regional level or across a diverse range of providers, where fee-for-service reimbursement may remain a substantial part of payment. The main thing is that ACOs

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involve setting up a different kind of tracking system for payments than you get with fee for service. In the most basic form of ACOs, with shared savings, in addition to tracking the volume and intensity of services for traditional fee-for-service payments, the organization and its payers will also track some meaningful results for the population of patients being served and per-capita spending. If there are any savings compared with fee-for-service costs, those provide an additional source of reimbursement for the providers. As people get more used to thinking about things that they can do to improve care and to work on improving those patient-focused performance measures rather than just the fee-for-service billing, you can imagine more weight going to this patient-focused payment approach, and it can be gradual. In some examples, it may start out with shared savings. Then, as the providers get more used to working together in this kind of explicit goal-oriented way, as they identify some further steps that they can take together to improve performance, and as they get more comfortable with an explicit patient-level focus, you can imagine putting more weight on the ACO payment model as opposed to fee for service. So maybe reducing the fee-for-service payment by 20% across the board or for primary care services and putting that money into a partial capitation fund would enable the organization to do more to reform care than it can with the resources from shared savings alone. Different organizations may come out in various places. The whole point is to try to support incremental steps that are not too disruptive in the short-term, but that over time could lead to more fundamental improvements and care. Piper: A few skeptics question the readiness of provider organizations in areas such as governance, physician relationships, coordination, health information technology (HIT), and performance measurement. How do you respond? McClellan: Yes, this is hard, especially in the status quo, where it is very difficult for many healthcare providers and provider organizations. Their payment rates are being squeezed. They are facing new reimbursement and regulatory pressures because of rising healthcare costs. Unfortunately, I do not see the status quo getting better. So although this is a real challenge, there are some unique opportunities to support the move toward a different kind of payment, in which providers get better support for delivering better care, not just more squeezes. It makes now a really good time to consider moving forward on addressing these very hard challenges. For example, there is the federal HIT initiative, with Medicare and Medicaid incentive payments for adop-

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tion of electronic health record (EHR) systems and meaningful use of EHRs. The objectives of the meaningful use standards are tied directly to improving patient care. This sounds a lot like the goal of accountable care. There are some payments now and over the next few years in Medicare for physicians and other healthcare providers for reporting on performance. That is easier to do if you have an information system in place and if you are actually developing and using information systems to improve care. CMS now has 2 tracks for performance reporting. One is the traditional “fill out another claim form” approach, which is burdensome on providers and does not help improve quality. The other is to submit information from systems used to improve care at the patient level as a registry-based submission to CMS. An increasing number of provider organizations are doing that. There are also other opportunities in terms of medical homes and other payment reforms that can collectively add up to a significant amount of support for addressing things such as governance, effective information technology (IT) use, and improving physician relationships and coordination. But those opportunities are not going to be around forever. I think the next few years are probably the best time to take advantage of all of this support for building up systems that help providers do what they want to do, which is get better results for their patients at a lower cost. Piper: ACOs have been discussed mostly in terms of hospitals and physicians. Does the ACO model hold promise for other combinations of healthcare providers? McClellan: Yes, it does. It is essential to have a network of primary care physicians within an ACO. But there are certainly a lot of opportunities to expand broadly beyond specialist hospitals and other types of traditional healthcare providers. For example, we have heard from a number of communities that already have public health initiatives in place. They want to expand these initiatives to use wellness programs and schoolbased programs to support ACO goals. State Medicaid programs are finding that if they can expand the support from ACOs and Medicaid to areas like community-based mental health services, they can document some significant reductions in medical costs related to mental illnesses. There are issues that could be addressed through support of care in the community but that are not part of traditional healthcare delivery. I think ACOs actually make it easier to move toward less-traditional forms of delivering care and toward preventing complications and keeping people well. That’s because all these steps in the absence of an ACO run the

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risk of payer concerns that they may just lead to higher costs and more expenditures. Therefore, some reluctance. With the accountability of the ACO model, it becomes easier to bring in other types of providers, other types of services that may not even be traditional healthcare to get the better results and lower costs. Piper: The Engelberg Center for Health Care Reform, at the Brookings Institution, provides practical solutions to achieve high-quality, innovative, affordable healthcare. What else is the Engelberg Center working on? McClellan: Well, this is sort of high noon for healthcare reform implementation. A lot of people think that the big issues are not coming until 2014, but implementation of reform is under way now. And so we are not only trying to help with effective implementation around accountable care, quality and value, and healthcare payments, but also on other issues, such as evaluating other types of payment reform and other things that may not be viewed as within the traditional reform but probably should be. For example, we are doing work with a network of health plans and EHR systems on developing a better surveillance capability in this country for monitoring the safety of medical products. We have got an IT infrastructure now, incomplete as it is, that could provide much more timely information on potential safety problems. So we need to take steps to use that. Of course, healthcare reform is never done. So we are following up on some of our earlier work on bending the curve in healthcare, with ideas that may be considered in the next round of healthcare reform. The President has a commission on deficit reduction that will report later this year. In 2011, unquestionably there will be more healthcare legislation related to implementation of the new law, funding it, and perhaps building on it. So we are trying to provide some useful guidance for all of that too. What a lot of these projects have in common is a recognition that private sector leadership is needed for real reform in healthcare, and for making our publicprivate system work better, but that this needs to be aligned with effective federal, state, and local government policies to support shared goals. And one of the things we have tried to do here at the Engelberg Center—as a neutral, expert-oriented think tank—is to help bring together these different perspectives in practical ways to make progress on the big challenges of reform in all of these areas. Reference 1. McClellan MB, McKethan AN, Lewis JL, et al. A national strategy to put accountable care into practice. Health Aff (Millwood). 2010;29:982-990.

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DEXILANT WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

DEXILANT is the first and only PPI with a Dual Delayed Release™ (DDR) formulation, which provides a second release of drug Mean plasma concentration (in healthy subjects; day 5; ng/mL)1 1200 1000 800 600 400

DEXILANT 60 mg 200

DEXILANT 30 mg

0 0

6

12

18

24

Time (h)

s DEXILANT 30 mg provided full 24-hour heartburn relief in a majority of symptomatic non-erosive gastroesophageal reflux disease patients at week 41 Conclusions of comparative efficacy cannot be drawn from this information. Indications DEXILANT is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Important Safety Information DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Most commonly reported treatment-emergent adverse reactions: diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations. Please see adjacent brief summary of prescribing information for DEXILANT.

FORMERLY

KAPIDEX™ (dexlansoprazole)


BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE DEXILANT is indicated for:  K D85851<9>7?61<<7B145C?65B?C9F55C?@8179D9C6?BE@D?G55;C  K =19>D19>9>7851<9>7?66?BE@D?=?>D8C1>4  K D85DB51D=5>D?6851BD2EB>1CC?391D54G9D8>?>5B?C9F571CDB?5C?@81751<   B56<EH49C51C5(6?BG55;C CONTRAINDICATIONS -"$*9C3?>DB19>4931D549>@1D95>DCG9D8;>?G>8I@5BC5>C9D9F9DID?1>I 3?=@?>5>D?6D856?B=E<1D9?>I@5BC5>C9D9F9DI1>41>1@8I<1H9C81F5255> B5@?BD54G9D8-"$*EC5[see Adverse Reactions]. WARNINGS AND PRECAUTIONS Gastric Malignancy )I=@D?=1D93B5C@?>C5G9D8-"$*4?5C>?D@B53<E45D85@B5C5>35?6 71CDB93=1<97>1>3I ADVERSE REACTIONS Clinical Trials Experience *85C165DI?6-"$*G1C5F1<E1D549>@1D95>DC9>3?>DB?<<541>4 E>3?>DB?<<543<9>931<CDE495C9>3<E49>7 @1D95>DCDB51D546?B1D<51CD =?>D8C1>4

@1D95>DCDB51D546?B?>5I51B&1D95>DCB1>7549>1756B?= D? I51BC=5491>175I51BCG9D865=1<51E31C91> <13;C91>1>4 ?D85BB135C)9HB1>4?=9J543?>DB?<<543<9>931< DB91<CG5B53?>4E3D546?BD85DB51D=5>D?6=19>D5>1>35?6851<541>4 CI=@D?=1D93(G89389>3<E454@1D95>DC?>@<1352?@1D95>DC ?>-"$* =7

@1D95>DC?>-"$* =71>4  @1D95>DC ?><1>C?@B1J?<5 =7?>35419<I C3<9>931<DB91<C1B53?>4E3D54E>45BG945<IF1BI9>73?>49D9?>C14F5BC5 B513D9?>B1D5C?2C5BF549>D853<9>931<DB91<C?614BE731>>?D2549B53D<I 3?=@1B54D?B1D5C9>D853<9>931<DB91<C?61>?D85B4BE71>4=1I>?DB56<53D D85B1D5C?2C5BF549>@B13D935 #?CD?==?><I(5@?BD544F5BC5(513D9?>C *85=?CD 3?==?>14F5BC5B513D9?>C D81D?33EBB541D189785B 9>3945>356?B-"$*D81>@<1352?9>D853?>DB?<<54CDE495C1B5@B5C5>D54 9>*12<5  Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies Placebo

DEXILANT 60 mg (N=2218) %  



DEXILANT Total (N=2621) %  



Lansoprazole 30 mg (N=1363) % 

 

Adverse Reaction 91BB851 24?=9>1<&19> $1EC51

(N=896) %

 



DEXILANT 30 mg (N=455) %   

+@@5B(5C@9B1D?BI Tract Infection











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4F5BC5(513D9?>C(5CE<D9>79>9C3?>D9>E1D9?> >3?>DB?<<543<9>931<CDE495CD85=?CD3?==?>14F5BC5B513D9?><5149>7D? 49C3?>D9>E1D9?>6B?=-"$*D85B1@IG1C491BB851  %D85B4F5BC5(513D9?>C %D85B14F5BC5B513D9?>CD81DG5B5B5@?BD549>3?>DB?<<54CDE495C1D1>9>3945>35 ?6<5CCD81> 1B5<9CD5425<?G2I2?4ICICD5=Blood and Lymphatic System Disorders:1>5=91<I=@8145>?@1D8ICardiac Disorders: 1>79>1 1BB8ID8=912B14I31B491385CD@19>545=1=I?31B491<9>61B3D9?>@1<@9D1D9?> D138I31B491Ear and Labyrinth Disorders: 51B@19>D9>>9DECF5BD97?Endocrine Disorders: 7?9D5BEye Disorders: 5I59BB9D1D9?>5I5CG5<<9>7Gastrointestinal Disorders: 124?=9>1<49C3?=6?BD124?=9>1<D5>45B>5CC12>?B=1<6535C 1>1<49C3?=6?BD1BB5DDC5C?@817EC25J?1B2?G5<C?E>4C12>?B=1< 2B51D8?4?B3?<9D9C=93B?C3?@933?<?>93@?<I@3?>CD9@1D9?>4BI=?ED8 4E?45>9D9C4IC@5@C914IC@817915>D5B9D9C5BE3D1D9?>5C?@8179D9C71CDB93 @?<I@71CDB9D9C71CDB?5>D5B9D9C71CDB?9>D5CD9>1<49C?B45BC71CDB?9>D5CD9>1< 8I@5B=?D9<9DI49C?B45BC(E<35BC1>4@5B6?B1D9?>85=1D5=5C9C 85=1D?385J9185=?BB8?94C9=@19B5471CDB935=@DI9>79BB9D12<52?G5< CI>4B?=5=E3ECCD??<C>1EC511>4F?=9D9>7?B1<=E3?C1<2<9CD5B9>7 @19>6E<456531D9?>@B?3D9D9C@1B5CD85C91?B1<B53D1<85=?BB8175General Disorders and Administration Site Conditions: 14F5BC54BE7B513D9?>1CD85>91 385CD@19>389<<C655<9>712>?B=1<9>6<1==1D9?>=E3?C1<9>6<1==1D9?> >?4E<5@19>@IB5H91Hepatobiliary Disorders: 29<91BI3?<9338?<5<9D891C9C 85@1D?=571<IImmune System Disorders: 8I@5BC5>C9D9F9DIInfections and Infestations: 31>49419>653D9?>C9>6<E5>J1>1C?@81BI>79D9C?B1<85B@5C @81BI>79D9CC9>EC9D9CF9B1<9>653D9?>FE<F?F179>1<9>653D9?>Injury, Poisoning and Procedural Complications: 61<<C6B13DEB5C:?9>DC@B19>C?F5B4?C5

@B?354EB1<@19>CE>2EB>Laboratory Investigations: "&9>3B51C54"* 9>3B51C54)*9>3B51C5429<9BE29>453B51C54 9>3B51C542<??43B51D9>9>5 9>3B51C542<??471CDB9>9>3B51C542<??47<E3?C59>3B51C542<??4@?D1CC9E= 9>3B51C54<9F5B6E>3D9?>D5CD12>?B=1<@<1D5<5D3?E>D453B51C54D?D1<@B?D59> 9>3B51C54G5978D9>3B51C5Metabolism and Nutrition Disorders: 1@@5D9D5 381>75C8I@5B31<35=918I@?;1<5=91 Musculoskeletal and Connective Tissue Disorders: 1BD8B1<7911BD8B9D9C=EC3<53B1=@C=EC3E<?C;5<5D1<@19> =I1<791 Nervous System Disorders: 1<D5B54D1CD53?>FE<C9?>49JJ9>5CC 85141385C=97B19>5=5=?BI9=@19B=5>D@1B5CD85C91@CI38?=?D?B 8I@5B13D9F9DIDB5=?BDB975=9>1<>5EB1<791Psychiatric Disorders: 12>?B=1< 4B51=C1>H95DI45@B5CC9?>9>C?=>91<9294?381>75CRenal and Urinary Disorders: 4ICEB91=93DEB9D9?>EB75>3IReproductive System and Breast Disorders: 4IC=5>?BB8514IC@1B5E>91=5>?BB81791=5>CDBE1<49C?B45B; Respiratory, Thoracic and Mediastinal Disorders: 1C@9B1D9?>1CD8=1 2B?>389D9C3?E784IC@>?518933E@C8I@5BF5>D9<1D9?>B5C@9B1D?BIDB13D 3?>75CD9?>C?B5D8B?1D Skin and Subcutaneous Tissue Disorders: 13>5 45B=1D9D9C5BID85=1@BEB9D9CB1C8C;9><5C9?>EBD931B91 Vascular Disorders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ostmarketing Experience 4F5BC5B513D9?>C81F5255>945>D969544EB9>7@?CD1@@B?F1<?6-"$* CD85C5B513D9?>C1B5B5@?BD54F?<E>D1B9<I6B?=1@?@E<1D9?>?6E>35BD19> C9J59D9C>?D1<G1IC@?CC92<5D?B5<912<I5CD9=1D5D859B6B5AE5>3I?B5CD12<9C8 131EC1<B5<1D9?>C89@D?4BE75H@?CEB5 Eye Disorders: 2<EBB54F9C9?> Gastrointestinal Disorders: ?B1<545=1 General Disorders and Administration Site Conditions: 61391<545=1 Immune System Disorders: 1>1@8I<13D93C8?3;B5AE9B9>75=5B75>3I 9>D5BF5>D9?>)D5F5>C ?8>C?>CCI>4B?=5D?H935@945B=1<>53B?<IC9C C?=561D1< Respiratory, Thoracic and Mediastinal Disorders: @81BI>751<545=1D8B?1D D978D>5CC Skin and Subcutaneous Tissue Disorders: 75>5B1<9J54B1C8<5E3?3ID?3<1CD93 F1C3E<9D9C DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics -"$*31EC5C9>8929D9?>?671CDB931394C53B5D9?>-"$*9C<9;5<I D?CE2CD1>D91<<I453B51C5D85CICD5=933?>35>DB1D9?>C?6D85,@B?D51C5 9>8929D?B1D1J1>1F9BG89389C45@5>45>DE@?>D85@B5C5>35?671CDB931394 6?B12C?B@D9?>1>4=1IB5CE<D9>1<?CC?6D85B1@5ED9356653D?61D1J1>1F9B 1>4D8545F5<?@=5>D?6,B5C9CD1>35*85B56?B5-"$*C8?E<4>?D25 3?14=9>9CD5B54G9D81D1J1>1F9B D9CD85?B5D931<<I@?CC92<5D81D-"$*=1I9>D5B65B5G9D8D8512C?B@D9?> ?6 ?D85B 4BE7C G85B5 71CDB93 @ 9C 1> 9=@?BD1>D 45D5B=9>1>D ?6 ?B1< 29?1F19<129<9DI571=@939<<9>5CD5BC497?H9>9B?>C1<DC;5D?3?>1J?<5 Warfarin ?14=9>9CDB1D9?>?6-"$* =71>4G1B61B9> =7494>?D16653D D85@81B=13?;9>5D93C?6G1B61B9>?B$(?G5F5BD85B581F5255>B5@?BDC ?69>3B51C54$(1>4@B?D8B?=29>D9=59>@1D95>DCB5359F9>7&&C1>4 G1B61B9>3?>3?=9D1>D<I>3B51C5C9>$(1>4@B?D8B?=29>D9=5=1I<514 D?12>?B=1<2<5549>71>45F5>451D8&1D95>DCDB51D54G9D8-"$*1>4 G1B61B9>3?>3?=9D1>D<I=1I>554D?25=?>9D?B546?B9>3B51C5C9>$(1>4 @B?D8B?=29>D9=5 Tacrolimus ?>3?=9D1>D14=9>9CDB1D9?>?645H<1>C?@B1J?<51>4D13B?<9=EC=1I9>3B51C5 G8?<52<??4<5F5<C?6D13B?<9=EC5C@5391<<I9>DB1>C@<1>D@1D95>DCG8?1B5 9>D5B=5491D5?B@??B=5D12?<9J5BC?6.&   USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects &B57>1>3I1D57?BI*85B51B5>?145AE1D51>4G5<<3?>DB?<<54CDE495C G9D845H<1>C?@B1J?<59>@B57>1>DG?=5>*85B5G5B5>?14F5BC565D1<56653DC 9>1>9=1<B5@B?4E3D9?>CDE495C?645H<1>C?@B1J?<59>B1229DC531EC51>9=1< B5@B?4E3D9?>CDE495C1B5>?D1<G1IC@B5493D9F5?68E=1>B5C@?>C5-"$* C8?E<425EC544EB9>7@B57>1>3I?><I963<51B<I>55454


A reproduction study conducted in rabbits at oral dexlansoprazole doses up to 30 mg per kg per day (approximately 9-fold the maximum recommended human dexlansoprazole dose (60 mg) revealed no evidence of harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole. Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Carcinogenesis, Mutagenesis, Impairment of Fertility], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established. Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole. Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C). OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive. CLINICAL PHARMACOLOGY Pharmacodynamics Antisecretory Activity The effects of DEXILANT 60 mg (n=20) or lansoprazole 30 mg (n=23) once daily for five days on 24-hour intragastric pH were assessed in healthy subjects in a multiple-dose crossover study. Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment. Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months. During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology]. Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day. Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology]. In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended lansoprazole human dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended lansoprazole human dose based on BSA). The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended lansoprazole human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats. PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in the full prescribing information] Information for Patients Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued. To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following: DEXILANT is available as a delayed release capsule. DEXILANT may be taken without regard to food. DEXILANT should be swallowed whole.  K <D5B>1D9F5<I-"$*31@CE<5C31>25?@5>541>414=9>9CD5B541C follows: - Open capsule; - Sprinkle intact granules on one tablespoon of applesauce; - Swallow immediately. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 5,045,321; 5,093,132; 5,433,959; 6,462,058; 6,664,276; 6,939,971; and 7,285,668. DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners. ©2009, 2010 Takeda Pharmaceuticals America, Inc. For more detailed information, see the full prescribing information for DEXILANT or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327. KAP0110 R6-Brf; March 2010 L-LPD-0310-2

Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANTâ&#x201E;˘, KAPIDEXâ&#x201E;˘ (dexlansoprazole), and Dual Delayed Releaseâ&#x201E;˘ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc. Š2010 Takeda Pharmaceuticals North America, Inc. LPD-01139 6/10 Printed in U.S.A.


BUSINESS

Expect the Unexpected: A Role for Behavioral Economics in Understanding the Impact of CostSharing on Emergency Department Utilization Albert Tzeel, MD, MHSA; Jack Brown, BA Stakeholder Perspective, page 255

Background: As employers and payers address increasing healthcare costs, they resort to the tenets of classical economics: if one increases the price for a service (defined as an individual’s cost-sharing), then that individual’s demand for services should decrease. This, however, may not necessarily be true, and raises the question of whether increased costsharing for emergency department services will lead to decreased utilization of those services as would be expected in classical economics. Objective: To assess the effect of emergency department cost-sharing on patient utilization of emergency department services. Method: In 2002, we retrospectively reviewed 2001 claims and identified 797 members who have had at least 2 nonemergent visits to the emergency department. This cohort was comprised of members with high emergency department utilization patterns who also had potentially differing emergency department copayment changes from one health insurance plan year to the next. Participants had to be covered by Humana for a minimum of 12 consecutive months. Of the original cohort, 415 remained covered by Humana after the end of the first year, 322 remained covered after the second year, and 194 after the end of the third year. After completions of three 12-month blocks of time with appropriate claims run out, we assessed changes in the cohort’s emergency department encounters from the previous year to the current year relative to emergency department copayment changes, using matched pairs t-test. Results: Surprisingly, in the first 12 months, reductions in emergency department copayments resulted in decreases in patient utilization (–58.3% change, P <.007), and increases in emergency department copayment resulted in an increased utilization (1096.0% change, P <.001). This unexpected trend continued in the second and third periods. Overall, in our cohort, increases in emergency department copayments were significantly associated with increased emergency department encounters by different individuals in each of the 3 study periods. In contrast, in the 2 groups with no increases in emergency department copayments, utilization of these services decreased or remained flat. Conclusion: When assessing the need for emergency department services, many factors besides cost play a role in choosing to obtain emergency department care, including individual assessments of the probability of a given illness and the financial or temporal implications for the care sought in terms of “gains” or “losses” relative to a reference point. Behavioral economics can therefore play a role in understanding why healthcare consumers behave as they do. The implications of behavioral economics need to be factored in when considering a healthcare benefit design.

Albert Tzeel

Am Health Drug Benefits. 2010;3(4):248-256. www.AHDBonline.com Disclosures are at end of text

Dr Tzeel is Market Medical Officer, and Mr Brown is Financial Analyst, Humana, Inc, Great Lakes Region, Milwaukee, WI.

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We economists always think that waving money under people’s noses will make them behave according to some theoretical script. But we’ve tried that with healthcare for decades and it hasn’t worked. Healthcare isn’t just about financial incentives; it’s also about anxiety, fear, habit, guan-xi—a Chinese word that, loosely translated, means “family or business ties”—and professional pride. We’ve neglected to study the impact that human behavior has on the system, and I don’t think we can do much to improve it unless we address the noneconomic dimensions of healthcare issues.1 —Uwe Reinhardt, PhD

E

xpect the unexpected, or you won’t find it.”2 This admonition, offered by the Greek Heraclitus more than 2500 years ago, still rings true today. Employer-sponsored healthcare coverage continues to subscribe to classical economics with respect to demand and price. Many employers providing insurance coverage believe that if they shift costs to those employees who consume medical care by increasing copayments or coinsurance, then those individuals will respond to a new price point for medical services by curbing their own demand for healthcare.3-7 Choices on whether to utilize healthcare can be made in a rational context when one does not have the pressure of a limited time horizon in which to make the decision. In an emergency situation, however, seconds count in the choice to seek care: whether a true emergency exists lies within the discretion and perception of the consumer making that decision. O’Grady and colleagues showed that cost-shifting has an impact on emergency department (ED) use.8 Selby and colleagues showed that after introducing a copayment ranging from $25 to $35 for using the ED, utilization decreased significantly, with the largest decreases in lesser severity of illness.9 Yet, even with such cost-shifting, ED utilization continues to increase.10-12 If cost-shifting by itself cannot control increasing ED utilization, what else could be playing a role? Do people behave differently from what is predicted under classical economics? And, if so, why? Are people irrational when seeking ED services? Given the premise that people are irrational decision makers when it comes to ED utilization, and as part of a broader educational initiative to decrease ED utilization in southeastern Wisconsin, we at Humana wanted to confirm that increased cost-sharing (ie, ED copayment increases) for ED services indeed resulted in decreases in ED utilization.

