February/March 2009, Vol 2, No 2

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ FEBRUARY/MARCH 2009

VOLUME 2, NUMBER 2

REGULATORY

What Changes Can Your Health Plan Expect from the New Administration?

Interview with Dan Mendelson Stakeholder Perspective by Joseph R. Antos, PhD BUSINESS

Patient Cost-Sharing on the Rise: Results from the Benefit Design Index ™

Melinda C. Haren, RN; Kirk McConnell Stakeholder Perspective by David Williams

Employer-Based Health Initiative: Impact on Employees’ Cardiovascular Outcomes Claiborne E. Reeder, RPh, PhD; Christine H. Divers, PhD, MS; Del Deem; Becky J. Cherney; Gaye Fortner, RN, BSN, MSN; Louise Y. Probst Stakeholder Perspective by Charles E. Collins, Jr, MS, MBA CLINICAL

Methicillin-Resistant Staphylococcus aureus : A Growing Risk in the Hospital and in the Community Jose L. Raygada, MD; Donald P. Levine, MD Stakeholder Perspective by Dennis M. Perrotta, PhD, CIC DEPARTMENTS ◆ FDA Watch Commentary by Nirav R. Shah, MD, MPH Commentary by F. Randy Vogenberg, RPh, PhD ◆ Generic Drug Trends

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

How fast do noses demand seasonal allergy relief?

Fast seasonal allergic rhinitis relief is here.

t The only nasal spray approved to work in 30 minutes1 t Sustained symptom relief over 2 weeks2,3 t Steroid-free1 t From a proven, potent H1 antagonist4 Prescribe the nasal spray that starts working ASAP. PATANASEÂŽ Nasal Spray is an H1 receptor antagonist indicated for the relief of symptoms of seasonal allergic rhinitis in patients 12 years of age or older.

The most common adverse reactions (>1%) included bitter taste, headache, epistaxis, pharyngolaryngeal pain, post-nasal drip, cough, and urinary tract infection. Nasal ulceration and nasal septal perforation occurred at a rate of <1%; patients should be monitored periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with nasal disease other than allergic rhinitis. Please see highlights of prescribing information on reverse page.

For full prescribing information, please visit www.patanase.com

Š2008 Alcon, Inc.

8/08

PTN08510JA

HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use PATANASEÂŽ Nasal Spray safely and effectively.

See full prescribing information for PATANASE Nasal Spray.

PATANASE (olopatadine hydrochloride) Nasal Spray Initial U.S. Approval: 1996 INDICATIONS AND USAGE PATANASE Nasal Spray is an H1 receptor antagonist indicated for the relief of the symptoms of seasonal allergic rhinitis in patients 12 years of age and older. (1) DOSAGE AND ADMINISTRATION For intranasal use only.

The recommended dose of PATANASE Nasal Spray in patients 12 years and older is two sprays per nostril twice daily. (2) Priming Information: Prime PATANASE Nasal Spray before initial use and when PATANASE Nasal Spray has not been used for more than 7 days. (2.2) DOSAGE FORMS AND STRENGTHS Nasal spray 0.6%: 665 mcg of olopatadine hydrochloride in each 100-microliter spray. (3) Supplied as a 30.5 g bottle containing 240 sprays.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS s %PISTAXIS NASAL ULCERATION AND NASAL SEPTAL PERFORATION -ONITOR patients periodically for signs of adverse effects on the nasal mucosa. Avoid use in patients with nasal disease other than allergic rhinitis. (5.1) s !VOID ENGAGING IN HAZARDOUS OCCUPATIONS REQUIRING COMPLETE mental alertness such as driving or operating machinery when taking PATANASE Nasal Spray. (5.2) s !VOID CONCURRENT USE OF ALCOHOL OR OTHER CENTRAL NERVOUS SYSTEM depressants with PATANASE Nasal Spray. (5.2) ADVERSE REACTIONS 4HE MOST COMMON ADVERSE REACTIONS INCLUDED BITTER TASTE

HEADACHE EPISTAXIS PHARYNGOLARYNGEAL PAIN POST NASAL DRIP

COUGH AND URINARY TRACT INFECTION To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

References: 0ATEL $ 'ARADI 2 "RUBAKER - ET AL /NSET AND DURATION OF ACTION OF NASAL SPRAYS IN SEASONAL ALLERGIC rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate. Allergy Asthma Proc. 2007;28:592-599.

-ELTZER %/ (AMPEL &# 2ATNER 0( ET AL 3AFETY AND EFFICACY OF OLOPATADINE HYDROCHLORIDE NASAL SPRAY for the treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 2005;95(6):600-606.

2ATNER 0( (AMPEL &# !MAR .* ET AL 3AFETY AND EFFICACY OF OLOPATADINE HYDROCHLORIDE NASAL SPRAY for the treatment of seasonal allergic rhinitis to mountain cedar. Ann Allergy Asthma Immunol. 2005; 95(5):474-479.

2OSENWASSER ,* / "RIEN 4 7EYNE * -AST CELL STABILIZATION AND anti-histamine effects of olopatadine ophthalmic solution: A REVIEW OF PRE CLINICAL AND CLINICAL RESEARCH #URR -ED 2ES /PIN 2005;21(9):1377-1387.

Š2008 Alcon, Inc.

8/08

PTN08510JA

FEBRUARY/MARCH 2009

VOLUME 2, NUMBER 2

™

™

TABLE OF CONTENTS REGULATORY

55

What Changes Can Your Health Plan Expect from the New Administration?

Interview with Dan Mendelson

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Stakeholder Perspective by Joseph R. Antos, PhD

BUSINESS

70

Patient Cost-Sharing on the Rise: Results from the Benefit Design Index Melinda C. Haren, RN; Kirk McConnell

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Stakeholder Perspective by David Williams

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Employer-Based Health Initiative: Impact on Employees’ Cardiovascular Outcomes Claiborne E. Reeder, RPh, PhD; Christine H. Divers, PhD, MS; Del Deem; Becky J. Cherney; Gaye Fortner, RN, BSN, MSN; Louise Y. Probst

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Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889 Associate Editor Dawn Lagrosa 732-992-1892 Senior Production Manager Lynn Hamilton

Stakeholder Perspective by Charles E. Collins, Jr, MS, MBA

Business Manager Blanche Marchitto President Brian F. Tyburski brian@engagehc.com Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

CLINICAL

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

Methicillin-Resistant Staphylococcus aureus: A Growing Risk in the Hospital and in the Community Jose L. Raygada, MD; Donald P. Levine, MD Stakeholder Perspective by Dennis M. Perrotta, PhD, CIC Continued on page 52

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Benefit designs are greatly affected by clinical, business, and policy conditions.

This publication provides benefit design decision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

American Health & Drug Benefits is included in the following indexing and database services: CINAHL: Cumulative Index to Nursing and Allied Health Literature EBSCO: EBSCO research databases

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February/March 2009

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com T: 732-992-1880 F: 732-992-1881

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NO. 2

756,000 patients enrolled in pharmacy adherence programs

12 All numbers current as of January 2008.

MG54484 COPYRIGHT © 2008 ELI LILLY AND COMPANY.

products for diabetes and mental health

1

happier, healthier, more compliant patient

If it matters to patients, it matters to us. That’s why Eli Lilly and Company is committed to providing the programs, services, and manpower that help you deliver positive outcomes for the patients under your care. And while health care may be a numbers game, we’re interested in the one number that matters most.

One focus. One promise. One patient at a time.

FEBRUARY/MARCH 2009

VOLUME 2, NUMBER 2

™

TABLE OF CONTENTS

™

(Continued)

DEPARTMENTS

67

FDA WATCH Prominent Cardiologist Hammers the FDA: Insufficient Funding Compromises the Science of Drug Approvals

By Wayne Kuznar

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Commentary: Funding for the FDA Nirav R. Shah, MD, MPH

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Commentary: Innovation in Drug Development F. Randy Vogenberg, RPh, PhD

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GENERIC DRUG TRENDS Will 2009 Usher in the Era of Biogenerics?

Dalia Buffery, MA, ABD

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Address all editorial correspondence to: editorial@AHDBonline. com, Telephone: 732-992-1889. Fax: 732-992-1881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

EXECUTIVE SUMMARIES

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

CAPTION CONTEST

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WEB EXCLUSIVE www.AHDBonline.com

INDUSTRY TRENDS • Effects of High-Deductible Plans on Employers and Employees • Medication Errors in Ambulatory Oncology Drug Dispensing Not Yet Over GI CANCER MEETING HIGHLIGHTS • Genetic Testing in Metastatic Colon Cancer May Save $604 Million Annually PAYER PULSE • Use of Compendia in Managed Care

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American Health & Drug Benefits, ISSN 19422962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

Copyright © 2009 by Engage Healthcare Communications, LLC. All rights reserved.

American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

February/March 2009

The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned.

Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831.

Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD.

VOL. 2

NO. 2

4th Law of Healthonomics:

Investing to keep employees working and healthy beats paying for them when they’re out and sick.

More employers are rethinking their responses to escalating healthcare costs. Why? They recognize chronic diseases are the root problem. Example: An employee managing his diabetes might cost $5,000 per year.1 An employee not managing his diabetes could cost up to $45,000.1 The win-win here is that by providing employees incentives to lead healthier lives and helping them manage their chronic diseases, you reduce your healthcare costs. And you’ll have healthier employees. Sure beats the alternative.

Learn about lowering costs now at www.CenterVBHM.com

Reference: 1. Health Partners. Beyond Benefits. January 2006. http://www.healthpartners.com:747/media/beyondbenefits/BB0106_ br.htm. Last accessed 8/3/07.

EDITORIAL BOARD

CLINICAL EDITOR

HEALTH OUTCOMES RESEARCH

PHARMACY BENEFIT DESIGN

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

Gordon M. Cummins, MS Director, IntegriChain

Jan Berger, MD, MJ President, Health Intelligence Partners Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

GOVERNEMENT EDITOR

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

Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA

ACTUARY

David Williams Health Consultant Milliman, Windsor, CT

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

CARDIOLOGY RESEARCH

MANGED CARE & GOVERNEMENT AFFAIRS

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

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

ENDOCRINOLOGY RESEARCH

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

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lakewood, FL

Jeffrey A. Bourret, MS, RPh, FASHP Executive Director, Customer-Centric Strategy and Innovation, Healthcare Systems Marketing Wyeth Pharmaceuticals, Collegeville, PA Charles E. Collins, Jr, MS, MBA Associate Director, Managed Markets Marketing, Boehringer-Ingelheim Ridgefield, CT

Paul Anthony Polansky, BSPharm, MBA Executive VP and Chief Pharmacy Officer Sanovia Corp., Philadelphia, PA Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA PHARMACY & SPECIALTY PRODUCTS

James T. Kenney, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA POLICY & PUBLIC HEALTH

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Poloicy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO

ONCOLOGY RESEARCH

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

Alex Hathaway, MD, MPH, FACPM Senior Medical Policy Advisor Government Programs GlaxoSmithKline, Philadelphia, PA J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago

F. Randy Vogenberg, RPh, PhD Chief Strategy Officer Employer-based Pharmaceutical Strategies Senior Scholar, Department of Health Policy, Thomas Jefferson University

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

EPIDEMIOLOGY

PERSONALIZED MEDICINE

Grant D. Lawless, BSPharm, MD, FACP Executive Director for Payor Relations Corporate Account Amgen, Thousand Oaks, CA

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

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

Michael Schaffer, PharmD, MBA Director, Pharmacy Programs Sanovia Co., Philadelphia, PA

PHARMACOECONOMICS

RESEARCH & DEVELOPMENT

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

Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials Faculty, Center for Experimental, Pharmacology and Therapeutics, HarvardMIT Division of Health Sciences and Technology, Cambridge, MA

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

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

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

AMERICAN HEALTH & DRUG BENEFITS

February/March 2009

REIMBURSEMENT POLICY

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REGULATORY

What Changes Can Your Health Plan Expect from the New Administration?

Interview with Dan Mendelson The new administration has already begun to introduce changes in some areas of government. To outline potential key changes to the US healthcare system and their impact on health plans, Robert Henry and Kip Piper of AHDB asked Dan Mendelson to draw on his experience as current president and founder of Avalere Health, as well as on his previous role as Associate Director for Health at the White House’s Office of Management and Budget during the Clinton Administration. Mr Mendelson focuses on what he sees as key changes that will have direct implications for decision makers in healthcare, including (1) a greater emphasis on plan beneficiaries’ protection, and (2) increased regulatory focus on plan operations. Plans can expect to have less government trust in actuarial submissions and probably more oversight and supervision of the daily operation of a plan. The triangle of quality, access, and cost will likely reflect the point of view of the beneficiary rather than that of plan administrators. Other topics discussed include the potential benefits of postmarketing surveillance, new opportunities for expediting drug approvals, and the new and increasing emphasis on comparative effectiveness research and health information technology.

[AHDB. 2009;2(2):55-60.]

Robert Henry: Our editorial focus is on balancing the clinical, business, and regulatory criteria that guide the US healthcare system. As a new administration is taking over, we would like to ask you what you think those involved in healthcare, especially payers, can expect from this new environment.

Dan Mendelson: The new administration will look at the relationship between health plans and the government in a fundamentally different way from the previous administration.

First, the new group will be motivated by beneficiary protection, that is, their perception of what is best for Medicare patients. They will likely be less concerned with making a market for Medicare Part D and accommodating the operations of health plans. They will assess the ability of the beneficiary to access a consistently high-quality, low-cost product. This, I think, is the first fundamental change in mindset that will take place—a focus on the beneficiary.

The second likely result will be a higher degree of skepticism about plan operations. And that means there will be more scrutiny of the marketing guidelines.

Mr Mendelson is President and Founder, Avalere Health LLC, Washington, DC. He is former Associate Director for Health, Office of Management and Budget, the White House.

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This will play out in the review of the bids. Plans can expect less trust of the actuarial submissions and probably more oversight and supervision of the day-to-day plan operations. These I think are the 2 major characteristics of the coming change for health plans.

Henry: Could this push plans from cost-minimization to cost-effectiveness?

Mendelson: The term cost-effectiveness has different implications for different people, so I am a little reluctant to use it here. The key is that there are going to be fundamental changes in the mindset that will shift the focus to the beneficiary perspective.

The pending changes in Medicare Part D are a good example. The Medicare Modernization Act gives very broad flexibility to the Medicare Administrator. For example, there is a very general medication therapy management (MTM) provision in the law; to date the Centers for Medicare & Medicaid Services (CMS) has not issued detailed regulations on requirements for this program, and plans have had broad flexibility in implementing their MTM programs. I would expect the new administration to consider what beneficiaries should be able to expect from health plans with respect to MTM; this again is a beneficiary focus. For example, beneficiaries

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KEY POINTS

The coming administration signals a fundamental change in the relationship between health plans and the government.

The new administration will be very motivated by what is best for beneficiaries and less with accommodating the operations of health plans.

Consequently, plans can expect to have less government trust in actuarial submissions and probably more oversight of the day-to-day plan operations.

In the short-term, Congress is not overly concerned with cost control relative to stimulus of the economy. The policy over the next year is not likely to be very motivated by demographic or by social problems.

A strong postmarketing program can sometimes help move drugs more rapidly through the approval process when a drug is helpful, knowing that realworld data will be collected later on.

There will be a great opportunity for health plans if they rise to the opportunity to help the government shape what types of investment should be made in the area of e-health.

with heart failure or diabetes or another chronic disease may expect a quality improvement program organized around medications in a Part D plan. The next step is that CMS may specify it expects to see such plans operationalized, especially if there is evidence on improved patient outcomes associated with certain types of plans.

Henry: One of the realities facing the new administration is the aging of the baby boomers and the massive increase in healthcare utilization. Part and parcel of this is the issue of biologics for cancer care. Biologics offer unprecedented advances in life expectancy for a number of cancers, but these medications are also exponentially more expensive than their predecessors. How are we going to fund this?

Mendelson: There’s a short-term and a long-term perspective. In the short-term, the Congress is not overly concerned with cost control relative to stimulus of the economy. Much of the policy that is being discussed right now is about the stimulus (which is spending money), as opposed to cost control (which is saving money). So in the short-term I don’t think we are going to see very aggressive cost containment along the lines

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of the Balanced Budget Act being pushed aggressively by the administration or by Congress.

There will be some exceptions to that, as the Congress will want to show that it cares about longterm Medicare spending growth. For the plans, this probably means that a modest reduction in managed care payments will be legislated within the next year. It also likely means a new law to establish a regulatory pathway for follow-up on biologics, and a budget proposal in the spring, with modest provider cuts. But I don’t think there will be large rate reductions in the hospital, in the physician areas in legislation this year, or in the areas that really count with respect to getting costs under control.

In the long-term, of course the program costs are unsustainable. There is a demographic as well as a cost imperative that will play out, but I just don’t see the policy over the next year being very motivated by fundamental demographic and social problems.

Kip Piper: There has been talk regarding the drug pipeline that connects to the discussion about the current risk-aversion environment and the need for balance. Is that real? And if so, have we swung the pendulum, or is it just too insufficiently nuanced of an approach that requires a look at the market and the regulations, especially regarding the US Food and Drug Administration (FDA)?

Mendelson: There are a number of issues embedded in your question. Whoever comes in to run the FDA will have the opportunity to shape a new paradigm for how drugs are approved. This will not necessarily hurt the ability to bring drugs to the market, but right now there is a lot of confusion and uncertainty around how the FDA is going to be looking at drugs in the future, especially with respect to the new requirement for postmarket or postlaunch data.

Strong postmarket evaluation programs focused on safety and efficacy might help the FDA get more comfortable with certain types of approvals and even enable the FDA during a period of time to move more quickly. With all the concerns about safety, the FDA has not set any “speed records” during the past 4 years, and there is an opportunity to help the FDA regain its footing as a science agency at this point.

In addition, there are other topics of real importance with respect to health reform. A topic of great importance and consistent focus from the Obama Administration is health information technology (HIT), which includes a variety of subtopics, such as e-prescribing, electronic medical records, and personal

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Healthcare Changes in the New Administration

health records (PHRs). President Obama has made statements about the importance of this area, and he wants to do something about it. I think we are going to see a significant level of activity around electronic health records this year. And it will happen from within the government, the regulatory agencies (eg, the Agency for Healthcare Research and Quality, CMS, and the FDA) that will focus on what they can do to improve e-health, and through legislation that will be designed to promote some aspects of e-health.

Much of the policy to date—including what is presently included in the stimulus bill—is focused on helping providers to be able to pay for new technologies. But there is a great opportunity for health plans if they rise to the opportunity to help the government shape what types of investment should be made in that area. President Obama has specifically linked a $50billion commitment to the economic stimulus, which is significant.

Henry: Are there any advantages to embarking on a HIT infrastructure initiative at this point that may be a cause for optimism?

Mendelson: There is going to be money funneled into this channel. The fundamental question is what that policy is going to be. Specifically, there are 3 ways that this could be done. One would be to give incentives to physicians and for hospitals to acquire better technology that operates in a clinical environment. A second would be to give incentives to individuals to invest in PHRs that could be brought into the clinical environment. A third is to work it through health plans. Many health plans have already started to invest significant amounts of money in PHRs that would distinguish themselves as commercial offerings.

The question becomes, how does this shape the operating environment for health plans that are reading the material they are producing, to say that they have an opportunity to be the leaders in this area or to see their materials commoditized.

dence-based medicine, clinical effectiveness review, and the like. Several organizations, including the National Committee for Quality Assurance and the National Quality Forum, are starting to make some progress on defining clinical measures. There is certainly a greater level of discussion in government, and I do think that this year we will see the passage of a separate comparative effectiveness research entity that is charged with beginning to evaluate some of these issues on behalf of the government.

What is discouraging, though, and what I think will cause this concept to move slowly, is the relative lack of actionable evidence in most clinical areas, where we just don’t have the right information. In addition, researchers can do all the literature reviews that they want, but this type of research and the quality guidelines produced will never completely substitute for physician judgment, nor can the research substitute for the interest of a patient to navigate her or his own solutions.

There is a thin line between applying a cost-effectiveness construct and a rationing of healthcare. I don’t think that the US population is ready for a policy that will restrict access to care in a structured and organized way. Likewise, I don’t expect to see the evolution of strict criteria around cost-effectiveness that would result in the denial of a product on the basis of how many lives it saves. I do think that the American public is ready for more availability of evidence, more scrutiny of the evidence, and more benefit to increase the visibility of evidence. And I expect to see that happen, including major progress this year in reform.

Henry: Quality of life has always been a measure used by the European healthcare systems, and it never quite made its way intact into the US healthcare system. Do you think that will be a prospect for the future?

Henry: Going back to something we mentioned earlier, are we moving toward a more sophisticated level of evidence as it pertains to health and drug benefits? Will we be able, with comparative effectiveness and HIT measures, to amass data and analyze the evidence on health and drug interventions better than before?

Mendelson: I think we will evolve in a different direction. I don’t think we’re going to have a UK-type NICE (National Institute for Health and Clinical Excellence)-like entity in our healthcare system in the near future. The American vision of a pluralistic healthcare system will drive more availability of information, but it will not yet embrace a fully top-down approach, where the relevant government agency in essence makes binding decisions for regional health plans. Remember that we still have a ban on the practice of medicine contained in the Social Security Act.

Mendelson: What is encouraging is the stronger level of interest from the plans in the concepts of evi-

Henry: Briefly, how do you see this translating into realworld action on the part of a medical director at one plan or

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a pharmacy director at another plan? What practical or tactical change will this bring in the way they do business?

Mendelson: Of course the plans are encouraging the government to get into this, as it helps them tactically.

The more the government leads in the evaluation of cost-effectiveness and the dissemination of evidence, the easier it is for plans to help make decisions on behalf of their beneficiaries and to stick with those decisions, which is often a difficult thing to do. So the plans would very much like the government to take a more aggressive role in that direction. For example, if the government looked at cancer therapy A and found that it was not indicated, it would be easier for plans to deny cancer therapy A. But, as I’ve argued, I don’t think we’re quite ready for product-specific government judgments in most cases.

