January/Feburary 2011, Vol 4, No 1

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ JANUARY/FEBRUARY 2011

VOLUME 4, NUMBER 1

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

PERSPECTIVE

Five Steps Healthcare Leaders Can Take to Address Childhood Obesity Jennifer Lovejoy, PhD

CLINICAL ™

When Information Is Insufficient: Inspiring Patients for Medication Adherence and the Role of Social Support Networking Maureen Hennessey, PhD, CPCC; John W. Heryer, MD, FACS

Stakeholder Perspective by Gary M. Owens, MD

REGULATORY

Postapproval Development Options in COPD: A Case Study in Value-Based Healthcare Systems Michael F. Murphy, MD, PhD; Paola Antonini, MD, PhD; Zhihong Vicki Lai, PhD

BUSINESS

Perspectives in Value-Based Insurance Design for Patients with Diabetes: Assessment and Application Jennifer Decker Arevalo, MA

Stakeholder Perspective by Scott R. Taylor, RPh, MBA

Addressing Costs and Continuity of Care through Innovative Solutions for Infused Therapies: A Collaborative Experience with Infliximab Rhett Johnson, MA; Edward N. Freeman, FACMPE, MBA

Stakeholder Perspectiveby by Richard F. Radzin, PharmD

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EDITORIAL BOARD

CLINICAL EDITOR

HEALTH INFORMATION TECHNOLOGY

PHARMACY BENEFIT DESIGN

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

J. B. Jones, PhD, MBA Research Associate, Geisinger Health System, Danville, PA

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

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.

William J. Cardarelli, PharmD Director of Pharmacy Atrius Health Harvard Vanguard Medical Associates

GOVERNMENT EDITOR

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

David Williams Milliman Health Consultant Windsor, CT Eric G. Tangalos, MD, FACP, AGSF Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Gordon M. Cummins, MS Director, IntegriChain

AGING AND WELLNESS

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 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

Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta

HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals Inc., Chadds Ford, PA

Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA

POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute

Timothy S. Regan, BPharm, RPh Executive Director, Xcenda Palm Harbor, FL

Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City

MANAGED CARE & GOVERNMENT AFFAIRS

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

Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality and biomedical research consultancy

CARDIOLOGY RESEARCH

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

MANAGED MARKETS

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers Pfizer, Specialty Care Business Unit, PA

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

Charles E. Collins, Jr, MS, MBA Vice President, Managed Markets Strategy Fusion Medical Communications

EMPLOYERS

PATIENT ADVOCACY

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare Sharon, MA EPIDEMIOLOGY RESEARCH

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

Vol 4, No 1

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January/February 2011

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

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

www.AHDBonline.com

Leslie S. Fish, PharmD Sr. Director of Pharmacy Services Fallon Community Health Plan, MA

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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 RESEARCH & DEVELOPMENT

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 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

American Health & Drug Benefits

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JANUARY/FEBRUARY 2011

VOLUME 4, NUMBER 1

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

CLINICAL

10

When Information Is Insufficient: Inspiring Patients for Medication Adherence and the Role of Social Support Networking Maureen Hennessey, PhD, CPCC; John W. Heryer, MD, FACS

15

Stakeholder Perspective by Gary M. Owens, MD

REGULATORY

19

Postapproval Development Options in COPD: A Case Study in Value-Based Healthcare Systems Michael F. Murphy, MD, PhD; Paola Antonini, MD, PhD; Zhihong Vicki Lai, PhD

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 Senior Production Manager Lynn Hamilton

BUSINESS

Quality Control Director Barbara Marino

27

Business Manager Blanche Marchitto

Perspectives in Value-Based Insurance Design for Patients with Diabetes: Assessment and Application Jennifer Decker Arevalo, MA

32

Stakeholder Perspective by Scott R. Taylor, RPh, MBA

39

Addressing Costs and Continuity of Care through Innovative Solutions for Infused Therapies: A Collaborative Experience with Infliximab Rhett Johnson, MA; Edward N. Freeman, FACMPE, MBA

45

Stakeholder Perspective by Richard F. Radzin, PharmD Continued on page 6

American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Bibliographic Database SCOPUS/Elsevier Bibliographic Database Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory MEMBER: Committee on Publication Ethics (COPE) BPA Worldwide membership applied for August 2010.

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Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

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.

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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THERE COULD BE DANGER BELOW

Renal impairment is the leading microvascular complication associated with type 2 diabetes (over 40%), followed by retinopathy (28.5%) and neuropathy (19.4%)— it is important to recognize these complications as soon as possible1-4 According to the National Kidney Foundation, diabetes and renal impairment are considerably underdiagnosed, which may lead to disease progression because of missed opportunities to provide appropriate care for patients with these conditions5 Microalbuminuria (albumin in the urine *30 mg/day or * 20 µg/min) is the earliest clinical evidence of renal disease 6 Patients with renal impairment may have poor glycemic control (A1C *7%), may have hypertension (BP *130/80 mm Hg), and may have dyslipidemia as well as other comorbidities 5,7

It’s important to recognize microvascular complications in patients with type 2 diabetes as early as possible.

Microalbuminuria is the earliest sign of renal disease, the leading microvascular complication, in type 2 diabetes.

References: 1. Plantinga LC, Crews DC, Coresh J, et al; for the CDC CKD Surveillance Team. Prevalence of chronic kidney disease in US adults with undiagnosed diabetes or prediabetes. Clin J Am Soc Nephrol. 2010;5(4):673-682. 2. Parving H-H, Lewis JB, Ravid M, Remuzzi G, Hunsicker LG; for the DEMAND Investigators. Prevalence and risk factors for microalbuminuria in a referred cohort of type II diabetic patients: a global perspective. Kidney Int. 2006;69:2057-2063. 3. Zhang X, Saaddine JB, Chou C-F, et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA. 2010;304(6):649-656. 4. Gregg EW, Gu Q, Williams D, et al. Prevalence of lower extremity diseases associated with normal glucose levels, impaired fasting glucose, and diabetes among U.S. adults aged 40 or older. Diabetes Res Clin Pract. 2007;77(3):485-488. 5. National Kidney Foundation. KDOQI clinical practice guidelines and clinical practice recommendations for diabetes and chronic kidney disease. Am J Kidney Dis. 2007;49(2 suppl 2):S1-S179. 6. American Diabetes Association. Nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1):S79-S83. 7. Mogensen CE, Poulsen PL. Microalbuminuria, glycemic control, and blood pressure predicting outcome in diabetes type 1 and type 2. Kidney Int. 2004;66(suppl 92):S-40–S-41.

ExploringDiabetes.com

Copyright ©2011, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

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JANUARY/FEBRUARY 2011

VOLUME 4, NUMBER 1

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

DEPARTMENT

48

GENERIC DRUG TRENDS First Generic ARB Approval Draws a Wave of Comparative Studies Dalia Buffery, MA, ABD

PERSPECTIVE

50

Five Steps Healthcare Leaders Can Take to Address Childhood Obesity Jennifer Lovejoy, PhD

53

The Association for Value-Based Cancer Care First Annual Conference

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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.

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January/February 2011

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Vol 4, No 1

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)

t 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.

Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. 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.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed release capsules INDICATIONS AND USAGE DEXILANT is indicated for: M C74 740;8=6 >5 0;; 6A034B >5 4A>B8E4 4B>?7068C8B 5>A D? C> F44:B M <08=C08=8=6 740;8=6 >5 5>A D? C> <>=C7B 0=3 M C74 CA40C<4=C >5 740AC1DA= 0BB>280C43 F8C7 BH<?C><0C82 =>= 4A>B8E4 60BCA>4B>?70640; A4K DG 38B40B4 ' 5>A F44:B CONTRAINDICATIONS , ! #) 8B 2>=CA08=3820C43 8= ?0C84=CB F8C7 :=>F= 7H?4AB4=B8C8E8CH C> 0=H 2><?>=4=C >5 C74 5>A<D;0C8>= H?4AB4=B8C8E8CH 0=3 0=0?7H;0G8B 70E4 144= A4?>AC43 F8C7 , ! #) DB4 [see Adverse Reactions] WARNINGS AND PRECAUTIONS Gastric Malignancy (H<?C><0C82 A4B?>=B4 F8C7 , ! #) 3>4B =>C ?A42;D34 C74 ?A4B4=24 >5 60BCA82 <0;86=0=2H Bone Fracture (4E4A0; ?D1;8B743 >1B4AE0C8>=0; BCD384B BD664BC C70C ?A>C>= ?D<? 8=7818C>A %% C74A0?H <0H 14 0BB>280C43 F8C7 0= 8=2A40B43 A8B: 5>A >BC4>?>A>B8B A4;0C43 5A02CDA4B >5 C74 78? FA8BC >A B?8=4 )74 A8B: >5 5A02CDA4 F0B 8=2A40B43 8= ?0C84=CB F7> A4248E43 7867 3>B4 34J =43 0B <D;C8?;4 308;H 3>B4B 0=3 ;>=6 C4A< %% C74A0?H 0 H40A >A ;>=64A %0C84=CB B7>D;3 DB4 C74 ;>F4BC 3>B4 0=3 B7>AC4BC 3DA0C8>= >5 %% C74A0?H 0??A>?A80C4 C> C74 2>=38C8>= 148=6 CA40C43 %0C84=CB 0C A8B: 5>A >BC4>?>A>B8B A4;0C43 5A02CDA4B B7>D;3 14 <0=0643 022>A38=6 C> 4BC01;8B743 CA40C<4=C 6D834;8=4B ADVERSE REACTIONS Clinical Trials Experience )74 B054CH >5 , ! #) F0B 4E0;D0C43 8= ?0C84=CB 8= 2>=CA>;;43 0=3 D=2>=CA>;;43 2;8=820; BCD384B 8=2;D38=6 ?0C84=CB CA40C43 5>A 0C ;40BC <>=C7B 0=3

?0C84=CB CA40C43 5>A >=4 H40A %0C84=CB A0=643 8= 064 5A>< C>

H40AB <4380= 064 H40AB F8C7 54<0;4 0D20B80= ;02: B80= 0=3 >C74A A024B (8G A0=3><8I43 2>=CA>;;43 2;8=820; CA80;B F4A4 2>=3D2C43 5>A C74 CA40C<4=C >5 <08=C4=0=24 >5 740;43 0=3 BH<?C><0C82 ' F7827 8=2;D343 ?0C84=CB >= ?;0241> ?0C84=CB >= , ! #) <6

?0C84=CB >= , ! #) <6 0=3 ?0C84=CB >= ;0=B>?A0I>;4 <6 >=24 308;H B 2;8=820; CA80;B 0A4 2>=3D2C43 D=34A F834;H E0AH8=6 2>=38C8>=B 03E4AB4 A402C8>= A0C4B >1B4AE43 8= C74 2;8=820; CA80;B >5 0 3AD6 20==>C 14 38A42C;H 2><?0A43 C> A0C4B 8= C74 2;8=820; CA80;B >5 0=>C74A 3AD6 0=3 <0H =>C A4K 42C C74 A0C4B >1B4AE43 8= ?A02C824 ">BC ><<>=;H '4?>AC43 3E4AB4 '402C8>=B )74 <>BC 2><<>= 03E4AB4 A402C8>=B â&#x2030;Ľ C70C >22DAA43 0C 0 78674A 8=2834=24 5>A , ! #) C70= ?;0241> 8= C74 2>=CA>;;43 BCD384B 0A4 ?A4B4=C43 8= )01;4

Table 2: Incidence of Treatment-Emergent Adverse Reactions in Controlled Studies %;0241>

DEXILANT !0=B>?A0I>;4

<6 )>C0; # #

#

DEXILANT

<6 #

DEXILANT

<6 #

80AA740

13><8=0; %08=

#0DB40

*??4A '4B?8A0C>AH )A02C =542C8>=

3E4AB4 '402C8>=

+><8C8=6

;0CD;4=24

3E4AB4 '402C8>=B '4BD;C8=6 8= 8B2>=C8=D0C8>= = 2>=CA>;;43 2;8=820; BCD384B C74 <>BC 2><<>= 03E4AB4 A402C8>= ;4038=6 C> 38B2>=C8=D0C8>= 5A>< , ! #) C74A0?H F0B 380AA740

$C74A 3E4AB4 '402C8>=B $C74A 03E4AB4 A402C8>=B C70C F4A4 A4?>AC43 8= 2>=CA>;;43 BCD384B 0C 0= 8=2834=24 >5 ;4BB C70= 0A4 ;8BC43 14;>F 1H 1>3H BHBC4< Blood and Lymphatic System Disorders: 0=4<80 ;H<?7034=>?0C7H Cardiac Disorders: 0=68=0 0AA7HC7<80 1A03H20A380 274BC ?08= 434<0 <H>20A380; 8=50A2C8>= ?0;?8C0C8>= C027H20A380 Ear and Labyrinth Disorders: 40A ?08= C8==8CDB E4AC86> Endocrine Disorders: 6>8C4A Eye Disorders: 4H4 8AA8C0C8>= 4H4 BF4;;8=6 Gastrointestinal Disorders: 013><8=0; 38B2><5>AC 013><8=0; C4=34A=4BB 01=>A<0; 5424B 0=0; 38B2><5>AC 0AA4CC B 4B>?706DB 14I>0A 1>F4; B>D=3B 01=>A<0; 1A40C7 >3>A 2>;8C8B <82A>B2>?82 2>;>=82 ?>;H? 2>=BC8?0C8>= 3AH <>DC7 3D>34=8C8B 3HB?4?B80 3HB?70680 4=C4A8C8B 4AD2C0C8>= 4B>?7068C8B 60BCA82 ?>;H? 60BCA8C8B 60BCA>4=C4A8C8B 60BCA>8=C4BC8=0; 38B>A34AB

60BCA>8=C4BC8=0; 7H?4A<>C8;8CH 38B>A34AB ' D;24AB 0=3 ?4A5>A0C8>= 74<0C4<4B8B 74<0C>274I80 74<>AA7>83B 8<?08A43 60BCA82 4<?CH8=6 8AA8C01;4 1>F4; BH=3A><4 <D2DB BC>>;B =0DB40 0=3 E><8C8=6 >A0; <D2>B0; 1;8BC4A8=6 ?08=5D; 345420C8>= ?A>2C8C8B ?0A4BC74B80 >A0; A42C0; 74<>AA7064 General Disorders and Administration Site Conditions: 03E4AB4 3AD6 A402C8>= 0BC74=80 274BC ?08= 278;;B 544;8=6 01=>A<0; 8=K 0<<0C8>= <D2>B0; 8=K 0<<0C8>= =>3D;4 ?08= ?HA4G80 Hepatobiliary Disorders: 18;80AH 2>;82 27>;4;8C780B8B 74?0C><460;H Immune System Disorders: 7H?4AB4=B8C8E8CH Infections and Infestations: 20=3830 8=542C8>=B 8=K D4=I0 =0B>?70AH=68C8B >A0; 74A?4B ?70AH=68C8B B8=DB8C8B E8A0; 8=542C8>= ED;E> E068=0; 8=542C8>= Injury, Poisoning and Procedural Complications: 50;;B 5A02CDA4B 9>8=C B?A08=B >E4A3>B4 ?A>243DA0; ?08= BD=1DA= Laboratory Investigations: !% 8=2A40B43 !)

8=2A40B43 () 8=2A40B43 18;8AD18= 342A40B43 8=2A40B43 1;>>3 2A40C8=8=4 8=2A40B43 1;>>3 60BCA8= 8=2A40B43 1;>>3 6;D2>B4 8=2A40B43 1;>>3 ?>C0BB8D< 8=2A40B43 ;8E4A 5D=2C8>= C4BC 01=>A<0; ?;0C4;4C 2>D=C 342A40B43 C>C0; ?A>C48= 8=2A40B43 F4867C 8=2A40B4 Metabolism and Nutrition Disorders: 0??4C8C4 270=64B 7H?4A20;24<80 7H?>:0;4<80 Musculoskeletal and Connective Tissue Disorders: 0AC7A0;680 0AC7A8C8B <DB2;4 2A0<?B <DB2D;>B:4;4C0; ?08= <H0;680 Nervous System Disorders: 0;C4A43 C0BC4 2>=ED;B8>= 38II8=4BB 74030274B <86A08=4 <4<>AH 8<?08A<4=C ?0A4BC74B80 ?BH27><>C>A 7H?4A02C8E8CH CA4<>A CA864<8=0; =4DA0;680 Psychiatric Disorders: 01=>A<0; 3A40<B 0=G84CH 34?A4BB8>= 8=B><=80 ;8183> 270=64B Renal and Urinary Disorders: 3HBDA80 <82CDA8C8>= DA64=2H Reproductive System and Breast Disorders: 3HB<4=>AA740 3HB?0A4D=80 <4=>AA70680 <4=BCAD0; 38B>A34A; Respiratory, Thoracic and Mediastinal Disorders: 0B?8A0C8>= 0BC7<0 1A>=278C8B 2>D67 3HB?=>40 7822D?B 7H?4AE4=C8;0C8>= A4B?8A0C>AH CA02C 2>=64BC8>= B>A4 C7A>0C Skin and Subcutaneous Tissue Disorders: 02=4 34A<0C8C8B 4AHC74<0 ?ADA8C8B A0B7 B:8= ;4B8>= DAC820A80 Vascular Disorders: 344? E48= C7A><1>B8B 7>C K DB7 7H?4AC4=B8>= 338C8>=0; 03E4AB4 A402C8>=B C70C F4A4 A4?>AC43 8= 0 ;>=6 C4A< D=2>=CA>;;43 BCD3H 0=3 F4A4 2>=B834A43 A4;0C43 C> , ! #) 1H C74 CA40C8=6 ?7HB8280= 8=2;D343 0=0?7H;0G8B 0D38C>AH 70;;D28=0C8>= 24;; ;H<?7><0 1DAB8C8B 24=CA0; >14B8CH 27>;42HBC8C8B 02DC4 342A40B43 74<>6;>18= 347H3A0C8>= 38014C4B <4;;8CDB 3HB?7>=80 4?8BC0G8B 5>;;82D;8C8B 60BCA>8=C4BC8=0; ?08= 6>DC 74A?4B I>BC4A 7H?4A6;H24<80 7H?4A;8?834<80 7H?>C7HA>838B< 8=2A40B43 =4DCA>?78;B " 342A40B4 =4DCA>?4=80 >A0; B>5C C8BBD4 38B>A34A A42C0; C4=4B<DB A4BC;4BB ;46B BH=3A><4 B><=>;4=24 C7A><1>2HC74<80 C>=B8;;8C8B $C74A 03E4AB4 A402C8>=B =>C >1B4AE43 F8C7 , ! #) 1DC >22DAA8=6 F8C7 C74 A024<0C4 ;0=B>?A0I>;4 20= 14 5>D=3 8= C74 ;0=B>?A0I>;4 ?02:064 8=B4AC + '( ' ) $#( B42C8>= Postmarketing Experience 3E4AB4 A402C8>=B 70E4 144= 834=C8J 43 3DA8=6 ?>BC 0??A>E0; >5 , ! #) B C74B4 A402C8>=B 0A4 A4?>AC43 E>;D=C0A8;H 5A>< 0 ?>?D;0C8>= >5 D=24AC08= B8I4 8C 8B =>C 0;F0HB ?>BB81;4 C> A4;801;H 4BC8<0C4 C748A 5A4@D4=2H >A 4BC01;8B7 0 20DB0; A4;0C8>=B78? C> 3AD6 4G?>BDA4 Eye Disorders 1;DAA43 E8B8>= Gastrointestinal Disorders >A0; 434<0 General Disorders and Administration Site Conditions 50280; 434<0 Immune System Disorders 0=0?7H;02C82 B7>2: A4@D8A8=6 4<4A64=2H 8=C4AE4=C8>= (C4E4=B >7=B>= BH=3A><4 C>G82 4?834A<0; =42A>;HB8B B><4 50C0; Musculoskeletal System DisorderB 1>=4 5A02CDA4 Respiratory, Thoracic and Mediastinal Disorders ?70AH=640; 434<0 C7A>0C C867C=4BB Skin and Subcutaneous Tissue Disorders 64=4A0;8I43 A0B7 ;4D2>2HC>2;0BC82 E0B2D;8C8B DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics , ! #) 20DB4B 8=7818C8>= >5 60BCA82 0283 B42A4C8>= , ! #) 8B ;8:4;H C> BD1BC0=C80;;H 342A40B4 C74 BHBC4<82 2>=24=CA0C8>=B >5 C74 + ?A>C40B4 8=7818C>A 0C0I0=0E8A F7827 8B 34?4=34=C D?>= C74 ?A4B4=24 >5 60BCA82 0283 5>A 01B>A?C8>= 0=3 <0H A4BD;C 8= 0 ;>BB >5 C74A0?4DC82 45542C >5 0C0I0=0E8A 0=3 C74 34E4;>?<4=C >5 + A4B8BC0=24 )74A45>A4 , ! #) B7>D;3 =>C 14 2> 03<8=8BC4A43 F8C7 0C0I0=0E8A C 8B C74>A4C820;;H ?>BB81;4 C70C , ! #) <0H 8=C4A54A4 F8C7 C74 01B>A?C8>= >5 >C74A 3AD6B F74A4 60BCA82 ? 8B 0= 8<?>AC0=C 34C4A<8=0=C >5 >A0; 18>0E08;018;8CH 4 6 0<?828;;8= 4BC4AB 386>G8= 8A>= B0;CB :4C>2>=0I>;4 Warfarin > 03<8=8BCA0C8>= >5 , ! #) <6 0=3 F0A50A8= <6 383 =>C 05542C C74 ?70A<02>:8=4C82B >5 F0A50A8= >A #' >F4E4A C74A4 70E4 144= A4?>ACB >5 8=2A40B43 #' 0=3 ?A>C7A><18= C8<4 8= ?0C84=CB A4248E8=6 %% B 0=3 F0A50A8= 2>=2><8C0=C;H =2A40B4B 8= #' 0=3 ?A>C7A><18= C8<4 <0H ;403 C> 01=>A<0; 1;4438=6 0=3 4E4= 340C7 %0C84=CB CA40C43 F8C7 , ! #) 0=3 F0A50A8= 2>=2><8C0=C;H <0H =443 C> 14 <>=8C>A43 5>A 8=2A40B4B 8= #' 0=3 ?A>C7A><18= C8<4 Tacrolimus >=2><8C0=C 03<8=8BCA0C8>= >5 34G;0=B>?A0I>;4 0=3 C02A>;8<DB <0H 8=2A40B4 F7>;4 1;>>3 ;4E4;B >5 C02A>;8<DB 4B?4280;;H 8= CA0=B?;0=C ?0C84=CB F7> 0A4 8=C4A<4380C4 >A ?>>A <4C01>;8I4AB >5 -%

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed.