Methods Data Patterns Early in 2002, we reviewed 2001 data for Humana Milwaukee HMO ED utilization. Through this review we identified a cohort of 797 unique members for a selfcare promotion. Each of these individuals had at least 2

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KEY POINTS ➤

In designing health insurance coverage, many employers believe that shifting some of the cost of medical care to employees will reduce demand for such care and lower utilization. However, some studies have suggested that emergency department utilization continues to rise, regardless of any copayment considerations. This raises the question about any potential association between cost-shifting and emergency department utilization. An analysis of the association between costsharing and emergency care utilization unexpectedly showed that increasing emergency department copayments was significantly associated with increased, rather than decreased, emergency department utilization. In contrast, among employees with no increase in emergency department copayments, utilization decreased or remained flat. The authors suggest that there is a distinct role for behavioral economics when attempting to control healthcare costs. Contrary to classical economic theory, people often do not make rational decisions when it comes to their health. To affect behavior change in covered populations, employers and payers must understand how people view medical risk, especially potentially emergency risk, unlike other risks, and incorporate behavioral economics in their benefit design decisions.

nonemergent ED visits that were amenable to self-care, according to informational books we provided to all of them,13,14 as part of our study. Many in the cohort had ED copayment adjustments for a given benefit year through their employer-sponsored health insurance instituted to mitigate premium cost increases. We followed this cohort for 3 consecutive 12-month blocks. At the end of each 12-month period, in addition to assorted demographic data, we collected information on ED utilization and on benefit changes (including ED

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Table 1 General Demographic Data for Available Cohort after Second Year Characteristic

Total (N = 322)

Children (N = 50)

Adults (N = 272)

Male (N = 113)

Female (N = 209)

Average age, yr (SD)

32.6 (18.1)

5.0 (3.7)

37.7 (14.9)

31.7 (20.0)

33.1 (17.1)

Males, N (%)

113 (35.1)

21 (42.0)

92 (33.8)

113 (100)

0 (0.0)

SD indicates standard deviation.

copayments) for members who remained with Humana throughout that entire 12-month period. Collecting this information for consecutive years allowed for direct comparison with each preceding period. Data analysis at the conclusion of each time period showed that of the original 797 participants, 415 (52.1%) remained covered by Humana after the first year, 322 (40.4%) remained covered after the second year, and 194 (24.3%) remained Humana members when data were collected after the third year.

Statistical Analysis We realize that observational analysis could not substitute for a well-designed study, but we were compelled to examine the findings statistically to see if the data showed something of potential interest and, if it did, to proffer a possible explanation. Statistical analyses were performed using Microsoft Excel 97 for Windows and XLSTAT, a Microsoft Excel add-in package.15 We assessed changes in the cohort’s ED encounters from the previous year to the current one relative to ED copayment changes, using matched pairs t-test. Results Demographics As noted, study participants had to remain active Humana members for an entire 12-month block of time. Because the study period overlapped calendar years, we lost some members at the time of their employer group’s renewal (especially on January 1). Table 1 outlines the demographic data for 322 members who were active through the first 2 years, categorized by age and by sex. Changes in ED Utilization Associated with Copayment Adjustments In reviewing the data, we found a specific pattern in each year: the groups who had an ED copayment increase had an increased number of ED visits (Table 2). As shown in Table 2, in the first year, if the ED copayment increased in a given period (relative to the 12-month period before it), ED utilization actually increased by a factor of nearly 12. Given the low rate of ED utilization

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in the group with the increasing ED copayment in the preceding period, this finding might have simply been a case of regression to the mean. But what if we find similar patterns during the following 2 years? In the second year, a similar pattern emerged. For the 2 groups whose ED copayment did not increase during this period, decreases in ED utilization occurred. However, in the third group, whose ED copayment increased during the period, we observed a significant (P = .022) and rather large increase in ED utilization— that is, an average increase of nearly 1 full ED visit for each person in that group, for a total of 46 ED visits. A comparable pattern continued during the third year. In the groups whose ED copayment did not increase, we found either a small, nonsignificant increase or a significant decrease in ED utilization. The remaining group continued to show that when the ED copayment increased in a given period, a noteworthy, albeit not significant ( = .05, P = .09) increase in ED utilization occurred. All 3 time frames showed the same counterintuitive pattern: ED copayment increases were associated with increased ED utilization. Although there were no individuals who had ED copayment increases in 2 consecutive periods during any of the 3 intervals, we observed consistency among unique individuals’ responses to ED copayment increases.

Discussion Significant Implications for Employers Our original presumption was that individuals respond to having their ED copayment increased by decreasing their ED utilization, according to classical economics. But that is not what our data revealed to us year after year. Why? This inconsistency has tremendous implications for employer groups that provide health benefits to their employees. A given employer may choose to rely on the tenets of classical economics (ie, increasing ED copayments to promote decreased ED utilization). Yet, without a general understanding of key ideas from behavioral economics, that employer may not necessarily achieve the desired results.

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Table 2 Changes in Average ED Visits in 3 Years, by ED Copayment Changes

Year (period)

ED visits per Patients, person at onset N of period

First 12 mo Group 2: No copay changes

ED visits per person at end of period

Change in ED visits per person

Change, %

P

304

0.80

2.41

1.61

201.3

<.001

Group 2: Copay decreased

8

3.00

1.25

–1.75

–58.3

<.007

Group 3: Copay increased

103

0.23

2.75

2.52

1096.0

<.001

All participants, period 1

415

0.70

2.47

1.77

252.9

<.001

Second 12 mo Group 1: No copay changes

226

0.98

0.91

–0.07

–7.9

NS

Group 2: Copay decreased

47

1.77

0.81

–0.96

–54.2

<.001

Group 3: Copay increased

49

0.92

1.86

0.94

102.2

.022

All participants, period 2

322

1.08

1.04

–0.04

–3.7

NS

Third 12 mo Group 1: No copay changes

176

0.85

0.97

0.12

14.1

NS

Group 2: Copay decreased

11

2.09

0.36

1.73

–82.8

<.003

Group 3: Copay increased

7

0.57

1.29

0.72

126.3

NS

All participants, period 3

194

0.91

0.94

0.03

3.3

NS

ED indicates emergency department; NS, not significant ( = .05).

Several behavioral concepts may influence this finding and promote the association that our results show for ED utilization.

Prospect Theory: Behavioral Economics Explains Emergency Care Utilization A review of our results showed an association in which, on average, if the ED copayment increased, then ED utilization increased as well. We speculate that there is a legitimate reason for this finding, and we defer on this to behavioral economics, specifically to “prospect theory.” This theory arose from experimental proof that people repeatedly violate the principles of expected utility theory when making particular decisions. Prospect theory was first proposed by Kahneman and Tversky in 1979.16 Although a formal discussion of prospect theory is beyond the scope of this article, 2 of its key elements are pertinent to this discussion. First, according to prospect theory, a person multiplies his or her distinct expected utility by a subjective probability. However, individuals tend to distort those probabilities by overweighting low-probability events and underweighting high-probability events (eg, if a child only has the symptoms of fever, neck pain, and difficulty swallowing, the more likely probability of

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streptococcal pharyngitis may be underweighted, whereas the less likely probability of bacterial meningitis may be overweighted). This finding would imply that the probability of a particular healthcare event (eg, vomiting in gastroenteritis, generalized fever, ear pain) being extremely serious or even life-threatening would most likely be exaggerated by the individual or the caregiver. Burns and colleagues corroborate that the overweighting of the high-risk, low-probability event tends to promote a utilization profile of increased consumption.17 Second, individuals view these expected utilities as changes from a reference point.18 With respect to “changes from a reference point,” Kahneman and Tversky propose that individuals make decisions as if they had a “value” function for gains and losses (Figure).16 The horizontal axis in the Figure reflects either monetary gain (to the right) or monetary loss (to the left) relative to one’s reference point (ie, the origin). The value function shows that individuals perceive losses as more significant than equivalent gains: the value function increases the slope as one moves to the right, until the origin, and decreases the slope as one moves to the right, away from the origin. Baron describes this Figure as meaning “that, for sim-

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Figure Prospect Theory Value Function 4

2 Risk-averse profile

0 –8

–6

–4

–2

Change in utility/value

–10

0

2

4

6

8

10

–2 Value: “gains” vs “losses”

–4

Risk-seeking profile

–6

–8

–10 Change from the reference point Adapted from Kahneman D, et al. Econometrica. 1979;47:263-292.

ple gambles, subjects tend to avoid risks in the domain of gains and tend to seek risks in the domain of losses where gains and losses are defined in terms of expected monetary change from their reference point.”18 An increased ED copayment, relative to the previous copayment, would in theory tend to make an individual “risk-seeking,” because a potential loss, coupled with an exaggerated probability for a potentially adverse event, drives ED utilization. Perceived value versus cost. In other words, there is more perceived value (because of the higher ED copayment/“loss”) for that ED visit than existed before the copayment change. In addition, from a cognitive standpoint, the individual can rationalize perceived value in the decision to seek services despite a greater personal financial cost. As early as 1969, Doob and colleagues noted that according to cognitive dissonance theory, the more something costs, the more people find value in it, and the more they can feel internal pressure to buy it.19 Prospect theory’s role may perhaps be better viewed

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through the following example. Two families each have a young child who complains of a nonspecific sore throat on a Sunday afternoon. Each family is concerned that the child has strep throat, which may develop into rheumatic fever or worse. For family A, the most recent insurance changes resulted in a $50 decrease in ED copayment (from $100 to $50). For family B, the most recent insurance changes have resulted in a $50 increase in ED copayment (from $50 to $100). Family A may view this event as a choice between 2 alternatives—going to the ED removes a certain monetary gain (compared with last year) for diagnosing a potentially low-probability event—estimated in the past as a probability of 11% for strep throat for all ED visits in which the chief complaint is sore throat, and as 15% to 36% in the pediatric population.20,21 Family B may also view this event as a choice between 2 alternatives— going to the ED may yield a greater monetary loss (compared with last year), but the cost of not going may be even higher—the financial cost and/or disability

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incurred by the child whose strep throat develops into something worse, such as acute rheumatic fever in 0.01% of all childhood throat infections.20,21 For this example, we use a cost of approximately $25,000 for each case of acute rheumatic fever (adapted from Webb and others).22 From an expected value standpoint, family A now views the decision as a choice between a certain “gain” of $50 versus only a possible “gain” of $2.50 (0.0001 ⳯ $25,000). The $2.50 is considered the expected financial value for diagnosing 1 case of acute rheumatic fever; it represents the “cost” of removing uncertainty in diagnosis. Certain versus possible gain. This value in information gain does not include additional potential costs of the disability or of the financial impact as a result of missed time off from work. Family A is risk-averse and would wait to see if the symptoms worsen before seeking ED care, because a sure gain of $50 is preferable to a possible gain of only $2.50. Family B, however, views the choice as one of a sure loss of $50 compared with only a risk of a loss of $2.50. For them, this choice is easy—taking a chance on losing only $2.50 is significantly better than losing $50 for sure. Studies also show that anything constraining one’s sense of an unlimited future shifts motivations and priorities away from a future orientation toward a present orientation.23 Family B, then, is “risk-seeking” and therefore seeks ED care for their child. If urgent care were substituted for ED care, neither family in our example would change its decision unless the urgent care copay/personal cost was less than $2.50. Even rapid-care clinics found in most national drugstore chains charge more than that for a typical visit. In fact, our data showed that the greater the dollar differential between ED visit copays and copays at alternate sites of care (eg, office visits or urgent care), the more likely the member was to go to the ED.

The Psychology of Time: Behavioral Economics Explains Non–Emergency Care Utilization Another way of looking at ED-seeking behavior that would be consistent with our data is to apply the “psychology of time.” For the purposes of explaining the patterns we saw earlier, the economic curves of demand versus price perform adequately for most conditions in which the majority of the “cost” to the individual is time, because the reference value for the ED copayment did not change. Tucker and Davison suggest that, “When monetary costs to consumers are minimal or nonexistent, time costs function to reduce and regulate demand….Once time is ‘spent,’ it cannot be recovered as one might recover a monetary loss or replace a tangible good.”24

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Time, then, becomes the “currency of choice” when money is not a factor. This may explain why, when an ED copayment change was not the key issue (ie, it either had not changed or had decreased), individuals tended to consider time their “currency” and might have chosen to use self-care strategies over seeking ED care. In fact, probably because of time’s lack of fungibility, studies show that in hypothetical choice situations, individuals tend to be either more risk-averse or risk-neutral about potential time losses, but they tend to be more risk-seeking with respect to monetary losses.25 Although Leclerc and colleagues based their conclusions on hypothetical choices,25 these findings have tremendous implications for employer groups who provide health benefits. A given employer may choose to rely on the tenets of classical economics (ie, increasing ED copayments to promote decreased ED utilization, or promotion of a wider gap between ED copayments and office visit copayments to drive utilization toward the physician’s office as an ED substitute). Yet, without a general understanding of, as well as an incorporation of, some basic ideas from behavioral economics, those employer groups may not necessarily achieve the results they desire. Phelps once asked if anybody behaved as a “rational economic actor” in the healthcare market.26 The answer comes from Heraclitus’ quote at the beginning of this present article, “expect the unexpected, or you won’t find it.”2

Limitations As with any study, there are potential limitations to interpreting our findings. First, we did not collect data on certain specific characteristics of the cohort. Oftentimes, these traits may influence patient behavior and may help to explain why ED encounter rates varied at the onset of our review period and in response to changing ED copayments. It is known, for example, that patient characteristics, such as socioeconomic status and chronicity of illness, can impact ED utilization.27,28 However, all the individuals for whom we reviewed data were insured and therefore relatively insulated from the actual cost of the ED visit (outside of an expected copayment). We would therefore expect that the results would tend to be biased toward an increased ED copayment yielding decreased ED utilization and not the other way around (assuming the effect of classical economics). Second, a selection bias may also be noted, because the cohort from which all members were drawn came from an initial pool of “nonemergent ED utilizers.” Such a cohort may prejudice the results.29 However, just as we see a potential association in our data between ED utilization and increasing ED copayments, the door now

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opens for assessing other areas of potential individualdriven overutilization with increased cost-sharing (eg, specialist office visits). Third, we cannot state with complete certainty that we did not observe a simple regression to the mean. Regression to the mean effects, however, can take several years to manifest, and it is therefore possible that this cohort could see a return to baseline ED utilization over the next several years.30

Conclusion Analyzing how individuals reconcile their cost for emergency care relative to obtaining emergent services can lead to the discovery of pertinent facts that can have some bearing on the control of healthcare costs. First and foremost, there is a distinct role for behavioral economics within the sphere of controlling healthcare costs. To achieve behavior changes in their covered populations, employers and payers must understand how people view medical risk, how they make decisions regarding financial tradeoffs, and how information alters these perceptions. Attempting to influence one area, such as personal financial responsibility, without fully understanding the systemic implications, can be shortsighted. Second, although classical economic theory still exerts the most influence in health economics, to affect behavior change one must realize that people do not tend to be rational actors when it comes to their health. After taking account of the potential impact of behavioral economics in ED or other medical care utilization, further evaluation and analysis are certainly warranted to better understand how individuals choose to respond to increasing financial responsibility in the context of overall medical care. If employers and payers want to contain increasing ED (or potentially other medical care) utilization, they will need to consider the implications of behavioral economics in their benefit design and programmatic decisions. Acknowledgment Financial support for this article was provided by Humana Insurance Corporation, a subsidiary of Humana Inc, Louisville, Kentucky (doing business in Wisconsin). The funding agreement insured the authors’ independence in designing our pilot study, interpreting the data, and writing the article. Disclosure Statement Dr Tzeel and Mr Brown did not report any potential conflict of interest.

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References 1. McCue MT. Whither sociology? Princeton economist Uwe Reinhardt says healthcare needs to account for human behavior, not just dollar signs. Managed Healthcare Executive. September 1, 2009. http://managedhealthcareexecutive.modernmedicine. com/mhe/Executive+Profile/Whither-sociology/ArticleStandard/Article/ detail/121923?searchString=whither%20sociology. Accessed May 1, 2010. 2. Von Oech R. Expect the Unexpected (Or You Won’t Find It). San Francisco, CA: Berrett-Koehler; 2002. 3. Huskamp HA, Deverka PA, Epstein AM, et al. The effect of incentive-based formularies on prescription-drug utilization and spending. N Engl J Med. 2003;349:2224-2232. 4. Piette JD, Heisler M, Wagner TH. Problems paying out-of-pocket medication costs among older adults with diabetes. Diabetes Care. 2004;27:384-391. 5. Lohr KN, Brook RH, Kamberg CJ, et al. Use of medical care in the Rand Health Insurance Experiment: diagnosis- and service-specific analyses in a randomized controlled trial. Med Care. 1986;24(suppl 9):S1-S87. 6. Cherkin DC, Grothaus L, Wagner EH. The effect of office visit copayments on preventive care services in an HMO. Inquiry. 1990;27:24-38. 7. Simon GE, VonKorff M, Durham ML. Predictors of outpatient mental health utilization by primary care patients in a health maintenance organization. Am J Psychiatry. 1994;151:908-913. 8. O’Grady KF, Manning WG, Newhouse JP, Brook RH. The impact of cost sharing on emergency department use. N Engl J Med. 1985;313:484-490. 9. Selby JV, Fireman BH, Swain BE. Effect of a copayment on use of the emergency department in a health maintenance organization. N Engl J Med. 1996;334:635-641. 10. Young GP, Wagner MB, Kellerman AL, et al. Ambulatory visits to hospital emergency departments. Patterns and reasons for use. 24 hours in the ED study group. JAMA. 1996;276:460-465. 11. Tufts Managed Care Institute. Emergency department utilization: trends and management. November-December 2001. www.thci.org/downloads/topic1112_01.pdf. Accessed July 7, 2010. 12. US Government Accountability Office. Report to the Chairman, Committee on Finance, US Senate. Hospital emergency departments: crowding continues to occur, and some patients wait longer than recommended time frames. GAO 09-347. April 2009. www.gao.gov/new.items/d09347.pdf. Accessed June 28, 2010. 13. Pantell RH, Fries JF, Vickery DM. Taking Care of Your Child: A Parent’s Guide to Complete Medical Care. Reading, MA: Perseus Books; 1999. 14. Vickery DM, Fries JF. Take Care of Yourself. Cambridge, MA: Perseus Books; 2001. 15. XLSTAT Statistical Software. Paris, France: Addinsoft, 1995-2004. 16. Kahneman D, Tversky A. Prospect theory: an analysis of choice under risk. Econometrica. 1979;47:263-292. 17. Burns Z, Chiu A, Wu G. Overweighting of small probabilities. Prepared for Wiley Encyclopedia of Operations Research and Management Science. March 15, 2010. http://faculty.chicagobooth.edu/george.wu/research/papers/burns%20chiu%20 wu%202010%20Overweighting%20of%20Small%20Probabilities.pdf. Accessed July 7, 2010. 18. Baron J. Thinking and Deciding. New York, NY: Cambridge University Press; 2000:268. 19. Doob AN, Carlsmith JM, Freedman JL, et al. Effect of initial selling price on subsequent sales. J Pers Soc Psychol. 1969;11:345-350. 20. Kaufman A, Murray D, Starita L, Brickner PW. Streptococcal sore throat followup program in a hospital clinic, New York City. Public Health Rep. 1975;90:369-372. 21. Linder JA, Bates DW, Lee GM, Finkelstein JA. Antibiotic treatment of children with sore throat. JAMA. 2005;294:2315-2322. 22. Webb KH. Does culture confirmation of high-sensitivity rapid streptococcal tests make sense? A medical decision analysis. Pediatrics. 1998;101:E2. 23. Zimbardo P, Boyd J. The Time Paradox. New York, NY: Free Press; 2008. 24. Tucker JA, Davison JW. Waiting to see the doctor: the role of time constraints in the utilization of health and behavioral health services. In: Bickel WK, Vuchinich RE, eds. Reframing Health Behavior Change with Behavioral Economics. Mahwah, NJ: Lawrence Erlbaum; 2000:219-264. 25. Leclerc F, Schmitt BH, Dube L. Waiting time and decision making: is time like money? J Consumer Res. 1995;22:110-119. 26. Phelps CE. Health Economics. NewYork, NY: HarperCollins; 1992. 27. Sun BC, Burstin HR, Brennan TA. Predictors and outcomes of frequent emergency department users. Acad Emerg Med. 2003;10:320-328. 28. Wong MD, Andersen R, Sherbourne CD, et al. Effects of cost sharing on care seeking and health status: results from the Medical Outcomes Study. Am J Public Health. 2001;91:1889-1894. 29. Zenner PA, Parke R, Mirkin DP, for Milliman. Insight into two analytical challenges for disease management. Milliman Research Report. April 2004. http://publications.milliman.com/research/health-rr/archive/pdfs/Two-AnalyticalChallenges-Disease-Management-RR04-01-04.pdf. Accessed August 11, 2004. 30. Johnson A. Measuring DM’s net effect is harder than you might think. Manag Care. 2003;12:28-32.