We will, however, see more government-sponsored therapy-related information being brought into the public domain. And plans are going to have to anticipate the information that is brought to consumers, what that means, and how that information should interact with their own decisions about what they should approve or deny. So in the short-term, comparative effectiveness research will impose more burden on plans to understand what the government is doing and to navigate the information that is being provided to consumers.

Henry: The Dartmouth Atlas Project and other reports have pointed out great variation in the US healthcare system. The system as a whole scores as number 22 in the world, but if we break the system into states, Minnesota is the number 2 healthcare system in the world. So how can we avoid throwing out the good practices in the interests of a nationwide system?

Mendelson: The issue of regional variation is complex and doesn’t bring easy answers to those trying to limit increases in costs. Variations in physician practice patterns, prescription patterns, and hospitalization patterns are in part due to regional standards of practicing medicine and in part due to differences in disease burden and insurance rates. Also, if one geography has a lower utilization rate than another, we don’t know whether this is efficiency or underuse, without further analytic work. It is fair to say that there is a lot to learn, and don’t underestimate how difficult it will be to bring practical learnings from the presence of regional variation.

It is different, however, with temporal variation. For

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example, when we look at Caesarean (C)-section rates, we see actual temporal variations, and we learn more from temporal variation than we do from regional variation. If C-section rates are highest on Fridays, when the weekend calls, that becomes a justification for policy action. That’s clearer than the observation that there are more percutaneous transluminal coronary angioplasty procedures being performed in Houston than in Boston, or vice versa. This is a more difficult pattern to act on. So although I am interested in regional variation, I’m skeptical that there are immediate learning points that could bring down the costs of healthcare in the short-term as a result of regional variation.

Henry: On a slightly different topic, elsewhere you discussed the recent move from a 4-tier formulary to a 5-tier design among prescription drug plans. Could you explain the implications of this move and what’s causing it?

Mendelson: What has happened over time in Medicare Part D is that the 4-tier design has emerged as a de facto standard. At the beginning of the program, a plan could profitably operate a 3-tier design.

However, that time is gone, because there was adverse selection into the 3-tier design, which forced most plans into a 4-tier design (Figure 1), or a 3-tier design with very high cost-sharing or prior authorization for specialty products on the third tier. That caused the 4tier design to emerge as standard. The 5-tier design is happening for 2 reasons (Figure 2). First, many plans are beginning to split the biologic tier into 2 tiers, with a preferred and a nonpreferred biologics tier. This is an interesting trend, because some of these categories are becoming competitive, such as the therapies used to treat multiple sclerosis (MS). And some plans are choosing a preferred and nonpreferred MS agent, and the 5-tier design enables that.

The second reason for the 5-tier design is that some plans are splitting generics into 2 tiers—preferred and nonpreferred generic products. The new administration is going to very carefully scrutinize the design, and the question I think they’ll raise is—Does a 4-tier or a 5-tier design discriminate against patients who have chronic illness? And we could make a case that asking a patient with MS to pay for 33% of the cost of whatever agent they choose is discriminatory against the patient with MS. This is the debate that is going to be playing out. And again, I am not saying what the correct answer is, but only that they will scrutinize benefit design relative to antidiscrimination concepts.

February/March 2009

VOL. 2

NO. 2

Healthcare Changes in the New Administration

Figure 1 Among PDPs Using 4-Tier Formularies, Tier 1 Holds the Highest Number of Drugs

833

617

164

2006: 35%

447

1038

2007: 74%

787

716

2008: 72%

2009: 58%

Percentage of PDPs offering 4 tiers Note: Annual decreases in the number of drugs covered by plans in 2009 may be attributed to the smaller universe of drugs in the Formulary Reference File.

PDPs indicates prescription drug plans.

Used with permission of Avalere Health analysis using DataFrame, a proprietary database of Medicare Part D plan features: 2009 data from November 2008; 2008 data from July 2007; 2007 data from May 2006; 2006 data from July 2006. Copyright Avalere Health, LLC.

Henry: On average, it costs about $1.3 billion to develop a new drug, and the developers are looking for a return on investment. At a certain point their interest in the beneficiary waxes or wanes. It is difficult to find the balance that will keep private enterprise investing in new products.

Mendelson: The pharmaceutical industry is going to need to rethink some of its development plans with respect to changes in the market. There will also need to be a very strong push from the pharmaceutical industry around issues of compliance and adherence to ensure that some of the pending price reductions are met with increases in volume of drugs taken. It is not a time for complacency with respect to pharmaceutical industry strategy. I do see that there is a very

10

19

157 462

559 527

955

5 tiers + 4 tiers 3 tiers

172

552 514

Tier 2 Tier 1

PDP by tier structure, %

Drugs in a tier, N (average)

193

Tier 4 Tier 3

Figure 2 The 4-Tier Formulary Remains Most Popular, but More PDPs Move to 5-Tier Design in 2009 2 tiers 1 tiers

15 27

35 74

72 58

37

8 2006 (N = 1429)

16

10

2007 (N = 1866)

2008 (N = 1824)

1

1 2

13 2 2009* (N = 1648)

Year (plans) *A

small number of plans are using 1-tier formularies in 2009. Most plans using 5-tier formularies in 2009 will add either a preferred generics tier or a second coinsurance tier.

PDPs indicates prescription drug plans.

Used with permission of Avalere Health analysis using DataFrame, a proprietary database of Medicare Part D plan features: 2009 data from November 2008; 2008 data from July 2007; 2007 data from May 2006; 2006 data from July 2006. Copyright Avalere Health, LLC.

strong demand for pharmaceutical products by the American consumer.

If anything, the pharmaceutical industry has weathered the present economic crisis really well, in terms of its share price as well as revenues; perhaps better than most other American industries, and this is a cause for optimism. So the pharmaceutical industry has to be thinking carefully about how these changes, both political and environmental, will affect it and if it can anticipate these changes appropriately, there is tremendous upside for new products to be developed and brought to the market. â&#x2013;

STAKEHOLDER PERSPECTIVE Health Policy in the New Administration The confluence of severe recession and a oneparty government has overcome the usual procedural barriers that typically shove health legislation into

the last few months of the year. On February 4, 2009, the State Childrenâ&#x20AC;&#x2122;s Health Insurance Program (SCHIP) was reauthorized, and eligibility was Continued next page

VOL. 2

NO. 2

www.AHDBonline.com

59

REGULATORY

Continued expanded to include children in families with income up to 300% of the federal poverty level, or $66,000 for a family of 4. The economic stimulus bill, signed into law on February 17, 2009, included a plethora of provisions to expand health information technology (HIT), fund comparative effectiveness research, subsidize health insurance for people who become unemployed, and bail out states by increasing Medicaid matching rates.

In less than a month since he was sworn in, President Obama and the largely Democratic Congress have committed to spend $227 billion over the next decade in the health sector. No wonder we have been spared the usual blather about “the first 100 days.” That would be a substantial sum for health policy in any other year. Could this early success lead to even more (and more expensive) health legislation later in the year? Or have the easy decisions already been made and future legislation will be slow to emerge from the political meat grinder?

Health reformers—at least those whose idea of reform consists of massive increases in government health programs—should not get their hopes up.

Senator Tom Daschle’s withdrawal from the Health and Human Services secretary’s job has dealt a blow to the administration’s plans that will be felt late this year, when the administration’s health legislation needs help getting through the Senate.

But even if Daschle had been able to take the lead on health reform, he would not have been able to sell a proposal costing hundreds of billions in the nearterm and imposing an obligation on future generations of tens of trillions of dollars. If a provision was not in the stimulus package, some way will have to be found to “pay” for it—through offsetting costs in other parts of the health budget or higher taxes. The president has stated the need for fiscal prudence, and that means adherence to budget limits that so far have been swept away by the hope that massive deficit spending will restart the economy.

It will not be easy to find savings to offset the cost of new reform proposals. When he was director of the Congressional Budget Office, Peter Orszag initiated a study of over 100 policy options, mostly to cut federal health spending. The conclusion is clear: there is no pain-free way to save money in healthcare. Incentives to adopt HIT? Instead of saving money, that will cost an additional $800 billion to $1 trillion over 10 years.

60

AMERICAN HEALTH & DRUG BENEFITS

Fund comparative effectiveness research? Another $800 billion. Pay for a medical home in Medicare?

Only about $5 billion in new spending but no savings over the next decade. Now that Orszag is President Obama’s budget director, he will have to live with those judgments.

Proposals for universal coverage are expensive— likely to exceed $200 billion annually before savings offsets are identified—and complex: key ingredients in political stalemate. It is far more likely that smaller initiatives will be advanced, targeting particularly vulnerable populations rather than offering insurance to everyone. Even that is uncertain this year, given the huge new subsidies that have already been enacted to cover kids, unemployed workers, and lowincome individuals.

In addition, the new administration will have to manage existing programs, despite the distractions of more exciting policy development. Medicare’s Sustainable Growth Rate calls for a 20% reduction in physician fees next year, and additional cuts as far as the eye can see. With the cost of a permanent “fix” now over $400 billion, count on Congress once again giving a 1-year reprieve. Medicare Advantage payment rates will again come under scrutiny, but cuts in those rates come at the risk of disrupting millions of seniors enrolled in such plans. Sharp increases in Medicare Part D premiums for 2009, coupled with ongoing concern about the cost of pharmaceuticals, are likely to trigger a renewed call for direct government price negotiation and tougher benefit standards for the plans. Medicaid drug rebates may be applied to drugs sold under Part D to low-income enrollees. The administration will push hard to expedite approval of biosimilars, and the shift at the US Food and Drug Administration toward greater evidence on the safety of new drugs in the approval process is likely to persist.

President Obama’s first year in office is like a meal eaten in reverse order. We started with dessert, in the form of new subsidies for insurance. Whether we like it or not, we will have to eat our vegetables before the year is out.

February/March 2009

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

VOL. 2

NO. 2

For high-risk patients* with mixed dyslipidemia...

Introducing NEW TRILIPIX The FIRST and ONLY Fibrate With an FDA-Approved Indication for Use With Statins:

Proceed With Confidence

Go beyond the statin quo

*High-risk Hig patients are those with CHD or CHD risk equivalent.

CH

Indications: Indications s: TRILIPIX is indicated as an adjun adjunct nct to diett in combination with a st statin atin to reduce TG and increase HDL-C in patients with mixed dyslipidemia an and d CHD or a CHD riskk equiv eequivalent alent who are on optimal statin statin therapy to achieve their LDL-C goal. gooal.

Limitation n of Use: No incremental benefit of o TRILIPIX on cardiovascular morb morbidity bidity and morta mortality alityy over and above that demonst demonstrated trated for statin monothera monotherapy pyy hass been established. establishe ed. elevations creatinine have & Reversible elev ations in serum cr eatiinine ha ave v been rreported eported in patients rreceiving eceiving TRILIPIX T X as monotherapy co-administered with monother apy or co-administer ed wit th statins, as well as in patients rreceiving eceiving fenofi fenofibrate. fibrate. monitored Renal function should be monitor ed in i patients with or at risk for rrenal enal insufficienc insufficiency. cy.

& Pancr Pancreatitis, eatitis, hhypersensitivity ypersenssitivity rreactions, eactions, hematological cchanges, hangess, and venothromboembolic & TRILIPIXX iiss contr contraindicated aindicated in patients with events ha have ave v been rreported eported with the use of severee renal impairment; sever renal e impair ment; active liver disease fibrates. fibr ates. or une unexplained xplained persistent liver function Co-administration & Co-administr ation withh the maximum dose off a abnormalities; preexisting abnor mallities; pr eexisting gallbladder disease; statin has not been ev evaluated a aluated in clinical studies in nursingg mothers; or in patients with aree and should be aavoided voided v unless the benefits ar daily & TRILIPIX at a dose off 135 mg once da aily hhypersensitivity ypersensitivityy to fenofibric acid, ccholine holine eexpected xpected to outweigh the t risks. administer administered ed as monother monotherapy apy or co-a co-administered administered fenofibr fenofibrate atte or fenofibr fenofibrate. ate. withh incr increases with statins has been associated wit eases & The most commonly rreported e eported adverse events & Fibrate aand nd statin monotherapy increase the in serum tr transaminases. ansaminases. Regular live liver er function ((≥4% ≥4% off patients rreceiving eceivving TRILIPIXX or TRILIPIX myositis myopathy, risk off my yositis orr myopathy y, and have been performed monitoring should be perfor med for the t co-administer co-administered ed with a statin) wer weree ddyspepsia, yspepsia, associate associated ed with rhabdomyolysis.. Data from dur duration ation off ther therapy apy with TRILIPIX, andd ther therapy apy nasopharyngitis, tract nausea, nasophar yngittis, upper rrespiratory espiratory tr act observational obser vatiional studies suggestt that the risk for above discontinued iff enzyme levels persistt abo ve infection, arthr arthralgia, algia, ba back ack pain, pain in eextremity, xtremityy, rhabdom rhabdomyolysis myolysis is increased when fibrates 3 times the upper limit off nor normal. mal. headache. dizziness, and headac h . The mostt common he co-administered are co-ad dministered with a statin. The riskk for adverse rreactions eactions rreported epoorted bbyy ≥ ≥3% 3% off patients holelithiasis. serious musc m muscle le toxicity appears to be increased & TRILIPIX mayy lead to ccholelithiasis. treated fenofibrate tr eated with fenofibr atee and ggreater reater than placebo Iff ccholelithiasis holelithiasis is confir confirmed, med, TRILIPIXX should in elderlyy patients and in patients with diabetes, wer weree abdominal pain, bac bbackk pain, headac headache, he, be discontinued. renal failure, failuure,, orr hypothyroidism. abnormal increased abnor mal liver functionn tests, incr eased CPK, & Myopath Myopathyy should be consider considered ed in patients & TRILIPIX mayy potentiate the effects of of or oral al and rrespiratory espiratory disor disorder. deerr. muscle tenderness, with mus scle pain, tender ness, or weakness. adjustment coumarin anticoagulants. Dosage adj justment Iff mark markedly eddly elev elevated ated CPKK levels occur or based on fr frequent equent prothrombin time/ time/INR /INR myopathy/myositis myopath y y/myositis is diagnosed, TRILIPIXX and determinations deter minations is rrecommended. ecommended. statin the therapy erapy should be discontinued.

Important Importan nt Safetyy Information

Please see s adjacent page for brieff su summary ummaryy of full Pr Prescribing escribing IInformation. n nformation.

TRILIPIX is a trademark of Abbott Laboratories.

©2008 Abbott Abb bott Laboratories Abbott Park, IL 60064 600 064 032-184615 032-18461 5 Decemberr 2008 Printed in U.S.A.

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

WARNINGS AND PRECAUTIONS Skeletal Muscle Fibrate and statin monotherapy increase the risk of myositis or myopathy, and have been associated with rhabdomyolysis. Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates are co-administered with a statin. Refer to the respective statin labeling for important drug-drug interactions that increase statin levels and could increase this risk.

The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal failure, or hypothyroidism.

Myalgia was reported in 3.3% of patients treated with Trilipix monotherapy and 3.1% to 3.5% of patients treated with Trilipix co-administered with statins compared to 4.7% to 6.1% of patients treated with statin monotherapy. Increases in creatine phosphokinase (CPK) to > 5 times upper limit of normal occurred in no patients treated with Trilipix monotherapy and 0.2% to 1.2% of patients treated with Trilipix co-administered with statins compared to 0.4% to 1.3% of patients treated with statin monotherapy.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of CPK levels. Patients should promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

CPK levels should be assessed in patients reporting these symptoms, and Trilipix and statin therapy should be discontinued if markedly elevated CPK levels occur or myopathy or myositis is diagnosed.

TM

Trilipix

(fenofibric acid) delayed release capsules INDICATIONS AND USAGE Co-administration Therapy with Statins for the Treatment of Mixed Dyslipidemia Trilipix is indicated as an adjunct to diet in combination with a statin to reduce TG and increase HDL-C in patients with mixed dyslipidemia and CHD or a CHD risk equivalent who are on optimal statin therapy to achieve their LDL-C goal.

CHD risk equivalents comprise: • Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease); • Diabetes; • Multiple risk factors that confer a 10-year risk for CHD > 20%

Treatment of Severe Hypertriglyceridemia Trilipix is indicated as adjunctive therapy to diet to reduce TG in patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacological intervention. Markedly elevated levels of serum triglycerides (e.g. > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of Trilipix therapy on reducing this risk has not been adequately studied.

Serum Creatinine Reversible elevations in serum creatinine have been reported in patients receiving Trilipix as monotherapy or co-administered with statins as well as patients receiving fenofibrate. In the pooled analysis of three double-blind controlled studies of Trilipix administered as monotherapy or in combination with statins, increases in creatinine to > 2 mg/dL occurred in 0.8% of patients treated with Trilipix monotherapy and 1.1% to 1.3% of patients treated with Trilipix co-administered with statins compared to 0% to 0.4% of patients treated with statin monotherapy.

Elevations in serum creatinine were generally stable over time with no evidence for continued increases in serum creatinine with long-term therapy and tended to return to baseline following discontinuation of treatment. The clinical significance of these observations is unknown.

Monitoring renal function in patients with renal impairment taking Trilipix is suggested. Renal monitoring should be considered for patients at risk for renal insufficiency, such as the elderly and those with diabetes.

Treatment of Primary Hyperlipidemia or Mixed Dyslipidemia Trilipix is indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, TG, and Apo B, and to increase HDL-C in patients with primary hyperlipidemia or mixed dyslipidemia.

Important Limitations of Use No incremental benefit of Trilipix on cardiovascular morbidity and mortality over and above that demonstrated for statin monotherapy has been established.

General Considerations for Treatment Fenofibrate at a dose equivalent to 135 mg of Trilipix was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus.

Laboratory studies should be performed to establish that lipid levels are abnormal before instituting Trilipix therapy.

Every reasonable attempt should be made to control serum lipids with non-drug methods including appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that may be contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible, and excessive alcohol intake should be addressed before triglyceride-lowering drug therapy is considered. If the decision is made to use lipid-altering drugs, the patient should be instructed that this does not reduce the importance of adhering to diet.

Drug therapy is not indicated for patients who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of VLDL.

Liver Function Trilipix at a dose of 135 mg once daily administered as monotherapy or co-administered with low to moderate doses of statins has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In a pooled analysis of three double-blind controlled studies of Trilipix administered as monotherapy or in combination with statins, increases to > 3 times the upper limit of normal on two consecutive occasions in ALT and AST occurred in 1.9% and 0.2%, respectively, of patients receiving Trilipix monotherapy and in 1.3% and 0.4%, respectively, of patients receiving Trilipix co-administered with statins.

Increases to > 3 times the upper limit of normal in ALT and AST occurred in no patients receiving low- to moderate-dose statin monotherapy. Increases to > 3 times the upper limit of normal in ALT and AST occurred in 0.8% and 0.4%, respectively in patients receiving high-dose statin monotherapy. In a long-term study of Trilipix co-administered with statins for up to 52 weeks, increases of > 3 times the upper limit of normal on two consecutive occasions of ALT and AST occurred in 1.2% and 0.5% of patients, respectively. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. Increases in ALT and/or AST were not accompanied by increases in bilirubin or clinically significant increases in alkaline phosphatase.

In a pooled analysis of 10 placebo-controlled trials of fenofibrate, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. The incidence of increases in transaminases observed with fenofibrate therapy may be dose related. In an 8-week dose-ranging

CONTRAINDICATIONS Trilipix is contraindicated in: • patients with severe renal impairment, including those receiving dialysis.

• patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities.

• patients with preexisting gallbladder disease.

• nursing mothers.

• patients with hypersensitivity to fenofibric acid, choline fenofibrate or fenofibrate [see WARNINGS and PRECAUTIONS].

When Trilipix is co-administered with a statin, refer to the Contraindications section of the respective statin labeling.

1

study of fenofibrate in hypertriglyceridemia, the incidence of ALT or AST elevations â&#x2030;Ľ 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 90 mg to 135 mg Trilipix once daily and was 0% in those receiving dosages equivalent to 45 mg Trilipix once daily or less, or placebo. Hepatocellular, chronic active, and cholestatic hepatitis observed with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

Regular monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with Trilipix, and therapy discontinued if enzyme levels persist above 3 times the upper limit of normal.

There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p = < 0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (N = 4081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p = 0.19, 95% confidence interval for relative risk G:P = 0.91-1.64).

Although cancer deaths trended higher in the gemfibrozil group (p = 0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from WHO study (RR = 1.29). A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).

Cholelithiasis Trilipix, like fenofibrate, clofibrate, and gemfibrozil, may increase cholesterol excretion into the bile, potentially leading to cholelithiasis.

If cholelithiasis is suspected, gallbladder studies are indicated. Trilipix therapy should be discontinued if gallstones are found.

Concomitant Oral Anticoagulants Caution should be exercised when Trilipix is given in conjunction with oral coumarin anticoagulants. Trilipix may potentiate the anticoagulant effects of these agents resulting in prolongation of the prothrombin time/INR. Frequent monitoring of prothrombin time/INR and dose adjustment of the oral anticoagulant are recommended until the prothrombin time/INR has stabilized in order to prevent bleeding complications.

Venothromboembolic Disease In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal PE or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01).

Pancreatitis Pancreatitis has been reported in patients taking drugs of the fibrate class, including Trilipix. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

Hypersensitivity Reactions Acute hypersensitivity reactions including severe skin rashes requiring patient hospitalization and treatment with steroids have occurred very rarely during treatment with fenofibrate, including rare spontaneous reports of Stevens-Johnson Syndrome and toxic epidermal necrolysis.

ADVERSE REACTIONS Clinical Studies Experience

Hematological Changes

Because clinical studies are conducted under widely varying conditions, adverse event rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug.

Trilipix (fenofibric acid) Monotherapy Treatment-emergent adverse events reported in 3% or more of patients treated with Trilipix during the randomized controlled trials are listed in Table 1 below.

