September 2008, Vol 1, No 7

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ SEPTEMBER 2008

VOLUME 1, NUMBER 7

EDITORIAL

The Governing Dynamics of the Healthcare Universe: Thinking Lagrangian Robert E. Henry

Quality in the Pharmacy Environment Jan E. Berger, MD, MJ BUSINESS

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Delaware’s Wellness Program: Motivating Employees Improves Health and Saves Money Jennifer “J. J.” Davis REGULATORY

The Better Quality Information to Improve Care for Medicare Beneficiaries Project: Exploring Approaches to Physician Performance Measurement Aucha Prachanronarong, MHS CLINICAL

Chronic Obstructive Pulmonary Disease: An Overview John F. Devine, DO, FACP CONTINUING EDUCATION

The Promise of Evidence-Based Medicine for Clinical Decision-Making Nirav R. Shah, MD, MPH DEPARTMENTS ◆ ◆ ◆ ◆

Generic Drug Trends Medical Tourism FDA Watch Industry Trends

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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.

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Reference examples: 1. Peters JL, Sutton AJ, Jones DR, et al. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676-680.

2. McGrath JJ, Murray RM. Risk factors for schizophrenia: from conception to birth. In: Hirsch SR, Weinberger DR, eds.

Schizophrenia. Oxford, England: Blackwell Press; 2003.

3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg News. March 12, 2008. http://www.bloomberg.com/apps/news?pid=newsarchive&sid=a LfUw7_sYMRY. Accessed March 13, 2008.

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SEPTEMBER 2008

VOLUME 1, NUMBER 7

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EDITORIAL

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The Governing Dynamics of the Healthcare Universe: Thinking Lagrangian Robert E. Henry

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Quality in the Pharmacy Environment

Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895

Jan E. Berger, MD, MJ

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Correction

BUSINESS

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Delaware’s Wellness Program: Motivating Employees Improves Health and Saves Money Jennifer “J. J.” Davis Stakeholder Perspective by F. Randy Vogenberg, RPh, PhD

The Better Quality Information to Improve Care for Medicare Beneficiaries Project: Exploring Approaches to Physician Performance Measurement Aucha Prachanronarong, MHS Stakeholder Perspective by Kip Piper, MA, CHE

Associate Editor Lara J. Reiman 732-992-1892

Director of Human Resources Blanche Marchitto President Brian F. Tyburski brian@engagehc.com Editor-in-Chief Robert E. Henry rhenry@AHDBonline.com 732-992-1885

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Editorial Director Dalia Buffery dalia@AHDBonline.com 732-992-1889

Senior Production Manager Robyn Jacobs

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

Chronic Obstructive Pulmonary Disease: An Overview John F. Devine, DO, FACP Stakeholder Perspective by Paul Anthony Polansky, BSPharm, MBA

Mission Statement CONTINUING EDUCATION

44 45

CE Information The Promise of Evidence-Based Medicine for Clinical Decision-Making Nirav R. Shah, MD, MPH Stakeholder Perspectives by Michael Cantor, MD; Scott R. Taylor, RPh, MBA; Nirav R. Shah, MD, MPH

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

AHDB is now included in the Cumulative Index to Nursing and Allied Health Literature (CINAHL)

Contact Information: For reprints, subscription information, and editorial queries, please contact: editorial@AHDBonline.com

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AMERICAN HEALTH & DRUG BENEFITS

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 drug benefit designs. Benefit designs are greatly affected by numerous clinical, business, and policy conditions.

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thousand patients helped through Lilly patient assistance programs

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customer service agents to answer patient and managed care partner questions

amore patient in charge of her family’s health

Healthcare may be a numbers game, but we’re only interested in one number.

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Lilly is working towards one focus... one patient at a time.

All numbers current as of December 2006. MG45573 COPYRIGHT © 2007 ELI LILLY AND COMPANY.

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Continued DEPARTMENTS

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GENERIC DRUG TRENDS Switching to Generic Antiepileptic Drugs: Growing Concerns Dalia Buffery, MA, ABD

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MEDICAL TOURISM Emerging Trends in Outsourcing Healthcare: Medical Tourism

Clinical Editor Thomas McCarter, MD, FACP Chief Clinical Officer Executive Health Resources tmccarter@AHDBonline.com Business/Government Editor Kip Piper, MA, CHE President, Health Results Group kpiper@AHDBonline.com

J. Warren Salmon, PhD

Actuary David Williams

FDA WATCH Potayto—Potahto? The Meaning of the FDA’s “Complete Response” Letters Mark Senak, JD

Clinical Research Nirav R. Shah, MD, MPH Samuel M. Silver, MD, MPH Michael A. Weber, MD

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INDUSTRY TRENDS e-Prescribing: Stakeholders Collaborating to Reduce Medication Errors

Employers Alberto M. Colombi, MD, MPH Arthur F. Shinn, PharmD, FASCP F. Randy Vogenberg, RPh, PhD

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Executive Summaries

Health Information Technology J.B. Jones, ABD, MBA

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Healthcare Outcomes Gary M. Owens, MD Managed Care & Government Affairs Sharad Mansukani, MD Managed Markets Marketing Jeffrey A. Bourret, RPh, MS, FASHP Charles E. Collins, Jr, MS, MBA

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Patient Advocacy William E. Fassett, PhD, RPh, MBA

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Pharmacoeconomics Jeff Jianfei Guo, BPharm, MS, PhD

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AMERICAN HEALTH & DRUG BENEFITS

Outcomes Research Gordon M. Cummins, MS Timothy S. Regan, BPharm, RPh

September 2008

Pharmacy Benefit Design Jan E. Berger, MD, MJ Joel V. Brill, MD Paul A. Polansky, BSPharm, MBA Scott R. Taylor, RPh, MBA Pharmacy Reimbursement Policy Michael Schaffer, PharmD, MBA Pharmacy & Specialty Products James T. Kenney, RPh, MBA Rebecca M. Shanahan, Esq Policy & Public Health Joseph R. Antos, PhD Alex A. Hathaway, MD, MPH, FACPM Jack E. Fincham, PhD, RPh Research & Development Michael F. Murphy, MD, PhD Wayne A. Rosenkrans, Jr, PhD

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FROM THE EDITOR

The Governing Dynamics of the Healthcare Universe: Thinking Lagrangian

T

he core editorial mission of American and rotating, and keeping it from colliding Health & Drug Benefits is to provide a or falling out of orbit. It is an inviting simile forum for a managerial discussion for healthcare, one referred to by Dr Michael among stakeholders about evidence in benMurphy in the March issue of AHDB. efit design during this crucial time in which The figurative application of Lagrangian we are witnessing the transformation of points suggests ways for all parties to bring healthcare to a value-based system. Our goal forth their systems and propositions for is to showcase trends and innovations and healthcare reform. examine their effects on the different parThe key to this simile is that no staketicipants in the process of care. We shed holder holds the superior ground in terms of Robert E. Henry light on the interaction of forces—clinical, providing for the best interests of healthcare. business, and regulatory—within the context of the Consequently, our premise is to foster an understanding interaction of stakeholders: patients, providers, payors, of the managerial strategies of all stakeholder groups. purchasers, manufacturers, distributors, regulatory agenThus we will be covering the activities of AHIP and cies, evaluators, and academia.

AMCP, IOM and AMA, AHRQ and CMS, PhRMA It is one thing to understand empirical study results, and BIO, medical associations and think tanks, foundaquite another to understand what holds up the healthtions and ISPOR. The scope of inquiry of AHDB is care “universe.” Both types of understanding are needequal to the decision makers’ need to know, and that is ed to achieve health and drug benefits competency. It profoundly broad. If today’s health and drug benefits is our proposition that each stakeholder needs to be decision makers are to survive, they must understand empowered properly, its actions supporting the viabilithe Lagrangian points of balance between research, ty of the others. Unilateral initiatives benefiting one’s finance, and regulation; between cost, quality, and access—between all parties affected by their formulary and benefit design decisions.