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STAKEHOLDER PERSPECTIVE

Medical Homelessness and Emergency Department Utilization: Economic and Moral Implications EMPLOYERS/PAYERS: The implications of behavioral economics may differ by medical condition and by geography. At PPG Industries, we wanted to verify the status of hospital admissions for acute coronary artery disease (CAD), in which the “concern” factor is self-evident in 29 of our geographically diverse, active working populations. We wanted to see the effect of copayment, coinsurance, or patient outof-pocket (OOP) contribution, and the availability of primary care inside and outside the worksite. This may have scientific and philosophical implications. We calculated the variance of acute CAD hospital admissions and emergency department (ED) visit rates per 1000 active employees, based on the presence or absence of (1) worksite wellness programs (high/low rank), (2) worksite occupational health professionals (ie, nurse) on staff, and (3) the availability of primary care physicians (PCPs) in the county where the worksite is located, according to the County Health Rankings.1 In our data set, PCP availability rate at the county level is significantly associated with a reduction in CAD and in ED visit (P <.05) and CAD acute admissions rates per 1000 active employees (P <.05). Having worksite wellness programs (high rank) is associated with 2.8-fold fewer acute CAD admissions but has no effect on CAD-related ED visit rates. Having a worksite occupational health nurse on staff is associated with 2.1-fold fewer acute CAD admissions but has no effect on ED visit rates. What is the role of patient copayment and coinsurance, namely, patient OOP contribution? As much as 48% of the variance in acute hospital admissions for CAD in 29 worksites is explained by 3 factors—worksite wellness (P <.01), worksite nurse (P <.05), and OOP cost (P <.05). These interactions are shown in the prediction profiler (Figure, Panel A, page 256). The practical implications vary by factor. CAD admissions could be halved from 8/1000 to 4/1000 employees by increasing the OOP from 10% to 30%, or by having a worksite nurse or high-rank wellness programs on site. If a nurse and such programs are combined, the hospital admission rate is practically reduced to zero. The implications of this are serious. Acting on the

behavioral economic ramifications would require a 30% penalty to “scare” half of the admissions away— an ethically questionable, and not plausible, solution. Instead, providing education and frontline professional assistance does provide a win-win situation, where patients seemingly are healthier and more informed decision makers. What if we enter in the model the PCP availability at the county level? This overrides the significance of having a worksite nurse, confirms the relevance of worksite wellness programs, while OOP costs lose statistical significance (Figure, Panel B, page 256). This leads us to hypothesize that health education and primary care do matter, and that occupational nurse support to some extent compensates for the lack of “outside” primary care by providing some medical home function, where that is faltering. These results lead us to the philosophical argument. In the present study by Dr Tzeel and Mr Brown, it is unclear whether reducing the ED copayment was associated with discretionary spending on primary care and/or health promotion and, therefore, shifted purchasing from ED visits to primary care and/or wellness. But even if that were not the case, establishing a medical home would have tangible and intangible effects on many factors and behaviors. In a fair system, a better incentive to counteract the overuse of ED rather than copayments would be to provide education and primary care. In sound bites, this may translate to, “If you want health benefits, find yourself a PCP first.” But the game is not neutral. If we could for a moment make room for evidence-based discussion instead of falling into our preferred prejudices, we would see that the system is such that primary care is penalized, because the provider requires time—good information is hard to organize, and there is no reimbursement for “medical intelligence” oversight. Medical homelessness is attracting increasing attention.2 Medical homelessness has been defined in a blog by Dr Bob as, “Not having access to a consistent familiar medical setting. Not having a care location where one is known, or where the medical information is accurate.”2 In a recent article on medical homelessness published in Health Affairs, Jack Colwill, MD, describes what happens to educated and willing people Continued

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STAKEHOLDER PERSPECTIVE (Continued) Figure Acute CAD Admission Rate per 1000 Active Employees (a multifactorial analysis)

15 8.265651 ±2.829813

Admissions/1000 acute CAD

Panel A (r 2 = 0.48; P <.001)

10 5 0 No

Yes

0

Nurse

1

High/low rank (1-0)

0

0.1

0.2 0.3 0.0833

0.4

Coinsurance + copay

2

15 6.789074 ±2.4413

Admissions/1000 acute CAD

Panel B (r = 0.45; P <.002)

10 5 0 50

100 150 130.93

200

PCP rate

0

1

High/low rank (1-0)

0

0.1

0.2 0.3 0.06185

0.4

Coinsurance + copay

CAD indicates coronary artery disease; PCP, primary care physician.

when they are left without primary care coordination in spite of a wealth of disjointed specialty care offerings.3 One can imagine what would happen to less educated people whose suffering may be needlessly magnified by their medical homelessness, despite their insurance access. Health insurance companies pretending to become the medical home may introduce an additional moral hazard, where what is best for the patient is not necessarily what is best for their shareholders, because doctors are paid by procedures, not by outcomes, and are included in networks based on price and not on patient needs. Dr Colwill describes how medical homes are discouraged by the payment system for physicians and by the nation’s shortage of PCPs. Given the current US healthcare system, many patients end up being their own medical home and the prime healthcare decision makers, albeit without appropriate information, knowledge, or assistance. Patients are reduced to consumers vulnerable to sales pitches rather than informed citizens. In many instances, rather than patient empowerment, this becomes a case of patient

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abandonment in a confusing, complex, fragmented and “dis”-integrated, when not adversarial, system. With primary care becoming increasingly scarce, notable primary care “deserts” are becoming evident in semirural areas. So, we welcome behavioral economics rather than just “deterministic” economics; however, we should wonder if people “buy” not only based on their emotions but also based on what is available in their territory. In primary care “deserts,” perhaps they accept what is for what is best, not knowing better, and end up “buying” emergency care because there is no other medical safe haven to fall back on. In that case, ED overuse is a symptom of medical homelessness, a deeper problem than mere access to health insurance. 1. County Health Rankings. 2010. http://www.countyhealthrankings.org/. Accessed July 26, 2010. 2. Dr Rob. The Problem of Medical Homelessness. Better Health Network. Opinion. Published September 2, 2009. http://getbetterhealth.com/the-problem-of-medical-homelessness/ 2009.09.29. Accessed July 27, 2010. 3. Colwill JM. Narrative matters. A case of ‘medical homelessness.’ Health Aff (Millwood). 2010;29:1067-1070.

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Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

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Partnership. People. Programs. Passion. The Flexibility You Need. The Integrity You Deserve.

| MANAGED MARKETS

Leaders in Business. Partners in Care. Visit Takeda on the Web at www.tpna.com.


CALL FOR PAPERS American Health & Drug Benefits offers an open forum for all healthcare stakeholders to exchange ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Evaluators, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers. Readers are invited to submit articles that aim at improving the quality of patient care and the US healthcare delivery system in general and of benefit design strategies in particular. All articles will undergo a blind peer review, and acceptance is based on that review.

Areas of high interest include: • Adherence Issues • Benefit Design • Comparative Effectiveness Analyses • Cost-Effectiveness Analyses • Decision-Making Tools

• Healthcare Trends • Health Economics • Health Plan Initiatives/Innovation • Health Information Technology • Innovation in Patient Care

• Off-label Use/Misuse • Original Research • Pharmacoeconomics • Reimbursement Strategies • Wellness Programs

Clinical topics of interest include: AGING/DEMENTIA—With the aging of the US population, there is a growing need for early implementation of outcome-based preventive and therapeutic strategies for older people. ALLERGIES—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Undertreatment and lack of adherence are common obstacles to patient management. ARTHRITIS—Musculoskeletal conditions, such as rheumatoid arthritis or osteoporosis, are on the increase, yet many patients are undiagnosed and untreated. Comparing new and available therapies is a key target for improving patient outcomes and reducing costs.

DIABETES, OBESITY—The increasing comorbid epidemics of these twin conditions mandates a thorough examination of best therapies, adherence issues, access, and prevention strategies. We invite articles that will address how to improve patient outcomes and best individualized patient care. GASTROINTESTINAL CONDITIONS— Recognizing GI conditions, such as hepatitis C, Crohn’s disease, or inflammatory bowel disorder, remains a challenge. INFECTIOUS DISEASES—The spread of common and emerging pathogens within the hospital and in the community remains a major concern requiring increased vigilance.

CANCER CARE—The growing focus on biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies, costmanagement, industry trends, and the biologic pipeline updates.

MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative effectiveness analyses, best practices, and reimbursement.

CARDIOVASCULAR DISEASE—Still a leading cause of morbidity and mortality among men and women. Original, outcome-based research on appropriate therapies, cost-comparisons, emerging prevention strategies, and comparative effectiveness of best practices will enhance readers’ decision-making.

PAIN MANAGEMENT—Chronic pain is associated with a slew of complicated medical disorders and an enormous economic burden, yet pain medications are still underused. Appropriate topics include best therapies, diagnosis, and clinicians’ anxiety about addiction issues and potential misuse.

Manuscripts should follow the Guidelines for Authors, available at www.AHDBonline.com For more information, call 732-992-1892

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HEALTHCARE REFORM

The New Accountable Care Organizations and Medicare Gain-Sharing Program Kip Piper, MA, FACHE

See also Interview with Dr McClellan, page 242

T

he accountable care organization (ACO) model is a new Medicare option for physicians, hospitals, and other providers to share in cost-savings. ACOs represent a dramatic change in Medicare policy and an opportunity to transform care delivery and provider alignment. The Medicare Gain-Sharing Program, part of the newly enacted healthcare reform law, creates the option for healthcare providers to form ACOs. Through an ACO, providers will take responsibility for quality and overall care of their Medicare patients. Medicare will then share with ACO providers the savings from improved quality, fewer hospitalizations, and the elimination of unnecessary costs.1,2 Starting in 2012, the ACO model will be a nationwide option in Medicare fee-for-service (FFS). In addition to shared savings, the ACO option includes freedom of choice for Medicare beneficiaries, national quality measures, evidence-based medicine, patient-centered care delivery, advanced care coordination, and information sharing. Because the ACO model is designed to break down old barriers for providers to work together to improve care and reduce medical costs, state Medicaid programs and private health insurers will likely join Medicare in supporting the ACO model. Medicare may give preference to ACOs that are participating in similar arrangements with Medicaid, private payers, and other third parties. Specifically, Section 1899 of the Social Security Act governs the new Medicare Shared Savings Program and the option for providers to form ACOs. The law was created by Section 3022 of the Patient Protection and Affordable Care Act of 2010 (PPACA). The Centers for Medicare & Medicaid Services (CMS) must implement the ACO option no later than January 1, 2012.

Option for Physicians, Hospitals, and Other Providers A variety of providers will be able to form an ACO: • Physicians and other professionals in group practices or a network of practices, such as a large medical group, an independent provider association, a network Kip Piper is a Senior Advisor to TogoRun, Sellers Dorsey, and Fleishman-Hillard. He is Health Policy Editor of American Health & Drug Benefits.

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of solo and small group physician practices, and, presumably, a community health center • Hospitals, physicians, physician groups, and other healthcare professionals via a joint venture or partnership arrangement • Hospitals that employ physicians and other healthcare professionals, such as an integrated hospital– physician system. Although the ACO is of keen interest to many hospital systems, an ACO need not include a hospital. Physician participation, however, is mandatory. CMS may permit other combinations or types of providers to form an ACO. Therefore, other possibilities include hospitals, physicians, and postacute providers, such as skilled nursing facilities and home health agencies. Providers are ineligible to participate in an ACO if they participate in a Medicare shared-savings demonstration, such as the Physician Group Practice Demonstration project or the new Independence at Home medical practice pilot.3

Medicare Beneficiary Assignment Assignment of Medicare beneficiaries to ACOs will be invisible to the beneficiary. Receiving services from an ACO will not affect Medicare coverage, benefit design, or a beneficiary’s freedom to choose physicians and other providers. Beneficiaries in Medicare Part A or Part B FFS programs may receive covered services from any Medicare provider, regardless of whether the provider is part of an ACO. Medicare beneficiaries who elect a Medicare Advantage plan are excluded from the ACO program. Minimum Requirements for ACOs An ACO must have a patient base of at least 5000 Medicare FFS beneficiaries, with participating providers agreeing to accept responsibility for overall patient care and quality for at least 3 years. In addition, to gain Medicare recognition as an ACO, the provider organization, partnership, or joint venture forming the ACO must meet the following minimum requirements: • A sufficient number of primary care physicians to serve the ACO’s patient population • A formal legal structure to receive and distribute shared savings

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• A leadership and management structure that includes clinical and administrative systems • Provide sufficient information on participating providers and their services to support beneficiary tracking and the determination of payments for shared savings • Defined processes and systems to: • Promote the practice of evidence-based medicine • Meet federal criteria for patient-centered care • Coordinate care • Report the necessary data for CMS to monitor and assess the ACO’s performance compared with federally defined clinical performance measures and cost benchmarks • Meet federal requirements for electronic prescribing and electronic health records • Participate in the existing Medicare Physician Quality Reporting Initiative, which is expanding under PPACA.4

Medicare Payment and Shared Savings Several payment methods are possible for ACOs. Under the primary method, ACO providers will be incentivized to improve clinical performance while controlling Medicare spending through, for example, reducing hospitalizations and eliminating unnecessary costs. Specifically, the ACO will receive additional payments from Medicare if (1) the ACO meets federal expectations for clinical performance, and (2) the ACO’s Medicare per-capita FFS costs are a certain percentage below a benchmark. CMS will set the clinical performance measures and the proportion of Medicare cost-savings that will be shared with ACOs. The law sets a methodology for setting a benchmark for predicted per-capita Part A and Part B costs. The law allows CMS to create other payment methods for ACOs, such as partial capitation or global fees. Risk-based payments may be limited to highly integrated health systems and ACOs capable of bearing risk. Learning from Other Gain-Sharing Projects Providers planning to form Medicare ACOs in 2012 may learn from the Brookings-Dartmouth ACO Collaborative, which currently has 5 private sector pilot ACOs operating in Arizona, California, Kentucky, and Virginia.5-7 Many of the requirements for Medicare ACOs are modeled on recommendations from the Brookings-Dartmouth ACO Collaborative.5-7 Meanwhile, PPACA extended the existing Medicare gain-sharing demonstration through September 2011 and created the Medicare Independence at Home program, a gain-sharing demonstration to test in-home

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primary care services for Medicare patients with multiple chronic conditions.8

Obstacles The ACO option and the accompanying sharedsavings model raise some potential legal obstacles that must be resolved before 2012. In the rules setting up the ACO option, the Secretary of the Department of Health and Human Services (HHS) will have to waive certain laws and rules that conflict with the gain sharing and provider alignment in ACOs. Specifically, aspects of longstanding federal antikickback and physician selfreferral laws must be waived for ACO-participating providers. HHS will need to waive the laws enough for the ACO model to work well but not to create unintended loopholes. The new law provides the HHS secretary with the necessary waiver authority. In addition, the ACO model may run afoul of federal or state antitrust laws. The Federal Trade Commission (FTC), which oversees and enforces antitrust laws regarding healthcare providers, will have to offer specific guidance. Like the FTC, state attorneys general will have to adapt their traditional antitrust thinking to the new business relationships contemplated under the ACO model. Next Steps ACOs offer the potential for a genuine win-win situation for physicians, hospitals, beneficiaries, and taxpayers. The precise details for forming and operating an ACO will be laid out in federal regulations. CMS is expected to release a proposed rule on ACOs in late 2010, with a final rule likely by mid-2011. Developing rules governing ACOs is one of many tasks facing the new CMS Administrator, Donald Berwick, MD. References 1. US Social Security Administration. Compilation of the Social Security laws: shared savings program. www.ssa.gov/OP_Home/ssact/title18/1899.htm. Accessed June 15, 2010. 2. Centers for Medicare & Medicaid Services, Office of Legislation. Medicare “accountable care organizations” Shared Savings Program—New Section 1899 of Title XVIII: Preliminary Questions and Answers. June 2010. www.cms.gov/Officeof Legislation/Downloads/AccountableCareOrganization.pdf. Accessed June 15, 2010. 3. Centers for Medicare & Medicaid Services, Office of Research, Development, and Information. Medicare Physician Group Practice Demonstration. August 2009. www.cms. gov/DemoProjectsEvalRpts/downloads/PGP_Fact_Sheet.pdf. Accessed June 15, 2010. 4. Centers for Medicare & Medicaid Services Medicare Physician Quality Reporting Initiative (PQRI). www.cms.gov/pqri/. Accessed June 15, 2010. 5. McClellan M, McKethan AN, Lewis JL, et al. A national strategy to put accountable care into practice. Health Aff (Millwood). 2010;29:982-990. 6. Fisher ES, Staiger DO, Bynum JP, Gottlieb DJ. Creating accountable care organizations: the extended hospital medical staff. Health Aff (Millwood). 2007;26:44-57. Epub 2006 Dec 5. 7. Engelberg Center for Health Care Reform at Brookings, Brookings Institution, and the Dartmouth Institute for Health Policy & Clinical Practice. Brookings-Dartmouth ACO Learning Network. 2010. www.acolearningnetwork.org. Accessed June 15, 2010. 8. The Patient Protection and Affordable Care Act, 42 USC 18001, §1866D of federal Social Security Act, as enacted under §3024 (Pub L No. 111-148), March 23, 2010. www.gpo.gov/fdsys/pkg/PLAW-111publ148/pdf/PLAW-111publ148.pdf. Accessed June 15, 2010.

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ULORIC powerfully lowers serum uric acid levels for long-term control of gout. In the largest phase 3 study (6 months): • 45% of patients who received ULORIC 40 mg achieved serum uric acid level <6 mg/dL (N=757) compared to 42% of patients who received allopurinol 300 mg (N=755; p=0.233)1 • 67% of patients who received ULORIC 80 mg achieved serum uric acid level <6 mg/dL (N=756) compared to 42% of patients who received allopurinol 300 mg (N=755; p<0.001)1

Indication ULORIC is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia.

Important Safety Information • ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline. • An increase in gout flares is frequently observed during initiation of anti-hyperuricemic agents, including ULORIC. If a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e. - NSAIDs or colchicine) upon initiation of treatment may be beneficial for up to six months. • Cardiovascular Events: In randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial

For more information, please visit www.ULORIC.com

infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke. • Liver Enzyme Elevations: In randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter. • Adverse reactions occurring in at least 1% of ULORICtreated patients, and, at least 0.5% greater than placebo, are liver function abnormalities, nausea, arthralgia, and rash.

Individual results may vary based on factors such as baseline serum uric acid levels. Please see brief summary of complete Prescribing Information on adjacent pages. Reference: 1. ULORIC® (febuxostat) full prescribing information, February 2009.

ULORIC® is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc. ©2009 Takeda Pharmaceuticals North America, Inc. TXF-00321 08/09


BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for ULORIC® (febuxostat) tablets INDICATIONS AND USAGE ULORIC® is a xanthine oxidase (XO) inhibitor indicated for the chronic management of hyperuricemia in patients with gout. ULORIC is not recommended for the treatment of asymptomatic hyperuricemia. CONTRAINDICATIONS ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Drug Interactions]. WARNINGS AND PRECAUTIONS Gout Flare After initiation of ULORIC, an increase in gout flares is frequently observed. This increase is due to reduction in serum uric acid levels resulting in mobilization of urate from tissue deposits. In order to prevent gout flares when ULORIC is initiated, concurrent prophylactic treatment with an NSAID or colchicine is recommended. Cardiovascular Events In the randomized controlled studies, there was a higher rate of cardiovascular thromboembolic events (cardiovascular deaths, non-fatal myocardial infarctions, and non-fatal strokes) in patients treated with ULORIC [0.74 per 100 P-Y (95% CI 0.36-1.37)] than allopurinol [0.60 per 100 P-Y (95% CI 0.16-1.53)] [see Adverse Reactions]. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of myocardial infarction (MI) and stroke. Liver Enzyme Elevations During randomized controlled studies, transaminase elevations greater than 3 times the upper limit of normal (ULN) were observed (AST: 2%, 2%, and ALT: 3%, 2% in ULORIC and allopurinol-treated patients, respectively). No dose-effect relationship for these transaminase elevations was noted. Laboratory assessment of liver function is recommended at, for example, 2 and 4 months following initiation of ULORIC and periodically thereafter. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 2757 subjects with hyperuricemia and gout were treated with ULORIC 40 mg or 80 mg daily in clinical studies. For ULORIC 40 mg, 559 patients were treated for r 6 months. For ULORIC 80 mg, 1377 subjects were treated for r 6 months, 674 patients were treated for r 1 year and 515 patients were treated for r 2 years. Most Common Adverse Reactions In three randomized, controlled clinical studies (Studies 1, 2 and 3), which were 6 to 12 months in duration, the following adverse reactions were reported by the treating physician as related to study drug. Table 1 summarizes adverse reactions reported at a rate of at least 1% in ULORIC treatment groups and at least 0.5% greater than placebo. Table 1: Adverse Reactions Occurring in r 1% of ULORIC-Treated Patients and at Least 0.5% Greater than Seen in Patients Receiving Placebo in Controlled Studies Placebo

Adverse Reactions Liver Function Abnormalities Nausea Arthralgia Rash

ULORIC

allopurinol*

(N=134)

40 mg daily (N=757)

80 mg daily (N=1279)

(N=1277)

0.7%

6.6%

4.6%

4.2%

0.7%

1.1%

1.3%

0.8%

0%

1.1%

0.7%

0.7%

0.7%

0.5%

1.6%

1.6%

*Of the subjects who received allopurinol, 10 received 100 mg, 145 received 200 mg, and 1122 received 300 mg, based on level of renal impairment. The most common adverse reaction leading to discontinuation from therapy was liver function abnormalities in 1.8% of ULORIC 40 mg, 1.2% of ULORIC 80 mg, and in 0.9% of allopurinol-treated subjects. In addition to the adverse reactions presented in Table 1, dizziness was reported in more than 1% of ULORIC-treated subjects although not at a rate more than 0.5% greater than placebo. Less Common Adverse Reactions In phase 2 and 3 clinical studies the following adverse reactions occurred in less than 1% of subjects and in more than one subject treated with doses ranging from 40 mg to 240 mg of ULORIC. This list also includes adverse reactions (less than 1% of subjects) associated with organ systems from Warnings and Precautions.

Blood and Lymphatic System Disorders: anemia, idiopathic thrombocytopenic purpura, leukocytosis/leukopenia, neutropenia, pancytopenia, splenomegaly, thrombocytopenia; Cardiac Disorders: angina pectoris, atrial fibrillation/flutter, cardiac murmur, ECG abnormal, palpitations, sinus bradycardia, tachycardia; Ear and Labyrinth Disorders: deafness, tinnitus, vertigo; Eye Disorders: vision blurred; Gastrointestinal Disorders: abdominal distention, abdominal pain, constipation, dry mouth, dyspepsia, flatulence, frequent stools, gastritis, gastroesophageal reflux disease, gastrointestinal discomfort, gingival pain, haematemesis, hyperchlorhydria, hematochezia, mouth ulceration, pancreatitis, peptic ulcer, vomiting; General Disorders and Administration Site Conditions: asthenia, chest pain/discomfort, edema, fatigue, feeling abnormal, gait disturbance, influenza-like symptoms, mass, pain, thirst; Hepatobiliary Disorders: cholelithiasis/cholecystitis, hepatic steatosis, hepatitis, hepatomegaly; Immune System Disorder: hypersensitivity; Infections and Infestations: herpes zoster; Procedural Complications: contusion; Metabolism and Nutrition Disorders: anorexia, appetite decreased/increased, dehydration, diabetes mellitus, hypercholesterolemia, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypokalemia, weight decreased/increased; Musculoskeletal and Connective Tissue Disorders: arthritis, joint stiffness, joint swelling, muscle spasms/twitching/tightness/weakness, musculoskeletal pain/stiffness, myalgia; Nervous System Disorders: altered taste, balance disorder, cerebrovascular accident, Guillain-Barré syndrome, headache, hemiparesis, hypoesthesia, hyposmia, lacunar infarction, lethargy, mental impairment, migraine, paresthesia, somnolence, transient ischemic attack, tremor; Psychiatric Disorders: agitation, anxiety, depression, insomnia, irritability, libido decreased, nervousness, panic attack, personality change; Renal and Urinary Disorders: hematuria, nephrolithiasis, pollakiuria, proteinuria, renal failure, renal insufficiency, urgency, incontinence; Reproductive System and Breast Changes: breast pain, erectile dysfunction, gynecomastia; Respiratory, Thoracic and Mediastinal Disorders: bronchitis, cough, dyspnea, epistaxis, nasal dryness, paranasal sinus hypersecretion, pharyngeal edema, respiratory tract congestion, sneezing, throat irritation, upper respiratory tract infection; Skin and Subcutaneous Tissue Disorders: alopecia, angio edema, dermatitis, dermographism, ecchymosis, eczema, hair color changes, hair growth abnormal, hyperhidrosis, peeling skin, petechiae, photosensitivity, pruritus, purpura, skin discoloration/altered pigmentation, skin lesion, skin odor abnormal, urticaria; Vascular Disorders: flushing, hot flush, hypertension, hypotension; Laboratory Parameters: activated partial thromboplastin time prolonged, creatine increased, bicarbonate decreased, sodium increased, EEG abnormal, glucose increased, cholesterol increased, triglycerides increased, amylase increased, potassium increased, TSH increased, platelet count decreased, hematocrit decreased, hemoglobin decreased, MCV increased, RBC decreased, creatinine increased, blood urea increased, BUN/creatinine ratio increased, creatine phosphokinase (CPK) increased, alkaline phosphatase increased, LDH increased, PSA increased, urine output increased/decreased, lymphocyte count decreased, neutrophil count decreased, WBC increased/decreased, coagulation test abnormal, low density lipoprotein (LDL) increased, prothrombin time prolonged, urinary casts, urine positive for white blood cells and protein. Cardiovascular Safety Cardiovascular events and deaths were adjudicated to one of the pre-defined endpoints from the Anti-Platelet Trialists’ Collaborations (APTC) (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in the randomized controlled and long-term extension studies. In the Phase 3 randomized controlled studies, the incidences of adjudicated APTC events per 100 patient-years of exposure were: Placebo 0 (95% CI 0.00-6.16), ULORIC 40 mg 0 (95% CI 0.00-1.08), ULORIC 80 mg 1.09 (95% CI 0.44-2.24), and allopurinol 0.60 (95% CI 0.16-1.53). In the long-term extension studies, the incidences of adjudicated APTC events were: ULORIC 80 mg 0.97 (95% CI 0.57-1.56), and allopurinol 0.58 (95% CI 0.02-3.24). Overall, a higher rate of APTC events was observed in ULORIC than in allopurinoltreated patients. A causal relationship with ULORIC has not been established. Monitor for signs and symptoms of MI and stroke. DRUG INTERACTIONS Xanthine Oxidase Substrate Drugs ULORIC is an XO inhibitor. Drug interaction studies of ULORIC with drugs that are metabolized by XO (e.g., theophylline, mercaptopurine, azathioprine) have not been conducted. Inhibition of XO by ULORIC may cause increased plasma concentrations of these drugs leading to toxicity [see Clinical Pharmacology]. ULORIC is contraindicated in patients being treated with azathioprine, mercaptopurine, or theophylline [see Contraindications]. Cytotoxic Chemotherapy Drugs Drug interaction studies of ULORIC with cytotoxic chemotherapy have not been conducted. No data are available regarding the safety of ULORIC during cytotoxic chemotherapy. In Vivo Drug Interaction Studies Based on drug interaction studies in healthy subjects, ULORIC does not have clinically significant interactions with colchicine, naproxen, indomethacin, hydrochlorothiazide, warfarin or desipramine. Therefore, ULORIC may be used concomitantly with these medications.


USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. ULORIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Febuxostat was not teratogenic in rats and rabbits at oral doses up to 48 mg per kg (40 and 51 times the human plasma exposure at 80 mg per day for equal body surface area, respectively) during organogenesis. However, increased neonatal mortality and a reduction in the neonatal body weight gain were observed when pregnant rats were treated with oral doses up to 48 mg per kg (40 times the human plasma exposure at 80 mg per day) during organogenesis and through lactation period. Nursing Mothers Febuxostat is excreted in the milk of rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ULORIC is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients under 18 years of age have not been established. Geriatric Use No dose adjustment is necessary in elderly patients. Of the total number of subjects in clinical studies of ULORIC, 16 percent were 65 and over, while 4 percent were 75 and over. Comparing subjects in different age groups, no clinically significant differences in safety or effectiveness were observed but greater sensitivity of some older individuals cannot be ruled out. The Cmax and AUC24 of febuxostat following multiple oral doses of ULORIC in geriatric subjects (r 65 years) were similar to those in younger subjects (18-40 years). Renal Impairment No dose adjustment is necessary in patients with mild or moderate renal impairment (Clcr 30-89 mL per min). The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended. There are insufficient data in patients with severe renal impairment (Clcr less than 30 mL per min); therefore, caution should be exercised in these patients. Hepatic Impairment No dose adjustment is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Class A or B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C); therefore, caution should be exercised in these patients. Secondary Hyperuricemia No studies have been conducted in patients with secondary hyperuricemia (including organ transplant recipients); ULORIC is not recommended for use in patients whom the rate of urate formation is greatly increased (e.g., malignant disease and its treatment, Lesch-Nyhan syndrome). The concentration of xanthine in urine could, in rare cases, rise sufficiently to allow deposition in the urinary tract. OVERDOSAGE ULORIC was studied in healthy subjects in doses up to 300 mg daily for seven days without evidence of dose-limiting toxicities. No overdose of ULORIC was reported in clinical studies. Patients should be managed by symptomatic and supportive care should there be an overdose. CLINICAL PHARMACOLOGY Pharmacodynamics Effect on Uric Acid and Xanthine Concentrations: In healthy subjects, ULORIC resulted in a dose dependent decrease in 24-hour mean serum uric acid concentrations, and an increase in 24-hour mean serum xanthine concentrations. In addition, there was a decrease in the total daily urinary uric acid excretion. Also, there was an increase in total daily urinary xanthine excretion. Percent reduction in 24-hour mean serum uric acid concentrations was between 40% to 55% at the exposure levels of 40 mg and 80 mg daily doses. Effect on Cardiac Repolarization: The effect of ULORIC on cardiac repolarization as assessed by the QTc interval was evaluated in normal healthy subjects and in patients with gout. ULORIC in doses up to 300 mg daily, at steady state, did not demonstrate an effect on the QTc interval. Special Populations Renal Impairment: Following multiple 80 mg doses of ULORIC in healthy subjects with mild (Clcr 50-80 mL per min), moderate (Clcr 30-49 mL per min) or severe renal impairment (Clcr 10-29 mL per min), the Cmax of febuxostat did not change relative to subjects with normal renal function (Clcr greater than 80 mL per min). AUC and half-life of febuxostat increased in subjects with renal impairment in comparison to subjects with normal renal function, but values were similar among three renal impairment groups. Mean febuxostat AUC values were up to 1.8 times higher in subjects with renal impairment compared to those with normal renal function. Mean Cmax and AUC values for 3 active metabolites increased up to 2- and 4-fold, respectively. However, the percent decrease in serum uric acid concentration for subjects with renal impairment was comparable to those with normal renal function (58% in normal renal function group and 55% in the severe renal function group).

No dose adjustment is necessary in patients with mild to moderate renal impairment [see Dosage and Administration and Use in Specific Populations]. The recommended starting dose of ULORIC is 40 mg once daily. For patients who do not achieve a sUA less than 6 mg per dL after 2 weeks with 40 mg, ULORIC 80 mg is recommended. There is insufficient data in patients with severe renal impairment; caution should be exercised in those patients [see Use in Specific Populations. ULORIC has not been studied in end stage renal impairment patients who are on dialysis. Hepatic Impairment: Following multiple 80 mg doses of ULORIC in patients with mild (Child-Pugh Class A) or moderate (Child-Pugh Class B) hepatic impairment, an average of 20-30% increase was observed for both Cmax and AUC24 (total and unbound) in hepatic impairment groups compared to subjects with normal hepatic function. In addition, the percent decrease in serum uric acid concentration was comparable between different hepatic groups (62% in healthy group, 49% in mild hepatic impairment group, and 48% in moderate hepatic impairment group). No dose adjustment is necessary in patients with mild or moderate hepatic impairment. No studies have been conducted in subjects with severe hepatic impairment (Child-Pugh Class C); caution should be exercised in those patients [see Use in Specific Populations. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Two-year carcinogenicity studies were conducted in F344 rats and B6C3F1 mice. Increased transitional cell papilloma and carcinoma of urinary bladder was observed at 24 mg per kg (25 times the human plasma exposure at maximum recommended human dose of 80 mg per day) and 18.75 mg per kg (12.5 times the human plasma exposure at 80 mg per day) in male rats and female mice, respectively. The urinary bladder neoplasms were secondary to calculus formation in the kidney and urinary bladder. Mutagenesis: Febuxostat showed a positive mutagenic response in a chromosomal aberration assay in a Chinese hamster lung fibroblast cell line with and without metabolic activation in vitro. Febuxostat was negative in the in vitro Ames assay and chromosomal aberration test in human peripheral lymphocytes, and L5178Y mouse lymphoma cell line, and in vivo tests in mouse micronucleus, rat unscheduled DNA synthesis and rat bone marrow cells. Impairment of Fertility: Febuxostat at oral doses up to 48 mg per kg per day (approximately 35 times the human plasma exposure at 80 mg per day) had no effect on fertility and reproductive performance of male and female rats. Animal Toxicology A 12-month toxicity study in beagle dogs showed deposition of xanthine crystals and calculi in kidneys at 15 mg per kg (approximately 4 times the human plasma exposure at 80 mg per day). A similar effect of calculus formation was noted in rats in a six-month study due to deposition of xanthine crystals at 48 mg per kg (approximately 35 times the human plasma exposure at 80 mg per day). PATIENT COUNSELING INFORMATION [see FDA-Approved Patient Labeling in the full prescribing information] General Information Patients should be advised of the potential benefits and risks of ULORIC. Patients should be informed about the potential for gout flares, elevated liver enzymes and adverse cardiovascular events after initiation of ULORIC therapy. Concomitant prophylaxis with an NSAID or colchicine for gout flares should be considered. Patients should be instructed to inform their healthcare professional if they develop a rash, chest pain, shortness of breath or neurologic symptoms suggesting a stroke. Patients should be instructed to inform their healthcare professional of any other medications they are currently taking with ULORIC, including over-the-counter medications. Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 U.S. Patent Nos. - 6,225,474; 7,361,676; 5,614,520. ULORICŽ is a registered trademark of Teijin Pharma Limited and used under license by Takeda Pharmaceuticals America, Inc. All other trademark names are the property of their respective owners Š2009 Takeda Pharmaceuticals America, Inc. February 2009 For more detailed information, see the full prescribing information for ULORIC (febuxostat) tablets (PI1114 R1; February 2009) or contact Takeda Pharmaceuticals America, Inc. at 1.877.825.3327. PI1114 R1-Brf; February 2009 L-TXF-0209-3


CLINICAL

Effectiveness of Anti-Tumor Necrosis Factor Agents in the Treatment of Rheumatoid Arthritis: Observational Study Anna D’Souza, PhD; Brian L. Meissner, PharmD, PhD; Boxiong Tang, MD, PhD; R. Scott McKenzie, MD; Catherine T. Piech, MBA Stakeholder Perspective, page 273

Objective: The efficacy of anti-tumor necrosis factor therapies in rheumatoid arthritis has been demonstrated in randomized clinical trials. The purpose of the present study was to evaluate the effectiveness of these agents for the treatment of rheumatoid arthritis in a realworld setting. Method: This retrospective chart review included patients from 6 clinics in the United States. Eligibility criteria included age ≥18 years, diagnosis of rheumatoid arthritis, and having been initiated with anti-tumor necrosis factor therapy (ie, adalimumab, etanercept, or infliximab) between January 1, 2002, and November 30, 2004. Patients were assessed for up to 2 years after therapy initiation. Primary outcomes of interest were improvements in 4 effectiveness measures—joint pain, joint swelling, joint stiffness, and fatigue. A total of 496 patients met the study’s inclusion criteria: 84 (16.9%) in the adalimumab group, 146 (29.4%) in the etanercept group, and 266 (53.6%) in the infliximab group. Results: Improvement in 1 of the 4 effectiveness measures was documented in 36.8% (n = 25) who received adalimumab, in 47.7% (n = 62) of those who received etanercept, and in 48.7% (n = 115) of patients who received infliximab. The infliximab group was the only cohort to demonstrate significant improvements from baseline in joint pain, joint swelling, and joint stiffness. The adalimumab group had significant improvement in joint pain (P = .004). No significant change in fatigue scores was reached with any of these agents. Conclusion: In the real-world setting of patients with rheumatoid arthritis, anti-tumor necrosis factor therapy shows significant improvements in joint pain, joint swelling, and joint stiffness, although there are differences in effectiveness in the 4 measures among the 3 agents assessed in this study.

A

nti-tumor necrosis factor (TNF) therapy has emerged as a major advancement in the management of rheumatoid arthritis (RA). The anti-TNF agents adalimumab, etanercept, and infliximab are often used with conventional disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and have been shown in clinical trials to be effective in reducing the signs and symptoms of RA and in preventing the progression of joint damage.1-6

Dr D’Souza is a Manager, and Dr Meissner was a Director (when this research was conducted), Xcenda, Palm Harbor, FL; Dr Tang was Director of Outcomes Research, Medical Affairs Operations, Dr McKenzie is Regional Director, Clinical Affairs, and Ms Piech is Vice President, Outcomes Research and Biometrics, Centocor Ortho Biotech, Horsham, PA.

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Am Health Drug Benefits. 2010;3(4): 266-273. www.AHDBonline.com Disclosures are at end of text

Significant limitations have been noted in the literature as to outcomes of clinical trials and observational studies of anti-TNF therapy.7,8 Clinical trial inclusion and exclusion criteria specify select patient populations, which may not necessarily reflect the diversity of patient and disease characteristics in real-world clinical scenarios.8 Therefore, real-world studies can offer unique insights over controlled clinical trials.9 Although there is greater diversity of patient and disease characteristics in real-world studies, there may be bias, because patients receive various treatments. Nevertheless, healthcare decision makers are increasingly relying on studies of real-world outcomes for decisions related to coverage and reimbursement.10 Many studies have evaluated the effectiveness of anti-TNF therapies in patients with RA,1-6 but few real-world studies have

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evaluated the clinical effectiveness of adalimumab, etanercept, and infliximab. The objective of this analysis was to assess the effectiveness of these agents in improving joint pain, joint swelling, joint stiffness, and fatigue among patients with RA.

KEY POINTS ➤

Methods We conducted a retrospective, observational chart review using data from 6 rheumatology clinics across the United States, and evaluated treatment effectiveness among a sample of patients with RA who were treated with anti-TNF therapy (ie, adalimumab, etanercept, or infliximab). The study period was from January 1, 2001, to November 30, 2006. For each patient, the observation period included a 1-year period before the index date, which was the date of the first anti-TNF prescription or administration, and a 2-year follow-up period after the index date (Figure). Baseline status was assessed during the year before the index date. Data were collected for a maximum of 2 years after the index date, or until discontinuation of antiTNF therapy, whichever occurred first. Patient selection was based on the following inclusion criteria: age ≥18 years; diagnosis of RA; and therapy initiated with adalimumab, etanercept, or infliximab between January 1, 2002, and November 30, 2004, with no documentation of previous anti-TNF therapy. Patients were required to be under the care of the participating physician or physician group, or have complete documentation (related to RA) from another provider for a minimum of 12 months before the index date and up to 24 months after the index date (no minimum follow-up period was required). Patients with a diagnosis of psoriasis, ulcerative colitis, Crohn’s disease, or ankylosing spondylitis were excluded from the study, because of the differences in anti-TNF dosage recommendations. In addition, patients were excluded if they had a history of anti-TNF therapy or any of the following diagnoses any time before the index date—malignancy (eg, lymphoma, solid organ malignancy), infection (eg, tuberculosis, bacterial pneumonia), seizures, demyelinating disorders (eg, multiple sclerosis), heart failure, or drug-induced lupus. Participating clinics identified and provided charts for all patients meeting the study inclusion criteria. Patient privacy was maintained through the use of unique alphanumeric values for each patient in compliance with the Health Insurance Portability and Accountability Act (HIPAA). The study protocol was approved by the New England Institutional Review Board. Data were collected using a standardized chart review form with a graphical user interface developed in Microsoft Access. Patient demographics and con-

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Previous evidence from clinical trials has shown that anti-TNF agents are effective for the treatment of arthritis. The goal of this study was to evaluate the effectiveness of these agents (ie, adalimumab, etanercept, and infliximab) in reducing joint pain, swelling, and stiffness, and fatigue for patients with rheumatoid arthritis in the real-world setting. Approximately 76% of patients were using concomitant DMARD therapy; this was more common in patients taking infliximab than etanercept or adalimumab. Nearly half of the patients reported an improvement in all 4 measures, but not all improvements reached significant difference in the 2-year follow-up. The only group with significant improvements in 3 measures (all but fatigue) was the infliximab cohort. The adalimumab cohort had significant improvements from baseline in joint pain. The etanercept cohort had the highest percentage of patients who had improvement in joint stiffness. None of the cohorts had significant improvements in fatigue.

Figure Study Design Pretreatment assessment

Outcomes assessment

1 year before Index date 1 year after 2 years after index date index date index date (treatment initiated with adalimumab, etanercept, or infliximab)

comitant DMARD use were collected. For this study, concomitant DMARD therapy included hydroxychloroquine, leflunomide, sulfasalazine, azathioprine, penicillamine, and auranofin. Response to therapy was evaluated for joint pain, joint swelling, joint stiffness, and fatigue. Because of intra- and intervariability in documentation among physicians, a data abstraction form was used so that the chart reviewer could document both qualitative and quantitative data.

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An algorithm was developed to translate qualitative data into quantitative values. Because there were no relevant studies available to guide the development of the algorithm, a clinical and psychometric rationale was applied to develop an algorithm that could be consistently applied to the varying levels of physician documentation. A visual analog scale (VAS; 0-10 cm) was the preferred method for evaluating all 3 joint assessments (ie, pain, swelling, stiffness) and fatigue. If documented VAS was not available, the following algorithm was used: A. Categorical documentation was converted to a numerical value using midpoints of a 0-to-10 scale (median [range]: mild = 1.65 [1-3.3], moderate = 4.95 [3.4-6.6], severe = 8.25 [6.7-9.9]) B. Dichotomous documentation was converted to a numerical scale using the midpoints of a 1-to-10 scale (yes = 5, no = 0). If more than 1 form of documentation was present for a patient visit, the VAS was the preferred type of documentation, followed by categorical and dichotomous documentation. Baseline scores were determined through available documentation on the index date or, if not available, documentation from the closest encounter before the index dates. The mean scores for joint pain, swelling, and stiffness, and fatigue were determined for the 2-year follow-up period. If a patient had multiple assessments, an average was derived. The following criteria were used to define improvement from baseline: A. Decrease in VAS of at least 1 point B. Change in categorical documentation from “severe” to “moderate/mild” or from “moderate” to “mild” C. Change in dichotomous documentation from yes to no. Improvement was defined as any improvement during the 2-year follow-up period among any of the 3 documentation types. Overall improvement was based on improvement in any of the 4 effectiveness measures. Mean scores were based only on patients with documented information for each joint assessment at the given time point (baseline or follow-up period). Basic descriptive statistics and univariate statistical testing were applied to this analysis. Analysis of variance or Kruskal-Wallis tests (as applicable) were applied to continuous variables to determine if differences existed among the 3 cohorts. If differences did exist (ie, P <.05), post-hoc multiple comparison tests (Tukey or Mann-Whitney) that controlled for the family-wise type 1 error rate were conducted. For the multiple comparison tests, P <.017 (Bonferroni correction) was considered statistically significant. Paired t-tests were conducted to determine if differences existed

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among the VAS scores at baseline and during the 2year follow-up period within each cohort. Chi-square tests were conducted to assess differences between the 3 cohorts on categorical variables. All analyses were conducted using SAS version 9.1 (Cary, NC).

Results This study enrolled 496 patients, including 84 patients (16.9%) in the adalimumab group, 146 (29.4%) in the etanercept group, and 266 (53.6%) in the infliximab group (Table 1). Overall, 74.0% of the patients were female, and the mean age (standard deviation [SD]) was 56.1 (14.8) years. The mean age was 52.6 years in the etanercept group and 57.6 years in the infliximab group (P <.017). Of patients with documented ethnicity (n = 217), whites comprised 80.2% of the overall population. The mean (SD) length of disease duration before initiation of anti-TNF therapy was 3.9 (3.5) years, and the mean (SD) length of follow-up after the index date was 614.8 (156.0) days. Approximately 76% of patients received concomitant DMARD therapy, which was more common (79.7%) in the infliximab cohort than in the etanercept (68.5%) or adalimumab (75.0%) cohorts (P <.040). The average time that patients remained on anti-TNF therapy ranged from 367 days to 423 days (etanercept, 423 days; adalimumab, 371 days; infliximab, 367 days; P = .126). Overall Clinical Improvement There was wide variation in the type of documentation used to indicate patient improvement (Table 2). For example, 99% of the patients had documentation for joint pain, using a dichotomous approach (yes, pain exists; no, pain does not exist), and 29% had VAS documentation for this assessment. In total, 12.5% (n = 62) of all patients did not have joint assessment data to evaluate clinical improvement during the follow-up period. Of the 434 patients who had documented information for at least 1 of the 4 effectiveness measures, 46.5% (n = 202) reported a clinical benefit, including 48.7% (n = 115/236) in the infliximab group, 47.7% (n = 62/130) in the etanercept group, and 36.8% (n = 25/68) in the adalimumab group. Joint Pain Overall, 150 of the 429 patients (35.0%) had an improvement from baseline in joint pain scores during the 2-year follow-up (Table 3). The adalimumab and infliximab groups reported significant improvements from baseline in joint pain scores (P = .004 and P <.001, respectively). The infliximab group had the highest percentage of patients with documented improvement in

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Table 1 Patient Demographics, Baseline Characteristics, and DMARD Therapy Adalimumab Etanercept Infliximab (N = 84, 16.9%) (N = 146, 29.4%) (N = 266, 53.6%) Mean age, yrsa (SD)

57.1 (12.0)

Female, n (%)

65 (77.4)

52.6 (13.8) 108 (74.0)

57.6 (15.8) 194 (72.9)

Total (N = 496)

P

56.1 (14.8)

.003

367 (74.0)

.720

b

Ethnicity, n (%)

.241

White

29 (70.7)

50 (79.4)

95 (84.1)

174 (80.2)

Black

3 (7.3)

1 (1.6)

2 (1.8)

6 (2.8)

Asian

0 (0.0)

2 (3.2)

3 (2.7)

5 (2.3)

Hispanic

9 (22.0)

10 (15.9)

13 (11.5)

32 (14.8)

Unknown

43 (51.2)

83 (56.9)

153 (57.5)

279 (56.3)

Mean disease duration, yrs (SD)

3.9 (2.8)

4.1 (4.0)

3.8 (3.4)

3.9 (3.5)

.719

Mean length of follow-up, days (SD)

606.9 (151.0)

617.8 (153.7)

615.7 (159.3)

614.8 (156.0)

.870

Concomitant DMARD therapy,c n (%)

63 (75.0)

100 (68.5)d

212 (79.7)d

375 (75.6)

.040

a

Calculated from 2006. computed based on total in each group, not including unknown. Defined as overlap between anti-TNF therapy and DMARD therapy. dIndicates difference between etanercept and infliximab is significant. The difference in the mean age between these groups was also significant (P <.017). DMARD indicates disease-modifying antirheumatic drug; SD, standard deviation; TNF, tumor necrosis factor. bPercentages c

Table 2 Patients with Available Documentation of RA Improvement

Outcome Joint pain Joint swelling Joint stiffness Fatigue

Any type of documentation N (%)

Dichotomous N (%)

Categorical N (%)

Comparison N (%)

VASa N (%)

Joints N (%)

492 (99)

492 (99)

214 (43)

379 (76)

145 (29)

194 (39)

442 (89)

442 (89)

221 (45)

312 (63)

37 (7)

112 (23)

473 (95)

473 (95)

183 (37)

332 (67)

83 (17)

71 (14)

305 (61)

305 (61)

62 (12)

148 (30)

72 (14)

â&#x20AC;&#x201D;

a

VAS, 0-10 cm. RA indicates rheumatoid arthritis; VAS, visual analog scale.

joint pain (36.9%) compared with the etanercept group (36.4%) and the adalimumab group (25.3%), although the difference was not significant.

Joint Swelling Approximately 35% (122 of 348) of patients had an improvement from baseline in joint swelling scores. Among all patients, mean (SD) joint swelling scores significantly improved from baseline during the 2-year follow-up period (3.2 [1.9] vs 3.0 [1.8], P = .004). In the infliximab group, the mean (SD) score decreased from 3.2 (1.9) at baseline to 3.0 (1.8) during the follow-up

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period (P <.001). There were no significant differences between the mean scores at baseline and during the follow-up period in the adalimumab or the etanercept groups. The percentage of patients with improvement in joint swelling was highest in the infliximab group (38.0%), followed by the etanercept group (33.7%), and the adalimumab group (26.8%); however, these differences were not significant.