A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9-times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or 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 lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole 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.

Enterochromaffi n-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 human lansoprazole 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 lansoprazole 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 human lansoprazole 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 lansoprazole 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 human lansoprazole 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 human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

PATIENT COUNSELING INFORMATION Information for Patients 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: Tell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued. Advise your patients to tell you if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes.

DEXILANT is available as a delayed release capsule.

DEXILANT may be taken without regard to food.

DEXILANT should be swallowed whole.

M ;C4A=0C8E4;H , ! #) 20?BD;4B 20= 14 >?4=43 0=3 03<8=8BC4A43 as follows: â&#x20AC;&#x201C; Open capsule; â&#x20AC;&#x201C; Sprinkle intact granules on one tablespoon of applesauce; â&#x20AC;&#x201C; Swallow immediately. Granules should not be chewed. â&#x20AC;&#x201C; Do not store for later use.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. Š2009, 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.

DEX006 R8-Brf; August 2010 L-LPD-0810-2

Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. DEXILANT and Dual Delayed Release are trademarks of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.

Š2011Takeda Pharmaceuticals North America, Inc. LPD-01450R1 01/11 Printed in U.S.A.

CLINICAL

ORIGINAL ARTICLE

When Information Is Insufficient: Inspiring Patients for Medication Adherence and the Role of Social Support Networking Maureen Hennessey, PhD, CPCC; John W. Heryer, MD, FACS

Maureen Hennessey

Stakeholder Perspective, page 15

Am Health Drug Benefits.

2011;4(1):10-16 www.AHDBonline.com Disclosures are at end of text

Background: A report presented by the RAND Corporation for the Agency for Healthcare Research and Quality recommends that patient self-management programs should include supportive coaching, and the World Health Organization has suggested that the enhancement of patient motivation and behavioral skills is crucial to increasing patient care adherence. The US healthcare reform legislation also provides incentives for evidence-based activities (eg, coaching) that promote healthy behaviors.

Objectives: To review the current research on evidence-based coaching methods and their impact on medication adherence, as well as offer practical applications for such coaching interventions.

Discussion: The authors review the role of medication adherence in reducing the burden of chronic diseases, using the definitions of coaching and Network Coaching as a starting point for interventions that can enhance providers’ skills in motivating patients to improve their treatment adherence. Practical examples are included throughout the article to illustrate the benefits of these coaching methods for patients and providers. The mnemonic COPE is used to assist providers in the recall of 4 significant coaching and Network Coaching concepts—connectedness and collaboration, open-ended questions, positive attitude, and encourage support. Following COPE can reinforce physicians and pharmacists in their attempt to improve patient medication adherence.

Conclusion: The article presents healthcare providers, including physicians and pharmacists, with a rationale for developing evidence-based coaching skills and offers suggestions for the application of key coaching concepts.

A

ccording to the World Health Organization (WHO), “Without a system that addresses the determinants of adherence, advances in biomedical technology will fail to realize their potential to reduce the burden of chronic illness.”1 The WHO has recommended that adherence challenges are most effectively solved by individualized interventions addressing multiple factors impeding adherence.1 In its report, Adherence to Long-Term Therapies: Evi-

Dr Hennessey is President & CEO, Gardener Health Systems and Principal & Co-Owner, Paritas Health, Kansas City, MO; Vice President of Clinical Coaching Services, Health Integrated, Tampa, FL; and Clinical Assistant Professor, University of Missouri-Kansas City School of Medicine; Dr Heryer is Principal, Heryer Consulting, and Medical Director, Gardener Health Systems, Kansas City, MO.

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dence for Action, the WHO has identified 5 interactive “dimensions” or factors affecting adherence, including1: 1. Social/economic factors, such as unemployment, lack of health insurance, and limited social networks for support 2. Health system factors, such as lack of provider clinical training in chronic disease management and followup systems 3. Condition-related factors, which describe the inadequacy of our clinical systems to address the impact of disabilities (eg, memory impairment) and disease comorbidities (eg, depression associated with diabetes) on patient medication-taking persistency 4. Therapy-related factors, which deal with problems such as complex medication regimens and side effects 5. Patient-related factors, describing some of the more pernicious obstacles to treatment adherence, such as

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healthcare illiteracy, a lack of motivation for medication persistence, and wavering confidence or self-efficacy in one’s abilities to manage a chronic condition.

All these factors create powerful cognitive, emotional, and spiritual disincentives that sap the willpower of individuals to adhere to treatment recommendations.

Recognizing that successful behavior change is not simply a cognitive decision to get healthy, the WHO declared that, “information is a prerequisite for changing behavior, but in itself is insufficient to achieve this change. Motivation and behavioral skills are critical determinants.”1 Clearly, from the viewpoint of an organization that assists the most challenging health populations around the world, “information alone is not enough”1; motivating or inspiring the individual to change his or her behavior is also needed.

Research further confirms that improved medication adherence reduces the financial burden of illness.2 In their analysis of the costs of medication adherence, Sokol and colleagues have concluded that, “For some chronic conditions, increased drug utilization can provide a net economic return when it is driven by improved adherence with guidelines-based therapy.”2 RAND Health has called for programs that strike a balance between customized, patient-specific variables and population-based programs.3 Gellad and colleagues at RAND advocate the development of programs for large groups or classes of patients that identify “unique” barriers among patients as individuals and customized interventions for patients based on those barriers.3

Coaching Interventions Disease management programs have responded to this call for individualized, motivational interventions, and Geyman has commented on their emerging availability not only to patients served by commercial, employersponsored health plans but to patients served by Medicare and Medicaid plans as well.4 Interest in individualized, motivational change has grown to the extent that the Agency for Healthcare Research and Quality commissioned a report from RAND regarding patient self-management support programs.5 The report recommended that programs include “both supportive coaching interventions and educational interventions as part of the program content.”5 This is not surprising, because multiple studies have associated coaching with improved health behaviors.6-11 Coaching interventions address unhealthy behaviors associated with health and behavioral health disparities12; these can be employed across the plethora of healthcare delivery systems, such as disease management programs,13 medical care homes,14 home healthcare,15 pharmacy adherence programs,16,17 and peer coaching

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KEY POINTS ➤

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Systemic approaches that combine individualized interventions with population-based methodologies are necessary to improve medication adherence.

Improved patient adherence to medication therapy yields a net economic return when it is driven by established treatment guidelines.

Coaching interventions to enhance patient motivation are essential components of patient selfmanagement support programs.

The authors introduce the new mnemonic device COPE—Connectedness and collaboration, Openended questions, Positive attitude, and Encourage support—which summarizes 4 concepts used to develop coaching skills that can be applied across healthcare delivery systems to improve patient adherence.

networks18 that have been promoted to enhance patient self-care, as described below.

The 2010 Patient Protection and Affordable Care Act (ACA) for healthcare reform also provides financial incentives for health coaching. Specifically, according to the ACA, health plans will be permitted to include expenditures for healthcare quality improvement, including those that “increase wellness and promote health,”19 such as coaching programs, in the calculations of their 2011 medical loss ratios.

Nevertheless, many clinicians still receive little, if any, training in coaching and motivational techniques for treatment adherence. RAND Health has commented on the lack of professional school training to support patient self-management5 and has called for coaching interventions that are “patient-centered and tailored to the needs and concerns defined by the patient and his or her situation.”5 Some clinicians have opined that not only professional clinicians but also paraprofessionals in networking or supervisory relationships with clinicians could benefit from coaching skills training.9,18 This article provides clinicians and paraprofessionals with some practical coaching suggestions to promote patient motivation for adherence improvement. The article will focus on some leading-edge concepts such as connectedness, and will describe key coaching concepts that can be used when speaking with patients to promote motivation for medication adherence and to minimize other factors impinging on adherence.

Definitions: Coaching Concepts For the purposes of this article, “coaching” is defined as “a collaborative process of self-discovery, support,

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Figure COPE—4 Coaching Concepts to Inspire Patient Adherence

C = connectedness and collaboration

O = open-ended questions

C

O

P

E

P = positive attitude

E = encourage support

has been found to be an important determinate factor in the quality of care received by a patient.21 This study from Harvard researchers showed that people who felt connected to a specific doctor were more likely to complete recommended testing for prevention and care of chronic illness.21 In another recent study, Schoenthaler and colleagues found that collaborative communication between provider and patient was associated with improved medication adherence.22 These 2 studies suggest that connectivity and collaborative communication may indeed be connected.

Travaline and colleagues have written about the importance of collaboration in furthering connectivity or close physician–patient relationships.23 They cited a physician’s empathy and sensitivity to a patient’s nonverbal signals as key factors in encouraging a collaborative sense of teamwork in their care.23

This graphic provides a mnemonic and visual aid to assist in the recollection and use of 4 key coaching and Network Coaching concepts. Clinicians and coaches can integrate these concepts into patient care to facilitate patient motivation for adherence.

inspiration, and confidence building. Coaching motivates participants to use information for realistic goal setting, to identify their motivations for change, and to develop and maintain personalized strategies based on individual strengths.”18 The coaching process may be applied in multiple contexts, including health, business, professional development, sports, and other life spheres. This article focuses on the application of coaching concepts to enhance medication and treatment adherence for health improvement.

Network Coaching integrates coaching with social networking concepts by recognizing that all individuals and families have complementary team and network participating strengths whose successful use is essential to personal values of self-worth.20 Clinicians seeking to enhance patient adherence through improved motivation may be helped by remembering the mnemonic COPE (Figure) that assists in the recall of these 4 significant coaching concepts that help inspire patients for medication persistence: • Connectedness and collaboration • Open-ended questions • Positive attitude • Encourage support.

Connectedness and Collaboration Connectedness, connectivity, or the quality of the personal relationship between patient and physician

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EXAMPLE Noticing patients’ verbal and nonverbal cues of anxiety and inviting them to ask questions will encourage patients to seek information and reassurance about a new medication. An open invitation such as “What questions do you have about this medication?” affirms the importance of patients and their inquiries. An abrupt or dismissive “Any more questions?” will probably be perceived as perfunctory and uninviting.

In addition, Rollnick and colleagues indicate that the directive, authoritative communication style frequently practiced in healthcare may actually discourage patient–clinician collaboration.24 The authors advise that a collegial, inclusive style promotes patient participation. Patients respond more favorably when clinicians adopt a collaborative tone that conveys, “I’m here to assist you in solving your health-related problems.”24 EXAMPLE When a patient continually forgets to take his medication, some clinicians ask a mindful question such as, “When you take your pills, what helps you to remember to take them?” Prompting for helpful cues assists patients in identifying their own solutions and in increasing their feelings of inclusion as members of a collaborative team of problem solvers.

The patient motivation problems associated with adherence to care widen the treatment playing field to include not just the traditional clinical, multidisciplinary team but also patients and healthcare professionals and paraprofessionals, serving as coaches and participating team members. Research indicates that this

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inclusion strategically shifts the care to favor the importance of connectivity and collaboration.25,26

Open-Ended Questions Open-ended questions inviting self-reflections as in the example above establish a more personal exchange of information conducive to furthering clinician–patient relationships.24 Frequently, these self-reflections will involve feelings that reveal personal incentives and avoidances. These patient reports on emotional states are useful in expediting the development of individualized interventions.

As diagnosticians, clinicians often use a criteriadriven, deductive approach as an efficient method for narrowing diagnostic possibilities. But efficiency may be gained at a price costly to the emotional nuances involved in individual motivation and treatment adherence. The medical criteria and processes used in making an accurate diagnosis are not the same as the personal information needed to coax a unique individual’s adherence to care. Open-ended questions help bridge the chasm between clinician and coach.

EXAMPLE Asking a patient with asthma a question such as “How do you feel when you forget your medicine?” helps the patient to identify his/her personal, intrinsic motivations for medication adherence. A question such as “How are you feeling since you began taking this medicine?” can open the door to discussing therapy-related factors, such as living with a particular medication’s side effects.

Positive Attitude A positive attitude or a belief in one’s self and the confidence to make self-care decisions can greatly impact treatment efficacy.27 Philosopher coach Reginald Gant compared his management of 2 chronic, life-threatening conditions (diabetes and atherosclerosis) to “running a marathon—small strides are still steps in the right direction, pacing is more important than sprinting, expect setbacks with equanimity, and the water bottle is always half full.”28 Just as a positive mental attitude fosters optimal marathon performance,29 it can foster optimal condition self-management. Not surprisingly, Matthews found a correlation between positive patient attitude and glycemic control among adults with diabetes.30 Yet, the changes required for successful self-care can be daunting. Negative thoughts learned from childhood become formative in adulthood, stymieing a positive outlook. Psychologist coach Anthony Grant31 and colleague Jane Greene summarized more than 6000

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research articles and concluded that performanceenhancing thoughts can effectively alter ingrained, negative thought patterns if they are short, specific, and simple.31 They encourage readers to minimize doubts during problem planning and resolution stages by repeatedly substituting debilitating thoughts with simple, short, and specific positive thoughts.31

EXAMPLE When a patient with diabetes is discouraged, being mindful of short, specific, simple performanceenhancing thoughts, such as “I feel empowered when I exercise,” “With portion control I can still eat many foods I’ve previously enjoyed,” and “Insulin injections are not nearly as evil as they look,” can effectively counter negative, self-defeating thoughts.

Another enhancement to positive or confident thinking is devising personalized, problem-surmounting strategies that emphasize and use our personal strengths.32 In a study of care management recipients, Brun and Rapp found that reinforcing what patients believed were their personal strengths contributed to positive care-management relationships.33 Although many clinicians report a methodological dissonance in reconciling an emphasis on patient strengths when their formal training dwells on human pathologies, they are gradually recognizing the coaching logic of using personal strengths to reinforce the confidence of patients in sustaining healthy changes.

EXAMPLE A grandmother who has infinite patience with her grandchildren can be encouraged to use that strength when coping with chronic illness; an accountant can use his attention to detail for better medication tracking; and an imaginative writer can devise novel ways to remind herself to take her medication regularly.

Encourage Support: Social Support Networks There is strong evidence that when clinicians focus on issues of patient support they and their patients are rewarded with improved outcomes. Several studies have suggested that social and support networks have significant impact on healthy behaviors.34-36 The experience of chronic disease often includes traumatic experiences for the patient and the family, and research indicates that network support is one of the key factors in motivating growth and resilient coping.37 Interventions to change unhealthy behaviors, such as overeating, smoking, and alcohol abuse, are more suc-

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cessful when they offer peer support.35,38-40 When patients adopt healthier habits, their untreated family members often emulate them and improve as well.34 Data culled from studies such as the Framingham Heart Study suggest that healthy and unhealthy behaviors pass like contagions among networks of peers.41 Furthermore, Christakis and Fowler found that these contagions or behaviors may even spread among people who have no contact with each other.42 When patients lose weight, their weight loss may positively influence the weight of their spouse, their spouse’s friend, and their friend’s coworker.41 The authors conclude that this kind of behavioral change typically has 3 degrees of influence, including people unknown to the initial subject of change.41 Additional analyses have shown subtle factors, such as type of behavior problem and type of relationship (eg, friend or spouse), influencing the spread of behavioral contagions. For example, men in the Framingham Heart Study doubled their risks for obesity if a male friend became obese, but their risk increased only 37% if their wives became obese.41 Smoking cessation by one spouse decreased the other spouse’s chance of smoking by an impressive 67%, whereas smoking cessation by a friend only decreased smoking by 36%.42

Social Networking Research Social networking research introduces novel approaches to notions of disease and population management in healthcare. In the future, clinicians who understand the subtle interplay of social networks may find innovative ways of seeding a patient’s support network with beneficial influences; pair the treatment of patients with either spouses, family, friends, or selected unknowns; and weigh how cultural and psychosocial factors beyond the interpersonal differentially reinforce the success or failure of behavioral change.

For example, Excel Venture Management is investing in the future of social networking to improve health.

They recently bankrolled MedNetworks, a startup firm offering services derived from Nicholas Christakis’ work.43 The company intends to sell its services to entities such as health plans, disease management companies, and wellness programs. They will use MedNetworks’ services

EXAMPLE One day a clinician may have data regarding whether a large condition-management class that offers more potential network influences is more effective than a much smaller conditionmanagement class that offers more personal time with the instructor.

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and software to identify key connectors within networks who may potentially promote behavior change for healthier lifestyles within individuals and populations.43

Conclusion COPE represents just some of the elements from the coaching “playbook” that facilitate adherence to clinical care and medication management. At its highest and most visible levels in professional and collegiate sports, coaches routinely exact the highest levels of motivation and performance from their athletes. As we launch this era of healthcare reform, there has never been a more promising time for healthcare professionals and paraprofessionals to adopt coaching methods that inspire effective performances from patients facing challenges with care and medication adherence. ■ Author Disclosure Statement Dr Hennessey and Dr Heryer have reported no conflicts of interest in relation to this article.

References 1. World Health Organization. Adherence to Long-Term Therapies: Evidence for Action. Geneva, Switzerland: World Health Organization. 2003. www.who.int/chp/ knowledge/publications/adherence_full_report.pdf. Accessed February 1, 2010.

2. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care. 2005;43:521-530.

3. Gellad WF, Grenard J, McGlynn EA. A Review of Barriers to Medication Adherence: A Framework for Driving Policy Options. Santa Monica, CA: RAND Corporation; 2009. www.rand.org/pubs/technical_reports/TR765/. Accessed September 12, 2010.

4. Geyman JP. Disease management: panacea, another false hope, or something in between? Ann Fam Med. 2007;5:257-260.

5. Pearson ML, Mattke S, Shaw R, et al. Patient Self-Management Support Programs: An Evaluation. Final Contract Report. Prepared by RAND Health under Contract No. 282-00-0005. Rockville, MD: Agency for Healthcare Research and Quality; November 2007. AHRQ Publication No. 08-0011. www.ahrq.gov/qual/ptmgmt/ ptmgmt.pdf. Accessed September 12, 2010.

6. Oliver JW, Kravitz RL, Kaplan SH, Meyers FJ. Individualized patient education and coaching to improve pain control among cancer outpatients. J Clin Oncol.

2001;19:2206-2212.

7. Vale MJ, Jelinek MV, Best JD, et al. Coaching Patients On Achieving Cardiovascular Health (COACH): a multicenter randomized trial in patients with coronary heart disease. Arch Intern Med. 2003;163:2775-2783.

8. Holland SK, Greenberg J, Tidwell L, et al. Community-based health coaching, exercise, and health service utilization. J Aging Health. 2005;17:697-716.

9. Sacco WP, Morrison AD, Malone JI. A brief, regular, proactive telephone “coaching” intervention for diabetes: rationale, description, and preliminary results. J Diabetes Complications. 2004;18:113-118.

10. Whittemore R, Melkus GD, Sullivan A, Grey M. A nurse-coaching intervention for women with type 2 diabetes. Diabetes Educ. 2004;30:795-804.

11. Wolever RQ, Dreusicke, M, Fikkan J, et al. Integrative health coaching for patients with type 2 diabetes: a randomized clinical trial. Diabetes Educ. 2010;36:629639. Epub 2010 Jun 9.

12. Brondolo E, Gallo LC, Myers HF. Race, racism and health: disparities, mechanisms, and interventions. J Behav Med. 2009;32:1-8. Epub 2008 Dec 17.

13. Gillespie JL, Rossiter LF. Medicaid disease management programs: findings from three leading US state programs. Dis Manage Health Outcomes. 2003;11:345-361.

14. Ginsburg PB, Maxfield M, O’Malley AS, et al. Making Medical Homes Work: Moving from Concept to Practice. Washington, DC: Center for Studying Health System Change; December 2008. www.hschange.com/CONTENT/1030/. Accessed September 12, 2010.

15. Huffman M. Health coaching: a new and exciting technique to enhance patient self-management and improve outcomes. Home Healthc Nurse. 2007;25:271-274; erratum 2007;25:398.

16. Lee JK, Grace KA, Taylor AJ. Effect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a

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randomized controlled trial. JAMA. 2006;296:2563-2571. Epub 2006 Nov 13.

17. Herborg H, Haugbølle LS, Sørensen L, et al. Developing a generic, individualised adherence programme for chronic medication users. Pharm Pract. 2008;6:148-157.

18. Hennessey M, Hunt M, Heryer JW. Filling the nonadherence and lifestyle matters gap: the roles of coaching and mindfulness in our 21st-century healthcare delivery system. Grand Rounds Presentation, University of Missouri-Kansas City, School of Medicine; December 18, 2008.

19. Regulation for uniform definitions and standardized methodologies for calculation of the medical loss ratio for plan years 2011, 2012, and 2013 per section 2718 (b) of the Public Health Service Act. Washington, DC: National Association of Insurance Commissioners; October 2010:190-1-190-42. www.naic.org/documents/ committees_ex_mlr_reg_asadopted.pdf. Accessed November 25, 2010.

20. Hennessey M. The Choice Revolution. White paper prepared as an unpublished manuscript for the Gardener Study Group, November 2009.

21. Atlas SJ, Grant RW, Ferris TG, et al. Patient-physician connectedness and quality of primary care. Ann Intern Med. 2009;150:325-335.

22. Schoenthaler A, Chaplin WF, Allegrante JP, et al. Provider communication effects medication adherence in hypertensive African Americans. Patient Educ Couns.

2009;75:185-191. Epub 2008 Nov 14.

23. Travaline JM, Ruchinskas R, D’Alonzo GE Jr. Patient-physician communication: why and how. J Am Osteopath Assoc. 2005;105:13-18.

24. Rollnick S, Miller WR, Butler CC. Motivational Interviewing in Health Care. New York, NY: Guilford Press; 2008:17-18, 45-49.

25. Joseph D, Griffin M, Hall R, et al. Peer coaching: an intervention for individuals struggling with diabetes. Diabetes Educ. 2001;27:703-710.

26. Heisler M, Vijan S, Makki F, et al. Diabetes control with reciprocal peer support versus nurse care management. Ann Intern Med. 2010;153:507-515.

27. Wang L, Dong J, Gan H, Wang T. Empowerment of patients in the process of rehabilitation. Perit Dial Int. 2007;27(suppl 2):S32-S34.

28. Personal communication with Reginald Gant, philosopher coach. January 28, 2010.

29. Medical News Today. Mental attitude crucial for marathon running. April 17, 2004. www.medicalnewstoday.com/articles/7356.php. Accessed February 4, 2010.