The factors and participants are sufficiently vast to Our goal is simply to open the eyes of invite bewilderment and discouragement, but medicine was always a work in progress from the time of Galen. benefit decision makers to the possibilities Our goal is simply to open the eyes of benefit decision for progress coming from all fronts. makers to the possibilities for progress coming from all fronts, and to encourage the proper humility toward one’s agendas and consideration for others’. It is to sugsector only are divisive and destructive of the pursuit of gest a managerial style—not a conclusive set of metrics a productive healthcare system, because every initiawith a definitive P value—that will empower decision tive must ultimately find a degree of acceptance from makers to order up the allocation of healthcare each stakeholder group. Any initiative must not only resources in ways supportive of all the planets in the be good but must also be understood and accepted by solar system. Patients need them all to align cohesively others, if it is to find translational application in the and achieve equilibrium that is also compatible with real world of health and drug benefits. the dynamic quality of healthcare progress. We invite The question is one of perspective. How does one your propositions for progress and welcome you to the stakeholder group understand the place of the others in great healthcare debate and the unending search for the healthcare firmament? A time-honored source of new points of equilibrium that benefit us all. ■ comparison is offered in the system of mechanics devised by mathematician John Louis Lagrange. In 1788 he introduced the concept of Lagrangian points, in which Robert E. Henry the 2 heavenly bodies work together to establish points Editor-in-Chief of equilibrium for another planet, keeping it in position

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AMERICAN HEALTH & DRUG BENEFITS

September 2008

VOL. 1

NO. 7

EDITORIAL

Quality in the Pharmacy Environment Jan E. Berger, MD, MJ

H

ealthcare is like a team sport with 3. Promoting the attainment of national active participation from a variety goals through education and outreach of position players, including programs. patients, physicians, nurses, pharmacists, During the past 8 years, the NQF has and many others. Although they each have brought diverse healthcare stakeholders a different responsibility, they would all together to endorse more than 200 performagree that quality is the foundation for all ance measures. their activities. The confusion arises when For a very visible example of diffuse defithey are asked to define quality. nitions and measurements, one has to look Toward the end of the past century, a no further than the practice of pharmacy.

Jan E. Berger, MD, MJ number of organizations put forth measures Until recently, pharmacists did not have that defined their position on quality. These included measurements of their own to define their quality goals. the Centers for Medicaid and Medicare Services This has begun to change over the past few years, when (CMS), the American Medical Association, Bridges to a variety of quality initiatives focusing on the pharmacy Excellence, URAC (formerly Utilization Review space began to appear, including URAC, the Pharmacy Accreditation Commission), the National Committee Quality Alliance, JCAHO, and CMS. But, once again, for Quality Assurance (NCQA), the Joint Commission there is confusion about the various goals. Without on the Accreditation of Healthcare Organizations (JCAHO), the American Board of Medical Specialties, and Leapfrog. The health plan community was able to Confusion about quality goals and quality decrease some of its confusion about quality through improvement still remains across much of the the use of external measurements, such as the Health healthcare environment.

Plan Employer Data and Information Set measures, and accreditation through organizations such as the NCQA. Unfortunately, confusion about quality goals and agreed on goals, no coordinated process for selecting quality improvement still remains across much of the standardized measures existed. In June 2006, the NQF healthcare environment. To reduce this confusion and launched the Therapeutic Drug Management (TDM) allow members of the healthcare community to focus project.1 The goals of the project are to: 1. Achieve consensus on comprehensive framework for their efforts, there is a great need for a single national TDM entity to take a lead in helping to define healthcare 2. Identify and endorse performance standards and quality improvement. This is the role of the National measures Quality Forum (NQF)—a voluntary, consensus-based 3. Identify preferred practices for TDM. standards-setting organization that became operational The TDM project was kicked off with a framework in 2000. paper and a workshop in 2006. This was followed by The mission of the NQF is to improve the quality of evaluation of the framework and preferred practice.

American healthcare by: The framework focused on several areas that were artic1. Setting national priorities and goals for performulated in other pharmacy and medication management ance improvement quality initiatives, including: 2. Endorsing national consensus standards for meas• Therapeutic decision-making: diagnosis, documenuring and publicly reporting on performance tation, monitoring • Medication adherence and education Dr Berger is Senior Vice President and Chief Clinical Officer, • Safe medication use: side effects, proper use/handling CVS Caremark, Woonsocket, RI, and a Steering Committee • Efficiency: formulary system management, medicaMember for the Therapeutic Drug Management, National Quality Forum. tion options, drug utilization review

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www.AHDBonline.com

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EDITORIAL EDITORIAL

Regardless of whether one is a healthcare consumer, a payer of healthcare benefits, or a healthcare provider, quality and quality improvement should be healthcare’s essential business strategy.

• System coordination and communication.

The NQF councils and public comment period occurred in 2007, with NQF member organizations voting on the proposed practices late in the spring of 2008.

So what does this mean for pharmacies and pharmacists? I believe that this is all positive. First, that which is measured matters. This allows pharmacists, who are among the most trusted providers in the healthcare arena and often the most utilized, to be recognized for the work they do. Second, it allows pharmacists to work from a single set of uniform measures and become ambassadors for quality drug management.

Third, it focuses quality improvement activities in the pharmacy space so there is no confusion or conflict as to what constitutes quality activity around medication management.

Regardless of whether one is a healthcare consumer, a payer of healthcare benefits, or a healthcare provider, quality and quality improvement should be healthcare’s essential business strategy. It has been shown many times, as with the appropriate medication management of diabetes and asthma, that quality does not cost more, and, in fact, it often costs less. Embracing these focused efforts to improve quality in the pharmacy setting, which many have found to be the most utilized of the healthcare benefits, helps all of us. By doing so, we can help to decrease the 1.5 million medication errors cited in the Institute of Medicine study,2 reduce healthcare costs, and save many lives. ■ References 1. For information on the current National Voluntary Consensus Standards for the Reporting of Therapeutic Drug Management Quality, see http://www.qualityforum.org/projects/ongoing/therapeutic/index.asp.

2. Institute of Medicine. To Err is Human: Building a Safer Health System.

1999. http://www.iom.edu/CMS/8089/5575.aspx. Accessed August 14, 2008.

CAPTION CONTEST Winners Receive $50

Submit your caption at www.AHDBonline.com Submission deadline: September 30, 2008.

Winners’ names posted: October 6, 2008.

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AMERICAN HEALTH & DRUG BENEFITS

September 2008

VOL. 1

NO. 7

For the treatment of hypertension

Introducing BYSTOLIC. A novel beta blocker with efficacy and favorable tolerability across a broad range of patients.

1-3

n Unique mechanism of action includes cardioselective beta blockade and vasodilation1* n Once-daily antihypertensive, with efficacy maintained over 24 hours1

Please see brief summary of full Prescribing Information on adjacent page.

For full Prescribing Information visit www.BYSTOLIC.com.

Important Safety Information Patients being treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported following the abrupt cessation of therapy with beta blockers. When discontinuation is planned, the dosage should be reduced gradually over a 1- to 2-week period and the patient carefully monitored.

BYSTOLIC is contraindicated in severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

BYSTOLIC should be used with caution in patients with peripheral vascular disease, thyrotoxicosis, in patients treated concomitantly with beta blockers and calcium channel blockers of the verapamil and diltiazem type (ECG and blood pressure should be monitored), severe renal impairment, and any degree of hepatic impairment or in patients undergoing major surgery. Caution should also be used in diabetic patients as beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

In general, patients with bronchospastic disease should not receive beta blockers.

BYSTOLIC should not be combined with other beta blockers.

The most common adverse events with BYSTOLIC versus placebo (approximately >1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. *In extensive metabolizers (most of the population) and at doses <10 mg, BYSTOLIC is preferentially â?¤1 selective. The mechanism of action of the antihypertensive response of BYSTOLIC has

not been definitively established. Possible factors that may be involved include: (1) decreased heart rate, (2) decreased myocardial contractility, (3) diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, (4) suppression of renin activity, and (5) vasodilation and decreased peripheral vascular resistance.

References: 1. BYSTOLIC [package insert]. St. Louis, Mo: Forest Pharmaceuticals, Inc.; 2007. 2. Data on file. Forest Laboratories, Inc. 3. Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens. 2007;9:866-875. Š2008 Forest Laboratories, Inc.