Joint Stiffness Among all patients, 107 of 380 patients (28.2%) had an improvement in joint stiffness score, and a significant

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Table 3 Improvement in Clinical Effectiveness Measures

Clinical measure Joint pain

Adalimumab

Etanercept

Infliximab

Total

68

132

233

433

4.2 (2.5)

4.4 (2.2)

4.3 (2.2)

4.3 (2.2)

Follow-up period Patients, na

67

129

233

429

Mean (SD) score

4.0 (2.4)

4.2 (2.3)

4.0 (2.1)

4.1 (2.2)

.004

.208

<.001

<.001

17 (25.3)

47 (36.4)

86 (36.9)

150 (35.0)

57

98

205

360

3.3 (1.7)

3.2 (1.9)

3.2 (1.9)

3.2 (1.9)

56

92

200

348

3.3 (1.8)

3.0 (1.9)

3.0 (1.8)

3.0 (1.8)

.795

.523

<.001

.004

15 (26.8)

31 (33.7)

76 (38.0)

122 (35.1)

63

115

214

392

3.8 (2.0)

3.8 (1.8)

3.8 (1.8)

3.8 (1.9)

60

111

209

380

3.6 (2.2)

3.9 (2.0)

3.6 (1.8)

3.7 (1.9)

.124

.520

.001

.022

15 (25.0)

33 (29.7)

59 (28.2)

107 (28.2)

29

63

111

203

5.0 (1.9)

5.1 (1.8)b

4.4 (2.0)b

4.7 (1.9)

19

55

95

169

Baseline Patients, na Mean (SD) score

P (vs baseline) Patients with improvement, n (%)

P

.867

.730

.200

Joint swelling Baseline Patients, na Mean (SD) score Follow-up period Patients, na Mean (SD) score P (vs baseline) Patients with improvement, n (%)

.880

.456

.284

Joint stiffness Baseline Patients, na Mean (SD) score Follow-up period Patients, na Mean (SD) score P (vs baseline) Patients with improvement, n (%)

.986

.351

.806

Fatigue Baseline Patients, na Mean (SD) score Follow-up period Patients, na Mean (SD) score P (vs baseline) Patients with improvement, n (%)

b

b

4.8 (2.1)

5.2 (1.7)

4.2 (2.0)

4.6 (2.0)

.631

.153

.296

.290

5 (26.3)

21 (38.2)

26 (27.4)

52 (30.8)

.031

.009

.348

a

Values in this row indicate the number of patients with data during period of assessment. that the pairwise difference between etanercept and infliximab is significant (P <.017). NOTE: Scores in each of the outcomes measures (joint pain, swelling, and stiffness, and fatigue) ranged from 0 (no symptoms) to 10 (severe symptoms). SD indicates standard deviation. bIndicates

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decrease from baseline was observed in mean scores (P = .022). There were no significant differences between the mean scores at baseline and during the follow-up period within the adalimumab group and the etanercept group (Table 3). In the infliximab group, the mean (SD) score decreased significantly from 3.8 (1.8) at baseline to 3.6 (1.8) during the follow-up period (P = .001). However, the etanercept group had the highest percentage of patients who had an improvement in joint stiffness score (29.7%), followed by the infliximab group (28.2%), and the adalimumab group (25.0%); however, these differences were not significant.

Fatigue Mean fatigue scores decreased from baseline for all patients and within each therapy group; however, these decreases were not significant. The percentage of patients with improvement in fatigue was greatest in the etanercept cohort (38.2%), followed by the infliximab group (27.4%), and the adalimumab group (26.3%); however, these differences were not significant. When pairwise comparisons were conducted, the mean (SD) fatigue score for the infliximab group was significantly lower (4.2 [2.0]) than in the etanercept (5.2 [1.7]) cohort during follow-up (P <.017). However, the scores at baseline were also lowest in the infliximab group. Discussion The introduction of anti-TNF therapy is a valuable addition to the armamentarium of RA treatment options. The efficacy and safety of adalimumab, etanercept, and infliximab have been demonstrated in multiple randomized controlled trials with favorable results.3-5,11-13Anti-TNF therapy can improve symptoms, increase physical function, and slow or prevent radiographic joint damage in many patients with RA.2,14 Overall, the findings of this real-world analysis from 6 US rheumatology clinics support the benefit of antiTNF therapy in patients with RA as reported in clinical trials.1,2,11 In general, the age and sex of the populations were similar to those typically reported in RA clinical trials with anti-TNF agents. Disease duration before anti-TNF agent intervention was shorter (ie, about 4 years) than that of patients who participated in previous clinical trials (ie, 9-11 years),1,2,11 which may be the result of recent evidence supporting earlier interventions or may reflect referral patterns within the participating rheumatology clinics. Many patients in this analysis were treated with an anti-TNF therapy and concomitant DMARD therapy (75.6%). The data indicate that concomitant DMARD use was more common with infliximab treatment than

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with the other anti-TNF agents. This combination therapy is supported by clinical trials showing that anti-TNF therapy concomitant with methotrexate has improved benefit over methotrexate monotherapy.2,4,13

There is no standardized measure to assess outcomes in routine clinical practice; therefore, physicians typically utilize several measures. Nearly half of the patients included in this study reported an improvement in joint pain, joint swelling, joint stiffness, or fatigue during the 2-year follow-up period. The infliximab group was the only cohort to demonstrate significant improvements from baseline in 3 (joint pain, joint swelling, and joint stiffness) of the 4 clinical effectiveness measures. None of the cohorts demonstrated a significant change from baseline in the fatigue score, although numerical improvements were noted. There is no standardized measure to assess outcomes in routine clinical practice; therefore, physicians typically utilize several measures, including laboratory tests, radiographic scores, joint counts, measures of functional status, global measures, and patient self-reported questionnaires.15-17 Indeed, wide variability has been demonstrated regarding the frequency with which different outcome measures are documented by providers.17 The present analysis assessed variable outcome measures with the development of an algorithm to integrate intra- and intervariability among providers reporting clinical status in patients with RA. A number of tools are currently available (eg, Simplified Disease Activity Index; Clinical Disease Activity Index; Disease Activity Score, including 28 joints).18,19 However, further exploration of a validated practical tool that could be adopted for widespread use to monitor RA treatment response is warranted, followed by exploration of the incentives needed to improve such data collection. An advantage of this study is that it provides realworld outcomes associated with anti-TNF therapy for drugs that have already demonstrated efficacy and safety in controlled clinical trials. The 2-year follow-up period allowed for the assessment of long-term outcomes. However, because this analysis was designed to evaluate anti-TNF agents, other biologic therapies used for RAâ&#x20AC;&#x201D; including anakinra (Kineret),20 abatacept (Orencia),21 and rituximab (Rituxan)22â&#x20AC;&#x201D;were not assessed. Randomized clinical trials and observational studies in routine clinical practice are important for the evaluation of therapies and have unique advantages and limitations. Although not as scientifically rigorous, real-

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world studies can complement the information gained from clinical trials. Specifically, one observational cohort study of the effectiveness of anti-TNF therapy in patients who would have been ineligible for a clinical trial demonstrated that the majority of such patients would benefit from these treatments.23 Well-designed observational studies can be invaluable in gaining further understanding of response to therapy.

Limitations Consistent with observational research, the limitations of this study include missing data and inconsistencies with documentation. Lack of standardized outcome measures in clinical practice was confirmed by the results and limited the quantitative and qualitative nature of this study, thereby requiring the development of an algorithm to capture variability in assessment of clinical outcomes among providers. As such, this approach has not been validated. Although the study was designed to evaluate patients who were newly initiated with antiTNF therapy, it is possible that patients might have received anti-TNF treatments before the pre-index assessment period.

Well-designed observational studies can be invaluable in gaining further understanding of response to therapy. Notable limitations of the study are inherent in the nature of observational studies. There exists the possibility of confounding by indication associated with lack of randomization, because other unmeasured factors might have influenced the selection of one anti-TNF agent over another, and variable reasons for changes in therapy may influence the outcomes. Also, the retrospective nature of the analysis prevented the collection of patient-reported outcomes. In addition, quantification of tender or swollen joints and radiographs to assess joint damage were not available. These factors may have also contributed to the lack of significant improvements among patients who received etanercept in this analysis. Although these patients did not show significant improvements in the clinical response measures used in this study, etanercept has been shown to be effective for treating RA in randomized, placebo-controlled clinical trials.4,6 This discrepancy may also be a result of the different methods used in measuring treatment response.

Conclusion Data from this analysis demonstrate the 2-year clinical effectiveness of anti-TNF therapy in patients with

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RA. This real-world study shows improvements in joint pain, joint swelling, joint stiffness, and fatigue. Overall clinical improvement was reported in 36.8% of the adalimumab group, 47.7% of the etanercept group, and 48.7% of the infliximab group over the 2-year followup period. These results are beneficial in that they provide confirmation that benefits seen in clinical trials are being translated into actual practice. Future observational research, with more uniform patient and provider assessments during the course of anti-TNF therapy, is warranted. â&#x2013; Acknowledgments The authors thank Rebecca E. Clemente, PhD, and Robert Achenbach of Centocor Ortho Biotech, Inc, for editorial support. Disclosure Statement This study was supported by funding from Centocor Ortho Biotech, Inc.

References 1. Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human antitumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum. 2003;48:35-45. 2. Lipsky PE, van der Heijde DM, St. Clair EW, et al, for the Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med. 2000;343:1594-1602. 3. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50:1400-1411. 4. van der Heijde D, Klareskog L, Rodriquez-Valverde V, et al. Comparison of etanercept and methotrexate, alone and combined, in the treatment of rheumatoid arthritis: two-year clinical and radiographic results from the TEMPO study, a doubleblind, randomized trial. Arthritis Rheum. 2006;54:1063-1074. 5. Maini RN, Breedveld FC, Kalden JR, et al. Sustained improvement over two years in physical function, structural damage, and signs and symptoms among patients with rheumatoid arthritis treated with infliximab and methotrexate. Arthritis Rheum. 2004;50:1051-1065. 6. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343: 1586-1593. 7. Wolfe F, Michaud K, DeWitt EM. Why results of clinical trials and observational studies of anti-tumour necrosis factor (anti-TNF) therapy differ: methodological and interpretive issues. Ann Rheum Dis. 2004;63(suppl 2):ii13-ii17. 8. Pincus T, Sokka T. Should contemporary rheumatoid arthritis clinical trials be more like standard patient care and vice versa? Ann Rheum Dis. 2004;63(suppl 2):ii32-ii39. 9. Hawley DJ, Wolfe F. Are the results of controlled clinical trials and observational studies of second line therapy in rheumatoid arthritis valid and generalizable as measures of rheumatoid arthritis outcome: analysis of 122 studies. J Rheumatol. 1991;18: 1008-1014. 10. Garrison LP Jr, Neumann PJ, Marshall D, Mullins CD. Using real-world data for coverage and payment decisions: the ISPOR real-world data task force report. Value Health. 2007;10:326-335. 11. Maini R, St Clair EW, Breedveld F, et al, for the ATTRACT Study Group. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT study group. Lancet. 1999;354:1932-1939. 12. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial. Ann Intern Med. 1999;130:478-486. 13. Breedveld FC, Weisman MH, Kavanaugh AF, et al, for the PREMIER Investigators. A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adali-

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Effectiveness of Anti-TNF Agents in Rheumatoid Arthritis

mumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54:26-37. 14. Taylor PC. Anti-TNF alpha therapy for rheumatoid arthritis: an update. Intern Med. 2003;42:15-20. 15. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 update. Arthritis Rheum. 2002;46:328-346. 16. Pincus T, Sokka T. Quantitative measures for assessing rheumatoid arthritis in clinical trials and clinical care. Best Pract Res Clin Rheumatol. 2003;17:753-781. 17. Furst DE, Halbert RJ, Bingham CO, et al. Evaluating the adequacy of disease control in patients with rheumatoid arthritis: a RAND appropriateness panel. Rheumatology (Oxford). 2008;47:194-199. Epub 2008 Jan 4. 18. Leeb BF, Andel I, Sautner J, et al. Disease activity measurement of rheumatoid arthritis: comparison of the simplified disease activity index (SDAI) and the dis-

ease activity score including 28 joints (DAS28) in daily routine. Arthritis Rheum. 2005;53:56-60. 19. Aletaha D, Smolen J. The simplified disease activity index (SDAI) and the clinical disease activity index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin Exp Rheumatol. 2005;23(5 suppl 39):S100-S108. 20. Kineret (anakinra). Prescribing information. Thousand Oaks, CA: Amgen Inc; 2001. 21. Orencia (abatacept). Prescribing information. Princeton, NJ: Bristol-Myers Squibb; 2008. 22. Rituxan (rituximab). South San Francisco, CA: Biogen, Idec Inc, and Genentech, Inc; 2008. 23. Zink A, Strangfeld A, Schneider M, et al. Effectiveness of tumor necrosis factor inhibitors in rheumatoid arthritis in an observational cohort study: comparison of patients according to their eligibility for major randomized clinical trials. Arthritis Rheum. 2006;54:3399-3407.

STAKEHOLDER PERSPECTIVE

Effectiveness of Anti-TNFs in Patients with RA, and Coverage Considerations PAYERS: Over the past several years, rheumatoid arthritis (RA) has become a difficult condition to manage from a managed care standpoint. Drugs for the treatment of RA are among the few medication classes to keep a double-digit trend year after year and have become some of the largest cost contributors on a percentage of per-member per-month basis. Anti-tumor necrosis factor (TNF) agents discussed in this article were the first medications for RA that broke $20,000 for 1 year of treatment. Recently, several anti-TNF biologics have been introduced to the market that have different modes of action but similar efficacy and similar cost. For these reasons, RA drugs have become a prominent concern for payers, including health insurance companies and employer groups. However, very little comparative data are available for these agents. Until such data become available, coverage decisions will need to be based solely on placebocontrolled trials, postmarketing claims-based or chartbased retrospective analysis, and cost. In 2008, the American College of Rheumatology (ACR) released its recommendations for the use of both nonbiologic disease-modifying antirheumatic drugs (DMARDs) and biologics.1 The recommendations emphasize the importance of starting therapy with traditional DMARDs, which may be much more cost-effective than starting immediately with a biologic. Another ACR recommendation is using a concomitant DMARD when a biologic is needed. The majority of clinical trials show a better response with biologics when used in combination with a DMARD such as methotrexate. However, several retrospective claims analyses have shown the combination use rate to be lower

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than might be expected (based on efficacy results from pivotal clinical trials). Another challenge has been the need to encourage providers to prescribe combination therapy in support of available evidence-based recommendations. Drug manufacturers will likely hesitate to conduct comparative trials for their products. This means more reliance on retrospective analysis or “realworld” data to determine if enough data are available to recommend coverage of one biologic over another for first-line treatment, after failure of a different biologic, as well as the extent or length of coverage for these products. PATIENTS: The past decade has given patients with RA several novel biologic options for the treatment of this painful, progressing condition. The variety of options also gives patients the opportunity to receive therapy at their provider’s office on a regular basis, or the option to receive a self-injectable therapy from their pharmacy or specialty pharmacy. Besides the difficult decision of determining the most appropriate therapy based on efficacy and safety, is the necessity of cost-sharing. Patients need to be insurance-savvy to realize not only which products may be covered but also the type and amount of costsharing that is required. Medical versus pharmacy benefit differences may also create challenges to understanding optimal coverage opportunities. 1. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59:762-784.

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

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Enhanced Generic Utilization Saved US Healthcare $139.6 Billion in 2009 By Dalia Buffery, MA, ABD

Table 1 Generic Drug Savings in 2000-2009 (in $ billions) $139

140 $121

120 $101

Sales, $

100 $78

80 60

$86

$60 $51

$65

$69

40 35

$32

30 25 20 15 10 5 0

$20

$18 $13 $5 2010

2011

2012

2013

2014

Used with permission from GPhA. Savings achieved through the use of generic pharmaceuticals 2000-2009. July 2010. Copyright © 2010 GPhA.

This growth trend can be expected to continue at least through 2014, as sales of top-selling brand-name agents will be losing their patent protection (Table 2), including 5 of the 10 best-selling pharmaceuticals— Lipitor, Plavix, Aricept, Singulair, and Zyprexa.1 Thus makers of generic drugs have their work cut out for the next 5 years, and payers can begin to design new strategies to capitalize on this enhanced cost-saving strategy. And those in charge of Medicaid state plans have room to implement new strategies to garner significant savings from improved generic utilization.

References

20 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

Used with permission from GPhA. Savings achieved through the use of generic pharmaceuticals 2000-2009. July 2010. Copyright © 2010 GPhA.

274

Table 2 Expected Brand-Name Sales to Expire by 2014 (in $ billions)

$55

40

0

translates to an additional $1-billion savings annually, but generics utilization by Medicaid beneficiaries is 10% lower than among non-Medicaid plan members • Utilization of generic central nervous system (CNS) drugs topped the list from 2008 ($41 billion) to 2009 ($49 billion), a 20% savings • The 3 therapeutic categories with the highest savings from generics in 2009 were CNS conditions, cardiovascular diseases, and metabolic disorders, totaling almost three fourths of the savings.

Sales, $

A

report prepared by IMS Health for the Generic Pharmaceutical Association (GPhA) and released in July 2010 shows that the utilization of generics substituted for brand-name products has been making great leaps since 2006.1 The report spans the decade from 2000 through 2009, comparing the rate of generic utilization in each of the past 10 years, and highlighting the exponential rate increase in the past 4 years (Table 1).1 This uptake in utilization has resulted in savings of $139.6 billion in 2009 alone, representing a 15% growth from the previous year. Not only does this mean a significant cost-reduction to the US healthcare system, it also represents a substantial share—inching toward 50%—of the net US sales of all prescription drugs, which amounted to $300.3 billion in 2009, according to IMS.2 Some of the key findings of the new report are1: • In the past decade, generic drugs have saved the US healthcare system $824 billion • Much of the increase in cost-savings in the past 3 years has been driven by new generic versions of blockbuster drugs, such as Norvasc, Zocor, and Zoloft • Substantial savings from generics are expected to continue in the next 5 years, when $89 billion in brandname drug sales will lose their patent protection • Every 2% increase in Medicaid generic drug utilization

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1. Generic Pharmaceutical Association. Savings achieved through the use of generic pharmaceuticals 2000-2009. July 2010. http://gphaonline.org/sites/default/ files/GPhA%20Savings%20Study%20Book%20Updated%20Web%20FINAL%20 Jul23%2010_0.pdf. Accessed August 2, 2010. 2. IMS Health. IMS Health reports US prescription sales grew 5.1 percent in 2009, to $300.3 billion. April 1, 2010. www.imshealth.com/portal/site/imshealth/menuitem. a46c6d4df3db4b3d88f611019418c22a/?vgnextoid=d690a27e9d5b7210VgnVCM10 0000ed152ca2RCRD&vgnextchannel=41a67900b55a5110VgnVCM10000071812 ca2RCRD&vgnextfmt=default. Accessed August 2, 2010.

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We Live And Breathe Generics.

Throughout every department in every facility within our domestic and global network, there is a singular commitment to generics that guides and drives every individual at Mylan. That commitment embodies everything we do and ensures that patients will have the affordable medicine that they need. It’s why our research and development team is constantly searching for innovative technologies; why our manufacturing team is always looking for more efficient ways to produce and distribute the generics in our ever-expanding line; and why our quality assurance team is continually monitoring our products to be sure they meet our standards. Our singular commitment has continued to earn us the trust of pharmacists who rank our products highest in quality* … and it’s why the Mylan name is synonymous with quality generics.

800.RX.MYLAN • www.mylanpharms.com *U.S. Pharmacist Generic Company Surveys. 2006-2009 ©2010 Mylan Pharmaceuticals Inc.

MYNMKT393A


BUSINESS

Comparing Medical Cost of Care for Patients with Metastatic Breast Cancer Receiving Taxane Therapy: Claims Analysis Rex W. Force, PharmD; Brooke A. Pugmire, PharmD; Vaughn L. Culbertson, PharmD Stakeholder Perspective, page 284

Background: It has been estimated that more than $8 billion is spent annually on the management of breast cancer in the United States. The taxane chemotherapeutic agents are cornerstones in the treatment of breast cancer, yet no study has assessed whether the choice of a taxane affects the economic outcomes of metastatic breast cancer treatment. Objective: To determine if differences exist in the medical cost of care in patients receiving taxane-based chemotherapy for metastatic breast cancer, and to compare the use of ancillary medications (for neutropenia, anemia, and nausea and vomiting) and their associated costs among taxanes. Method: We identified women with metastatic breast cancer based on diagnosis codes and the womenâ&#x20AC;&#x2122;s previous adjuvant chemotherapeutic regimens. Paid medical insurance claims were captured for the 24-month study period, from January 1, 2006, through December 31, 2007. The groups were determined according to the specific taxane administered. Total medical costs were captured from the date of first taxane administration to the end of data availability. Outpatient pharmacy costs were not available. A multivariate analysis was used to evaluate the total medical costs in each group. Median total medical costs per patient per month during the study period were adjusted using a multiple regression analysis. Utilization and cost of medications administered in the office or hospital for chemotherapy-induced adverse effects were captured and adjusted with Tobit models. Results: Of the 2245 study participants, 1035 received docetaxel, 997 received generic paclitaxel, and 213 received nab-paclitaxel. On average, patients in the nab-paclitaxel group received more doses (9.6) than those in the generic paclitaxel (6.0) or docetaxel (4.8) groups. The multivariate analysis was robust, explaining 72% of the variability in total medical costs across the 3 taxane groups. Median per-patient per-month total medical costs for study participants were within approximately $800 of each other among the groups. Generic paclitaxel had the lowest total medical costs. The total costs for docetaxel and nab-paclitaxel were not significantly different. Nab-paclitaxel had the lowest utilization and lowest costs associated with colony-stimulating factors. The proportion of patients receiving erythropoiesis-stimulating agents was not significantly different among the 3 drugs, but the costs for these agents were significantly lower in patients receiving nab-paclitaxel than in those receiving docetaxel. Antiemetic use was highest in the docetaxel group, but the costs for antiemetics were not different among the 3 taxane groups. Conclusion: The differences in total medical costs among the 3 taxanes were modest. Total medical costs were lowest for patients receiving generic paclitaxel and comparable between the docetaxel and nab-paclitaxel groups. Patients taking nab-paclitaxel received more doses than patients taking the other taxanes. Nab-paclitaxel was associated with lower utilization and costs for colony-stimulating factors compared with generic paclitaxel and docetaxel.

Rex W. Force

Am Health Drug Benefits. 2010;3(4):276-284. www.AHDBonline.com Disclosures are at end of text

Dr Force is Professor and Director of Research, Family Medicine and Pharmacy Practice, Idaho State University, and Partner, improveRX, LLC; Dr Pugmire is Clinical Assistant Professor, Pharmacy Practice, Idaho State University, and Clinical Project Manager, improveRX; Dr Culbertson is Professor, Pharmacy Practice, Idaho State University, and Partner, improveRX; all at Pocatello, ID.

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B

reast cancer is the most frequently diagnosed cancer in US women, and ranks second among cancer-related deaths in women, after lung cancer.1 It is estimated that $8.1 billion (in 2004 $US) in total healthcare costs are spent annually on breast cancer diagnosis and treatment in the United States.2 Chemotherapeutic agents represent a significant portion of the cost of breast cancer treatment, and health plans are managing these costs with care pathways and other utilization management strategies.

