November/December 2010, Vol 3, No 6

REGULATORY

Implications of the New Political Realities on Healthcare ReformInterview with Dan Mendelson

CLINICAL

Engaging Providers in Medication Adherence: A Health Plan Case StudyAmy B. Scott, BSPharm, RPh; Jane E. McClure, BA, RN

Stakeholder Perspective by F. Randy Vogenberg, PhD, RPh

BUSINESS

The H-E-B Value-Based Health Management Program: Impact on AsthmaMedication Adherence and Healthcare CostAnna O. D’Souza, PhD; Roshan Rahnama, MPH; Timothy S. Regan, BPharm, RPh; Beth Common, MBA; Steven Burch, PhD

Stakeholder Perspective by Richard F. Radzin, PharmD

◆ Industry Trends

◆ Generic Drug Trends

◆ AMCP Highlights

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NOVEMBER/DECEMBER 2010 VOLUME 3, NUMBER 6

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

Covers_Cover 12/14/10 11:52 AM Page 357

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

goal

Covers_Cover 12/14/10 11:52 AM Page 358

©2010 Millennium Pharmaceuticals, Inc. All rights reserved.

To learn more, visit us at millennium.com.

One goal: discovering and delivering breakthrough medicines to combat cancer.

Now the innovative science of a leading American biopharmaceutical company joins

the global assets of Takeda, Japan’s largest pharmaceutical company, for a global

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Millennium: The Takeda Oncology Company is developing an extensive pipeline —

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360 l American Health & Drug Benefits l www.AHDBonline.com November/December 2010 l Vol 3, No 6

EDITORIAL BOARD

CLINICAL EDITOR Thomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PA

GOVERNMENT EDITORKevin B. “Kip” Piper, MA, FACHEPresident, Health Results GroupSr. Counselor, Fleishman-Hillard Washington, DC

ACTUARY David WilliamsMilliman Health ConsultantWindsor, CT

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie Comprehensive CancerCenter, Northwestern UniversityPresident, ACCCPast Chair, Board of Directors, NCCN

Samuel M. Silver, MD, PhD, FACPProfessor, Internal MedicineDirector, Cancer Center NetworkDivision of Hematology/OncologyAssistant Dean for ResearchUniversity of Michigan Health Systems

CARDIOLOGY RESEARCH Michael A. Weber, MDProfessor of MedicineDepartment of Medicine (Cardiology)State University of New York

ENDOCRINOLOGY RESEARCHJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ

EMPLOYERSAlberto M. Colombi, MD, MPHCorporate Medical DirectorPPG Industries, Pittsburgh, PA

Wayne M. Lednar, MD, PhDGlobal Chief Medical OfficerDirector, Integrated Health ServicesDuPont, Wilmington, DE

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

F. Randy Vogenberg, RPh, PhDPrincipal, Institute of Integrated HealthcareSharon, MASenior Fellow, Jefferson School ofPopulation Health

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

Nirav R. Shah, MD, MPHAssistant Professor of MedicineNYU School of Medicine, NYCSenior Investigator, Geisinger HealthSystem, Danville, PA

HEALTH INFORMATION TECHNOLOGY J. B. Jones, PhD, MBAResearch Associate, Geisinger Health System, Danville, PA

Victor J. Strecher, PhD, MPHProfessor and Director, Center for HealthCommunications ResearchUniversity of Michigan Schools of PublicHealth and Medicine, Ann ArborFounder and Chief Visionary OfficerHealthMedia, Johnson & Johnson Co.

HEALTH OUTCOMES RESEARCH Gordon M. Cummins, MSDirector, IntegriChain

Kavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver

Gary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PA

Timothy S. Regan, BPharm, RPhExecutive Director, XcendaPalm Harbor, FL

MANAGED CARE & GOVERNMENT AFFAIRSSharad Mansukani, MDChief Strategic Officer, Nations HealthSenior Advisor, Texas Pacific Group, FL

MANAGED MARKETS Jeffrey A. Bourret, MS, RPh, FASHPSenior Director, Customer Marketing & Innovation, US Specialty CustomersPfizer Specialty Business Unit, PA

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

PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhDProfessor of Pharmacy Law & EthicsVice Chair, Dept. of PharmacotherapyCollege of Pharmacy, Washington StateUniversity, Spokane, WA

PERSONALIZED MEDICINE Wayne A. Rosenkrans, Jr, PhDChairman and President, Personalized Medicine Coalition, Distinguished Fellow,MIT Center for Biomedical Innovation

PHARMACOECONOMICSJeff Jianfei Guo, BPharm, MS, PhDAssociate Professor of Pharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

PHARMACY BENEFIT DESIGN Joel V. Brill, MDChief Medical Officer, Predictive Health, Phoenix, AZ

William J. Cardarelli, PharmDDirector of PharmacyAtrius HealthHarvard Vanguard Medical Associates

Leslie S. Fish, PharmDSr. Director of Pharmacy ServicesFallon Community Health Plan, MA

Michael S. Jacobs, RPhNational Clinical Practice LeaderBuck Consultants, Atlanta

Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT

Paul Anthony Polansky, BSPharm, MBAFormer Executive VP and Chief PharmacyOfficer, Sanovia Corp., Philadelphia, PA

Scott R. Taylor, RPh, MBAAssociate Director, Industry RelationsGeisinger Health System, Danville, PA

POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in Health CareRetirement PolicyAmerican Enterprise Institute

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

Alex Hathaway, MD, MPH, FACPMPresident & Founder, J.D. BioEdgeHealth quality and biomedical research consultancy

J. Warren Salmon, PhDProfessor of Health Policy & AdministrationSchool of Public HealthUniversity of Illinois at Chicago

REIMBURSEMENT POLICYGrant D. Lawless, BSPharm, MD, FACPExecutive Director for Payor RelationsCorporate Account, Amgen, CA

RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhDChief Medical Officer and Scientific Officer Worldwide Clinical TrialsFaculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences andTechnology, Cambridge, MA

SPECIALTY PHARMACYAtheer A. Kaddis, PharmDVice President, Managed MarketsDiplomat Specialty PharmacySwartz Creek, MI

James T. Kenney, RPh, MBAPharmacy Operations Manager Harvard Pilgrim Health Care, Wellesley, MA

TOC_EditBoard_Cover 12/14/10 11:55 AM Page 360

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Editor-in-ChiefRobert E. [email protected]

American Health & Drug Benefits is foundedon the concept that health and drug benefitshave undergone a transformation: the econo -metric value of a drug is of equal importanceto clinical outcomes as it is to serving as thebasis for securing coverage in formularies andbenefit designs. Because benefit designs aregreatly affected by clinical, business, and pol-icy conditions, this journal offers a forum forstakeholder integration and collaborationtoward the improvement of healthcare.

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Mission Statement

REGULATORY

368 Implications of the New Political Realities on Healthcare ReformInterview with Dan Mendelson

CLINICAL

372 Engaging Providers in Medication Adherence: A Health Plan Case StudyAmy B. Scott, BSPharm, RPh; Jane E. McClure, BA, RN

380 Stakeholder Perspective by F. Randy Vogenberg, PhD, RPh

BUSINESS

394 The H-E-B Value-Based Health Management Program: Impact on AsthmaMedication Adherence and Healthcare CostAnna O. D’Souza, PhD; Roshan Rahnama, MPH; Timothy S. Regan, BPharm, RPh; Beth Common, MBA; Steven Burch, PhD

402 Stakeholder Perspective by Richard F. Radzin, PharmD

TABLE OF CONTENTS

Continued on page 364

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), ispublished 6 times a year by Engage HealthcareCommunications, LLC, 241 Forsgate Drive,Suite 205A, Monroe Township, NJ 08831.Copyright © 2010 by Engage Healthcare Communications, LLC. All rights reserved.American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in BenefitDesign are trademarks of Engage HealthcareCommunications, LLC. No part of this publication may be reproduced or transmittedin any form or by any means now or hereafterknown, electronic or mechanical, includingphotocopy, recording, or any informationalstorage and retrieval system, without writtenpermission from the Publisher. Printed in theUnited States of America.

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DEPARTMENTS

383 INDUSTRY TRENDSMoving Beyond Good Intentions: Making Collaborative Care a

Successful Reality

Gordon Norman, MD, MBA

391 GENERIC DRUG TRENDS

Generic Pipeline Predicts Continued Market Share Gain Through 2014

Dalia Buffery, MA, ABD

AMCP HIGHLIGHTS

404 Cost May Not Drive Formulary Choice After All

Method Used to Measure MPR Influences Adherence Rate

Pharmacists’ Monitoring of ESAs Leads to Cost-Savings

405 Adding a Pharmacist to a Medical Home May Cut Costs

Step-Therapy Program to Lower Rx Costs, Keep Members Happy

406 Disease State Impacts Medication Adherence

Targeting Waste in Targeted Therapies

406 Correction

408 Manuscript Instructions for Authors

371 The Association for Value-Based Cancer Care First Annual Conference

TABLE OF CONTENTS (Continued)



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Online Only

• 2010 Annual Index

• US Provider Practices Bracing for Change:

New Survey Results


FORMERLYKAPIDEX™

(dexlansoprazole)

1200

1000

800

600

400

200

00 6 12 18 24

Time (h)

Mean plasma concentration (in healthy subjects; day 5; ng/mL)1

DEXILANT 60 mgDEXILANT 30 mgDEXILANT 60 mgDEXILANT 60 mgDEXILANT 30 mgDEXILANT 30 mgDEXILANT 30 mg

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 effi cacy cannot be drawn from this information.

IndicationsDEXILANT is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

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

Please see adjacent brief summary of prescribing information for DEXILANT.

DEXILANT WORKS ASECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

DEXILANT is the fi rst and only PPI with a Dual Delayed Release™ (DDR) formulation, which provides a second release of drug

11:00:12 AM


BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONDEXILANT (dexlansoprazole) delayed release capsulesINDICATIONS AND USAGEDEXILANT is indicated for:

CONTRAINDICATIONS

[see Adverse Reactions].WARNINGS AND PRECAUTIONSGastric Malignancy

ADVERSE REACTIONS Clinical Trials Experience

Table 2: Incidence of Treatment-Emergent Adverse Reactionsin Controlled Studies

Adverse Reaction

Placebo

(N=896)%

DEXILANT30 mg

(N=455)%

DEXILANT60 mg

(N=2218)%

DEXILANTTotal

(N=2621)%

Lansoprazole30 mg

(N=1363)%

Tract Infection

Blood and Lymphatic System Disorders: Cardiac Disorders:

Ear and Labyrinth Disorders: Endocrine Disorders: Eye Disorders: Gastrointestinal Disorders:

General Disorders and Administration Site Conditions:

Hepatobiliary Disorders: Immune System Disorders: Infections and

Infestations: Injury, Poisoning

and Procedural Complications:

Laboratory Investigations:

Metabolism and Nutrition Disorders: Musculoskeletal and Connective

Tissue Disorders: Nervous System Disorders:

Psychiatric Disorders: Renal and Urinary

Disorders: Reproductive System and Breast Disorders: ; Respiratory, Thoracic and Mediastinal Disorders:

Skin and Subcutaneous Tissue Disorders: Vascular Disorders:

Postmarketing Experience

Eye Disorders: Gastrointestinal Disorders: General Disorders and Administration Site Conditions: Immune System Disorders:

Respiratory, Thoracic and Mediastinal Disorders:

Skin and Subcutaneous Tissue Disorders:

DRUG INTERACTIONSDrugs with pH-Dependent Absorption Pharmacokinetics

Warfarin

Tacrolimus

USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects

T


A reproduction study conducted in rabbits at oral dexlansoprazole doses up to 30 mg per kg per day (approximately 9-fold the maximum recommended human dexlansoprazole dose (60 mg) revealed no evidence of harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole.Nursing MothersIt 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 UseIn 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 ImpairmentNo 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 ImpairmentNo 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).OVERDOSAGEThere 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 PHARMACOLOGYPharmacodynamicsAntisecretory ActivityThe 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 EffectsThe effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.Enterochromaffin-Like Cell (ECL) EffectsThere 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 RepolarizationA 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 TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityThe carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day. Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology].In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended lansoprazole human dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat. In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 mg to 600 mg per kg per day, 2 to 80 times the recommended human dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 mg and 600 mg lansoprazole per kg per day (40 to 80 times the recommended lansoprazole human dose based on BSA) and female mice treated with 150 mg to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice. Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended lansoprazole human dose based on BSA).The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended lansoprazole human dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.PATIENT COUNSELING INFORMATION[see FDA-Approved Patient Labeling in the full prescribing information]Information for PatientsTell your patients to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued.To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved patient labeling should be discussed with the patient. Inform patients of the following:DEXILANT is available as a delayed release capsule.DEXILANT may be taken without regard to food.DEXILANT should be swallowed whole.

follows: - Open capsule; - Sprinkle intact granules on one tablespoon of applesauce; - Swallow immediately.Distributed byTakeda Pharmaceuticals America, Inc.Deerfield, IL 60015U.S. Patent Nos. - 5,045,321; 5,093,132; 5,433,959; 6,462,058; 6,664,276; 6,939,971; and 7,285,668.DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.All other trademark names are the property of their respective owners.©2009, 2010 Takeda Pharmaceuticals America, Inc.For more detailed information, see the full prescribing information for DEXILANT or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.KAP0110 R6-Brf; March 2010L-LPD-0310-2

Reference: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc.

DEXILANT™, KAPIDEX™ (dexlansoprazole), and Dual Delayed Release™ are trademarks of Takeda Pharmaceuticals North America, Inc., and are used under license by Takeda Pharmaceuticals America, Inc.

©2010 Takeda Pharmaceuticals North America, Inc. LPD-01139 6/10 Printed in U.S.A.


REGULATORY

368 American Health & Drug Benefits l www.AHDBonline.com November/December 2010 l Vol 3, No 6

Dalia Buffery: What changes can healthcare decisionmakers expect to see in the near future as a result of therecent national elections and their potential implications onthe reform bill?

Dan Mendelson: First, it is important for everyoneinvolved in healthcare to understand that this is a veryfundamental change. The Patient Protection andAffordable Care Act (PPACA, now often referred to asthe Affordable Care Act [ACA]), was passed by theDemocrats without bipartisan support. Now that therewill be a Republican-controlled House, we are in anenvironment of split government, and in such an envi-ronment, compromise and negotiation become neces-sary for government to run. That is the main implicationof the midterm elections, and that is not going to changefor at least another 2 years. In fact, we are probably goingto be living with some type of power sharing for a longtime. This is a fundamental change, and it is the startingpoint for a heated discussion of healthcare.Some have dismissed the election, saying, “Well, it is

not important, because in order to repeal reform, theRepublicans would need a two-thirds majority to over-ride a presidential veto”; in fact, there will be funda-mental effects, now and in the future, by virtue ofRepublican oversight, appropriations, and the fact that

many of the new Republican members effectively usedthe healthcare debate to get elected. Second, it is important to think about the timing of

health system change that was passed under the ACA.There are basically 3 phases of reform. The first involvespayment reduction, which has resulted in reductions inprofit margins that managed care organizations, hospitals,physician groups, and pharmaceutical companies willendure. That is happening now, and it will intensifythrough 2012. No one is talking about repealing those cuts.The second phase of reform is an effort by the federal

government to transfer risk from the government toproviders. This phase of risk transfer starts in 2012 andcontinues to 2014. It is proceeding rapidly, and it isclearly going to happen. The part of the reform that is at risk at this point is

the third phase—the coverage expansion. The coverageexpansion is not even slated to start until 2014. This is along lead time, and there is going to be a very rancorousdebate during the next couple of years as to how the cov-erage expansion is going to play out.

Buffery: You seem to suggest that repeal is not in thecards, even though there may be an attempt to repeal the bill?

Mendelson: Full repeal will not happen in the next 2years. But reform is going to be modified over the com-ing years, and some legislation may pass that modifiesthe reform construct. Nobody is talking about repealingthe payment reductions. More important, nobody is

Mr Mendelson is Chief Executive Officer and Founder ofAvalere Health, LLC, Washington, DC. Ms Buffery is EditorialDirector of American Health & Drug Benefits.

COMMENTARY

Implications of the New PoliticalRealities on Healthcare ReformInterview with Dan Mendelson

With the recent change in power in the US House of Representatives that will take effectin January, questions arise regarding potential modifications to some features in thehealthcare reform bill and its implementation. With many provisions scheduled to takeeffect between 2011 and 2014, the political implications of the elections have an imme-diate practical relevance to health plans, employers, and other healthcare stakeholders.American Health & Drug Benefits discussed some of these issues with Dan Mendelson, whoserved in the Clinton administration between 1997 and 2000, when there was a similardivision of party power between Congress and the administration.