44-1012269R1

02/08

2.5 mg, 5 mg and 10 mg Tablets Rx Only Brief Summary: For complete details please see full Prescribing Information for BYSTOLIC. INDICATIONS AND USAGE BYSTOLIC is indicated for the treatment of hypertension. BYSTOLIC may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), or severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

WARNINGS Abrupt Cessation of Therapy Patients with coronary artery disease treated with BYSTOLIC should be advised against abrupt discontinuation of therapy. Severe exacerbation of angina and the occurrence of myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. Even patients without overt coronary artery disease should be cautioned against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of BYSTOLIC is planned, patients should be carefully observed and advised to minimize physical activity. BYSTOLIC should be tapered over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, it is recommended that BYSTOLIC be promptly reinstituted, at least temporarily.

Cardiac Failure Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and β-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In patients who have compensated congestive heart failure, BYSTOLIC should be administered cautiously.

If heart failure worsens, discontinuation of BYSTOLIC should be considered.

Angina and Acute Myocardial Infarction BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI. Bronchospastic Diseases In general, patients with bronchospastic diseases should not receive β-blockers.

Anesthesia and Major Surgery If BYSTOLIC is to be continued perioperatively, patients should be closely monitored when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

The β-blocking effects of BYSTOLIC can be reversed by β-agonists, e.g., dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with β-blockers.

Diabetes and Hypoglycemia β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be advised about these possibilities and nebivolol should be used with caution.

Thyrotoxicosis β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia.

Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in these patients.

Non-dihydropyridine Calcium Channel Blockers Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, caution should be used in patients treated concomitantly with these agents and ECG and blood pressure should be monitored.

PRECAUTIONS Use with CYP2D6 inhibitors Nebivolol exposure increases with inhibition of CYP2D6 (see Drug Interactions).

The dose of BYSTOLIC may need to be reduced.

Impaired Renal Function BYSTOLIC should be used with caution in patients with severe renal impairment because of decreased renal clearance. BYSTOLIC has not been studied in patients receiving dialysis.

Impaired Hepatic Function BYSTOLIC should be used with caution in patients with moderate hepatic impairment because of decreased metabolism. Since BYSTOLIC has not been studied in patients with severe hepatic impairment, BYSTOLIC is contraindicated in this population (see CLINICAL PHARMACOLOGY, Special Populations and DOSAGE AND ADMINISTRATION).

Risk of Anaphylactic Reactions While taking β-blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

In patients with known or suspected pheochromocytoma, an alpha-blocker should be initiated prior to the use of any β-blocker.

Information for Patients Patients should be advised to take BYSTOLIC regularly and continuously, as directed. BYSTOLIC can be taken with or without food. If a dose is missed, the patient should take the next scheduled dose only (without doubling it). Patients should not interrupt or discontinue BYSTOLIC without consulting the physician.

Patients should know how they react to this medicine before they operate automobiles, use machinery, or engage in other tasks requiring alertness.

Patients should be advised to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of worsening congestive heart failure such as weight gain or increasing shortness of breath, or excessive bradycardia.

Patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned that β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nebivolol should be used with caution in these patients.

Drug Interactions BYSTOLIC should be used with care when myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide, are used concurrently. Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

BYSTOLIC should not be combined with other β-blockers. Patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity. In patients who are receiving BYSTOLIC and clonidine, BYSTOLIC should be discontinued for several days before the gradual tapering of clonidine.

CYP2D6 Inhibitors: Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) (see CLINICAL PHARMACOLOGY, Drug Interactions).

Carcinogenesis, Mutagenesis, Impairment of Fertility In a two-year study of nebivolol in mice, a statistically significant increase in the incidence of testicular Leydig cell hyperplasia and adenomas was observed at 40 mg/kg/day (5 times the maximally recommended human dose of 40 mg on a mg/m2 basis). Similar findings were not reported in mice administered doses equal to approximately 0.3 or 1.2 times the maximum recommended human dose. No evidence of a tumorigenic effect was observed in a 24-month study in Wistar rats receiving doses of nebivolol of 2.5, 10 and 40 mg/kg/day (equivalent to 0.6, 2.4, and 10 times the maximally recommended human dose). Co-administration of dihydrotestosterone reduced blood LH levels and prevented the Leydig cell hyperplasia, consistent with an indirect LH-mediated effect of nebivolol in mice and not thought to be clinically relevant in man.

A randomized, double-blind, placebo- and active-controlled, parallel-group study in healthy male volunteers was conducted to determine the effects of nebivolol on adrenal function, luteinizing hormone, and testosterone levels. This study demonstrated that 6 weeks of daily dosing with 10 mg of nebivolol had no significant effect on ACTH-stimulated mean serum cortisol AUC0-120 min, serum LH, or serum total testosterone.

Effects on spermatogenesis were seen in male rats and mice at ≥40 mg/kg/day (10 and 5 times the MRHD, respectively). For rats, the effects on spermatogenesis were not reversed and may have worsened during a four week recovery period. The effects of nebivolol on sperm in mice, however, were partially reversible.

Mutagenesis: Nebivolol was not genotoxic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex-linked recessive lethal, and in vivo mouse bone marrow micronucleus tests).

Pregnancy: Teratogenic Effects. Pregnancy Category C: Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance.

In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD).

Labor and Delivery Nebivolol caused prolonged gestation and dystocia at doses ≥5 mg/kg in rats (1.2 times the MRHD). These effects were associated with increased fetal deaths and stillborn pups, and decreased birth weight, live litter size and pup survival rate, events that occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation).

No studies of nebivolol were conducted in pregnant women. BYSTOLIC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk. It is not known whether this drug is excreted in human milk.

Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during nursing.

Geriatric Use Of the 2800 patients in the U.S.-sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older. No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility (see Carcinogenesis, Mutagenesis and Impairment of Infertility).

ADVERSE REACTIONS The data described below reflect worldwide clinical trial exposure to BYSTOLIC in 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received BYSTOLIC for up to 24 months, with over 1900 patients treated for at least 6 months, and approximately 1300 patients for more than one year. In placebo-controlled clinical trials comparing BYSTOLIC with placebo, discontinuation of therapy due to adverse events was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%) and bradycardia (0.2%).

Adverse Reactions in Controlled Trials Table 1 lists treatment-emergent signs and symptoms that were reported in three 12-week, placebo-controlled monotherapy trials involving 1597 hypertensive patients treated with either 5 mg, 10 mg or 20-40 mg of BYSTOLIC and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group.

Table 1. Treatment-Emergent Adverse Events with an Incidence (over 6 weeks) ≥1% in BYSTOLIC-treated Patients and at a Higher Frequency than PlaceboTreated Patients Placebo

Headache Fatigue Dizziness Diarrhea Nausea Insomnia Chest pain Bradycardia Dyspnea Rash Peripheral edema

(n = 205) (%) 6 1 2 2 0 0 0 0 0 0 0

Nebivolol 5 mg (n = 459) (%) 9 2 2 2 1 1 0 0 0 0 1

Nebivolol 10 mg (n = 461) (%) 6 2 3 2 3 1 1 0 1 1 1

Nebivolol 20-40 mg (n = 677) (%) 7 5 4 3 2 1 1 1 1 1 1

Other Adverse Events Observed During Worldwide Clinical Trials Listed below are other reported adverse events with an incidence of at least 1% in the more than 5300 patients treated with BYSTOLIC in controlled or open-label trials, whether or not attributed to treatment, except for those already appearing in Table 1, terms too general to be informative, minor symptoms, or events unlikely to be attributable to drug because they are common in the population. These adverse events were in most cases observed at a similar frequency in placebotreated patients in the controlled studies.

Body as a whole: asthenia.

Gastrointestinal System Disorders: abdominal pain Metabolic and Nutritional Disorders: hypercholesterolemia and hyperuricemia Nervous System Disorders: paraesthesia Laboratory In controlled monotherapy trials, BYSTOLIC was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count.

Events Identified from Spontaneous Reports of BYSTOLIC Received Worldwide.