Co-Administration Therapy with Statins (Double-blind Controlled Trials) Treatment-emergent adverse events reported in 3% or more of patients treated with Trilipix co-administered with statins during the randomized controlled trials are listed in Table 1 below.

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of Trilipix and fenofibrate therapy. Extremely rare spontaneous reports of thrombocytopenia and agranulocytosis have been received with fenofibrate therapy.

Mortality and Coronary Heart Disease Morbidity The effect of Trilipix on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established. Because of similarities between Trilipix and fenofibrate, clofibrate, and gemfibrozil, the findings in the following large randomized, placebo-controlled clinical studies with these fibrate drugs may also apply to Trilipix.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate.

Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p = 0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p = 0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p = 0.18) and 19% (HR 1.19 [0.90, 1.57], p = 0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.

In the Coronary Drug Project, a large study of post-myocardial infarction patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was, however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).

In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year.

2

Table 1. Treatment-Emergent Adverse Events Reported in â&#x2030;Ľ 3% of Patients Receiving Trilipix or Trilipix Co-Administered with a Statin During Double-Blind Controlled Studies [Number (%)] Adverse Event

Gastrointestinal Disorders Constipation Diarrhea Dyspepsia Nausea General Disorders and Administration Site Conditions Fatigue Pain Infections and Infestations Nasopharyngitis Sinusitis Upper Respiratory Tract Infection Investigations ALT Increased Musculoskeletal and Connective Tissue Disorders Arthralgia Back Pain Muscle Spasms Myalgia Pain in Extremity Nervous System Disorders Dizziness Headache

Vascular Disorders Hypertension.

Fenofibrate Fenofibric acid is the active metabolite of fenofibrate. Adverse events reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials are listed in Table 2. Adverse events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo.

Increases in liver tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.

Trilipix Low-Dose Trilipix + Moderate- Trilipix + High-Dose (N = 490) Statin Low-Dose Dose Statin ModerateStatin (N = 493) Statin (N = 491) Dose Statin (N = 245) (N = 490) (N = 489)

16 (3.3) 19 (3.9) 18 (3.7) 21 (4.3)

11 (2.2) 16 (3.2) 13 (2.6) 18 (3.7)

16 (3.3) 15 (3.1) 13 (2.7) 17 (3.5)

13 (2.6) 24 (4.9) 17 (3.5) 22 (4.5)

15 (3.1) 18 (3.7) 23 (4.7) 27 (5.5)

6 (2.4) 17 (6.9) 6 (2.4) 10 (4.1)

10 (2.0) 13 (2.6) 13 (2.7) 17 (3.5) 9 (1.8) 16 (3.3)

13 (2.6) 8 (1.6)

16 (3.3) 7 (1.4)

5 (2.0) 8 (3.3)

17 (3.5) 29 (5.9) 23 (4.7) 16 (3.3) 4 (0.8) 14 (2.9)

16 (3.3) 8 (1.6)

21 (4.3) 17 (3.5)

9 (3.7) 4 (1.6)

26 (5.3) 13 (2.6) 18 (3.7)

23 (4.7)

23 (4.7)

7 (2.9)

6 (1.2)

2 (0.4)

15 (3.1)

2 (0.4)

12 (2.5)

4 (1.6)

19 (3.9) 31 (6.3) 8 (1.6) 16 (3.3) 22 (4.5)

22 (4.5) 31 (6.3) 18 (3.7) 24 (4.9) 24 (4.9)

21 (4.3) 30 (6.1) 12 (2.4) 17 (3.5) 14 (2.9)

21 (4.3) 32 (6.5) 24 (4.9) 23 (4.7) 21 (4.3)

17 (3.5) 20 (4.1) 15 (3.1) 15 (3.1) 13 (2.7)

12 (4.9) 8 (3.3) 6 (2.4) 15 (6.1) 9 (3.7)

Table 2. Adverse Events Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials BODY SYSTEM Adverse Event BODY AS A WHOLE Abdominal Pain Back Pain Headache DIGESTIVE Nausea Constipation INVESTIGATIONS Abnormal Liver Tests Increased AST Increased ALT Increased Creatine Phosphokinase RESPIRATORY Respiratory Disorder Rhinitis

Fenofibrate* (N = 439)

Placebo (N = 365)

4.6% 3.4% 3.2%

4.4% 2.5% 2.7%

2.3% 2.1%

1.9% 1.4%

7.5% 3.4% 3.0% 3.0%

1.4% 0.5% 1.6% 1.4%

6.2% 2.3%

5.5% 1.1%

* Dosage equivalent to 135 mg Trilipix The following adverse events have been identified during postapproval use of fenofibrate: myalgia, rhabdomyolysis, increased creatinine phosphokinase, pancreatitis, increased alanine aminotransaminase, increased aspartate aminotransaminase, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, nausea, abdominal pain, anemia, headache, arthralgia, and asthenia. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure.

20 (4.1) 8 (1.6) 19 (3.9) 11 (2.2) 16 (3.3) 2 (0.8) 62 (12.7) 64 (13.0) 64 (13.1) 82 (16.7) 58 (11.9) 32 (13.1)

Low-dose statin = rosuvastatin 10 mg, simvastatin 20 mg, or atorvastatin 20 mg Moderate-dose statin = rosuvastatin 20 mg, simvastatin 40 mg, or atorvastatin 40 mg High-dose statin = rosuvastatin 40 mg, simvastatin 80 mg, or atorvastatin 80 mg Co-Administration Therapy with Statins (Long-Term Exposure for up to 64 Weeks) Patients successfully completing any one of the three double-blind, controlled studies were eligible to participate in a 52-week long-term extension study where they received Trilipix co-administered with the moderate dose statin. A total of 2201 patients received at least one dose of Trilipix co-administered with a statin in the double-blind controlled study or the long-term extension study for up to a total of 64 weeks of treatment. Additional treatment-emergent adverse events (not listed in Table 1 above) reported in 3% or more of patients receiving Trilipix co-administered with a statin in either the double-blind controlled studies or the long-term extension study are provided below.

Infections and Infestations Bronchitis, influenza, and urinary tract infection.

Investigations AST increased, blood CPK increased, and hepatic enzyme increased.

Musculoskeletal and Connective Tissue Disorders Musculoskeletal pain.

Psychiatric Disorders Insomnia.

Respiratory, Thoracic, and Mediastinal Disorders Cough and pharyngolaryngeal pain.

DRUG INTERACTIONS Oral Anticoagulants Caution should be exercised when oral coumarin anticoagulants are given in conjunction with Trilipix [see WARNINGS AND PRECAUTIONS].

Bile Acid Resins Since bile acid resins may bind other drugs given concurrently, patients should take Trilipix at least 1 hour before or 4-6 hours after a bile acid resin to avoid impeding its absorption.

Cyclosporine Because cyclosporine can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of drugs of the fibrate class including Trilipix, there is a risk that an interaction will lead to decline of renal function. The benefits and risks of using Trilipix with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category: C The safety of Trilipix in pregnant women has not been established.

There are no adequate and well controlled studies of Trilipix in pregnant women. Trilipix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

3

in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males.

A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes and testicular interstitial cell tumors in males at 2 times the MRHD. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females.

Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.

In an 80-week study in mice, fenofibrate 10, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 93-week study at 10, 60, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male and female mice at 3 times the MRHD. Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.

Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, and micronucleus in vivo/rat. In addition, fenofibric acid, has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and sister chromatid exchange in human lymphocytes, and unscheduled DNA synthesis in primary rat hepatocytes.

In a fertility study, rats were given oral dietary doses of fenofibrate.

Males received doses for 61 days prior to mating and females for 15 days prior to mating through weaning, which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2 surface area comparisons).

When Trilipix is administered with a statin in a woman of childbearing potential, refer to pregnancy category and product labeling for the statin [see Precautions, Pregnancy]. All statins are contraindicated in pregnant women.

In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the maximum recommended human dose [MRHD], based on body surface area comparisons; mg/m2). At higher multiples of human doses evidence of maternal toxicity was observed.

In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons; mg/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2).

In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m2.

Nursing Mothers Trilipix should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug.

Pediatric Use The safety and effectiveness of Trilipix monotherapy or co-administration with a statin in pediatric patients have not been established.

Geriatric Use Trilipix is substantially excreted by the kidney as fenofibric acid and fenofibric acid glucuronide, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Since elderly patients have a higher incidence of renal impairment, the dose selection for the elderly should be made on the basis of renal function. Consider monitoring renal function in elderly patients taking Trilipix.

Renal Impairment The use of Trilipix should be avoided in patients who have severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment. Monitoring renal function in patients with renal impairment is recommended.

PATIENT COUNSELING INFORMATION Patient Counseling Patients should be advised: • of the potential benefits and risks of Trilipix.

• to read the Medication Guide before starting Trilipix therapy and to reread it each time the prescription is renewed.

• of medications that should not be taken in combination with Trilipix.

• to continue to follow an appropriate lipid-modifying diet while taking Trilipix.

• to take Trilipix once daily, without regard to food, at the prescribed dose, swallowing each capsule whole. If Trilipix is co-administered with a statin, they may be taken together.

• to return for routine monitoring.

• to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking Trilipix.

• to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. ©Abbott Manufactured for Abbott Laboratories, North Chicago, IL 60064, U.S.A. by Fournier Laboratories Ireland Limited, Anngrove, Carrigtwohill Co. Cork, Ireland, or Abbott Pharmaceutical PR Ltd., Barceloneta, PR 00617.

Revised: December, 2008 Ref.: 03-A192 032-191711 MASTER

Hepatic Impairment The use of Trilipix has not been evaluated in subjects with hepatic impairment [see CONTRAINDICATIONS].

OVERDOSAGE There is no specific treatment for overdose with Trilipix. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because Trilipix is highly bound to plasma proteins, hemodialysis should not be considered.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Trilipix (fenofibric acid) No carcinogenicity and fertility studies have been conducted with choline fenofibrate or fenofibric acid. However, because fenofibrate is rapidly converted to its active metabolite, fenofibric acid, either during or immediately following absorption both in animals and humans, studies conducted with fenofibrate are relevant for the assessment of the toxicity profile of fenofibric acid. A similar toxicity spectrum is expected after treatment with either Trilipix or fenofibrate.

Fenofibrate Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, rats were dosed with fenofibrate at 10, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (6 times the MRHD), the incidence of liver carcinomas was significantly increased

032-184615 4

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FDA WATCH

Prominent Cardiologist Hammers the FDA: Insufficient Funding Compromises the Science of Drug Approvals

By Wayne Kuznar

A

t a January 2009 Speaker Series sponsored by Cleveland State University, Steven Nissen, MD, Chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, said that inadequate funding and an approval system that encourages the development of noninnovative drugs has contributed to a US Food and Drug Administration (FDA) that is ineffective at ensuring the safety of drugs. It has also led to an environment that has resulted in a shortage of drugs to meet the medical needs of consumers. According to Dr Nissen, the FDA’s budget, currently at $2.2 billion annually, needs to double for proper staffing and for thorough reviews of drugs, in addition to ensuring the safety of the food supply. By comparison, the Centers for Disease Control and Prevention’s budget is 4-fold bigger.

A larger FDA budget would pave the way for more inspectors, enhanced testing of generics, and potentially more independence of the agency overall.

To partially make up for that, the FDA must rely on user fees from the pharmaceutical industry in exchange for expedited review of certain new drug applications.

“User fees make the industry the client, not the American public,” said Dr Nissen.

Too Many “Me Too” Drugs The plethora of noninnovative products, known as “me too” drugs that are only slight variations of existing drugs, can be partially attributed to the FDA’s willingness to approve these molecules based on noninferiority studies, he says. These studies are designed to show that the new version of an existing drug is not more than 50% worse than the existing drug. Once approved, these products are heavily promoted directly to the consumer, creating demand for their use, while diminishing the market for generic drugs that often work just as well.

“Where are the drugs we need to treat Alzheimer’s disease or antibiotic-resistant bacterial infections?” he asks.

“If the enormous biomedical enterprise is focused on ‘me too’ products…our real medical problems go unsolved.”

To promote the development of new molecular entities to treat unmet medical needs, the FDA should use a

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sliding scale of evidence for approval, Dr Nissen emphasizes. Noninferiority trials should not be used as the basis for approval for a new entry into a category of drugs that has existed for decades, such as sleep-promoting medicines, in which case the new entry would have to be proved better or safer than the old choices. Rather, the FDA should consider less robust evidence for drug approvals for difficult-to-treat cancers, which would force pharmaceutical manufacturers to divert research money to innovative products.

Safety Concerns The FDA has lost its way ethically, Dr Nissen believes.

“The current FDA policy is a consequence of a misguided philosophy that views clinical trials as proprietary; this approach is morally and ethically indefensible.”

Much of what the FDA knows about drugs is never revealed publicly, he says. “This atmosphere of secrecy is antithetical to good science and good government,” he said. The problem of FDA secrecy is exacerbated by “publication bias,” the common practice of suppressing and never publishing drug studies with unfavorable results, Dr Nissen claims.

Drug safety is compromised through 2 other phenomena that lack sufficient oversight: off-label marketing of drugs and the voluntary Adverse Event Reporting System (AERS). Current estimates are that 35% of pharmaceutical sales represent off-label prescribing. The risk for unexpected harm rises exponentially when drugs are prescribed for indications for which they have not been approved, said Dr Nissen. The outgoing Bush administration relaxed rules on promoting drugs for offlabel uses just before its term expired.

The concern is that AERS is an insufficient tool to detect serious side effects. Because this reporting system is voluntary, “only 1% to 10% of adverse events are ever reported to the FDA,” Dr Nissen said. “Accordingly, serious drug safety problems go unrecognized for many years,” as in the case of serious muscle toxicity with cerivastatin that prompted its eventual removal from the market.

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The budget shortfall at the FDA has also compromised the safety and possible efficacy of imported generic drugs, as evidenced by many recalls of generics made in India. “The FDA needs to be constantly testing the

generics, verifying that they are containing the amounts of the drug that they are supposed to, and they work as advertised,” he said. “It takes more resources and more vigilance on the part of the FDA.”

COMMENTARY

Funding for the FDA Nirav R. Shah, MD, MPH, Assistant Professor of Medicine, New York University, New York City, and Senior Investigator, Center for Health Research, Geisinger Health System, Danville, PA

D

r Steven Nissen has an ax to grind with the FDA. Although the general principles he espouses are correct, such as the need for greater transparency and for improvements in the evidence base underlying FDA decisions, not all his arguments make sense in today’s environment.

For example, Dr Nissen points to the reliance on user fees from the pharmaceutical industry as the reason for the FDA being “captured” by Pharma. User fees in and of themselves do not lead to being “captured”; how the money is spent, and transparency (or lack thereof) in reporting the flow of funds, may lead to such a state.

What is required is smarter regulation to dictate how user fees are incurred and subsequently spent, rather than simply looking for alternative (perhaps nonexistent) sources of funding.

Dr Nissen suggests that the FDA should use a sliding scale of evidence for approval to promote the development of new molecular entities to treat unmet medical needs. The FDA’s primary mission, however, is to protect public health by ensuring the safety, efficacy, and security of drugs, biologics, devices, and the food supply.

Although facilitating innovation is certainly a priority, evidence standards cannot be relaxed for generics relative to “me too” drugs.

The evidence required for FDA decision-making should more closely match the specific needs in each case. For example, instead of focusing on noninferiority studies for a new entry in a category of drugs that has existed for decades, a careful review of the gaps in the evidence base should be conducted and studies in populations not initially studied may be required for FDA approval.

For orphan conditions or difficult-to-treat cancers, innovation cannot be achieved by using a less robust evidence base. Rather, stakeholder-focused means to promote innovation, such as longer periods of exclusiv-

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ity or other rewards, should be used as the carrot to drive innovation.

It is true that the FDA has relied on clinical trials at the expense of other types of evidence; however, it is only recently that observational studies, registries, and associated analytic techniques have matured. The use of postmarketing surveillance registries and phase 4 studies should be encouraged. To date, only a small fraction of such studies have been completed.

As for publication bias, this problem has been solved.

All trials (including phase 1) have to be registered at ClinicalTrials.gov as per Section 113 of the FDA Modernization Act for investigational new drug regulations, and the International Committee of Medical Journal Editors now requires trial registration as a condition for publication of clinical trial results. Many sponsors, reviewers, ethics boards, and other groups also require registration before the enrollment of the first participant. Therefore, going forward, publication bias of trials will not be an issue, at least in the United States.

Dr Nissen is correct about the problems of off-label marketing of drugs and the voluntary AERS. But it is important to note the distinction between off-label marketing and off-label use. Off-label use can drive innovation, as it did with selective serotonin reuptake inhibitors for premenstrual syndrome. Although the current system for reporting adverse events is broken, it likely cannot be fixed. New ways of mining data from electronic health records hold much promise for replacing the system wholesale, with a thorough and more complete approach to reporting and surveillance.

As evidenced by the recent fiasco in peanut factories, the safety of our food and drug supply, often taken for granted, cannot be ignored. Broad calls for more resources and more vigilance on the part of the FDA focus attention away from the real issue: smarter—not just more—regulation is needed.

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FDA WATCH

COMMENTARY

Innovation in Drug Development F. Randy Vogenberg, RPh, PhD, Chief Strategy Officer, Employer-Based Pharmaceutical Strategies, and Senior Scholar, Department of Health Policy, Thomas Jefferson University, Jefferson Medical School, Philadelphia, PA

I

nnovation in drug development has never been easy or uncomplicated in the United States, nor has the relationship between Congress and the FDA. Going from savior to scapegoat in less than 75 years, the FDA continues to be caught between societal priorities, all of which have potent advocates for their point of view. Dr Nissen, a frequent FDA critic, continues to offer his mixed messages on this federal agency (as well as advocating for some drugs that others have argued are high-risk “me too” agents).

Although it is easy to point to the failings and problems of any government agency, offering solutions to improve programs or systems that can at least incrementally move us forward in patient care safety and outcomes of care would seem more worthwhile. The presidential election and current recession have put a momentary pause on the engine of healthcare innovation, but offer all of us an opportunity to rethink drug development.

Biologic product research, along with nanotechnology and molecular medicine, will be changing healthcare delivery and finance. During the transition to this brave new world of products, we must not forget the traditional drugs and generic products that are available today.

Finding the right balance between yesterday and tomorrow is the dilemma facing all industries, along with the agencies that regulate them.

For health plan sponsors, what is important remains the same as in previous years—a value proposition for healthcare products or services that meet the needs of patient populations in an affordable system reflective of our capitalist societal goals. Aligning new drug development, innovation, and regulation to that purpose is a good starting point to bring all parties together toward a meaningful, positive direction for US healthcare—refocusing on 21st-century drug product innovation.

CAPTION CONTEST Submit your caption at www.AHDBonline.com Winners Receive $50 Submission deadline: March 16, 2009 Winners’ names posted: March 18, 2009

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Patient Cost-Sharing on the Rise: Results from the Benefit Design Index Melinda C. Haren, RN; Kirk McConnell Objective: The relationship between healthcare insurers and employers plays a critical role today in decisions about benefit design, cost-sharing, and even the coverage of individual products and services. To better understand how these 2 stakeholders interact in the creation of healthcare benefit design, the Zitter Group conducted a large national study of insurer– employer relationship.

Methods: This study is based on a primary web-based survey with 100 top decision makers in large national and important regional commercial managed care plans, and a similar survey of 100 employers and employer benefit consultants, including medical directors and benefit decision makers. This article reviews the results of this research, especially in relation to insurMelinda C. Haren er and employer opinions on patient cost-sharing.

Results: Findings from this study show that cost-shifting remains the prevailing cost-containment strategy used by insurers and employers. These stakeholders expect that additional cost-shifting will have minimal impact on patient health outcomes.

Conclusion: Despite accumulating evidence that cost-shifting leads to undesirable health and cost consequences and has largely failed to slow health cost growth, employers and insurers will likely continue to rely on this modality as their primary cost-containment strategy. [AHDB. 2009;2(2):70-77]

T

he cost of employee health coverage continues to grow faster than inflation,1 putting additional economic pressure on employers and raising critical questions about how best to provide health benefits while ensuring optimal employee health and productivity. As a result, employers have grown increasingly important in benefit design decisions—decisions that ultimately determine beneficiaries’ access to medical products and services. At the same time, employers have remained hesitant to pass too many costs to employees, fearing that high out-of-pocket costs will translate into reduced adherence and, ultimately, deteriorating employee health and productivity.

Despite slowing significantly since 2003, premium growth still outpaces inflation and growth in workers’ earnings, placing significant strain on employers and on insurers to contain costs while maintaining quality.1 The consequences of this steady growth in premiums have been predictable: the number of employers offering health benefits is steadily declining. According to a 2007 survey from the Kaiser Family Foundation, 3% of companies reported that they would drop health cover-

Ms Haren is Director of Business Content, and Mr McConnell is Senior Analyst, the Zitter Group, Millburn, NJ.

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age for their employees and another 5% said they would limit coverage within the next year.2 Health plan financial performance has also deteriorated, reflecting the so-called soft phase of the underwriting cycle, adverse selection, and slow enrollment growth.3,4 Today, the relationship between insurers and employers plays a critical role in decisions about benefit design, cost-sharing, and even the coverage of individual products and services. Most benefit design and cost-containment strategies have had limited, if any, impact on hospital costs, which remain the single largest component of overall healthcare costs.1 This present research was conducted to understand the evolving market for health benefits, the respective roles of insurers and employers in benefit design decisions, and the implications for patient access to care.

Key questions included: • Which external and internal factors influence employers’ decisions on benefit design? How do they differ from those that affect insurers’ decisions?

• How will changes in benefit design affect overall prescription drug utilization and category-specific product utilization?

• What are the successes and barriers to adoption of “innovative” benefit designs?

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In addition, the study sought to track and understand key market events, such as changes in employersponsored healthcare benefits and patient out-of-pocket costs, management trends for certain therapeutic categories and products, and developments in benefit design implementation.