Am Health Drug Benefits.2010;3(6):368-370.www.AHDBonline.com

Mendelson Interview_Cover 12/14/10 11:48 AM Page 368

Healthcare Reform

369www.AHDBonline.com l American Health & Drug BenefitsVol 3, No 6 l November/December 2010

talking explicitly about repealing the expansion ofhealth insurance coverage to low-income individualsunder Medicaid. Some 16 million additionalAmericans earning less than 133% of the poverty linewill be insured through Medicaid under the ACA, andno one is talking about repealing their coverage—abenefit that will add about $0.5 trillion to federalspending over 10 years. The part that the new House majority will be focused

on is the mandate, and all the associated changes in thecommercial marketplace. The best way to think aboutthis is that it is going to be revised serially over the next4 years, depending on whether the 2 parties actuallycome together to compromise on this issue and anyfuture changes in the balance of power going forward. Some other changes will start now. The House major-

ity has 2 tools that it will use to engage with the Obamaadministration, and having lived through split govern-ment, I am familiar with these tools. I was a politicalappointee in the latter period of the Clinton administra-tion, and at the time I was there, we had split govern-ment. The Senate and House had a Republican majori-ty, and we did not do anything of substance withoutconsulting with the committees of jurisdiction. House Republicans have 2 tools, or powers, in partic-

ular that they will use to engage. One is oversight; theHouse Republican oversight committees will increasing-ly be bringing the administration up to discuss the regu-lations, how they are evolving, and the role of differentindividuals in crafting the regulations. HouseRepublicans will also exercise power through the appro-priations process. To fund the government, Congress hasto pass a law that says how much is going to be spent,and the House Republicans can affect every aspect ofgovernment in that appropriations process.

Buffery: What do you think will be the focus in terms ofoversight in relation to the healthcare reform?

Mendelson: Congress will focus on the coveragemandate for individuals, because this mandate isunpalatable to the majority of Americans, and especial-ly because the purchase of insurance may be burdensomefor middle-income Americans. The administration is inan awkward position, because they have spent a lot oftime vilifying the insurance industry, and now they aretelling Americans that they must purchase that indus-try’s product. They will also hold oversight hearings onthe effects of health reform on business, that is, the real-ity that for many small- and medium-sized businesses itwill be more cost-effective to discontinue insurance andmove their employees over to the new healthcare cover-age exchanges.

In addition, important insurance regulations arecoming up within the next 6 months. The first regula-tion is the one that defines medical loss ratio; anotherwill define the health insurance exchanges. These willbe the focus of much debate, and depending on howaggressive Congress gets, they may try to slow downand stop these regulations through oversight hearingsand through the appropriations process.

Buffery: What do you envision as the biggest changes tothe mandate?

Mendelson: When thinking about “real” change inthe reform construct, there are 2 possibilities. The first iscompromise between the 2 sides, which would involvein-depth discussions about the bill, and possibly replacingthe mandate with other policy designed to ensure thatmost Americans are insured. This will only happen ifboth sides come to the belief that they will benefit fromdiscussions. Republicans in particular would have tobelieve that having responsibility for the health economyafter the 2012 election is less desirable than stonewallingto try to unseat the president with this issue.The second possibility is that the Republicans will

conclude that they do not want to compromise, andthey will continue to use the mandate, the expansionof government, and other issues of interest to their con-stituents to engage the administration in advance ofthe 2012 election. In that case, they would engage onthe regulations, and then they would conduct hearingsand talk about all the problems, and use that as a wayto build momentum for the presidential candidacy of adesignated person. Frankly, based on what I have seen so far and in talk-

ing with some members of Congress, Republicans aremore likely to take the second route of discussing prob-lems, which will mean that it is likely to take anextended period of time before we get more clarity onwhat will be the final configuration of reform.

Buffery: Are there other implications to consider?

Mendelson: Two more clinical aspects to the ACAmerit some discussion as they relate directly to healthplans and those involved in clinical care. The first is thegrowing interest in the use of evidence-based medicine(EBM) by government and private sector payers.Making decisions based on EBM is a growing trend, andwe are going to see comparative effectiveness researchand a generation of new evidence become more applica-ble to what health plans cover. This trend will continue,irrespective of the repeal discussion. My guess is that theRepublicans will start to embrace concepts of evidence-


REGULATORY


generation more fully now, because it is one of the fewtools that most analysts believe can be put in place tocontrol costs in the long run. This will be a Congressthat is dominated by fiscal austerity. It is at times when there is split government that cost-

control emerges as an honest priority, as evidenced bythe 1995 Budget Act and by the Balanced Budget Act of1997. It is when the Republicans control the appropria-tions process and the Democrats control the administra-tion that we can actually get some true fiscal discipline.When we have a concept like EBM—which has thepotential for cost-control and strong buy-in from theinsurance industry and from the pharmaceutical industryat this point, within certain parameters—there is goingto be a movement toward embracing EBM. TheRepublicans may take issue with some of the structuresthat were put in place under the ACA—for example,they may try to disband or modify the IndependentPayment Advisory Board. But cost-reduction is going tobe very popular, and that plays well in the long run forthe health plans and for benefit managers, because theyknow how to do that. The second clinically oriented observation is that the

Center for Medicare Innovation at the Centers forMedicare & Medicaid Services (CMS) will continue toattract bipartisan support. Although CMS generally doesnot always have that kind of support, the Center forMedicare Innovation is responsible for cost-savingchanges in the Medicare payment systems. Rick Gilfillan,who came from Geisinger Health System and is now run-ning this center, will have solid bipartisan support.

Buffery: What about appropriations?

Mendelson: Appropriations will become a negotia-tion over which programs are going to flourish andwhich are not. And that, I think, will be shaped by theirhealth policy priorities. Programs like the Center forMedicare Innovation and much of the EBM work shouldhave House Republican support, but House Republicanswill attempt to defund other spending, such as the con-sumer outreach around health insurance exchanges.House Republicans are going to go line by line throughthe law and figure out what they want to appropriate andwhat they do not. Of course, any such bill ultimatelymust be signed by the president, so we can expect somecompromise on both sides.

Buffery: Finally, are there any implications to drug de -velopment and innovation?

Mendelson: A couple of things relate specifically tothe pharmaceutical industry and drug development.The first is that the need to generate evidence, and inparticular, evidence of the viability of the product on apostmarketing or a postapproval basis, is increasing.That is going to be firmly cemented over the next cou-ple of years and will have bipartisan support. The second point is that the PDUFA (Prescription

Drug User Fee Act) is up for renegotiation, and havingan antiregulatory climate in the House will benefit thepharmaceutical industry significantly in that negotia-tion. This new climate will also give the pharmaceuti-cal industry some leverage at the US Food and DrugAdministration (FDA). It is good timing for the phar-maceutical industry.For regulatory policy in the FDA, the presence of

split government is most likely positive for the devel-opment pathways, because it creates more operatingstability. It is on the commercial side that there isinstability.

Buffery: As a conclusion, keeping our readers in mind,what do you expect that health insurance companies will bedoing now?

Mendelson: Good question. They will do a coupleof things. First, they will have a new way to engage inthe regulations that are being produced by the OCIIO(Office of Consumer Information and InsuranceOversight) and by CMS. They will be able to engage inthese regulations in a much fuller way. They will be tes-tifying on them publicly; there will be much more com-munication about the implications of these regulations,and the insurance industry will engage fully in thosediscussions. Second, the insurance industry will be able to talk

more freely about the implications of some of thesechanges. There has been, in essence, an unwritten rulethat insurance companies could not talk about premi-um increases that result from reform, and that nowchanges. At the same time, the insurance industry facesa very critical choice as to how to position itself aroundthe mandate. The mandate is the thing that makes thisentire construct work, and if they want to play with theRepublicans at all, health insurance companies have tofigure out whether there is a substitute that wouldenable them to ensure that more people are going topurchase insurance under a construct that is morepalatable to the House majority, as well as to theAmerican people. �


www.ValueBasedCancer.com/associationREGISTER ONLINE AT

Tuesday, March 294:00 – 6:00 pm 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 in the Exhibit Hall

Wednesday, March 307:30 – 8:30 am Corporate-Sponsored Breakfast Symposium

8:30 – 8:45 am Intro/Opening

8:45 – 9:30 am General Session 1 – NCCN Guidelines Acceptance and Compliance

9:30 – 10:15 am General Session 2 – The Impact of Personalized Oncology Therapies

10:20 – 10:50 am Morning Break in the Exhibit Hall

11:00 – 12:30 pm Provider Track• Community Oncology: Trends• Patient Navigation: Impact• Oncology Practices: Issues with Managed Care

Payer Track• Medicare and Reimbursement Issues• Drug Reimbursement and Administration Issues• Evolutions in Oncology Pharmacy Management

12:30 – 2:00 pm CE Lunch SymposiumBest Practices for Management of CINV: A Value-Based Approach

2:00 – 2:45 pm General Session 3 – Cancer Care and the New Healthcare Legislation: What to Expect Next

2:45 – 3:30 pm General Session 4 – Strategies for Improving Oncology Pharmacy and Care Management Models

3:35 – 4:05 pm Afternoon Break in the Exhibit Hall

4:10 – 4:55 pm General Session 5 – Clinical Trends: Impact of Oral, Injected, and Infused Therapies

5:00 – 6:00 pm Cocktails/Networking in the Exhibit Hall

*Preliminary agenda is subject to change.

MEETING AGENDA*PROGRAM OVERVIEWThis is the first national stakeholder integration meeting dedicated to advanc-ing the understanding of value in cancer care. Guided by the expertise of leadersin these fields, attendees will receive a thorough understanding of the evolutionof the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while im-proving access for patients and ultimately patient care.

WHO SHOULD ATTENDAll stakeholders in a position to impact cancer patient care are invited tojoin 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)

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

OBJECTIVES• Examine the impact of healthcare reform on all stakeholders involved in themanagement of patients with cancer

• Identify issues and potential solutions to challenges with access andaffordability of oncology therapeutics

• Determine the value equation of cost, quality, and access when evaluatingthe diagnosis, treatment, and overall management of cancer patients

• Define appropriate comparative effectiveness research and clinical pathwaysas tools to evaluate current recommendations for patient management

• Analyze trends in the delivery of care in the management of cancer patients

THE ASSOCIATION FOR

March 29-30, 2011Philadelphia, PA

Loews Philadelphia Hotel

First Annual Stakeholder Integration ConferenceIntegrating Payers, Providers, and the Entire Oncology Team

� �� Mendelson Interview_Cover 12/14/10 11:48 AM Page 371

Prescription drug therapy is the mainstay of treat-ment for many chronic conditions, such as hyper-tension, hyperlipidemia, diabetes, asthma, and

attention-deficit/hyperactivity disorder (ADHD). It iswell known that adherence to a prescribed drug regimenis crucial for positive health outcomes. Medicationadherence—the extent to which patients take medica-

tion as prescribed by their healthcare provider—requiresa shared responsibility between patient and physician.1Nonadherence is sometimes referred to as America’s

“other drug problem.”2 This widespread problem is oftenoverlooked; nonadherence is common, costly, and com-plex. One of every 4 medical visits results in patients notfollowing the advice they were given.3 Each year, nonad-herence contributes between 33% and 69% of medica-tion-related hospital admissions.1Studies show that within 1 year of being prescribed a

medication, patients stop taking 50% of their long-term

CLINICAL


Ms Scott is Clinical Pharmacy Specialist, and Ms McClure isMedical Management Consultant, Highmark, Inc,Pittsburgh, PA.

ORIGINAL RESEARCH

Engaging Providers in MedicationAdherence: A Health Plan Case StudyAmy B. Scott, BSPharm, RPh; Jane E. McClure, BA, RN

Background: Nonadherence to treatment regimens is a common, costly, and complexproblem that is often overlooked in a busy primary care setting.Objective: The goals of this study were to raise providers’ awareness of nonadherenceamong their patients, to identify the reasons for lack of adherence, and engage physiciansin addressing these barriers.Method: Five primary care practices agreed to participate. The project began in the fall of2008 with a therapy gap analysis, using prescription drug data from the previous 18 monthsto identify nonadherent patients. Initially, 237 members were identified as potential nonad-herent patients. Each practice was presented with the data related to its patients; the groupthen narrowed its sample using a chart review and/or patient outreach. Each practice had todetermine the barriers to adherence, and was then asked to create action steps to improvepatient adherence based on the group’s unique results and the specific patient population. Results: Barriers to adherence identified included prescription drug cost, multiple med-ications and dosing schedules, and patient as well as family level of understanding andacceptance of disease state. Each group gained an awareness of nonadherence as it relat-ed to their patients. For example, in the internal medicine practice, 33% (n = 17) of thepatients reported stopping their medication because of cost. A common reason for pooradherence in the pediatric groups was that parents decided to stop their child’s medica-tion on weekends and in the summer, without a physician’s recommendation. Using suchfeedback, each practice then developed its own methods to improve medication adher-ence within its patient population.Conclusion: Although the final numbers in this case study were small, the providersgained valuable insights regarding nonadherence in their practice. This study shows theimportance of engaging providers in medication adherence as a way to improve this com-mon problem. Making this universal issue a personal problem for providers is key to over-coming many of the adherence barriers.

Am Health Drug Benefits.2010;3(6):372-380.www.AHDBonline.comDisclosures are at end of text

Jane E. McClure

Stakeholder Perspective,page 380

“Drugs don’t work in patients who don’t take them.”1—C. Everett Koop, MD, ScD, former US Surgeon General

Amy B. Scott

Scott_Cover 12/14/10 12:07 PM Page 372

medications, and up to 1 of 5 new prescriptions is neverfilled.4,5 In addition, nonadherence is estimated to con-tribute to 125,000 deaths annually in the United States,and nonadherence costs an estimated $100 billion annu-ally in direct and indirect healthcare costs.4,5Based on the available literature, adherence depends

to a large extent on the patient’s perceived health bene-fit; however, the healthcare provider must work with thepatient and/or caregiver to educate, cooperate with, andhelp the patient to focus on such benefits.

Barriers to Medication Adherence Many patients engage (intentionally or not) in nega-

tive medication-taking behaviors—resulting from for-getfulness, cost, inconvenience, and attitudes—that mayresult in negative health outcomes. These behaviorsinclude pill splitting, drug holidays, taking medicationsevery other day, or never filling a prescription, all ofwhich adversely affect health outcomes.6An important barrier to adherence is low health lit-

eracy. Health literacy can be defined as the ability toread, understand, and make appropriate health deci-sions.7 Poor or low literacy level results in a patient’sinability to follow treatment recommendations and areduced ability to navigate through the prescribedtreatment plan (in this case, following prescribed med-ication regimens).7Contributing to nonadherence is the high cost of pre-

scription medications and out-of-pocket (OOP) expens-es. It is known that 1 of 5 patients chooses not to fill aprescription because of cost.8 Financial barriers cannotbe overlooked; therefore, influencing patient behaviorwith monetary incentives or other rewards for appropri-ate adherence to medication regimens may be useful.9However, essential to improving patient compliance andadherence—to ultimately improve health outcome—isgood communication between the patient and the entirehealthcare team.1Previous studies have shown that by engaging the

patient and forming collaborative relationships,healthcare professionals can significantly influenceadherence.2,10,11In their recent commentary, Cutler and Everett sug-

gest that with an investment of time and resources,healthcare providers can optimize and reconcile patientmedication regimens in an attempt to manage nonad-herence directly.9 Cutler and Everett further note thatusing proved adherence assessment tools at the time ofthe visit can predict risk for nonadherence. Having thisinformation can enable providers to encourage adher-ence at the point of prescribing and during any follow-up contact with patients.9Participating in any negative prescription-taking be -

havior can and does affect all patient types, yet noncom-pliance remains largely unrecognized in clinical practice.8

Highmark’s Project DesignTo address this problem, in the fall of 2008,

Highmark, Inc, a large regional managed care healthplan located in Pittsburgh, PA, with more than 4.5 mil-lion health insurance members and approximately 2.5million prescription drug benefit members, embarked ona project to increase the awareness of its providers tononadherence. The authors are Highmark employeeswho concentrate on building relationships with networkproviders to improve the quality of care for the healthplan members.A total of 5 distinct network primary care practices

agreed to take part in this study. The goal was to illus-trate to the physicians, by the use of prescription drugclaims, the extent to which many of their patients werenot following their medication regimens as prescribed.Through conversation and discussion with these net-work providers we found that physicians in generalbelieve that nonadherence is a global issue but does notdirectly affect their own patient population. This beggedthe question as to who is accountable for the resolutionof the problem. Is it the clinician, the health plan, or thepatient? As previously suggested, nonadherence is a jointresponsibility that needs to be addressed by all parties.1This current case study was conceived as a way to

engage and challenge these Highmark network primarycare physicians (PCPs) and staff to develop steps toimprove medication adherence rates of plan membersand ultimately of all their patients. Because each group

Engaging Providers in Medication Adherence

373www.AHDBonline.com l American Health & Drug Benefits lVol 3, No 6 l November/December 2010

KEY POINTS

➤ Medication nonadherence is a well-known problemthat is costly and complex but is often overlookedin a busy primary care setting.

➤ The goal of this case study was to increasephysicians’ awareness of the existence of thisproblem among their own patients, and to engagethem in this problem.

➤ Barriers to adherence identified in the 5 practicesincluded drug cost, multiple medications and dosingschedules, and level of understanding/acceptance ofdisease state.

➤ The participating physicians were surprised to findthat some of their patients were not following theirrecommended drug regimens.

➤ These findings highlight the need to engage providersin the issue of medication adherence in relation totheir own patients.


CLINICAL


differed in population and targeted disease state, theproject developed according to the dynamics of the indi-vidual practice. To minimize the time a practice wouldneed to commit to this project, patient samples werekept to a minimum. However, once the prescription drugdata were shared with each group, their interest peaked.