30. Matthews SM. The effect of individual attitudes toward diabetes on glycemic control. Presented at the 18th International Nursing Research Congress Focusing on Evidence-Based Practice. July 11-14, 2007. http://stti.confex.com/stti/congrs07/tech

program/paper_35186.htm. Accessed January 28, 2010.

31. Grant AM, Greene J. Coach Yourself: Make Real Change in Your Life. Cambridge, MA: Basic Books; 2001:87-107.

32. Buckingham M, Clifton DO. Now, Discover Your Strengths. New York, NY: The Free Press; 2001.

33. Brun C, Rapp RC. Strengths-based case management: individuals’ perspectives on strengths and the case manager relationship. Soc Work. 2001;46:278-288.

34. Gorin AA, Wing RR, Fava JL, et al. Weight loss treatment influences untreated spouses and the home environment: evidence of a ripple effect. Int J Obes (Lond).

2008;32:1678-1674. Epub 2008 Sep 2.

35. Verheijden MW, Bakx JC, van Weel C, et al. Role of social support in lifestylefocused weight management interventions. Eur J Clin Nutr. 2005;59(suppl 1):S179-S186.

36. Kanaan SB. Promoting Effective Self-Management Approaches to Improve Chronic Disease Care: Lessons Learned. California HealthCare Foundation. April 2008. www.chcf.org/~/media/Files/PDF/S/PDF%20SelfMgmtLessonsLearned.pdf.

Accessed December 16, 2010.

37. Tedeschi RG, Calhoun LG. Posttraumatic growth: conceptual foundations and empirical evidence. Psychol Inq. 2004;15:1-18.

38. Albrecht S, Payne L, Stone CA, Reynolds MD. A preliminary study of the use of peer support in smoking cessation programs for pregnant adolescents. J Am Acad Nurse Pract. 1998;10:119-125.

39. Dijk F, Reubsaet A, de Nooijer J, de Vries H. Smoking status and peer support as the main predictors of smoking cessation in adolescents from six European countries.

Nicotine Tob Res. 2007;9(suppl 3):S495-S504.

40. Laudet AB, Magura S, Vogel HS, Knight E. Support, mutual aid and recovery from dual diagnosis. Community Ment Health J. 2000;36:457-476.

41. Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N Engl J Med. 2007;357:370-379. Epub 2007 Jul 25.

42. Christakis NA, Fowler JH. The collective dynamics of smoking in a large social network. N Engl J Med. 2008;358:2249-2258.

43. McBride R. MedNetworks, co-founded by Harvard’s Nicholas Christakis, aims to tap healthcare’s hidden social networks. Xconomy: Boston; October 27, 2010. http://www.xconomy.com/boston/2010/10/27/mednetworks-co-founded-by-harvards -nicholas-christakis-aims-to-tap-healthcares-hidden-social-networks/. Accessed January 11, 2011.

STAKEHOLDER PERSPECTIVE Health Plans Must “COPE” with Chronic Diseases PAYERS: The growing burden of chronic illness is a major issue for all health plans. New treatments and new therapeutic approaches to chronic illness are in the news almost daily. Yet for healthcare professionals involved in managed care, we have long recognized that innovation alone is not enough to solve the problem of chronic illness. Patient adherence to treatment and understanding what motivates patients to effectively manage the many aspects of chronic diseases are in the forefront of every health system medical director’s mind.

The National Council on Patient Information and Education published a landmark report in 2007 on medication adherence.1 According to the press release that announced the publication of the report, the report was issued as a “nationwide call to action.”2 According to this report, lack of medication adherence has reached crisis proportions in the United States and around the world, “leading to unnecessary disease progression, disease complications, reduced functional abilities, a lower quality of life, and even death.”2

According to studies cited in the report, only about 50% of American patients “typically take their medicines as prescribed, resulting in approximately $177 billion annually in direct and indirect costs to the U.S. economy. Besides an estimated $47 billion each year for drug-related hospitalizations, not taking medicines as prescribed has been associated with as many as 40 percent of admissions to nursing homes and with an additional $2,000 a year per patient in medical costs for visits to physicians’ offices.”2 The magnitude of this problem—especially the annual $2000 per patient additional cost of nonadherence—is certainly enough to grab the attention of any medical director. Yet, as managed care professionals, we fully understand that we have much to learn about patient nonadherence. According to a 2003 article, thousands of articles written over more than 2 decades failed to reach conclusions about the optimum way to manage medication compliance.3 In the present article, Drs Hennessey and Heryer explore a novel approach to evidence-based coaching, Continued

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(Continued)

and how it can potentially impact medication adherence. The authors recommend a coaching approach to address unhealthy behaviors. In this case, coaching is defined as a “collaborative process of self-discovery, support, inspiration, and confidence building.” They recommend the combination of individualized intervention and population-based strategies to improve adherence. Furthermore, they offer a mnemonic, COPE, to summarize the 4 essential concepts that can be developed and applied across the delivery system.

Essentially, this is a system to better understand patients’ motivation and to motivate them to take control of their healthcare. Embedded in this article are a few key examples of these principles that clinicians can use immediately. They close by encouraging professionals to take a “page from the playbook” of coaches to motivate patients to achieve higher performance in their care.

POLICYMAKERS: Regardless of whether this approach can be universally applied to all or even to most patients, certainly innovative approaches such as this one must be tried out. Ultimately, our healthcare system must fund the development and the measurement of clinical and economic outcomes and the

application of such systems. By such rigorous analysis, we can learn what works and what doesn’t, and on whom different techniques are effective.

Only by using scientific measurement methodologies of behavioral interventions will we begin to better understand the complex world of patient adherence.

Technology alone cannot solve either the clinical issues or the cost-related issues of chronic illness. For it is only when we can apply technology to people based on a better understanding of human behavior that the system will learn to “COPE” with the growing population of patients with chronic illness.

1. National Council on Patient Information and Education. Enhancing prescription medicine adherence: a national action plan. August 2007. www.talk aboutrx.org/documents/enhancing_prescription_medicine_adherence.pdf. Accessed January 23, 2011.

2. National Council on Patient Information and Education. America’s other drug problem: poor medication adherence. August 1, 2007. www.marketwire.com/pressrelease/Americas-Other-Drug-Problem-Poor-Medication-Adherence-756583.htm.

Accessed January 23, 2011.

3. Wertheimer AI, Santella TM. Medication compliance research: still so far to go. J Appl Res Clin Exp Ther. 2007;3:254-261. www.jarcet.com/articles/Vol3Iss3/ Wertheimer.htm. Accessed January 23, 2011.

Gary M. Owens, MD President, Gary Owens Associates Philadelphia, PA

CAPTION CONTEST Submit your caption at www.AHDBonline.com Winners receive $50 Winners’ names will be posted online

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See also COPD Supplement accompanying this issue

POSITION STATEMENT

Postapproval Development Options in COPD: A Case Study in Value-Based Healthcare Systems Michael F. Murphy, MD, PhD; Paola Antonini, MD, PhD; Zhihong Vicki Lai, PhD

Michael F. Murphy

Am Health Drug Benefits.

2011;4(1):19-23 www.AHDBonline.com Disclosures are at end of text

Background: Research and development activities in an era of globalization encounter a mosaic of providers, products, services, and intermediaries; regulatory and other government institutions; and consumers. The introduction of novel therapeutics into this environment mandates research programs that are relevant to the registration process, payers and purchasers, transparent pricing, and rule-driven business practices, while providing data relevant to marketing initiatives internationally.

Objective: To outline an example for clinical development programs that incorporate the perspective of multiple stakeholders into a portfolio of study designs to provide optimal data platforms that can resonate with diverse recipients.

Discussion: A contract research organization directly involved in the design, execution, and analysis of clinical trials for new drugs and devices across pharmaceutical and biotechnology companies provides a unique perspective regarding opportunities and challenges within the international clinical research environment. Drs Murphy, Antonini, and Lai, representing Worldwide Clinical Trials, utilize chronic obstructive pulmonary disease as a demonstration project exploiting its prevalence, direct and indirect costs, and the rapid infusion/diffusion of innovative therapy into practice as a rationale for focus, and illustrate methods of informing registration and technology assessments during a prototypical development process.

Conclusion: By virtue of its chronicity, prevalence, and pattern of healthcare utilization, chronic obstructive pulmonary disease provides an ideal case for illustrating the application of clinical trial methodology that can facilitate data evaluation through the prism of multiple stakeholders. Adding an international dimension exacerbates system complexity and serves to illustrate the breadth of issues that can be addressed within this therapeutic area.

R

esearch and development (R&D) activities in an era of globalization encounter a mosaic of providers, products, services, and intermediaries; regulatory and other government institutions; and consumers. Within the next 10 years, new product introductions within the United States and Western Europe in particular must navigate through a labyrinth of payers and purchasers, address the realities of transparent pricing and rule-driven business practices, and provide

Dr Murphy is Chief Medical Officer and Scientific Officer, Worldwide Clinical Trials, King of Prussia, PA, and Research & Development Editor for American Health & Drug Benefits; Dr Antonini is Senior Vice President, Medical and Scientific Affairs, Drug Safety, for Worldwide Clinical Trials. Dr Lai is Associate Director, Medical and Scientific Affairs, Worldwide Clinical Trials.

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research and data as a differentiator of sales and marketing initiatives. The information required for healthcare decisions will vary appreciably within this extended audience and is significantly influenced by the therapeutic area and local standards of care.

In this setting, the commercial viability of novel therapeuticsâ&#x20AC;&#x201D;particularly for chronic illnesses that have established pharmacotherapyâ&#x20AC;&#x201D;is influenced by perceived value more than by mechanistic novelty. Review processes in the United Kingdom (ie, National Institute for Health and Clinical Excellence [NICE]), the German national system, and the Australian national formulary provide examples of oversight anticipated in many countries over the next decade.1 Correspondingly, R&D activity supporting new product introductions must anticipate systems of oversight that mandate a stream of evidence confirming clinical utility in the presence of therapeutic uncertainty (eg, in

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the United States, the Centers for Medicare & Medicaid Services’ coverage with evidence development).

Chronic obstructive pulmonary disease (COPD) provides a useful demonstration project of the methods by which R&D teams can address the perspective of multiple stakeholders in peri-approval research programs given its prevalence, direct and indirect costs, and the rapid infusion/diffusion of innovative therapy into practice. Adding an international dimension for consideration exacerbates system complexity and illustrates the breadth of issues that must be addressed within this therapeutic area.

An International Perspective Pharmaceutical expenditure is a major concern in many European countries that use specific criteria in the process of identifying drugs that can be reimbursed by public funds, attempting to concentrate expenditures on key compounds that contribute to the treatment of illness deemed “serious.” The method by which compound attributes are evaluated—cost-benefit assessment in Europe or comparative-effectiveness research in the United States—uses postapproval and peri-approval clinical research to generate evidence for clinical utility and cost-effectiveness in representative patients and in clinical practices to address key market access concerns.

For example, NICE has recommended additional research for a significant number of the drugs it appraised, including head-to-head comparisons (45%), investigation of the drug(s) in different patient populations (62%), and use of the drugs in typical clinical practice (87%).2 Uncertainty around clinical effectiveness, typically resulting from inadequate study design given intended audiences or the use of inappropriate comparators and surrogate end points, has been identified as a key issue in coverage decisions in Britain, Australia, and Canada, although factors as diverse as competition and differences in risk tolerance can also have an impact on decisions.3 The Disease COPD—an illness characterized by airflow limitation not fully reversible with bronchodilators because of progressive structural changes—is a major cause of chronic morbidity and mortality throughout the world, with growing impact on patients, families, healthcare systems, and society as a whole.4 In the European Union, the total direct costs of respiratory disease are estimated to be approximately 6% of the total healthcare budget, with COPD accounting for 56% (ie, 38.6 billion Euros) of this cost of respiratory disease.5 The guidelines for the management of COPD have

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evolved over the past 10 years and are represented by the American Thoracic Society guidelines6 and the Global Initiative for Obstructive Lung Disease (GOLD).5 Both guidelines include clinical symptoms in addition to lung function measurements,5,6 acknowledging the reality that approximately 60% of primary care physicians never perform a lung function test on patients with respiratory symptoms.7

A Postapproval Clinical Program for COPD The process of establishing an equilibrium between quality, access, and cost requires that peri-approval clinical research modifies any study objectives in a manner consistent with the audience intended for receipt of data. For example, managers of healthcare plans, hospitals, and pharmacy benefit management make decisions on formulary inclusion and limitations on utilization mainly based on data submitted during health technology assessments. Individuals making these assessments may not have an interest in understanding the subtlety of patient management for outcomes that are not directly relevant to their remit.

In this diverse setting, information on representative patients (including those with comorbidities and concomitant medications excluded during clinical development) and representative physicians (as opposed to clinical trialists) are weighed heavily. Comparative costeffectiveness data are particularly useful as a means to inform formulary decisions and reimbursement guidelines.

As an example, medical directors of large international employers are interested in the impact of novel therapeutic interventions on workplace productivity and absenteeism when considering benefit coverage under employer-based plans.8 Direct loss of productivity occurs when people are sick and absent from work. Indirect loss of productivity (ie, presenteeism) can include additional time spent on tasks, decreased quality of work, impaired initiative, reduction in performance, decreased quantity of work completed, and limited social functioning with coworkers. All these outcomes are potentially measurable, as discussed below.

Although commercially insured employer-sponsored health plans may err on the side of caution by providing new medications to employees and their dependents regardless of expenditures, many employers are engaged in cost-shifting to employees and would be incentivized to favorably review data that could be used to promote healthier workforces to reduce healthcare expenditures.

For example, given the impact of cigarette smoking on absenteeism and on presenteeism, clinical trial eligibility criteria during a registration program that also permitted evaluation of the impact of smoking with or without novel medication on healthcare utilization and work-

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place productivity will be far more important than trials that solely monitor medical respiratory outcomes (eg, forced expiratory volume in 1 second [FEV1]). These data permit modeling of the annual cost burden per employee that may be associated with new product introduction.

A Portfolio of Design Options Depending on the scope and objectives (eg, safety, efficacy, quality-of-life outcomes) for postmarketing clinical studies in COPD, different study designs may be appropriate, including interventional or observational studies using randomized versus nonrandomized designs, with a prospective or a retrospective focus.

Randomized Clinical Trials The use of randomization minimizes bias regarding comparability of treatment groups, because known and unknown prognostically important variables are allocated between treatment groups randomly. Individual patient–randomized versus cluster-randomized designs (eg, at this level of clinical practice) permit inferences under assumptions that differences detected in outcomes reflect random variation plus the effect of intervention.

Benefits include the ability to capture multiple outcomes of interest spanning domains of safety and efficacy (eg, FEV1), patient-reported outcomes, and healthcare utilization (eg, hospitalization for COPD exacerbation)—critically parsing the impact of an intervention using methods that have universal acceptance biostatistically. An enabling technological infrastructure for randomization and data acquisition with minimal costs from direct site monitoring reduces concerns regarding excessive operational overhead.

Registry/Prospective Observational Studies With broad eligibility criteria and unrestricted site participation, this approach is a “hypothesis-generating exercise” that can include large and diverse groups of patients. Treatment patterns reflect “real-life” situations—everyday clinical decision-making that can inform subsequent controlled studies in patients with comorbidities and concomitant medications that may have been excluded from a registration program. Lack of randomization—and the limitation in potential inferences—can be partially addressed through analytic techniques, such as propensity score analyses, and has been utilized in COPD in the evaluation of healthcare utilization and costs.9 The range of quantitative study designs not including randomization in quality improvement research, for example, includes stepped wedge designs, time-series designs, and controlled or uncontrolled before-after studies that create a body of evidence for practical decision-making purposes.10

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In this setting, electronic data acquisition is mandatory coupled with a “user-friendly” web-based “wraparound” interface, permitting unencumbered access to an electronic data capture platform by all participants.

During this process, access to electronic health records using a limited data set is a laudable objective with technological and privacy considerations acknowledged.11 Efficient use of health information technology and interoperable data in which a single point of entry can provide research and clinical information has been the subject of key initiatives.12 When fully articulated, electronic data capture methodology may transform every physician– patient interaction into an opportunity for research.

Particularly attractive are studies placed in a “closed environment” in which all transactions can be monitored (eg, physician visits, laboratory tests, pharmacy claims, and specialist contact). Although available in the United States (eg, Geisinger Clinic, Kaiser Permanente) and applied in COPD within the Veterans Affairs healthcare system,13 this type of setting is more difficult to replicate in European countries. Patient registries that use observational study methods to evaluate outcomes provide an alternative.14 For example, similar to techniques employed with antihypertensive medications,15 an investigation of the influence of prescription costsharing on medication refill persistence may be entertained by evaluating 2 therapeutic classes of bronchodilators that are differentially reimbursed in an observational trial.

Patient Population COPD severity and comorbidity significantly modify implications extracted from any research. Patients with moderate-to-severe COPD (GOLD II and III) represent the majority of patients with COPD requiring continuous treatment. For example, in the Social Impact of Respiratory Integrated Outcomes (SIRIO) study of 748 Italian patients, in which COPD severity levels were based on the GOLD 2001 guidelines, 24.2% of patients were classified as mild, 53.7% moderate, and 16.8% severe.16 Because patients with COPD tend to be older (eg, the mean age was 70.3 years in the SIRIO study),16 comorbid conditions are frequent, including common pathway comorbidities (ie, smoking-related diseases such as ischemic heart disease); complicating comorbidities (ie, pulmonary hypertension); coincidental morbidities related to aging (ie, depression or diabetes); and intercurrent comorbidities (ie, upper respiratory infections) occurring during the course of observation. In comparative trials, all modifying elements need to be either constrained by design or randomly allocated, or adjusted between groups analytically to permit appropriate between-group comparisons.

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Patients with COPD and these comorbidities are often not eligible for participation in clinical trials, and would therefore not be represented sufficiently in a typical registration dossier. For example, in a study conducted in Norway, only 17% of the patients with COPD were estimated to meet the inclusion criteria used in clinical trials for moderate-to-severe COPD.17 In addition, comorbidities may create problems of conflicting therapies—for example, evaluation of corticosteroids in patients with COPD and hypertension or diabetes, or the impact of beta-blockers in COPD patients who are at high cardiovascular risk. Because comorbidities and concomitant therapy drive healthcare utilization in many diagnoses, however, generating data in such patients would be very relevant to organizations that must make coverage decisions.

Typology of Sites Primary care versus specialized centers for respiratory disorders offer intriguing insights regarding the impact of the clinical setting on health outcomes. In primary care centers, the management of patients with COPD may be tangentially related to guidelines, although very representative of the “real-world” practice. The benefits include access to physicians who provide care for the majority of patients with COPD. The disadvantages include the inconsistency among private providers regarding diagnosis and treatment,7 despite the high regard in which COPD guidelines are held.18 For example, in the primary care setting, one obstacle for evaluating the efficacy of the therapy using “gold standard” methodology is represented by limited access to spirometry equipment.

In specialized centers for respiratory disorders, the management of patients with COPD may not be representative of the population that will eventually be covered, although procedures and medication use by specialists better adhere to guidelines. Benefits to clinical research in this setting include staffing and infrastructure necessary to conduct sophisticated controlled clinical trials, including, but not limited to, high-quality spirometry. Disadvantages are primarily related to the selection bias associated with tertiary care centers, because only the most severe or intractable COPD population is referred to these sites. A retrospective and prospective cost-of-illness study in France provides a model approach to the evaluation of disease impact in COPD, including general practitioners and lung specialists.19 Outcome Measures Although FEV1 measurement is a standard for the evaluation of respiratory function in COPD, the absence of high-quality spirometry in the primary care setting

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can be attenuated by the use of a peak flow meter for lung function. Alternatively, protocol design with clinical symptoms as primary outcomes can be particularly useful. For example, of the chronic symptoms characteristic of COPD (ie, cough, sputum, dyspnea), dyspnea is the symptom that interferes most with a patient’s daily life and health status. Therefore, it is important to explore the impact of dyspnea and other chronic symptoms on daily activities and work. Dyspnea and qualityof-life indices qualify the disease burden of COPD and patients’ perceived quality of life, such as the British Medical Research Council questionnaire (for daily activities); the Clinical COPD Questionnaire (for COPD-related symptoms, functional status, and mental health); or the St. George’s Respiratory Questionnaire (for impaired health; and perceived well-being).

Event studies are particularly useful for reimbursement purposes, because they reflect the healthcare utilization (eg, hospitalization) and cost-effectiveness of therapies that may be anticipated with chronic medication use. However, the duration of an investigation would extend to 1 year if exacerbation is included as an end point compared with 12 weeks if FEV1 is the primary end point. Therefore, the proposed study design would require a longer horizon for data accrual if exacerbation rates are requirements for health technology decisions.

Active Comparator and Concomitant Medications for COPD Given the standard of care represented by tiotropium/ipratropium, fixed combinations of inhaled corticosteroids (ICSs) and long-acting beta-agonists (LABAs) or ICS plus LABA combined with tiotropium/ipratropium provide optimal therapeutic combinations for study. As a result of its long mechanism of action, tiotropium is the antimuscarinic drug of choice for patients with COPD in the European Union, and it serves as a standard comparator for any antimuscarinic drugs or other bronchodilators.

For example, tiotropium was the drug of choice for comparison in the recent phase 3 Study to Compare the Lung Effect of Indacaterol and Tiotropium in Chronic Obstructive Pulmonary Disease (INTENSITY),20 even though the drug under evaluation is of a different pharmacologic class (ie, a novel LABA) and can possibly be used in combination with tiotropium. The rationale of this head-to-head comparison is that bronchodilator medications are central to symptom management in COPD, and the choice between a LABA or an anticholinergic depends on individual response in terms of symptom relief. Because of the prevalent use of a fixed combination of ICS plus LABA in this patient population for randomized clinical trials, it may be worthwhile

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to permit stable dosage of the ICS (if used) as background therapy.

Use of Inhaler Devices For COPD drugs delivered through inhalation devices, it is important to evaluate ease of use and patients’ preference of different devices, because these variables are determinants of medication adherence and success of COPD therapy.21 For example, the use of a multidose dry powder inhaler may be more convenient and provide improved drug deposition compared with that of a different device, with an equivalent drug product. Patients’ preference and adherence to therapy may be included as secondary end points. Cost-effectiveness can be discerned through the use of a variety of analytic techniques represented by the first published study comparing cost-effectiveness of an ICS, a LABA, and a combination of both agents from the perspective of US healthcare payers.22

Reviewing the implications of this paradigm through a prism of international clinical development is particularly useful as systems for vetting clinical trial results that have been used as a platform for determining product access and reimbursement.