Methodology In the spring of 2008, the Zitter Group conducted a large national study of the insurerâ&#x20AC;&#x201C;employer relationship to understand how these 2 stakeholders interact in the creation of healthcare benefit design. The 2-arm study consisted of concurrent web-based quantitative surveys with commercial managed care executives, large employers, and major employer benefits consultants, designed to provide a richly detailed snapshot of trends in employer-sponsored healthcare coverage.

Each survey had approximately 80 questions and required 1 hour to complete. Respondents received an honorarium for their participation.

The managed care arm included 102 commercial managed care decision makers from large national and important regional and independent plans. The employer arm included 96 large employers from a variety of industries across the United States and 11 major employee benefits consultants. The Table lists expanded sample demographics.

Participants in both groups reported their healthcare management priorities, perceptions of benefit designs and strategies, and involvement in benefit design decision-making and category/product management. Both groups predominantly answered the same questions to compare responses between groups. Where applicable, data were segmented by industry and company/plan size to provide greater insight.

Results Despite having varying ideas on specific healthcare benefit design strategies, employers and insurers assign similar weights to the importance of cost, quality, and access when making benefit design decisions. For both groups, the importance assigned to cost is 1.5 times higher in value than healthcare access or healthcare quality (Figure 1). Throughout the survey both groups cited access and quality concerns, but in the current environment of steadily rising cost growth, the importance assigned to cost takes on greater overall significance.

According to the survey results, 64.7% of insurers and 49.5% of employers do not expect slower premium growth rates to be sustainable and, in fact, more than

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KEY POINTS

The cost of employee health coverage continues to grow, raising questions for employers about how best to provide health benefits to employees.

The relationship between health insurers and employers plays a critical role in decisions about health-related benefit design and cost-sharing.

This studyâ&#x20AC;&#x2122;s findings show that despite significant differences in benefit design strategies between employers and insurers, both stakeholder groups assign greater importance to cost than to the access to or the quality of healthcare.

More than 50% of employers and 75% of insurers report having increased premiums and deductibles over the past 12 months. Both groups appear to default to various forms of cost-sharing to curb rising healthcare costs.

The survey also reveals important differences about the point at which cost-shifting will trigger undesirable consequences for the insurance pool.

In the absence of a strategy widely embraced by insurers and employers, no dramatic changes in benefit design appear likely.

Table Sample Demographics Employers

Employee Benefit Consultants

Title, n Human resources benefit managers: 42 Chief financial officers: 14 VP, human resources: 16 Directors, health benefits: 9 Medical directors: 10 Other (ie, executive/clinical): 2

Covered lives, n Average: 21,622 Total: 237,845

Insurance agreement, n Completely self-funded: 25 Self-funded w/ 3rd-party benefits administrator: 38 Self-funded w/ stop-loss coverage: 22 Insured by commercial insurance company: 11 Covered lives, n Average: 11,619 Total: 115,480

Managed Care Representatives Title, n Pharmacy directors: 54 Chief medical officers/Medical directors: 48 Organization type, % Independent plan: 43.1 Blue affiliate: 21.6 Large national plan: 19.6 Regional affiliate of larger national plan: 15.7 Covered lives, n Average: 907,000 Total: 92.5 million

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50% of employers and 75% of insurers report having increased premiums and deductibles during the past 12 months (Figure 2). Cost increases are not restricted to premiums and deductibles. A majority of insurers have also increased cost-sharing for prescription drugs and physician office visits. In addition, 44.1% of insurers and 30.8% of employers have increased patient cost-sharing for inpatient hospital stays.

When asked to assess their satisfaction with increased cost-sharing, both groups reported high levels of satisfaction, a view consistent with their stated plans to continue with this strategy (Figure 3).

Both employers and insurers believe that member cost-sharing could be increased in all categories surveyed, without negatively affecting patient outcomes. As illustrated in Figure 4, a majority of stakeholders believe that premiums could be increased up to 30% without

Figure 1 Importance of Cost, Access, and Quality of Care Q: We would like to understand how you rank the relative importance of the cost, access, and quality of healthcare to each other when designing health benefits. Please use a 0 to 100 scale to rate how important each of these 3 factors is when developing benefit choices for your clients.

Degree of importance, points

100 Insurers (n = 102) Employers/EBCs (n = 107)

80 60 44.85 43.79

40 25.47 27.77

29.68 28.45

Access to medically necessary care

Quality healthcare

20 0

Healthcare costs

EBCs indicates employee benefit consultants.

Figure 2 Health Plan Strategies Implemented in the Past 12 Months Q: Please select all of the following strategies your organization has implemented in the past 12 months: 58.9*

Increase health insurance premiums

72.5*

Increase deductibles

54.2* 78.4*

Increase copayments/coinsurance rates for prescription drugs

43.9*

Increase copayments/coinsurance rates for physician visits

43.9*

68.6*

57.8*

Increase benefit caps/patient out-of-pocket limits

33.6* 49.0*

Increase copayments/coinsurance rates for inpatient hospital stays

30.8* 44.1*

Add a benefit design option with high levels of patient costsharing (eg, high deductible plans, health savings accounts, consumer-driven healthcare plans) Reduce patient cost-sharing for medications for chronic conditions (eg, reduce copayments for patients with type 2 diabetes) Switch from copayments to coinsurance for prescription drugs Add a benefit design option with reduced patient out-ofpocket costs based on clinical benefit to targeted patient population (eg, lower copayment for product with demonstrable ability to reduce hospitalization)

25.2* 72.5* 22.4 25.5 17.8 29.4

Employers/EBCs (n = 107) Insurers (n = 107)

11.2 18.6 0

20

40

60

80

100

*

Significant difference between means.

EBCs indicates employee benefit consultants.

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Respondents, %

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Patient Cost-Sharing on the Rise

Figure 5 Maximum Coinsurance/Copay Increase without Reduction in Demand for Medical Care Q: How much can cost-sharing (copayments/coinsurance) increase for medical visits without reducing demand for necessary medical care?

Figure 3 Employer/Insurer Satisfaction with Cost-Shifting Q: We would like to know what results you have seen after increasing patient cost-sharing. Please indicate whether you have adopted these techniques and if you were satisfied with the results: Employers/EBCs (n = 107)

Insurers (n = 102)

100

Respondents satisfied, %

Respondents satisfied, %

100 75 50 25

0

75 50 25

0 0

25

50

75

0

100

25

50

75

100

Insurers adopting cost-sharing, %

Employers adopting cost-sharing, %

■ Maximum patient out-of-pocket responsibility ■ Contribution to health insurance premiums ■ Deductibles ■ Prescription drugs ■ Inpatient hospital stays ■ Physician visits EBCs indicates employee benefit consultants.

Figure 4 Maximum Insurance Cost Increase without Reduction in Demand for Healthcare Q: How much can premiums increase without reducing demand for necessary healthcare?

Premiums 59.8

60

Respondents, %

reducing demand for necessary healthcare, with similar results found when surveyed about increases in deductibles. Furthermore, Figure 5 indicates that there is ample room to increase member cost-sharing for office visits without reducing necessary demand.

However, not all cost-sharing is created equal. As shown in Figure 6, employers and insurers believe that out-of-pocket costs for prescription drugs will have varying degrees of impact on behavior, depending on the therapeutic category. For example, employers and insurers believe that the member threshold for absorbing out-of-pocket costs without foregoing necessary care is approximately 3 to 4 times higher for cancer care than for hyperlipidemia or depression. Of note, current levels of prescription drug cost-sharing are well below the threshold at which insurers and employers believe patients would forego necessary care for all therapeutic categories. Insurers report an average costsharing level of $27.50 for all prescription drugs, and employers report a level of $25.36. Depending on the therapeutic category, respondents believe that this number may increase to between $50 and $350 before suppressing demand for medically necessary care.

Stakeholder interest in increased cost-sharing is paired with the belief that additional cost-sharing will not have a substantial effect on patient outcomes.

Figure 7 shows that a majority of employers and more than two thirds of insurers believe that increasing costsharing for physician visits, inpatient hospitalization, and prescription drugs will not affect patient outcomes; similar sentiment holds for increasing premiums and deductibles.

As insurance premiums rise, the risk of adverse selection—the phenomenon in which healthier members exit the risk pool—grows. As healthier members

Employers/EBCs (n = 107)

51.0

50

Insurers (n = 102)

43.1

40 30.8

30 20 10 0

4.7 3.9

1.9 2.0

0

1-10

11-30

31-50

2.8

0.0

*51

Q: How much can deductibles increase without reducing demand for necessary healthcare?

Deductibles 50

40 30 20 10 0

Employers/EBCs (n = 107)

47.7

43.1 36.3

Insurers (n = 102)

33.6 15.7

7.5

9.3

3.9

0

1.9 1.0

1-10

11-30

31-50

*51

Increase, % Note: No significant differences between payer and employer means.

EBCs indicates employee benefit consultants.

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Respondents, %

Respondents, %

45.1

50

39.3 40.2

40

39.3

Employers/EBCs (n = 107) Insurers (n = 102)

30 20 10 0

12.1 10.8 4.7

4.7 1.0

0

1-10

11-30

31-50

2.9

*51

Increase, % EBCs indicates employee benefit consultants.

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Figure 6 Mean Maximum Out-of-Pocket Cost before Patient Foregoes Necessary Care

Maximum monthly out-of-pocket level, $

Q: For each of the following disease categories/conditions, what monthly out-of-pocket cost do you believe is the maximum amount that may be shifted to the member without the member foregoing medically necessary care?

500 Employers/EBCs (n = 105)

400

354

377

Insurers (n = 102)

339

300

Current average out-of-pocket cost ($26.43)

256

200 131

152

100

126

123* 87

0

Cancer

Infertility agents

Rheumatoid arthritis

Drug/alcohol dependence

112*

84*

Diabetes

111

82*

Asthma

109

86

76

Low back pain

Depression

106

74

105

77

Hyperlipidemia Osteoporosis

*Significant

difference between means.

EBCs indicates employee benefit consultants.

Figure 7 Impact of Benefit Design on Health Outcomes Q: What impact do you expect each of the following factors would have on health outcomes?

Reporting outcomes will deteriorate, %

Insurers (n = 102) Employers/EBCs (n = 107)

Increase cost-sharing for physician visits Increase cost-sharing for prescription drugs

22.5 30.8

0.0 2.8

77.5

32.4

1.0

66.7

37.4 21.6

58.9

2.0

76.5

27.1

11.2

37.3

61.7

2.0

60.8

27.1

15.0 12.7

Increase cost-sharing for inpatient hospital stays

84.3

6.5

16.7

74.8

3.9

17.8

79.4

7.5

29.4

74.8

8.8

34.6

61.8 19.6

1.0

Reduce cost-sharing for select chronic conditions (eg, diabetes)

57.9

2.9

18.7

Increase member/employee contributions to premiums Adopt plans with higher levels of cost-sharing (consumer-driven healthcare plans)

66.4

3.7

Increase member/employee deductibles Switch from copays to coinsurance for prescription drugs

Reporting outcomes will stay the same, %

Reporting outcomes will improve, %

9.3

45.8 60.8

39.2

59.8

30.8

EBCs indicates employee benefit consultants.

exit the risk pool, the per-member costs of those remaining in the pool rise further, which, in turn, leads others to leave the risk pool.5 Both employers and insurers believe that increases in premiums and deductibles of between 0% and 30% will trigger adverse selection. However, the subpopulations in the survey exhibit important differences about the point at which

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cost-shifting will trigger undesirable consequences for the insurance pool (Figure 8): â&#x20AC;˘ 46.7% of employers and 43.1% of insurers believe that a premium increase of 10% or less will result in adverse selection; 43.9% of employers and 39.2% of insurers believe that an increase in the deductible of 10% or less will have negative consequences

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Q: How much can premiums increase without increasing adverse selection in the insured population (eg, only the really sick will purchase health insurance)?

Premiums 50

Respondents, %

Discussion Although employers in the survey report greater overall concern than insurers for indirect cost drivers, such as productivity and presenteeism (Figure 9), their ability to manage, or even track, indicators other than direct healthcare and drug costs may impede their ability to optimize overall workforce performance. As a consequence—and given insurers’ comparatively more narrow focus on direct cost drivers—healthcare discussions between the 2 groups tend to focus more on costs than on outcomes. Both groups appear to default to various forms of cost-sharing as the only tool that they can agree has any impact on rising healthcare costs.

Both groups are pessimistic about the ability to sustain the recent slowdown in premium growth rates.

Payers identify several factors that will challenge their ability to hold premium growth rates down6: • Consistent with their concerns about rising specialty pharmacy costs, payers express significant concerns about new technologies and their inability to manage their utilization (a factor that has contributed to the growth of biologics overall7) • An aging population, particularly when accompanied by a significant chronic disease burden, represents another key factor • Inefficient healthcare delivery systems that insurers feel they have limited ability to improve.

Although employers express more confidence than insurers in the durability of slower premium growth, nearly half of employers believe that the current slowdown cannot be sustained. One employer participant opined that anyone who thinks that the current situation will continue is “indulging in wishful thinking.”

This implicit acknowledgment of the ineffectiveness of increasing cost-sharing should spur innovation. It appears from this research, however, that this will not be happening in the near-term.

This research also highlights a lack of clear communication between employers and insurers. Insurers believe that employers change benefit designs every 12 to 18 months; employers state they only change them as needed.6 Often programs that focus on improving health outcomes and consequent down-the-line healthcare costs require a longer time frame to show return on investment.8

Figure 8 Maximum Insurance Increase without Adverse Selection Increases

46.7

47.1 43.1

40

41.1

Employers/EBCs (n = 107) Insurers (n = 102)

30 20 8.8

8.4

10

3.7

0 <10

10-30

1.0

*51

31-50

Q: How much can deductibles increase without increasing adverse selection in the insured population (eg, only the really sick will purchase health insurance)?

Deductibles

50 43.9

Respondents, %

• Roughly comparable percentages of both subpopulations believe that there is more room to increase member/employee costs, by up to 30%, before adverse selection in the insurance risk pool becomes a problem.

40

39.2

39.3 40.2

Employers/EBCs (n = 107) Insurers (n = 102)

30 20

14.7 10.3

10 0

6.5

<10

10-30

31-50

5.9

*51

Increase, % EBCs indicates employee benefit consultants.

The implicit acknowledgment of the ineffectiveness of increasing cost-sharing should spur innovation. It appears from this research, however, that this will not be happening in the near-term.

Working within the short time frame insurers believe employers have set, opportunities for cost-savings from disease management programs or innovative benefit designs intended to improve health outcomes are limited. Both groups acknowledge that there are benefit designs that will improve health outcomes (Figure 7), but insurers do not believe that these costsavings can be realized within the 12- to 18-month

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Figure 9 Influential Factors in Benefit Design Development Q: Please tell us how influential each of the following factors is when developing commercial benefit designs. Please use a 1 to 4 scale, where 1 indicates no influence and 4 indicates significant influence.

3.50 3.60

Limits or lowers overall healthcare cost growth Promotes generic drug utilization

3.41 3.52

Increases appropriate healthcare utilization

3.32 3.29

Encourages wellness/prevention

3.30 3.11

Provides benefits that are competitive

3.29 3.40

Improves health outcomes

3.27 3.32

Promotes early detection of disease

3.24 3.04

Improves quality of care

3.21 3.14

Reduces absences from work because of sickness or disability

3.17* 2.73*

Retains qualified employees

3.10* 2.58* 3.07 3.03

Incentivizes members to make informed benefit choices Increases worker productivity

3.04* 2.60*

Maintains the same member cost-sharing level Other

2.78 2.70 2.50

Employers/EBCs (n = 107)

2.25

Insurers (n = 102) *Significant

difference between means.

EBCs indicates employee benefit consultants.

1

deadline set by their customers, and they refrain from presenting or explaining the benefits of more innovative benefit designs to employers. Insurers believe that employers are not receptive to these types of programs.

Employers either are not knowledgeable enough or lack the resources to investigate these options on their own, so they do not push insurers to innovate beyond the traditional healthcare benefit designs. This has created a marketplace in which employers remain confused about innovative options and insurers have limited business reasons to invest in new benefit designs. In the absence of fundamental changes in benefit design, patient cost-sharing becomes, almost by default, a primary point of stakeholder focus.

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2

No influence

3

4

Significant influence

Conclusions The survey results suggest few reasons for optimism.

In the absence of a strategy widely embraced by insurers and employers, no dramatic changes in benefit design appear on the horizon. Both groups will continue to rely on increasing cost-shifting to patients to keep premium costs to businesses under control.

In addition, given the potential downstream risks associated with continued cost-shifting and an aging population, hospital costs will likely increase. More fundamentally, the word â&#x20AC;&#x153;noâ&#x20AC;? is still too rarely heard in US healthcare, leading to upwardly spiraling costs for technically impressive interventions and yielding only modest benefits or affecting only small populations.

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Finally, although the threat of government intervention may yet induce downward pressure on costs, the fundamentals of access, quality, and cost have deteriorated so significantly that it may be too late for government intervention to have an impact.

The US government may be the only party in the healthcare debate with the power to affect meaningful change as well as the only party that cannot afford to sit and wait for a better option. As the number of underinsured and uninsured grows in the United States, policymakers are very aware that the government may eventually have to pick up the tab. This may lead them to make a decision that everyone else will have to live with. The question becomes, is that what we really want? And if not, who will take the first step toward true change? ■

References 1. Blue Cross Blue Shield Association. Medical cost reference guide: facts and trends driving healthcare costs, quality and access. 2008. www.bcbs.com/blueresources/mcrg. Accessed September 18, 2008.

2. Kaiser Family Foundation and Health Research and Educational Trust. Employer health benefits: 2007 annual survey. 2007. www.kff.org/ insurance/7672/upload/76723.pdf. Accessed September 18, 2008.

3. Grossman JM, Ginsberg PB. As the health insurance underwriting cycle turns: what next? Health Aff (Millwood). 2004;23:91-102.

4. S&P Credit Research. Midyear 2008 US Health Insurance Outlook: In 2008, Managed Care Could Need A Little Care Itself. New York, NY: Standard & Poors; May 27, 2008.

5. Chandler SJ. Adverse selection. Wolfram Demonstrations Project. http://demonstrations.wolfram.com/AdverseSelection/. Accessed September 18, 2008.

6. The Zitter Group. The benefit design index, spring 2008. Data on file at the Zitter Group.

7. The Zitter Group. The managed care injectables index, fall 2007.

Data on file at the Zitter Group.

8. Wilson TW. Evaluating ROI in state disease management programs.

State Coverage Initiate Issue Brief. 2003;4:1-6.

STAKEHOLDER PERSPECTIVE Cost-Shifting—Where Does It Stop?

EMPLOYERS/PHARMACY DIRECTORS: The article touches on the elusive tipping point where the shifting of healthcare costs to employees may result in negative health consequences. A subsequent costshifting question is how to avoid, or at least manage, the negative health consequences that result from these cost shifts. As the authors point out, the healthcare environment is changing and becoming more complex faster than employers or carriers are able to effectively manage. Both employers and carriers, especially medical directors and pharmacy directors, should watch for signs of the negative consequences of cost-shifting and be prepared to suggest adjustments to plan designs and copay structures. This may require a more sophisticated analytical approach than has previously been used.

POLICYMAKERS: An emerging issue in healthcare reform related to cost-shifting is the implicit subsidies of government-run programs, such as Medicaid and Medicare, whose costs are borne by commercial healthcare offerings—employers and their employees.

Ultimately, it is the patient who bears the burden of these cost shifts, and this burden is increasing as employers choose to shift additional costs to their employees. As policymakers consider changes in the overall healthcare system, it will be increasingly important to understand how shifting costs from pub-

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lic entities to private entities will affect an employer’s decisions to shift costs to its employees.

PROVIDERS: Hospitals and physicians are seeing their revenue streams change. No longer is the bulk of compensation coming directly from insurers.

Increasing amounts are coming from patients. The growing bifurcation of payments may increase overhead for collections and should raise awareness about the economic decisions patients face when seeking medical care. Physicians may need to ask questions about a patient’s ability to pay and be sensitive to the patient’s financial worries while considering treatment options.

PATIENTS: Employers and carriers expect that increasing patient cost-sharing will reduce the overall cost of care, by reducing incentives for patients to overuse the healthcare system. Each patient will be affected in a different way. The patient, who is ultimately the final stakeholder in the economic dialogue between employer, insurer, and provider, bears the burden of becoming as knowledgeable as possible about his or her healthcare choices.

David Williams Healthcare Consultant Milliman at Hartford, CT

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Will 2009 Usher in the Era of Biogenerics?

By Dalia Buffery, MA, ABD

W

hile the market share of small-molecule generics continues to expand—now at 67% of all prescription drugs dispensed in the United States, according to the Generic Pharmaceutical Association (GPhA)1—the issue of biogenerics (or biosimilars, or biologics follow-on) remains unresolved.

Unlike the European Union, which has established a regulatory system for the approval of biogenerics, the US Food and Drug Administration (FDA) has so far resisted moving in that direction, awaiting legislation from Congress, according to Biosimilars Business Review.2 With a greater percentage of FDA approvals now involving biologics, their impact on patient care is considerable, especially in cancer, infectious diseases, and autoimmune disorders. More than 400 biologic drugs and vaccines have so far been added to the market, treating more than 325 million patients.3 By 2010, biologics are expected to account for 50% of all drug approvals.4 Cost concerns and safety issues are finally forcing Congress to address the question of biogenerics, which would enable many patients to benefit from the unique properties of these products, without the attendant exorbitant cost. According to one source, between 1998 and 2006 “the average cost of biologics has gone up 505 percent,”3 at an annual cost of $100,000 to $500,000 to patients.5,6 In today’s economy, this means many patients will have to forego the benefits of these therapies, unless the cost and access issues are resolved.

Of the safety concerns unique to biologics, immunogenicity—“the patient’s adverse antibody reaction to a drug in which the body perceives a drug to be a foreign microorganism or virus”3—which claimed the lives of several patients in 2001, may lead to a more rigorous regulatory system for biogenerics than the current system for traditional generics.