This study was conducted from the fall of 2008through the spring of 2009; it began with a medicationgap analysis using prescription drug claims data from theprevious 18 months. Once practice-specific barriers toadherence were identified, solutions were developed forthe varied populations. Collaboration between theproviders and the health plan consultants was key inthese processes. These claims data helped to identify potential nonad-

herent patients from the 5 primary care practices—1 internal medicine, 1 family practice, and 3 pediatricgroups. Each group was provided with a small sample ofpatients (Table 1).These groups were selected based on their positive

relationship with the Highmark team and on their will-ingness to join in this process improvement initiative thatcould be submitted to QualityBLUE, the health plans’physician pay-for-performance (P4P) incentive program.Once potential nonadherent patients with hyperten-

sion, hyperlipidemia, or ADHD were identified, the fol-lowing questions were considered: 1. Are these patients truly nonadherent as illustrated bythe claims data?

2.What are their reasons for nonadherence (barriers toadherence)?

3.What can the practice do to resolve these? 4. Is quality of care being affected by nonadherence? The providers had to research patient charts to verify

the prescription drug information and answer thesequestions. To determine the specific barriers to adherence, the

clinicians were asked to reach out to their patients.Some clinicians chose to contact each patient by tele-phone to discuss the patient’s medication regimen; oth-

ers opted to use a survey tool provided by the healthplan for a more structured approach. Each practice wasencouraged to create a plan of action to deal with theidentified barriers.

MethodologyThe first step involved data collection for each of the

5 group practices; prescription drug claims were pulledfor all of 2007 and for the first 6 months of 2008 (ie, 18months). Data were extracted using membership ofeach practice, followed by therapeutic drug categoriesfor hypertension, hyperlipidemia, and ADHD. Thisensured that prescriptions ordered by a specialist otherthan the PCP would be included. Next, the projectmanagers analyzed the information, identifying eachmember, and then looked for gaps or lack of claims thatseemed excessive. We designated <80% adherence asthe determining factor. Sample spreadsheets were developed as a visual tool

for each practice to illustrate the gaps in therapy(Figure). Each practice had to determine whether thegaps in claims corresponded to true gaps in therapy orwere a result of another reason that could not be deter-mined by claims analysis, such as physician discontinua-tion of medication, a patient leaving the practice, or achange in insurance coverage. After sharing the findings with the plan consultants,

a chart review was prepared for each group, and the nextsteps and interventions suggested. This is where eachgroup differed.

ResultsIndividual Practice Group

Group A: Family Practice. This group was a large,urban, multiprovider practice with 3 locations and fullyautomated electronic medical records (EMRs). Thepractice administrator reviewed each of the 51 electron-ic charts of patients identified as nonadherent and wasskeptical of these results. The administrator personallycalled every patient to discuss the importance of takingprescribed medications or contacted the pharmacy whenthe patient was unavailable. She found that 71% (n =36) of these members were in fact getting their prescrip-tions filled. However, their claims were being paid for incash and were not being submitted by the retail pharma-cies, because they were part of a promotional genericdrug program. This alerted the authors to a claims sub-mission problem.Indirectly, the lack of these claims also signified that

the high cost of prescription drug therapy could be a bar-rier to adherence. However, these patients were satisfiedwith getting a generic product filled that reduced theirOOP spending. In addition, of patients identified as

Table 1 Practices Participating in MedicationAdherence Project

Group/practice typePatients identified as nonadherent, N

A: Family practice 51

B: Internal medicine 51

C: Pediatrics, rural 54

D: Pediatrics, suburban 49

E: Pediatrics, urban 32



1Mem

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Lipitor

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me

Practice X

Figure

Medication Compliance Sample Data Sheet

Rx filled

Not filled

Rx filled

Not filled

2007

2008


CLINICAL


nonadherent, 12% (n = 6) were getting sample medica-tion from the PCP or the specialist; samples do not gen-erate a claim and, therefore, appear as a gap in therapy.Patients could fall into more than 1 of these categories,because they were taking multiple medications. Otherreasons for apparent gaps are listed in Table 2. As a result, group A was confident that a high per-

centage of the targeted patients were adherent to theirmedication regimens. The authors found that flaws,errors, and discrepancies exist in the claims data, butthe drug data presented a starting point for identifyingnonadherence.

Group B: Internal Medicine. This rural group con-sisted of 4 physicians, with a cardiology subspecialty, andhad a partially automated EMR. The practice managerexamined each of the 51 electronic charts identified. Insome cases the physician discontinued the medication inquestion, and in others, a lack of claim was the use ofpromotional generic drug programs in the marketplace(in which case claims are not submitted under a pre-scription benefit). Other reasons included a patienttransfer to a skilled nursing facility and medication sam-ples being provided to defray high OOP costs (whichmight have related to a tiered drug benefit, a nonformu-lary agent, or a coinsurance design). This information again alerted the Highmark team

that errors in drug data could be misleading. Anotherimportant finding was that 33% (n = 17) of the plan-identified patients stopped the medication on their own,because of high cost. In each case, the clinician suggest-ed an alternative therapy or recommended a patient-assistance program. Without these data, this practicewould not have known that those patients had stoppedtaking their medications. Overall, the clinicians’ awareness was heightened,

and they realized that chart review alone was an insuf-ficient source of information for a subset, approximate-ly 30% (n = 14), of the 51 patients who had been ini-tially identified as nonadherent. A more formalapproach to identifying specific barriers to adherencewas needed. The Highmark team recommended the ASK-20SM

Survey as a tool to identify and address barriers to adher-ence. This validated survey, originally developed byGlaxoSmithKline (and used with permission for thisstudy), examines categories related to medication-takingbehaviors. The categories used in this study and theresults are listed in Table 3.12-14Again, the number of patients in this group was small,

but the findings were astounding. The lead physicianrealized that changes were needed to reduce nonadher-ence among their patient population. The next step forgroup B was to create a gap-free system through theire-prescribing and EMR. This group is now developing an electronic alert that

is built into the EMR system, which would be activatedwhen the patient does not get a medication filled orrefilled in a timely manner. This would enable the officestaff to reach out to the patient and determine the rea-son for nonadherence.

Groups C, D, and E: Pediatrics. Three pediatricgroups participated in the adherence project, usingADHD as the chronic condition studied. Pediatric groupC was a large, rural, multiprovider site with multiplelocations and a partially automated EMR system, whichwas closely aligned with a hospital system. Pediatricgroup D was a large, independent, suburban, multi-provider group with multiple locations yet without anEMR system. Pediatric group E was a large, independent,urban, multiprovider practice with multiple locations. Ingroup E, a behavioral health physician specialist isemployed in the practice, and it has a fully automatedEMR system. The findings for pediatric groups C and D were simi-

lar. After careful chart review identified nonadherentpatients (Table 1), a few common barriers were identi-fied (Table 4). Some of the plan-identified gaps were determined to

be appropriate, such as a change of medication by a

Table 2 Group A, Family Practice: Additional Explanations for Nonadherence

Reason for nonadherencePatients, N (%)(N = 51)a

Patient transferred to a nursing facility, medications provided in house, or no prescription claim submitted

1 (2)

Patient deceased 2 (4)

Patient moved; however, prescriptions werestill filled but practice had no contact withpatient

2 (4)

Patient cited high cost 2 (4)

Patient noncompliant with office appointments: did not get required writtenprescription

1 (2)

Patient stopped medication on his/her own for varied reasons

1 (2)

Patient taking drug twice weekly instead of daily

1 (2)

Data error: patient not part of practice 3 (6)aOf these 51 patients, 36 were taking a generic, and 6 were taking samples oftheir medications. NOTE: Patients could fall into >1 category, because many were taking multiple agents.




physician or discontinuation of therapy. The providersrationalized that because of the high sensitivity of thisdiagnosis, there was no easy method of intervention toimprove adherence. Pediatric group E was the most engaged participant.

The behavioral health specialist was intrigued by thedata, took ownership of the issue, and ultimately createdan updated, modified management approach to ADHDfor the group. Using claims data as a starting point, shereviewed each of the 32 electronic patient charts origi-nally identified by the plan and found similar barriers toadherence compared with the other pediatric practices.However, 11 (33%) of the 32 patients identified werefound to be of college age, which encompassed a uniqueset of barriers to adherence (Table 5).

DiscussionThe main goal of this study was to increase the physi-

cians’ awareness of medication nonadherence. Althoughit is well-documented in the medical and pharmacy lit-erature that nonadherence is a significant problem, thesephysicians did not realize that this was a problem forsome of their own patients. Overall, the physicians weresurprised to learn that nonadherence existed amongtheir patient population. Despite the small number ofpatients involved, the value of this study was theproviders’ heightened awareness of nonadherence. Each practice learned something about nonadher-

ence, from simply gaining awareness of the problem tofinding specific barriers to medication adherence. Somepractices developed methods to improve adherence andworked toward implementing change. Practices withEMRs realized the advantage of technology in defining aproblem as well as in the development of an improve-ment process. They learned that a gap analysis can be avaluable tool. The providers realized that improved communication

with their patients is necessary to determine adherencebarriers and how to alleviate them; good communicationwith the patient and the entire healthcare team is essen-tial for improving patient adherence.15 Literacy level,English-language proficiency, understanding of basicmedical instruction, and socioeconomic status are fac-tors that affect communication and adherence.7 Eachfactor needs to be taken into consideration wheninforming and educating patients on the importance ofmedication regimens. Adherence issues cross over all populations of

patients, regardless of age and/or condition,1,2 and inter-ventions will vary based on that population. It is crucialthat programs targeted to improve adherence are cus-tomized in a manner meaningful to the specific popula-tion being addressed.

The information depicted in the Figure may be usefulwhen talking to physicians about adherence among theirown patient populations. Health plans may be able tocreate a similar visual tool from their claims data thatcould be shared with providers to engage them in med-

Table 3 Group B, Internal Medicine: ASK Survey Results

Survey resultsPatients, N (%) (N = 14)

Lifestyle

I just forget to take my medication some of the time 7 (50)

I run out of my medicine because I don’t getrefills on time

7 (50)

I sometimes forget things that are important to me 1 (7)

Attitudes and beliefs

I feel confident that each one of my medications help me

10 (71)

I know if I am reaching my health goals 10 (71)

Help from others

I have someone I can call with questions aboutmy medications

13 (93)

Talking with the healthcare team

I understand my doctor’s/nurse’s instructionsabout the medicines I take

13 (93)

My doctor/nurse and I work together to makedecisions

14 (100)

I am able to read and understand pill bottlelabels

14 (100)

Taking medicines

Taking medicines more than once daily isinconvenient

2 (14)

I have to take too many medicines daily 3 (21)

It is hard for me to swallow the pills I have to take 0 (0)

Have you…

Taken a medicine more or less often than prescribed?

7 (50)

Skipped or stopped taking a medicine becauseyou didn’t think it was working?

5 (36)

Skipped or stopped taking a medicine because it made you feel bad?

1 (7)

Skipped, stopped, not refilled, or taken lessmedicine because of the cost?

7 (50)

Not had medicine with you when it was time to take it?

4 (29)

NOTE: Patients were interviewed by clinician by telephone; therefore, responsesmight have been inadvertently influenced by the interviewer.


CLINICAL


ication adherence. An unexpected value of this sampletool (Figure) was that other Highmark employees mayreplicate it and share it with their physician groups.It has been shown that the quality of the doctor–

patient relationship is one of the most important fac-tors affecting adherence.16 A supportive relationshipthat features encouragement, reinforcement, and moti-vation from the provider will improve adherence; con-versely, poor provider communication can contributeto medication nonadherence.16If left unattended, nonadherent patients might have

experienced negative health outcomes, and conse-quently medical costs for the plan could have escalat-ed.5 In the scope of this case study, cross-referencingwith medical claims was not completed. However,other health plans interested in a more quantitativeapproach may take the next step of cross-referencingmedical and pharmacy claims to define the costs asso-ciated with nonadherence.The clinicians did recognize the value of collabora-

tion with the health plan consultants who could pro-vide data as identifiers of a problem. Groups C and Dwere interested in reviewing similar claims data forother chronic conditions related to pediatrics, namely,asthma, but no action was taken by either group.

Unique Features of Group EThe common denominator among group E’s small

subset population was that they were all college-agedstudents. This alerted the behavioral health specialistthat college-aged patients have additional barriers toadherence that she and her colleagues were unaware of,and so this subset of patients was falling through thecracks. For each of these patients, the physician createda detailed care plan. Just as important, the variation among the 12 pedia-

tricians in group E—all of whom treated and managedpatients with ADHD—was evident. The behavioralhealth physician realized yet another significant prob-lem: ADHD was not being managed consistently amongthe providers in the group. Using this information, shecreated a quality improvement guide for ADHD man-agement, which was to be used by all physicians in thepractice, at all locations, when diagnosing patients withADHD and interacting with their families. This guide addressed all facets of ADHD manage-

ment, including errors of monitoring and addressingcompliance. The steps involved in addressing adherencein the practice include:1.At every visit inquire about barriers to medicationtherapy

2. Emphasize benefits of daily medication adherence3.At time of medication check, encourage scheduling ofnext appointment

4.Offer reminder options, such as an e-mail or a postcard5. To address appointment no-show, patient or parentwill be contacted by telephone to reschedule• If unable to reach after 2 attempts, a certified letterwill be sent, requesting patient/parent call to sched-ule an appointment

6. The practice will develop a policy for college-agedpatients taking ADHD medication• To monitor efficacy and side effects• To provide for timely refills to reduce nonadherence.To improve adherence and the understanding of the

value of daily medication regimens, future enhance-ments to the practice’s website are planned. Links toquality, reliable, evidence-based sites will be accessible;downloadable medication questionnaires will be madeavailable for patients to fill out and bring to eachappointment; and medication question-and-answer ses-sions, similar to a chat room, will be scheduled. As a result of this project, group E’s physician aware-

ness of nonadherence was increased. This pediatric prac-tice transformed their approach to ADHD management.They implemented new practice guidelines, disseminat-ed the information to the clinical staff, and used theirEMRs for theirs and their patients’ advantage. Withthese improvements, communication between patient

Table 4 Pediatric Groups C, D: Common Barriers to Adherence

Parents stopped the attention-deficit/hyperactivity disordermedication on the weekend or in the summer, without aclinician’s recommendationVarying family situations (eg, children living between 2 homeswhere 1 parent supports medication therapy and the otherdoes not)Insurance benefit changeAppointment noncomplianceSocioeconomic/health literacy/education levels of parentsaffected adherenceCost of medications

Table 5 Barriers to Adherence in College-Age Patients

Resistance to taking medications, because it interfered withtheir newfound independenceDifficulty remembering to take medications, because they werenow expected to manage their regimen without guidance froma parent/guardianAdverse side effects interfered with their schedule and/or sleep patternReduced compliance with appointments and prescriptionrenewal requests, because they were away at school


and provider is expected to be enhanced, reduce nonad-herence, and improve patient outcomes. Participating in this case study also enabled group E

to document improvements regarding medicationadherence to the health plan, which fulfilled a P4Prequirement.

Collaboration and Care Coordination We realized the value of physician buy-in and collab-

oration as critical elements to the success of this project.It became evident that the practice with a physicianchampion—one who was very engaged and passionate—made the greatest effort to develop process improve-ments. In addition, we learned that it is crucial to iden-tify the responsible parties, develop a work plan withtargeted dates, and use telephone and e-mail remindersas a way to guide and direct the participants, while beingcareful to appreciate time constraints common to busyprimary care practices. With current shifts in healthcare and payment

methodology, adherence is being affected by a lack ofcoordination of care. This includes provider and patientcommunication, increased use of technology (includingdata-sharing among providers), and expanded P4P pro-grams, which promote patient-centered medical homesand care transitions. Collectively, advancements inthese areas will improve coordination of care and health-care delivery, particularly in primary care, where the cri-sis of nonadherence is most evident.9

LimitationsVarious limitations to this case study exist. We recog-

nize that the limitations of prescription drug claim data(eg, nonsubmission of claims, errors of membership oreligibility, and lack of integration of medical and phar-macy claims) may have affected the results. However,the claims data were useful as a starting point.The small sample size was another limitation of the

project, but this was necessary to keep the workloadmanageable for the staff. In addition, medical claims and pharmacy claims

were both available but were not cross-referencedbecause of the limited scope of this study. This proved tobe a limitation in that escalation of care costs was nottruly determined in this case study; the care costs weresimply assumed. Also, it was not validated that quality ofcare was being affected by the nonadherence.Finally, a major limitation of this case study was the

realization that this problem is widespread and there isno simple solution. Recognizing this, some physiciangroups chose to avoid the challenge; they were not pres-sured to assume the responsibility of improving nonad-herence. This reinforces the question of who is account-

able for the resolution of the problem—is it the clini-cian, the health plan, or the patient?

ConclusionsUltimately, all involved parties learned that nonad-

herence is a reality and affects the patients they treat.The authors learned that using prescription drug datacan provide valuable information, including the need totailor any intervention to the individual patient’s char-acteristics (ie, age, disease state, socioeconomic status).Three key potential benefits of improved adherence

are a decrease in total healthcare costs, a decline inhospitalizations, and improved health outcomes.However, for these benefits to be realized, providersmust become a part of the solution. By identifying bar-riers to adherence, steps to improve adherence ratescan be put into place. These include collaboration,open communication between healthcare professionalsand patients regarding medication regimens, as well aseducation provided to patients about the benefits ofmedication adherence.12-14Changing patient behavior is difficult. It involves

more than simply telling patients what to do or prescrib-ing a medication. Healthcare professionals need to iden-tify barriers to adherence and then help motivatepatients to take control of their disease. Much of thisrevolves around medication-taking behavior and educa-tion on the disease state. Increasing primary care physi-cians’ and staff awareness of medication nonadherenceand working toward improving medication adherencerates may lead to a decrease in total healthcare costs, adecline in hospitalizations, and improved patients’health outcomes. ■

Disclosure StatementMs Scott and Ms McClure have nothing to disclose.