The Taxanes Taxanes are among the most frequently used forms of systemic therapy for the treatment of breast cancer.3 These chemotherapeutic agents can be prescribed alone or in combination with other systemic therapies or with local treatment, such as surgery and/or radiation. Taxanes are mitotic inhibitors originally isolated from the bark of the Pacific yew tree, Taxus brevifolia. Three taxanes are currently available in the United States, although this is an area of active drug development. The first of these agents to be marketed in the United States, paclitaxel injection (Taxol), was approved by the US Food and Drug Administration (FDA) in 1992 as an injectable formulation dissolved in a proprietary version of polyethoxylated castor oil called Cremophor EL and ethanol as a delivery agent.4 The second agent—docetaxel (Taxotere)—received FDA approval in 1996; docetaxel is a semisynthetic taxane dissolved in polysorbate 80 and 13% ethanol and water for injection.5 The toxicity of these 2 solvent-based taxanes includes bone marrow suppression (principally neutropenia), alopecia, and hypersensitivity reactions.6 Irizarry and colleagues reviewed 171 reported cases of anaphylaxis associated with the Cremophor EL–based paclitaxel. A total of 34% were fatal reactions, although the authors suggested that this adverse event (AE) is underreported.7 Although neurotoxicity and myalgias/ arthralgias have been cited as potential AEs with paclitaxel and docetaxel, these events are of greater clinical concern with paclitaxel—again, likely because of the Cremophor EL solvent.6 However, docetaxel has been associated with the development of significant fluid retention (eg, edema, ascites, pleural effusions), the incidence and severity of which appear to be reduced by premedication with corticosteroids.6 These toxicities may result in dose reductions, delays in continuation of treatment, or even discontinuation of chemotherapy. In an attempt to reduce the significant toxicity associated with the solvent-based taxanes, a new formulation of paclitaxel was developed—nab-paclitaxel (Abraxane)—in which the active drug is bound to albumin.8 Nab-paclitaxel received FDA approval in 2005.

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KEY POINTS ➤

Medication costs for oncology continue to increase dramatically. The treatment of metastatic breast cancer consists of several treatment modalities, including a taxane. Taxane use in metastatic breast cancer should be evaluated with cost of care analyses to account for differences in ancillary medication use, costs of complications, and other chemotherapeutic strategies. These factors contribute to total medical cost, which may be used as the primary outcome measure in a pharmacoeconomic evaluation rather than simply drug acquisition cost alone. This is the first study to evaluate the total cost of care for metastatic breast cancer from the perspective of taxane choice among the 3 available taxanes—generic paclitaxel, docetaxel, and nabpaclitaxel. Per-patient per-month medical costs for women receiving 1 of the 3 taxanes were within $800 of each other. As can be expected, generic paclitaxel was the least expensive. The overall costs of breast cancer management are related to the entire chemotherapeutic regimen, potential side effects, and costs of hospitalization. In this study, women receiving nab-paclitaxel had the lowest expenditures for colony-stimulating factors.

This albumin-bound paclitaxel has demonstrated superior efficacy over the solvent-based paclitaxel in the treatment of metastatic breast cancer (MBC), as well as a more favorable AE profile.9,10 Although the solvent-based taxanes—paclitaxel and docetaxel—have lower drug acquisition costs than nabpaclitaxel, nab-paclitaxel offers potential clinical advantages, such as better tumor responses with lower rates of severe neutropenia and infusion-related reactions.9,10 Systematic reviews have indicated that taxanes are among the most active regimens in MBC.11 However, differences in the toxicity and efficacy of the taxanes exist. Gradishar and colleagues found that nab-paclitaxel was associated with better response rates compared with the solvent-based generic paclitaxel in MBC (33% vs 19%, respectively; P = .001), with a longer time to tumor progression (23.0 weeks vs 16.9 weeks, respectively; P = .006).10 In addition, the rates of severe neutropenia were significantly lower in the nab-paclitaxel group (9% vs 22%, respectively; P <.001).10 Similarly, in another study, nab-paclitaxel was associated with a significantly longer progression-free survival (12.9 months vs 7.5 months, respectively; P = .0065) compared with docetaxel in women with MBC.12

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Grade-3 or -4 neutropenia occurred in 94% of the patients receiving docetaxel and in 38% of patients receiving nab-paclitaxel.12 To evaluate the economic implications of these differences in efficacy and toxicity, Dranitsaris and colleagues performed a pharmacoeconomic analysis of nabpaclitaxel in MBC.13 Nab-paclitaxel was less expensive than docetaxel per quality-adjusted life-year in the costutility model, but more expensive than generic paclitaxel.13 The disadvantages of this type of analysis include a variety of model assumptions that render the real-world implications of the results difficult to interpret by pharmacy and medical directors at health plans. In 2008, Barron and colleagues evaluated all-cause costs in women treated for breast cancer using claims from 5 US health plans.14 The authors reported mean unadjusted per-patient per-month (PPPM) all-cause costs of $4421 in women receiving treatment for breast cancer compared with PPPM costs of $3352 for agematched controls without breast cancer.14 The top 3 cost categories included hospitalizations, drug therapy, and surgical intervention.14 The components of total cost are of interest to payers, because they manage increasing costs associated with breast cancer treatment. PPPM cost calculations provide plan managers with an estimate of the cost of treating patients with a specific condition. These costs are quite different and generally much higher than typical actuarial estimates of permember per-month dollar amounts. The benefits and costs with any new treatment option need to be fully evaluated. At a December 2009 ICORE Healthcare Managed Care Advisory Board meeting in Bethesda, MD, payers questioned the value of nab-paclitaxel because of its higher acquisition cost. However, a comparison between nab-paclitaxel and solvent-based taxanes should include the costs associated with toxicity, drug utilization, and ancillary medication use rather than drug acquisition costs alone. These factors contribute to total medical cost, which may be used as the primary outcome measure in a pharmacoeconomic evaluation. To clarify these issues surrounding the use of the taxanes, we performed a pragmatic, retrospective evaluation of paid medical claims, with the intent of determining the impact of taxane choice on total medical costs in the treatment of MBC.

Methods This study was a cost comparison using paid medical claims from all locations of service from national commercial payer sources. Medical claims include all office visits, hospital charges, procedures (eg, laboratory tests, x-rays), and medications administered in the physician office, infusion center, or hospital. Total medical costs

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were derived from these data elements. Outpatient pharmacy claims and costs were not available and therefore were not included. Data were handled in compliance with the Health Insurance Portability and Accountability Act of 1996. Because the data analysis did not involve any patient intervention and used a limited data set with blinded patient identification, a certificate of exemption was obtained from our Institutional Review Board. The sponsor had no role in the study design, analysis, or writing of the paper. Investigators had exclusive access to the data and independently developed the research design and wrote the manuscript.

Study Population and Case Definitions The data set was derived from a total of 95,530,675 procedure claims from 6,130,088 unique patients (Ingenix Consulting, Eden Prairie, MN). Claims data were analyzed for 24 months, from January 1, 2006, to December 31, 2007. Only allowed charges from patients coded with a diagnosis of breast cancer were included in the final analysis. Patients receiving taxane therapy were identified using stepwise computerized algorithms to define a subset of taxane use in MBC (Figure 1). Initially, all patients with breast cancer with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code of 174.X were identified. Patients with a single taxane administration were then removed from the analysis. Next, patients who may have developed breast cancer as a secondary site were excluded (1) if any other cancer diagnosis (ICD-9-CM codes 140.XX-173.XX; 175.XX195.XX; and 200.XX-208.XX) occurred in the 6 months preceding the initial breast cancer diagnosis, or (2) if they received any chemotherapy other than office- or hospital-administered adriamycin-cyclophosphamide in the 6 months before their first breast cancer diagnosis. Taxane use within this subgroup was subject to the following criteria to define taxane use in MBC: • Taxane administration occurring more than 30 days after an established doxorubicin-cyclophosphamidetaxane adjuvant regimen • Concurrent (±3 days) taxane administration with either doxorubicin or cyclophosphamide in which doxorubicin-cyclophosphamide use did not conform to established adjuvant treatment regimens • Taxane administration occurring after a secondary (metastatic) cancer diagnosis (ICD-9-CM codes 140.XX-173.XX and 175.XX-199.XX) • Taxane use not described by these rules was eliminated from further analysis, because this subgroup of patients tended to have incomplete data and therefore an accurate assessment of chemotherapy use could not be done.

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Figure 1 Study Flow Diagram Breast cancera in 2006-2007 with ≥1 taxaneb dose (n = 6986)

Exclude patients with only 1 taxane dose (n = 1700)

Breast cancer with ≥2 taxane doses (n = 5286)

Exclude other primary cancer occurring before breast or second cancerc (n = 941)

Second cancer sitec after breast cancer diagnosis (n = 1676)

Breast cancer only (n = 2669)

Metastatic taxane use Taxane administration occurring: • After a new cancer diagnosis (n = 1152) • Where no established A-C adjuvant regimen could be identified after breast cancer diagnosis (n = 618) • After a breast cancer diagnosis where A-C were not administered on the same day (n = 475). Excluded taxane adjuvant or other regimens ➤ (n = 2100) ➤

Final metastatic group (n = 2245)

a ICD-9-CM diagnosis codes 174.0 to 174.9. b Taxanes include J codes J9170, J9264, and J9265. c

Secondary cancer, defined as any other primary cancer (ICD-9-CM codes 140.XX-195.XX or ICD-9-CM codes 196.XX-199.XX). A-C indicates adriamycin-cyclophosphamide; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification.

Drug use was identified by the following J codes: • J9170 indicating docetaxel 20 mg • J9265 indicating generic paclitaxel 30 mg • J9264 indicating nab-paclitaxel 1 mg. For analytical purposes, the index date was defined as the date of a patient’s first dose of taxane; from this point onward, total paid charges were captured. Patients were placed in generic paclitaxel, docetaxel, and nab-paclitaxel groups according to their first taxane use. Patients were not required to be continuously enrolled over the study

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period, because multiple regression analysis was used to adjust for individual patient enrollment period variability (eg, total months with a claim was a control variable).

Analytical Outcomes and Cost Analysis Mean age was determined for each of the 3 groups based on the patients’ date of birth and date of first taxane use (index date). The number of taxane doses received was determined. In addition, the mean dosing interval for each taxane was calculated; however, inter-

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Table 1 Sample Characteristics Drug

Patients, N

Total doses, Mean/patient (95% N CI)a

Mean interval, day (SD)

Mean database residence, mo (SD)

Docetaxel

1035

5009

5.9 (5.5-6.3)

20.5 (6.2)

12.6 (6.3)

Generic paclitaxel

997

6078

7.0 (6.6-7.3)

16.2 (8.8)

13.5 (6.4)

Nab-paclitaxel

213

2088

9.4 (8.5-10.2)

15.8 (8.9)

16.5 (6.6)

a

Adjusted for months of database residence. CI indicates confidence interval; SD, standard deviation.

vals longer than 60 days were excluded from the interval calculations. Duration of months in the database was measured from the date of first taxane administration (index date) to the time of last claim, because of disenrollment, end of the data period, or death. Chemotherapy and biologic agent utilization— specifically bevacizumab (Avastin), trastuzumab (Herceptin), gemcitabine (Gemzar), and vinorelbine (Navelbine)—was determined before, concurrent with, and post-taxane utilization; each was included as a control variable in the multivariate analysis (SAS, SAS Institute, Inc, Cary, NC). The total medical cost statistical model also adjusted for age; number of procedures (ie, office visits, hospitalizations, laboratory tests) after index date; number of unique diagnoses after index date; number of months with claims in the data set after index date; number of taxane doses; and the presence of a taxane claim in the first month. Procedures and diagnoses were included in the multivariate analysis and served as surrogates for severity of illness. Medical costs are reported in actual US dollars, from 2006 and 2007, without discounting. While adjusting for these variables, total medical cost comparisons were calculated, as well as PPPM total medical costs for managing patients with MBC for the 3 taxane groups. All medical costs were captured from the index date through the end of the data collection period, while controlling for the duration of available data and duration of enrollment for each patient. Utilization of ancillary medications was defined as a claim for colony-stimulating factors (CSFs) or erythropoiesis-stimulating agents (ESAs) between days 0 and +21, or antiemetics between days 0 and +5 after each taxane administration. Cost comparisons of CSFs or ESAs between days 0 and +21 after taxane administration, or antiemetics between days 0 and +5 after taxane administration, were made using Tobit models. Tobit models are utilized when the entire study population does not undergo the same interventions. For example, not all patients received CSFs; Tobit models can control for unbalanced utilization and allow for an

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appropriately adjusted evaluation of cost. For the purposes of this analysis, all the variables included in the multivariate analysis were also included in the Tobit analyses. Throughout the study, all comparisons were considered significantly different at P <.05.

Results Taxane Utilization A total of 2245 women with a mean (± standard deviation [SD]) age of 53 years (± 10 years) receiving a taxane for MBC were included in the study. The docetaxel group included 1035 patients, the generic paclitaxel group included 997 patients, and the nab-paclitaxel group included 213 patients. Mean (± SD) residence in the database was longer for patients receiving nab-paclitaxel (16.5 ± 6.6 months) compared with docetaxel (12.6 ± 6.3 months) and generic paclitaxel (13.5 ± 6.4 months). Nab-paclitaxel had a significantly higher mean number of doses per patient (9.4; 95% confidence interval [CI], 8.5-10.2), followed by generic paclitaxel (7.0; 95% CI, 6.6-7.3) and docetaxel (5.9; 95% CI, 5.5-6.3), which was adjusted for residence in the database by pairwise comparisons using the Bonferroni method. The mean (± SD) dosing intervals for patients receiving docetaxel, generic paclitaxel, and nab-paclitaxel were 20.5 ± 6.2 days, 16.2 ± 8.8 days, and 15.8 ± 8.9 days, respectively (Table 1). Other Chemotherapy Utilization A higher proportion of patients received chemotherapy before the initiation of nab-paclitaxel than before initiating either generic paclitaxel or docetaxel (P <.05 for both); a greater proportion of patients taking generic paclitaxel than patients taking docetaxel (P <.05) received previous chemotherapy (Table 2). The rate of concurrent chemotherapy use was greater in patients taking docetaxel compared with those taking generic paclitaxel or nab-paclitaxel (P <.05 for both); the use for the latter 2 drugs was not significantly different. Posttaxane chemotherapy utilization was not significantly different among the 3 groups (P >.05). Analyses of the concurrent use of bevacizumab

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revealed that a greater proportion of patients in the nabpaclitaxel group received bevacizumab concurrently compared with patients receiving generic paclitaxel and docetaxel, and the rate of patients using generic paclitaxel who received concurrent bevacizumab was greater (P <.05 for all) than patients taking docetaxel (Table 3). A higher proportion of patients receiving nab-paclitaxel also received bevacizumab after the taxane; the rate of bevacizumab use was greater after generic paclitaxel than after docetaxel (P <.05 for both), but the difference was not significant (P >.05) between patients receiving nabpaclitaxel and generic paclitaxel (Table 2). The proportion of patients receiving concurrent or post-taxane trastuzumab was not significantly different (P >.05) among the 3 groups (Table 3). The rate of patients using nab-paclitaxel who received concurrent and post-taxane gemcitabine was greater than in the generic paclitaxel and the docetaxel groups (P <.05 for both), which were not significantly different (P >.05) from each other in either setting. The proportion of patients taking nab-paclitaxel who received vinorelbine concurrently was greater than patients taking generic paclitaxel or docetaxel (P <.05 for both), and the proportion of generic paclitaxel patients who received concurrent vinorelbine was more than those taking docetaxel (P <.05). The proportion of patients receiving post-taxane vinorelbine was not significantly different among the 3 groups (P >.05).

Total Medical Cost Analysis The total medical cost model was robust (r2 = 0.72). Increased total medical cost was attributable to a number of factors, whereas decreased total medical cost was attributable to advancing age and previous chemotherapy (see Appendix at www.AHDBonline.com). Over the 24-month study period, adjusted median PPPM total medical costs were higher in patients receiving nab-paclitaxel ($3997; 95% CI, $3634-$4396) and docetaxel ($4042; 95% CI, $3844-$4251) (P <.05 for both comparisons) than in patients receiving generic paclitaxel ($3203; 95% CI, $3029-$3388). However, these costs were not significantly different between the nab-paclitaxel and docetaxel groups (Table 4). When nab-paclitaxel was used as the initial treatment, the adjusted total medical costs were 25% (95% CI, 15%-36%) higher than when generic paclitaxel was used first, holding other factors constant. Similarly, when docetaxel was used as the initial treatment, the adjusted total medical costs were 26% (95% CI, 20%33%) higher than when treatment was initiated with generic paclitaxel. There was no significant difference in adjusted total medical costs of care between docetaxel and nab-paclitaxel.

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Table 2 Before, Concurrent, and Post-Taxane Chemotherapy Use Generic Docetaxel paclitaxel (N = 1035) (N = 997)

Chemotherapy and taxane use Pre-taxane chemotherapy, % Concurrent taxanechemotherapy use, % Post-taxane chemotherapy, %

Nab-paclitaxel (N = 213)

34.4

43.0a

56.3b

73.8c

65.2

62.0

40.0

44.5

47.0

a P b P c

<.05 compared with docetaxel. <.05 compared with docetaxel and generic paclitaxel. P <.05 compared with generic paclitaxel and nab-paclitaxel.

Table 3 Concurrent and Post-Taxane Bevacizumab, Trastuzumab, Gemcitabine, and Vinorelbine Use Chemotherapy Generic concurrent/ Docetaxel paclitaxel Nab-paclitaxel post-taxane use (N = 1035), % (N = 997), % (N = 213), % 4.9 Concurrent 13.1a 36.6b bevacizumab 4.7 Post-taxane 7.6a 12.2a bevacizumab 23.6 25.3 27.2 Concurrent trastuzumab 18.5 19.6 15.5 Post-taxane trastuzumab 4.8 5.4 Concurrent 18.3b gemcitabine 6.8 8.2 Post-taxane 14.6b gemcitabine 1.8 Concurrent 3.9a 11.7b vinorelbine 3.6 Post-taxane 4.0 7.0 vinorelbine a P b

<.05 compared with docetaxel. P <.05 compared with docetaxel and generic paclitaxel.

Ancillary Medication Utilization and Cost Analysis In the analysis of ancillary medication use, rates of CSF use were significantly higher for docetaxel than for generic paclitaxel and nab-paclitaxel (P <.05 for both); the latter 2 agents were not significantly different (P >.05) from each other (Table 5). Rates of ESA use were not significantly different among the 3 groups (P >.05). Antiemetic use was significantly greater for docetaxel than for generic paclitaxel (P <.05) but not significantly different between nab-paclitaxel and generic paclitaxel or nab-paclitaxel and docetaxel (P >.05 for both; Table 5). Figure 2 outlines the differences in ancillary medica-

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Table 4 Per-Patient Per-Month Total Medical Costs of Care for the Taxanes in Metastatic Breast Cancer Adjusted median PPPM (95% CI), $ Generic paclitaxel

3203 (3029-3388)

Docetaxel

4042 (3844-4251)

Nab-paclitaxel

3997 (3634-4396)

CI indicates confidence interval; PPPM, per patient per month.

Table 5 Ancillary Medication Utilization among Patients Receiving a Taxane Ancillary Docetaxel Generic paclitaxel Nab-paclitaxel drug use (N = 1035), % (N = 997), % (N = 213), % CSFs

61.6a

43.4

38.0

ESAs

44.5

49.5

53.1

87.5

88.3

b

Antiemetics

92.6

a P b

<.05 compared with generic paclitaxel and nab-paclitaxel. P <.05 compared with generic paclitaxel with the Marascuillo procedure. CSFs indicates colony-stimulating factors; ESAs, erythropoiesis-stimulating agents.

Figure 2 Mean Ancillary Medication Costs per Member during 24 Months Compared with Docetaxel CSFs

ESAs

Antiemetics

2000 101

0

–552a

–136 –235

–2000 –4000 –6000 –8000

–7933a

Generic paclitaxel Nab-paclitaxel

–10,000 –12,000 –12,410a –14,000

a P <.05. CSFs indicates colony-stimulating factors; ESAs, erythropoiesis-stimulating agents.

tion costs associated with generic paclitaxel and nabpaclitaxel compared with docetaxel. Per-patient CSF costs were significantly lower with generic paclitaxel (–$7933) and with nab-paclitaxel (–$12,410) compared with docetaxel (P <.05); patients in the generic paclitaxel group had greater expenditures for CSFs compared with nab-paclitaxel (P <.05). Per-patient ESA costs were significantly lower with nab-paclitaxel (–$552) com-

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pared with docetaxel (P <.05). There were no differences in the costs of antiemetics between the groups (Figure 2).

Discussion In this retrospective claims analysis, we were able to identify patients with MBC and effectively control for an array of variables, while evaluating total medical costs in this population. This type of analysis reflects the expenditures incurred by a health plan and underscores the importance of a comprehensive analysis that controls for patient and treatment variability; this is preferred to a simple comparison of drug acquisition costs or of mean (or median) total medical costs. The median adjusted PPPM total medical costs for patients receiving taxanes for MBC were within about $800 of each other (Table 4). Median PPPM total medical costs for docetaxel and nab-paclitaxel were not statistically different, although total medical costs associated with generic paclitaxel treatment were about 25% lower than docetaxel and nab-paclitaxel when analyzed with multiple regression. The cost model explained 72% of the variability in total medical costs. To evaluate the total medical costs associated with the use of nab-paclitaxel instead of generic paclitaxel, we performed a post-hoc analysis of a hypothetical health plan covering 1 million lives. If the annual incidence of breast cancer is 122.9 per 100,000 patients and approximately 33% have MBC, then 406 patients ([1,000,000 ⳯ 0.001229] ⳯ 0.33 = 406) from the hypothetical cohort would have MBC.15 The median total PPPM medical cost difference between nab-paclitaxel and generic paclitaxel is $794 (Table 4). If this cost were distributed across the entire insured population, each 10% increase in the proportion of patients receiving nab-paclitaxel instead of generic paclitaxel would represent a $0.032 incremental increase in total medical expenditures per member per month. The patients receiving nab-paclitaxel would be expected to realize a reduction in neutropenia and related costs. In the present study, patients received more doses of nab-paclitaxel than either docetaxel or generic paclitaxel; this may be attributed to a number of factors, including stage of treatment, tolerability, and efficacy. Because nab-paclitaxel is often used in late-stage MBC,8 patients observed receiving this taxane might have required more aggressive treatment. This was confirmed in our study, because nab-paclitaxel was administered more frequently in combination with bevacizumab, gemcitabine, and vinorelbine, which were used more often by patients with advanced MBC. Other studies have underscored the impact of cost elements in addition to drug acquisition cost in determining total costs.3,14 An analysis by Barron and col-

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Comparing Medical Cost of Care for MBC

leagues demonstrated that the significant economic burden of breast cancer is driven mainly by hospitalizations, which contribute to the total cost at a rate more than twice that of chemotherapy.14 However, the costs of chemotherapy were significant, and the analysis was performed before the availability of several expensive agents used by patients with MBC.14 More recently, Kruse and colleagues found that chemotherapeutic agents accounted for nearly 60% of costs associated with breast cancer.3 In the present analysis, chemotherapy expenses (taxane plus all other chemotherapy) represented between 44% and 62% of unadjusted mean total medical costs, exclusive of outpatient pharmacy chemotherapy, in the 3 taxane groups. The sum of hospital, office visit, and other charges (eg, laboratory tests, x-rays) represented less than 41% of unadjusted mean total medical costs in the 3 taxane groups. In the analyses by Barron and colleagues and Kruse and colleagues, the mean PPPM total medical costs were $4996 and $4421, respectively,3,14 compared with our median values, which ranged from $3203 to $4042. In our analysis, patients receiving nab-paclitaxel had significantly lower expenditures for CSFs compared with docetaxel or generic paclitaxel. This may be explained by the improved tolerability and lower rates of neutropenia observed with the albumin-bound formulation. In a study based on a database of patients hospitalized for febrile neutropenia, Kuderer and colleagues concluded that a number of patient-specific factors, such as severity of disease, type of malignancy, and comorbidities contribute to increased mortality, length of stay, and hospitalization costs.16 Such factors should be taken into consideration, and appropriate therapies should be utilized, to address these concerns as a means of improving outcomes and controlling costs.