The following adverse events have been identified from spontaneous reports of BYSTOLIC received worldwide and have not been listed elsewhere. These adverse events have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to BYSTOLIC. Events common in the population have generally been omitted. Because these events were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to BYSTOLIC exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second and third degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), myocardial infarction, pruritus, psoriasis, Raynaud’s phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.

OVERDOSAGE In clinical trials and worldwide postmarketing experience there were reports of BYSTOLIC overdose. The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension. Other important adverse events reported with BYSTOLIC overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse events associated with β-blocker overdose include bronchospasm and heart block.

The largest known ingestion of BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhidrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered.

Due to extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance.

If overdose occurs, BYSTOLIC should be stopped and general supportive and specific symptomatic treatment should be provided. Based on expected pharmacologic actions and recommendations for other β-blockers, the following general measures should be considered when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful.

Heart Block (second or third degree): Patients should be carefully monitored and treated with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics.

In certain cases, consideration should be given to the use of inotropic and vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as a short-acting inhaled β2-agonist and/or aminophylline.

Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required.

In the event of intoxication where there are symptoms of shock, treatment must be continued for a sufficiently long period consistent with the 12-19 hour effective half-life of BYSTOLIC. Supportive measures should continue until clinical stability is achieved.

Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.

Forest Pharmaceuticals, Inc. Subsidiary of Forest Laboratories, Inc. St. Louis, MO 63045, USA Licensed from Mylan Laboratories, Inc. Under license from Janssen Pharmaceutica N.V., Beerse, Belgium Rev. 12/07 © 2007 Forest Laboratories, Inc.

BUSINESS

Delaware’s Wellness Program: Motivating Employees Improves Health and Saves Money Jennifer “J. J.” Davis Background: Every year, employers around the country evaluate their company benefits package in the hopes of finding a solution to the ever-rising cost of health insurance premiums. For many business executives, the only logical choice is to pass along those costs to the employee.

Objectives: As an employer, our goal in Delaware has always been to come up with innovative solutions to drive down the cost of health insurance premiums while encouraging our employees to take responsibility for their own health and wellness by living a healthy and active lifestyle, and provide them with the necessary tools.

Methods: The DelaWELL program (N = 68,000) was launched in 2007, after being tested in initial (N = 100) and expanded (N = 1500) pilot programs from 2004 to 2006 in which 3 similar groups were compared before and after the pilot. Employee health risk assessment, education, and incentives provided employees the necessary tools we had assumed would help them make healthier lifestyle choices.

Results: In the first pilot, fewer emergency department visits and lower blood pressure levels resulted in direct savings of more than $62,000. In the expanded pilot, in all 3 groups blood pressure was significantly reduced (P <.001) from preprogram to postprogram; body fat reduction was also significant (P <.001); and glucose levels dropped (P <.001) in 2 groups. The overall saving was about $450,000. And in only about 4 months this year, 729 employees participating in DelaWELL had a combined weight loss of 5162 lb.

Conclusions: Decision makers in the State of Delaware have come up with an innovative solution to controlling costs while offering employees an attractive benefits package. The savings from its employee benefit program have allowed the state to pass along the savings to employees by maintaining employee-paid health insurance contributions at the same level for the past 3 years. DelaWELL has already confirmed our motto, “Although it may seem an unusual business investment to pay for healthcare before the need arises, in Delaware we concluded that this makes perfect sense.” This promising approach to improving health and reducing healthcare costs could potentially be applied to other employer groups. [AHDB. 2008;1(7):9-16.]

E

mployers around the country evaluate their company benefits package every year in the hopes of finding solutions to the ever-rising costs of health insurance premiums. For many business executives, however, the only logical choice is to pass along those increased costs to the employee. This is a matter of simple economics, especially when we consider that health insurance expenses are the fastest growing cost component for employers.1 “Health insurance premiums have increased rapidly over the recent past, growing a cumulative 78% between 2001 and 2007 and far outpacing

Ms Davis is Director, State of Delaware Office of Management and Budget, Dover, DE.

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cumulative wage growth of 19% over the same period.”1 The price of health insurance can be a heavy burden for families, as premiums for employer-sponsored health insurance in the United States have been rising 4 times faster on average than workers’ earnings since 2000.2 In Delaware alone, as an employer the state paid approximately $433 million in healthcare expenditures for fiscal year 2008.3 Not only is the cost of health insurance premiums increasing exponentially, but more Americans are dealing with chronic and sometimes preventable conditions.4 We have all read the headlines regarding the nation’s obesity epidemic, and as our waistlines are expanding, more Americans are dealing with the con-

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KEY POINTS ▲ Health insurance expenses are the fastest growing cost com-

ponent for employers today. Many employers deal with this cost escalation by shifting some of the cost to the employee. ▲ As employers, we need to come up with innovative solutions

to drive down the cost of health insurance premiums while encouraging our employees to lead a healthy and active lifestyle. ▲ Findings from 2 pilot programs in the State of Delaware,

applying employee incentives and motivation techniques, showed that empowering employees to take charge of their own health can improve their health and cut overall healthcare costs to employers. ▲ Preliminary findings from the DelaWELL program, launched

in 2007 based on the principles used in the pilot studies, further show the success of this approach. In only about 4 months, a group of 729 employees had a combined weight loss of 5162 lb. ▲ A key component of DelaWELL is the electronic health risk

assessment, completed to date by more than 10,000 employees. This is followed by tools that address personalized lifestyle and disease management issues.

Table 1 Group Demographics Factor Female, n (%) Male, n (%) Age, yr Mean (SD) Range Age group, yr 18-39, n 40-64, n 65+, n

Group A N = 499 355 (71.1) 144 (28.9)

Group B N = 502 383 (76.3) 119 (23.7)

Group C N = 500 376 (75.2) 124 (24.8)

47.4 (9.8) 18-68

47.6 (9.1) 18-72

48.1 (9.1) 18-68

102 390 7

97 400 5

88 401 11

Note: Age was calculated as of program start on January 1, 2005.

The 3 groups were very similar in age, sex, and composition.

SD indicates standard deviation.

sequences of living an unhealthy lifestyle. This is evident by the rise in high-risk diseases such as asthma, congestive heart failure, and coronary artery disease.4 As employers, we need to do our part to come up with innovative solutions to drive down the cost of health insurance premiums while encouraging our employees to live a healthy and active lifestyle. We embarked on such a program based on the assumption that if our employees become more involved in their healthcare,

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they will take the steps to reduce their risk factors and improve their health. Our motto has been, “Although it may seem an unusual business investment to pay for healthcare before the need arises, in Delaware we concluded that this makes perfect sense.” Employer-initiated pilot programs are beginning to emerge in this country and in other countries, representing a new approach to improving health outcomes and controlling costs.5-7

The State as the Largest Employer The State of Delaware, as an employer, is unique, because we employ more people than any other organization from the public or private sectors in Delaware.

The state covers approximately 110,000 individuals— state workers, their families, and those who have retired from state service. Therefore, driving down the cost of healthcare represents not only a benefit to our employees but also an expectation held by every taxpaying citizen of the state.

Although cost is a major component of benefit development, we recognize that it is only one aspect of the total picture. Many conventional employee wellness programs—such as disease management programs—target people who already have been diagnosed with a certain condition. These programs can be beneficial, but they ignore the fact that people often have risk factors or conditions that have not been diagnosed.

If ignored, these risk factors may develop into a serious or chronic disease that can quickly become more serious and expensive to treat. The goal of the State of Delaware as an employer has been to educate, motivate, and inspire employees to get involved in their own wellness journey and to be aware of any possible risk factors in their own lives.

For private companies or public entities, it can often be difficult and cost-prohibitive to embark on an ambitious new benefit program. How do you get decision makers to buy into the idea of spending money on keeping employees healthy, especially when America has favored a system that addresses the needs of those who are sick or injured instead of addressing potential risk factors before a patient becomes symptomatic?

To help overcome these hurdles, we instituted from the beginning a phased-in approach to our employee wellness program. Although it is difficult to have a paradigm shift in state government, we moved forward based on the assumption that change could happen through demonstrated success and research results.