Conclusions The introduction of the Patient Protection and Affordable Care Act in the United States in 2010 has prompted a reevaluation of research priorities across therapeutic areas. Reviewing the implications of this paradigm through a prism of international clinical development is particularly useful as systems for vetting clinical trial results that have been used as a platform for determining product access and reimbursement.

Much is known regarding the character and extent of data required for consideration. By virtue of its chronicity, prevalence, and pattern of healthcare utilization, COPD provides an ideal demonstration case illustrating the application of innovative clinical trial methodology that could service the perspectives of multiple stakeholders. ■ Author Disclosure Statement Dr Murphy, Dr Antonini, and Dr Lai are employees of Worldwide Clinical Trials, an international, full-service con-

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tract research organization that specializes in clinical trial research activities in support of drug development by pharmaceutical companies. As part of their primary business activities, relationships exist with multiple (more than 100) pharmaceutical companies. These activities include consultation regarding design, execution, analysis, and interpretation of clinical trials within the pharmaceutical and biotechnology industry. None of the authors receives any personal financial remuneration for any drug product or device.

References 1. Celini NE. The provider/public health/academia perspective: an interview with Dr David Nash. Global Forum. 2010;2:22-24.

2. Mason A, Drummond M, Towse A. Economic post-launch studies: matching the desirable with the feasible. London: Office of Health Economics; September 2006.

3. Clement FM, Harris A, Li JJ, et al. Using effectiveness and cost-effectiveness to make drug coverage decisions: a comparison of Britain, Australia, and Canada.

JAMA. 2009;302:1437-1443.

4. World Health Organization. The Global Burden of Disease. 2004 Update. www.who.int/whr/2000/en/whr00_en.pdf. Accessed December 19, 2010.

5. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.

Updated 2009. www.goldcopd.com/Guidelineitem.asp?l1=2&l2=1&intId=2003.

Accessed December 19, 2010.

6. American Thoracic Society, European Respiratory Society. Standards for the diagnosis and management of patients with COPD. 2004. www.thoracic.org/clinical/ copd-guidelines/resources/copddoc.pdf. Accessed December 19, 2010.

7. Tinkelman DG, Price DB, Nordyke RJ, Halbert RJ. Misdiagnosis of COPD and asthma in primary care patients 40 years of age and over. J Asthma. 2006;43:75-80.

8. Vogenberg FR. COPD management in a value-based healthcare system: interview with David Tinkelman, MD. Am Health Drug Benefits. 2009;2:195-197.

9. Akazawa M, Stearns S, Biddle AK. Impact of early initiation of inhaled corticosteroids on resource utilization and costs in patients with COPD: a propensity score matching approach. Presented at the International Society for Pharmacoeconomics and Outcomes Research 12th Annual International Meeting; May 19-23, 2007; Arlington, VA. Abstract RS4.

10. Fan E, Laupacis A, Pronovost PJ, et al. How to use an article about quality improvement. JAMA. 2010;304:2279-2287.

11. Bleicher P. Secondary use of electronic health records: a personal perspective.

Global Forum. 2010;2:25-28.

12. Kush R, Alschuler L, Ruggeri R, et al. Implementing Single Source: the STARBRITE proof-of-concept study. J Am Med Inform Assoc. 2007;14:662-673.

Epub 2007 Jun 28.

13. Onukwugha E, Mullins CD, DeLisle S. Using cost-effectiveness analysis to sharpen formulary decision-making: the example of tiotropium at the Veterans Affairs health care system. Value Health. 2008;11:980-988. Epub 2008 Jan 11.

14. Agency for Healthcare Research and Quality. Registries for evaluating patient outcomes: a user’s guide. 2nd ed. AHRQ Publication No. 10-EHC049. September 2010. http://ihps.medschool.ucsf.edu/pdf/Registries%20for%20EvalPtOutcomes.

Guide.2nd%20ed.pdf. Accessed December 19, 2010.

15. Zhang D. Medication refill persistence: does prescription cost sharing matter?

Presented at the International Society for Pharmacoeconomics and Outcomes Research 12th Annual International Meeting; May 19-23, 2007; Arlington, VA. 16. Dal Negro RW, Micheletto C, Tosatto R, et al. Costs of asthma in Italy: results of the SIRIO (social impact of respiratory integrated outcomes) study. Respir Med. 2007;101:2511-2519. Epub 2007 Sep 5.

17. Herland K, Akselsen JP, Skjønsberg OH, Bjermer L. How representative are clinical study patients with asthma or COPD for a larger “real life” population of patients with obstructive lung disease? Respir Med. 2005;99:11-19.

18. Glaab T, Banik N, Rutschmann OT, Wencker M. National survey of guidelinecompliant COPD management among pneumologists and primary care physicians.

COPD. 2006;3:141-148.

19. Detournay B, Pribil C, Fournier M, et al; for the SCOPE Group. The SCOPE study: health-care consumption related to patients with chronic obstructive pulmonary disease in France. Value Health. 2004;7:168-174.

20. Dunn LJ, Buhl R, Lassen C, et al. Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD. Chest. 2010;138:719A. 21. Al-Showair RA, Tarsin WY, Assi KH, et al. Can all patients with COPD use the correct inhalation flow with all inhalers and does training help? Respir Med. 2007; 101:2395-2401. Epub 2007 Jul 12.

22. Oba Y. Cost-effectiveness of salmeterol, fluticasone, and combination therapy for COPD. Am J Manag Care. 2009;15:226-232.

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in su 3 pr rvi yea M ev va r ul io l a ov tip us d er le ly van all M un ta ye tre ge lo a m te a d

If You Define Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT 3-YEAR UPDATE- SUSTAINED BENEFIT UPDATED VISTA* OVERALL SURVIVAL (OS) ANALYSIS: VcMP† vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

90

% Patients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

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Months Kaplan-Meier estimate.

Patients treated with VELCADE + MP as initial therapy sustained an overall survival benefit over patients randomized to MP alone The overall survival benefit was sustained despite subsequent treatments Median duration of VcMP treatment was 46 weeks/54 planned1 At the initial analysis (median 16.3-month follow-up), median TTP was 20.7 months with VELADE in combination with MP vs 15 months for MP alone (P=0.000002) * VISTA was a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. Primary endpoint was TTP and secondary endpoints were CR, ORR, PFS, and OS. At a prespecified interim analysis (median follow-up 16.3 months) VcMP resulted in significantly superior results for TTP, PFS, OS, and response rates. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. † VcMP=VELCADE + melphalan/prednisone (MP).

If You Define Value as Medication Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1398.00 per 3.5mg vial as of January 1, 2011.

Health plans should consider medication cost, length of therapy, and dosing regimens when determining the value of a prescription drug regimen. This list of considerations is not meant to be all-inclusive; there are multiple other factors to consider when determining value for a given regimen.

VELCADE Warnings, Precautions, and Adverse Events VELCADE is contraindicated where hypersensitivity to bortezomib, boron, or mannitol exists. Warnings and Precautions for VELCADE include: advising women to avoid pregnancy and breastfeeding; peripheral neuropathy, sometimes severe may occur—manage with dose modifications or discontinuation and carefully consider risk/benefit in pre-existing severe neuropathy; hypotension may occur, use caution with patients on antihypertensives, history of syncope, dehydration; closely monitor patients with risk factors for or existing heart disease; acute diffuse infiltrative pulmonary disease has been reported; nausea, diarrhea, constipation, and vomiting may require symptomatic treatment; regular monitoring of blood counts throughout treatment for thrombocytopenia or neutropenia. Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and acute hepatic failure have been reported. In patients with moderate or severe hepatic impairment use a lower starting dose. In addition, patients with diabetes may require close monitoring of blood glucose and antidiabetic medication.

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported.

Please see Brief Summary for VELCADE on the next page of this advertisement.

To contact a reimbursement specialist: Please call 1-866-VELCADE, option 2 (1-866-835-2233).

www.VELCADE.com 1. San Miguel, Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. New England Journal of Medicine 2008.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone.

The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib.

Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, 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: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency.

Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., The Takeda Oncology Company. Cambridge, MA 02139 Copyright ©2009, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA V1215 12/09

BUSINESS

REVIEW ARTICLE

Perspectives in Value-Based Insurance Design for Patients with Diabetes: Assessment and Application Jennifer Decker Arevalo, MA

Stakeholder Perspective, page 32

Am Health Drug Benefits.

2011;4(1):27-33 www.AHDBonline.com Disclosures are at end of text

Background: Value-based insurance design initiatives have been developed in an effort to reduce long-term healthcare costs and improve health quality. Value-based insurance design promotes the use of services or therapies that have been shown to have clinical benefits that outweigh the cost, such as encouraging medication adherence, and discourages those that produce results that do not justify the cost.

Objective: The goal of this analysis is to determine the impact of value-based insurance design as it relates specifically to drug therapy, including adherence, for patients with diabetes.

Method: This article analyzes data collected by Milliman, a large actuarial group, using MedStat claims, National Health and Nutrition Examination Surveys, and its own 2008 health cost guidelines to develop an actuarial assessment of value-based insurance design programs for diabetes care and therapy. This assessment models the impact that copay structures and other management techniques have on adherence and incremental costs.

The model provides a framework for assessing the value of benefits and directs patients toward cost-effective services supported by strong evidence-based medicine.

Discussion: Analysis of actuarial modeling shows that adjusting patient copayment designs is in line with other value-based approaches designed to improve patient care and reduce long-term costs. Evidence from value-based insurance design initiatives suggests that reducing patient copayment has the potential to improve clinical outcomes, including medication adherence, and reduce overall healthcare costs.

Conclusion: This analysis, coupled with results from other value-based insurance design initiatives and related research, provides support for employers and health insurance plans to consider adopting value-based insurance design programs for patients with diabetes to improve quality of care, while potentially reducing healthcare costs.

M

ore than 23 million Americans have diabetes, and of these, 5.7 million are undiagnosed.1 This disease prevalence cost the United States an estimated $174 billion in 2007.2 As the prevalence rate of chronic diseases such as diabetes continues to escalate, along with soaring healthcare costs and an aging population (Table 1, page 28), payers as well as employers are seeking alternative strategies to control costs, obtain value from their healthcare spending, and improve clinical outcomes.

Many payers are turning to initiatives such as valuebased insurance design (VBID) for their members,

Ms Arevalo is a medical writer employed by Catalyst Medical Communications, San Diego, CA.

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including those with diabetes, to encourage patient adherence to cost-effective therapies and potentially avoid expensive medical costs in the future.3 VBID initiatives originated in response to the challenges faced by private and public purchasers of healthcare to control costs, while maximizing health outcomes with available healthcare dollars.3 VBID is just one of many value-based leversâ&#x20AC;&#x201D;such as health risk assessments or lifestyle coachingâ&#x20AC;&#x201D;that have been developed to influence patient behavior and improve clinical outcomes, while attempting to control costs. For optimal impact, multiple levers are typically used together to initiate such changes.

According to A. Mark Fendrick, MD, Co-Director of the Center for Value-Based Insurance Design,

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KEY POINTS ➤

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The prevalence of chronic diseases and their associated costs continue to escalate, along with the aging of the US population. Patient lack of adherence has been shown to increase overall healthcare costs.

More than 23 million Americans have diabetes, and of these, 5.7 million are undiagnosed.

Value-based insurance design initiatives have developed as a strategy that is focused on improving clinical outcomes, while potentially also controlling costs.

Evidence has shown that overall healthcare costs decrease for patients with diabetes as their adherence to medication therapy increases.

Using actuarial data and modeling related to patients with diabetes, the author suggests that implementing value-based insurance design for patients with diabetes can help improve clinical outcomes, including adherence, and potentially reduce overall costs.

own quadrant interpretations based on their specific circumstances and their patient populations.4 The Figure is based on modeling of MedStat commercial claims data, National Health and Nutrition Examination Survey population data sets from the Centers for Disease Control and Prevention, and the actuarial group’s internal Health Cost Guidelines, which are used to determine health claim costs and premium rates for various health plans.4 Key concepts targeted by VBID initiatives include4: • High-value services without differentiating among individuals who receive the intervention • Patients with certain clinical diagnoses • Providers who meet quality outcome criteria • Patients’ medication adherence behavior.

The present article analyzes data collected by Milliman, a large actuarial group, using MedStat claims, National Health and Nutrition Examination Surveys, and its own 2008 health cost guidelines to develop an

Drivers of Change in Healthcare in the Table 1 United States Cost

University of Michigan, a VBID plan adjusts patients’ out-of-pocket expenses based on the clinical benefit value achieved for the money being spent; therefore, the more clinically beneficial the service is for patients, the lower their cost-sharing would be.3 VBID directs plan members toward services or benefits that have been shown to have high value based on strong evidence through clinically sensitive copayment structures: reduced or waived copayment for strong evidence-based, cost-effective services and increased or high copayments or no coverage for weak evidencebased services. The initial focus of VBID has been on drug therapy copayment designs that lower or eliminate patient copayments for chronic disease drug therapy, although the VBID concept can apply to all medical services, not only drugs.3,4 In general, VBID moves benefit design toward value and price rather than legacy or price, tying copayments at the point of service to the evidence base and the value of specific services for certain groups or certain individuals. VBID strategies may adjust copayment designs for physician, hospital, or ancillary services, as well as for prescription drugs.4 The Figure (page 29) presents a graphic algorithm for evaluating health insurance services or benefits. The placement of services or benefits in a particular quadrant depicted in the Figure is presented for illustration purposes only; health plans are encouraged to create their

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• 85% of healthcare spending is for patients with chronic diseasea • >$2.5 trillion ($8160/resident) was spent on healthcare in 2009b • Healthcare expenditures were >16% of the gross domestic product in 2007c Chronic diseases • 45% of all Americans have 1 or more chronic diseasesd • 90% of Americans 65 years of age and older have 1 or more chronic diseasesd • Between 1960 and 2004, diagnosis of childhood chronic diseases nearly quadrupledd • Lost productivity costs the United States $1 trillion/yrd a Anderson G. Chronic Conditions: Making the Case for Ongoing Care.

Johns Hopkins University; November 2007. www.fightchronic disease. org/news/pfcd/documents/ChronicCareChartbook_FINAL.pdf.

Accessed October 28, 2010. b Kaiser Family Foundation. Trends in health care costs and spending.

Publication #7692-02. March 2009. www.kff.org/insurance/upload/ 7692_02.pdf. Accessed October 28, 2010. c Keehan S, et al. Health spending projections through 2017: the babyboom generation is coming to Medicare. Health Aff (Millwood). 2008; 27:w145-w155. d Partnership to Fight Chronic Disease. Almanac of Chronic Disease, 2008 edition. 2008. www.fightchronicdisease.org/pdfs/PFCD_FINAL_ PRINT.pdf. Accessed October 28, 2010.

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➤

High value

Most weightloss programs

Statins and ACEIs for target populations Smoking cessation

Value Weak

Wellness

➤ Strong

Evidence base for efficacy

Total body scan for low risk Some health products sold through TV infomercials ➤

Value-Based Levers in Healthcare Value in healthcare has been defined as the clinical or medical benefit achieved for the money spent,3 and this is at the very core of a current nationwide trend in healthcare that reflects many stakeholders’ belief that the “value of care” should replace “volume of care” in the way healthcare is being provided and consumed in the United States.5 This trend comprises many existing and evolving value-based strategies, such as: • Consumer-driven health plans • Wellness and prevention programs and benefits • Health information technology (HIT) to collect, analyze, measure, and disseminate data • Patient-centered medical home • Pay-for-performance initiatives • Employee engagement.

Each of these strategies encompasses a vast array of actionable levers or measures that can be implemented and integrated with one another to influence patient behavior and improve healthcare outcomes. Some examples of these levers include health risk assessments, biometric screening, lifestyle coaching,6 nurse and employee-assistance program hotlines, onsite health center access, medical home resources,7 and waived or reduced copayments or coinsurance, as in VBID. In fact, the Center for Health Value Innovation—a panel of healthcare experts, headed by Cyndy Nayer, who are focused on innovation in benefit design—states that there are more than 100 levers available.8 In a survey of various-sized US-based companies that have had a value-based design in place for more than 2 years, many levers, including the following strategies, were used successfully by many of the organizations surveyed7: • Disease management programs—implemented by 80% of organizations • Reduced/waived copay for utilizing the lowest cost appropriate site of care, such as urgent care, convenient care, and onsite services—70% • Incentives for the use of employee-assistance programs—58% • Insurance premium incentive for completion of a health risk assessment—40%.

The Center for Health Value Innovation has suggested that payers determine the combination of levers that

Figure Framework for Evaluating the Value of Benefits

➤

actuarial assessment of VBID programs for diabetes care and therapy.4 The actuarial group’s findings were compiled into a client report4 that is the basis for much of the present article. The VBID model provides a framework for assessing the value of benefits provided and directs patients toward cost-effective services supported by strong evidence-based medicine.

Low value

ACEIs indicates angiotensin-converting enzyme inhibitors.

Reprinted with permission from Reference 4.

are best suited for their organizations to use them to their advantage.9 But with so many levers to choose from, this may not be easy to do. Health plans and other payers must first understand the needs and capacities of their members to determine the levers that will be most beneficial. For payers considering VBID, this requires data, technology, and due diligence.4,10 For example, health plans can use HIT to collect and analyze data on their members to help them identify high-value services, target specific patient populations, and understand challenges with medication adherence.3 Sophisticated data systems are therefore necessary; HIT can be implemented internally or outsourced to a vendor. Although the initial outlay may mean a short-term rise in operational costs, the use of HIT is critical, because “you can’t qualify what you can’t quantify.” Benchmark information must be obtained and data—which are captured on an ongoing basis—must be measured against it to determine if improvements have been achieved.

In addition, health plans may want to review the existing evidence-based research. For example, applying the concepts of VBID within the scope of diabetes care shows that: • Only 55.7% of patients with diabetes are reaching the American Diabetes Association–recommended goal of hemoglobin (Hb) A1c <7%, even with improvements in glycemic control11 • Approximately 35% of patients are nonadherent with antidiabetic therapy12

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Table 2 Cost and Adherence Impact of 3 Benefit Designs for Patients with Type 2 Diabetes Plan

Standard

VBID1

Copay structure: generic/preferred brand/nonpreferred brand, $

10/25/40 0/12.50/30

VBID2 VBID3 0/0/0

10/10/10

Net of copayment 60

79

102

80

PMPM, $

2.16

2.82

3.65

2.85

PMPM increment to base, $

NA

0.67

1.49

0.69

Patients adherent, %

49

60

69

57

Increment to base, %

0

22

41

16

Per patient per month, $

Virtual adherence

NOTE: Copayments are listed by tier 1/tier 2/tier 3. Model uses data on the actuarial impact of copayments. Virtual population is based on typical employee population.

NA indicates not applicable; PMPM, per member per month; VBID, value-based insurance design.

Adapted with permission from Reference 4.

• Doubling patient copayments can result in a 25% decline in the use of antidiabetic drugs13 • A 47.6% reduction in copayments for diabetes medications resulted in a significant 73.3% improvement in medication adherence, and the number of nonadherent patients decreased by 33.4%14 • Healthcare costs decrease as the level of adherence to antidiabetic therapy increases; improving adherence and glycemic control can help to reduce costs, according to a 2005 study.15

VBID and Diabetes Drug Therapy: An Actuarial Assessment As with most value-based levers, payers may also consider professional assessments of VBID programs for diabetes care and therapy. One such assessment by the actuarial group models 3 prospective VBID strategies and contrasts their expected impact on adherence, the extent to which a patient’s behavior coincides with medical advice, with that of a standard copayment model (Table 2).4 In this model, costs are calculated as dollars per patient per month and per member per month (PMPM).

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Per patient per month results are costs spread across patients with type 2 diabetes, whereas PMPM results are costs spread across all health plan members.4 Because employers may not be able to measure adherence directly, the actuarial group developed a different approach based on the belief that the nature of prescription changes, and the progressive nature of diabetes indicates that simple approaches to tabulating adherence from utilization data might understate adherence.4 Using this information, “virtual adherence” was created, defined as a medication possession ratio of ≥80% days annually. This was based on standards that translate available utilization rate into useful information to measure VBID according to the following methodology4: • Distinguishing between patients with type 1 and type 2 diabetes • Identifying utilization of multiple pharmacies within broad drug categories • Making assumptions for changing therapies and doses.

These measures are derived from actuarial modeling rather than from treatment arm/control arm studies.4 Such modeling shows that when copayments are reduced, adherence increases; it does not attempt to model any medical cost offsets that may be achieved with better diabetes drug therapy adherence.4 Medical cost offsets are difficult to model, because there is often insufficient knowledge about the impact of incremental improvements in adherence on health status.4 This approach to modeling used actuarial assumptions to convert utilization into adherence and was done using several steps4: 1. Each diabetes drug claim was classified by linking every claim to plan descriptions, placing each claim into component class by National Drug Code and therapeutic class, and using International Classification of Diseases, Ninth Revision codes to determine diabetes type 2. Elasticity curves were developed by component class and type of diabetes, the total day supply of diabetes prescriptions for patients with full-year membership by component class calculated, as well as the copayment for each component class, and the total day supply of patients in the same copayment averaged to construct 8 sets of data for regression analysis 3. Elasticity curves for each of the 8 combinations were developed using previously established internal guidelines, which were developed for all drug classes and patients, and then these elasticity curves were used to calculate the aggregate adherence rate and virtual adherence in the copay structures.

Table 2 shows a consistent increase in adherence for patients with type 2 diabetes when copayments are low-

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ered from the standard design of $10/$25/$40 copayment. Although each plan increases cost and virtual adherence, the only benefit design model with a nocopay ($0/$0/$0) structure (VBID2) resulted in the most dramatic increase in virtual adherence.4 Milliman’s findings show that improving access to diabetes drugs through VBID can lead to better adherence; adherence to diabetes drug therapy is inversely proportional to patient copayments.4 Table 3 highlights the different benefit approaches that can be implemented and compares them with analogous management techniques to reduce costs and improve value. Actuarial modeling shows that adjusting copayment designs is in line with other value-based approaches aimed at reducing long-term cost.4

Successful Application of VBID within Diabetes Management The concept of VBID is still evolving, but when it is used in conjunction with other value-based levers, success in the form of improved clinical outcomes and potential cost-savings is achievable. Early adopters of VBID, such as Marriott, Pitney Bowes, and the city of Asheville, NC, have already demonstrated improved patient adherence and clinical outcomes, as well as cost-savings, through the use of reduced or waived copayments,3 along with disease management, onsite clinics, and patient education and coaching by community pharmacists.