Limitations The most obvious limitation of this analysis is the retrospective nature of the study, which does not control for drug selection biases related to the stage of therapy. We went to considerable effort to identify patients with MBC; however, it is difficult to identify second- and third-line therapies in a relatively short period of followup. Continuous enrollment was not an inclusion criterion for patient selection, but duration of residence in the data set was used as a control variable. Requiring continuous enrollment of our population of patients with MBC would have significantly limited our sample sizes. Furthermore, in this type of analysis it is difficult to control for patient severity of illness, because the clinical status of the patient is not available. We did, however, control for the number of procedures and the number

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of unique diagnoses for the patients included in this analysis. Both of these variables were associated with significant increases in total costs. In addition, this analysis did not specifically identify AE rates, such as infusion-related AEs; however, the costs associated with AEs are included in the total medical cost calculations. These data represent a snapshot in time rather than a comprehensive view of disease progression from early- to late-stage illness. Tobit analyses have been criticized in healthcare claims analyses, because of highly variable costs over time. Although outpatient drug therapy costs were not captured, any bias should be equally applied across all 3 taxane groups. Finally, the clinical efficacy of the taxanes was not assessed in this study.

Conclusions Analysis of the myriad factors besides drug acquisition cost is necessary to make a determination of the costs of a particular therapy. The efficacy and tolerability of various treatments are reflected in total costs, where reductions in AEs and the use of ancillary medications offset higher drug acquisition costs. In the case of the taxanes, the overall costs of breast cancer management are related to the entire chemotherapeutic regimen, as well as to the costs of hospitalization. These factors contribute to total medical cost, which may be used as the primary outcome measure in a pharmacoeconomic evaluation rather than simply drug acquisition cost. In this analysis of total medical costs, generic paclitaxel was the least expensive, whereas nab-paclitaxel and docetaxel resulted in similar overall medical expenditures. â&#x2013; Acknowledgment The authors thank Teri Peterson, MS, for her assistance with the statistical analyses. Disclosure Statements This project was sponsored by Abraxis Oncology, manufacturer of Abraxane (nab-paclitaxel). The sponsor had no role in the study design, analysis, or writing of the manuscript. The investigators had exclusive access to the data and independently developed the research design and wrote this report. Dr Force, Dr Pugmire, and Dr Culbertson have received research/grant support from Abraxis and ICORE Healthcare. Dr Force is also a Consultant to Abraxis and ICORE Healthcare.

References 1. American Cancer Society. Cancer Facts & Figures 2008. Atlanta, GA: American Cancer Society; 2008. 2. Brown ML, Riley GF, Schussler N, Etzioni R. Estimating health care costs related to cancer treatment from SEER-Medicare data. Med Care. 2002;40(suppl 8):IV104-IV-117. 3. Kruse GB, Amonkar MM, Smith G, et al. Analysis of costs associated with admin-

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women with breast cancer. J Clin Oncol. 2005;23:7794-7803. Epub 2005 Sep 19. 11. Ghersi D, Wilcken N, Simes J, Donoghue E. Taxane containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 2005;2:CD003366. 12. Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly longer progressionfree survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009;27:3611-3619. Epub 2009 May 26. 13. Dranitsaris G, Cottrell W, Spirovski B, Hopkins S. Economic analysis of albumin-bound paclitaxel for the treatment of metastatic breast cancer. J Oncol Pharm Pract. 2009;15:67-78. Epub 2008 Nov 26. 14. Barron JJ, Quimbo R, Nikam PT, Amonkar MM. Assessing the economic burden of breast cancer in a US managed care population. Breast Cancer Res Treat. 2008;109:367-377. Epub 2007 Aug 3. 15. Horner MJ, Ries LAG, Krapcho M, et al (eds). SEER Cancer Statistics Review, 1975-2006. National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/statfacts/ html/breast.html. Accessed June 10, 2010. 16. Kuderer NM, Dale DC, Crawford J, et al. Mortality, morbidity, and cost associated with febrile neutropenia in adult cancer patients. Cancer. 2006;106:2258-2266.

istration of intravenous single-drug therapies in metastatic breast cancer in a U.S. population. J Manag Care Pharm. 2008;14:844-857. 4. Taxol (paclitaxel) injection prescribing information. New York, NY: Bristol-Myers Squibb; July 2007. 5. Taxotere (docetaxel) prescribing information. Bridgewater, NJ: sanofi-aventis; 2007. 6. Markman M. Managing taxane toxicities. Support Care Cancer. 2003;11:144-147. Epub 2002 Oct 15. 7. Irizarry LD, Luu TH, McKoy JM, et al. Cremophor EL-containing paclitaxelinduced anaphylaxis: a call to action. Community Oncol. 2009;6:132-134. 8. Abraxane (paclitaxel) prescribing information. Los Angeles, CA: Abraxis BioScience; 2007. 9. Desai, N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12:1317-1324. 10. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in

STAKEHOLDER PERSPECTIVE

Can We Afford Improved Clinical Outcomes? PAYERS: The beauty of this article by Force and colleagues is that it makes the reader think. In this day and age when we are all focused on cost of care, drug acquisition costs, cost-sharing, and the like, we tend to forget about clinical outcomes, and what is best for the patient. Although it is ideal to find therapies within a therapeutic class that are lowest in cost and provide equal or better clinical outcomes than comparator therapies, this is rarely the case. Have we found our answer based on the published results of this retrospective analysis? Metastatic breast cancer is a serious, life-threatening condition. Metastatic breast cancer treatment is very expensive. This is fact. The use of a generic product, paclitaxel, as the preferred taxane for treating metastatic breast cancer as the means to keep cost of care in check based on this article may be non sequitur. The National Comprehensive Cancer Network Clinical Practice Guidelines for breast cancer list all 3 marketed taxanes (paclitaxel, docetaxel, and nabpaclitaxel) as preferred agents for the treatment of metastatic breast cancer.1 The product labeling for nab-paclitaxel cites a clinical trial that compared nab-paclitaxel with paclitaxel and demonstrated significantly better overall response rate with nab-paclitaxel.2 In addition, several clinical trials cited in this article demonstrated advantages for using nab-paclitaxel compared with paclitaxel and docetaxel in terms of progression-free survival and lower rates of adverse events. Note, however, that nab-paclitaxel has not demonstrated better overall survival compared with paclitaxel. Force and colleagues found that the per-patient permonth medical cost of care was approximately $800 lower with paclitaxel compared with nab-paclitaxel or

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docetaxel. When comparing nab-paclitaxel and docetaxel, there was no significant difference in cost of care. Patients receiving nab-paclitaxel received more doses than patients receiving the other taxanes, and these patients also had the lowest utilization and costs associated with colony-stimulating factors. The limitations of this study were few but significant. This is a retrospective study that does not control for drug selection based on the stage of therapy. It is also difficult to control for severity of illness in a retrospective study. Finally, the clinical efficacy of the taxanes was not assessed in this study. Many payers have already implemented strategies making paclitaxel the preferred taxane for their membership, based on its generic availability and its acquisition costs that are lower than for the other taxanes. These payers can demonstrate significant savings related to drug cost trends and spending. It would be interesting to evaluate the impact of taxane product preferencing on clinical outcomes in addition to drug cost trends and spending. I am confident that payers put more importance on improved clinical outcomes than on cost trends. When implementing product preferencing strategies, proactively developing analyses that demonstrate improved clinical outcomes while resulting in costsavings is what the industry needs. 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer V.2.2010. www.nccn.org/professionals/physician_ gls/PDF/breast.pdf. Accessed July 23, 2010. 2. Abraxane (paclitaxel protein-bound particles for injectable suspension). Prescribing information. Bridgewater, NJ: Abraxis Bioscience; March 2010.

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Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy

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For your members with moderate to severe plaque psoriasis

Indication STELARA™ is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Dosing STELARA™ is administered by subcutaneous injection. • For patients weighing ≤100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks • For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks In patients weighing >100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these patients. The safety and efficacy of STELARA™ have not been evaluated beyond two years.

Dosage forms and strengths STELARA™ contains 90 mg of ustekinumab per mL. • 45 mg/0.5 mL in a single-use, prefilled syringe, with an NDC number of 57894-060-03 • 90 mg/1 mL in a single-use, prefilled syringe, with an NDC number of 57894-061-03

Please see Important Safety Information and Brief Summary of Prescribing Information for STELARA™ on the following pages. www.STELARAinfo.com


IMPORTANT SAFETY INFORMATION Infections STELARA™ may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were reported. Infections requiring hospitalization included cellulitis, diverticulitis, osteomyelitis, gastroenteritis, pneumonia, and urinary tract infections. STELARA™ should not be given to patients with a clinically important active infection and should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering use of STELARA™ in patients with a chronic infection or a history of recurrent infection. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacterium, Salmonella, and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA™ will be susceptible to these types of infections. Consider appropriate diagnostic testing as dictated by clinical circumstances. Pre-Treatment Evaluation of Tuberculosis (TB) Evaluate patients for TB prior to initiating treatment with STELARA™. STELARA™ should not be given to patients with active TB. Initiate treatment of latent TB before administering STELARA™. Patients should be monitored closely for signs and symptoms of active TB during and after treatment with STELARA™. Malignancies STELARA™ is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among patients who received STELARA™ in clinical studies. The safety of STELARA™ has not been evaluated in patients who have a history of malignancy or who have a known malignancy. Reversible Posterior Leukoencephalopathy Syndrome (RPLS) One case of RPLS has been reported in a STELARA™-treated patient. If RPLS is suspected, discontinue STELARA™ and administer appropriate treatment. RPLS is a neurological disorder, which is not caused by an infection or demyelination. RPLS can present with headache, seizures, confusion, and visual disturbances. RPLS has been associated with fatal outcomes. Immunizations Prior to initiating therapy with STELARA™, patients should receive all immunizations recommended by current guidelines. Patients being treated with STELARA™ should not receive live vaccines. BCG vaccines should not be given during treatment or within one year of initiating or discontinuing STELARA™. Exercise caution when administering live vaccines to household contacts of STELARA™ patients, as shedding and subsequent transmission to STELARA™ patients may occur. Non-live vaccinations received during a course of STELARA™ may not elicit an immune response sufficient to prevent disease. Concomitant Therapies The safety of STELARA™ in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone. The relevance of these findings in mouse models for malignancy risk in humans is unknown.

Please see Brief Summary of Prescribing Information for STELARA™ on the following page. Reference: STELARA™ Prescribing Information 12/2009. Horsham, PA: Centocor Ortho Biotech Inc.

representing the products of www.STELARAinfo.com

©2010 Centocor Ortho Biotech Services, LLC

4/10

25STPMC10012

25US10030

Most Common Adverse Reactions The most common adverse reactions (≥3% and higher than that with placebo) in clinical trials for STELARA™ 45 mg, STELARA™ 90 mg, or placebo were: nasopharyngitis (8%, 7%, 8%), upper respiratory tract infection (5%, 4%, 5%), headache (5%, 5%, 3%), and fatigue (3%, 3%, 2%), respectively.


Brief Summary of Prescribing Information for STELARA™ (ustekinumab) STELARA™ Injection, for subcutaneous use See package insert for Full Prescribing Information INDICATIONS AND USAGE: STELARA™ is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. CONTRAINDICATIONS: None. WARNINGS AND PRECAUTIONS: Infections STELARA™ may increase the risk of infections and reactivation of latent infections. Serious bacterial, fungal, and viral infections were observed in subjects receiving STELARA™ (see Adverse Reactions). STELARA™ should not be given to patients with any clinically important active infection. STELARA™ should not be administered until the infection resolves or is adequately treated. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. Exercise caution when considering the use of STELARA™ in patients with a chronic infection or a history of recurrent infection. Serious infections requiring hospitalization occurred in the psoriasis development program. These serious infections included cellulitis, diverticulitis, osteomyelitis, viral infections, gastroenteritis, pneumonia, and urinary tract infections. Theoretical Risk for Vulnerability to Particular Infections Individuals genetically deficient in IL-12/IL-23 are particularly vulnerable to disseminated infections from mycobacteria (including nontuberculous, environmental mycobacteria), salmonella (including nontyphi strains), and Bacillus Calmette-Guerin (BCG) vaccinations. Serious infections and fatal outcomes have been reported in such patients. It is not known whether patients with pharmacologic blockade of IL-12/IL-23 from treatment with STELARA™ will be susceptible to these types of infections. Appropriate diagnostic testing should be considered, e.g., tissue culture, stool culture, as dictated by clinical circumstances. Pre-treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis infection prior to initiating treatment with STELARA™. Do not administer STELARA™ to patients with active tuberculosis. Initiate treatment of latent tuberculosis prior to administering STELARA™. Consider anti-tuberculosis therapy prior to initiation of STELARA™ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. Patients receiving STELARA™ should be monitored closely for signs and symptoms of active tuberculosis during and after treatment. Malignancies STELARA™ is an immunosuppressant and may increase the risk of malignancy. Malignancies were reported among subjects who received STELARA™ in clinical studies (see Adverse Reactions). In rodent models, inhibition of IL-12/IL-23p40 increased the risk of malignancy (see Nonclinical Toxicology). The safety of STELARA™ has not been evaluated in patients who have a history of malignancy or who have a known malignancy. Reversible Posterior Leukoencephalopathy Syndrome One case of reversible posterior leukoencephalopathy syndrome (RPLS) was observed during the clinical development program which included 3523 STELARA™-treated subjects. The subject, who had received 12 doses of STELARA™ over approximately two years, presented with headache, seizures and confusion. No additional STELARA™ injections were administered and the subject fully recovered with appropriate treatment. RPLS is a neurological disorder, which is not caused by demyelination or a known infectious agent. RPLS can present with headache, seizures, confusion and visual disturbances. Conditions with which it has been associated include preeclampsia, eclampsia, acute hypertension, cytotoxic agents and immunosuppressive therapy. Fatal outcomes have been reported. If RPLS is suspected, STELARA™ should be discontinued and appropriate treatment administered. Immunizations Prior to initiating therapy with STELARA™, patients should receive all immunizations appropriate for age as recommended by current immunization guidelines. Patients being treated with STELARA™ should not receive live vaccines. BCG vaccines should not be given during treatment with STELARA™ or for one year prior to initiating treatment or one year following discontinuation of treatment. Caution is advised when administering live vaccines to household contacts of patients receiving STELARA™ because of the potential risk for shedding from the household contact and transmission to patient. Non-live vaccinations received during a course of STELARA™ may not elicit an immune response sufficient to prevent disease. Concomitant Therapies The safety of STELARA™ in combination with other immunosuppressive agents or phototherapy has not been evaluated. Ultraviolet-induced skin cancers developed earlier and more frequently in mice genetically manipulated to be deficient in both IL-12 and IL-23 or IL-12 alone (see Nonclinical Toxicology). ADVERSE REACTIONS: The following serious adverse reactions are discussed elsewhere in the label: Infections (see Warnings and Precautions); Malignancies (see Warnings and Precautions); and RPLS (see Warnings and Precautions). Clinical Studies Experience The safety data reflect exposure to STELARA™ in 2266 psoriasis subjects, including 1970 exposed for at least 6 months, 1285 exposed for at least one year, and 373 exposed for at least 18 months. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions listed below are those that occurred at a rate of at least 1% and at a higher rate in the STELARA™ groups than the placebo group during the placebo-controlled period of STUDY 1 and STUDY 2. The numbers (percentages) of adverse reactions reported for placebo-treated patients (n=665), patients treated with 45 mg STELARA™ (n=664), and patients treated with 90 mg STELARA™ (n=666), respectively, were: Nasopharyngitis: 51 (8%), 56 (8%), 49 (7%); Upper respiratory tract infection: 30 (5%), 36 (5%), 28 (4%); Headache: 23 (3%), 33 (5%), 32 (5%); Fatigue: 14 (2%), 18 (3%), 17 (3%); Diarrhea: 12 (2%), 13 (2%), 13 (2%); Back pain: 8 (1%), 9 (1%), 14 (2%); Dizziness: 8 (1%), 8 (1%), 14 (2%); Pharyngolaryngeal pain: 7 (1%), 9 (1%), 12 (2%); Pruritus: 9 (1%), 10 (2%), 9 (1%); Injection site erythema: 3 (<1%), 6 (1%), 13 (2%); Myalgia: 4 (1%), 7 (1%), 8 (1%); Depression: 3 (<1%), 8 (1%), 4 (1%). Adverse drug reactions that occurred at rates less than 1% included: cellulitis and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, bruising, and irritation). One case of RPLS occurred during clinical trials (see Warnings and Precautions). Infections In the placebo-controlled period of clinical studies of psoriasis subjects (average follow-up of 12.6 weeks for placebo-treated subjects and 13.4 weeks for STELARA™-treated subjects), 27% of STELARA™-treated subjects reported infections (1.39 per subject-year of follow-up) compared with 24% of placebo-treated subjects (1.21 per subject-year of follow-up). Serious infections occurred in 0.3% of STELARA™-treated subjects (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated subjects (0.02 per subject-year of follow-up) (see Warnings and Precautions). In the controlled and non-controlled portions of psoriasis clinical trials, 61% of STELARA™-treated subjects reported infections (1.24 per subject-year of follow-up).

Serious infections were reported in 0.9% of subjects (0.01 per subject-year of follow-up). Malignancies In the controlled and non-controlled portions of psoriasis clinical trials, 0.4% of STELARA™-treated subjects reported malignancies excluding non-melanoma skin cancers (0.36 per 100 subject-years of follow-up). Non-melanoma skin cancer was reported in 0.8% of STELARA™-treated subjects (0.80 per 100 subject-years of follow-up) (see Warnings and Precautions). Serious malignancies included breast, colon, head and neck, kidney, prostate, and thyroid cancers. Immunogenicity The presence of ustekinumab in the serum can interfere with the detection of anti-ustekinumab antibodies resulting in inconclusive results due to assay interference. In STUDIES 1 and 2, antibody testing was done at time points when ustekinumab may have been present in the serum. In STUDY 1 the last ustekinumab injection was between Weeks 28 and 48 and the last test for anti-ustekinumab antibodies was at Week 52. In STUDY 2 the last ustekinumab injection was at Week 16 and the last test for anti-ustekinumab antibodies was at Week 24. In STUDY 1 (N=743), antibody results were found to be positive, negative, and inconclusive in 38 (5%), 351 (47%), and 354 (48%) patients, respectively. In STUDY 2 (N=1198), antibody results were found to be positive, negative, and inconclusive in 33 (3%), 90 (8%), and 1075 (90%) patients, respectively. The data reflect the percentage of subjects whose test results were positive for antibodies to ustekinumab in a bridging immunoassay, and are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications and underlying disease. For these reasons, comparison of the incidence of antibodies to ustekinumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: Drug interaction studies have not been conducted with STELARA™. Live Vaccines Live vaccines should not be given concurrently with STELARA™ (see Warnings and Precautions). Concomitant Therapies The safety of STELARA™ in combination with immunosuppressive agents or phototherapy has not been evaluated (see Warnings and Precautions). CYP450 Substrates The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNF , IFN) during chronic inflammation. Thus, ustekinumab could normalize the formation of CYP450 enzymes. A role for IL-12 or IL-23 in the regulation of CYP450 enzymes has not been reported. However, upon initiation of ustekinumab in patients who are receiving concomitant CYP450 substrates, particularly those with a narrow therapeutic index, monitoring for therapeutic effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) should be considered and the individual dose of the drug adjusted as needed (see Clinical Pharmacology). USE IN SPECIFIC POPULATIONS: Pregnancy Pregnancy Category B There are no studies of STELARA™ in pregnant women. STELARA™ should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. No teratogenic effects were observed in the developmental and reproductive toxicology studies performed in cynomolgus monkeys at doses up to 45 mg/kg ustekinumab, which is 45 times (based on mg/kg) the highest intended clinical dose in psoriasis patients (approximately 1 mg/kg based on administration of a 90 mg dose to a 90 kg psoriasis patient). Ustekinumab was tested in two embryo-fetal development toxicity studies. Pregnant cynomolgus monkeys were administered ustekinumab at doses up to 45 mg/kg during the period of organogenesis either twice weekly via subcutaneous injections or weekly by intravenous injections. No significant adverse developmental effects were noted in either study. In an embryo-fetal development and pre- and post-natal development toxicity study, three groups of 20 pregnant cynomolgus monkeys were administered subcutaneous doses of 0, 22.5, or 45 mg/kg ustekinumab twice weekly from the beginning of organogenesis in cynomolgus monkeys to Day 33 after delivery. There were no treatment-related effects on mortality, clinical signs, body weight, food consumption, hematology, or serum biochemistry in dams. Fetal losses occurred in six control monkeys, six 22.5 mg/kg-treated monkeys, and five 45 mg/kg-treated monkeys. Neonatal deaths occurred in one 22.5 mg/kg-treated monkey and in one 45 mg/kg-treated monkey. No ustekinumab-related abnormalities were observed in the neonates from birth through six months of age in clinical signs, body weight, hematology, or serum biochemistry. There were no treatment-related effects on functional development until weaning, functional development after weaning, morphological development, immunological development, and gross and histopathological examinations of offsprings by the age of 6 months. Nursing Mothers Caution should be exercised when STELARA™ is administered to a nursing woman. The unknown risks to the infant from gastrointestinal or systemic exposure to ustekinumab should be weighed against the known benefits of breast-feeding. Ustekinumab is excreted in the milk of lactating monkeys administered ustekinumab. IgG is excreted in human milk, so it is expected that STELARA™ will be present in human milk. It is not known if ustekinumab is absorbed systemically after ingestion; however, published data suggest that antibodies in breast milk do not enter the neonatal and infant circulation in substantial amounts. Pediatric Use Safety and effectiveness of STELARA™ in pediatric patients have not been evaluated. Geriatric Use Of the 2266 psoriasis subjects exposed to STELARA™, a total of 131 were 65 years or older, and 14 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects. OVERDOSAGE: Single doses up to 4.5 mg/kg intravenously have been administered in clinical studies without dose-limiting toxicity. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment be instituted immediately. PATIENT COUNSELING INFORMATION: Instruct patients to read the Medication Guide before starting STELARA™ therapy and to reread the Medication Guide each time the prescription is renewed. Infections Inform patients that STELARA™ may lower the ability of their immune system to fight infections. Instruct patients of the importance of communicating any history of infections to the doctor, and contacting their doctor if they develop any symptoms of infection. Malignancies Patients should be counseled about the risk of malignancies while receiving STELARA™. Prefilled Syringe Manufactured by: Vial Manufactured by: Centocor Ortho Biotech Inc., Centocor Ortho Biotech Inc., Horsham, PA 19044, Horsham, PA 19044, License No. 1821 at License No. 1821 at Baxter Pharmaceutical Solutions, Cilag AG, Bloomington, IN 47403 Schaffhausen, Switzerland 1-800-457-6399 25US10041 © Centocor Ortho Biotech Inc. 2009 December 2009


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HEALTHCARE REFORM

The Impact of Healthcare Reform on Payers’ Products, Provider Reimbursement, and Member Engagement Sam Muppalla and Robert Capobianco

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Sam Muppalla

he Healthcare Reform Act—officially called the Patient Protection and Affordable Care Act (PPACA)—institutes sweeping changes across all healthcare stakeholders, including payers, providers, and plan members. In fact, the amount of change required by the PPACA is so extensive, distilling all the changes down and accounting for their impact is a serious challenge for the industry as a whole. However, if we focus on the apparent macro changes that affect payers—an increase in competition for the group market, an increase in overall access, and new regulations on expense caps for medical costs—a rational set of assumptions becomes apparent for predicting the direct impact on stakeholders. The implementation of these changes will cause payers to: 1. Develop new products and provider networks that are aligned based on the benefit structure and the needs of the covered population; these tailored, personalized products and provider networks will enable payers to more effectively serve their customers’ needs 2. Design new provider-reimbursement models that shift methodology from paying for individual services to reimbursing for improved member health and wellness, the latter being driven by provider performance, quality measurement, and member outcomes 3. Create new provider- and member-engagement strategies that enable greater information sharing and transparency for improved decision support 4. Implement/redesign internal payer processes to further drive down administrative costs. Although some reform requirements have enactment dates as far as 2018, we consider reform a complete overhaul of the healthcare system, necessitating a phased approach to ensure success. Payers, providers, and plan members need to begin preparing for these changes, because the changes will affect the traditional stakeholder relationships we take part in today.