References1.Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497.2. National Council on Patient Information and Education. Enhancing PrescriptionMedicine Adherence: a National Action Plan. August 2007. www.talkaboutrx.org/documents/enhancing_prescription_medicine_adherence.pdf. Accessed July 14, 2009.3. DiMatteo MR. Variations in patients’ adherence to medical recommendations: aquantitative review of 50 years of research. Med Care. 2004;42:200-209.4. Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions toimprove medication adherence. Am J Health Syst Pharm. 2003;60:657-665.5. The Task Force for Compliance. Noncompliance with medications: an economictragedy with important implications for health care reform. Baltimore, MD; 1993. 6. Zwillich T. Patients, Doctors Don’t Discuss Rx Prices. WebMD Health News.March 17, 2009. www.webmd.com/news/20090317/patients-doctors-dont-discuss-rx-prices. Accessed July 14, 2009.7. American Society on Aging and American Society of Consultant PharmacistsFoundation. Adult Meducation. Overview of medication adherence. www.adultmeducation.com/OverviewofMedicationAdherence.html. Accessed July 14, 2009.8. Taylor H, Leitman R, eds. Out-of-pocket costs are a substantial barrier to pre-scription drug compliance. Health Care News. 2001;1:1-2. 9. Cutler DM, Everett W. Thinking outside the pillbox—medication adherence as apriority for health care reform. N Engl J Med. 2010;362:1553-1555. Epub 2010 Apr 7.10. Lowes R. Patient-centered care for better patient adherence. Fam Pract Manag.1998;5:46-47,51-54,57. www.aafp.org/fpm/980300fm/patient.html. Accessed November10, 2010.



Continued


11.Haynes RB, Yao X, Degani A, et al. Interventions to enhance medication adher-ence. Cochrane Database Syst Rev. 2005;(4):CD000011.12.Hahn SR, Park J, Skinner EP, et al. Development of the ASK-20 adherence bar-rier survey. Curr Med Res Opin. 2008;24:2127-2138. Epub 2008 Jun 12.13. GlaxoSmithKline. ASK-20 Taking Medicine: What Gets in the Way [Survey].August 2008. www.takingmeds.com/pdf/hcp/HMI719R0_ASK20SurveyEngl.pdf.Accessed August 25, 2010. 14.Matza LS, Yu-Isenberg KS, Coyne KS, et al. Further testing of the reliability andvalidity of the ASK-20 adherence barrier questionnaire in a medical center outpa-

tient population. Curr Med Res Opin. 2008;24:3197-3206.15. Burnier M. Long-term compliance with antihypertensive therapy: another facetof chronotherapeutics in hypertension. Blood Press Monit. 2000;5(suppl 1):S31-S34.16. Krueger KP, Berger BA, Felkey B. Appendix D. Medication adherence andpersistence. In: Wu HW, Nishimi RY, Kizer KW, eds. Improving use of prescrip-tion medications: a national action plan. Washington, DC: National QualityForum; 2005. www.qualityforum.org/Publications/2005/10/Improving_Use_of_Prescription_Medications__A_National_Action_Plan.aspx. Accessed Novem ber16, 2010.

CLINICAL


Stakeholder Integration Crucial to Improved Patient Outcomes:Lessons from a Health Plan’s ExperiencePAYERS: The issue of medication ad herence has

implications for many healthcare stakeholders, as thisstudy from a large health plan indicates. For Highmarkin Pennsylvania and for many other health insuranceplans, this study may also have value in preparing forthe various pay-for-performance programs that arebeing encouraged by employers and other payers, aswell as by the 2010 Patient Protection and AffordableCare Act. In the course of their research, the authors identified

different reasons for medication nonadherence thatwere both expected and unexpected. Many of the rea-sons have been known for many years in the medicaland pharmacy provider community, as well as by phar-macy benefit managers, but there had been little incen-tive to aggressively act on that knowledge. With therecessionary impact on discretionary income, alongwith loss of jobs and insurance coverage, cost issues forpatients have become even more of a major concern.This concern influences other cost issues for employerswho pay premiums and shared costs of prescribed drugs,providers who are at risk for total dollars spent bypatients, and health insurance plans that are unable tooffer cost-effective products that could result in posi-tive patient outcomes.PROVIDERS: Studies have shown that improved

medication adherence will increase pharmacy costswhile lowering medical costs, as was seen in the well-known cases of the City of Asheville Project in NorthCarolina and Pitney Bowes in Connecticut. This find-ing is further reinforced by the present study by Scottand McClure, which also sheds an unexpected light onprimary care providers’ lack of awareness of nonadher-ence among their own patients. Having a health plan

focus on this subject adds weight to the need forexpanded multistakeholder collaborations to addressthe issue of medication adherence. MANUFACTURERS: Value-based quality im -

provements to reach better patient outcomes withappropriate medication use should involve not onlypatients themselves but also manufacturers of drugs,medical devices, and diagnostic products. Becausecare for patients with chronic diseases consumes a lotof time for primary care providers and a good portionof health plan coverage resources, all healthcarestakeholders can play a role toward improving out-comes as opposed to the continuing divisiveness anddistrust we have observed in the marketplace. Suchmultistakeholder collaborations will increase inimportance as we move toward personalized medicinein the coming decade.In the end, all stakeholders have a role to play in,

and can benefit from, improved medication adherenceby patients. Engaging patients is consistently emergingas one of the key drivers toward achieving improvedoutcomes. In addition, this study by Scott andMcClure shows that engaging providers in medicationadherence is an important piece to the patient engage-ment puzzle. It is time that all healthcare system par-ticipants work together with employees, members, orpatients to reach the common goal of increased effi-ciencies, better cost management, and improvedpatient outcomes.

F. Randy Vogenberg, PhD, RPhPrincipal, Institute for Integrated Healthcare and

Strategic Pharmacy Advisor, Business GroupPharmacy Collaborative

Sharon, MA

STAKEHOLDER PERSPECTIVE


INDUSTRY TRENDS


Finding ways to care for chronically ill Americans isquickly becoming one of the singular most criticalhealthcare challenges of our nation. Nearly 1 of 2

Americans has diabetes, heart disease, or another chron-ic disease.1 Millions more are at risk, and this generationof youngsters may be the first in history to have poorerhealth at an earlier age and lower levels of longevitythan their parents.2Government initiatives, as well as programs from

private payers, are championing more collaborativeapproaches to care. Although they show promise, suchprograms will require more than legislation, increasedpayment to providers, and good intentions to be success-ful; they will demand a concerted effort from all partici-pants along the healthcare continuum to work togethertoward a common goal to control costs and improve thehealth of all Americans.3-8

The Promise of Collaborative CareThe new emphasis on collaborative approaches to

care holds the promise to:• Enable care providers to function as an effective,coordinated team to access and manage patient infor-mation across dispersed organizations and settings,ensuring that patients receive recommended, evi-dence-based care

• Improve health outcomes through aligned efforts thatharness the physician–patient relationship andachieve shared clinical goals

• Support physicians who seek to practice efficient,team-based clinical care and the realization ofpatient-centered medical homes.To reach their potential, collaborative care programs

must ensure connectivity between all parties, the use ofdecision support, the alignment of goals and financialincentives, and a focus on finding innovative ways tobetter engage and involve patients in their own care.

The Obstacles to Coordinated Care In the past several years, private and public health

plans, large employers, and coalitions have createdsmall yet promising programs designed to achieve bet-

ter care. These programs, however, are currently theexception, not the rule. Overall, the nation’s chroniccare system is fragmented, poorly coordinated, andoften of inferior quality and value.6,9Most troubling is that even patients with access to

healthcare often receive poor care.10 For example,patients with chronic diseases frequently receive treat-ments from multiple primary and specialty care physi-cians across various sites of care, and rarely are all treat-ing providers able to readily access relevant patientinformation. Even providers utilizing electronic medicalrecords (EMRs) often struggle with electronic forms instructured and unstructured formats, making accessingand sharing information difficult.11Such an environment leads to substandard care and

makes it difficult to ascertain the scope of impact forchronic diseases and to aggregate critical health infor-mation on a patient- or population-specific basis. Inaddition, this lack of coordination makes it challengingto provide more proactive care, as well as meaningfulanalysis and healthcare decision support based on evi-dence-based care guidelines.

Need for New Payment StructuresAlthough multiple factors contribute to poor adop-

tion of the technology and processes necessary to createa more united care environment, it is clear that the cur-rent fee-for-service payment structure does not encour-age cooperation or collaboration among payers andproviders.12 But change is coming. The Patient Protec -tion and Affordable Care Act (PPACA) and theAmerican Recovery and Reinvestment Act, along withthe Health Information Technology for Economic andClinical Health Act that came with it, together arehelping to establish a basis for greater collaborative care.Demonstration pilots for accountable care organiza-

tions (ACOs) made possible under the PPACA aregathering considerable attention. ACOs are defined asprovider groups that accept responsibility for the costand quality of care delivered to a specific population ofpatients cared for by the groups’ clinicians. The USDepartment of Health and Human Services’ efforts to

PERSPECTIVE

Moving Beyond Good Intentions: Making Collaborative Care aSuccessful RealityGordon Norman, MD, MBAChief Innovation Officer, Alere Health, Atlanta, GA

Industry Trends_Norman_Cover 12/14/10 11:52 AM Page 383

INDUSTRY TRENDS


relax antitrust provisions (eg, the Stark law) are expect-ed to help foster greater physician and hospital collabo-ration. Another key feature of ACOs—bundled pay-ments for episodes of care, including acute and 30-daypostdischarge—could also encourage hospitals and com-munity physicians to work more closely together.Healthcare advocates and executives also believe that

the government’s push for adoption of technology, par-ticularly through electronic health records, will createmore opportunities for collaborative care.13 Strongincentives—up to $44,000 per physician with a largeMedicare patient population and $64,000 for physiciansserving predominantly Medicaid patients—as well ashefty fines for nonadoption beginning in 2015, may bean important impetus required to finally move physi-cians toward greater use of technology.

Roots of Collaborative CareIf the tenets of collaborative care sound familiar, it is

for a good reason. Historically, what is now referred to ascollaborative care was once considered more of a health-care philosophy or movement. Over time, the concepthad many names, including integrated care, primary carebehavioral health, and shared care. Today’s approach to collaborative care is much broad-

er than its predecessors, because there is collaborationacross and among:• Sites of care, including ambulatory care clinics, urgentcare, retail clinics, worksite clinics, hospitals, surgerycenters, pharmacies, home, online and other virtualcare (disease management vendors), alternative care,and fitness centers

• Care providers, specifically primary care, specialists,pharmacists, nutritionists, health coaches, case man-agers, caregivers, social workers, and therapists

• Data repositories at clinics (eg, paper, EMRs), hospi-tals (eg, laboratory information systems, hospitalinformation systems), pharmacies and pharmacy ben-efit managers, reference laboratories (eg, LabCorp),imaging centers, personal health records, healthplans, and associated care management vendors.Collaborative care initiatives also strive to establish

more personalized and proactive care at convenient sitesof care (eg, home, work, retail), while providing more

efficient care and optimized healthcare resource use.Some of the most promising care initiatives involve cor-porate and community partnerships, in which employersfocus on what happens with employees at home as wellas on the job. Additional characteristics of collaborativecare programs include:• Avoidance of duplicative care• Emphasis on error reduction• Promotion of more comprehensive services, includingmental health

• Establishing a clearly defined team with roles andresponsibilities for each person

• Focus on improved quality and reduced costs.

Example of Collaborative Care: Optimal PrescriptionTherapy, Medication AdherenceAlthough considerable emphasis is placed on tech-

nology within collaborative care programs, technologyalone is not the solution. To more readily see how col-laborative care works in the real world of healthcaretoday, consider what happens during the seeminglysimple process of prescribing a new medication, begin-ning with the simple question—Is there strong evi-dence for prescribing a specific medication for apatient? Under collaborative care, answering thisquestion begins with evidence-based guidelines—specifically class A evidence—and continues withissues such as the impact of direct-to-consumer andphysician marketing. Once a medication is prescribed, providers must con-

sider a range of additional issues, including polypharma-cy, potential drug–drug interactions, contraindications,and the patient-specific formulary and benefit design,because affordability is a leading cause of low medicationadherence.Next, consider what happens once the patient begins

taking the medication. Is it taken as prescribed? How canwe confirm persistency and adherence? Options foranswering these questions include patient-reported data,pill counts, devices, caregiver statements, and refillanalysis. If the medication is not taken as reported,providers must then determine the reason, which canrange from affordability and side effects to the patient’sown perception of medication effectiveness.Medication use must also be monitored over time for

efficacy, and titrated as necessary to meet patients’ needs(eg, age, weight). All this information must be recordedin a practice management and/or e-prescribing systemfor optimal provider communication and overall coordi-nation of care. Without every element involved,providers and payers have insufficient knowledge anddata, and ultimately, costs and outcomes could be nega-tively impacted.

Collaborative care initiatives strive toestablish more personalized and proactivecare at convenient sites of care, whileproviding more efficient care and optimizedhealthcare resource use.


Collaborative Care


Key Attributes Needed for Optimal Outcomes inCollaborative Care Collaborative care initiatives cannot exist in a vacuum.

All healthcare stakeholders must take responsibility fordecisions as well as health outcomes. There must also beclear insight and transparency across the care continu-um, as well as role definition and clarity among care sitesand providers. As Sevin and colleagues suggest, the fol-lowing attributes are necessary for the success of collab-orative care14:

Empowered primary care physicians. The primarycare physician must have the tools and authority to actas the care team leader, coordinating and working withpractice staff, specialists, and other care providers.Providers must always recognize that patient needs, val-ues, and the context of their lives must dictate allhealthcare decisions.

Appropriate structure. Operational issues must alsobe addressed. For example, it is important to addressorganizing principles, including business models andpayment reforms, to ensure coordination and coopera-tion. Such models are exemplified by emerging ACOsand patient-centered medical homes, which encompasstactics such as bundled payments, quality-based pay-ments, and care coordination fees. Care collaboration isalso enhanced by gainsharing agreements and risk-adjusted capitation.

Effective technology. Data exchange, interoperabili-ty, and aggregation are ultimately controlled by con-nected patient EMRs/health information technology.EMRs often represent data silos; current EMRs are goodat storage, not communication and connectivity (think“meaningful use”). Robust data integration aggregatedacross silos and transformed into computable data formore automated analysis and timely decision support atthe point of care are important considerations.

Connection between providers, payers, and patients.Although steps are being made to better connectproviders, effective collaborative models must extendthat connectivity to payers, and most important, topatients. Engaging patient portals that provide relevantand tailored information, personalized health supportavailable via cell phones and the internet, and expan-sion of communication to smartphones are all necessaryto a successful care model.

Care architecture. Connectivity and technology areimportant, but the next step in the process must be thenecessary architecture to take patient data and conductanalysis and research. Such findings can then be used tohelp in care management, evidence-based decision sup-port, and population management. Of equal importance,the data and insights contained would be of significantinterest and value to payers and providers through

reports and analyses that confirm guideline compliance,highlight quality achievements, and provide other valu-able insights for measuring and improving care.

A Model for Our FutureAlthough factors ranging from new models of care to

technology will help collaborative care programsbecome a reality, ultimately such programs will not workunless steps are taken to educate, engage, and fullyinvolve patients in their own health. The onus is onproviders, as well as plan sponsors, to develop the edu-cation, technology, and outreach to help foster moreengaged patients who take an active role in the collabo-rative care process.15The coming years will remain challenging for the

healthcare industry—providers and payers alike. With -out a commitment to change, the best intentions of cur-rent healthcare reform efforts will fail. Collaborativecare programs represent an innovative approach thatcan address these challenges with pragmatic solutions.When we, as an industry, embrace such approaches, wecan begin to lead our nation toward necessary, meaning-ful, and lasting changes in our healthcare system. ■

Disclosure StatementDr Gordon has nothing to disclose.