Although the question of marketing exclusivity remains the Achilles’ heel of the industry, as more and more biologics go off patent in the coming years, the route to biogenerics seems inevitable. Of the 4 proposals now in Congress for the creation of a pathway for FDA approval of biogenerics, 3 would give biologic manufacturers longer marketing exclusivity than for small-molecule drugs—“up to an additional 3 to 12 years” longer.7 But not so fast.

At the 2009 annual meeting of GPhA, House Energy and Commerce Committee Chairman Henry Waxman

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said (via video) that “a workable scientific regulation and legal pathway for biogenerics and biosimilar pharmaceuticals will ensure more affordable medications for Americans, and we believe it will spur innovation in the biotech markets,” adding, however, that the HatchWaxman Act model of exclusivity should also work well for biogenerics (expressing dismay at suggestions of longer exclusivity periods).1 Waxman emphasized that creating a biogenerics pathway “will be an important contribution to health reform….I intend to use my position as chairman to improve the health and well-being of this nation, and I know that a critical piece of achieving this goal is to bring generic competition to the biotech drug market.”1 Representing the biotech industry, however, BIO President and Chief Executive Officer Jim Greenwood agreed that the time for biogenerics has come, but said his company’s position is “that there should be 14 years of market exclusivity.”1 GPhA President Kathleen Jaeger expressed GPhA’s position that “biogenerics are achievable, imperative, and inevitable,” noting that the “FDA has clearly stated that the science exists to ensure safety and efficacy.”1 With health reform and cost-cutting now top priorities for the new administration, 2009 may indeed be the year that ushers in biogenerics to the United States. ■

References 1. Generic Pharmaceutical Association. The “inevitability” of biogenerics takes center stage at GPhA’s annual meeting. February 24, 2009. www.gphaonline.org/media/press-releases/2009/%E2%80%9Cine vitability%E2%80%9D-biogenerics-takes-center-stage-gpha%E2% 80%99s-annual-meeting. Accessed February 24, 2009.

2. Espicom. Biosimilars Business Review. January 15, 2009. www.espicom. com/ProdCat.nsf/Product_ID_Lookup/00001795?OpenDocument.

Accessed February 20, 2009.

3. Kaldre I. The future of generic biologics: should the United States “follow-on” the European pathway? 2008 Duke Law Tech Rev. 0009. www.law.duke.edu/journals/dltr/articles/2008dltr009.html. Accessed February 20, 2009.

4. Sarnes M. Impact of market trends on drug pipeline: the need for value-based R & D. Am Health Drug Benefits. 2009;1(suppl 1):S55-S60.

5. Berenson A. A cancer drug shows promise, at a price that many can’t pay. New York Times. February 15, 2006:A1.

6. Jaeger K. Creating a workable biogenerics pathway for patients. J Generic Med. 2007;5:1-3. www.palgrave-journals.com/jgm/journal/v5/n1/ full/4950094a.html. Accessed February 20, 2009.

7. Lawler B. Will generic biologics get special treatment? The Motley Fool. September 23, 2008. www.fool.com/server/printarticle.aspx?file=/ investing/high-growth/2008/09/23/will-generic-biologics-get-specialtreatment.aspx. Accessed February 20, 2009.

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American Roots. Global Reach.

For 48 years, the generic products from Mylan Pharmaceuticals have met the uncompromising standards established by Chairman and Co-Founder Milan (Mike) Puskar. His philosophy—“We either do it right or we don’t do it at all”—has helped Mylan become the largest U.S.-based manufacturer of generics by total prescriptions.* As patients’ demands for a wider array of generics have increased, Mylan has responded. Under the leadership of Vice Chairman and CEO Robert J. Coury and COO Heather Bresch, Mylan now provides products to patients in more than 140 countries and territories.

As we have expanded, one constant has remained… the philosophy upon which our company was established. That’s why all Mylan generics will continue to offer the quality and affordability that patients need and the peace of mind that pharmacists have always counted on.

*IMS National Prescription Audit. Total Prescriptions: June 2007 - June 2008. ©2009 Mylan Pharmaceuticals Inc. MYNMKT290

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Employer-Based Health Initiative: Impact on Employees’ Cardiovascular Outcomes Claiborne E. Reeder, RPh, PhD; Christine H. Divers, PhD, MS; Del Deem; Becky J. Cherney; Gaye Fortner, RN, BSN, MSN; Louise Y. Probst Background: Cardiovascular disease is the primary cause of mortality among men and women in the United States. The Ready, Set, Goal program was an employer-based initiative designed to identify individuals at risk for cardiovascular disease and to offer an intervention to alter those risk factors. The program involved cardiovascular education, screening, behaviorchange incentives, continuing assessment, and follow-up. Pharmacologic treatment was not part of the intervention.

Objective: To analyze the effects of the Ready, Set, Goal pilot program in 5 employers in the United States on salient cardiovascular end points for employees who completed the program.

Methods: The analysis used a pretest/posttest within-subjects design to compare baseline Claiborne E. Reeder measurements with measurements for all subjects who completed a second assessment 6 months after baseline measurements. Enrollment began in June 2004 in the first site and in May 2005 in the last site; it ended in January 2006. Patient clinical data from the pilot interventions were aggregated to assess the effects of the intervention on salient cardiovascular end points for individuals who completed the Ready, Set, Goal program. Changes in short-term cardiovascular risk factors were evaluated. Descriptive measures with paired t-tests (α = 0.05) were calculated at the aggregate level for each dependent variable. Range checks were conducted on all variables for clinical validity.

Results: A total of 589 subjects from 5 employer group pilot interventions completed the program. Of these, 43% were men, 60% were white, 9% were African-American, 11% were Hispanic, and 20% were categorized as “other.”

After the intervention, mean blood pressure, total cholesterol, and low-density lipoprotein cholesterol levels were significantly lower (P <.05) compared with baseline measurements. On average, systolic blood pressure declined by 1.9 mm Hg; diastolic blood pressure by 1.3 mm Hg; total cholesterol decreased by 5.2 mg/dL and low-density lipoprotein cholesterol by 3.4 mg/dL. Triglyceride levels increased and high-density lipoprotein levels decreased, although these changes were not significant, and neither were the mean increases in body weight. But increases in body mass index were significant.

Conclusions: A worksite cardiovascular health program can have positive effects on salient cardiovascular end points for employees. The increases in triglyceridnes and body mass index should be further explored. [AHDB. 2009;2(2):80-85.]

C

ardiovascular (CV) disease (CVD) is the primary cause of mortality among men and women in the United States. An estimated 80.7 million American adults (1 in 3) have 1 or more types of CVD;

Dr Reeder is Director, Xcenda, and Distinguished Professor Emeritus, University of South Carolina, Columbia, SC; Dr Divers is Field Economics Director, AstraZeneca, Wilmington, DE; Mr Deem is Senior Account Director, Employer Segment, AstraZeneca, Wilmington, DE; Ms Cherney is President/CEO, Florida Health Care Coalition, Orlando, FL; Ms Fortner is Senior Vice President/COO, HealthCare 21 Business Coalition, Knoxville, TN; Ms Probst is Executive Director, St. Louis Area Business Health Coalition, St. Louis, MO.

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of these, about 47% are estimated to be 60 years or older.1 From an employer’s perspective, the economic burden of CVD has grown steadily over the past decade, fueled by rising medical costs coupled with the indirect costs associated with CV morbidity and mortality.

Approximately 17% of all medical expenditures (about $149 billion annually) and nearly 30% of Medicare expenditures are attributable to CVD.2 The 2008 direct and indirect costs of CVD in the United States are estimated to be $448.5 billion.3 Healthcare costs for individuals with multiple CV risk factors are typically 3 times higher than for those without such risk factors.

Much of the medical literature has focused on factors associated with increasing risk for CVD or on factors

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associated with poorer outcomes in the presence of CVD. The beneficial effects of healthy lifestyles on lowering CV risks and improving CVD outcomes and longevity have been reported in the literature.4,5 It has also been suggested that the prevention of risk factors at a young age may be key to “successful aging”; the investigators emphasize the need for intensive prevention in younger and middle-aged individuals with CV risk factors as a way to improve their overall health and longevity.6 Early intervention to identify and manage CV risk factors may offer the opportunity to reduce employer healthcare costs, increase worker productivity, and improve worker quality of life.

The Centers for Disease Control and Prevention (CDC) has identified 5 controllable or modifiable major risk factors for CVD: tobacco use, elevated cholesterol levels, physical inactivity, poor nutrition, and hypertension.7 Each of these risk factors is amenable to change through appropriate behavior modification and pharmacotherapy. Risk reduction for CVD translates into decreased morbidity, mortality, and healthcare costs.

The Ready, Set, Goal (RSG) program was an employer-based initiative funded by AstraZeneca and implemented at the worksites by employers and employerselected vendors. These vendors were primarily responsible for collecting the biometrics, compiling the data, and providing descriptives on the enrolled population. The program was designed to identify individuals at risk for CVD and to offer interventions to alter these risk factors. The RSG program was developed in response to frequent requests from employers to address their desire to affect their employees’ CV health.

The RSG program was designed to focus on high-risk employees who were not being captured in the healthcare system and to evaluate the impact of the program on important clinical measurements. This program involved disease awareness and education, screenings, patient education, behavioral incentives, and ongoing assessment and follow-up. The general model at each worksite was to evaluate the prevalence of CVD at the employer level, develop nonpharmacologic interventions to modify risk factors present in the employee population, and then evaluate the impact of the interventions on health outcomes and costs. Key features of the RSG program were: • It was designed for US employers engaged in preventive medicine and health education programs • The intervention centered around a health risk assessment that encouraged interaction between the employee, a physician, or another third-party health administrator

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KEY POINTS

The 2008 direct and indirect costs of cardiovascular disease in the United States are estimated to be $448.5 billion.

In response to expressed need from employers, a program focused on improving employees’ cardiovascular health was initiated by 5 employer groups at 7 worksites.

The Ready, Set, Goal program was designed to evaluate the impact of cardiovascular education intervention on employees’ cardiovascular risk factors and the cost to their employers.

This study shows that the intervention had significant improvements in some cardiovascular measures, such as low-density lipoprotein and blood pressure, although triglyceride and body mass index levels increased.

Results from this program suggest that worksiteinitiated cardiovascular education intervention may have positive effects on employees’ health and may reduce employers’ costs.

• The core component, an RSG packet developed by AstraZeneca, was used consistently among all 5 employers (7 worksites) and contained patient education materials, focusing on CV risk factors • Flexibility to allow employers to engage in other educational activities that best fit their abilities to implement onsite programs • Measurable results were obtained, including biometrics based on the Adult Treatment Panel III guidelines and healthcare utilization.

One of the strongest elements of this program was its flexibility to be implemented by a variety of employers and employer groups. Because different employers have varying capabilities and demographics, it was critical to the success of this program to allow flexibility in what types of education programs could be offered. It was also critical to have a core component that was consistent among all employers. Therefore, the RSG packet was developed and contained patient education materials that were used at all sites. Other education modalities included onsite speaker programs, heart-healthy nutrition programs, and exercise competitions. Some of these programs used education materials that had been developed by the employers, by AstraZeneca, or by professional organizations (eg, the American Heart Association). Employers implemented the education

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RSG program at their respective worksites. The original intent of the analysis was to assess change in risk factors, resource use, and outcomes from baseline Employees Employees Employer measurements taken at the time of proIntervene to improve: Impact Reduced: Reduced direct/ gram initiation to 6 months after the on health • Lifestyles indirect cost intervention was initiated. However, this outcomes • Absenteeism • Goal attainment burden (work-related) analysis has been limited to clinical • Treatment • Cardiovascular events measures and CV end points that were • Hospitalizations consistently collected and reported for • Rehabilitation the 5 employer groups (at 7 worksites).

• Short-term disability The following dependent variables • Workers’ compensation were included in the analysis: systolic blood pressure (BP), diastolic BP, total cholesterol, triglycerides, high-density RSG indicates Ready, Set, Goal. lipoprotein cholesterol (HDL-C), lowdensity lipoprotein cholesterol (LDL-C), total cholesterol to HDL-C ratio, glucose levels, weight, Table 1 RSG Program Participant Demographics (N = 589) body mass index (BMI), and coronary risk profile. Data Race Male,% Female, % Total, % were pooled across sites for the primary analysis on short31.1 28.5 59.6 White term CV variables. Insufficient data on resource use and absenteeism were available to conduct a meaningful and 1.5 7.8 9.3 African-American informative analysis of those measures.

2.6 8.8 11.4 Hispanic The analysis followed a pretest/posttest design, in 8.3 11.4 19.7 Other a which baseline measurements were compared with measurements for all subjects who completed a second 43.5 56.5 100.0 Total a assessment 6 months after the baseline measurements.

Other includes 2 subjects with missing data.

Descriptive analyses (means, standard deviations) were RSG indicates Ready, Set, Goal. conducted at the aggregate level for each dependent intervention over 3 to 9 months, depending on their variable for which a sufficient number of observations needs and capabilities. were available; paired t-tests were used to assess statistiThe RSG program was staged initially by an employcal differences between baseline and 6-month measureer creating awareness, followed by an initial baseline ments. The basic analysis focused on the effects of the assessment, and follow-up assessments at 6 and 9 months intervention on the short-term surrogates of CVD— after initial assessment. In addition to baseline measureBP, cholesterol panel (total cholesterol, LDL-C, and ments, which included CV risk assessment, physical HDL-C), weight, and BMI. assessment, and blood work, patients also self-reported Clinical data for subjects from the 5 US employer healthcare and resource use (eg, physician, hospital, groups that participated in the RSG initiative were emergency department visits, sick leave) during the 6obtained from the vendors who were contracted to month period before the baseline date. The Figure implement the program and coordinate data collection. depicts the RSG initiative and potential impacts for Enrollment began at the first worksite in June 2004, employers. The duration of the RSG program at each with the last site starting enrollment in May 2005; all worksite was 12 months. sites completed enrollment by January 2006. Vendors provided data as Excel spreadsheets. Although a uniMethods and Design form set of data was to be collected at each site, not all The purpose of this study was to analyze and evaluate data were collected by every site, and completeness of data collected from pilot tests of the RSG program at 7 the data varied somewhat across sites. Therefore, this worksites for 5 employer groups. Patient clinical data analysis used the clinical CV measures that were from the pilot groups have been aggregated to assess the thought to be the most valid, reliable, and complete. effects of the intervention on modifiable risk factors and The analysis included only subjects who completed at clinical parameters for employees who completed the least 6 months of the intervention.

Figure The RSG Employer Cardiovascular Initiative: Goals, Results

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Table 2 RSG Program: Cardiovascular End Points, Change from Baseline Baseline mean (SD)

Post-RSG mean (SD)

Change from baseline

128.6 (17.0)

126.7 (14.6)

−1.9

Effect ↓

75.9 (11.6)

74.6 (10.9)

−1.3

↓

0.008

Total cholesterol, mg/dL

196.1 (39.9)

191.0 (38.0)

−5.1

↓

0.000

Triglycerides, mg/dL

130.2 (74.0)

134.7 (82.7)

4.5

↑

0.199

HDL-C, mg/dL

49.3 (15.3)

47.3 (15.3)

−2.0

↓

0.000

LDL-C, mg/dL

119.6 (36.4)

116.1 (34.4)

−3.5

↓

0.012

4.3 (1.4)

4.1 (1.8)

−0.2

↓

0.024

96.9 (26.0)

94.6 (17.8)

−2.3

↓

0.040

179.8 (41.6)

180.2 (41.9)

0.4

↑

0.203

0.5

↑

0.023

−0.1

↓

0.550

Clinical end point Systolic BP, mm Hg Diastolic BP, mm Hg

Total cholesterol to HDL-C ratio Glucose level, mg/dL Weight, lb Body mass index, kg/m

2

Coronary risk profile, %

27.6 (7.3) 6.4

28.1 (6.7) 6.3

Paired t-test probability 0.003

BP indicates blood pressure; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; RSG, Ready, Set, Goal.

Applying the inclusion criteria of having reasonably completed clinical data as well as completion of the RSG program yielded a total of 589 subjects. This study group served as the basis for all analyses presented in this report. Table 1 depicts the number of subjects, by gender, from each site that was retained for a “completer” analysis.

Data were analyzed to evaluate the effect of the intervention on the primary clinical end points and risk factors of interest listed in Table 1. Two-tail, paired t-tests with a type 1 error of 0.05 were used to assess the change scores in each variable of interest. (All analyses were conducted using Microsoft Excel.)

Results The effects of the RSG intervention were significant and in the expected direction for the majority of clinical parameters, except for triglycerides, HDL-C, body weight, and BMI (Table 2). The post-RSG increases in triglycerides and weight were not significant, whereas the increase in BMI was significant (P >.05). Of note, the mean baseline weight was approximately 180 lb, with a BMI averaging 27.6 kg/m2, which suggests that employees who participated in the RSG program were mildly obese. Recognizing that the participant population was skewed toward women, who are generally more health conscience,8 these findings suggest that diet and exercise alone were not enough to contribute significant reductions in weight and BMI. It is possible, however, that the employees who volunteered to par-

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ticipate in the RSG program were generally in better health than the overall US population.

Particularly noteworthy are the changes in BP (systolic and diastolic), glucose levels, total cholesterol, and LDL-C levels. There was also a small, but not significant, decrease in the mean percent 10-year coronary risk profile. As noted earlier, the CDC has identified high cholesterol levels and hypertension as 2 of 5 key risk factors for CVD. Moderating and mitigating these morbidity drivers can have a favorable impact on the long-term well-being of an employed population such as the one included in this analysis. Elevated glucose levels are also associated with negative long-term consequences, such as neuropathies, visual loss, and amputations. In monetary terms, the costs associated with uncontrolled diabetes, hypertension, or dyslipidemia can be extraordinary for the employee and employer.

Discussion The success of the RSG CV initiative should be judged in terms of the goals for the program and against the clinical objectives specified for the intervention.

The overarching goal of the RSG program was to identify and communicate CV risk factors in an employee population. Overall, the program resulted in employees achieving significant decreases in BP, total cholesterol, LDL-C, and glucose levels. These measures are important predictors for improvements in general CV health, which should, in turn, translate into lower morbidity.

The decline in 10-year coronary risk profile, although

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not significant, was in the desired direction. One of the major benefits of workplace wellness initiatives is to keep workers in better health and more productive.

Limited data from 2 worksites showed a decline in the average number of days of work lost as a result of illness (absenteeism) from 2.3 days for an employee in the preintervention period to 2.07 days per employee in the postintervention period. Because CVD is one of the primary cost drivers for employer health programs, a decrease in absenteeism, coupled with improved CV health, has positive economic implications for employers.9 These findings are also consistent with other studies, which have shown that behavioral and clinical risk factors are predictive of absenteeism.5,10

Taken as a whole, the RSG program achieved the intrinsic goals of the sponsor, as well as the desired benefits for the employer groups and their employees.

The RSG program was implemented with the assistance of wellness and disease management vendors at the local worksites, demonstrating that such worksite interventions are feasible when done in collaboration.

Data from 2 worksites suggest very high levels of employee satisfaction with the RSG initiative. When asked about the overall value of the program, participants were very satisfied (mean score of 4.4 on a 5-point scale).

Moreover, participants indicated that they were “very happy” that their employer had made the program available at the workplace.

The effects of a broad-based intervention, like the RSG program, may be influenced by a variety of factors endogenous and exogenous to the study. The magnitude of the effects depends not only on the intervention but also on the subjects’ willingness to participate and the many environmental influences in the workplace.

Therefore, it is not surprising that the observed changes in clinical end points were not substantial in nominal terms. It is, however, most encouraging that the majority of indicators of the impact of the RSG initiative were positive or pointed in the desired direction in terms of clinical, economic, and patient-reported outcomes.

Taken as a whole, the RSG program seems to achieve the intrinsic goals of the sponsor, as well as the desired benefits for the employer groups and their employees.

The importance of interventions such as the RSG pro-

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gram is supported by a recent report of the American Heart Association.1 Based on the findings of this study and others, employers still have much work to do in the wellness arena.

Limitations Interpretation of this analysis should be tempered by several limitations. First, the analysis was conducted on subjects who completed the study and had sufficient preand postintervention measures on clinical variables. The effects of the RSG intervention on subjects who partially completed the program are not known.

Second, because subjects volunteered for the program, selection bias could influence the findings.

Therefore, the results of this analysis should not be generalized beyond employees who completed the RSG intervention.

Third, data were abstracted from the original data sets supplied by the RSG vendors for the respective study sites. There was significant variability in the data reporting formats and data elements. Range checks were conducted to provide some assurance that data were within reasonable and expected limits. Finally, some data were self-reported and other data were measured by different study personnel within and across sites. The issues of self-reporting and inter-rater variability must be considered.

Conclusion Future research on the RSG program or similar initiatives should try to capture the effects of the program on employee productivity (absenteeism and presenteeism). Understanding the relationship between decreased morbidity or improved clinical outcomes and worker productivity is critical to establishing the value of worksite health and wellness programs to the employer community. Although decreased morbidity and improved clinical outcomes should intuitively improve productivity, this relationship needs to be demonstrated empirically. ■ Disclosure Statement Dr Reeder, Ms Cherney, Ms Fortner, and Ms Probst have received a research grant from AstraZeneca. Dr Divers and Mr Deem are employees of AstraZeneca.

References 1. American Heart Association. Heart disease and stroke statistics— 2008 update. www.americanheart.org/presenter.jhtml?identifier=3037327.

Accessed November 5, 2008.

2. Trogdon JG, Finkelstein EA, Nwaise IA, et al. The economic burden of chronic cardiovascular disease for major insurers. Health Promot Pract.

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2007;8:234-242.

3. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics—2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation.

2008;117:e25-e146.

4. Daviglus ML, Liu K, Greenland P, et al. Benefit of a favorable cardiovascular risk-factor profile in middle age with respect to Medicare costs.

N Engl J Med. 1998;339:1122-1129.