Mr Muppalla is Executive Vice President and Chief Strategy and Marketing Officer, and Mr Capobianco is Director of Marketing, Portico Systems, Blue Bell, PA.

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Greater Differentiation for Payer Products The needs of plan members vary across the spectrum of benefit designs—some need only preventive health benefits, whereas others require preventive and catastrophic coverage levels. The PPACA will drive approximately 32 million more members into the healthcare system.1 Some of these new members will fall into traditional lines of business for a payer; however, estimates by the Congressional Budget Office and PriceWaterhouseCoopers predict that these members will drive expansion in the individual market.2 The government-mandated healthcare exchanges, stipulated by the PPACA, are poised to be the principal avenue for competition within the individual market. The benefit structures will be defined by the government, so the area for differentiation from the payer’s perspective will be on price, the member’s experience, and compatibility of the network with the plan member’s needs. In addition, as the individual insurance market increases, the group insurance market is estimated to decrease by 3 million members.2 This potential decrease in the member population, coupled with increased payer dependence on the profitability experience in the group market, will cause increased competition for the valued group customer. Continued emphasis on differentiation by product and network, furthered by benefit designs that align with a group’s individual healthcare needs, will drive success in this area of the payer market. Redefining Provider-Reimbursement Models Along with membership population changes, the regulatory change that excludes payers from denying coverage, combined with the change that institutes new spending caps on medical costs, is already beginning to drive innovation in provider-reimbursement methodologies. Traditional fee-for-service (FFS) reimbursement methodologies do not enable payers to optimally manage new member populations with fluctuating/nonpredictable risk profiles, and they do not account for physician/provider performance and quality programs.

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The Massachusetts Attorney General’s 2010 report, Examination of Health Care Cost Trends and Cost Drivers,3 provides evidence supporting the need for changes in the reimbursement model. The report relates substantial evidence that nonstandard and non–quality-based provider contracts are a major contributor to rising healthcare costs.3 The emergence of provider reimbursement models based on episodic and global payments is likely in reaction to these developments. These reimbursement models will not completely eliminate the FFS model, but they enable hybrid pricing models that combine FFS payments with reimbursement payments for the delivery of reliable evidence-based care.

ment in point-of-service tools, such as electronic medical records, e-prescribing, and e-laboratory order entry systems. These assets between payers and providers are needed to facilitate the exchange and analysis of clinical information by all parties to better serve members and improve their overall health status. The member’s interactions with their providers and payers will also take on a new dynamic. With the rise of an individual market and a likely acceleration of payer products like health savings accounts, members will share a greater amount of financial responsibility for the care services provided. In line with this greater financial responsibility, payers and providers will need to be able to provide quality and cost information to members in a more seamless and transparent fashion to improve member decision-making capability.

Changing Payer-to-Provider-to-Member Engagement Models Although these reimbursement and product changes are derivative in nature, stemming from changes in multiple parts of the PPACA, the anticipated payer-toprovider-to-member engagement changes are primarily driven by the PPACA’s call for improved collaboration and information-sharing among all stakeholders. The PPACA reignites the focus on how to increase the clinical collaboration between payers and providers and how to better engage members to improve their healthcare decisions. The healthcare marketplace has shown movement in this direction via patient-centered medical home pilot projects and other team-based delivery programs. Such programs intend to facilitate evidence-based medicine and coordination between the care-delivery team and the particular member’s care program. These types of collaborative care environments, in conjunction with the American Reinvestment and Recovery Act, are fueling a new round of payer invest-

Conclusion As a result of increased competition, expanded access, and amplified cost-containment pressures caused by the Reform Act, payers will need to change their operational DNA to achieve product differentiation, administrative and medical cost-containment, and quality-based relationships with their provider networks. Changes in the payer industry will have a ripple effect, driving all stakeholders toward taking the evolutionary steps necessary for successful operation in the overhauled healthcare delivery system of tomorrow. References 1. Congressional Budget Office. Letter to Nancy Pelosi. March 20, 2010. www.cbo. gov/ftpdocs/113xx/doc11379/AmendReconProp.pdf. Accessed June 30, 2010. 2. PriceWaterhouseCoopers’ Health Research Institute. Health Reform: Prospering in a Post-reform World. May 2010. http://pwchealth.com/cgi-local/hcregister. cgi?link=reg/prospering-in-a-post-reform-world.pdf. Accessed June 30, 2010. 3. Office of Attorney General Martha Coakley, Examination of Health Care Cost Trends and Cost Drivers. March 16, 2010. www.mass.gov/Cago/docs/healthcare/ final_report_w_cover_appendices_glossary.pdf. Accessed June 30, 2010.

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INDUSTRY TRENDS

The Current State of Bundled Payments Jim Evans Vice President, McKesson Health Solutions

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uch attention is now focused on bundled payment as a promising mechanism of healthcare reform. Early signs point to the potential of this initiative to reduce fragmentation in healthcare delivery, while improving quality and addressing spiraling costs. Bundled payment requires the involved parties to agree on a defined package of care and services for a particular condition; this treatment episode is then paid in a single payment that is apportioned among multiple providers (both professionals and facilities) across many settings. This bundled payment—or “episode-based payment”— is currently the subject of ongoing pilot projects across the United States. Payer and provider organizations can learn from these experiments as they shape their own programs and then bring them to scale.

Successful Experiments One of the earliest experiments in bundled payment began with a Medicare pilot program in the early 1990s for a handful of surgical procedures. Within the next decade, global payments became more widely used for certain procedures; obstetrics may be the best-known, with a single payment for prenatal and postdelivery professional services and often a separate diagnosis-related group payment to the hospital for facility services. Episode-based payment expands the scope of global payment into a single payment shared by multiple providers as a means to encourage care coordination. Several successful experiments have been seen primarily in staff models or integrated healthcare settings. Geisinger’s ProvenCare. The most notable example is the ProvenCare program at Geisinger Health System in Pennsylvania, which accepts a single payment for several procedures, including elective coronary artery bypass graft (CABG), percutaneous transluminal coronary angioplasty, total hip replacement, cataract surgery, and low back pain treatment.1 Using evidence-based medicine and other input from professional associations, Geisinger defined critical patient care steps that must be accomplished in each clearly defined bundle.1,2 To ensure quality, physician payment may be tied, in part, to adherence to process-of-care performance measures.3 Results at Geisinger have included reduced

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lengths of stay, lower readmission rates, and outcomes that exceed national averages.1 Medicare. Recently, the Centers for Medicare & Medicaid Services launched the Acute Care Episode Demonstration project at 5 sites in 4 states to test bundled payments for Medicare Part A (for inpatient hospital care, skilled nursing care, and hospice care) and Medicare Part B (includes doctors’ fees and outpatient hospital visits) for 9 orthopedic and 28 cardiac inpatient surgical services and procedures. A portion of the costsavings is designated to be shared with Medicare beneficiaries. Results are expected after 2013.4 Prometheus. The Prometheus Payment model, sponsored largely by the Robert Wood Johnson Foundation, is the subject of ongoing pilot projects. The model takes into account 3 components in determining payment5: • Evidence-informed base payment • Patient-specific severity adjustment • Allowance for “potentially avoidable complications.” This last element is essential in most current bundled payment scenarios. If complications are avoided, the providers may be paid more than they would have received under conventional fee-for-service, with the ultimate aim of reducing complications and overall cost. Although this retrospective approach limits the opportunity to influence provider behavior, the Prometheus model continues to provide an important example as experiments in bundled payment move forward.

Lessons from Early Initiatives: Payer-Provider Collaboration, and Transparency A key lesson learned from these early initiatives is that clinicians must play a leading role in decision-making—physicians need to be involved in defining the bundle, in managing care, and in defining the responsibility of each provider involved. Transparency is also critical. This requires a fundamental cultural shift away from adversarial relationships between payers and providers. Bundled payments should represent a true alignment of incentives among the payer, provider, and the patient. All providers and patients must have access to what they can expect with a bundled payment, what the bundle includes and excludes, who the participants are, and how it all works.

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Everyone needs to know what they stand to gain through better coordination and quality of care. To recruit members, plans may need to remind them that providers involved in any bundled payment initiative typically are those who meet quality standards and are committed to working collaboratively to achieve the best patient outcomes. Patients also may be expected to play a role, as they do in the Geisinger program, by signing a “patient compact” that they will comply with care recommendations.

Tools and Processes Require Automation Most experiments in bundled payments thus far have occurred in staff model organizations (in which the physicians work for the organization), prompting the questions of how and whether these successes can be adapted in more open networks. The answer lies in automation, which can create a virtual system to achieve similar results. Automation will be essential to bring to scale the experiments that now rely on manual processes during their pilot phases. Contract management, claim processing, and waste and abuse functions must be integrated to support new payment frameworks. This requires: • Episodes of care that are defined in such a way that logic can be built and applied in an automated fashion • Dynamic contracting that incorporates episodes of care terms and definitions • Systems that automatically convert contract terms to terms in the payment system • Claims processing technology that can look across facility and professional claims, and across time, to associate all services that should be included or excluded as part of an episode of care; slow response may result in inappropriate payment, which could jeopardize payer confidence • Autoadjudication of complex contracts with multiple payment arrangements • The ability to apply clinical knowledge to claim payment decisions so that payments will be defensible to providers • Waste and abuse systems that can detect new means of inappropriate optimization of payment that may spring up in response to a new payment model

• Interoperability between payment and quality data • Systems with the flexibility to adapt as new payment mechanisms evolve • Transparency among all stakeholders.

Time Is Ripe to Start a Pilot Project A good starting point for organizations that wish to design a bundled payment project is to focus on what you, or your providers, do best, and to create partnerships with those providers. Hospitals are probably in the best position to spearhead quality improvements around bundled payments by creating incentives for care coordination. The areas that are well-suited for initial ventures into bundled payment are high-complexity procedures that are common, well-defined, and have a clear standard of care, such as joint replacement, CABG, and therapeutic cardiac catheterization. Measurable quality goals, such as shorter hospital stays or length of time to ambulation, should be in place from the outset. The ultimate focus should always be on the delivery of quality care. An additional, intriguing way to look at success would be whether claim appeals decrease. Although government programs are investigating how to integrate bundled payment into Medicare, the industry does not need to stand by and wait for those results. Collaboration among payers, providers, and patients will bring them closer to their shared goals of reducing cost and improving quality. Organizations that work collaboratively to innovate, and have the tools to do so, will lead the way. ■ References 1. Geisinger Health System. About ProvenCare. www.geisinger.org/provencare/. Accessed July 8, 2010. 2. Agency for Healthcare Research and Quality. Innovation profile: use of clinical “bundles,” fixed pricing, and patient compact enhances adherence with guidelines and improves outcomes in bypass surgery, diabetes, and other areas. May 25, 2009. www.innovations.ahrq.gov/content.aspx?id=2373. Accessed July 8, 2010. 3. Casale AS, Paulus RA, Selna MJ, et al. “ProvenCareSM”: a provider-driven payfor-performance program for acute episodic cardiac surgical care. Ann Surg. 2007; 246:613-621. 4. Centers for Medicare & Medicaid Services. Medicare news: CMS announces sites for a demonstration to encourage greater collaboration and improve quality using bundled hospital payments. January 6, 2009. www.cms.gov/DemoProjects EvalRpts/downloads/ACEPressRelease.pdf. Accessed July 8, 2010. 5. de Brantes F, Rosenthal MB, Painter M. Building a bridge from fragmentation to accountability—the Prometheus Payment model. N Engl J Med. 2009;361:10331036. Epub 2009 Aug 19.

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Victoza® (liraglutide [rDNA origin] injection) Rx only BRIEF SUMMARY. Please consult package insert for full prescribing information. WARNING: RISK OF THYROID C-CELL TUMORS: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications and Warnings and Precautions]. INDICATIONS AND USAGE: Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Important Limitations of Use: Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied. CONTRAINDICATIONS: Victoza® is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). WARNINGS AND PRECAUTIONS: Risk of Thyroid C-cell Tumors: Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice. Malignant thyroid C-cell carcinomas were detected in rats and mice. A statistically significant increase in cancer was observed in rats receiving liraglutide at 8-times clinical exposure compared to controls. It is unknown whether Victoza® will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors could not be determined by clinical or nonclinical studies [see Boxed Warning, Contraindications]. In the clinical trials, there have been 4 reported cases of thyroid C-cell hyperplasia among Victoza®-treated patients and 1 case in a comparator-treated patient (1.3 vs. 0.6 cases per 1000 patient-years). One additional case of thyroid C-cell hyperplasia in a Victoza®-treated patient and 1 case of MTC in a comparator-treated patient have subsequently been reported. This comparator-treated patient with MTC had pre-treatment serum calcitonin concentrations >1000 ng/L suggesting pre-existing disease. All of these cases were diagnosed after thyroidectomy, which was prompted by abnormal results on routine, protocol-specified measurements of serum calcitonin. Four of the five liraglutide-treated patients had elevated calcitonin concentrations at baseline and throughout the trial. One liraglutide and one non-liraglutide-treated patient developed elevated calcitonin concentrations while on treatment. Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. The serum calcitonin assay used in the Victoza® clinical trials had a lower limit of quantification (LLOQ) of 0.7 ng/L and the upper limit of the reference range was 5.0 ng/L for women and 8.4 ng/L for men. At Weeks 26 and 52 in the clinical trials, adjusted mean serum calcitonin concentrations were higher in Victoza®treated patients compared to placebo-treated patients but not compared to patients receiving active comparator. At these timepoints, the adjusted mean serum calcitonin values (~ 1.0 ng/L) were just above the LLOQ with between-group differences in adjusted mean serum calcitonin values of approximately 0.1 ng/L or less. Among patients with pre-treatment serum calcitonin below the upper limit of the reference range, shifts to above the upper limit of the reference range which persisted in subsequent measurements occurred most frequently among patients treated with Victoza® 1.8 mg/day. In trials with on-treatment serum calcitonin measurements out to 5-6 months, 1.9% of patients treated with Victoza® 1.8 mg/day developed new and persistent calcitonin elevations above the upper limit of the reference range compared to 0.8-1.1% of patients treated with control medication or the 0.6 and 1.2 mg doses of Victoza®. In trials with on-treatment serum calcitonin measurements out to 12 months, 1.3% of patients treated with Victoza® 1.8 mg/day had new and persistent elevations of calcitonin from below or within the reference range to above the upper limit of the reference range, compared to 0.6%, 0% and 1.0% of patients treated with Victoza® 1.2 mg, placebo and active control, respectively. Otherwise, Victoza® did not produce consistent dose-dependent or time-dependent increases in serum calcitonin. Patients with MTC usually have calcitonin values >50 ng/L. In Victoza® clinical trials, among patients with pre-treatment serum calcitonin <50 ng/L, one Victoza®-treated patient and no comparator-treated patients developed serum calcitonin >50 ng/L. The Victoza®-treated patient who developed serum calcitonin >50 ng/L had an elevated pre-treatment serum calcitonin of 10.7 ng/L that increased to 30.7 ng/L at Week 12 and 53.5 ng/L at the end of the 6-month trial. Follow-up serum calcitonin was 22.3 ng/L more than 2.5 years after the last dose of Victoza®. The largest increase in serum calcitonin in a comparator-treated patient was seen with glimepiride in a patient whose serum calcitonin increased from 19.3 ng/L at baseline to 44.8 ng/L at Week 65 and 38.1 ng/L at Week 104. Among patients who began with serum calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of Victoza®-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients, with an incidence of 1.1% among patients treated with 1.8 mg/day of Victoza®. The clinical significance of these findings is unknown. Counsel patients regarding the risk for MTC and the symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea or persistent hoarseness). It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate the potential risk of MTC, and such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Patients with thyroid nodules noted on physical examination or neck imaging obtained for other reasons should be referred to an endocrinologist for further evaluation. Although routine monitoring of serum calcitonin is of uncertain value in patients treated with Victoza®, if serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. Pancreatitis: In clinical

trials of Victoza®, there were 7 cases of pancreatitis among Victoza®-treated patients and 1 case among comparator-treated patients (2.2 vs. 0.6 cases per 1000 patient-years). Five cases with Victoza® were reported as acute pancreatitis and two cases with Victoza® were reported as chronic pancreatitis. In one case in a Victoza®-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. One additional case of pancreatitis has subsequently been reported in a Victoza®-treated patient. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. There are no conclusive data establishing a risk of pancreatitis with Victoza® treatment. After initiation of Victoza®, and after dose increases, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza® and other potentially suspect medications should be discontinued promptly, confirmatory tests should be performed and appropriate management should be initiated. If pancreatitis is confirmed, Victoza® should not be restarted. Use with caution in patients with a history of pancreatitis. Use with Medications Known to Cause Hypoglycemia: Patients receiving Victoza® in combination with an insulin secretagogue (e.g., sulfonylurea) may have an increased risk of hypoglycemia. In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients and in no comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea or other insulin secretagogues [see Adverse Reactions]. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug. ADVERSE REACTIONS: Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Victoza® was evaluated in a 52-week monotherapy trial and in four 26-week, add-on combination therapy trials. In the monotherapy trial, patients were treated with Victoza® 1.2 mg daily, Victoza® 1.8 mg daily, or glimepiride 8 mg daily. In the add-on to metformin trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or glimepiride 4 mg. In the add-on to glimepiride trial, patients were treated with Victoza® 0.6 mg, Victoza® 1.2 mg, Victoza® 1.8 mg, placebo, or rosiglitazone 4 mg. In the add-on to metformin + glimepiride trial, patients were treated with Victoza® 1.8 mg, placebo, or insulin glargine. In the add-on to metformin + rosiglitazone trial, patients were treated with Victoza® 1.2 mg, Victoza® 1.8 mg or placebo. Withdrawals: The incidence of withdrawal due to adverse events was 7.8% for Victoza®-treated patients and 3.4% for comparator-treated patients in the five controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza®-treated patients and 0.5% of comparator-treated patients. The most common adverse reactions leading to withdrawal for Victoza®-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. Tables 1 and 2 summarize the adverse events reported in ≥5% of Victoza®-treated patients in the five controlled trials of 26 weeks duration or longer. Table 1: Adverse events reported in ≥ 5% of Victoza®-treated patients or ≥5% of glimepiride-treated patients: 52-week monotherapy trial All Victoza® N = 497 Glimepiride N = 248 (%) (%) Adverse Event Term Nausea 28.4 8.5 Diarrhea 17.1 8.9 Vomiting 10.9 3.6 Constipation 9.9 4.8 Upper Respiratory Tract Infection 9.5 5.6 Headache 9.1 9.3 Influenza 7.4 3.6 Urinary Tract Infection 6.0 4.0 Dizziness 5.8 5.2 Sinusitis 5.6 6.0 Nasopharyngitis 5.2 5.2 Back Pain 5.0 4.4 Hypertension 3.0 6.0 Table 2: Adverse events reported in ≥ 5% of Victoza®-treated patients and occurring more frequently with Victoza® compared to placebo: 26-week combination therapy trials

Adverse Event Term Nausea Diarrhea Headache Vomiting

Adverse Event Term Nausea Diarrhea Constipation Dyspepsia

Add-on to Metformin Trial Glimepiride + Placebo + All Victoza® + Metformin Metformin Metformin N = 242 N = 121 N = 724 (%) (%) (%) 15.2 4.1 3.3 10.9 4.1 3.7 9.0 6.6 9.5 6.5 0.8 0.4 Add-on to Glimepiride Trial All Victoza® + Placebo + Glimepiride Rosiglitazone + Glimepiride N = 695 N = 114 Glimepiride N = 231 (%) (%) (%) 7.5 1.8 2.6 7.2 1.8 2.2 5.3 0.9 1.7 5.2 0.9 2.6


Add-on to Metformin + Glimepiride Placebo + Metformin Glargine + Metformin Victoza® 1.8 + Metformin + + Glimepiride + Glimepiride Glimepiride N =114 N =232 N =230 (%) (%) (%) Adverse Event Term Nausea 13.9 3.5 1.3 Diarrhea 10.0 5.3 1.3 Headache 9.6 7.9 5.6 Dyspepsia 6.5 0.9 1.7 Vomiting 6.5 3.5 0.4 Add-on to Metformin + Rosiglitazone Placebo + Metformin All Victoza® + Metformin + Rosiglitazone N = 355 + Rosiglitazone N = 175 (%) (%) Adverse Event Term Nausea 34.6 8.6 Diarrhea 14.1 6.3 Vomiting 12.4 2.9 Decreased Appetite 9.3 1.1 Anorexia 9.0 0.0 Headache 8.2 4.6 Constipation 5.1 1.1 Fatigue 5.1 1.7 Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related. Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®-treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. Among Victoza®-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions. Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®-treated patients (2.6 cases per 1000 patient-years) and in no comparator-treated patients. Six of these 7 patients treated

with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 3). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake). Table 3: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials Victoza® Active Placebo Treatment Comparator Comparator Glimepiride None Monotherapy Victoza® (N = 497) (N = 248) Patient not able to self−treat 0 0 — Patient able to self−treat 9.7 (0.24) 25.0 (1.66) — Not classified 1.2 (0.03) 2.4 (0.04) — Glimepiride + Placebo + Add-on to Victoza® + Metformin Metformin Metformin Metformin (N = 724) (N = 242) (N = 121) Patient not able to self−treat 0.1 (0.001) 0 0 Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) Rosiglitazone + Placebo + Add-on to Glimepiride Victoza® + Glimepiride Glimepiride Glimepiride (N = 695) (N = 231) (N = 114) Patient not able to self−treat 0.1 (0.003) 0 0 Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) Not classified 0.9 (0.05) 0.9 (0.02) 0 Placebo + Add-on to Victoza® + Metformin + None Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 355) (N = 175) Patient not able to self−treat 0 — 0 Patient able to self−treat 7.9 (0.49) — 4.6 (0.15) Not classified 0.6 (0.01) — 1.1 (0.03) Insulin glargine Placebo + Add-on to Victoza® + Metformin + + Metformin + Metformin + Metformin + Glimepiride Glimepiride Glimepiride Glimepiride (N = 230) (N = 232) (N = 114) Patient not able to self−treat 2.2 (0.06) 0 0 Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) Not classified 0 1.7 (0.04) 0 In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparatortreated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. More detailed information is available on request. For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: January 2010 Version: 1 Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark Victoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending. © 2010 Novo Nordisk A/S 140586-R1 4/2010


Once-daily Victoza® : Can provide the additional benefit of weight loss Safety and tolerability were studied in clinical trials that included nearly 4000 patients

Targets beta cells Provides powerful and sustained reductions in A1C*

Victoza® is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials.

Visit VictozaPro.com to learn more.

Indications and usage Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. The concurrent use of Victoza® and insulin has not been studied.

Important safety information Liraglutide causes dose-dependent and treatment-durationdependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed. When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza ® or any other antidiabetic drug. The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients. Victoza® should be used with caution in patients with renal impairment and in patients with hepatic impairment. Please see brief summary of Prescribing Information on adjacent page. *Victoza® was evaluated in a 52-week monotherapy trial and in four 26-week, add-on combination trials.

Victoza® is a registered trademark of Novo Nordisk A/S. © 2010 Novo Nordisk A/S

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