References1. Partnership for Solutions. Chronic conditions: making the case for ongoing care.September 2004 update. www.partnershipforsolutions.org/DMS/files/chronicbook2004.pdf. Accessed October 18, 2010.2.Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectan-cy in the United States in the 21st century. N Engl J Med. 2005;352:1138-1145.3. Rosenthal TC. The medical home: growing evidence to support a new approachto primary care. J Am Board Fam Med. 2008;21:427-440.4. Rittenhouse DR, Casolino LP, Gillies RR, et al. Measuring the medical homeinfrastructure in large medical groups. Health Aff (Millwood). 2008;5:1246-1258.5. DMAA: The Care Continuum Alliance. The medical home and populationhealth improvement: common ground. October 2008: 1-13. http://carecontinuum.org/pdf/DMAA_PHI-PCMH_102108.pdf. Accessed October 18, 2010.6.Ginsburg PB, Maxfield M, O’Malley AS, et al; for the Center for Studying HealthSystem Change. Making medical homes work: moving from concept to practice.2008;1:1-20. www.rwjf.org/files/research/1208.policyperspective1.pdf. AccessedOctober 18, 2010.7. Nutting PA, Miller WL, Crabtree BF, et al. Initial lessons from the first nationaldemonstration project on practice transformation to a patient-centered medicalhome. Ann Fam Med. 2009;7:254-260.8. Reid RJ, Fishman PA, Yu O, et al. Patient-centered medical home demonstration:a prospective, quasi-experimental, before and after evaluation. Am J Manag Care.2009;15:e71-e87.9. Institute of Medicine, Committee on Quality of Health Care in America. Crossingthe Quality Chasm: A New Health System for the 21st Century. Washington, DC:National Academy Press; 2001.10. Kohn KT, Corrigan JM, Donaldson MS, eds. To Err Is Human: Building a SaferHealth System. Washington, DC: National Academy Press; 1999.11. Chen TL, Chung YF, Lin FY. A study on agent-based secure scheme for elec-tronic medical record system. J Med Syst. 2010 Sep 21. Epub ahead of print. 12. Tynan A, Draper D; for the Center for Studying Health System Change. Gettingwhat we pay for: innovations lacking in provider payment reform for chronic dis-ease care. Research Brief No 6. June 2008. www.hschange.com/CONTENT/995/.Accessed October 18, 2010.13.Dorr DA, Jones SS, Wilcox A. A framework for information system usage in col-laborative care. J Biomed Inform. 2007;40:282-287. 14. Sevin C, Moore G, Shepherd J, et al. Transforming care teams to provide the bestpossible patient-centered, collaborative care. J Ambul Care Manage. 2009;32:24-31.15. Epstein RM, Fiscella K, Lesser CS, Stange KR. Why the nation needs a policypush on patient-centered health care. Health Aff (Millwood). 2010;29:1489-1495.


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 AbuseEXALGO 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 SelectionEXALGO 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 UseEXALGO 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 signifi cant 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 sulfi tes. • 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 insuffi ciency, 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.


®

h

h

Avoid concurrent use of alcohol and EXALGO. Concurrent use of EXALGO with CNS depressants, including a

Use with caution and in reduced doses in older or debilitated patients, as well as patients with renal

o

Keep pain waiting.

C

With once-daily EXALGO®, 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 fi nd out more, visit www.keeppainwaiting.com.


EXALGO™ (hydromorphone HCl)Extended-Release Tablets

WARNING: POTENTIAL FOR ABUSE, IMPORTANCE OF PROPER PATIENTSELECTION AND LIMITATIONS OF USE

Potential for AbuseEXALGO 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 SelectionEXALGO 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 UseEXALGO 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)].

CONTRAINDICATIONSOpioid Non-Tolerant PatientsEXALGO is contraindicated in opioid non-tolerant patients. Fatal respiratory depression could occur in patients who are not opioid tolerant. Impaired Pulmonary FunctionEXALGO 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 IleusEXALGO is contraindicated in patients who have or are suspected of having a paralytic ileus. Preexisting Gastrointestinal (GI) Surgery or Narrowing of GI TractEXALGO 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 HypersensitivityEXALGO 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 PRECAUTIONSInformation Essential for Safe AdministrationEXALGO 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 AbuseEXALGO 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 DepressantsThe 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 PressureIn 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 EffectEXALGO 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 EffectsBecause 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.

SulfitesEXALGO 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 InhibitorsEXALGO 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 GroupsEXALGO 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 DiseaseEXALGO 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 MachineryEXALGO 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 REACTIONSThe 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 ExperienceBecause 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

Preferred Term Open-Label Double-Blind Treatment Phase 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 Fatigue was grouped and reported with asthenia b Decreased appetite was grouped and reported with anorexia c 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 Patientswith Chronic Pain Receiving EXALGO in 14 Clinical Studies by Preferred TermPreferred 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)Anorexia b 139 (6) Dry Mouth 121 (5) Abdominal Pain c 115 (5) Anxiety 95 (4) Back Pain 95 (4) Dyspepsia d 88 (4) Depression 81 (3) Dyspnea e 76 (3) 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) Chest Discomfort f 51 (2)

a Fatigue was grouped and reported with asthenia b Decreased appetite was grouped and reported with anorexia c Abdominal pain upper was grouped and reported with abdominal pain d Reflux esophagitis, gastroesophageal reflux disease and Barrett’s esophagus were grouped and

reported with dyspepsia e Dyspnea exacerbated and dyspnea exertional were grouped and reported with dyspnea f Chest pain and non-cardiac chest pain were grouped and reported with chest discomfort

BRIEF SUMMARY - Consult fullprescribing information before use.


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, extrasystolesEar and labyrinth disorders: vertigo, tinnitus Endocrine disorders: hypogonadismEye disorders: vision blurred, diplopia, dry eye, miosis Gastrointestinal disorders: �atulence, dysphagia, hematochezia, abdominal distension, hemorrhoids, abnormal feces, intestinal obstruction, eructation, diverticulum, gastrointestinal motility disorder, large intestine perforation, anal �ssure, 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, di�culty in walking, feeling drunk, hypothermiaInfections and infestations: gastroenteritis, diverticulitisInjury, poisoning and procedural complications: contusion, overdoseInvestigations: weight decreased, hepatic enzyme increased, blood potassium decreased, blood amylase increased, blood testosterone decreased, oxygen saturation decreasedMetabolism and nutrition disorders: dehydration, �uid retention, increased appetite, hyperuricemiaMusculoskeletal 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, hyperre�exia, encephalopathy, cognitive disorder, convulsion, psychomotor hyperactivityPsychiatric disorders: confusional state, nervousness, restlessness, abnormal dreams, mood altered, hallucination, panic attack, euphoric mood, paranoia, dysphoria, listless, crying, suicide ideation, libido decreased, aggressionRenal and urinary disorders: dysuria, urinary retention, urinary frequency, urinary hesitation, micturition disorderReproductive system and breast disorders: erectile dysfunction, sexual dysfunction Respiratory, thoracic and mediastinal disorders: rhinorrhoea, respiratory distress, hypoxia, bronchospasm, sneezing, hyperventilation, respiratory depressionSkin and subcutaneous tissue disorders: erythema Vascular disorders: �ushing, hypertension, hypotension

DRUG INTERACTIONSCNS DepressantsThe concomitant use of EXALGO with central nervous system depressants such as hypnotics, sedatives, general anesthetics, antipsychotics and alcohol may cause additive depressant e�ects 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 AnalgesicsThe concomitant use of EXALGO with morphine agonist/antagonists (buprenor-phone, nalbuphine, pentazocine) could lead to a reduction of the analgesic e�ect by competitive blocking of receptors, thus leading to risk of withdrawal symptoms. Therefore, this combination is not recommended.AnticholinergicsAnticholinergics 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 EnzymesIn 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 POPULATIONSPregnancy Teratogenic E�ects 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 bene�t justi�es the potential risk to the fetus [see Use in Speci�c 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 mal formations (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 ossi�cation of the paws and ectopic ossi�cation 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 E�ectsIn the pre- and post-natal e�ects 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 re�exes, 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 DeliveryEXALGO 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 MothersLow 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 UseThe safety and e�ectiveness of EXALGO in pediatric patients 17 years of age and younger have not been established.Geriatric UseElderly patients have been shown to be more sensitive to the adverse e�ects of EXALGO compared to the younger population. Therefore, use extra caution when prescribing EXALGO in elderly patients and reduce the initial dose. Neonatal Withdrawal SyndromeChronic 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 di�er 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 ImpairmentIn a study that used a single 4 mg oral dose of immediate-release hydromor-phone 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 ImpairmentRenal impairment a�ected the pharmacokinetics of hydromorphone and its metabolites following administration of a single 4 mg dose of immediate-release tablets. The e�ects 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 �exibility with the dosing interval in patients with severe renal impairment [see Dosage and Administration (2.4)].

DRUG ABUSE AND DEPENDENCEControlled SubstanceEXALGO 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 in�uencing 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. Drug-seeking tactics include emergency calls or visits near the end of o�ce 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 su�ering 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 in�ammation 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.DependenceTolerance 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 e�ects over time.

Tolerance could occur to both the desired and undesired e�ects of drugs, and may develop at di�erent rates for di�erent e�ects.Physical dependence is a state of adaptation that is manifested by an opioid speci�c 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 di�culties and withdrawal symptoms [see Use in Speci�c Populations (8.1, 8.2)].

OVERDOSAGESymptomsAcute overdosage with opioids can be manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle �accidity, 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 e�ects. 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. TreatmentGive 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 speci�c 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 signi�cant 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 e�ects 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 speci�c 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


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GENERIC DRUG TRENDS

391www.AHDBonline.com l American Health & Drug BenefitsVol 3, No 6 l November/December 2010

The outlook for generics for the next 4 or 5 yearscontinues to shine, judging from patent expira-tion dates for many of the top-selling drugs. The

generics “pipeline,” therefore, practically ensures thatthe past several years’ trend of increasing market sharefor generics will continue with a vengeance. This doesnot bode well for brand-name manufacturers, whichwill each be losing billions in annual sales (Table), butit does foretell greater access to top-rated yet less-expensive medications—a positive step overall in thecurrent state of economic morass.But while the success of nonbiologic generics con-

tinues, the future for biogenerics or biosimilars remainsin limbo, despite the passing of the Biologic PriceCom petition and Innovation Act earlier this year. Thisfirst legislation toward the creation of a path forbiosimilars still requires much work, as RasmusRojkajaer, MD, PhD, Head of Global BiologicsResearch & Develop ment at Mylan, suggested onbehalf of the Generic Pharmaceutical Association toindustry attendees at the November 3 public hearingconvened by the US Food and Drug Administration.Dr Rojkajaer stressed the need to ensure “that patientsgain access to more affordable biogeneric and biosimi-lar products, while at the same time maintaining incen-tives to innovate new medicines.”1As a result, the predictable increased growth in gener-

ics market share will continue to consist for the mostpart of nonspecialty drugs, even while the pharmaceuti-cal research and development efforts are leaning heavilyon specialty rather than nonspecialty products. Of the current 50 top-selling nonspecialty drugs, 25

should become available in a generic formulation with-in the next 5 years, according to Brian W. Kolling,PharmD, Director, Pipeline and Trend Forecasting,Part D, at Prescription Solutions.2 Specifically, signifi-cant generic activity will occur in 5 key clinical areas—cardiovascular (CV) disease, central nervous system(CNS), diabetes, gastrointestinal (GI), and respiratoryconditions. This includes the patent expiration for 2 of

the top-selling statins—Lipitor in 2011 and Crestor in2016, which garnered >$5 billion and >$2 billion,respectively, in 2009 sales, and the top GI drug(Nexium), with >$5 billion (Table).3As shown in the Table, of the 29 major nonspecialty

drugs to lose patent in the next 5 years, almost half (N =14) had billions of dollars in sales in 2009, amounting tojust under $43 billion ($42.8 billion)3 combined.Of the 10 top-selling agents worldwide, 3 top CV

agents in 3 different classes—a statin (Lipitor), anangiotensin receptor blocker (Diovan), and anantiplatelet (Plavix)—will lose patent by 2012, to thetune of $10.94 billion (in 2009) combined3 in lost rev-enue to their manufacturers. In addition, the patent expiration of 8 key CNS

drugs—with billions of dollars in 2009 sales, each, for 5of them (Abilify, Cymbalta, Lexapro, Seroquel, andZyprexa)3—further reinforces the potential impact ofthis trend toward greater access to generic medicationson patient management, as well as on overall drug costreductions for patients and health plans. Therefore, despite the lack of significant progress on

the biosimilars front by the end of 2010, the outlook fornonspecialty generic drug activity remains bright andwill continue to lead the rapidly approaching 80% ingeneric market share as a percentage of total prescrip-tions written in the United States, and with it theincreased access to popular drugs, albeit wrapped innew clothes, as well as considerable cost reductions forpatients, health plans, and employers. �

References1. Rojkajaer R. GPhA tells FDA that science-based biogeneric approval process isneeded to assure lower costs for patients. Generic Pharmaceutical Association pressrelease. November 3, 2010. http://www.gphaonline.org/media/press-releases/2010/gpha-tells-fda-science-based-biogeneric-approval-process-needed-assure-low.Accessed November 29, 2010.2. Kolling BW. Scanning the pharmaceutical pipeline: what’s on the horizon? 2010Educational Conference, Academy of Managed Care Pharmacy, St. Louis, MO,October 14, 2010. 3. Pharmaceutical sales 2009-top US drugs by sales. www.drugs.com/top200.html.Accessed December 7, 2010.

Generics “Pipeline” Predicts ContinuedMarket Share Gains Through 2014By Dalia Buffery, MA, ABD

Generic Drug Trends_Cover 12/14/10 11:44 AM Page 391

GENERIC DRUG TRENDS


Table Generics Pipeline: Major Nonspecialty Drugs to Lose Patent in the Next 5 Years

Drug brand name (generic) ManufacturerExpected generic launcha

2009 Annual sales ($ thousands)b

CARDIOVASCULAR DISEASES

TriCor (fenofibrate) Abbott March 2011-July 2012 1,224,894

Lipitor (atorvastatin calcium) Pfizer November 2011 5,363,193

Avapro (irbesartan) Bristol-Myers Squibb March 2012 398,768

Plavix (clopidogrel bisulfate) Bristol-Myers Squibb May 2012 4,223,124

Atacand (candesartan cilexetil) AstraZeneca December 2012 152,603

Diovan (valsartan and hydrochloro -thiazide, USP)

Novartis September 2012 1,328,515

Niaspan (niacin) Abbott September 2013 716,589

Crestor (rosuvastatin calcium) AstraZeneca July 2016 2,308,138

CENTRAL NERVOUS SYSTEM CONDITIONS

Zyprexa (olanzapine) Eli Lilly October 2011 1,855,436

Lexapro (escitalopram oxalate) Forest March 2012 2,334,422

Seroquel (quetiapine fumarate) AstraZeneca March 2012 3,117,591

Geodon (ziprasidone hydrochloride) Pfizer September 2012 873,952

Provigil (modafinil) Cephalon April 2012 883,339

Abilify (aripiprazole) Bristol-Myers Squibb April 2015 3,083,351

Lunesta (eszopiclone) Sepracor May 2014 813,087

Cymbalta (duloxetine hydrochloride) Eli Lilly July 2014 2,404,353

DIABETES

Avandia (rosiglitazone maleate) GlaxoSmithKline March 2012 407,906

Actos (pioglitazone hydrochloride) Takeda August 2012 2,531,621

GASTROINTESTINAL CONDITIONS

Aciphex (rabeprazole sodium) Eisai May 2013 996,052

Nexium (esomeprazole sodium) AstraZeneca April 2014 5,014,827

RESPIRATORY CONDITIONS

Clarinex (desloratadine) Schering/Merck January 2012 181,215

Xopenex nebulizer (levalbuterol) Sepracor August 2012 356,898

Singulair (montelukast sodium) Merck August 2012 3,027,378

Advair (fluticasone propionate, salmeterol xinafoate)

GlaxoSmithKline TBD 3,653,410

OTHER CATEGORIES

Xalatan (latanoprost) Pfizer March 2011 457,121

Levaquin (levofloxacin) Ortho-McNeil-Janssen June 2011 1,373,131

Uroxatral (alfuzosin hydrochloride) sanofi-aventis July 2011 174,034

Boniva (ibandronate sodium) Genentech March 2012 511,277

Actonel (risedronate sodium, calcium carbonate)

Warner Chilcott June 2014 435,977

aSource: Brian W. Kolling, PharmD. 2010 Educational Conference, Academy of Managed Care Pharmacy, October 13-15, 2010; St. Louis, MO. bSource: Pharmaceutical sales 2009-top US drugs by sales. www.drugs.com/top200.html. Accessed December 7, 2010. Used with permission.

Continued from page 391

Generic Drug Trends_Cover 12/14/10 11:44 AM Page 392

One And The Same

©2010 Mylan Pharmaceuticals Inc. MYNMKT394A

For nearly 50 years, Mylan Pharmaceuticals has helped set the standards for quality ingeneric medicines. Today, the same standards that guide our manufacturing facilities inthe U.S. also guide our facilities around the globe.

By meticulously adhering to time-tested procedures and following rigorous quality assurance steps, we are confident that every batch of every product manufactured byMylan is the same as the one before. It’s a consistency that comes from the commitmentmade by more than 7,400 employees in our manufacturing facilities … and it’s whypharmacists continue to rank our products highest in quality.*

800.RX.MYLAN • www.mylanpharms.com

*U.S. Pharmacist Generic Company Surveys. 2006-2009

Page 1Generic Drug Trends_Cover 12/14/10 11:44 AM Page 393

BUSINESS


Asthma is one of the nation’s most common, cost-ly, and increasingly prevalent diseases. In 2008,approximately 23.3 million people had asthma

in the United States, of whom 12.7 million had experi-enced asthma attacks.1 The economic cost of asthma for2010 is projected at $20.7 billion, of which $15.6 billionis expected to reflect direct costs of healthcare-relatedexpenditures (ie, hospital care, physician services, andprescription drugs).1,2

Asthma medications, combined with patient educa-tion, are the cornerstones of asthma management.2 In

Dr D’Souza is a Manager, Ms Rahnama is a HealthcareStrategy Consultant, and Mr Regan is an Executive Director,Xcenda, Palm Harbor, FL; Ms Common is CorporateBenefits Manager, H-E-B, San Antonio, TX; and Dr Burchis a Director, GlaxoSmithKline, Durham, NC.