This allowed us to effectively meet the needs of our target participants, while using the results from our pilot programs (see below) to garner support from

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lawmakers. Throughout the process, we reviewed the concept and strategy at each phase, making adjustments when necessary.

Table 2 Claims-Based Group Comorbidities Comorbidity

The Initial Pilot Program In 2003, the State of Delaware partnered with its health insurance carrier, Blue Cross Blue Shield of Delaware, to launch its first 100-person feasibility pilot after looking at some successful private sector programs. Our goal was to show that it is possible to motivate people to take responsibility for their health and wellness if they are provided with the necessary tools.

Pilot participants underwent a health assessment, which was comprised of: 1. Complete health history 2. Resting and exercise blood pressure 3. Cholesterol level check 4. Body composition 5. Strength testing.

Immediate results revealed that some participants may already have high-risk conditions (ie, elevated blood pressure, elevated cholesterol levels) that have not yet been detected. All participants also received recommendations on an exercise regimen to improve their physical outcomes in all risk areas. They all received feedback and were reassessed after 1 year.

We wanted to motivate participants to take a more active role in their health by educating them on their own cardiometabolic risk factors, and then give them an opportunity to make lifestyle changes in an effort to improve their overall health. Throughout the pilot, we used a process that involved evaluating, educating, motivating, and reevaluating participants.

The results of the initial pilot were encouraging.

Not only did participants improve their health in the short-term, including reductions in hypertension and emergency department visits, but most also opted to make healthier lifestyle choices as a direct result of their involvement in the program. That was great news for our participants, but the bigger news for lawmakers was that these health-related changes had resulted in immediate direct savings of more than $62,000, which were calculated based on savings from blood pressure reductions and fewer visits to the emergency department. This success gave us the momentum we needed to broaden the scope and number of participants in subsequent phases of the program.

The Expanded Pilot Program In 2004, with the support of Governor Ruth Ann Minner and the State Employee Benefits Committee,

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Coronary artery disease Congestive heart failure Diabetes COPD HIV infection Depression Arrhythmia Arthritis Osteoporosis CVA Hypertension Urinary tract infection

Group A n = 499 (%)

Group B n = 502 (%)

Group C n = 500 (%)

10 (2.00)

12 (2.39)

9 (1.80)

5 (15.00) 30 (6.01) 4 (0.80) 0 (0.00) 29 (5.81) 8 (1.60) 23 (4.61) 3 (0.60) 0 (0.00) 88 (17.64)

3 (0.60) 27 (5.38) 3 (0.60) 1 (0.20) 21 (4.18) 7 (1.39) 30 (5.98) 8 (1.59) 1 (0.20) 67 (13.35)

2 (0.40) 30 (6.00) 3 (0.60) 0 (0.00) 32 (6.40) 5 (1.00) 32 (6.40) 4 (0.80) 2 (0.40) 87 (17.40)

11 (2.20)

10 (1.99)

13 (2.60)

Note: The 3 groups were very similar in prevalence of comorbidities.

COPD indicates chronic obstructive pulmonary disease; CVA, cerebrovascular accident.

Table 3 Year 1 Pre- and Postprogram Healthcare Costs (Unadjusted) Program Preprogram, PMPM Mean cost, $ (SD), $ Postprogram Mean follow-up, mo Mean cost, PMPM, $ (SD) Mean change, PMPM Postbaseline, $

Group A n = 499

Group B n = 502

Group C n = 500

Control n = 2990

252.06 (577.13)

241.98 (711.65)

226.68 (539.70)

239.46 (562.99)

8.98 294.50 (626.74)

10.34 312.98 (960.07)

9.16 329.71 (1530.68)

12.00 312.64 (831.45)

71.00

103.03

73.18

42.44

PMPM indicates per member, per month; SD, standard deviation.

we launched the second wellness program pilot, which included 1500 state employees. The employees in this expanded pilot underwent the same initial health assessment as in the 100-person pilot.

Participants were randomized into 3 intervention groups, with very similar demographics (Table 1) and comorbidities (Table 2).

In addition, we collected information on the participants’ average healthcare costs before and after the pilot (Tables 3, 4) to be used as a baseline measure to assess the program’s effectiveness.

The groups were set up in the following manner:

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Table 4 Year 1 Pre- and Postprogram Cost of Care Breakout (Unadjusted) Group A, $ (n = 499) Pre Post 24.53 56.04

Group B, $ (n = 502) Pre Post 60.74 74.19

Group C,* $ (n = 500) Pre Post 21.46 106.21‡

Emergency 2.59 department§ 4.44 Outpatient 69.15 60.60 Office visits 70.04 78.17 All others 24.88 28.33 Pharmacy 59.02 68.77 Total 252.06 294.50

2.48 3.27 51.99 89.60 58.57 66.22 20.54 28.00 47.65 51.71 241.98 312.98

0.97 1.40 67.70 65.12 55.56 65.71 22.68 24.66 58.30 66.60 226.68 329.71

Factor Inpatient†

*Significant

drivers of costs for group C appear to be physician services and pharmacy products; these may reflect achievement of goals in pursuit of incentive payments. †The rate of increase in inpatient costs was influenced by a very small number of employees within each group. ‡One employee accounted for the vast majority of this increase. §Emergency department costs were relatively low.

Group A had pre- and postassessments, with “fit stops.”

Group B also had the pre- and postassessments, with fit stops, plus regular e-mails. Finally, group C underwent the pre- and postassessments, with fit stops, and they were also offered a $100 financial incentive for

achieving or maintaining 5 of 6 goals. These fit stops consisted of 2 personalized sessions with an exercise physiologist, with each session targeting a specific cardiometabolic risk factor. All employees were welcomed to participate in fit stops.

The results from this expanded program, which ran from September 2004 through March 2006, were even more impressive than the initial pilot. In addition to realizing significant reductions in their body fat percentage, participants also improved their overall fitness levels substantially, and their blood pressure and cholesterol levels were reduced (Tables 5, 6).

As can be seen in Table 5, group C was the only negative short-term net margin group. Our assumption is that the incentive payment may have motivated the group C employees to seek more extensive care to reach goals earlier than the other 2 groups. We realize that reevaluation of the program on an annual basis will be necessary to confirm persistency of short-term net margin and to evaluate intermediate- and longterm program impact. We estimate that we will require 4 or 5 years of analyses before we can measure a consistent trend.

Even so, these preliminary findings from the pilot program are very encouraging. In addition to the improved health of the participants, the program has

Table 5 Expanded Pilot Program: Clinical Results, October 2005-March 2006 Group A Mean (95% CI) P –.77* <.001 (–1.2, –.38)

Group B Mean (95% CI) P –.86* <.001 (–1.3, –.48)

Glucose (drop)

–1.87 (–4.3, .5)

.12

–.77 (–3.6, 2.1)

.59

–3.95* (–6.3, –1.6)

<.001

–2.30* (–3.8, –.85)

.002

Systolic BP (drop)

–2.46* (–3.4, –2.6)

.006

–3.74* (–3.8, –1.1)

<.001

–1.87* (–5.2, –2.3)

.005

–2.64* (–3.2, –1.9)

<.001

Diastolic BP (drop)

–2.8* (–3.6, –2.8)

<.001

–3.22* (–4.3, –2.2)

<.001

–2.24* (–3.0, –1.5)

<.001

–2.72* (–3.2, –2.2)

<.001

Cholesterol ratio

–.02 (–.18, .14)

.83

–.16 (–.38, .05)

.14

–.03* (–.16, .09)

.63

–.07 (–.16, .03)

.17

Fitness level (+VO2)

.28 (–.18, .75)

.23

.41 (–.05, .87)

.08

.38* (–.003, .76)

.05

.36* (.11, .61)

.005

Body fat (% reduction)

Group C Mean (95% CI) P –.37 .08 (–.78, .04)

Total Mean (95% CI) P –.65* <.001 (–.87, –.42)

*

Statistically significant difference.

BP indicates blood pressure; CI, confidence interval; VO2, oxygen consumption.

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Delaware’s Wellness Program

also resulted in a trended healthcare savings of approximately $450,000 for the state (Table 7, Figure).