5. Logston KH, ter Riet LB. Employee health program improves blood pressure, diabetes control. Science Daily. May 13, 2007. www.sciencedaily.com/ releases/2007/05/070510202249.htm. Accessed November 5, 2008.

6. Newman AB, Arnold AM, Naydeck BL, et al. “Successful aging”:

effect of subclinical cardiovascular disease. Arch Intern Med. 2003;163: 2315-2322.

7. Centers for Disease Control and Prevention. Heart disease risk factors. www.cdc.gov/heartdisease/risk_factors.htm. Accessed November 5, 2008.

8. Experian Simmons. Women have higher food IQ’s than men. Fall 2006. www.marketresearchworld.net/index.php?option=content&task= view&id=1295&Itemid=. Accessed January 26, 2009.

9. Centers for Disease Control and Prevention. Moving into Action: Promoting Heart-Healthy and Stroke-Free Communities (State Legislators).

Atlanta, GA: US Dept of Health and Human Services; 2005.

10. Aldana SG. Financial impact of health promotion programs: a comprehensive review of the literature. Am J Health Promot. 2001;15:296-320.

STAKEHOLDER PERSPECTIVE Employer-Based Wellness Initiatives: Lifestyle Modifications Insufficient in Employees at High Risk for Cardiovascular Disease EMPLOYERS: Anytime health awareness initiatives like the Ready, Set, Goal (RSG) program can engage an employer to actively promote a wellness venue to benefit the health and wellness of employees, that is definitely a step in the right direction.

Back in the 1990s, these types of initiatives were known as disease management programs. Because there were numerous programs introduced with varying degrees of participation, many in the healthcare community were not sure if such programs were, in fact, successful in managing a disease. We have now reached a new height with a reclassification of these initiatives, by referring to them more appropriately as “wellness” programs.

In the particular program discussed in the article, the main goal was to identify and communicate cardiovascular risk factors to the employee base. More specifically, the RSG initiative focused on high-risk employees who are not being captured in the healthcare system, implemented an action plan for them, and then analyzed the outcomes. The 5 employer groups should be recognized and commended for their respective efforts to raise the awareness and the impact of cardiovascular disease on their employees’ overall health and well-being.

That said, reviewing the overall results would lead us to believe that patient education, diet, and exercise alone are in general not enough to have a substantial impact on this type of high-risk population.

Although many of the clinical end points did reach significant outcomes, the absolute numerical changes in elevated blood pressure, body mass index, and cholesterol levels were far from acceptable, given the

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length of time the participants were in the program.

No one can dispute the fact that patient awareness and patient education, diet, and exercise are important. On the contrary, these are key elements for the formula of building health and well-being.

However, clearly missing in this program is the one element that makes the sum of all the aforementioned parts much greater than the individual pieces. By this I mean the culmination of decades of intense research and development to produce welldocumented results in reducing blood pressure, cholesterol, and other lipid levels to guideline goals, namely, pharmacotherapy.

With today’s knowledge of pharmaceutical advances, pharmacotherapy should be part of the armamentarium in the equation of wellness, especially for populations at high risk for cardiovascular disease. As an employer-based initiative, integrating the pharmacotherapy component into any wellness program—in addition to patient awareness and patient education, diet, and exercise—will complete the formula for more successful outcomes that are closer to acceptable guideline levels. It should also, in turn, keep employees more motivated to stay with their respective regimens well after the program ends, and will ultimately provide lifestyle modifications toward an increase in overall wellness. Isn’t that the overall goal?

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

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Methicillin-Resistant Staphylococcus aureus : A Growing Risk in the Hospital and in the Community Jose L. Raygada, MD; Donald P. Levine, MD Methicillin-resistant Staphylococcus aureus is a common and continuously growing cause of nosocomial and community-acquired infections. The type, disease severity, and clinical outcomes of these infections, as well as the genotypic and susceptibility patterns of the bacteria differ according to the setting in which the infection occurs—a healthcare facility or the community setting. The incidence of these infections in the community setting has been growing consistently in the past decade or so. In addition, resistance to the many current antibiotics used to treat these infections is also growing, further complicating management. Rapid-diagnosis tests and new therapeutic agents are constantly under investigation. The authors review the current understanding of the epidemiology, clinical manifestations, and management of Jose L. Raygada methicillin-resistant Staphylococcus aureus infection, including the growing problem of resistance. In addition, they discuss promising diagnostic and therapeutic alternatives, as well as new control strategies to prevent its transmission or the development of infection among carriers. [AHDB. 2009;2(2):86-95.]

M

ethicillin-resistant Staphylococcus aureus (MRSA) refers to isolates that are resistant to β-lactam antibiotics (including penicillins and cephalosporins).1 According to the Clinical and Laboratory Standards Institute (CLSI), MRSA is defined as isolates with a methicillin minimum inhibitory concentration (MIC) ≥4 µg/mL; however, S aureus already is considered nonsusceptible to oxacillin if the MIC is >2 µg/mL.2 Methicillin resistance is mediated by the penicillinbinding protein (PBP)-2a encoded by the mecA gene. βlactam antibiotics have poor affinity for this altered PBP, and organisms are not killed when exposed to common therapeutic concentrations. The mecA gene is located on a mobile genetic element, the staphylococcal chromosome cassette (SCCmec). Sequencing SCCmec from many MRSA strains reveals that there are at least 5 SCCmec types (I-V) that vary in genetic base-pair construction and size.3

Epidemiology MRSA emerged in England in 1961, 2 years after the Dr Raygada is a Fellow, Division of Infectious Diseases, Department of Medicine, and Dr Levine is Professor, Division of Infectious Diseases, Department of Medicine, Wayne State University, Detroit, MI.

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introduction of methicillin, and its incidence has increased steadily since then. In the United States, MRSA was first reported in 1968.

Hospital- or healthcare-associated (HA)-MRSA is different from community-associated (CA)-MRSA in terms of epidemiology, phenotype, and genotype. CAMRSA is an important pathogen that has become prevalent during the past decade and, according to some reports, is replacing nosocomial MRSA strains. In one study, during a 7-year period, MRSA bloodstream infections caused by CA-MRSA increased from 26% to 49%.4

HA-MRSA HA-MRSA is associated with severe infections, with high morbidity and mortality rates, such as ventilatorassociated and hospital-associated pneumonia, surgical site infections, as well as catheter-related infections.

In the early 1990s, MRSA accounted for 20% to 25% of S aureus isolates from hospitalized patients. In 1999, MRSA represented more than 50% of S aureus isolates from patients in intensive care units (ICUs) according to the National Nosocomial Infection Surveillance System.5,6 In 2003, that percentage was approaching 60%. It is now estimated that approximately 70% of all S aureus isolated from ICUs are MRSA.5,6 HA-MRSA carries SCCmec type II and is typified as USA100 or USA200 by pulse-field gel elec-

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Table 1 Risk Factors for HA-MRSA Infection

KEY POINTS

Old age Previous antibiotic use (particularly cephalosporins and quinolones) Prolonged hospitalization

The incidence of MRSA has increased steadily during the past 50 years. Community-associated infection has been on the increase in the past decade and may be replacing nosocomial MRSA strains.

Central venous catheter insertion

Most community-associated MRSA infections are susceptible to doxycycline, minocycline, clindamycin, trimethoprim-sulfamethoxazole, rifampin, and linezolid.

Vancomycin has been the drug of choice for hospitalized patients with invasive infections, but emerging treatment failure has been reported.

Familiarity with local antibiotic patterns and cultures with susceptibility data are critical for tailoring treatment.

In addition to proper drug therapy, basic infection control practices are integral to the prevention and control of hospital-associated MRSA.

Ventilator dependency Hemodialysis MRSA colonization Proximity to a patient with MRSA colonization or infection

Table 2 Risk Factors for CA-MRSA Infection Injection drug use Skin trauma (eg, lacerations, abrasions, tattoos) Higher body mass index Cosmetic body shaving Physical contact with a person who has a draining lesion or is a carrier of MRSA Incarceration Military personnel Previous skin infection with MRSA Men who have sex with men

trophoresis (PFGE).7 The major risk factors associated with HA-MRSA are listed in Table 1.

CA-MRSA In the 1980s, MRSA was isolated among injection drug users who had a history of antibiotic exposure. In 1993, a genetically unique MRSA isolate was reported in Australia among aborigines who had no previous contact with a healthcare system. By the mid-1990s, CAMRSA infections emerged in New Zealand, the United Kingdom, France, Finland, Canada, Samoa, and the United States.

Initial outbreaks of CA-MRSA in the United States occurred in Native American children in Minnesota, Nebraska, and North Dakota. Later, CA-MRSA infections were identified in other populations, including homosexual men, incarcerated people, athletes, and soldiers. Compared with HA-MRSA, most CA-MRSA cases contain SCCmec type IV or type V, which encode for resistance to methicillin and other β-lactam antibiotics, but generally not for other agents. They are typi-

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fied by a USA300 or USA400 PFGE pattern and frequently carry genes for the cytotoxin Panton-Valentine leukocidin that is associated with the propensity of S aureus to cause tissue necrosis.8 In 3 US communities, 1647 cases of CA-MRSA infection were reported between 2001 and 2002.9 Of all MRSA isolates, 8% to 20% were not associated with traditional risk factors and were classified as CAMRSA.9 Most caused clinically relevant infections that required treatment; many patients were children and required hospitalization.

CA-MRSA infection often presents as skin and softtissue infection (SSTI) in previously healthy individuals. SSTIs may be mild or severe and include pyomyositis or necrotizing fasciitis, osteomyelitis, septic arthritis, Waterhouse-Friderichsen syndrome, pneumonia, and bacteremia.

The risk factors for CA-MRSA, which differ from those of HA-MRSA, are listed in Table 2. Transmission of MRSA from colonized pets has also been reported.10 In many circumstances, a single risk factor could not be identified.

Pathogenesis The difference between MRSA and methicillin-sensitive strains is that the former may have acquired a genetic background, which is believed to enhance virulence or the development of more severe and atypical manifestations of the disease.

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Table 3 Important Virulent Factors of Staphylococcus aureus Virulent factor

Role

Clinical consequences

Attachment to blood clots and traumatized tissue

Endocarditis, prosthetic infections

Fibronectin/fibrinogen binding proteins

Attachment to fibronectin/ fibrinogen

Septic arthritis, osteomyelitis

Collagen and bone sialoproteinbinding protein

Attachment to collagen, bone

Surface proteins or MSCRAMMs Clumping factors

Invasines Proteases, lipases, nucleases, hyaluronidase

Promote bacterial penetration into tissues

Tissue invasion and destruction

Promote host defenses’ destruction

Dermonecrosis, necrotizing pneumonia

Protein A Capsular polysaccharides

Evade opsonization and phagocytosis

Deep and metastatic infections

Polysaccharide intercellular adhesion Accumulation-associated protein

Biofilm production

Persistant infection, specially associated with foreign materials

Potent gastrointestinal toxins and superantigens that stimulate nonspecific T-cell proliferation

Gastroenteritis, food poisoning

Toxic shock syndrome toxin-1

Release several cytokines, specifically tumor necrosis factor and interleukin-1

Toxic shock syndrome

Exfoliative toxin (A & B)

Cleave desmoglein 1, a cadherin that is found in desmosomes in the epidermis

Scalded skin syndrome

Elastase, phospholipase C Leukocidal toxins or leucocidins Proliferative verrucous leukoplakia, δ-toxin

Biofilm-associated protein Exotoxins Enterotoxins

MSCRAMMs indicate microbial surface components recognizing adhesive matrix molecules.

For diseases caused by S aureus, the pathogenesis is considered to be multifactorial. Progress in molecular biology techniques has allowed identification of many virulence factors (specific genes have been cloned and sequenced, and protein toxins purified); however, it is difficult to determine precisely the role of many of them.

Staphylococcal infections occur frequently but usually remain localized at the portal of entry by normal host defenses. MRSA colonization is an important risk factor for the development of infection. It is estimated that 20% to 30% of individuals carry S aureus in their nares and in other areas, such as the axillae, groin, or gastrointestinal tract. When the host barriers are broken, “commensal” S aureus may invade deeper structures and produce subsequent infection. Another por-

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tal of entry is the respiratory tract. Staphylococcal pneumonia is a severe condition affecting young, previously healthy individuals during or after influenza.11 Table 3 summarizes the most important virulence factors and their roles in the disease.

CA-MRSA Clinical Syndromes Almost 80% of CA-MRSA infections in the United States are SSTIs. Abscess and cellulitis are the most common, and 60% of SSTIs seen in emergency departments are produced by MSRA. The median age for CA-MRSA infection in adults ranges from 20 to 47 years, and SSTIs are more frequent among nonwhite men. The majority of CA-MRSA infections, particularly those involving the skin and soft structures, are

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not severe and are considered to have a low mortality rate (as compared with infections caused by nosocomial MRSA strains); however, severe and life-threatening episodes of invasive CA-MRSA infections have been reported with increased frequency worldwide.12 Less common, but severe forms of disease caused by CA-MRSA are: • Necrotizing fasciitis, a life-threatening infection that requires urgent surgical and medical therapy; associated conditions or risk factors include previous MRSA infection, hepatitis C, diabetes mellitus, current or past injection drug use, cancer, and HIV infection • Pyomyositis, initially considered a tropical disease, is now recognized in areas of temperate climates and especially in patients with HIV and intravenous drug users • Necrotizing community-acquired pneumonia (CAP) is associated with influenza, and generally occurs in previously healthy young individuals. During the 2003-2004 influenza season, 15 cases of MRSACAP, with 4 deaths (fatality rate 26.7%), were reported from 9 states.13 In January 2007, the Centers for Disease Control and Prevention (CDC) received reports of 10 cases of severe MRSA-CAP, including 6 deaths, among previously healthy persons in Louisiana and Georgia14 • Infective endocarditis is a common and often devastating complication of S aureus bacteremia15; risk factors include prosthetic valve, underlying valvular defects, injection drug use, intravascular catheter infection, and persistent bacteremia • Septic arthritis and osteomyelitis may be caused by direct injury or as a complication of S aureus bacteremia • Sepsis (with or without Waterhouse-Friderichsen syndrome). Waterhouse-Friderichsen syndrome is characterized by petechial rash, coagulopathy, cardiovascular collapse, and bilateral adrenal hemorrhage. It generally is associated with fulminant meningococcemia; however, 3 fatal cases produced by S aureus were reported in 2005 in children, 2 of which were caused

by CA-MRSA.16

HA-MRSA Clinical Syndromes HA-MRSA infections are associated with prolonged hospital stay, increased mortality, and increased costs. In 2003, 64.4% of S aureus infections in ICUs were associated with methicillin-resistant strains.5,6 MRSA is a suspected pathogen in nearly all types of hospital infections.

The most common manifestations of HA-MRSA infections are:

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• Surgical wound skin and skin structure infection (SSSI) • Osteomyelitis and septic arthritis as complications of orthopedic surgery, including prosthetic device infections • Bacteremia • Healthcare- and ventilator-associated pneumonia.

Treatment of MRSA Infection Outpatient Drug Therapy Uncomplicated SSTIs (ie, those without associated sepsis or hemodynamic instability) can be managed with incision and drainage if an abscess is present. Topical antimicrobial therapy sometimes is used to treat limited and superficial MRSA skin infections (eg, impetigo).

The most known agents are bacitracin (alone or in combination with polymyxin and neomycin), mupirocin, and retapamulin. Emerging resistance to mupirocin is now being reported worldwide, particularly in healthcare facilities where it is used extensively to prevent infection and transmission from carriers.

The drug of choice for the ambulatory setting has not been clearly established. Most CA-MRSA are susceptible to doxycycline, minocycline, clindamycin, trimethoprim-sulfamethoxazole (TMP-SMX), chloramphenicol, rifampin, and linezolid. Familiarity with local antibiotic patterns and cultures with susceptibility data are critical for tailoring treatment. Table 4 lists oral agents available for the treatment of CA-MRSA. Susceptibility to erythromycin ranges from 5% to 64% in different geographic areas.11 Clindamycin has good activity against MRSA and is capable of inhibiting bacterial toxin production. Awareness of local clindamycin resistance rates is important. Some experts recommend avoiding use of this antibiotic empirically if the local rate of resistance is 10% to 15%. In addition, isolates that appear susceptible to clindamycin but are resistant to erythromycin by standard susceptibility testing may be capable of inducing resistance to clindamycin.

The double disk-diffusion test detects isolates that may become resistant to clindamycin during treatment.

TMP-SMX and tetracyclines are generally not recommended as sole empirical therapy in the treatment of nonpurulent cellulitis, because group A streptococci, which are usually resistant to these antibiotics, may be involved in coinfection. Resistance of group A streptococci to tetracyclines has been well documented, whereas resistance to TMP-SMX remains poorly known.8 Some physicians add an active β-lactam antibiotic to cover streptococci.

Few data exist on the efficacy of the long-acting tetracyclines (doxycycline and minocycline) against MRSA

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Table 4 Oral Agents Used for the Treatment of MRSA in the Community Setting Medication

Usual dose (adults) Main side effects/comments

Cost, $

Clindamycin (Cleocin)

300 mg 3 times daily

Clostridium difficile diarrhea Many patients dislike taste of suspension

6.62 (300 mg)

Trimethoprimsulfamethoxazole (Bactrim, Septra)

1-2 double strength tablet twice daily (tablet: 160/800 mg)

Nausea, vomiting, rash, photosensitivity, hematologic suppression (especially thrombocytopenia) No adequate controlled trials to prove efficacy

1.15 (160/800 mg)

Tetracyclines Doxycycline (Doryx, Monodox, Vibramycin, Vibra-Tabs)

100-200 mg/d, 1 or 2 divided doses

Nausea, photosensitivity

0.08-0.11 (100 mg)

Minocycline 200 mg/d, in 2 (Dynacin, Minocin, Myrac) divided doses

Nausea, photosensitivity

3.40 (100 mg)

Linezolid (Zyvox)

600 mg twice daily

Myelosuppression (especially thrombocytopenia, can also cause anemia, neutropenia), mostly with prolonged use Cost is relatively high

65.00 (600 mg)

Rifampin (Rifadin, Rimactane)

20 mg/kg daily 1 or 2 divided doses; max: 600 mg/d

Discoloration of body fluids, liver function abnormalities, drug interactions Resistance mutation emergence if used alone

1.58 (150 mg) 2.24 (300 mg)

Cost source: Average wholesale price from Red Book, 2008. Evanston, IL: Thomson Healthcare; 2008.

infection. In one retrospective case series of 24 patients with serious tetracycline-susceptible MRSA infections, clinical cure was achieved in 83% of patients.17 Linezolid is active against almost all isolates of CAMRSA and streptococci; however, it should be reserved for patients who do not respond or cannot tolerate traditional agents. The disadvantages of using linezolid include cost, hematologic side effects, and the potential to induce resistance among S aureus strains.18 Rifampin has excellent activity against MRSA. It has been used with good results in combination with tetracycline or with TMP-SMX, although solid data are not available to support this approach. Rifampin monotherapy is contraindicated due to the rapid emergence of resistant mutants.

Fluoroquinolones should not be used to treat SSTIs caused by MRSA; resistance to ciprofloxacin develops rapidly during therapy and widespread resistance is prevalent in many regions.

Parenteral Therapy Parenteral therapy (Table 5) should be considered for patients with severe SSTIs, fever, or with other signs of systemic illness, and patients with diabetes, immunosuppression, or other significant comorbid conditions.

Vancomycin has been the drug of choice for hospi-

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talized patients with invasive MRSA infections.

Nevertheless serious problems with vancomycin have been identified. Recent studies have shown emergence of treatment failures in correlation with increasing, but still considered within the “susceptible” range, vancomycin MICs (<0.5 vs 2.0 µg/mL).19,20 Because of the results of those studies, the CLSI changed the susceptibility and resistance breakpoints from ≤4 µg/mL to ≤2 µg/mL for “susceptible” and from 8 µg/mL to 16 µg/mL to 4 µg/mL to 8 µg/mL for “intermediate” resistance.2 A significant concern remains for patients infected with MRSA who have MICs at the upper range of the susceptible zone—the trough levels of vancomycin (15 µg/mL-20 µg/mL) required to treat such patients may result in renal toxicity. In addition, treatment failure has been attributed to vancomycin intermediateresistant S aureus.19 Failure due to strains that exhibit heterogeneous resistance to vancomycin also occurs.19 These strains are missed by routine laboratory methodologies.

Vancomycin-resistant S aureus (VRSA) is now a threatening reality. A total of 7 cases were identified in the United States between 2002 and 2006; 5 in Michigan, 1 in Pennsylvania, and 1 in New York.20 All VRSA isolates carried the vanA gene and had a median vancomycin MIC of 512 µg/mL.20 For patients who fail

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Table 5 Intravenous Agents for the Treatment of MRSA in the Hospital Setting Medication

Usual dose (adults)

Side effects/comments

Cost, $

Vancomycin (Vancocin)

1 g every 12 h

Not as effective as β-lactam agents for MSRA Treatment failure reported with MRSA strains High MIC potentiates renal toxicity at high trough levels (ie, 15 g/mL-20 g/mL)

7.75 (1 g)

Linezolid (Zyvox)

600 mg every 12 h

Reversible myelosuppression, usually after 2 weeks of therapy; lactic acidosis, peripheral/optic neuropathy; serotonin syndrome Good tissue penetration, particularly in the epithelial-lining tissue

82.00 (600 mg)

Daptomycin (Cubicin)

SSTIs: 4 mg/kg daily Bacteremia/IE: 6 mg/kg daily

Potential muscle toxicity Recommended not to be used with statins Not recommended for pneumonia

206.00 (500 mg)

Tigecycline (Tygacil)

100 mg/d initially, then 50 mg every 12 h

High incidence of nausea, vomiting (>20%) Pregnancy category D Do not use in children <18 years

57.00 (50 mg)

Ceftobiprole (pending approval)

0.5 g every 12 h for grampositive infections (including MRSA)

Nausea (14%), taste disturbance (8%), vomiting (7%) For treatment of cSSSIs, including diabetic foot infections

N/A

Clindamycin (Cleocin)

600-900 mg every 8 h

May be given in regions with low likelihood of resistance Major cause of Clostridium difficile diarrhea

10.51 (600 mg)

Venous irritation (5%) with peripheral line use, asymptomatic indirect; hyperbilirubinemia; arthralgia

150.00 (350/150 mg)

Quinupristin + 7.5 mg/kg every 8 h dalfopristin (Synercid)

Cost source: Average wholesale price from Red Book, 2008. Evanston, IL: Thomson Healthcare; 2008. cSSSIs indicates complicated skin and skin structure infections; IE, infective endocarditis; MIC, minimum inhibitory concentration; SSTIs, skin and soft-tissue infections.

to respond or cannot tolerate vancomycin, the optimal alternative parenteral agent is not known.