ORIGINAL RESEARCH

The H-E-B Value-Based HealthManagement Program: Impact on Asthma Medication Adherence and Healthcare CostAnna O. D’Souza, PhD; Roshan Rahnama, MPH; Timothy S. Regan, BPharm, RPh; Beth Common, MBA; Steven Burch, PhD

Background: Recent publications have shown that copayment reductions increase med-ication adherence above the effects of existing disease management programs, demonstrat-ing an additive effect of combining a value-based insurance design with a disease manage-ment program. This effect, however, has yet to be demonstrated for medications used for thetreatment of asthma. Objective: To evaluate the impact of a value-based health management asthma program—which included providing patient education and lowering copayments for select asthma con-troller medications—on medication adherence and healthcare utilization and costs.Study Design: The study involved a quasi-experimental intervention versus control groupdesign of insured patients diagnosed with asthma.Method: After applying the inclusion/exclusion criteria for study participation, we obtainedinformed consent from the intervention group; those eligible to participate who did not returnthe forms served as the control group. The final sample size included 764 patients withasthma—298 in the intervention group and 466 in the control group. The intervention consist-ed of a reduction in copayment for select asthma controller medications from an average of$20 to $30 down to $5, as well as 3 mailings of educational materials for asthma manage-ment. Medical and pharmacy claims data for the study population were used to evaluate allstudy parameters and outcomes. Medication possession ratio was used to measure adher-ence to asthma controller medications. Statistical models were used to study differences inthe 2 study groups during the 12-month follow-up period for adherence and cost outcomes.Results: Participation in the value-based health management asthma program increasedpatients’ 12-month medication adherence by 10 absolute percentage points in the interven-tion group (53.9% for intervention vs 43.9% for control group, P <.001) and significantlydecreased average monthly medical costs ($170 intervention vs $229 control, P = .004). Thisincrease in adherence resulted in greater monthly pharmacy costs ($181 intervention vs $124control, P <.001). However, the increase in pharmacy costs was offset by lower medical costs,leading to a nonsignificant increase in average monthly total healthcare costs ($362 interven-tion vs $337 control, P = .276). Conclusion: Adoption of a value-based health management program that combines patienteducation with lowered copayments has a positive impact on medication adherence, resultingin a reduction in associated medical costs and no significant increase in total costs.

Am Health Drug Benefits.2010;3(6):394-402.www.AHDBonline.comDisclosures are at end of text

Stakeholder Perspective,page 402

Timothy S. Regan

Dsouza_Cover 12/14/10 11:46 AM Page 394

H-E-B Value-Based Health Management Program


addition, the clinical effectiveness of asthma treatmentdepends on patient adherence to prescribed medica-tions.3 However, only 37% of patients adhere to pre-scribed inhaled corticosteroids4,5 and adequately controltheir asthma.6 The consequences of nonadherence mayinclude poor symptom control, excessive use of beta-agonist agents, increased emergency department use,hospitalization, and death.4,7

Recent drug benefit design trends, including increas-ing patient copayments, may also contribute to medica-tion nonadherence.8-11 In the case of patients with asth-ma, high copayments have been associated withsignificant reductions in the use of necessary asthmamedications,12,13 as well as increases in emergency depart-ment visits and hospitalization days.8

The adoption of a value-based health management(VBHM) approach that recognizes the role of preven-tive public health and patient education may help toreduce advanced health complications and control risinghealthcare costs. VBHM includes disease state manage-ment (DM) and value-based insurance design (VBID).DM involves a system of coordinated interventions andcommunications, usually for patients with chronic con-ditions, with the ultimate goal of reducing avoidablecomplications, such as hospitalizations and emergencydepartment visits.14

The focus of VBID programs is to decrease patientcost-sharing for high-value services and increase cost-sharing for low-value services, thereby avoiding thedemand-dampening advantages and lessening theadverse health consequences of increased cost-sharing.15With 83% of health plans utilizing asthma DM pro-grams,16 VBID programs are becoming a common meansof augmenting provider-oriented strategies, aligningpatient and provider incentives.

H-E-B—a large retail/grocery store chain in Texasand Mexico, with approximately 300 stores and 65,000employees—has implemented aspects of a VBHM pro-gram, specifically the DM components, for their employ-ees and employees’ dependents diagnosed with asthma.H-E-B subsequently partnered with GlaxoSmithKline toimplement a VBID program, with the goal of improvingmedication adherence and healthcare utilization andreducing costs (asthma-related and overall). This pres-ent study assesses the impact of VBHM interventionswithin the H-E-B population, offering a real-world casestudy evaluation of a comprehensive VBHM program.

Study objectives were to compare the participants inthe intervention group and the control group in termsof their adherence to select asthma controller medica-tions, asthma-related healthcare costs and resource uti-lization, and overall (ie, any medical or pharmacy)healthcare costs.

MethodologyStudy Design

We used a quasi-experimental, intervention groupversus control group design. The study period was 24months, with the start of the intervention being theindex date (June 1, 2006), the 12-month period beforethe index date being the preindex period (June 1,2005-May 31, 2006), and the 12-month period afterthe index date (June 1, 2006-May 31, 2007) used as thefollow-up period. Patients’ baseline characteristics weremeasured during the preindex period. Medicationadherence and asthma-related resource utilization,costs, and overall healthcare costs were measured dur-ing the preindex and follow-up periods.

Data SourceMedical and pharmacy claims data of H-E-B

employees and their dependents were used for thisanalysis. All patients were enrolled in a preferredprovider organization plan. Claims data included inpa-tient and outpatient diagnoses, as well as prescriptionrecords classified by the National Drug Code. Paid andcharged amounts, as well as dates of service, were avail-able for all claims.

KEY POINTS

➤ Adherence to asthma medication is key to patientoutcomes but is often subpar.

➤ This study evaluated the effect of a value-basedhealth management program on medicationadherence and overall costs in patients with asthmawho were employed at H-E-B.

➤ The program consisted of 2 main components—disease management and value-based insurancedesign. The latter reduced the cost of copaymentfor select asthma medications from an average of$20 to $30 down to $5 for patients in theintervention group but not in the control group.

➤ During the 12-month follow-up period, medicationadherence increased by 10 absolute percentage pointsin the intervention group (53.9% for intervention vs43.9% for control group, P <.001).

➤ In addition, a significant reduction was found inoverall medical cost, which offset the increase inpharmacy costs.

➤ This analysis contributes to the growing body ofevidence demonstrating that decreases incopayment amounts may increase asthmamedication adherence and reduce associatedmedical costs.

Dsouza_Cover 12/14/10 11:46 AM 5

BUSINESS


Study Inclusion and Exclusion CriteriaInsured H-E-B employees with asthma and their

dependents with asthma who provided informed con-sent were eligible for inclusion in the interventiongroup; those who met the inclusion criteria but did notprovide informed consent comprised the control group.Additional inclusion and exclusion criteria wereapplied to enhance the study’s validity. To be included,employees had to (1) have at least 1 pharmacy claimfor the selected asthma controller medications in thepreindex period, (2) have a diagnosis of asthma at base-line, (3) be between age 4 and 64 years at baseline, and(4) be continuously eligible during the preindex andfollow-up periods.

Asthma diagnosis was defined as (1) a hospital oremergency department visit with a primary diagnosis ofasthma (International Classification of Diseases, NinthRevision, Clinical Modification [ICD-9-CM] code 493.xx),(2) at least 2 physician visits with asthma listed in anydiagnostic field, or (3) at least 2 pharmacy claims forasthma-related medications, except oral corticosteroidsand decongestants.

Exclusion criteria included (1) diagnosis of cysticfibrosis (ICD-9-CM code 277.0x) in the preindex peri-od, (2) diagnosis of chronic obstructive pulmonary dis-ease (ICD-9-CM codes 491.xx, 492.xx, 493.2x, 496) inthe preindex period, or (3) age ≥45 years at baselineand having ≥2 pharmacy claims for ipratropium bro-mide or combination albuterol plus ipratropium in thepreindex period.

Study InterventionH-E-B employees and dependents with at least 1

medical claim for asthma during the preindex periodwere the target population. Participation was voluntaryand was requested by an invitation letter that describedthe intervention and included consent and enrollmentforms. The intervention consisted of 2 components:

(1) An average reduction in the copayment frombetween $20 and $30 to $5 for selected (Table 1) asthmacontroller medications

(2) Three mailings of educational materials for asth-ma management.

All asthma controller medications in the preferredformulary list were eligible for copayment reduction(Table 1). Educational topics included medicationguides, asthma myths, patient–doctor action plan, asth-ma triggers, acute asthma management strategies, andthe Asthma Control Test.17 Sources referenced in devel-oping the patient communication materials included theStaywell Company, Asthma Action America, theRespiratory Institute, and QualityMetric Incorporated.English was the primary language, at an eighth-gradereading level, for all the educational materials.

Before the start of the study intervention in 2006,study participants were already enrolled in the Blue CareConnection (BCC) program, which provides patient-focused services to help H-E-B employees improve theirhealth outcomes and manage their healthcare costs. TheBCC program began in 2004 and was in effect until theend of the current study. Participation in the BCC pro-gram was voluntary. Among the final patient sampleincluded in the current study, 99% of patients in theintervention group and 25% of those in the controlgroup were enrolled in the BCC program.

The BCC program services included 24/7 access tohealth information for patients provided by licensednurses for managing their disease, periodic calls fromlicensed nurses to monitor patients’ health, access to anonline resource and information tool to manage theirhealth, and discounts on health-related products andservices that help to support healthy lifestyles (eg, gymmembership).

Outcome DefinitionsAdherence

Medication possession ratio (MPR) was used to meas-ure adherence to asthma controller medications. MPRrepresents the proportion of time that an asthma con-troller medication was available to a patient during theduration of therapy, and was calculated as the sum of thetotal days’ supply of medication for all prescriptions,except the last prescription, divided by the duration oftherapy (ie, total number of days from the first fill date to

Table 1 Selected Asthma Controller Medications

Advair Diskus (fluticasone propionate and salmeterol)Flovent (fluticasone)Flovent HFA (fluticasone) Flovent Rotadisk (fluticasone)Foradil (formoterol fumarate)Gastrocrom (cromolyn)Intal (cromolyn sodium)Pulmicort (budesonide)Qvar (beclomethasone dipropionate)Serevent (salmeterol xinafoate)Serevent Diskus (salmeterol xinafoate)Singulair (montelukast sodium)Slo-Bid 50 (theophylline) Slo-Bid 75 (theophylline)Theochron (theophylline)Tilade (nedocromil sodium) Uniphyl (theophylline)




the last fill date). MPR usually ranges from 0%, indicat-ing no adherence, to 100%, indicating perfect adher-ence. Therefore, a patient with a 50% MPR during a90-day therapy duration had 45 days of treatment (90days � 50% = 45 days).

All prescriptions had a start date (ie, fill date) and anend date (ie, fill date plus days’ supply). When prescrip-tions overlapped (ie, a patient refilled an additional pre-scription before the end date of the preceding prescrip-tion), residual days were added to the end date of thenext prescription. Therefore, patients were assumed tohave consumed all medications acquired during thestudy period. With the addition of overlapped prescrip-tion claims, it was possible for adherence to be >100%,particularly for patients who consistently received earlyrefills; in these instances, adherence was truncated to100%. For patients having only 1 prescription claim,MPR was assumed to be 0%. For patients who used >1 ofthe selected asthma controller drugs (Table 1) concomi-tantly, MPR was computed as the sum of total days’ sup-

ply of each of the medications, divided by the sum of thetotal duration of therapy for each medication.

Some researchers have questioned the use of MPR asa measure of adherence for inhaled medications, partic-ularly short-acting medications,18 because these areoften used on an as-needed basis, which renders thedays’ supply variable inaccurate for MPR calculations.However, we do not believe this applies to the asthmacontroller medications, because they are not indicatedto be used on an as-needed basis and have specificdosage instructions.

Healthcare Resource Utilization and CostsResource utilization in this study refers to the number

of different types of healthcare visits and/or prescriptionunits. These include the number of physician visits, hos-pitalizations, emergency department visits, short-actingbeta-agonist (SABA) canisters, and oral corticosteroidprescriptions. An asthma controller ratio was calculatedas the ratio of the number of controller medications (ie,

Table 2 Baseline Characteristics, by Study Intervention Group Status

Baseline characteristicsIntervention (N = 298)

Control (N = 466) P

Age in years, mean (SD) 29.1 (19.4) 25.7 (18.6) .016a

Male, N (%) 139 (46.6) 229 (49.1) .500

Blue Care Connection program, N (%) 297 (99.7) 118 (25.3) <.001a

Charlson Comorbidity Index, mean (SD) 0.93 (0.98) 0.81 (0.84) .081

Prescription utilization metrics to assess asthma severity

Number of SABA canisters in preindex period, mean (SD) 2.4 (3.9) 2.0 (3.3) .294

Number of oral corticosteroid Rxs in preindex period, mean (SD) 0.64 (1.15) 0.61 (1.07) .651

Presence of anti-inflammatory controller asthma medications in preindex period, N (%)

Inhaled corticosteroids 219 (73.5) 299 (64.2) .007a

Leukotriene antagonists 195 (65.4) 314 (67.4) .578

Total copayment for asthma medications in preindex period, mean (SD) 191.5 (124.2) 158.1 (106.8) <.001a

Total copayment for nonasthma medications in preindex period, mean (SD) 313.1 (361.7) 261.8 (342.8) .003a

Medical utilization metrics to assess asthma severity

Pulmonologist/allergist care, N (%) 69 (23.2) 107 (23.0) .951

Asthma-related hospitalization/ED visit in preindex period, N (%) 19 (6.4) 26 (5.6) .648

Number of asthma-related outpatient visits in preindex period, mean (SD) 1.68 (2.9) 1.25 (2.1) .031a

aP <.05.ED indicates emergency department; SABA, short-acting beta-agonist; SD, standard deviation.


inhaled corticosteroid, cromolyn, nedocromil canisters,and oral leukotriene) dispensed, divided by the sum ofthe number of controller medications and canisters ofinhaled SABAs dispensed during the study period.6

Costs were defined as the total amount paid for physi-cian visits, hospitalizations, emergency department vis-its, and prescription drugs. Asthma-specific and overallhealthcare costs were obtained for each patient duringthe 12-month follow-up period.

Asthma-specific medical resource utilization andcosts were identified by the presence of a primary diag-nosis code for asthma (ICD-9-CM 493.xx) on a claim.Asthma-related prescription drugs included reliever andcontroller medications (SABAs, oral corticosteroids,xanthines, long-acting beta-agonists, leukotriene antag-onists, cromolyn/nedocromil, and inhaled cortico -steroids). Monthly cost, rather than total costs incurredduring the study period, was used as the target outcometo permit comparison of baseline and follow-up periods.

Covariate and Statistical AnalysesCovariates included in multivariate analyses were

age, sex, comorbidity, preindex healthcare costs, andasthma severity. For overall comorbidity, a Dartmouth-Manitoba model adaptation of the CharlsonComorbidity Index score was calculated for each patient,based on the presence of ICD-9-CM codes during the12-month preindex period,19 with greater scores repre-senting a greater burden of comorbidity. TheDartmouth-Manitoba adaptation of the CharlsonComorbidity Index uses ICD-9-CM codes to representetiologies and manifestations or sequelae of the 19comorbidities specified in the original Charlson index.Overall healthcare costs for the preindex period werecomputed and categorized as medical or pharmacy costsand were included in the model as separate variables. Fordetermining asthma severity, prescription and medicalutilization metrics were used (Table 2).

Demographic and other baseline characteristics weresummarized by group using measures such as means andpercentages. Inferential statistics were used to assessintergroup differences in these parameters. Differencesbetween groups in adherence, resource utilization, andcosts were tested for statistical significance. Parametricor nonparametric tests were used, depending on distri -butional characteristics of these outcomes. Parametrictests for continuous variables included t-tests, and non-parametric tests included Mann-Whitney tests. Chi-square tests were used for categorical variables.Differences between baseline and follow-up measureswere assessed by paired t-tests or Wilcoxon signed-ranktests, as appropriate. Ordinary least square (OLS) regres-sion models, semi-log OLS models, or generalized linearmodels with a gamma distribution and log-link wereused for assessing differences in groups during follow-upfor adherence and cost outcomes, after controlling forbaseline covariates.

ResultsFigure 1 illustrates the sample selection procedure,

which yielded a final sample size of 764 patients withasthma, 298 in the intervention group and 466 in the

BUSINESS


Target populationN = 3885

H-E-B employees and/or dependents who were enrolled in theH-E-B health insurance plan and had ≥1 asthma-related claim

were mailed invitation letters to participate in the study

Initial sample size N = 3496 (100%)

H-E-B employees and/or dependents whose complete eligibility and claims information were obtained

Exclusion criteriaaPatients

excluded, N (%)

No diagnosis of asthma in preindex period, based on study definition

1670 (47.8)

Not continuously eligible during preindexand postindex periods

626 (17.9)

Age at baseline not between 4 and 64 years 89 (2.6)

Diagnosis of cystic fibrosis in preindex period 25 (0.7)

Diagnosis of COPD in preindex period 205 (5.9)

Age ≥45 years at baseline and having ≥2 phar-macy claims for ipratropium or combinationipratropium + albuterol during preindex period

60 (1.7)

No claim for any of the select asthma controller medications in preindex period

1814 (51.9)

Final sample size N = 764

Control group466 (61%)

No patient education materials or copayment reduction provided

Intervention group298 (39%)

Patient education materials and copayment reduction provided concurrently

aExclusion criteria are not mutually exclusive.COPD indicates chronic obstructive pulmonary disease.