More recently, results from the Diabetes Ten City Challenge have shown a $1079 (7.2%) average annual total healthcare cost reduction per patient (N = 573) participating in this program, which integrated disease management strategies and enrollment, waived copays on medications for people with diabetes, evidence-based diabetes care guidelines, community-based pharmacist coaching, and self-management strategies.16 In addition, participants’ mean HbA1c levels decreased from 7.5% to 7.1% (P = .002).16 Many large employers, such as Caterpillar, are achieving successful results with VBID.3,17 As many as 50% of enrollees in a diabetes disease management program at Caterpillar experienced an HbA1c reduction from 8.7% to 7.2% during the course of 1 year; 96% of the enrollees are measuring their HbA1c levels.17 Part of this success has been attributable to incentives, such as zero copayments for drugs for diabetes and its associated comorbidities, as well as a $900 reduction in yearly insurance premiums for employees who complete a health risk assessment and participate in a disease management program.3 Health plans are also achieving success in adopting VBID. The Hotel Employees and Restaurant Employees International Union saw its total medical cost trends

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Table 3 Comparative Values of Various Options and Techniques Analogous benefit options

Typical incremental costa

VBID diabetes options in this actuarial reportb

$0.81-$1.86

Diabetes disease management (total cost)

$0.50-$1.00

Wellness (total cost)

$0.40-$14.00

Analogous management techniques Decrease inpatient admissions by 1.7 per 1000 members (typically <4% reduction)

$1.40-$1.50

Decrease bariatric surgery by 20%

$0.30-$0.70

a Per member per month (PMPM): $0.40 PMPM includes basic promotion; $14.00 PMPM includes full range of services, such as health risk assessment incentives or gym subsidy. b See reference 4.

VBID indicates value-based insurance design.

Adapted with permission from Reference 4.

drop from 14.5% per year at baseline to <4.5% over a 2year period.18 One key way in which this was accomplished was by reducing the cost of prescribed medication and improving patient adherence through waived copayments for generics and some brand-name pharmaceuticals. In addition, employees were required to enroll in care management, health education, and pharmacy management programs through a health risk assessment that included biometric screenings.18 Using health coaching—which addressed patients’ needs and encouraged their active participation in their health management—and employee engagement that included incentives for no-cost supplies and reducedcost treatments, as well as rewards such as family trips to resorts, more than 60% of the participants knew their body mass index, blood pressure, blood glucose level, and cholesterol level, and had seen their physician within 3 months of starting the program.18

Conclusion The health plans and employers that are integrating VBID into their overall healthcare benefit designs for diabetes drug therapy to improve chronic diabetes management and reduce long-term healthcare costs related to diabetes are reaping the benefits of their decisions and finding “value—the health dividend they can achieve in terms of workforce performance and bottom-line results from the right investments in healthcare.”6 Payers who are considering implementing a VBID

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program can benefit from keeping abreast of the outcomes and data of these previous adopters of such benefit designs. In addition, they may benefit from analyzing and selecting other value-based levers that could be integrated with VBID to provide the most optimal healthcare benefits for their members with diabetes.

Although VBID is just one of many levers, it has been shown to produce effective and efficient care delivery, while maximizing clinical outcomes at any level of healthcare expenditure.3 VBID is a cost-containment and quality-improvement tool that has the potential to play a vital role in healthcare reform. ■ Acknowledgment The author wishes to thank Julie Gegner, PhD, for providing editorial support for the manuscript preparation.

Funding Source Funding for this article was provided by Takeda Pharmaceuticals North America, Inc. Author Disclosure Statement Ms Arevalo reported no conflicts of interest related to the contents of this article.

References 1. Centers for Disease Control and Prevention. Diabetes at a Glance 2009. 2009. www.cdc.gov/nccdphp/publications/aag/pdf/diabetes.pdf. Accessed October 21, 2010.

2. American Diabetes Association. Economic costs of diabetes in the U.S. in 2007.

Diabetes Care. 2008;31:596-615.

3. Fendrick AM. Value-Based Insurance Design Landscape Digest. National Pharmaceutical Council. July 2009. www.sph.umich.edu/vbidcenter/publications/pdfs/

NPC_VBIDreport_7-22-09.pdf. Accessed October 29, 2009.

4. Fitch K, Iwasaki K, Pyenson B. Value-Based Insurance Designs for Diabetes Drug Therapy: Actuarial and Implementation Considerations. Milliman client report; December 1, 2008. www.sph.umich.edu/vbidcenter/publications/pdfs/vbid-diabetesdrug-therapy-RR12-01-08.pdf. Accessed October 21, 2010.

5. Leavitt MO. Building a value-based healthcare system. The Prologue Series.

Speech presented at: Washington, DC: April 23, 2008. www.hhs.gov/secretary/pro logueseries/buildingvaluehc.pdf. Accessed October 21, 2010.

6. Towers Perrin. 2009 Health Care Cost Survey. The health dividend: capturing the value of employee health. 20th annual US results report. www.towersperrin.com/tp/ getwebcachedoc?webc=USA/2009/200901/2009_HCCS_Final_Report.pdf&cm_lm= sp:jarevalo@catalyst-med.com&cm_ven=Spop-Email&cm_ite= Health%20Care% 20Cost%20Survey%202009%20(1). Accessed October 29, 2009.

7. Center for Health Value Innovation. Value-Based Design 2009 Survey Report January 2010. www.vbhealth.org/wp-content/uploads/CHVI-BUCK-VBD-2009FINAL-Report1.pdf. Accessed July 27, 2010.

8. Center for Health Value Innovation. Leveraging the value of health: a decision matrix for value-based designs. November 2009. www.vbhealth.org/wp-content/ uploads/CHV_Report-11-24WEB-FINAL.pdf. Accessed October 28, 2010.

9. Hoke D; Center for Health Value Innovation. The value of health, the investments in design. Kentucky Long-Term Policy Research Center. November 2008. www.kltprc.net/pubs/presentations/2008conference/Hoke_2008conference.pdf.

Accessed October 28, 2009.

10. Nayer C; Center for Health Value Innovation. Disruption, value, improved health. Presented at the Academy of Managed Care Pharmacy 2008 Educational Conference, Kansas City, MO; October 15-18, 2008.

11. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86.

12. Rozenfeld Y, Hunt JS, Plauschinat C, Wong KS. Oral antidiabetic medication adherence and glycemic control in managed care. Am J Manag Care. 2008;14:71-75.

13. Goldman DP, Joyce GF, Escarce JJ, et al. Pharmacy benefits and the use of drugs by the chronically ill. JAMA. 2004;291:2344-2350.

14. MedImpact study highlights effects of value-based benefit design on adherence to diabetes medications. June 4, 2009. www.medicalnewstoday.com/articles/ 152589.php. Accessed October 28, 2010.

15. Sokol MC, McGuigan KA, Verbrugge RR, Epstein RS. Impact of medication adherence on hospitalization risk and healthcare cost. Med Care. 2005;43:521-530.

16. Fera T, Bluml BM, Ellis WM. Diabetes Ten City Challenge: final economic and clinical results. J Am Pharm Assoc. 2009;49:383-391.

17. Center for Health Value Innovation. Caterpillar case study. December 2007. www.vbhealth.org/papers/Caterpillar.pdf. Accessed October 28, 2010.

18. Center for Health Value Innovation. HEREIU Welfare-Pension Fund case study.

December 2007. www.vbhealth.org/papers/HEREIU.pdf. Accessed October 28, 2010.

STAKEHOLDER PERSPECTIVE Re-Engineering the Healthcare Continuum: Implementing Value-Based Insurance Design to Improve Diabetes Management PAYERS/EMPLOYERS: Over the past decade we have witnessed a dramatic shift back to the center in managed care insurance benefit designs, based on traditional cost-containment methods that provided limitations for specific populations and reduced customer satisfaction for patients and providers. During this same period, the US healthcare system has experienced its greatest challenge ever—how to fix a broken model. Within this process of repairing and reengineering the healthcare continuum, the term “value” evolved as a key concept to describe what is right or rational in the US healthcare, or at least that from which all stakeholders can derive benefit, as Michael E. Porter, PhD, describes in his recent discussion of value in healthcare.1

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Value-based insurance design (VBID) is part of the rebranding and new campaign led by national insurers and recognized employers who are actively engaged in containing healthcare costs, delivering efficient resources, and ultimately satisfying the end-paying consumer of healthcare—employers, government, and patients. This new approach of VBID described in the present article by Jennifer Decker Arevalo is our way of fixing one of the shortsighted methods used over the past few decades of managed care that, in our rush to reduce, maintain, and control the spending on medical resources (especially pharmaceuticals) and utilization management, created an imbalance in care.

VBID signifies our recognition of the importance of removing barriers to healthcare for those in greatest

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STAKEHOLDER PERSPECTIVE (Continued) need for care. Analogous to the medical home model of care, VBID offers managed care organizations and employers the ability to offer incentives for the “right behavior,” while reducing the burden of navigating an already twisted path to better health.

Diabetes and obesity—for which the term “diabesity” was recently coined—are the 2 key public health issues facing our nation today. As payers, we must endorse, support, and improve the marketing of VBID. Although we are not the caregivers, we are managing the care of an expensive and expansive population, and it is time that we support and stop blocking the core actors in this transaction—the provider and the patient. Using business principles, we can clearly see the short- and long-term payoff, the return on investment, and the applications of VBID in diabetes and in other chronic diseases.

It will take time to undo the past, and it is up to all healthcare stakeholders to generate the best evidence for the value of improved outcomes and efficient use of resources. Maximizing return equals getting our diabetic patients to goal in a timely manner that is safe and effective, expanding our efforts, addressing relevant measures of success in peer-reviewed journals, and communicating with consumers with clarity. Taking these steps will strengthen our position and demonstrate that we can achieve the optimal outcome when we align all parties to recognize the tradeoffs required.

If VBID works for diabetic patients and meets the 3 points of success—improved outcomes, increased access, and lowered cost—then what is stopping us from applying VBID to other chronic conditions? Are we waiting for the word “mandatory”?

The proof is contained in the present article, and it is now up to us to apply it to our local plans. It is not time to create more buzz words or fancy acronyms, nor is it time to generate mountains of paper or brochure programs. We need to innovate and solve these problems by extending our care community and involving all participants in shared responsibilities and benefits.

We need to make it simple for providers, patients, and employers to get the most from their healthcare dollar.

We can learn a lot from a recent example of a model market dynamic that may apply equally to healthcare—the example of Apple announcing the purchase of 10 billion applications from its App Store.2 The Motorola Droid is quickly catching up, with an alter-

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native platform. What we can learn from our current/future consumers is that they are willing to use technology, and we are beginning to rely on this tool to address business, human, and social needs that were not considered essential until recently. We engage in text messaging, e-mail, Skype, and instant messaging.

Unlimited data and low-cost entrants to the market enable us all to carry an electronic device. Let’s use the platform that is socially acceptable and see if we can build communities of care, share our success, and extend the value of our healthcare dollars by using similar social and humanistic techniques that will engage current and future generations. Maybe VBID will include unlimited data for chronic disease patients and beyond.

PATIENTS: It is time to engage in activating patients and encouraging their best performance to achieve optimal care. Offering patients with diabetes incentives to seek care, monitoring adherence, and reducing serious complications (eg, amputations, hospitalizations, and vision loss) all translates into great care, saves our system millions of dollars annually, and drives rational behavior by a system that is forced to solve the long-term care gap that threatens to overwhelm the United States.

I challenge all of us in managed care to look at the top 5 chronic disease categories; if you are like most plans, you will agree that diabetes, hypertension, chronic obstructive pulmonary disease, congestive heart failure, and inappropriate cholesterol levels create a entire case of disease management services to engage patients and employers in optimal chronic care management, healthier activities, and improved medication adherence.

Patients and providers will be rewarded in the new healthcare model by creating strategies such as the Asheville Project (pharmacist), the medical home (nurse/team), and Walmart’s $4.00 generic program (corporate), all of which will create continuity of care, increase patient contact and understanding, and improve access to healthcare.

1. Porter ME. What is value in health care? N Engl J Med. 2010;363:2477-2481.

2. Apple Inc. Apple’s app store downloads top 10 billion. Press release. January 22, 2011. www.apple.com/uk/pr/library/2011/01/22appstore.html. Accessed January 30, 2011.

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Scott R. Taylor, RPh, MBA Executive Director, Industry Relations Geisinger Health System, PA

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INDICATION EXALGO® tablets are an extended release oral formulation of the opioid agonist hydromorphone hydrochloride that is indicated for once daily administration for the management of moderate to severe pain in opioid tolerant patients requiring continuous, around-the-clock opioid analgesia for an extended period of time.

IMPORTANT RISK INFORMATION WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg oral oxycodone/day, 8 mg oral hydromorphone/day, 25 mg oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer.

EXALGO is for use in opioid tolerant patients only.

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain.

EXALGO is not intended for use as an as-needed analgesic.

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone.

• EXALGO is also contraindicated in patients who: - need management of mild pain or pain not expected to persist - have significant impaired respiratory function including those with acute or severe bronchial asthma or hypercarbia.

- have or are suspected to have paralytic ileus - have narrowed or obstructed gastrointestinal tract including those from previous surgery or “blind loops” in the GI tract - have known hypersensitivity to any components including hydromorphone hydrochloride and sulfites.

• Avoid concurrent use of alcohol and EXALGO. Concurrent use of EXALGO with CNS depressants, including alcohol, increases risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. EXALGO may impair the ability to drive a car or operate machinery.

• Not intended in patients who have received MAO inhibitors within 14 days of starting EXALGO. • Use with caution and in reduced doses in older or debilitated patients, as well as patients with renal or hepatic insufficiency, Addison’s disease, delirium tremens, myxedema or hypothyroidism, prosthetic hypertrophy or urethral stricture, toxic psychosis. May aggravate convulsions in patients with convulsive disorders; may induce or aggravate seizures in some clinical settings. Consider use of an alternate analgesic in patients with severe renal impairment.

• Respiratory depression, which occurs more frequently in elderly or debilitated patients, is the chief hazard with EXALGO. • Most common adverse events (>10%) seen in clinical studies (N=2474) were: constipation (31%), nausea (28%), vomiting, somnolence, headache, asthenia and dizziness. Serious adverse events could also include head injury, hypotensive effects, GI effects, cardiac arrest from overdose and precipitation of withdrawal.

• Use EXALGO with extreme caution in patients susceptible to intracranial effects of CO2 retention.

• Do not abruptly discontinue EXALGO Please see brief summary of Full Prescribing Information, including boxed warning on following pages.

COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and internationally registered trademarks of Covidien AG. EXALGO is a registered trademark of Mallinckrodt Inc. © 2010 Mallinckrodt Inc., a Covidien company. MK20010 September 2010 Printed in USA.

Keep pain waiting.

With once-daily EXALGO速, he might as well get used to it.

With 24-hour extended-release hydromorphone, EXALGO helps you keep pain at bay. You can minimize peaks and troughs at steady state for your opioid tolerant patients with moderate to severe chronic pain, and they can reduce their pill burden. To find out more, visit www.keeppainwaiting.com.

速

BRIEF SUMMARY - Consult full prescribing information before use.

EXALGO™ (hydromorphone HCl) Extended-Release Tablets WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENT SELECTION AND LIMITATIONS OF USE Potential for Abuse EXALGO contains hydromorphone, an opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics. EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when administering, prescribing, or dispensing EXALGO in situations where the healthcare professional is concerned about increased risk of misuse, abuse, or diversion. Schedule II opioid substances which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone and methadone have the highest potential for abuse and risk of fatal overdose due to respiratory depression [see Drug Abuse and Dependence (9)].

Proper Patient Selection EXALGO is an extended-release formulation of hydromorphone hydrochloride indicated for the management of moderate to severe pain in opioid tolerant patients when a continuous around-the-clock opioid analgesic is needed for an extended period of time. Patients considered opioid tolerant are those who are taking at least 60 mg oral morphine per day, 25 mcg transdermal fentanyl/hour, 30 mg of oral oxycodone/ day, 8 mg oral hydromorphone/day, 25 mg of oral oxymorphone/day or an equianalgesic dose of another opioid, for a week or longer [see Indications and Usage (1) and Dosage and Administration (2)].

EXALGO is for use in opioid tolerant patients only [see Indications and Usage (1) and Dosage and Administration (2)].

Fatal respiratory depression could occur in patients who are not opioid tolerant.

Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone [see Warnings and Precautions (5.1)].

Limitations of Use EXALGO is not indicated for the management of acute or postoperative pain [see Indications and Usage (1)].

EXALGO is not intended for use as an as-needed analgesic [see Indications and Usage (1)].

EXALGO tablets are to be swallowed whole and are not to be broken, chewed, dissolved, crushed or injected. Taking broken, chewed, dissolved or crushed EXALGO or its contents leads to rapid release and absorption of a potentially fatal dose of hydromorphone [see Warnings and Precautions (5)].

CONTRAINDICATIONS Opioid Non-Tolerant Patients EXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant.

Impaired Pulmonary Function EXALGO is contraindicated in patients with significant respiratory depression, especially in the absence of resuscitative equipment or in unmonitored settings and in patients with acute or severe bronchial asthma or hypercarbia.

Paralytic Ileus EXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus.

Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI Tract EXALGO is contraindicated in patients who have had surgical procedures and/or underlying disease that would result in narrowing of the gastrointestinal tract, or have “blind loops” of the gastrointestinal tract or gastrointestinal obstruction.

Allergy or Hypersensitivity EXALGO is contraindicated in patients with known hypersensitivity to any of its components including the active agent, hydromorphone hydrochloride or known allergy to sulfite-containing medications [see Warnings and Precautions (5.8)].

WARNINGS AND PRECAUTIONS Information Essential for Safe Administration EXALGO tablets are to be swallowed whole, and are not to be broken, chewed, crushed, dissolved or injected. Taking broken, chewed, crushed, dissolved EXALGO or its contents leads to the rapid release and absorption of a potentially fatal dose of hydromorphone [see Boxed Warning].

EXALGO is for use only in opioid tolerant patients. Ingestion of EXALGO may cause fatal respiratory depression when administered to patients who are not opioid tolerant [see Boxed Warning].

EXALGO tablets must be kept in a secure place out of the reach of children. Accidental consumption of EXALGO, especially in children, can result in a fatal overdose of hydromorphone.

Misuse and Abuse EXALGO contains hydromorphone, an opioid agonist, and is a Schedule II controlled substance. Opioid agonists have the potential for being abused and are sought by drug abusers and people with addiction disorders and are subject to criminal diversion.

EXALGO can be abused in a manner similar to other opioid agonists, legal or illicit.

This should be considered when prescribing or dispensing EXALGO in situations where the healthcare professional is concerned about an increased risk of misuse, abuse, or diversion.

Breaking, crushing, chewing, or dissolving the contents of an EXALGO tablet results in the uncontrolled delivery of the opioid and poses a significant risk of overdose and death [see Drug Abuse and Dependence (9)].

If attempts are made to extract the drug from the hard outer shell for purposes of parenteral abuse, the injection of tablet excipients may be toxic and may result in lethal complications.

Concerns about abuse, addiction, and diversion should not prevent the proper management of pain. However, all patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, since use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Respiratory Depression Respiratory depression is the chief hazard of EXALGO. Respiratory depression occurs more frequently in elderly or debilitated patients as well as those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation, and when opioids are given in conjunction with other agents that depress respiration.

Use EXALGO with extreme caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve such as asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea, myxedema, kyphoscoliosis or CNS depression. In these patients, even moderate therapeutic doses of hydromorphone may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. In these patients, consider alternative non-opioid analgesics, and use EXALGO only under careful medical supervision at the lowest effective dose.

Interactions with Alcohol and Other CNS Depressants The concurrent use of EXALGO with other central nervous system (CNS) depressants, including but not limited to other opioids, illicit drugs, sedatives, hypnotics, general anesthetics, phenothiazines, muscle relaxants, other tranquilizers, and alcohol, increases the risk of respiratory depression, hypotension, and profound sedation, potentially resulting in coma or death. Use with caution and in reduced dosages in patients taking CNS depressants. Avoid concurrent use of alcohol and EXALGO [see Clinical Pharmacology (12.3)].

Head Injury and Increased Intracranial Pressure In the presence of head injury, intracranial lesions or a preexisting increase in intracranial pressure, the respiratory depressant effects of EXALGO and its potential to elevate cerebrospinal fluid pressure (resulting from vasodilation following CO2 retention) may be markedly exaggerated. Furthermore, EXALGO can produce effects on pupillary response and consciousness, which may obscure neurologic signs of further increases in intracranial pressure in patients with head injuries.

Hypotensive Effect EXALGO may cause severe hypotension. There is added risk to individuals whose ability to maintain blood pressure has been compromised by a depleted blood volume, or after concurrent administration with drugs such as phenothiazines, general anesthetics, or other agents that compromise vasomotor tone.

Administer EXALGO with caution to patients in circulatory shock, since vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal Effects Because the EXALGO tablet is nondeformable and does not appreciably change in shape in the GI tract, do not administer EXALGO to patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders small bowel inflammatory disease, “short gut” syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudoobstruction, or Meckel’s diverticulum). There have been reports of obstructive symptoms in patients with known strictures or risk of strictures, such as previous GI surgery, in association with the ingestion of drugs in nondeformable extended-release formulations.

The administration of EXALGO may obscure the diagnosis or clinical course in patients with acute abdominal condition.

It is possible that EXALGO tablets may be visible on abdominal x-rays under certain circumstances, especially when digital enhancing techniques are utilized.

Sulfites EXALGO contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.

MAO Inhibitors EXALGO is not recommended for use in patients who have received MAO inhibitors within 14 days, because severe and unpredictable potentiation by MAO inhibitors has been reported with opioid analgesics.

Special Risk Groups EXALGO should be administered with caution in elderly (≥ 65 years) and debilitated patients and in patients who are known to be sensitive to central nervous system depressants, such as those with cardiovascular, pulmonary, renal, or hepatic disease [see Use in Specific Populations (8)].

EXALGO should also be used with caution in the following conditions: adrenocortical insufficiency (e.g., Addison’s disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and, toxic psychosis.

EXALGO may aggravate convulsions in patients with convulsive disorders, and all opioids may induce or aggravate seizures in some clinical settings.

Use in Pancreatic/Biliary Tract Disease EXALGO can cause an increase in biliary tract pressure as a result of spasm in the sphincter of Oddi. Caution should be exercised in the administration of EXALGO to patients with inflammatory or obstructive bowel disorders, acute pancreatitis secondary to biliary tract disease and in patients about to undergo biliary surgery.