DelaWELL In April 2007, armed with the data proving the success of the wellness initiative, we had the justification and enthusiasm we needed to push forward with our comprehensive wellness program—DelaWELL. This program uses the same basic concept as the pilot program but is tailored to appeal to a broader group of more than 40,000 state employees. We decided to use a confidential online health risk assessment (HRA), which is followed by personalized lifestyle and disease management tools, to target individuals based on their own specific risk factors. Using an electronic HRA allowed participants to immediately receive feedback about potential health risks in an anonymous and nonthreatening manner. To encourage participation, a $75 incentive was offered to the first 6000 participants to fill out their HRA. After completing the HRA, participants with 2 or more risk factors (eg, smoking, obesity) received behavior coaching. Those with 3 or more risk factors received more intensive intervention, including a comprehensive physical examination and a cardiometabolic screening, to give them detailed information about their health. All eligible participants were able to access online resources on topics such as living with chronic conditions, a drug reference guide, and health resources for different demographics—men, women, children, older adults, and pregnant women.

In the first year, nearly 9000 employees took advantage of the HRA, approximately 23,000 visited the online site, and more than 500 attended educational seminars.

The DelaWELL program encourages participants to take an active role in their personal health. To drive that message home, we wanted to show participants that management “walked the walk, and talked the talk” regarding health and fitness. On May 30, 2007, with the support of our governor, we held our first-ever Governor’s Cup 5K Run/Walk (Photo). The event was so successful that we had to close down registration early and set up a second walk for later in the year to accommodate all of the state employees who wanted to participate. The 2 walks accommodated staff in 2 counties in Delaware and approximately 1000 walkers and runners participated in the events. We are planning to incorporate more events like this as an annual component of DelaWELL.

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Table 6 Expanded Pilot Program: Clinical Results Summary • Statistically significant reductions of percent body fat in groups A and B and nearly so in group C • Statistically significant reductions in systolic and diastolic blood pressure in all 3 groups • Statistically significant reductions in total cholesterol and increase in high-density lipoprotein cholesterol • Improvement in the level of fitness as measured by treadmill stress testing (+VO2) in all 3 groups All 4 measures directly reflect the overall health improvement of these employees and will reduce their risks for subsequent cardiometabolic disease.

VO2 indicates oxygen consumption.

Table 7 Postprogram Total Healthcare Costs Savings (Outliers Extracted) Program Mean change postprogram PMPM Savings (adjusted by control)

Variable Mean change (postbaseline)

Group A, Group B, Group C, Control, $ $ $ $ 42.44

27.13

60.40

25.84

41.15

7.88

Annualized savings PMPY 310.08

493.80

94.56

Savings by group in PMPM

Total annual savings

68.28

154,729.92 247,393.80 47,185.44

Total program trended healthcare cost savings were $449,309.16.

PMPM indicates per member, per month; PMPY, per member, per year.

Employees’ Input: Weight Management As we embark on year 2 of the DelaWELL program, we have incorporated suggestions we received from participants in an effort to best meet the needs of our target population. Participants told us they would like to have options available for managing their weight. As a result, we have added Weight Watchers® offerings to our program. We chose Weight Watchers® because they had the resources necessary to accommodate the anticipated number of participants, and their program helped support the DelaWELL mission but did not require participants to buy special meals like some of the other programs.

Our partnership with Weight Watchers® provides membership reimbursements for employees, pensioners, and their dependents older than age 18 years.

Participants receive support materials at a reduced rate, with a potential 100% reimbursement through our health insurance vendors. To make this option available to as many participants as possible, we offer

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dependents. The screenings gave employees important information about their health (eg, their height, weight, body mass index, blood pressure, total and high-density lipoprotein cholesterols, and glucose level).

Savings per member, per month, $

Incentives Another lesson we have learned is that incentives work.

In DelaWELL year 2, all employees who completed their Delaware’s Governor Ruth Ann Minner (front row, first from right) joins hundreds of state employees HRA and biometric health at the starting line of the first-ever Governor’s Cup 5K Run/Walk in Dover, Delaware. screening by May 30, 2008, became eligible for a $100 pretax incentive.

Providing an incentive helped to motiFigure Expanded Pilot: Annual Savings Trends vate our employees to become active and involved in their own wellness journey. We have also provided gifts $247,394 for participating in DelaWELL activities, including Annualized $250,000 savings water bottles, beach towels, and T-shirts.

In the end, an incentive is a small cost for an $200,000 employer when the goal is maintaining its biggest $154,730 investment—its workforce. As an employer, our priori$150,000 ty in Delaware has always been to protect and empower our most valuable asset, our employees, and we are $100,000 reaping the rewards of this philosophy today. $47,185

$50,000

$0

$0 Group A

Group B

Group C

Control

Total program healthcare cost savings in 2007 was $449,309.

the meetings in state offices for groups of 15 or more.

The results have been very encouraging. In fact, one group with 40 participants has reported a more than 485-lb combined loss since the program started in February 2008. And in just more than 4 months, 729 members participating in “at-work” meetings had a combined weight loss of 5162 lb.

Free Screening We also learned from the HRAs that a large majority of our employees did not know their blood pressure, cholesterol, or glucose levels, and were therefore unable to provide that information on the HRA. In response, as of January 15, 2008, the State of Delaware began offering free onsite biometric health screenings at work locations for employees, pensioners, and their

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Incorporating Entire Family Finally, to increase the success of our program and in an effort to reach more of our target market, in January 2008, we have incorporated the entire family into our DelaWELL initiative. The program is currently available to approximately 68,000 state employees, retirees younger than age 65 years, and their families.

Current Scope of the Program At a time when many companies are faced with skyrocketing insurance premiums, we have managed an almost unprecedented feat. The savings we have realized from this program have allowed us to maintain employee contributions to the state’s health insurance at the same level for the past 3 years.

To date, more than 10,000 participants completed an HRA, and more than 9000 participants had a biometric screening. In addition, we extended invitations to individuals who had 2 or more risk factors identified by their HRA to participate in our NextSteps program. In this program, participants can choose from telephone coaching; mail-based options that include personalized letters, brochures, and help in setting goals and building

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Delaware’s Delaware’sWellness DelaWELL Program Program

skills; or online options, in which participants receive a self-paced, personalized online NextSteps program.

So far this year, we have more than 1500 employees enrolled in NextSteps. We also have approximately 1500 participants in various Weight Watchers® offerings, including local meetings, at-work programs, and online offerings. We are anticipating an even greater participation rate as we await reimbursement requests by individuals who elected to use the monthly pass option, where participants sign up online and pay 1 fee for all monthly Weight Watchers® meetings.

We are in the process of launching DelaWELL University—a series of free health seminars for employees focusing on topics such as the Active Workday, Managing Your Weight, Stress and Your Workday, and Eating for Performance and Health.

Our program is receiving national attention and in July 2008 was awarded the Eugene H. Rooney Award, given out annually by the National Association of State Personnel Executives. This award recognizes innovative human resource management practices that ensure access and equity while enhancing productivity and service delivery.

Conclusions It is too early to know the long-term financial results of our DelaWELL program, but we are encouraged by the evidence we have seen to date. It will take several years of collecting data on the program before we have benchmarks in place to accurately assess the return on investment. However, the feedback we have received in the second year of DelaWELL has been overwhelmingly positive. Our employees know that we

are doing our part to help them invest in their personal health by making these tools as convenient and accessible as possible.

As employers, we are all facing the same predicament of rising health insurance premiums and out-of-control costs. Delaware may be a small state, but we have come up with a big idea toward solving a substantial healthcare dilemma. With the support and leadership of innovative leaders like our governor, we have designed a comprehensive wellness program that saves money for the state while helping our employees live healthier, happier lives. A healthy workforce is a more productive workforce. It is our hope that our program may offer other employers a model for enhancing their employees’ health and reducing overall healthcare costs.

References 1. The Henry J. Kaiser Family Foundation. Employer Health Insurance Costs and Worker Compensation. March 2008. http://www.kff.org/insurance/ snapshot/chcm030808oth.cfm. Accessed August 6, 2008.