Linezolid, daptomycin, tigecycline, and quinupristindalfopristin are indicated for the treatment of SSTIs. Among this group, only daptomycin also has an indication for bacteremia and endocarditis.

Among the older agents, treatment data for MRSA are limited. Parenteral clindamycin may be given in regions where the likelihood of resistance is low, but this agent is considered bacteriostatic and may not be an effective choice for deep-seated infections. In a 1992 study, investigators compared parenteral TMPSMX with vancomycin for the treatment of invasive S aureus infections in intravenous drug users (43 patients received TMP-SMX and 58 received vancomycin).21 TMP-SMX proved to be inferior to vancomycin only in cases of methicillin-sensitive S aureus infections. TMP-SMX was successful in treating all MRSA infections, including tricuspid-valve endocarditis. The authors concluded that TMP-SMX could be

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considered as an alternative to vancomycin in selected cases of MRSA infection.21 Teicoplanin is another glycopeptide with similar efficacy to vancomycin, but with less toxicity; however, it is not available in the United States.

Daptomycin is a cyclic lipopeptide, with rapid bactericidal activity against MRSA produced by depolarization of the bacterial cell membrane. This drug has been approved by the US Food and Drug Administration (FDA) for the treatment of complicated SSTIs at a daily dose of 4 mg/kg, and at a daily dose of 6 mg/kg for the management of bacteremia and rightsided endocarditis. In a randomized trial that included 45 patients with complicated SSTIs caused by MRSA, daptomycin had similar efficacy to vancomycin, with a clinical success rate of 83%.22 In another randomized trial in patients with S aureus bacteremia with or without right-sided endocarditis, daptomycin monotherapy was not inferior to vancomycin plus gentamicin; 53 of 120 patients had a

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successful outcome with daptomycin compared with 48 of 115 patients who received vancomycin (99 of whom had MRSA infections).23 Daptomycin should not be used to treat pneumonia, because its activity is inhibited by pulmonary surfactant.

Linezolid is an alternative agent to glycopeptides. It inhibits the initiation of protein synthesis at the 50S ribosome. Although bacteriostatic for MRSA, it has excellent bioavailability and tissue penetration, particularly in the epithelial lining fluid of the lungs, making this antibiotic a potentially useful option in cases of MRSA pneumonia.

Tigecycline, a parenteral glycylcycline-minocycline derivative, was approved by the FDA in 2005 for the treatment of complicated SSTIs, including those infected with MRSA. A study that combined data from 2 clinical trials demonstrated tigecycline to be as effective as the combination of vancomycin and aztreonam for the management of complicated SSTIs. For MRSA infections, the cure rate was 78.4% for tigecycline compared with 76.5% for vancomycin plus aztreonam.24

Investigational Antimicrobials Several new agents are currently under developmentâ&#x20AC;&#x201D;dalbavancin, telavancin, and oritavancin are semisynthetic glycopeptides characterized by prolonged plasma half-lives. Dalbavancin is bactericidal against gram-positive cocci, including MRSA, and its estimated half-life of 6 to 12 days permits once-weekly dosing.

Clinical trials evaluating the efficacy of dalbavancin demonstrated that it is not inferior to vancomycin in the treatment of catheter-related infection caused by grampositive pathogens (including MRSA). The success rate for dalbavancin was 87% versus 50% for vancomycin.25 Dalbavancin was also as effective as linezolid for the treatment of complicated SSTIs, with a success rate of 91% compared with 89% for linezolid in patients with MRSA infections.26 Ceftobiprole is an advanced-generation pyrolidinone cephalosporin with capacity to bind to PBP-2a. The results of 2 multicenter noninferiority trials involving approximately 1600 patients with complicated SSSIs (cSSSIs) were reported recently. The first trial included patients with gram-positive cSSSI; cure rates were 93.3% and 93.5% for ceftobiprole treatment and vancomycin treatment, respectively. The second trial included a broad range of cSSSIs; clinical cure rate among patients with MRSA infections who received ceftobiprole was 91.4% compared with 86.1% for vancomycin plus ceftazidime.27 Ceftaroline, another new broad-spectrum cephalos-

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porin, is currently under investigation (in phase 2 and 3 clinical trials) in patients with S aureus cSSSIs.

Immunointervention Pooled staphylococcal antibody preparations that neutralize staphylococcal superantigen toxins are being prepared for the treatment of toxic shock syndrome.

Telfibazumab is a humanized monoclonal antibody directed at microbial surface compounds recognizing adhesive matrix molecule clumping factor A, a protein on the S aureus surface that binds to human fibrinogen. This drug is being investigated for the treatment of S aureus infections and also for potential prevention of disease.28 StaphVAX, a promising S aureus polysaccharide conjugate vaccine, has been demonstrated to offer protection against S aureus bacteremia in dialysis patients.

However, the effect is temporary, requiring a booster dose every 6 months.29 In a recent (yet to be published) phase 3, confirmatory study involving more than 3500 hemodialysis patients, StaphVAX did not offer any more benefit than placebo, and therefore, its development has been halted.30 New Test for Rapid Diagnosis of S aureus Bacteremia Based on a fluorescent in-situ hybridization (FISH) assay with peptide nucleic-acid (PNA) probes that target specific sequences of S aureus 16S rRNA, the new PNA FISH test allows for rapid diagnosis of S aureus bacteremia. The performance of the PNA FISH assay was evaluated using 285 blood cultures that had gram-positive cocci resembling staphylococci on Gramâ&#x20AC;&#x2122;s stain.

The sensitivity, specificity, and positive and negative predictive values of the PNA FISH test for the rapid identification of S aureus directly from positive blood culture bottles were 100%, 99.4%, 99.2%, and 100%, respectively. Results are available within 3 hours after blood cultures turn positive.31 The impact of the rapid differentiation of S aureus from coagulase-negative staphylococci in blood cultures using PNA FISH was evaluated in a recent retrospective, cost-effective analysis.32 When comparing the PNA FISH assay results with those for a control group (53 and 34 patients, respectively), a significant reduction was found with use of the new assay in median length of hospital stay from 6 to 4 days, as well as a trend toward reduced vancomycin use, with a decreased cost of $4000 per patient.32 Continued Emergence of Resistance in S aureus S aureus has developed resistance to most antibiotics, including penicillin, methicillin, linezolid, and dapto-

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mycin, rather rapidly. Resistant strains were reported from around the world, within 1 or 2 years after the introduction of each of these agents. With vancomycin, the history was different; after the introduction of vancomycin in 1958, the first vancomycin intermediateresistant S aureus was found in 1997 in Japan (39 years later). The first truly resistant isolate (ie, VRSA) was identified in Detroit, Michigan, in 2002. According to the CLSI, vancomycin intermediate-resistant S aureus (or glycopeptide intermediate-resistant S aureus) and VRSA are defined as having MICs of 4 µg/mL to 8 µg/mL, and ≥16 µg/mL, respectively.2 In VRSA strains, resistance is mediated by the presence of operons that encode enzymes that eliminate precursors with high affinity to vancomycin. In glycopeptide intermediate-resistant S aureus strains, reduced susceptibility is the result of the production of increased numbers of D-Ala-D-Ala residues on the nascent cell wall that serve as dead-end binding sites for vancomycin.

The result is a reduced vancomycin diffusion coefficient and sequestration of this drug within the cell wall by these false targets.33 A microbiological definition of daptomycin resistance has not been established yet; however, a value of MIC >1.0 µg/mL is considered nonsusceptible in accordance with the CLSI guidelines.2 Wild-type S aureus with MICs of >1.0 µg/mL are rare but have been recovered from patients who had previously received either vancomycin, daptomycin, or, in some cases, had not received antibiotics previously. At this time, multiple studies have reported that 90% of S aureus isolates in healthcare settings still have daptomycin MICs <0.5 µg/mL.34 It is thought that glycopeptide exposure induces the formation of a thicker cell wall, thus preventing the diffusion of daptomycin into the bacteria. In addition, mutations in certain genes, such as MPRF (which encodes lysylphosphatidylglycerol synthetase), YYCG (which encodes sensor histidine kinase), and RPOB/RPOC (encode β and β′ subunits of RNA polymerase), were found in S aureus strains with daptomycin MIC of more than 1.0 µg/mL.35 Linezolid resistance is associated with mutations in the central loop of domain V in the 23S ribosomal RNA, and increased MICs are associated with greater numbers of mutations. The most frequent mutation associated with linezolid resistance in both staphylococci and enterococci strains is G2576T. Another mutation (T2500A) was characterized in a single patient isolate of MRSA. Recently, the presence of the CFR gene (a gene encoding an rRNA methyltransferase, and is called CFR for chloramphenicol-florfenicol resistance) has been

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identified in a clinical MRSA isolate (designated CM-05) from Colombia.33,36 Linezolid resistance in MRSA is still considered rare.

Controlling MRSA Infection Optimal measures for the prevention of MRSA infections remain under investigation. The most common source of HA-MRSA is colonized or infected patients; the most important mode of transmission is via hands, especially from healthcare personnel. Basic infection control practices are integral to the prevention and control of MRSA in healthcare settings. In its “Information about MRSA for Healthcare Personnel” and the Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings 2007, the CDC emphasizes several standard and contact precautions to prevent the transmission of MRSA.37

Community-associated infections can recur in individuals and can spread within families.

Community-associated infections can recur in individuals and can spread within families. Clinicians should educate patients or their caretakers, and when possible, household members, on methods to limit further spread of infection. The CDC has recommended the following measures in an effort to prevent the spread of CAMRSA infections in the community37: • Keep hands clean by washing thoroughly with soap and water or by using an alcohol-based hand sanitizer • Keep cuts and scrapes clean and covered with a bandage until healed • Avoid contact with other people’s wounds or bandages • Avoid sharing personal items, such as towels, washcloths, razors, clothing, or uniforms.

To date, no data support the use of agents to eliminate colonization in patients with MRSA infection or their contacts. However, it may be reasonable to attempt decolonization if a patient has had multiple recurrences of MRSA infection or ongoing MRSA transmission is occurring in a well-defined, closely associated cohort (such as a household).38 The role of early screening for MRSA colonization in hospitalized patients is unclear. In a recent study involving more than 21,000 surgical patients, 2 MRSA control strategies (rapid screening on admission plus standard infection control measures vs standard infection control alone) were used to determine the effect of an early MRSA detection strategy on nosocomial

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MRSA infection rates. Rapid MRSA screening on admission did not reduce the rate of nosocomial MRSA infection.39

Conclusion MRSA now represents a common infectious agent in any environment. More virulent than ever, MRSA keeps producing high rates of morbidity and mortality.

MRSA also has the ability to become easily resistant every time a new therapeutic agent is introduced, except for vancomycin, which was considered useful for the past 40 years; however, increasing rates of treatment failure with strains reported to have MICs in the “susceptible” range have been widely documented. The continuous emergence of resistant strains has created an enormous difficulty for the management of MRSA infections. It is now crucial to make the diagnosis very early and in an effective way. Many potent antibiotics are being developed as well as promising vaccines; however, control measures to identify populations at risk and strategies to prevent transmission should play an essential aspect of care. ■ Disclosure Statement Dr Levine is on the Speakers’ Bureau of Cubist Pharmaceuticals and Novartis; receives research support from Cubist and Theravance Therapeutics (Astellas); and is on the advisory board of Cubist, Merck & Co, Novartis, and Theravance.

References 1. van Belkum A, Verbrugh H. 40 years of methicillin resistant Staphylococcus aureus. BMJ. 2001;323:644-645.

2. Division of Healthcare Quality Promotion, National Center for Preparedness, Detection, and Control of Infectious Diseases. Laboratory detection of oxacillin/methicillin-resistant Staphylococcus aureus. February 2005. www.cdc.gov/ncidod/dhqp/ar_lab_mrsa.html. Accessed July 29, 2008.

3. Ito T, Kuwahara K, Hiramatsu K. Staphylococcal cassette chromosome mec (SCCmec) analysis of MRSA. Methods Mol Biol. 2007;391:87-102.

4. Popovich K, Weinstein R, Hota B. Are community-associated methicillin-resistant Staphylococcus aureus (MRSA) strains replacing traditional nosocomial MRSA strains? Clin Infect Dis. 2008;46:787-794.

5. Siegel JD, Rhinehart E, Jackson M, Chiarello L; Healthcare Infection Control Practices Advisory Committee. Management of multidrugresistant organisms in healthcare settings, 2006. www.cdc.gov/ncidod/ dhqp/pdf/ar/mdroguideline2006.pdf. Accessed January 2, 2009.

6. Klevens RM, Morrison M, Nadle J, et al. Invasive methicillin-resistant Staphylococcus aureus infections, in the United States. JAMA. 2007;298: 1763-1571.

7. McDougal LK, Steward CD, Killgore GE, et al. Pulse-field gel electrophoresis typing of oxacillin-resistant Staphylococcus aureus isolates from the United States: establishing a national database. J Clin Microbiol.

2003;41:5113-5120.

8. Diep BA, Gill SR, Chang RF, et al. Complete genome sequence of USA300, an epidemic clone of community-acquired methicillin-resistant Staphylococcus aureus. Lancet. 2006;367:731-739.

9. Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;

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352:1436-1444.

10. Sing A, Tuschak C, Hörmansdorfer S. Methicillin-resistant Staphylococcus aureus in a family and its pet cat. N Engl J Med. 2008;358: 1200-1201.

11. Kallen AJ, Brunkard J, Moore Z, et al. Staphylococcus aureus community-acquired pneumonia during the 2006 to 2007 influenza season.

Ann Emerg Med. June 5, 2008. Epub ahead of print.

12. Stryjewski ME, Chambers HF. Skin and soft-tissue infections caused by community-acquired methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2008;46(suppl 5):S368-S377.

13. Hageman JC, Uyeki TM, Francis JS, et al. Severe communityacquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis. 2006;12:894-899.

14. Centers for Disease Control and Prevention: MMWR. Severe methicillin-resistant Staphylococcus aureus community-acquired pneumonia associated with influenza in Louisiana and Georgia, December 2006–January 2007. JAMA. 2007;297:2070-2072.

15. Millar BC, Prendergast BD, Moore JE. Community-associated MRSA (CA-MRSA): an emerging pathogen in infective endocarditis. J Antimicrob Chemother. 2008;61:1-7.

16. Adem PV, Montgomery CP, Husain AN, et al. Staphylococcus aureus sepsis and the Waterhouse-Friderichsen syndrome in children. N Engl J Med. 2005;353:1245-1251.

17. Ruhe JJ, Monson T, Bradsher RW, et al. Use of long-acting tetracyclines for methicillin-resistant Staphylococcus aureus infections: case series and review of the literature. Clin Infect Dis. 2005;40:1429-1434.

18. Stevens DL, Herr D, Lampiris H, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus infections. Clin Infect Dis. 2002;34:1481-1490.

19. Charles PG, Ward PB, Johnson PD, et al. Clinical features associated with bacteremia due to heterogeneous vancomycin-intermediate Staphylococcus aureus. Clin Infect Dis. 2004;38:448-451.

20. Sievert DM, Rudrik JT, Patel JB, et al. Vancomycin-resistant Staphylococcus aureus in the United States, 2002-2006. Clin Infect Dis. 2008;46:668-674.

21. Markowitz N, Quinn EL, Saravolatz LD. Trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of Staphylococcus aureus infection. Ann Intern Med. 1992;117:390-398.

22. Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis. 2004;38:1673-1681.

23. Fowler VG Jr, Boucher HW, Corey GR, et al. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med. 2006;355:653-665.

24. Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis. 2005;41(suppl 5):S341-S353.

25. Raad I, Darouiche R, Vasquez J, et al. Efficacy and safety of weekly dalbavancin therapy for catheter-related bloodstream infection caused by gram-positive pathogens. Clin Infect Dis. 2005;40:374-380.

26. Jauregui LE, Babazadeh Seltzer E, et al. Randomized, double-blind comparison of once weekly dalbavancin versus twice daily linezolid therapy for the treatment of complicated skin and skin structure infections.

Clin Infect Dis. 2005;41:1407-1415.

27. Deresinski SC. The efficacy and safety of ceftobiprole in the treatment of complicated skin and skin structure infections: evidence from 2 clinical trials. Diagn Microbiol Infect Dis. 2008;61:103-109.

28. John JF Jr. Drug evaluation: tefibazumab—a monoclonal antibody against staphylococcal infection. Curr Opin Mol Ther. 2006;8:455-460.

29. Shinefield HR, Black S. Prevention of Staphylococcus aureus infections: advances in vaccine development. Expert Rev Vaccines. 2005;4:669-676.

30. Schaffer AC, Lee JC. Vaccination and passive immunisation against Staphylococcus aureus. Int J Antimicrob Agents. 2008;32(suppl 1):S71-S78.

31. González V, Padilla E, Giménez M, et al. Rapid diagnosis of Staphylococcus aureus bacteremia using S aureus PNA FISH. Eur J Clin Microbiol Infect Dis. 2004;23:396-398.

32. Forrest GN, Mehta S, Weekes E, et al. Impact of rapid in situ

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hybridization testing on coagulase-negative staphylococci positive blood cultures. J Antimicrob Chemother. 2006;58:154-158.

33. Sakoulas G, Moellering RC Jr. Increasing antibiotic resistance among methicillin-resistant Staphylococcus aureus strains. Clin Infect Dis. 2008;46(suppl 5):S360-S367.

34. Boucher HW, Sakoulas G. Perspectives on daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis. 2007; 45:601-608.

35. Sharma M, Riederer K, Chase P, et al. High rate of decreasing daptomycin susceptibility during the treatment of persistent Staphylococcus aureus bacteremia. Eur J Clin Microbiol Infect Dis. 2008;27:433-437.

36. Arias CA, Vallejo M, Reyes J, et al. Clinical and microbiological

aspects of linezolid resistance mediated by the cfr gene encoding a 23sRNA methyltransferase. J Clin Microbiol. 2008;46:892-896.

37. Centers for Disease Control and Prevention. Information about MRSA for healthcare personnel. Updated October 2007. www.cdc.gov/ ncidod/dhqp/ar_mrsa_healthcareFS.html. Accessed August 8, 2008.

38. Strategies for clinical management of MRSA in the community: summary of an expertsâ&#x20AC;&#x2122; meeting convened by the Centers for Disease Control and Prevention. March 2006. www.cdc.gov/ncidod/dhqp/ pdf//ar/CAMRSA_ExpMtgStrategies.pdf. Accessed August 8, 2008.

39. Harbarth S, Fankhauser C, Schrenzel J, et al. Universal screening for methicillin-resistant Staphylococcus aureus at hospital admission and nosocomial infection in surgical patients. JAMA. 2008;299:1149-1157.

STAKEHOLDER PERSPECTIVE Prevention and Control of Methicillin-Resistant Staphylococcus aureus MEDICAL/PHARMACY DIRECTORS: The medical and operational complexities of responding to antimicrobial resistance, convincingly demonstrated by the nearly 50 years of human experience with methicillin-resistant Staphylococcus aureus (MRSA), are well described in this expansive review.

Formerly encountered only in tertiary care or long-term care settings, MRSA has become a significant infection control challenge in nearly all healthcare settings. The boundaries surrounding healthcare-associated (HA)-MRSA infections have rapidly dissolved with the recent evolution of strains that cause disease in persons within the community.

These new community-associated (CA)-MRSA strains have unique virulence factors that may facilitate the transmission of the microbe and the development of disease. Outbreaks of infection have occurred in group settings in the community, such as prisons, schools, military barracks, and households.

The cost of treating hospitalized patients with HA-MRSA infections is nearly double that of treating hospitalized patients without these infections, and the cost for treating CA-MRSA infections exceeds the cost of treating infections with methicillin-sensitive strains. These increased costs pose formidable challenges for health plans and insurers, and represent a growing burden on the US healthcare industry as a whole.

Antimicrobial treatment for MRSA is complex, dynamic, and subject to localized pressures, thereby requiring constant attention by pharmacy and formulary decision makers. The continuing emergence of additional resistance capacity as we use new drugs is especially troublesome and mandates adher-

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ence to standards of judicious use of current antimicrobial therapies.

Recent advances have increased the number of new and promising antimicrobials in our armamentarium pipeline. Ensuring that effective therapies successfully reach use in practice is as difficult now as it always has been. Attempts to develop effective vaccines against virulence factors of S aureus have had mixed results, and no new vaccine appears ready for use yet.

In the face of these complex medical challenges, nonpharmaceutical approaches, specifically, proven infection control measures, may represent our best chance to control the spread of MRSA in both the healthcare and community settings. Educating healthcare workers and family members in the basics of hand washing may represent the greatest weapon against drug-resistant microbes.

Addressing the many issues of multidrug-resistant organisms, such as MRSA, requires a long-term commitment from physicians, pharmacists, health plan directors, epidemiologists, and benefits designers. Policies and procedures for antimicrobial use and payer coverage must always consider the current local resistance patterns. Only when our response is coordinated and inclusive will we tip the balance against MRSA and for our patients.

Dennis M. Perrotta, PhD, CIC Associate Director for Emerging Infectious Diseases National Center for Emergency Medical Preparedness and Response Texas A&M Health Science Center College Station, TX

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What Changes Can Your Health Plan Expect from the New Administration?