Driving and Operating Machinery EXALGO may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Caution patients accordingly. Also warn patients about the potential combined effects of EXALGO with other CNS depressants, including other opioids, phenothiazines, sedative/hypnotics, and alcohol [see Drug Interactions (7)].

Precipitation of Withdrawal Mixed agonist/antagonist analgesics (i.e., pentazocine, nalbuphine, and butorphanol) should not be administered to patients who have received or are receiving a course of therapy with a pure opioid agonist analgesic, including EXALGO. In these patients, mixed agonists/antagonists analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms. Do not abruptly discontinue EXALGO. Clinical conditions or medicinal products that cause a sudden and significant shortening of gastrointestinal transit time may result in decreased hydromorphone absorption with EXALGO and may potentially lead to withdrawal symptoms in patients with a physical dependence on opioids.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling: • Respiratory Depression [see Warnings and Precautions (5.3)] • Head Injury and Increased Intracranial Pressure [see Warnings and Precautions (5.5)] • Hypotensive Effect [see Warnings and Precautions (5.6)] • Gastrointestinal Effects [see Warnings and Precautions (5.7)] • Cardiac Arrest [see Overdosage (10)] • Precipitation of Withdrawal [see Warnings and Precautions (5.13)]

Clinical Studies 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 clinical practice.

EXALGO was administered to a total of 2,524 patients in 15 controlled and uncontrolled clinical studies. Of these, 423 patients were exposed to EXALGO for greater than 6 months and 141 exposed for greater than one year.

The overall incidence of adverse reactions in patients greater than 65 years of age was higher, with a greater than 5% difference in rates for constipation and nausea when compared with younger patients. The overall incidence of adverse reactions in female patients was higher, with a greater than 5% difference in rates for nausea, vomiting, constipation and somnolence when compared with male patients.

A 12-week double-blind, placebo-controlled, randomized withdrawal study was conducted in opioid tolerant patients with moderate to severe low back pain [see Clinical Studies (14)]. A total of 447 patients were enrolled into the open-label titration phase with 268 patients randomized into the double-blind treatment phase. The adverse reactions that were reported in at least 2% of the patients are contained in Table 1.

Table 1.

Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Moderate to Severe Low Back Pain During the Open-Label Titration Phase or Double-Blind Treatment Phase by Preferred Term Open-Label Double-Blind Treatment Phase Preferred Term Titration Phase EXALGO (N=447) EXALGO (N=134) Placebo (N=134) Constipation 69 (15) 10 (7) 5 (4) Nausea 53 (12) 12 (9) 10 (7) Somnolence 39 (9) 1 (1) 0 (0) Headache 35 (8) 7 (5) 10 (7) Vomiting 29 (6) 8 (6) 6 (4) Drug Withdrawal Syndrome 22 (5) 13 (10) 16 (12) Pruritus 21 (5) 1 (1) 0 (0) Dizziness 17 (4) 3 (2) 2 (1) Asthenia a 16 (4) 2 (1) 6 (4) Insomnia 13 (3) 7 (5) 5 (4) Diarrhea 13 (3) 5 (4) 9 (7) Back Pain 13 (3) 6 (4) 8 (6) Dry Mouth 13 (3) 2 (1) 0 (0) Edema Peripheral 13 (3) 3 (2) 1 (1) Hyperhidrosis 13 (3) 2 (1) 2 (1) Anorexia b 10 (2) 2 (1) 0 (0) Arthralgia 9 (2) 8 (6) 3 (2) Anxiety 9 (2) 0 (0) 4 (3) Abdominal Pain c 9 (2) 4 (3) 3 (2) Muscle Spasms 5 (1) 3 (2) 1 (1) Weight Decreased 3 (1) 4 (3) 3 (2) a b c

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain

The adverse reactions that were reported in at least 2% of the total treated patients (N=2,474) in the 14 chronic clinical trials are contained in Table 2.

Table 2.

Number (%) of Patients with Adverse Reactions Reported in ≥2% of Patients with Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred Term Preferred Term All Patients (N=2,474) Constipation 765 (31) Nausea 684 (28) Vomiting 337 (14) Somnolence 367 (15) Headache 308 (12) Asthenia a 272 (11) Dizziness 262 (11) Diarrhea 201 (8) Pruritus 193 (8) Insomnia 161 (7) Hyperhidrosis 143 (6) Edema Peripheral 135 (5) 139 (6) Anorexia b Dry Mouth 121 (5) 115 (5) Abdominal Pain c Anxiety 95 (4) Back Pain 95 (4) Dyspepsia d 88 (4) Depression 81 (3) 76 (3) Dyspnea e Muscle Spasms 74 (3) Arthralgia 72 (3) Rash 64 (3) Pain in Extremity 63 (3) Pain 58 (2) Drug Withdrawal Syndrome 55 (2) Pyrexia 52 (2) Fall 51 (2) 51 (2) Chest Discomfort f a b c d e f

Fatigue was grouped and reported with asthenia Decreased appetite was grouped and reported with anorexia Abdominal pain upper was grouped and reported with abdominal pain Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and reported with dyspepsia Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

The following Adverse Reactions occurred in patients with an overall frequency of <2% and are listed in descending order within each System Organ Class: Cardiac disorders: palpitations, tachycardia, bradycardia, extrasystoles Ear and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadism Eye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: flatulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal fissure, bezoar, duodenitis, ileus, impaired gastric emptying, painful defecation General disorders and administration site conditions: chills, malaise, feeling abnormal, feeling hot and cold, feeling jittery, hangover, difficulty in walking, feeling drunk, hypothermia Infections and infestations: gastroenteritis, diverticulitis Injury, poisoning and procedural complications: contusion, overdose Investigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreased Metabolism and nutrition disorders: dehydration, fluid retention, increased appetite, hyperuricemia Musculoskeletal and connective tissue disorders: myalgia Nervous system disorders: tremor, sedation, hypoesthesia, paraesthesia, disturbance in attention, memory impairment, dysarthria, syncope, balance disorder, dysgeusia, depressed level of consciousness, coordination abnormal, hyperesthesia, myoclonus, dyskinesia, hyperreflexia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivity Psychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggression Renal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorder Reproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depression Skin and subcutaneous tissue disorders: erythema Vascular disorders: flushing, hypertension, hypotension DRUG INTERACTIONS CNS Depressants The concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant effects and respiratory depression. Additionally, hypotension and profound sedation or coma could occur. When this combination is indicated, the dose of one or both agents should be reduced. The concomitant use of alcohol should be avoided [see Clinical Pharmacology (12.3)].

Monoamine Oxidase (MAO) Inhibitors MAO inhibitors may cause CNS excitation or depression, hypotension or hypertension if co-administered with opioids including EXALGO. EXALGO is not intended for patients taking MAO inhibitors or within 14 days of stopping such treatment.

Mixed Agonist/Antagonist Opioid Analgesics The concomitant use of EXALGO with morphine agonist/antagonists (buprenorphone, nalbuphine, pentazocine) could lead to a reduction of the analgesic effect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended.

Anticholinergics Anticholinergics or other medications with anticholinergic activity when used concurrently with EXALGO may result in increased risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

Cytochrome P450 Enzymes In vitro data suggest that hydromorphone in clinically relevant concentrations has minimal potential to inhibit the activity of human hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 2D6, 3A4, and 4A11.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category C: There are no adequate and well-controlled studies in pregnant women. Hydromorphone crosses the placenta. EXALGO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations (8.2)].

Hydromorphone was not teratogenic in pregnant rats given oral doses up to 6.25 mg/kg/day or in pregnant rabbits administered oral doses up to 25 mg/kg/day during the period of organogenesis (~1.2 times the human exposure following 32 mg/day).

Hydromorphone administration to pregnant Syrian hamsters and CF-1 mice during major organ development revealed teratogenicity likely the result of maternal toxicity associated with sedation and hypoxia. In Syrian hamsters given single subcutaneous doses from 14 to 258 mg/kg during organogenesis (gestation days 8 to 10), doses ≥ 19 mg/kg hydromorphone produced skull malformations (exencephaly and cranioschisis). Continuous infusion of hydromorphone (5 mg/kg, s.c.) via implanted osmotic mini pumps during organogenesis (gestation days 7 to 10) produced soft tissue malformations (cryptorchidism, cleft palate, malformed ventricals and retina), and skeletal variations (supraoccipital, checkerboard and split sternebrae, delayed ossification of the paws and ectopic ossification sites). The malformations and variations observed in the hamsters and mice were at doses approximately three-fold higher and <one-fold lower, respectively, than a 32 mg human daily oral dose on a body surface area basis.

Nonteratogenic Effects In the pre- and post-natal effects study in rats, neonatal viability was reduced at 6.25 mg/kg/day (~1.2 times the human exposure following 32 mg/day).

Neonates born to mothers who have been taking opioids regularly prior to delivery will be physically dependent. The withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, increased respiratory rate, increased stools, sneezing, yawning, vomiting, and fever. The intensity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on the best method of managing withdrawal.

Approaches to the treatment of the syndrome have included supportive care and, if indicated, drugs such as paregoric or phenobarbital.

Labor and Delivery EXALGO is not recommended for use in women during and immediately prior to labor and delivery. Administration of EXALGO to the mother shortly before delivery may result in some degree of respiratory depression in the neonate.

However, neonates whose mothers received opioid analgesics during labor should be observed closely for signs of respiratory depression.

Nursing Mothers Low concentrations of hydromorphone have been detected in human milk in clinical trials. Withdrawal symptoms can occur in breastfeeding infants when maternal administration of an opioid analgesic is stopped. Nursing should not be undertaken while a patient is receiving EXALGO since hydromorphone is excreted in the milk.

Pediatric Use The safety and effectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established.

Geriatric Use Elderly patients have been shown to be more sensitive to the adverse effects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose.

Neonatal Withdrawal Syndrome Chronic maternal use of opiates or opioids during pregnancy coexposes the fetus. The newborn may experience subsequent neonatal withdrawal syndrome (NWS). Manifestations of NWS include irritability, hyperactivity, abnormal sleep pattern, high-pitched cry, tremor, vomiting, diarrhea, weight loss, and failure to gain weight. The onset, duration, and severity of the disorder differ based on such factors as the addictive drug used, time and amount of mother’s last dose, and rate of elimination of the drug from the newborn. Approaches to the treatment of this syndrome have included supportive care and, when indicated, drugs such as paregoric or phenobarbital.

Hepatic Impairment In a study that used a single 4 mg oral dose of immediate-release hydromorphone tablets, four-fold increases in plasma levels of hydromorphone (Cmax and AUC0- ) were observed in patients with moderate hepatic impairment (Child-Pugh Group B). Start patients with moderate hepatic impairment on a reduced dose and closely monitored during dose titration.

The pharmacokinetics of hydromorphone in severe hepatic impairment patients have not been studied. Further increase in Cmax and AUC0- of hydromorphone in this group is expected, therefore, use an even more conservative starting dose [see Dosage and Administration (2.4)].

Renal Impairment Renal impairment affected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The effects of renal impairment on hydromorphone pharmacokinetics were two-fold and four-fold increases in plasma levels of hydromorphone (Cmax and AUC0-48h) in moderate (CLcr = 40 to 60 mL/min) and severe (CLcr < 30 mL/min) impairment, respectively. In addition, in patients with severe renal impairment hydromorphone appeared to be more slowly eliminated with longer terminal elimination half-life (40 hours) compared to subjects with normal renal function (15 hours). Start patients with moderate renal impairment on a reduced dose and closely monitored during dose titration. As EXALGO is only intended for once daily administration, consider use of an alternate analgesic that may permit more flexibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)].

DRUG ABUSE AND DEPENDENCE Controlled Substance EXALGO contains hydromorphone, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymorphone. EXALGO can be abused and is subject to misuse, abuse, addiction, and criminal diversion [see Warnings and Precautions (5.2)]. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse.

Abuse All patients treated with opioids, including EXALGO, require careful monitoring for signs of abuse and addiction, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.

“Drug-seeking” behavior is very common to addicts and drug abusers. Drugseeking tactics include emergency calls or visits near the end of office hours, refusal to undergo appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, people suffering from untreated addiction and criminals seeking drugs to sell.

Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts.

In addition, abuse of opioids can occur in the absence of true addiction and is characterized by misuse for non-medical purposes, often in combination with other psychoactive substances. Since EXALGO may be diverted for non-medical use, careful record-keeping of prescribing information, including quantity, frequency, and renewal requests is strongly advised.

Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.

EXALGO is intended for oral use only. Misuse or abuse by breaking, crushing, chewing, or dissolving EXALGO poses a hazard of overdose and death. This risk is increased with concurrent abuse of EXALGO with alcohol and other substances.

With intravenous abuse, the tablet excipients, especially polyethylene oxide, can be expected to result in necrosis and inflammation of cardiac tissues. In addition, parenteral drug abuse is commonly associated with transmission of infectious disease such as hepatitis and HIV. Healthcare professionals should contact their State Professional Licensing Board or State Controlled Substances Authority for information on how to prevent and detect abuse or diversion of this product.

Dependence Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

Tolerance could occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.

Physical dependence is a state of adaptation that is manifested by an opioid specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. The opioid abstinence or withdrawal syndrome is characterized by some or all of the following: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, piloerection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.

Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms [see Use in Specific Populations (8.1, 8.2)].

OVERDOSAGE Symptoms Acute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia, hypotension and death. The extended release characteristics of EXALGO should also be taken into account when treating the overdose. Even in the face of improvement, continued medical monitoring is required because of the possibility of extended effects.

Deaths due to overdose could occur with abuse and misuse of EXALGO. Due to the delayed mean apparent peak plasma level of EXALGO occurring at 16 hours following administration as well as the 11 hour mean elimination half-life of EXALGO, patients who receive an overdose will require an extended period of monitoring and treatment that may go beyond 24 to 48 hours.

Treatment Give primary attention to the re-establishment of a patent airway and institution of assisted or controlled ventilation. Employ supportive measures (including oxygen and vasopressors) in the management of circulatory shock and pulmonary edema accompanying overdose as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

The pure opioid antagonists, such as naloxone and naltrexone are specific antidotes to respiratory depression from opioid overdose. Since the duration of reversal would be expected to be less than the duration of action of hydromorphone in EXALGO, the patient must be carefully monitored until spontaneous respiration is reliably re-established. EXALGO will continue to release and add to the hydromorphone load for up to 24 hours after administration and the management of an overdose should be monitored accordingly, at least 24 to 48 hours beyond the overdose.

Only administer opioid antagonists in the presence of clinically significant respiratory or circulatory depression secondary to hydromorphone overdose. In patients who are physically dependent on any opioid agonist including EXALGO, an abrupt or complete reversal of opioid effects may precipitate an acute abstinence syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. Please see the prescribing information for the specific opioid antagonist for details of their proper use.

OROS is a registered trademark of ALZA Corporation.

EXALGO is a trademark of Mallinckrodt Inc. COVIDIEN, COVIDIEN with logo and Covidien logo are U.S. and/or internationally registered trademarks of Covidien AG. © 2010 Mallinckrodt Inc., a Covidien company Distributed by: Mallinckrodt Brand Pharmaceuticals, Inc. Hazelwood, MO 63042 USA Issued 03/2010-B

Mallinckrodt

The 8th Annual Driving Post-Reform Innovation and Collaboration to Achieve Quality, Cost-Effective Care Featuring the 2nd Annual World Health Innovation Summit!

April 4-6, 2011 • Gaylord National Resort and Convention Center • Washington, DC The Cost Crisis in Health Care Just Confirmed!

Max Baucus United States Senator Chairman United States Senate Finance Committee

Mark B. McClellan, MD, PhD Director, Engelberg Center for Health Care Reform Brookings Institution

George C. Halvorson, Chairman and Chief Executive Officer, Kaiser Permanente Board of Directors, AHIP

Mark T. Bertolini Chief Executive Officer and President Aetna

Len M. Nichols, PhD Director, Center for Health Policy Research and Ethics; Professor of Health Policy George Mason University

Bart Asner, MD Chief Executive Officer Monarch HealthCare

Alfred B. Knight, MD Chief Executive Officer Scott & White Memorial Hospital/Foundation and Scott & White Health Plan

Innovation for the Health Care Consumer Joseph Jimenez Chief Executive Officer Novartis

Joseph F. Coughlin, PhD Founder and Director Massachusetts Institute of Technology AgeLab

Robert Blendon, ScD Senior Associate Dean, Policy Translation and Leadership Development; Professor of Health Policy and Political Analysis Department of Health and Policy Management Harvard School of Public Health

Bertram L. Scott President U.S. Commercial CIGNA Corporation

William A. Hawkins Chairman and Chief Executive Office Medtronic

Susan E. Voss President, National Association of Insurance Commissioners (NAIC) Commissioner, Iowa Insurance Division

Presidential Sponsor:

Official Well-Being Sponsor:

Leveraging Information and Technology to Drive Efficiencies Charles W. Sorenson, Jr, MD President and Chief Executive Officer Intermountain Health Care

Zoë Baird President Markle Foundation

Meg McCarthy Chief Information Officer, Senior Vice President of Innovation Technology and Service Operations Aetna, Inc.

David J. Brailer, MD, PhD Founder, Health Evolution Partners; Former and First National Coordinator for Health Information Technology, U.S. Department of Health and Human Services

Jonathan B. Perlin, MD, PhD President, Clinical Services and Chief Medical Officer HCA, Inc. / Hospital Corporation of America Bruce J. Goodman Senior Vice President, Chief Service and Information Officer Humana

Adapting International Best Practices His Excellency Hatem El-Gabali Minister of Health and Population Ministry of Health and Population (Egypt)

Hisham Diwani, MD General Manager, Health Insurance Ministry of Health of Syria; Member, Syrian Insurance Supervisory Commission (Syria)

Official Healthcare Decisions Sponsor:

Official Innovation Series Sponsor:

Official Public Relations Partner: Dr. Zakiuddin Ahmed National Coordinator of Telemedicine and eHealth Ministry of Health (Pakistan) Focal Person for Health, World Health Organization Chief Executive Officer, eHealth Service Pvt. Ltd

Educational Underwriters:

WHAT TO EXPECT AT THE 8TH ANNUAL WORLD HEALTH CARE CONGRESS The Next Stages of Health Reform — Through 13 keynote sessions, 10 executive summits, 10 emerging trend forums, 10 innovation and market insight series - WHCC features multi-perspective, high-level panel discussions that deliver expert opinions on the necessities to drive efficiency and quality in care — and the possibility of dismantling health reform Cross-Industry Collaboration! — WHCC is the ONLY event that breaks the industry silos and convenes ALL sectors of health care — over 1,800 executives from the Nation’s largest employers, hospitals, health systems, health plan and payers, pharmaceutical, government, academia under one umbrella for the common goal of reshaping care delivery Expanded Networking! — Over 14 hours of dedicated networking functions — An unrivaled opportunity to make new contacts and network with over 1,800 health care, business and government leaders to generate new business and share best practices Unparalleled Education — Take action and learn actionable and tangible strategies from best-in class organizations that help improve your business performance and ROI Featuring New Strategy Curriculums — Over 16 hours of unparalleled case studies and presentations on Accountable Care Organizations, State Health Policy Issues, Strategies for Prevention, Wellness and Health Promotion and Next Generation Health IT and mHealth — visit www.worldhealthcarecongress.com for updates!

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BUSINESS

ORIGINAL STUDY

Addressing Costs and Continuity of Care through Innovative Solutions for Infused Therapies: A Collaborative Experience with Infliximab Rhett Johnson, MA; Edward N. Freeman, FACMPE, MBA

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2011;4(1):39-46 www.AHDBonline.com Disclosures are at end of text

Background: Infused therapies are becoming more common as pharmaceutical and biotechnology companies increasingly focus their research and development efforts on biologic agents.

Objective: To understand how collaborative efforts among a health plan, providers, and specialty pharmacies can improve the efficiency of delivering infused therapies, using the example of a pilot program in southern Ohio for the administration of infliximab.

Methods: In October 2008, the authors conducted one-on-one, in-person interviews with representatives of a health plan, a specialty pharmacy, and the 3 largest gastroenterology practices in a southern Ohio community that collaborated to develop an innovative pilot program for delivering infliximab for patients with inflammatory bowel disease in a costeffective manner in the office setting. The 2 health plan and 1 specialty pharmacy representatives were directly involved with the development and implementation of the program.

Gastroenterology practice representatives included 3 practice managers, 2 infusion nurses, 2 billing managers, and 1 precertification specialist.

Results: The interviews revealed the opportunities and challenges associated with managing infused therapies, as well as the potential unintended consequences of unilateral action by health plans. As a result of changes introduced by a local health plan in southern Ohio, 3 of the largest gastroenterology practices in the region decided to discontinue in-office infliximab infusions for their patients and send them to local hospital outpatient infusion centers. However, before the implementation of this policy, a new collaboration between the health plan, the 3 practices, and the health planâ&#x20AC;&#x2122;s specialty pharmacy enabled these practices to continue to provide this medication in their offices. This collaboration avoided cost increases to all involved by preventing the shift of patients to hospital outpatient departments and allowing patients to continue their care in the office setting.

Conclusion: It will become increasingly important for payers to develop and support costeffective ways to provide physicians and patients with access to infused medications. This pilot program shows the benefits of collaboration among healthcare stakeholders to identify innovative solutions for delivering appropriate office-based infusion therapy. The specific approach that is most appropriate for a specific health plan will depend on the unique local market circumstances.

G

rowth in specialty pharmaceuticals (including biologic therapies) continues to outpace traditional small molecules,1 and many of the newly

Mr Johnson is Vice President, Charles River Associates, Boston, MA; Mr Freeman is Executive Director, River Valley Physicians Inc, Cincinnati, OH.

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developed specialty products will be infused. At the start of the fourth quarter of 2009, at least 19 infused specialty therapies were waiting for approval by the US Food and Drug Administration or were in phase 3 clinical trials.2 Therefore, managing the costs associated with infused therapies continues to increase in importance for private and public health insurance plans. The required involve-

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Growth in specialty pharmaceuticals, including biologic therapies, continues to outpace traditional small molecules, and many of the new medications currently in development will be administered by infusion.

Infused therapies usually require the involvement of a healthcare professional.

It is therefore critical that specialty products, such as infliximab, are distributed and administered efficiently to deliver quality patient care while controlling costs.

This case study demonstrates a successful collaborative effort between gastroenterology offices, a specialty pharmacy, and a health plan for the administration of infliximab for patients with Crohn’s disease or ulcerative colitis.

The program’s cost-savings resulted from avoiding hospital-based infusion, and these savings outweighed the moderate increases in payments to providers.