2. The Henry J. Kaiser Family Foundation and Health Research & Educational Trust. Employee Health Benefits: 2007 Annual Survey. http://www.kff.org/insurance/7672/index.cfm. Accessed July 30, 2008.

3. Data on file. State of Delaware.

4. Wu S, Green A. Projection of Chronic Illness Prevalence and Cost Inflation. Santa Monica, CA: RAND Health; October 2000.

5. Harris JR, Cross J, Hannon PA, et al. Employer adoption of evidencebased chronic disease prevention practices: a pilot study. Prev Chronic Dis. 2008;5:A92.

6. Renaud L, Kishchuk N, Juneau M, et al. Implementation and outcomes of a comprehensive worksite health promotion program. Can J Public Health. 2008;99:73-77.

7. Oberlinner C, Lang S, Germann C, et al. Prevention of overweight and obesity in the workplace. BASF-health promotion campaign “Trim Down the Pounds—Losing Weight Without Losing Your Mind.”

Gesundheitswesen. 2007;69:385-392.

Stakeholder Perspective The Lessons from Delaware’s Employee Benefits Program EMPLOYERS/HEALTH PLANS: Employer- or other types of municipal-sponsored health plans, such as the State of Delaware, remain focused on aggressive cost-management strategies for healthcare services that make sense, since they represent a fast-growing expense. It is important for employer plan sponsors to share their innovations and help colleagues to find ways to improve care processes, quality, and cost.

Leveraging wellness in an effective, equitable manner, as illustrated in this article, demonstrates that there

are employer-friendly alternatives for addressing the cost of healthcare without cost shifting to employees or reducing provider reimbursement.

Healthcare cost trend is always a concern, which makes alternatives such as value-based strategies even more valuable, as documented in this discussion of the Delaware plan. One of the many issues with the concept of “value” is a continued lack of consensus on what value is, as well as what works for both the employee and the employer—how to implement Continued

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BUSINESS BUSINESS

a value-based plan, and what program design is best for optimal economic outcomes for any individual plan sponsor. Delaware has offered one possible solution toward avoiding higher-cost healthcare services —engaging employees in their own health, an approach with health plans that may have merit for the short- and long-term. It is important for all stakeholders, including clinicians and health plans, to address fundamental issues in the healthcare market and take a serious look at reasonable and replicable success stories.

In addition, the basic premise of utilizing wellestablished behavior change science in benefit design makes good business sense. Testing the feasibility as well as programmatic elements that make up the goals and design, this effort in Delaware started with a 100-person pilot program. This experience in Delaware demonstrates how any employer can easily start to make change, then expand the effort to achieve broader results that are meaningful and

measurable in a much larger population.

Commenting or reporting alone on the clinical or scientific conclusions presented would undervalue the effort made in Delaware to try something different, using what was available to them in the marketplace. Being aware of the information and data available to document results can help all decision makers in making more informed and better health benefit plan decisions. Improving the data-collection metrics and statistical parameters can follow, as larger cohorts of patients, employers, and clinicians become actively engaged in a joint journey toward enhanced, cost-effective outcomes.

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

Request your FREE subscription to AMERICAN HEALTH & DRUG BENEFITS™ FREE Subscription Request ❑ YES! I would like to receive American Health & Drug Benefits™ as well as related educational supplements FREE! Signature (Required) ________________________________________ Date (Required) ________ _ _______ Name ______________________________________ Company ____________________________ Title _______________________________ Specialty _____________________________________ Address _________________________________________________________________________ City/State/ZIP ____________________________________________________________________ E-mail _____________________________ Phone ______________________________________ Please provide all information indicated, including date and signature. Incomplete cards will not be processed.

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AHDB 9/08

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Cultivated with Care.

To ensure that every Mylan product is manufactured to uncompromising standards, we have carefully and painstakingly refined our systems and controls for more than 45 years.

With the acquisition of the Generics Business of Merck KGaA, we now have a global team of professionals that shares our passion for perfection.

As we look to the future, we will be guided by the principles that have earned us the trust and respect of pharmacists throughout the United States.

After all, our roots are firmly planted in our conviction to make proven medicine more affordable for the patients who need them.

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MYNMKT228

GENERIC DRUG TRENDS

Switching to Generic Antiepileptic Drugs: Growing Concerns

By Dalia Buffery, MA, ABD

T

he total number of generic prescriptions continues to grow at a rapid pace (Table), and the US Food and Drug Administration (FDA) is having difficulties keeping up with the rate of new applications.1 In July 2008, Medco reported a record genericdispensing rate of 63.7%, which reflects a 4.8% increase compared with the second quarter in 2007.2 Keeping with this trend, on July 29, 2008, the FDA approved a generic version of yet another antiepileptic drug (AED)—Depakote—making it the 10th FDAapproved generic AED on the market.

Increasing reports raise questions about the therapeutic equivalence of generic AEDs. Despite this abundance of generic AEDs, increasing reports pose questions about the therapeutic equivalence of these generics, raising concerns among physicians and patients. A new survey of 550 adults with epilepsy and 660 physicians who treat such patients reported that 88% of the physicians were concerned with an increasing number of breakthrough seizures in switching patients to generic AEDs, and about 50% of them were very likely to request that a branded AED be used instead of a generic.3 In addition, a growing number of reports are relating adverse events associated with switching from brand-name to generic AEDs. A recent Canadian study compared the rates of patients switching from a branded drug to a generic formulation and vice versa. The rates of patients switching back from generics to brand-name drugs because of adverse events were 7.7% to 9.1% for non-AEDs, compared with 20.8% to 44.1% for those taking AEDs.4 In a previous analysis of the economic impact of generic versus branded formulations of the AED lamotrigine involving 671 patients, the authors found that overall healthcare costs with generic substitution were greater than without generic AEDs, despite the lower cost of the generic products.5 Healthcare utilization was significantly greater in those using generic AEDs, with more outpatient visits and greater mean hospital stay. The authors conclude that substituting with a generic does not always reduce costs when it comes to AEDs.5

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In yet another study just published in Neurology, which included 50 patients who were well controlled with different brand-name AEDs, breakthrough seizures occurred after switching to a generic AED (and without any other provoking factors).6 These and similar studies raise concerns about generic AEDs that have not been consistently documented in other therapeutic classes. Drs Shaw and Krauss, of Johns Hopkins School of Medicine, offer one explanation, noting that although generic AEDs “generally provide safe, effective, lower-cost alternatives to brand-name drugs,” the bioequivalence for AEDs “has not been evaluated in patients with epilepsy or in other special populations such as elderly patients or patients taking multiple AEDs.”7 Drs Shaw and Krauss suggest that most patients can initiate generic AED therapy and switch from brand to generic AEDs. However, the FDA “has not shown safety in generic-to-generic switches, which could potentially cause drug concentration changes of up to 40%.”7 All of this suggests that the current “bioequivalence standards may not be sufficient for certain patient populations and for certain drugs,”7 they conclude.

So although many patients are enjoying therapeutic success at reduced costs by switching to different classes of generics, it is prudent to exercise extra caution when prescribing generic AEDs. Physicians, pharmacists, and policymakers should be aware of such reports and address these concerns. ■ References 1. LaMotta L. Generics face uphill battle. Forbes. August 29, 2008. www.forbes.com/2008/08/29/mylan-barr-closer-markets-equitycx_lal_0829markets25.html. Accessed August 29, 2008.

2. Medco News sent via e-mail (news@medco.mediaroom.com). July 24, 2008.

3. Berg MJ, Gross RA, Haskins LS, et al. Generic substitution in the treatment of epilepsy: patient and physician perceptions. Epilepsy Behav.

2008 Jun 24. [Epub ahead of print.]

4. LeLorier J, Duh MS, Paradis PE, et al. Clinical consequences of generic substitution of lamotrigine for patients with epilepsy. Neurology.

2008;70:2179-2186.

5. LeLorier J, Duh MS, Paradis PE, et al. Economic impact of generic substitution of lamotrigine: projected costs in the US using findings in a Canadian setting. Curr Med Res Opin. 2008;24:1069-1081.