➤

➤ ➤

Figure 1 Study Sample Selection Algorithm


control group. Table 2 describes the study sample atbaseline. Intervention group participants were signifi-cantly older than those in the control group, by an aver-age of 3.4 years (P = .016), but gender proportions weresimilar (P = .500). A significantly greater proportion ofthe intervention group than the control group filled aninhaled corticosteroid prescription (73.5% vs 64.2%,respectively; P = .007) and had a greater mean numberof asthma-related outpatient visits in the preindex peri-od (1.68 vs 1.25, respectively; P = .031). Comparedwith the control group, the intervention group had sig-nificantly greater mean total copayments for asthma-related medications ($192 vs $158, respectively; P <.001)and non–asthma-related medications ($313 vs $262,respectively; P = .003) during the preindex period. Ingeneral, asthma severity for the intervention group wasgreater than for the control group, which might haveled to greater patient activation during the study inter-vention; adjustments for differences in asthma severitywere made in the analysis.

Adherence. During the 12-month preindex period,the control group had an average MPR of 45.7% com-pared with 52.4% in the intervention group (P = .002).During the 1-year follow-up period, adherence rates inthe intervention group increased by 4.5 absolute per-centage points compared with a decrease of 3.7 absolutepercentage points for the control group, which resultedin the intervention group having a significantly higherMPR during the 12-month postindex than the controlgroup (56.9% vs 42.0%, respectively; P <.001). Aftercontrolling for other covariates, the intervention grouphad a statistically higher adjusted MPR of 53.9% at theend of 1 year, compared with 43.9% for the controlgroup (Figure 2).

Asthma-related costs, utilization. Monthly asthma-related costs were compared between the interventionand the control groups. The intervention group had sig-nificantly greater asthma-related monthly medical costsat baseline ($43 vs $23, respectively; P = .030); however,by study end, the average monthly cost reduction wasgreater in the intervention group compared with the con-trol group (–$15 vs –$6, respectively). After controllingfor covariates and baseline differences in costs, the inter-vention group had a lower (but not significant) adjustedmonthly cost at 12 months of follow-up compared withthe control group ($18 vs $23, respectively; P = .067).

Asthma-related hospitalization and emergencydepartment visit costs were incurred by a very smallnumber of patients (1 patient in the intervention and 1in the control group had 1 hospitalization each, and 6patients in the control cohort and 2 in the interventioncohort had 1 emergency department visit each), preclud-ing stable mean estimates of number of visits, cost, and

multivariate analyses. At baseline, the interventioncohort had a nonsignificant greater mean number ofphysician visits than the control group (1.38 vs 1.08,respectively; P = .123). At follow-up, no differences wereseen between the 2 groups in the mean number of physi-cian visits (1.20 vs 0.96, respectively; P = .108).

In contrast to asthma-related medical costs, asthma-related monthly pharmacy costs were significantlygreater in the intervention group compared with thecontrol group during follow-up ($89 vs $53, respective-ly; P <.001); this, however, was expected with thereduced copayment for the intervention group. Thereduced copayment essentially increased the cost perprescription for the health plan for the interventiongroup compared with the control cohort after the inter-vention (data not shown).

The number of SABA canisters was greater in theintervention group compared with the control cohort,but this difference was not significant at baseline (1.72vs 1.57, respectively; P = .324) or after 12 months of fol-low-up (1.76 vs 1.49, respectively; P = .114). How ever,both cohorts had asthma controller ratios close to 1,indicating a good ratio of controller to SABA use. Theasthma controller ratio was significantly greater in theintervention cohort compared with the control cohortat 6 months of follow-up (0.80 vs 0.74, respectively; P =.014), but not at 12 months (0.79 vs 0.76, respectively;P = .051). The number of oral corticosteroid prescrip-tions was similar between cohorts at baseline (0.64 vs0.61, respectively; P = .756) and at 12 months of follow-up (0.68 vs 0.60, respectively; P = .314).

Overall healthcare costs. At baseline, the interven-tion cohort had significantly greater overall medical($224 vs $155, respectively; P = .002) and pharmacy($145 vs $113, respectively; P <.001) costs comparedwith the control cohort. At follow-up, differences in



Figure 2 Adjusted Adherence Rate Estimates During Follow-Up Period

6 months 12 monthsFollow-up period

P= .007

P<.001

47.3%

40.5%

53.9%

43.9%

Med

ication po

ssession

ratio

,% 60

50

40

30

InterventionControl


overall medical costs between the intervention and con-trol groups were similar to the asthma-related medicalcosts. After controlling for covariates, the interventiongroup had significantly smaller overall monthly medicalcosts compared with the control group during 12 monthsof follow-up ($170 vs $229, respectively; P = .004)(Figure 3). Although overall pharmacy costs were high-er ($181 vs $124, respectively; P <.001), total overallcosts were not statistically different between the inter-vention group and the control group ($362 vs $337,respectively; P = .276).

DiscussionThis study demonstrates that the VBHM asthma

program significantly improved adherence, as measuredby MPR, and reduced overall medical costs for the sam-ple of H-E-B employees and their dependents with asth-ma. During the 12-month follow-up study period, asth-ma medication adherence rates for patients in theintervention group were substantially greater than thosein the control group. In addition, asthma-related med-ical costs decreased for the intervention group afteradjusting for covariates, whereas asthma-related phar-macy costs increased.

When the impact on overall healthcare costs was cal-culated, a significant reduction in overall medical costswas successful in offsetting the higher overall pharmacycosts, resulting in no significant differences for the inter-vention group compared with the control group in totaloverall healthcare costs.

Increased asthma-related pharmacy expenditure isparticularly significant, because it implies that patients

were refilling their asthma medications, adhering totherapy, and improving asthma management. The high-er pharmacy costs found in this study reflect the effectsof the DM and VBID components of the VBHM pro-gram found in other studies.8,12,13,20,21 DM programs inasthma have been reported to increase awareness of theeffectiveness of controller medications, as well asincrease use and costs.20,21 Similarly, changes in copay-ment policies have been shown to influence medicationadherence.8,12,13 A recent study evaluated the effect of aVBID program by reducing the cost of inhaled cortico -steroids, resulting in a small positive (although not sig-nificant) increase in medication adherence.22 Theauthors attributed the insignificant result to the difficul-ty of measuring adherence to inhaled medications thatinvolve multiple doses in a single inhaler compared withother medications with individual doses, such as oraltablets.22 In the present study, copayment was reduced forinhaled and for oral asthma medications.

In effect, a lower copayment for patients with certainchronic conditions requiring ongoing medication usemay be a preventive public health measure. Despite theinitial higher short-term drug costs for insurers, areduced copayment may increase patient adherence andimprove health status and, in turn, decrease long-termhealthcare costs for insurers. This study shows that aVBHM intervention can improve patient medicationadherence and decrease medical costs. Even with anincrease in pharmacy costs as a result of improved adher-ence, the overall healthcare costs in this study were sim-ilar between the intervention and the control groups ofinsured H-E-B employees and their dependents.

Practice/Policy ImplicationsReduced medication adherence because of high

copayments is a complex issue that requires a multifac-eted strategy and collaborative approach.10 Researchsuggests that adherence to inhaled corticosteroidsdiminishes over time,23 but patient education on theregular use of asthma medications can be critical toincreasing adherence. Developing mechanisms toreport adherence status on a regular basis to providersand patients may also improve medication adherenceand asthma control.4 Furthermore, providers and payersmay help to reduce costs by taking a more proactiverole in assessing patient medication need against anyfinancial constraints and communicating potentialapproaches to confront these issues.24

LimitationsInterpretation of the study results must consider sev-

eral potential limitations. First, adherence to asthmamedications was determined based on pharmacy

BUSINESS


Mean ad

justed

mon

thly cost, $

400

350

300

250

200

150

100 Medical Pharmacy Total Medical Pharmacy Total 6 months 12 months

Costs

$337

$362

$124

$181

$229

$348$323

$170$173

$216

$160

$119

P<.001

P= .281

P<.001

P= .037P= .004

P= .276

Figure 3 Adjusted Overall Monthly Medical, Pharmacy, and Total Costs

InterventionControl


claims; as such, actual consumption of a medicationwas not available.

In addition, it was not determined in this study ifpatients read and understood the educational materials.

Because the study’s sample population was onlyselected from insured employees and their dependentsfrom the H-E-B grocery store chain in Texas, the geo-graphical concentration and health insurance status maypose a problem for the ability to generalize this study’sresults to other populations. Further research is necessaryto understand if and how barriers to adherence may varyfor other populations.

Finally, the voluntary participation in the VBHMprogram could possibly have influenced the findings inthe intervention cohort, because these patients were per-haps more motivated to manage their disease. However,despite an almost 100% participation rate in the inter-vention cohort in the BCC program—demonstratingsignificant motivation—the intervention cohort stillhad more severe disease than the control group beforethe study intervention. However, selection of a controlgroup from another source to avoid self-selection biascould have resulted in comparing patients in a differentgeographic, economic, and social environment, all ofwhich are minimized in this study.

ConclusionsThis study indicates that the H-E-B asthma program

improved patient adherence to controller medications,reduced medical costs, and increased prescription costs.Specifically, the program increased adherence by 10absolute percentage points without a significant increasein asthma-related resource utilization and total overallhealthcare costs.

The H-E-B VBHM asthma program analysis con-tributes to the growing body of research evidencedemonstrating that decreases in copayment amountsmay yield increased asthma medication adherence andreduce associated medical costs. Rapidly increasingcopayment costs can create a financial barrier and differ-ential access to necessary medications, affect patientadherence ability, and contribute to widening the eco-nomically driven disparities of health outcomes that cur-rently exist. Adopting a VBHM approach can minimizeadvanced medical complications and rising healthcarecosts associated with asthma management. ■

AcknowledgmentsWe sincerely appreciate the original vision for this

study provided by Sandy Debussey and contributionsfrom other GlaxoSmithKline, H-E-B, and Xcendateam members.

Source of FundingThis research was funded in part by GlaxoSmithKline.

H-E-B was responsible for all healthcare services reimburse-ment, including copayments.

Disclosure StatementDr D’Souza, Ms Rahnama, and Mr Regan are consult-

ants to GlaxoSmithKline; Dr Burch is an employee ofGlaxoSmithKline. Ms Common has nothing to disclose.

References1.American Lung Association. Asthma in adults fact sheet. February 2010. www.lungusa.org/lung-disease/asthma/resources/facts-and-figures/asthma-in-adults.html#1.Accessed June 29, 2010.2.National Heart, Lung, and Blood Institute, National Institutes of Health. www.nhlbi.nih.gov/health/prof/lung/asthma/naci/asthma-info/. Accessed November 15, 2010.3.Rand C, Bilderback A, Schiller K, et al. Adherence with montelukast or fluticasonein a long-term clinical trial: results from the mild asthma montelukast versus inhaledcorticosteroid trial. J Allergy Clin Immunol. 2007;119:916-923. Epub 2007 Mar 8.4.Williams LK, Pladevall M, Xi H, et al. Relationship between adherence to inhaledcorticosteroids and poor outcomes among adults with asthma. J Allergy Clin Immunol.2004;114:1288-1293. 5. Thier SL, Yu-Isenberg KS, Leas BF, et al. In chronic disease, nationwide data showpoor adherence by patients to medication and by physicians to guidelines. ManagCare. 2008;17:48-57.6. Schatz M, Zeiger RS, Vollmer WM, et al. The controller-to-total asthma medica-tion ratio is associated with patient-centered as well as utilization outcomes. Chest.2006;130:43-50.7. Bauman LJ, Wright E, Leickly FE, et al. Relationship of adherence to pediatricasthma morbidity among inner-city children. Pediatrics. 2002;110:e6.8. Goldman DP, Joyce GF, Escarce JJ, et al. Pharmacy benefits and the use of drugsby the chronically ill. JAMA. 2004;291:2344-2350.9. Gibson TB, Ozminkowski RJ, Goetzel RZ. The effects of prescription drug costsharing: a review of the evidence. Am J Manag Care. 2005;11:730-740.10. Thiebaud P, Patel BV, Nichol MB. The demand for statin: the effect of copay onutilization and compliance. Health Econ. 2007;17:83-97.11. Anis AH, Guh DP, Lacaille D, et al. When patients have to pay a share of drugcosts: effects of frequency of physician visits, hospital admissions and filling of pre-scriptions. CMAJ. 2005;173:1335-1340.12. Dormuth CR, Glynn RJ, Neumann P, et al. Impact of two sequential drug cost-sharing policies on the use of inhaled medications in older patients with chronicobstructive pulmonary disease or asthma. Clin Ther. 2006;28:964-978.13. Bender BG, Pedan A, Varasteh LT. Adherence and persistence with fluticasonepropionate/salmeterol combination therapy. J Allergy Clin Immunol. 2006;118:899-904.Epub 2006 Sep 8.14. Bodenheimer T. Disease management—promises and pitfalls. N Engl J Med. 1999;340:1202-1205.15. Fendrick AM, Chernew ME. Value based insurance design: maintaining a focuson health in an era of cost containment. Am J Manag Care. 2009;15:338-343.16. America’s Health Insurance Plans. 2002 AHIP Survey of Health Insurance Plans:Chart Book of Findings. April 2004. www.ahip.org/content/default.aspx?bc=38|82|2244. Accessed July 3, 2010.17.GlaxoSmithKline. Asthma control test. www.asthmacontrol.com/. Accessed July20, 2008.18. Fairman K, Motheral B. Evaluating medication adherence: which measure isright for your program? J Manag Care Pharm. 2000;696:499-504. www.amcp.org/data/jmcp/ce_v6_499-506.pdf. Accessed July 20, 2010.19. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifyingprognostic comorbidity in longitudinal studies: development and validation. J ChronDis. 1987;40:373-383.20. Lukacs SL, France EK, Barón AE, Crane LA. Effectiveness of an asthma man-agement program for pediatric members of a large health maintenance organization.Arch Pediatr Adolesc Med. 2002;156:872-876.21. NGA Center for Best Practices. Disease management: the new tool for cost con-tainment and quality care. Issue Brief. 2003. www.nga.org/Files/pdf/031403DISEASEMGMT.pdf. Accessed October 12, 2010.22. Chernew ME, Shah MR, Wegh A, et al. Impact of decreasing copayments onmedication adherence within a disease-management environment. Health Aff(Millwood). 2008;27:103-112.23. Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the longterm prevention of hospitalisation for asthma. Thorax. 2002;57:880-884.24.Heisler M, Langa KM, Eby EL, et al. The health effects of restricting prescriptionmedication use because of cost. Med Care. 2004;42:626-634.



Stakeholder Perspective next page


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Value-Based Insurance Design: Evolving Strategies to ImproveMedication Adherence, Control Healthcare UtilizationPAYERS: Value-based health management strives

to optimize the medical benefit received for the health-care resource purchased. It is frequently introduced toindividuals by what is now referred to as value-basedinsurance design (VBID), through a member’s employ-er or health plan. This benefit design rewards the use ofevidence-based practices through incentives such aswaived or reduced copayment/coinsurance to individu-als for services purchased or supplemental payment toproviders for services rendered. VBID typically focuseson benefits by a specific service (eg, cost waiver/reduc-tion for specific drugs or services for all patients); con-dition (eg, cost waiver/reduction for drug or servicerelated to a specific medical condition); conditionseverity (eg, cost waiver/reduction for drugs or servicesfor an individual classified as high risk); or as men-tioned in the present article by D’Souza and colleagues,by involving “health management participation” (eg,cost waiver/reduction for drugs or services with partici-pation in a particular program).1

Such strategies are thought to overcome the issuesdemonstrated by the increase in individuals’ cost-shar-ing of prescription drugs through the rise in drug copay-ments/coinsurance by means of improving drug adher-ence and reducing potentially preventable healthcareresource utilization (eg, emergency department visits).

Increased access to medications is an important toolin improving care. Rates of nonadherence to asthmamedication have been reported to be as high as 70%.2Reduced inpatient and emergency department visitshave been associated with adherence to asthma con-troller medication.3

Additional access to medication must also be tem-pered with the opportunity for increased fraud or abuseof the new benefits. Providers or individuals may be

encouraged to misrepresent information to benefitfrom reduced copayment/coinsurance or supplementalreimbursement for services. Expansion in fraud detec-tion services may be necessary. Organizations will alsoneed to be vigilant in monitoring shifts in healthcareresource utilization, in particular the purchase of low-value or less clinically supported medical services,because individuals may then have increased capacityto purchase such services. PATIENTS: Patients will need to understand that

value-based benefit offerings, such as the H-E-B pro-gram, are meant to optimize the quality of care theyreceive. Members/patients should be encouraged toengage in the process and take full advantage of theopportunity presented to help improve their health.

Patients should also be on alert for potential abuse ofthe process and advise their organization if they suspectthat abuse of services may have occurred. Value-basedbenefit strategies that provide a “carrot” to the individ-ual through reduced out-of-pocket expenses have notbeen embraced by all organizations, but they continueto grow in acceptance. Abuse of the system could slowthe use of such benefits and shift incentives away fromthe carrot and more toward the use of the “stick” (eg,excluded coverage, higher out-of-pocket expenses).