This example shows that solutions for delivering infused therapies through efficient sites of care can be achieved through good communication among all participants, aligned incentives, a comprehensive cost plan, and innovation.

ment of a healthcare professional in administering infused therapies, and the complexities of and variability in care delivery across patient types and sites of care, make cost-effective management of infused therapies a seemingly daunting challenge.

This article describes how one health plan collaborated with its network physicians and other stakeholders to develop a cost-effective approach for the administration of the infused therapy infliximab (Remicade).

Inflammatory Bowel Disease A collaborative effort between gastroenterology office practices, a specialty pharmacy, and a health plan in southern Ohio provides an example of a successful, integrated approach that maintained continuity of care for patients with inflammatory bowel disease (IBD) at the site of care as preferred by the health plan and its network physicians, as well as by many patients, according to their physicians.

Crohn’s disease and ulcerative colitis are chronic relapsing and remitting IBDs3 afflicting an estimated 1.4 million Americans.4,5 Treatments for patients with IBD may be administered by different means—orally with aminosalicylates, corticosteroids, azathioprine (Azasan, Imuran), or methotrexate (Trexall); injected

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intramuscularly with methotrexate or subcutaneously with adalimumab (Humira) or certolizumab (Cimzia); or administered by intravenous infusion with infliximab (Remicade) or natalizumab (Tysabri).5,6 Infliximab is an anti–tumor necrosis factor agent that has been approved for the treatment of Crohn’s disease and ulcerative colitis.7 Studies have demonstrated its effectiveness for the treatment of Crohn’s disease and ulcerative colitis,8-11 and infliximab has become a recognized therapeutic option for the management of moderate-to-severe active disease.12 To deliver infliximab to patients, gastroenterologists are faced with a choice of infusion delivery alternatives.

Some office practices have infusion capacity to enable in-office delivery of infliximab; other office practices refer patients to a local hospital for infusion services; still others refer patients to ambulatory infusion suites in the community or to home infusion providers for infusion administration at home.13 Each of these distribution models has different implications for physician office operations, patient out-ofpocket (OOP) cost burden, third-party health plan costs, and patient experience. In-office infusions may require physicians to invest in additional infrastructure, including product acquisition processes, inventory management, infusion chair and nurse capacity, and infusion billing procedures.

From a payer perspective, specialty pharmaceutical products such as infliximab pose unique opportunities and challenges. It is critical that specialty products are distributed and administered efficiently to deliver quality patient care and control costs. However, because a variety of administration options may be available to physicians (eg, in-office infusion, hospital-based infusion, home infusion), health plans must ensure that physician incentives are aligned with payers’ and patients’ site-ofcare preferences.

Ensuring that infusions are delivered in cost-effective sites of care requires a comprehensive and integrated solution to address the needs of different stakeholders— physicians, patients, payers, and intermediaries, such as distributors or third-party infusion therapy providers.

The purpose of this study was to investigate a program implemented by one health plan to encourage continued infliximab infusions in the low-cost physician office setting, identify the key determinants of its success, and describe the implications for health plans interested in managing the costs of infused therapies.

Methods In October 2008, the authors interviewed individuals involved with an infusion management pilot program implemented in southern Ohio by one of the leading

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regional health plans. Study participants were selected based on their direct involvement with developing and/or implementing the program and the relevance of their specific roles in assessing the program’s results and impact. Individuals interviewed included: • 6 practice managers from each of the 3 largest gastroenterology practices in the region. For one of these practices, members of the office staff were also interviewed, including the billing manager, the infusion nurse, and the precertification specialist. For the other 2 practices, the information provided by the practice manager was sufficient to understand the impact of the program on practice operations and decisions • 2 health plan representatives who directly oversaw program development and assessment • 2 specialty pharmacy representatives who were directly involved with program development and execution • 1 infusion therapy nurse affiliated with the infusion therapy provider used by 2 of the 3 practices.

Interviews were generally conducted in person, at the respondent’s place of business. In one case (the infusion therapy provider nurse), circumstances required that the interview be conducted by telephone. A structured discussion outline was developed before each interview, with adaptations made by the authors during the interviews, as appropriate. Interview content was structured around the following topics: • Circumstances before implementation of the pilot program • Motivation for the pilot program • Logistic aspects of the program • Results and outcomes from the program • Program success factors and lessons learned.

Participants’ responses were summarized based on the notes taken during the interviews. Cost and outcomes data before and after implementation of the program were not made available to the authors. The results summarized below are based exclusively on the interview findings.

Results Since the introduction of infliximab in 1999, many gastroenterologists in southern Ohio had been infusing infliximab in their offices. Practice managers from all 3 participating practices noted that their physicians believed that in-office infusion provided the most comfortable and convenient patient experience and allowed for effective monitoring of patients’ conditions. In-office infusion was also financially sustainable; the gastroenterologists were receiving sufficient payment from health plans to cover the costs of investing in infusion capacity, hiring and training infusion nurses, and developing business processes to support in-office infusion of infliximab.

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Health Plan’s Cost-Control Strategies By early 2008, as part of a broader attempt to control costs, while still delivering quality care, a local health plan implemented several cost-management strategies that affected the in-office infusion model for infliximab.

The health plan established prior authorization (PA) requirements to ensure that only appropriate patients received infliximab infusions, and changed its drug reimbursement strategy (for infliximab only) from being based on an average wholesale price to being based on an average sales price, resulting in a reduction in infliximab reimbursement rates. In addition, the plan began selling more high-deductible insurance policies to its employer and individual customers, effectively increasing the OOP cost burden for patients, as well as the collections burden for physicians. The plan believed that each of these activities would generate cost-savings, while continuing to provide quality care for patients.

The health plan did not anticipate that these changes would cause area gastroenterology practices to reconsider the sustainability of in-office infusions.

With declining drug reimbursement levels and no payment increases for administrative services, sustaining in-office infusion services became a burden. The practice managers and billing personnel interviewed noted that the proliferation of medical coinsurance and highdeductible health plans led to increasing numbers of patients struggling to pay their share of infliximab costs, higher receivables for the gastroenterology practices, and more bad debt being written off by the physicians. In addition, the PA burden required more nurse and office staff administrative time.

Providers Exacerbating the problem was a disruption to the infusion process at 2 of the 3 gastroenterology offices.

These 2 practices had partnered with a third-party infusion therapy provider to assist with the operations associated with in-office infusions. The infusion therapy provider ostensibly provided a turnkey operation, handling all aspects of infusion provision. The infusion therapy provider’s responsibilities included: • Acquisition of product and management of inventory • Provision of infusion supplies • Provision of a trained infusion nurse • Administering infusions to patients (within the walls of the physicians’ offices) • Securing PA • Billing third-party insurers.

The 2 practices were satisfied with the arrangement.

They referred patients to the infusion therapy provider, which specialized in addressing infusion-related issues and insurance coverage. In return, the gastroenterology

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nurses and office staff were able to focus their attention on the other core aspects of patient care.

When the infusion therapy provider unexpectedly shut down its operations in the area, the infusion process at these 2 practices was disrupted. This disruption coincided with the health plan’s implementation of the additional cost controls, contributing to the gastroenterology practices’ decision to terminate in-office infusions and to send patients who required infusion to the hospital. If the infusion therapy provider had continued operating, the practices would have continued infusing the patients in their offices without interruption, possibly obviating the need for this specialty pharmacy pilot program. However, without an infusion partner, and facing higher infusion costs and lower revenues from the health plan, the practices reconsidered their provision of office-based infusions.

Taken together, these factors caused the 3 practices to conclude that providing in-office infusions of infliximab was no longer feasible. All 3 practices decided that their best choice was to send the health plan’s patients to the hospital outpatient clinic for their infliximab infusions.

“We could not continue to provide infusions in our offices when reimbursement for infliximab from this health plan barely covered our costs, let alone the nonclinical burden of managing inventory and collecting patient copayments,” explained coauthor Edward Freeman, former chief operating officer for a 13-physician gastroenterology practice in the community, who was also one of the practice managers interviewed for this study.

Innovative Pilot Program Before the complete transition to a hospital referral model was implemented, a new collaboration between these practices and the health plan led to an innovative solution that enabled continuity of care for the patients in the physicians’ offices. The health plan, seeking to avoid the higher cost of hospital-based infusions and maintain access to in-office patient care, developed a pilot program that, it hoped, would enable the gastroenterologists to continue infusing infliximab in the office setting.

This pilot program consisted of 2 major components.

1. Specialty pharmacy distribution. Physicians would obtain infliximab vials from the Ohio-based specialty pharmacy, which was owned and operated by the health plan. The specialty pharmacy would verify patient benefits and collect the appropriate patient copayment before delivering the medication to the physician. In addition, office-friendly procedures, such as medication delivery scheduling and confirmation, were developed to meet the needs of the practices.

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2. Infusion case rate. The health plan chose to provide an additional payment to compensate the gastroenterology offices for infusion-related costs, such as nursing time, office-staff time spent securing PA, and infusionrelated supplies.

All 3 gastroenterology offices in the area chose to participate in the program, generating benefits for physicians, the health plan, and patients. Physicians were able to continue to provide consistent care in their offices, while reducing bad debts and receiving a fair payment for the infusion service.

The health plan avoided the transfer of patients to a more costly hospital outpatient clinic setting, continued to provide convenient access to infliximab, deepened its relationships with the provider network, and began capturing utilization data through its specialty pharmacy.

According to the gastroenterology practices interviewed, as well as representatives of the health plan, patients continued to receive high-quality infusion services in the office setting, their continuity of care was maintained, and many reduced their OOP costs by utilizing the more generous of their medical and pharmacy benefits with the help of the specialty pharmacy.

According to all participants interviewed, the program has been highly successful. As Mr Freeman described it, “We now have a win, win, win. Patients continue to receive their infusions in the more comfortable and convenient office setting. The practice is relieved of some of the burden associated with managing acquisition of the drug, along with improved reimbursement for nurse administration. And the health plan avoids the higher site-of-service costs incurred when patients are sent to the hospital.”

Representatives of the health plan acknowledged the avoidance of higher hospital-based infusion costs, noting that the associated cost-savings far outweighed the increased case rate that enabled continued inoffice infusions.

The authors do not have information on the specific cost-savings estimates associated with the implementation of the program. However, representatives of the health plan reported during the interviews that the program would be considered for expansion to other geographies, allowing its regional affiliates to adapt the program to fit the specific needs of their local markets. The health plan’s willingness to expand this pilot program likely reflects its success at balancing appropriate access to care with the potential to reduce costs.

Discussion Lessons Learned This example highlights the impact of health plan policies on physician site-of-care choice for patients and

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outlines one potential solution to encourage cost-effective infusion therapy. In particular, the combination of specialty pharmacy distribution and appropriate physician payment levels for in-office infusions can reduce costs and ensure continuity of care for patients.

Implementation of such a program requires a level of integration between the payer and specialty pharmacy that may be more likely when the specialty pharmacy and health plan have common ownership.

Health plans and physician practices seeking collaborative solutions to deliver efficient and high-quality patient care may wish to consider the following factors, which were critical to achieving success in this program.

Communication. Early communication between the gastroenterology offices and the health plan enabled identification of the problem and development of a solution before physicians were forced to send patients to the hospital.

Aligned incentives. The plan’s objective was to encourage infusions in the most efficient site of care (ie, the physicians’ office), which also met with patient desires and provided continuity in patient care. The program enabled physicians and the health plan to align their objectives by assisting with the physicians’ receivables and inventory concerns (through specialty pharmacy benefit checks and product distribution) and by providing a fair infusion case rate for in-office infusions.

Comprehensive perspective. The health plan took a comprehensive view of plan costs by understanding the linkages between physician payment rates and the flow of patients to the hospital. A more typical approach would have been separate efforts to minimize physician and hospital payment rates without appreciating the ways in which these payment schedules can become interrelated.

Innovation. Sometimes new tools need to be developed to address a problem; in this case, the adaptation of a patient-focused specialty pharmacy delivery mechanism into a system that addressed physicians’ needs was the innovation that enabled a successful rollout of the pilot program. Other solutions can also be considered, such as the nurturing of infusion therapy providers or the development of alternative cost-effective infusion sites (eg, retail clinics or free-standing infusion centers).

Health plans should carefully consider whether their payment rates to these alternative sites of care are sufficient to enable ongoing financial viability for the infusion providers. Success of infusion therapy providers or other alternatives to hospital-based infusion could be an important step toward minimizing costs and ensuring quality and continuity of patient care.

Increasingly, health plans will need to pursue innovative and integrated solutions that meet the needs of dif-

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ferent stakeholders and that can be customized toward addressing local market circumstances.

Implications for Payer-Owned versus Contracted Specialty Pharmacies Close cooperation between the specialty pharmacy and the local health plan was a critical ingredient in the development of a solution that resolved concerns of the gastroenterology practices and prevented the costly transfer of patients to the hospital. In the Ohio situation, the health plan owned and operated the specialty pharmacy, but does that mean that business innovations like these are achievable only by plans that are vertically integrated?

It is true that there has been a trend toward health plans’ ownership of specialty pharmacy capabilities, with several large health plans owning their own specialty pharmacies. Examples include Aetna Specialty Pharmacy, CIGNA’s Tel-Drug Specialty Pharmacy, and a consortium of Blue Cross Blue Shield plans’ joint ownership of PRIME Therapeutics and its Triessent subsidiary.14-16 There are undoubtedly operational efficiencies that direct ownership can help unlock.

However, although smaller health plans may never have the scale to justify vertical integration into specialty pharmacy distribution, in many cases it should be possible to develop innovative, locally driven initiatives through creative contractual relationships with partner specialty pharmacies.

Outlined below are 4 advantages afforded by specialty pharmacy ownership that likely contributed to the success of the program in Ohio, along with some steps that health plans without internal specialty pharmacy capabilities can take to facilitate appropriate cooperation for customized program development.

Communication. Extensive communication is required between a health plan and a specialty pharmacy to identify a business opportunity, agree on a clear objective, work through the operational aspects of a solution, and monitor the successes and failures of the program.

That kind of communication is challenging even between operating units within a single company; common ownership of the health plan and specialty pharmacy formalizes the communication channels, and corporate leadership can ensure that communication is a priority. It is likely more difficult, albeit not impossible, to achieve similar levels of communication between 2 separate companies.

Aligned incentives. Specialty pharmacy ownership helps to ensure that incentives are aligned between the specialty pharmacy and the health plan, which at some level contribute to a single corporate profit and loss.

Internal conflicts can be addressed through adequate

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corporate leadership and internal incentive structures.

Health plans that engage specialty pharmacies on a contracted basis would need to structure their contracts to encourage the desired behavior and/or explicitly compensate the specialty pharmacy for specific activities. In the present southern Ohio gastroenterologist example, if the specialty pharmacy had not been owned by the health plan, a contract that specified higher payments for each infliximab prescription or upfront payments to offset program development costs might have been required to align specialty pharmacy and health plan incentives.

Integrated health information systems. In some organizations, integrated health plan and specialty pharmacy information systems could simplify and expedite the extraction and analysis of relevant patient data required to inform treatment and coverage decisions.17 Using our gastroenterologist example, a health plan with integrated systems may be able to access members’ medical and pharmacy benefits or claims information to obtain a comprehensive view of the costs associated with infusions of infliximab in the physician’s office compared with in a hospital outpatient setting.

Effective systems could also support more streamlined rollout and administration of the program, for example, through easier benefit verification and patient copayment collection processes, leading to greater member, physician, and plan satisfaction. This issue can be partially addressed with external specialty pharmacy vendors by defining data needs upfront, establishing a common format for all data input and output fields, and agreeing on the mode and frequency of data sharing; however, the level of investment required for more comprehensive systems integration is unlikely without common ownership.

Long-term commitment. Gains from innovative programs may only be fully realized over the long run.

Therefore, a long-term relationship between health plans and the specialty pharmacies, and continued commitment to common goals, may be critical to program success.

In this present case, there were upfront investments in new infrastructure and business processes that could only be justified based on cost reductions that would occur over time. It is unlikely that the health plan would have funded the investment in additional specialty pharmacy capabilities if the partnership were to expire in just a few months. In addition, network gastroenterologists were more likely to support a program because of an expectation of efficiency improvements over time as a result of repeated dealings with the specialty pharmacy and a low likelihood of operational disruption from a possible future change in specialty pharmacy vendors.

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However, there is opportunity for health plans without fully owned specialty pharmacies to enter into long-term strategic partnerships with contracted specialty pharmacies that share the plan’s vision, values, and culture. For example, Medco had a 10-year partnership with Accredo18 before it merged with that organization in 2005.19 Such long-term relationships offer plans greater flexibility to test programs in which success is uncertain, and potentially benefit from joint investments.

Although in-house specialty pharmacies may offer plans greater flexibility to test and develop customized initiatives related to specialty products, in many cases it may be possible for health plans without such internal capabilities to pursue specialty pharmacy relationships to successfully execute customized programs. These efforts require detailed upfront planning that facilitates communication, aligns incentives, addresses systems differences, and enables the plan and specialty pharmacy to capture long-term program benefits.

Conclusion To maintain high-quality, cost-effective patient care, health plans need to develop efficient infusion options that address the needs of local providers, patients, and healthcare delivery systems. Unlike traditional pharmaceuticals that are dispensed at a retail pharmacy, processes for treating patients with infused therapies must be carefully crafted, and sometimes innovative approaches must be developed, lest infusion costs increase as patients transfer to nonpreferred sites of care. Health plans can begin with focused pilot programs that address specific local market needs, perhaps for a specific product or specialty.

Appropriate expansion to other product categories, physician specialties, and geographies can be evaluated as payers gain experience, enabling the potential realization of more extensive cost-savings and quality improvements. Future research focusing on the costsavings and patient outcomes associated with site-ofcare programs may offer additional valuable insights for the payer community. ■ Acknowledgment This manuscript was supported and reviewed in its original form by Centocor Ortho Biotech, Inc. Centocor Ortho Biotech had no input or involvement in the peerreview, editing, or editorial process of this article.

Author Disclosure Statement Mr Johnson is a Consultant to Centocor Ortho Biotech, Endo Pharmaceuticals, Novo Nordisk, and Sanofi Pasteur.

Mr Freeman has nothing to disclose.

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Author Disclaimer The views expressed in this article do not purport to reflect or represent the views of Charles River Associates, a registered trade name of CRA International, Inc, or any of the organizations with which the authors are affiliated. Charles River Associates and the authors accept no duty of care or liability of any kind whatsoever to any party, and no responsibility for damages, if any, suffered by any party as a result of decisions made, or not made, or actions taken, or not taken, based on this paper. For information regarding this article, please contact the authors at www.crai.com.

References 1. Medco. The Great Healthcare Debates: Prescriptions for Meaningful Reform.

Drug Trend Report. 2009;11.

2. Walgreens Specialty Pharmacy. Specialty Pharmaceutical Pipeline Report, Fourth Quarter 2009. www.walgreenshealth.com/common/pdf/Pipeline_Q4_2009.pdf.

Accessed December 9, 2010.

3. Geboes K. Histopathology of Crohn’s disease and ulcerative colitis. In: Satsangi J, Sutherland LR, Colombel JF, et al, eds. Inflammatory Bowel Diseases. 4th ed.

Edinburgh: Churchill Livingstone; 2003:255-261.

4. Crohn’s and Colitis Foundation of America. About the epidemiology of IBD. www.ccfa.org/about/press/epidemiologyfacts. Accessed December 22, 2009.

5. Lichtenstein GR, Hanauer SB, Sandborn WJ, for the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104:465-483. Epub 2009 Jan 6.

6. Kornbluth A, Sachar DB, for the Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults (update).

Am J Gastroenterol. 2004;99:1371-1385.

7. Remicade [prescribing information]. Malvern, PA: Centocor Ortho Biotech; 2009. www.remicade.com/remicade/assets/HCP_PPI.pdf. Accessed December 22, 2009.

8. Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N Engl J Med. 1999;340:1398-1405.

9. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541-1549.

10. Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn’s disease. N Engl J Med. 2004;350:876-885.

11. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2005;353:2462-2476.

12. Lichtenstein GR, Abreu MT, Cohen R, et al. American Gastroenterological Association Institute medical position statement on corticosteroids, immunomodulators, and infliximab in inflammatory bowel disease. Gastroenterology. 2006;130:935-939.

13. National Home Infusion Association. About infusion therapy. www.nhia.org/ about-home-infusion.cfm. Accessed July 5, 2010.

14. Aetna. Specialty medications. www.aetna.com/pharmacy-insurance/healthcareprofessional/specialty-medications/specialty-medications-index.html. Accessed December 23, 2009.

15. CIGNA. Specialty Pharmacy Prescription Program. www.cigna.com/pdf/ SpecialtyPharmacyMember.pdf. Accessed December 23, 2009.

16. Prime Therapeutics. Triessent. www.primetherapeutics.com/triessentindex.htm.

Accessed December 23, 2009.

17. Stern D, Reissman D. Specialty pharmacy cost management strategies of private health care payers. J Manag Care Pharm. 2006;12:736-744.

18. Medco Health Solutions. Medco Health Solutions and Accredo Health announce strategic alliance for specialty pharmacy care and management. Press release. February 10, 2004. http://medco.mediaroom.com/index.php?s=43&item=61.

Accessed December 29, 2009.

19. Medco Health Solutions, Form 10-K. Filed March 3, 2006. http://studio-5. financialcontent.com/edgar/quote/filings/quarterly?accesscode=119312506044742.

Accessed December 9, 2010.

STAKEHOLDER PERSPECTIVE New Strategies Needed to Combat Increasing Costs and Optimize Use of Infused Therapies PAYERS: Continued development of new strategies for infused pharmaceuticals is necessary to help combat the ever-increasing costs of such therapies, ensure appropriate use, and optimize clinical outcomes.

The drug spending trend for specialty injectables is anticipated to grow by as much as 14% in 2011,1 and by 2014, the value of specialty injectables in select key markets is anticipated to reach more than $90 billion.2 Current strategies used by payers to reduce the impact of the continuous rise in drug trends each year and support appropriate drug use may include a variety of benefit modifications, including benefit design wherein drug coverage is shifted to or shared with the pharmacy benefit; revised product distribution, such as required use of specialty pharmacy providers (SPPs); expanded utilization management techniques, such as prior authorization, step therapy, or clinical guidelines and preferred products; remodeling provider reimbursement, such as matching SPP average wholesale price

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discounts or average selling price, plus pricing; and widening patients’ share in the cost of treatment, with or without a maximum out-of-pocket limit.3 In this article, the authors outline a successful collaboration in an attempt to deal with the increasing costs of infused therapies. The authors describe a model that supports the strategy of cooperation between providers’ use of physician office–administered injectables and pharmacies for self-injectables and for distribution of specialty infused therapies to the physicians’ offices.