Interview with Dan Mendelson

A major change in mindset in the new administration will likely result in a new attitude toward health plans and patients, says Dan Mendelson. Drawing on his experience as President and Founder of Avalere Health and his previous role as Associate Director for Health at the White House’s Office of Management and Budget during the Clinton Administration, Mr Mendelson outlines key changes that will have direct implications for decision makers in healthcare, including (1) a greater emphasis on plan beneficiaries protection, and (2) increased regulatory focus on plan

operations. Plans can expect to have less government trust in actuarial submissions and probably more oversight and supervision of the daily operation of a plan.

This is a major shift we can expect to see in the coming months and years in Washington—from the administration of health plans to the point of view of the beneficiary. Other topics discussed include the potential benefits of new medication postmarketing surveillance, expediting drug approvals, and the new emphasis on comparative effectiveness research and health information technology.

Patient Cost-Sharing on the Rise Melinda C. Haren, RN; Kirk McConnell

The Zitter Group conducted a national survey of payers and employers to investigate how they interact in the creation of benefit design to employees and plan beneficiaries. The authors focus on the current trend of shifting costs to patients, suggesting that cost-sharing remains the prevailing cost-containment strategy used by insurers and employers, who assume that this strategy will have mini-

mal impact on health outcomes. In contrast, the authors claim, accumulating evidence shows that cost-shifting to the plan participant leads to undesirable health and cost outcomes, noting that this strategy has failed to slow health cost growth. Nevertheless, they anticipate that healthcare payers will continue to rely on this modality as a primary cost-containment strategy.

Employer-Based Cardiovascular Health Initiative Claiborne E. Reeder, RPh, PhD; Christine H. Divers, PhD, MS; Del Deem; Becky J. Cherney; Gaye Fortner, RN, BSN, MSN; Louise Y. Probst

The 2008 direct and indirect costs of cardiovascular disease in the United States are estimated to be $448.5 billion. The Ready, Set, Goal program that focused on improving employees’ cardiovascular health was initiated by 5 employer groups to evaluate the impact of education and behavior intervention on employees with cardiovascular risk factors, as well as the cost to

their employers. The intervention had significant improvements in some cardiovascular end points, including low-density lipoprotein levels and blood pressure.

Results from this program suggest that worksite-initiated cardiovascular education intervention may not only improve employees’ health but may also reduce employers’ costs.

Methicillin-Resistant Staphylococcus aureus Jose L. Raygada, MD; Donald P. Levine, MD

Two infectious disease experts review the current understanding of the epidemiology, clinical manifestations, and management of methicillin-resistant Staphylococcus aureus (MRSA), including the problem of drug resistance. MRSA is no longer confined to the hospital and is a growing cause of infections acquired in the community, which, in turn, are infecting hospitalized patients with novel strains not seen previously in the hospital set-

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ting. Antibiotic resistance has reached epidemic proportions in the United States, Drs Raygada and Levine say, which is particularly significant in potentially life-threatening MRSA-type infections. Resistance to many antibiotics used to treat these infections further complicates the management and spread of MRSA infections. The authors emphasize the need for controlling transmission and educating patients on prevention strategies.

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BANZEL™ (rufinamide) 200, 400 mg Tablets Brief Summary of full Prescribing Information: Please consult package insert for full Prescribing Information.

INDICATIONS AND USAGE BANZEL (rufinamide) is indicated for adjunctive treatment of seizures associated with LennoxGastaut syndrome in children 4 years and older and adults. CONTRAINDICATIONS BANZEL is contraindicated in patients with Familial Short QT syndrome (see PRECAUTIONS, QT Shortening). WARNINGS Suicidal Behavior and Ideation Antiepileptic drugs increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any antiepileptic drug for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different antiepileptic drugs showed that patients randomized to one of the antiepileptic drugs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 antiepileptic drug-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number of events is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior was observed as early as one week after starting drug treatment and persisted for at least 24 weeks. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with antiepileptic drugs of varying mechanisms of action and across a range of indications suggests that the risk applies to all antiepileptic drugs used for any indication. The risk did not vary substantially by age in the clinical trials analyzed. The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy (3.5) than in clinical trials for psychiatric (1.5) or other conditions (1.9), but the absolute risk differences were similar (2.4, 2.9, and 0.9, respectively). Anyone considering prescribing BANZEL or any other antiepileptic drug must balance this risk with the risk of untreated illness. Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that antiepileptic drugs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers. Central Nervous System Reactions: Use of BANZEL has been associated with central nervous system–related adverse reactions. The most significant of these can be classified into two general categories: 1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia (see ADVERSE REACTIONS). PRECAUTIONS QT Shortening Formal cardiac ECG studies demonstrated shortening of the QT interval (up to 20 msec) with BANZEL treatment. In a placebo-controlled study of the QT interval, a higher percentage of BANZEL-treated subjects (46% at 2400 mg, 46% at 3200 mg, and 65% at 4800 mg) had a QT shortening of greater than 20 msec at Tmax compared to placebo (5 – 10%). Reductions of the QT interval below 300 msec were not observed in the formal QT studies with doses up to 7200 mg/day. Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias. The degree of QT shortening induced by BANZEL is without any known clinical risk.

Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec. Nonclinical data also indicate that QT shortening is associated with ventricular fibrillation. Patients with Familial Short QT syndrome should not be treated with BANZEL (see CONTRAINDICATIONS). Caution should be used when administering BANZEL with other drugs that shorten the QT interval. Multi-organ Hypersensitivity Reactions Multi-organ hypersensitivity syndrome, a serious condition sometimes induced by antiepileptic drugs, has occurred in association with BANZEL therapy in clinical trials. One patient experienced rash, urticaria, facial edema, fever, elevated eosinophils, stuporous state, and severe hepatitis, beginning on day 29 of BANZEL therapy and extending over a course of 30 days of continued BANZEL therapy with resolution 11 days after discontinuation. Additional possible cases presented with rash and one or more of the following: fever, elevated liver function studies, hematuria, and lymphadenopathy. These cases occurred in children less than 12 years of age, within four weeks of treatment initiation, and were noted to resolve and/or improve upon BANZEL discontinuation. This syndrome has been reported with other anticonvulsants and typically, although not exclusively, presents with fever and rash associated with other organ system involvement. Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. If this reaction is suspected, BANZEL should be discontinued and alternative treatment started. All patients who develop a rash while taking BANZEL must be closely supervised. Withdrawal of AEDs As with all antiepileptic drugs, BANZEL should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus. If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision. In clinical trials, BANZEL discontinuation was achieved by reducing the dose by approximately 25% every two days. Status Epilepticus Estimates of the incidence of treatment emergent status epilepticus among patients treated with BANZEL are difficult because standard definitions were not employed. In a controlled Lennox Gastaut syndrome trial, 3 of 74 (4.1 %) BANZEL-treated patients had episodes that could be described as status epilepticus in the BANZEL-treated patients compared with none of the 64 patients in the placebo-treated patients. In all controlled trials that included patients with different epilepsies, 11 of 1240 (0.9%) BANZEL-treated patients had episodes that could be described as status epilepticus compared with none of 635 patients in the placebo-treated patients. Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with BANZEL and should counsel them in its appropriate use. A patient Medication Guide is available for BANZEL. The prescriber or healthcare professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking BANZEL. Suicidal Thinking and Behavior – Patients, their caregivers, and families should be informed that antiepileptic drugs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Patients should be instructed to take BANZEL only as prescribed. BANZEL should be taken with food.

As with all centrally acting medications, alcohol in combination with BANZEL may cause additive central nervous system effects. Patients should be advised about the potential for somnolence or dizziness and advised not to drive or operate machinery until they have gained sufficient experience on BANZEL to gauge whether it adversely affects their mental and/or motor performance. Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective (see Drug Interactions). Additional non-hormonal forms of contraception are recommended when using BANZEL. Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be advised to notify their physician if they are breast-feeding or intend to breast-feed. Patients should be advised to notify their physician if they experience a rash associated with fever. Laboratory Tests Leucopenia (white cell count < 3X109 L) was more commonly observed in BANZELtreated patients (43 of 1171, 3.7%) than placebo-treated patients (7 of 579, 1.2%) in all controlled trials. Drug Interactions In vitro and in vivo studies have shown that BANZEL is unlikely to be involved in significant pharmacokinetic interactions.

BANZEL can increase plasma concentrations of phenytoin by 21% or more due to non-linear pharmacokinetics. Valproate can increase BANZEL concentrations up to 70%. Patients stabilized on BANZEL before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a BANZEL dose lower than 400 mg. Coadministration of BANZEL with ethinyl estradiol and norethindrone can decrease AUC0-24 of these hormonal contraceptives by 22% and 14% and Cmax by 31% and 18%, respectively. Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL (see Information for Patients). Drug/Laboratory Test Interactions There are no known interactions of BANZEL with commonly used laboratory tests. Antiepileptic Drugs Effects of BANZEL on other AEDs Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide Cavss levels had little effect on the pharmacokinetics of other AEDs. Any effects, when they occur, have been more marked in the pediatric population. Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (Cavss 15 µg/mL) is predicted to increase plasma levels of phenytoin by 7 to 21%. As phenytoin is known to have non-linear pharmacokinetics (clearance becomes saturated at higher doses), it is possible that exposure will be greater than the model prediction. Effects of Other AEDs on BANZEL Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital appear to increase the clearance of BANZEL. Given that the majority of clearance of BANZEL is via a non-CYP-dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. Other factors explaining this interaction are not understood. Any effects, where they occurred were likely to be more marked in the pediatric population. Valproate: Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. In children, valproate administration may lead to elevated levels of rufinamide by up to 70%.

Patients stabilized on BANZEL before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a BANZEL dose lower than 400 mg. Effects of BANZEL on other Medications Hormonal contraceptives: Co-administration of BANZEL (800 mg BID for 14 days) and OrthoNovum 1/35® resulted in a mean decrease in the ethinyl estradiol AUC0-24 of 22% and Cmax by 18% and norethindrone AUC0-24 by 14% and Cmax by 18%, respectively. The clinical significance of this decrease is unknown. Female patients of childbearing age should be warned that the concurrent use of BANZEL with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL (see

Information for Patients). Triazolam: Co-administration and pre-treatment with BANZEL (400 mg bid) resulted in a 37% decrease in AUC and a 23% decrease in Cmax of triazolam, a CYP 3A4 substrate. Olanzapine: Co-administration and pretreatment with BANZEL (400mg bid) resulted in no change in AUC and Cmax of olanzapine, a CYP 1A2 substrate.

Carcinogenicity, Mutagenicity, Impairment of Fertility Carcinogenicity: Rufinamide was given in the diet to mice at 40, 120, and 400 mg/kg/day and to rats at 20, 60, and 200 mg/kg/day for two years. The doses in mice were associated with plasma AUCs 0.1 to 1 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day).

Increased incidences of tumors (benign bone tumors (osteomas) and/or hepatocellular adenomas and carcinomas) were observed in mice at all doses. Increased incidences of thyroid follicular adenomas were observed in rats at all but the low dose; the low dose is <0.1 times the MRHD on a mg/m2 basis. Mutagenicity: Rufinamide was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or the in vitro mammalian cell point mutation assay. Rufinamide was not clastogenic in the in vitro mammalian cell chromosomal aberration assay or the in vivo rat bone marrow micronucleus assay. Impairment of Fertility: Oral administration of rufinamide (doses of 20, 60, 200, and 600 mg/kg/day) to male and female rats prior to mating and throughout mating, and continuing in females up to day 6 of gestation resulted in impairment of fertility (decreased conception rates and mating and fertility indices; decreased numbers of corpora lutea, implantations, and live embryos; increased preimplantation loss; decreased sperm count and motility) at all doses tested. Therefore, a no-effect dose was not established. The lowest dose tested was associated with a plasma AUC ≈ 0.2 times the human plasma AUC at the MRHD. PREGNANCY Pregnancy Category C Rufinamide produced developmental toxicity when administered orally to pregnant animals at clinically relevant doses. Rufinamide was administered orally to rats at doses of 20, 100, and 300 mg/ kg/day and to rabbits at doses of 30, 200, and 1000 mg/kg/day during the period of organogenesis (implantation to closure of the hard palate); the high doses are associated with plasma AUCs ≈2 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Decreased fetal weights and increased incidences of fetal skeletal abnormalities were observed in rats at doses associated with maternal toxicity. In rabbits, embryo-fetal death, decreased fetal body weights, and increased incidences of fetal visceral and skeletal abnormalities occurred at all but the low dose. The highest dose tested in rabbits was associated with abortion. The no-effect doses for adverse effects on rat and rabbit embryo-fetal development (20 and 30 mg/kg/day, respectively) were associated with plasma AUCs ≈0.2 times that in humans at the MRHD). In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at oral doses of 5, 30, and 150 mg/kg/day (associated with plasma AUCs up to ≈1.5 times that in humans at the MRHD), decreased offspring growth and survival were observed at all doses tested. A no-effect dose for adverse effects on pre- and post-natal development was not established. The lowest dose tested was associated with plasma AUC <0.1 times that in humans at the MRHD. There are no adequate and well-controlled studies in pregnant women. BANZEL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Labor and Delivery The effect of BANZEL on labor and delivery in humans is not known. Nursing Mothers Rufinamide is likely to be excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants from BANZEL, a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother. Pediatric Use The safety and effectiveness in patients with Lennox-Gastaut syndrome have not been established in children less than 4 years. Geriatric Use Clinical studies of BANZEL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. A study evaluating the pharmacokinetics of rufinamide in elderly subjects showed that there were no significant differences in the plasma and urine pharmacokinetic parameters of rufinamide between the younger and elderly subjects under both single and multiple dose treatments. ADVERSE REACTIONS Placebocontrolled double-blind studies were performed in adults and in pediatric patients, down to age of 4, in other forms of epilepsy, in addition to the trial in Lennox-Gastaut syndrome. Data on CNS Reactions (see WARNINGS) from the LennoxGastaut study are presented first. Because there is no reason to suspect that adverse reactions would substantially differ between these patient populations, safety data from all of these controlled studies are then presented. Most of these adverse reactions were mild to moderate and transient in nature. Common central nervous system reactions in the controlled trial of patients 4 years or older with Lennox-Gastaut syndrome treated with BANZEL as adjunctive therapy (see WARNINGS): Somnolence was reported in 24.3% of BANZEL-treated patients compared to 12.5% of placebo patients and led to study discontinuation in 2.7% of treated patients compared to 0% of placebo patients. Fatigue was reported in 9.5% of BANZELtreated patients compared to 7.8% of placebo patients. It led to study discontinuation in 1.4% of treated patients and 0% of placebo patients. Dizziness was reported in 2.7% of BANZEL-treated patients compared to 0% of placebo patients, and did not lead to study discontinuation. Ataxia and gait disturbance were reported in 5.4% and 1.4% of BANZEL-treated patients, respectively, and in no placebo patients. Balance disorder and abnormal coordination were each reported in 0% of BANZELtreated patients and 1.6% of placebo patients. None of these reactions led to study discontinuation. All Adverse Reactions for All Treated Patients with Epilepsy, Double-blind Adjunctive Therapy Studies: The most commonly observed (≥10%) adverse reactions in BANZEL-treated patients, when used as adjunctive therapy at all doses studied (200 to 3200 mg/day) with a higher frequency than in placebo were: headache, dizziness, fatigue, somnolence, and nausea. At the target dose of 45 mg/kg/day in children, the most commonly observed (≥5%) adverse reactions in BANZEL-treated patients, given as adjunctive therapy, with a higher frequency than placebo were: somnolence, vomiting, headache, fatigue, dizziness, nausea, and convulsion. At doses up to 3200 mg/day in adults, the most commonly observed (≥5%) adverse reactions in BANZELtreated patients, given as adjunctive therapy, at all doses studied, with a higher frequency than placebo were: headache, dizziness, fatigue, nausea, somnolence, diplopia, nasopharyngitis, tremor, nystagmus, vision blurred and vomiting.

Treatment-emergent adverse reactions in all pediatric double-blind adjunctive trials at the recommended dose of 45 mg/kg/ day that occurred in at least 3% of BANZEL-treated patients (N=187) and occurred more frequently than in placebo patients (N=182) included somnolence, vomiting, headache, fatigue, dizziness, nausea, influenza, nasopharyngitis, decreased appetite, rash, ataxia, diplopia, bronchitis, sinusitis, psychomotor hyperactivity, abdominal pain upper, aggression, ear infection, disturbance in attention, and pruritis. Treatment-emergent adverse reactions in all adult double-blind adjunctive trials (up to 3200mg/day) that occurred in at least 3% of BANZEL-treated patients (N=823) and occurred more frequently than in placebo patients (N=376) included headache, dizziness, fatigue, nausea, somnolence, diplopia, tremor, nystagmus, vision blurred, vomiting, ataxia, abdominal pain upper, anxiety, constipation, dyspepsia, back pain, gait disturbance, and vertigo. In these studies, either BANZEL or placebo was added to current AED therapy. Discontinuation in Controlled Clinical Studies In controlled double-blind adjunctive clinical studies, 9.0% of patients receiving BANZEL as adjunctive therapy and 4.4% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (>1%) used as adjunctive therapy were generally similar in adults and children. In pediatric double-blind adjunctive clinical studies, 8.0% of patients receiving BANZEL as adjunctive therapy and 2.2% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (>1%) used as adjunctive therapy included convulsion, rash, fatigue, and vomiting. In adult double-blind adjunctive clinical studies (up to 3200 mg/day), 9.5% of patients receiving BANZEL as adjunctive therapy and 5.9% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (>1%) used as adjunctive therapy included dizziness, fatigue, headache, nausea, and ataxia.

Other Adverse Events Observed During Clinical Trials: BANZEL has been administered to 1978 individuals during all epilepsy clinical trials (placebo-controlled and open-label). Adverse events occurring during these studies were recorded by the investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of patients having adverse events, these events were grouped into standardized categories using the MedDRA dictionary. Adverse events occurring at least three times and considered possibly related to treatment are included in the System Organ Class listings below. Terms not included in the listings are those already included above, those too general to be informative, those related to procedures, and terms describing events common in the population. Some events occurring fewer than 3 times are also included based on their medical significance. Because the reports include events observed in open label, uncontrolled observations, the role of BANZEL in their causation cannot be reliably determined. Events are classified by body system and listed in order of decreasing frequency as follows: frequent adverse events– those occurring in at least 1/100 patients; infrequent adverse events– those occurring in 1/100 to 1/1000 patients; rare– those occurring in fewer than 1/1000 patients. Blood and Lymphatic System Disorders: Frequent: anemia. Infrequent: lymphadenopathy, leukopenia, neutropenia, iron deficiency anemia, thrombocytopenia. Cardiac Disorders: Infrequent: bundle branch block right, atrioventricular block first degree. Metabolic and Nutritional Disorders: Frequent: decreased appetite, increased appetite.

Renal and Urinary Disorders: Frequent: pollakiuria. Infrequent: urinary incontinence, dysuria, hematuria, nephrolithiasis, polyuria, enuresis, nocturia, incontinence. DRUG ABUSE AND DEPENDENCE The abuse and dependence potential of BANZEL has not been evaluated in human studies. OVERDOSAGE Because strategies for the management of overdose are continually evolving, it is advisable to contact a Certified Poison Control Center to determine the latest recommendations for the management of an overdose of any drug. One overdose of 7200 mg/day BANZEL was reported in an adult during the clinical trials. The overdose was associated with no major signs or symptoms, no medical intervention was required, and the patient continued in the study at the target dose. Treatment or Management of Overdose: There is no specific antidote for overdose with BANZEL. If clinically indicated, elimination of unabsorbed drug should be attempted by induction of emesis or gastric lavage. Usual precautions should be observed to maintain the airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of the patient. Hemodialysis: Standard hemodialysis procedures may result in limited clearance of rufinamide. Although there is no experience to date in treating overdose with hemodialysis, the procedure may be considered when indicated by the patient’s clinical state. For further product information, please visit www.BANZEL.com or call the Eisai Medical Services Department at 1-888-274-2378.

Rx Only BANZEL™ is a trademark of Novartis Pharma AG, used under license. Manufactured by Eisai Co., Ltd. Marketed by Eisai Inc., Woodcliff Lake, NJ 07677 ©2008 Eisai Inc. Printed in U.S.A. Revised November 2008 RUF000089

NEW treatment option for seizures associated with Lennox-Gastaut syndrome

Now Approved

BANZEL™ is indicated for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4 years and older and adults.

Important Safety Information Antiepileptic drugs (AEDs) increase the risk of suicidal thoughts or behavior in patients taking these drugs. Patients should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior.

Use of BANZEL has been associated with central nervous system– related adverse reactions, such as somnolence or fatigue, coordination abnormalities, dizziness, gait disturbances, and ataxia.

BANZEL is contraindicated in patients with Familial Short QT syndrome.

These patients should not be treated with BANZEL. Caution should be used when administering BANZEL with other drugs that shorten the QT interval.

As with all AEDs, BANZEL should be gradually withdrawn to minimize

the risk of increased seizure frequency. Multi-organ hypersensitivity syndrome has been reported in association with BANZEL therapy.

In clinical trials, hypersensitivity reactions occurred mostly in the pediatric population and usually within 4 weeks of starting BANZEL therapy. If this reaction is suspected, BANZEL should be discontinued and alternative treatment started. All patients who develop a rash while taking BANZEL must be closely supervised.

In all patients with epilepsy treated with BANZEL in double-blind, adjunctive therapy studies, the most commonly observed adverse reactions were headache, dizziness, fatigue, somnolence, and nausea.

Please see the brief summary of Prescribing Information on the following page.

Visit www.BANZEL.com for more information. ©2008 Eisai Inc. All rights reserved. RUF000067 December 2008 BANZEL™ is a trademark of Novartis Pharma AG, used under license.

Manufactured by Eisai Co., Ltd. Marketed by Eisai Inc., Woodcliff Lake, NJ 07677