1. Frederick AM. Value-Based Insurance Design Landscape Digest. NationalPharmaceutical Council. July 2009. www.sph.umich.edu/vbidcenter/publications/pdfs/NPC_VBIDreport_7-22-09.pdf. Accessed November 29, 2010.2. Rand CS, Wise RA. Measuring adherence to asthma medication regimens. AmJ Respir Crit Care Med. 1994;149:S69-S76;discussion S77-S78.3. Tan H, Sarawate C, Singer J, et al. Impact of asthma controller medications onclinical, economic, and patient-reported outcomes. Mayo Clin Proc. 2009;84:675-684.

Richard F. Radzin, PharmDExecutive Consultant

CGI FederalCleveland, OH

STAKEHOLDER PERSPECTIVE


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M Dsouza_Cover 12/14/10 11:46 AM Page 403

AMCP HIGHLIGHTS


A broad range of research, including poster sessions with direct relevance to pharmacy andmedical directors and other healthcare stakeholders, was presented at the Academy of ManagedCare Pharmacy’s 2010 Educational Conference, which was held October 13-15 in St Louis, MO.

The following summaries reflect some of the major research trends presented at the meeting.

There may be discordance between what pharmacistssay influences their formulary decision choices, and whatactually influences those choices, according to anexploratory study examining the importance of productand manufacturer attributes.Researchers from Mercer University College of

Pharmacy and Health Sciences in Atlanta, GA, wereinterested in understanding how pharmacists’ perceptionsof various product and manufacturer attributes impactedformulary decision-making. To do so, they conducted anonline survey in January 2010 using a convenience sam-ple of 176 managed care pharmacists. Participants wereasked to rate the importance of and performance of 14product and manufacturer attributes, and were asked tomake 2 hypothetical product choices in lipid-loweringagents and proton pump inhibitors (PPIs). A total of 30 (17%) surveys were completed. Factors

rated as high performance/high importance in formula-

ry decision-making were related to product (ie, safety,efficacy, net ingredient cost, product superiority, andavailable outcomes data). Factors given low performance/low importance were

related to manufacturers (ie, size, customer programs,current market share, and ability to drive marketshare). If safety and efficacy were the same amongproducts, 87% of respondents indicated that cost wouldbe the final basis for their decision. Costs were also professed as the decision-making

basis for the hypothetical scenarios; however, an exam-ination of published formularies reveals that only 27%had the lowest cost PPI on formulary and only 7% hadthe lowest cost fibrate.Despite rating net ingredient cost as important,

“most plans do not have branded products with thelowest ingredient cost in preferred positions on the for-mulary,” the authors concluded.

Cost May Not Drive Formulary Choice After All

Pharmacists’ Monitoring of ESAs Leads to Cost-SavingsA pilot program in which specialty pharmacists

monitored hemoglobin levels in patients whose physi-cians had requested refills of erythropoiesis-stimulatingagents (ESAs) resulted in some dosing changes and sig-nificant drug cost-savings for payers. The program was run by the Accredo Health Group

in Memphis, TN, and took place for 4.5 months betweenJune 2009 and October 2009. When an ESA refill wasrequested, specialty pharmacists requested hemoglobinlevels from prescribers. If data were more than 8 weeksold, or if the hemoglobin level was ≥12 g/dL, the phar-macists called prescribers to discuss US Food and Drug

Method Used to Measure MPR Influences Adherence RateThe method used to measure medication adherence

impacts the results of that measurement, and thereforeresearchers should use various methods depending onthe overall goals of the study, according to researchersfrom the Accredo Health Group and Medco HealthSolutions. They compared 4 different ways of measuring med-

ication possession ratio (MPR) in 8 specialty pharmacytherapeutic categories using 18 months of claims data. Apatient’s first use of a drug was re corded (index date),and then all subsequent claims for 360 days were record-ed. The 8 drug categories were multiple sclerosis,rheumatoid arthritis, hepatitis C, pulmonary hyperten-sion, growth hormone, osteoporosis, oral oncology, andfinally, the drug omalizumab (Xolair). The 4 methods included (1) continuously eligible

patients are followed for 360 days from the indexed pre-scription; (2) all patients with 2 or more prescriptionsare included, but the last prescription is not included;(3) the third approach is the same as the second one,but the last prescription is included; and (4) all patientswith 1 prescription filled are included, which includesthe last prescription. In every case, the first method provides the lowest esti-

mate of adherence rate, and each of the following meth-ods provides lower estimates than the next one above it.The difference in adherence rate between method 1 andmethod 4 for each of the drug categories was: 13% (mul-tiple sclerosis); 16.6% (rheumatoid arthritis); 44.4%(hepatitis C); 17.7% (pulmonary hypertension); 21.6%(growth hormone); 26.9% (osteoporosis); 16.4% (oraloncology); and finally, 21.6% (omalizumab).

AMCP highlights_Nov_Cover 12/14/10 11:47 AM Page 404

AMCP HIGHLIGHTS


Administration warnings, recommend therapy changes,and document prescribing decisions. Requests for hemoglobin measures were made for

6572 ESA refills, and 713 hemoglobin levels were notobtained. Of the total 6572 refills, 1447 (22%)required specialty pharmacist intervention (746 forelevated laboratories, 421 for outdated laboratories,and 280 others). Of the 1447 refills, 610 (42.2%) werenot dispensed because of therapy holds (416), dosechanges (107), cancellations (85), or other (2) rea-sons. Therapy was continued in 337 patients, despite

elevated/outdated hemoglobin levels. The authorsestimate that $3761 was saved per therapy hold, and$2498 per dose change; $555 was saved per member permonth for therapy dose changes. For each program month, the total drug cost-savings

was estimated at $398,796; total savings during thecourse of the program was estimated at $1,794,529.Although the pilot program has officially ended,

ESA monitoring continues, and the authors reportcontinued favorable acceptance by providers to supply-ing laboratory values and to the entire intervention.

Adding a Pharmacist to a Medical Home May Cut CostsPreliminary research on incorporating a clinical

pharmacist specialist into a team managing a patient-centered medical home (PCMH) shows an emergingbody of evidence to support the integration of these spe-cialists, and the potential for cost-savings once thesecaregivers are added to the team.The researchers note that there is currently no stan-

dard guideline for determining clinical pharmacist spe-cialist staffing needs or responsibilities in the PCMHmodel, and so they reviewed the published literature onPCMH pilot programs with available outcomes. Theultimate goal was to analyze the impact of clinical phar-macy services and potential cost-savings associated withimplementing a PCMH model at the Kansas City VAMedical Center (KCVA). The literature review revealed positive contributions

of a clinical pharmacist specialist in prescreenings, fol-

low-up care, and disease management. Outcome meas-ures included reductions in emergency department visitsand hospitalizations, and total per-patient cost-savings.The pharmacy leadership at KCVA determined nec-

essary staffing levels and clinical pharmacist specialistprocedures and responsibilities. Clinical pharmacistspecialist responsibilities focused on identifyingpatients at high risk for poor medication-related out-comes and working with patients in need of improvedcontinuity of care. Potential cost-savings for KCVA extrapolated from

the literature/data review were:• $6 million-$12 million in hospitalizations• $1 million-$8 million in emergency department visits• $630,000-$24 million in total patient costs.A 1-year evaluation of the PCMH program at this

institution will commence in the coming year.

Step-Therapy Program to Lower Rx Costs, Keep Members Happy A year-long step-therapy program focusing on 10

therapeutic drug classes that also attempted to mini-mize member dissatisfaction with any changes amongthese drugs lowered the average gross cost per claim bynearly 13% while denying only 10.2% of prior author-ization (PA) requests. The program was initiated by CVS/Caremark; the

drugs it focused on included proton pump inhibitors(PPIs), nonsedating antihistamines (NSAs), selectiveserotonin reuptake inhibitors, 3-hydroxy-3-methyl -glutaryl-coenzyme A reductase inhibitors, angiotensin-converting enzyme inhibitors/angiotensin receptorblockers, nasal steroids, hypnotics, bisphosphonates,urinary incontinence drugs, and cyclooxygenase-2(COX-2) inhibitors. As with other step-therapy programs, members are

required to fill a prescription for a generic before select-ing single-source brands, but the program also allows achoice of 1 select preferred brand in most classes.Members and physicians were notified about the pro-

gram 60 days and 30 days before implementation, anda dedicated call center was set up to handle PAs andother questions. The program effectiveness was meas-ured through average gross cost per claim and averagegeneric-dispensing rate. Following program implementation, gross cost per

claim fell from $72.75 to $64.50 per average claim, andgeneric-dispensing rate rose from 57.5% in August2009 to 72.8% by July 2010. Generic-dispensing rateimproved significantly in all classes except for COX-2inhibitors; the program had the greatest impact amongthe PPI and NSA classes, which saw average gross costper claim drop by $41.14 and $15.25, respectively. Thecall center handled 7600 calls between August 2009and March 2010; 16.7% of callers began the PA processbut were converted to a preferred brand or generic; and54.1% of PA requests were approved. The analysis did not adjust savings for increases in

wholesale price inflation or for the effects of new brandmedications. Continued


AMCP HIGHLIGHTS


Disease State Impacts Medication Adherence Medication adherence varies widely depending on

the condition for which a patient is taking that medica-tion, according to a retrospective study of more than15,000 patients in an integrated health system.Researchers investigated medication adherence

among patients with multiple sclerosis, cancer, hyper -cholesterolemia, hypertension, osteoporosis, depression,diabetes, and asthma/chronic obstructive pulmonarydisease (COPD). Patients were required to have only 1disease for which they were taking a single medication.By examining pharmacy claims records, the researchersidentified patients with a minimum of 2 prescription

fills for ≥28 days of medication supply within 1 year.Adherence was calculated using the medication posses-sion ratio, which had to be ≥80% for the patient to bedetermined adherent.There was wide variation in adherence by condi-

tion, ranging from 85% for multiple sclerosis to 32% forasthma/COPD. Efforts to improve adherence in condi-tions with the lowest compliance levels are needed,and, as such, the authors are now conducting follow-upresearch among patients with diabetes and asthma/COPD to better understand facilitators and barriers tooptimal medication use.

Employing mandatory 90-day supply requirementsfor oral chemotherapy agents leads to drug waste andincreased costs, and a shorter-term (30-day) supplyshould be considered for these agents, according to apharmacy claims database analysis.Researchers from Prime Therapeutics examined a

database of 5.7 million members from 3 Blue CrossBlue Shield plans from the Midwest and South, andextracted claims for erlotinib and imatinib between2006 and 2010. Members were tracked by theamount of time they spent under the insurance plan;the amount of erlotinib or imatinib supplied tomembers during their time in the plan was alsotracked. Waste was calculated as the differencebetween the member’s total days of supply of thedrugs and the number of days in the plan. Projectedwaste was then calculated if members had been given30-day supplies instead.

During the study period, the wholesale acquisitioncosts for erlotinib and imatinib increased anywherefrom 26.7% (for imatinib 100-mg tablets) to 57.8%(for imatinib 400-mg tablets). Seventy of 418 mem-bers had at least 1 fill with a 90-day supply; 19 of the418 members had actual waste (estimated to cost$23,952). Calculating projected waste, the authorsdetermined that more than 11,700 days of waste wouldhave occurred if 90-day supplies were used instead of30-day supplies. This excess waste totaled $1,433,723.The range of average excess supply per member was 34days to 56 days (for 90-day supplies) and 13 days to 16days (for 30-day supplies). The authors caution that actual waste cannot be

definitively known because of dosing changes and theestimation of time that members were in the plans. Afurther limitation is the small sample size (418 mem-bers of the total 5.7 million) in the plan.

Targeting Waste in Targeted Therapies


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policy conditions, the journal offers a forum for stakeholderintegration and collaboration toward the promotion ofvalue-based healthcare. AHDB further provides benefitdesign makers the integrated information they need todevise benefit designs and make coverage decisions thatstand up to today’s demand for value-based healthcarethat is founded on quality, cost, and access considerations.

AHDB welcomes articles on topics relevant to theintegration of the forces in healthcare that affect the costand quality of healthcare and ultimately result in accessto care, focusing on health organization structures andprocesses, health information, health policies, healthand behavioral economics, as well as health technolo-gies, products, and patient behaviors relevant to value-based quality of care.

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N =230

P

N =114

G

N =232

A

N = 355P

+ Rosiglitazone N = 175A

C

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140586-R1 4/2010

Victoza® (liraglutide [rDNA origin] injection)Rx onlyBRIEF 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, pre-scribe 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 dia-betes 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 syn-drome 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 car-cinoma (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, Contra-indications]. 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 devel-oped 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 calci-tonin 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-treat-ment 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 calci-tonin 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 endocrinolo-gist 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 pan-creatitis 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 con-clusive 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 treat-ment 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 con-clusive 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 = 248Adverse Event Term (%) (%)Nausea 28.4 8.5Diarrhea 17.1 8.9Vomiting 10.9 3.6Constipation 9.9 4.8Upper Respiratory Tract Infection 9.5 5.6Headache 9.1 9.3Influenza 7.4 3.6Urinary Tract Infection 6.0 4.0Dizziness 5.8 5.2Sinusitis 5.6 6.0Nasopharyngitis 5.2 5.2Back Pain 5.0 4.4Hypertension 3.0 6.0

Table 2: Adverse events reported in ≥ 5% of Victoza®-treated patients and occur-ring more frequently with Victoza® compared to placebo: 26-week combination therapy trials

Add-on to Metformin TrialAll Victoza® +

Metformin N = 724

Placebo + Metformin N = 121

Glimepiride + Metformin N = 242

Adverse Event Term (%) (%) (%)Nausea 15.2 4.1 3.3Diarrhea 10.9 4.1 3.7Headache 9.0 6.6 9.5Vomiting 6.5 0.8 0.4

Add-on to Glimepiride TrialAll Victoza® +

Glimepiride N = 695Placebo + Glimepiride

N = 114Rosiglitazone +

Glimepiride N = 231Adverse Event Term (%) (%) (%)Nausea 7.5 1.8 2.6Diarrhea 7.2 1.8 2.2Constipation 5.3 0.9 1.7Dyspepsia 5.2 0.9 2.6


Add-on to Metformin + GlimepirideVictoza® 1.8 + Metformin + Glimepiride

N =230

Placebo + Metformin + Glimepiride

N =114

Glargine + Metformin + Glimepiride

N =232

Adverse Event Term (%) (%) (%)Nausea 13.9 3.5 1.3Diarrhea 10.0 5.3 1.3Headache 9.6 7.9 5.6Dyspepsia 6.5 0.9 1.7Vomiting 6.5 3.5 0.4

Add-on to Metformin + RosiglitazoneAll Victoza® + Metformin +

Rosiglitazone N = 355Placebo + Metformin

+ Rosiglitazone N = 175Adverse Event Term (%) (%)Nausea 34.6 8.6Diarrhea 14.1 6.3Vomiting 12.4 2.9Decreased Appetite 9.3 1.1Anorexia 9.0 0.0Headache 8.2 4.6Constipation 5.1 1.1Fatigue 5.1 1.7

Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastroin-testinal 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, diar-rhea, 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 treat-ment. 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 dura-tion 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 antibod-ies 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 neutral-izing 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-con-trol-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 immu-nogenicity 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 ultra-sound. 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 combina-tion 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 hypoglyce-mia 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 intra-venous 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® Treatment

Active Comparator

Placebo Comparator

Monotherapy Victoza®

(N = 497)Glimepiride

(N = 248)None

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) —Add-on to Metformin

Victoza® + Metformin (N = 724)

Glimepiride + Metformin (N = 242)

Placebo + Metformin (N = 121)

Patient not able to self−treat 0.1 (0.001) 0 0Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06)Add-on to Glimepiride Victoza® +

Glimepiride (N = 695)

Rosiglitazone + Glimepiride

(N = 231)

Placebo + Glimepiride

(N = 114)Patient not able to self−treat 0.1 (0.003) 0 0Patient 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) 0Add-on to Metformin + Rosiglitazone

Victoza® + Metformin +

Rosiglitazone (N = 355)

None

Placebo + Metformin +

Rosiglitazone (N = 175)

Patient not able to self−treat 0 — 0Patient able to self−treat 7.9 (0.49) — 4.6 (0.15)Not classified 0.6 (0.01) — 1.1 (0.03)Add-on to Metformin + Glimepiride

Victoza® + Metformin + Glimepiride

(N = 230)

Insulin glargine + Metformin + Glimepiride

(N = 232)

Placebo + Metformin + Glimepiride

(N = 114)Patient not able to self−treat 2.2 (0.06) 0 0Patient 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 malig-nant 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 concentra-tions (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-comparator-treated 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, 1−877-484-2869Date of Issue: January 2010 Version: 1Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, DenmarkVictoza® 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


© 2010 Novo Nordisk A/S 141395 May 2010

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

Visit VictozaPro.com to learn more.

Targets beta cells

Provides powerful andsustained reductions in A1C*

Can provide the additional benefi t of weight loss

Safety and tolerability were studied in clinical trials that included nearly 4000 patients

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

Once-daily Victoza®:

Indications and usageVictoza® 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 fi ndings to humans, prescribe Victoza® only to patients for whom the potential benefi ts are considered to outweigh the potential risk. Victoza® is not recommended as fi rst-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 suffi ciently 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 informationLiraglutide 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 fi ndings 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 confi rmed. 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.

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November/December 2010, Vol 3, No 6

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Transcript of November/December 2010, Vol 3, No 6