Such a delivery model may already exist within an organization as part of their focus to address claim issues and incorrect J-code unit billings. For plans where such a program is not currently available, the authors point out a multitude of barriers that may affect their ability to roll out such a program within an organization and its partners. Barriers that may be grappled with include setting infusion case and drug reimbursement rate assignments.

Continued

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STAKEHOLDER PERSPECTIVE

(Continued)

The alignment of financial incentives may be difficult between the physician practices, SPPs, and the health plan. The use of internal or external subject matter experts may be necessary to ensure a fair balance is reached between all parties involved.

PATIENTS: The authors note that an increased number of patients are struggling to pay their portion of the cost-sharing arrangement for their therapy. Because overall treatment costs show no signs of stabilizing, patients should consider discussing with their providers opportunities to maximize first- and second-line noninjectable treatments before the use of injectable therapy, when appropriate, to assist in reducing the cost burden.

Of note, the authors in this case elected not to interview patients involved with the pilot program.

However, patients who offer constructive feedback to

their health plan or purchasing organization (eg, employer) regarding a pilot program can assist in refining the program to best address the needs of the specific population.

1. Sharon B. 2010 Health Care Survey. Aon Consulting. Summer 2010. www.aon. com/attachments/2010_health_care_trend_survey_summer.pdf. Accessed January 29, 2011.

2. Dearment A. Report: specialty injectable drugs market worth more than $90 billion by 2014. Drug Store News. November 2, 2010. www.drugstorenews.com/ article/report-specialty-injectable-drugs-market-worth-more-90-billion-2014.

Accessed January 29, 2011.

3. EMD Serono. EMD Serono Specialty Digest, 6th ed. www.amcp.org/amcp.ark? p=03B27726. Accessed January 29, 2011.

Richard F. Radzin, PharmD Executive Consultant CGI Federal Cleveland, OH

CALL FOR PAPERS American Health & Drug Benefits offers an open forum for all healthcare participants 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 patient well-being, the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest Include: • Health Economics Research • Health Plan Initiatives • Health Information Technology • Industry Trends • Innovations in Healthcare • Literature Reviews • Medicare/Medicaid

• Adherence Concerns • Benefit Design • Case Studies • Comparative Effectiveness Research • Cost Analyses • Decision-Making Tools • Ethics in Medicine

• Patient Advocacy/Patient Care • Pharmacoeconomics • Policy Issues • Prevention Initiatives • Reimbursement Strategies • Survey Results • Wellness Programs

NOTE TO AUTHORS: AHDB is a member of the Committee on Publication Ethics (COPE). Membership in COPE indicates that this journal upholds COPE’s Code of Conduct standards and intends to take appropriate action in cases of possible misconduct, such as plagiarism, attempted or actual redundant publication, any attempts to pass off fraudulent data, unethical research, or breaches of confidentiality.

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ARZERRA® HCPCS Code J9302 Announcing a NEW J-Code for ARZERRA ARZERRA will have a permanent HCPCS code effective January 1, 2011 The new J9302 Code replaces miscellaneous HCPCS Codes J9999, J3590, J3490, and C9260 that most providers have used to bill for ARZERRA to date

HCPCS code

Description

Effective

J9302

Injection, ofatumumab, 10mg

January 1, 2011

©2010 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. AZA228R0 January 2011

Contact your GSK representative for additional information or visit www.ARZERRA.com.

GENERIC DRUG TRENDS

First Generic ARB Approval Draws a Wave of Comparative Studies

By Dalia Buffery, MA, ABD

C

omparative effectiveness research (CER) received a boost last year by the Patient Protection and Affordable Care Act as an approach that will help to identify best therapies and will also work to reduce costs by improving outcomes when best therapies are used.

CER is already having an impact on the direction of new research, reflecting attempts by healthcare stakeholders to reduce overall costs. With the ever-increasing number of generics entering the market, it is not surprising that the first-in-class generic approval by the US Food and Drug Administration (FDA) will become a research priority in the current environment of a cost- and outcomes-focused healthcare system.

On April 9, 2010, the FDA approved the first generic angiotensin receptor blocker (ARB)—losartan—for the treatment of hypertension and cardiovascular disease. It is therefore not surprising that comparative studies are now focusing on the efficacy and cost implications of losartan versus one of the branded ARBs. Several articles have already been published in 2011, and more are coming.

Readers of American Health & Drug Benefits fully understand that the drug acquisition cost does not reflect the overall cost of therapy. Other considerations, such as a lack of medication adherence, adverse events, and copayments, can skew the balance in favor of a branded agent, despite the reduced cost of the generic.

The most recent study comparing losartan and a branded ARB was published online on February 1, 2011.1 In this meta-analysis, Dr Anthony Gross and colleagues compared the efficacy and costs in previous studies of losartan and candesartan (which will be losing patent later this year) for hypertension and heart failure (HF).

In addition to efficacy, Dr Gross and colleagues evaluated the comparative incremental cost-effectiveness of these drugs within a UK National Health Service

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(NHS) setting. Their results showed slightly superior efficacy in diastolic (–1.96 mm Hg) and systolic (–2.40 mm Hg) blood pressure (BP) with candesartan. Using a Markov model to assess the cost difference based on the efficacy difference in BP showed that using the generic ARB would save the NHS approximately €200 million annually. No difference in efficacy was found for HF. As tempting as this finding may be to come to conclusions, however, results from other studies complicate the picture. A new study comparing data from the Swedish Heart Failure Registry using the same agents for patients with HF shows an efficacy advantage for candesartan for HF, which also resulted in a lower mortality for patients using candesartan.2 Yet another new article conducted in the United States using another branded ARB, olmesartan (which will be losing patent in 2016), showed a significant difference in seated BP efficacy favoring the branded ARB, despite a similar adverse event profile.3 Clearly, more studies using real-world data in line with CER criteria are needed. The work is cut out for researchers and payers to develop mechanisms that will lead to greater coherence in interpreting clinical outcomes and cost comparisons. Considering the current state of economic affairs, the use of generics is likely to increase, and more accurate information will help payers to develop improved benefit designs to allow patients and the US system to reap the benefits of CER. ■

References 1. Gross A, Bodalia PN, Macallister RJ, et al. Comparative clinical- and cost-effectiveness of candesartan and losartan in the management of hypertension and heart failure: a systemic review, meta- and cost-utility analysis. Int J Clin Pract. 2011 Feb 1 [Epub ahead of print]. http://www.news-medical.net/news/20110203/Genericdrugs-to-treat-hypertension-heart-failure-could-help-NHS-save-c2a3200million.aspx?page=2.

2. Eklind-Cervenka M, Benson L, Dahlstrom U, et al. Association of candesartan vs losartan with all-cause mortality in patients with heart failure. JAMA. 2011; 305:175-182.

3. Weir MR, Punzi HA, Flack JM, et al. A randomized, double-blind, forced-titration study to compare olmesartan medoxomil versus losartan potassium in patients with stage 1 and 2 hypertension. Postgrad Med. 2011;123:80-87.

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Partnership. People.

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PERSPECTIVE

Five Steps Healthcare Leaders Can Take to Address Childhood Obesity Jennifer Lovejoy, PhD

D

espite educational programs, social stigma, and a plethora of popular diets, many American children— and their parents—remain far too heavy.

The number of obese children has more than tripled since 1980.1 The good news is that obesity levels appear to be leveling off or even declining in some groups.2 The bad news is that many of our children are still severely overweight. If we do not change things now, experts predict that American children may have shorter lifespans than their parents, in large part because of poor dietary and physical activity habits.3 The implications of this new reality are staggering.

According to a 2009 report from the Robert Wood Johnson Foundation, obese children cost the nation up to $14 billion each year.4 The costs will be even higher when they become adults, as we continue to pay for earlier onset of chronic diseases (eg, diabetes, heart disease) and perhaps an entire generation that is less healthy and far less productive than its predecessors and is destined to pass down health habits to yet another generation.

Although providers play a critical role, employers and health plans must also bear the responsibility for finding ways to address the obesity epidemic. This will require an intense, coordinated effort that brings together healthcare, business, and community leaders to ensure the well-being of our children and our nation.

The Scope of the Problem To start combating childhood obesity, we must recognize the scope of the problem, and more important, we must fully understand the demographics of the population that we target. Who does it include? What socioeconomic and environmental factors have influenced their obesity? What obstacles do they face?

Obesity cuts across socioeconomic lines, but it largely affects those Americans who are underserved by healthcare programs. According to a landmark study, Dr Lovejoy is Vice President for Clinical Development and Support for Free & Clear, a division of Alere Inc, and President of the Obesity Society. She has published many articles and book chapters on obesity and is the recipient of federal and private grants to study lifestyle approaches to address obesity.

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almost 45% of poor children were overweight or obese compared with 22.2% of children living in households with incomes above 400% of the poverty level.5 Obesity is increasing at particularly alarming rates among minority children. A recent study showed that obesity rates among white, Asian, and Hispanic girls and boys peaked in 2005 and dropped in 2008.6 Obesity levels were stable for black boys during that period but increased for black girls, who were 3 times more likely to be severely obese than white girls. The heaviest children—those in the 99th percentile—have seen no decrease in weight over the most recent study published this year.6 In short, we still have not found ways to help those in greatest need.

Of greatest concern is the increase in early-onset diabetes and heart disease resulting from childhood obesity. Emotional problems, including low self-esteem, depression, and suicides, are also more prevalent among these children. Clearly, an entire segment of our population is at risk for a substandard quality of life if steps are not taken.

Barriers, Lack of Access to Care Tackling weight-loss challenges has not been easy.

Children who are bombarded daily with messages of high-calorie, tempting foods—with little counteradvertising for healthy options—find it difficult to make good choices. Many studies show that increasing hours of television watching and video games have an adverse effect on children’s weight.7,8 In addition, many parents and caregivers are in denial about their children’s weight problems. They see overly dramatized stories on the news about obese children and tell themselves, “My child is not like that.”

The majority of overweight children—up to 80%— have overweight parents.9 Many adult caregivers, unwilling or unable to change their own habits, create an environment in which children have no role models or options for improving health. And again, the socioeconomic factors cannot be overlooked. Many low-income families have little to no access to affordable fresh fruit and vegetables or safe, attractive places to be physically active.

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One of the most difficult challenges for obese patients of any age is the lack of health insurance coverage and reimbursement for antiobesity drugs and behavioral treatments. In many cases, obese patients must pay for treatments out of pocket, whether it is to see a nutritionist, get a prescription for a medication, or in extreme cases, have bariatric surgery. With the prevalence of obesity in low-income families, this lack of support makes it almost impossible for some people to get the help they need.

A study comparing the prices of 384 foods sold at supermarkets in the Seattle area showed that foods with the most calories and fewest nutrients per gram were far less expensive than healthier foods, such as fruit and vegetables.10 Many people who want to improve their health do not know how to change dietary habits that have been ingrained for generations.

A Call to Action Pockets of progress are emerging. For example, Michelle Obama has made childhood obesity her number 1 priority as First Lady. She has set up a federal task force, created the “Let’s Move” initiative, and is actively reaching out to low-income communities and others to help provide education and facilitate the creation of targeted programs.

Healthcare leaders must join this effort and develop programs that reach across organizational silos to ensure coordination, integration, and collaboration. Employers and health plans can champion the 5 following steps to help combat obesity: 1. Build programs that begin to address obesity before birth. Research has shown that what a mother does during pregnancy plays a significant role in whether her child will be obese. According to an extensive British study, “during critical periods of prenatal growth, permanent changes in metabolism or structures result from adverse intrauterine conditions.”11 Studies in the United States and India have shown correlations between small birth size and cardiovascular disease, insulin resistance, and type 2 diabetes.12 Finally, women who gain more than the recommended amount of weight during pregnancy are significantly more likely to have a child who grows up overweight.13 Health plans should work closely with providers to develop targeted programs for their pregnant members.

Programs must be low-cost and easily accessible to urban and rural populations. Behavioral programs that also include cognitive elements have been shown to be effective for preventing excess gestational weight gain.14 Encouraging pregnant members to reduce fat intake, increase consumption of fruits and vegetables, and limit sugar intake, and then showing them how to access

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affordable food and prepare healthy meals should be a central component of any outreach program. Partnerships with local food retailers, farmers’ markets, health systems, employers, and community organizations can make such efforts a reality.

The reality of obesity today should encourage us to find better ways to educate children, not simply ignore the problem because of potential concerns.

2. Create engaging and empowering health education programs. As health educators, we have learned in recent years that reaching children involves more than just putting a cartoon on health messages created for adults. Programs have to be specifically designed, at ageappropriate levels, for children. Web-based interactive programs could increase engagement, awareness, and retention among children and parents. Health coaching and support can also play an important role. These programs must be expanded to schools and daycare centers, particularly in underserved communities where Internet access is not always readily available. Because we are dealing with children, approaches and messaging must be carefully developed to ensure that programs promote a healthy body image. Some mental health experts are concerned that too much emphasis on childhood obesity creates body image distortion and can trigger eating disorders; however, the reality of obesity today should encourage us to find better ways to educate children, not simply ignore the problem because of potential concerns.

3. Promote family involvement. As noted earlier, many parents of obese children do not recognize the problem even when pediatricians diagnose it. In addition, employers and health plans are often hesitant to get involved in programs that target dependents, but they must do so. Programs promoting healthy weight work best when they are focused on children, as well as their adult caregivers. Employers can help to facilitate that involvement through educational programs, health portals, and other work-based resources.

Teasing and bullying also involve the family and must be addressed. A recent study showed that obese children are 65% more likely to be bullied than their peers of average weight.15 Family members, from siblings to parents, can be a key source of teasing or even bullying in what are often well-intentioned but misguided attempts to get the child not to overeat.

Research shows that teasing and bullying, rather than producing positive changes in eating or exercise behavior frequently cause the reverse, encouraging over-

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weight persons to eat more as a coping mechanism, along with harming self-esteem.15 Education targeting the entire family fosters family involvement and support in an encouraging environment and provides the best options for long-term results. Education and outreach cannot be positioned in a way that makes parents feel guilty; if it is, the parents may pull back. Programs work best that focus on keeping kids healthy, reducing disease, improving happiness, and highlighting the importance of parental involvement.

Antismoking initiatives provide a good example of how the combination of education, taxation, expanded treatment options, and public awareness help to spur a lasting change.

4. Understand the significant healthcare costs of obesity. Employers and health plans must understand the full scope and impact of childhood obesity on their healthcare costs, and on the productivity of members.

Parents of obese children often miss time from work because of time needed to attend to obesity-related health problems for their children. A recent study conducted by a large employer indicates that average per capita health insurance claims costs were as high as $2907 in 2008 for an obese child and as high as $10,789 for a child with type 2 diabetes.16 Assessing employee productivity provides a strong tool to assess the true scope and costs of programs. Obesity should be monitored during key developmental stages. The risk for obesity increases during puberty because of changes in hormones as well as behavioral factors (eg, at puberty, girls’ activity levels often drop dramatically).

Instituting programs that encourage healthy eating and exercise throughout childhood and that change to meet the development stages of children will lead to best results.

5. Champion community and industry partnerships.

A growing number of companies and organizations are recognizing the importance of working as a team to address childhood obesity. Some large employers are reaching out to their communities to develop and support educational programs. For example, a health plan in a Midwestern community gave out pedometers to members, and local businesses provided incentives, such as product discounts, for those who met goals. Health plans are creating community health centers of excellence to better serve uninsured and underinsured populations.

Urban communities are working with grocers and health plans to create garden cooperatives to ensure greater

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access to affordable fresh fruit and vegetables.

Opportunities for partnerships and collaboration are growing—employers and health plans should take note and join in when and where possible.

Join the Fight against Childhood Obesity No one person or organization can address the childhood obesity epidemic on its own. Without a coordinated effort, the chance for success is near zero.

However, as shown by recent experience and growing support for programs such as First Lady Michelle Obama’s “Let’s Move” campaign, when health plans, communities, the public sector, and companies make efforts, change can be achieved.

Employers, health plans, providers, legislators, and other healthcare leaders must work together to continue this success and expand it to all populations.

Antismoking initiatives provide a good example of how the combination of education, taxation, expanded treatment options, and public awareness help to spur a lasting change. Using these lessons to target the equally important issue of childhood obesity can help to ensure that America’s children live healthy and productive lives. ■ Author Disclosure Statement Dr Lovejoy has nothing to disclose.

References 1. Centers for Disease Control and Prevention. Obesity: halting the epidemic by making health easier. February 2009. www.cdc.gov/nccdphp/publications/AAG/pdf/ obesity.pdf. Accessed November 2, 2010.

2. Han JC, Lawlor DA, Kimm SY. Childhood obesity. Lancet. 2010;375:1737-1748.

3. American Heart Association. Overweight in children. www.heart.org/HEART ORG/GettingHealthy/Overweight-in-Children_UCM_304054_Article.jsp. June 10, 2010. Accessed November 22, 2010.

4. Robert Wood Johnson Foundation. Childhood obesity. www.rwjf.org/childhood obesity/challenge.jsp. Accessed November 22, 2010.

5. Bethell C, Simpson L, Stumbo S, et al. National, state, and local disparities in childhood obesity. Health Aff (Millwood). 2010;29:347-356.

6. Madsen KA, Weedn AE, Crawford PB. Disparities in peaks, plateaus, and declines in prevalence of high BMI among adolescents. Pediatrics. 2010;126:434-442.

7. Temple JL, Giacomelli AM, Kent KM, et al. Television watching increases motivated responding for food and energy intake in children. Am J Clin Nutr.

2007;85:355-361.

8. Vandewater EA, Shim MS, Caplovitz AG. Linking obesity and activity level with children’s television and video game use. J Adoles. 2004;27:71-85.

9. American Academy of Child and Adolescent Psychiatry. Obesity in children and teens. Facts for Families. 2008;79. http://aacap.org/page.ww?name=Obesity+in+Children +and+Teens&section=Facts+for+Families. Accessed November 22, 2010.

10. Monsivais P, Drewnowski A. Lower-energy-density diets are associated with higher monetary costs per kilocalorie and are consumed by women of higher socioeconomic status. J Am Diet Assoc. 2009;109:814-822.

11. World Health Organization. Programming of chronic disease by impaired fetal nutrition. 2002. www.who.int/nutrition/publications/programming_chronicdisease.pdf.

Accessed November 22, 2010.

12. Langley-Evans SC, McMullen S. Developmental origins of adult disease. Med Princ Pract. 2010;19:87-98. Epub 2010 Feb 4.

13. Oken E, Taveras EM, Kleinman KP, et al. Gestational weight gain and child adiposity at age 3 years. Am J Obstet Gynecol. 2007;196:322.e1-322.e8.

14. Skouteris H, Hartley-Clark L, McCabe M, et al. Preventing excessive gestational weight gain: a systematic review of interventions. Obes Rev. 2010;11:757-768.

15. Lumeng JC, Forrest P, Appugliese DP, et al. Weight status as a predictor of being bullied in third through sixth grades. Pediatrics. 2010;125:e1301-e1307. Epub 2010 May 3.

16. Sepulveda MJ, Tait F, Zimmerman E, Edington D. Impact of childhood obesity on employers. Health Aff (Millwood). 2010;29:513-521.

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First Annual Stakeholder Integration Conference Integrating Payers, Providers, and the Entire Oncology Team March 29-30, 2011 Philadelphia, PA Loews Philadelphia Hotel REGISTER ONLINE AT

www.regonline.com/avbcc-2011 PROGRAM OVERVIEW This is the first national stakeholder integration meeting dedicated to advancing the understanding of value in cancer care. Guided by the expertise of leaders in these fields, attendees will receive a thorough understanding of the evolution of the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while improving access for patients and ultimately patient care.

CONFERENCE AGENDA Tuesday, March 29 1:30 – 3:30 pm

PAYER PRE-CONFERENCE (Off-site) Payer Trends in Oncology - Panel Discussion

4:00 – 6:00 pm

GENERAL PRE-CONFERENCE • Value-Based Insurance Design in Oncology • Cancer Care from a Large Insurer’s Perspective • The Role of Diagnostics from a PBM’s Standpoint

6:15 – 8:30 pm

Welcome/Networking Reception

WHO SHOULD ATTEND All stakeholders in a position to impact cancer patient care are invited to join this exciting forum. Specifically this conference is intended for: • Medical Oncologists • Advanced Practitioners • Hematologists/Oncologists • Managed Care Professionals • Surgical Oncologists • Medical Directors • Nurses • Practice Managers/Administrators • Pharmacists • Pharmacy Benefit Managers (PBMs)

GOAL The Association for Value-Based Cancer Care’s First Annual Stakeholder Integration Conference will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

Wednesday, March 30 7:30 – 8:30 am

Corporate-Sponsored Breakfast Symposium Havalen™ (eribulin mesylate) Injection: A New FDA-Approved Treatment Funded by Eisai Inc.

8:30 – 8:45 am

Intro/Opening

8:45 – 9:30 am

NCCN Guidelines Acceptance and Compliance

9:30 – 10:15 am

The Impact of Personalized Oncology Therapies

10:20 – 10:50 am

Morning Break

11:00 am –12:30 pm PROVIDER TRACK • Community Oncology: Trends • Patient Navigation/Patient Assistance • Oncology Practices: Issues with Managed Care

OBJECTIVES

PAYER TRACK • Medicare and Reimbursement Issues • Drug Reimbursement & Administration Issues • Evolutions in Oncology Pharmacy Management

• Examine the impact of healthcare reform on all stakeholders involved in the management of patients with cancer • Identify issues and potential solutions to challenges with access and affordability of oncology therapeutics • Determine the value equation of cost, quality, and access when evaluating the diagnosis, treatment, and overall management of cancer patients • Define appropriate comparative effectiveness research and clinical pathways as tools to evaluate current recommendations for patient management • Analyze trends in the delivery of care in the management of cancer patients

12:30 – 2:00 pm

LUNCH SYMPOSIUM Best Practices for Management of CINV: A Value-Based Approach Supported by an educational grant from Eisai Inc.

2:00 – 2:45 pm

Cancer Care and the New Healthcare Legislation: What to Expect Next

CONFERENCE REGISTRATION

2:45 – 3:30 pm

Strategies for Improving Oncology Pharmacy and Care Management Models

$250 Includes 1-year association membership $350 Includes 3-year association membership

3:35 – 4:05 pm

Afternoon Break

4:10 – 4:55 pm

Clinical Fragmentation: Impact of Oral, Injected, and Infused Therapies

5:00 – 6:00 pm

Cocktails/Networking

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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May 2010