6. Berg MJ, Gross RA, Tomaszewski KJ, et al. Generic substitution in the treatment of epilepsy: case evidence of breakthrough seizures. Neurology.

2008;71:525-530.

7. Shaw SJ, Krauss GL. Generic antiepileptic drugs. Curr Treat Options Neurol. 2008;10:260-268.

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GENERIC DRUG TRENDS

Table

Generic Drugs Approved May-July 2008

Brand (date generic approved) Cellcept: capsules, (7/29/08)

Generic Mycophenolate mofetil: capsules 250 mg; tablets 500 mg

Demadex injection (6/10/08)

Torsemide injection, 10 mg/mL; 2-mL and 5-mL vials

Depakote tablets/delayed-release tablets (7/29/08)

Divalproex sodium delayed-release tablets, USP, 125 mg, 250 mg, 500 mg (valproic acid activity) Calcipotriene topical (scalp) solution, 0.005% Indomethacin for injection, USP, 1-mg vial

Dovonex scalp solution (5/6/08) Indocin IV (7/16/08) Inspra (7/30/08) Loprox gel (6/10/08) Marinol capsules, 2.5 mg, 5 mg, 10 mg (6/27/08) Orapred oral solution (6/9/08) Precose (5/7/08) Prilosec delayed-release capsules (5/30/08) Requip (5/5/08) Risperdal (6/30/08) Sarafem pulvules (5/20/08) Sonata capsules (6/6/08) Sular extended-release (7/16/08) Vibramycin for oral suspension (7/16/08) Yasmin (5/9/08) Zyrtec syrup (Rx only) (5/7/08)

Eplerenone 25 mg, 50 mg Ciclopirox gel, 0.77% Dronabinol capsules, USP, 2.5 mg, 5 mg, 10 mg Prednisolone sodium phosphate oral solution 20 mg (base)/5 mL Acarbose 25 mg, 50 mg, 100 mg Omeprazole delayed-release capsules USP, 10 mg, 20 mg, 40 mg Ropinirole hydrochloride 0.25 mg (base), 0.5 mg (base), 1 mg (base), 2 mg (base), 3 mg (base), 4 mg (base) Risperidone USP, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg Fluoxetine capsules, USP, 10 mg, 20 mg Zalepon capsules 5 mg, 10 mg Nisoldipine extended-release 20 mg, 30 mg, 40 mg Doxycycline for oral suspension USP, 25 mg/5 mL Drospirenone/ethinyl estradiol, 3 mg/0.03 mg; 28-d cycle Cetirizine hydrochloride syrup, 1 mg/mL

Indications Organ rejection prophylaxis, tablets concomitantly with cyclosporine, corticosteroids Edema with heart failure; renal/hepatic disease; rapid onset of diuresis or if oral use impractical Seizures; bipolar disorder, manic phase; migraine prophylaxis Chronic, moderately severe scalp psoriasis Moderate-to-severe arthritis, ankylosing spondylitis, osteoarthritis; bursitis/ tendinitis; acute gouty arthritis Heart failure postâ&#x20AC;&#x201C;myocardial infarction; hypertension Interdigital tinea pedis, tinea corporis; seborrheic dermatitis of the scalp AIDS-related anorexia; cancer-related nausea, vomiting; chemotherapy for failure to respond to antiemetic therapies Allergies; edema; dermatologic, endocrine, gastrointestinal, hematologic, neoplastic, rheumatic disorders; central nervous system; many other conditions Type 2 diabetes Duodenal/gastric ulcers; erosive esophagitis; hypersecretory conditions; reflux disease Idiopathic Parkinsonâ&#x20AC;&#x2122;s disease; restless legs syndrome Schizophrenia; acute manic/mixed episodes of bipolar I disorder; autism-related irritability in 5- to 16-year olds Premenstrual dysphoric disorder Insomnia Hypertension Antibiotic Contraception Allergic rhinitis, chronic urticaria

Source: FDA CDEResearch. Generic First Approvals. www.fda.gove/cder/ogd/approvals/1stgen0708.htm; www.fda.gove/cder/ogd/approvals/1stgen06/08.htm; www.fda.gove/cder/ogd/approvals/1stgen05/08.htm. Accessed August 14, 2008.

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CALL FOR PAPERS

American Health & Drug Benefits (AHDB) offers an open forum for all healthcare stakeholders to exchange ideas and present their needs, data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Evaluators, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers.

Readers are invited to submit articles that aim at improving the quality of the US healthcare delivery system in general and of benefit design strategies in particular. All articles will undergo a blind peer review, and acceptance is based on that review.

Areas of high interest include: • Benefit Design Objectives • Comparative-Effectiveness Analyses • Decision-Making Tools • Drug Trends

• • • •

Health Plan Initiatives Health Information Technology Innovation in Patient Care Off-label Use/Misuse

• • • •

Original Research Pharmacoeconomics Reimbursement Issues Surveys of Health Trends

Clinical topics of interest include: Aging/Dementia—With the aging of the US population, there is a growing need for early implementation of proper diagnostic procedures, as well as outcome-based preventive and therapeutic strategies for older people.

Allergies—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Undertreatment and lack of adherence are common obstacles. In addition to new therapies, articles should address issues of prevention, early diagnosis, and patient education programs.

Arthritis—Musculoskeletal conditions, such as rheumatoid arthritis or osteoporosis, are on the increase, yet many patients are undiagnosed and untreated. Comparing new and available therapies is a key target for improving patient outcomes and reducing costs.

Cancer Therapy—The growing focus on biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies, cost-management, industry trends, and the biologic pipeline updates. Lung cancer presents major challenges for early diagnosis and for improved therapeutic modalities.

Cardiovascular Disease—Still a leading cause of morbidity and mortality among men and women, conditions such as atrial fibrillation, acute coronary syndrome, and venous thromboembolism remain key to heart health. Original, outcome-based research on appropriate therapies, diet, exercise, cost-comparisons, emerging prevention strategies, and comparative-effectiveness of best practices will enhance readers’ decision-making.

Diabetes, Obesity—The increasing comorbid epidemics of these twin conditions mandate a thorough examination of best therapies, adherence issues, access, and prevention strategies. We invite articles that will address how to improve patient outcomes and best individualized patient care.

Gastrointestinal Conditions—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, or inflammatory bowel disorder, remains a challenge. Evidence-based articles dealing with best approach to management, as well as cost and reimbursement issues, are highly desirable.

Infectious Diseases—The spread of common and emerging pathogens within the hospital and in the community is a growing problem requiring increased vigilance. Topics of interest include drug therapies, off-label uses, preventing medical errors, and reimbursement.

Pain Management—Chronic pain is associated with a slew of complicated medical disorders, such as fibromyalgia, and an enormous economic burden, yet pain medications, such as opioids, are still underused. Articles should address best therapies, diagnosis, and clinicians’ anxiety about addiction issues and potential misuse.

Please submit manuscripts electronically to editorial@AHDBonline.com, or mail to AHDB, 241 Forsgate Drive, Suite 205B, Monroe Twp, NJ 08831. For inquiries about submissions, call 732-992-1892.

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New Edition Now Available Award-winning Depression Benchmarks!

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Managing quality and cost is the foundation of today’s managed care structure. Wyeth recognizes that balancing quality and cost is a formidable challenge for managed health care professionals. We also recognize that success, in part, hinges on tools and resources that can aid in the evaluation of care management and may lead to reinforcing solutions. As part of our continuing efforts to improve the quality of care for patients with depression, we are proud to sponsor this comprehensive claims-based review to promote ongoing clinical and financial assessments that improve care in this patient population.

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REGULATORY REGULARTORY

The Better Quality Information to Improve Care for Medicare Beneficiaries Project: Exploring Approaches to Physician Performance Measurement

By Aucha Prachanronarong, MHS On August 22, 2006, President Bush issued an Executive Order calling on all federal agencies and those who do healthcare business with the government to engage in collaborative efforts to incorporate the 4 cornerstones of value-driven healthcare: health information technology standards, quality standards, price standards, and incentives. The Department of Health and Human Services has embarked on a campaign to make these 4 cornerstones a reality by encouraging the public and private sectors to work collaboratively at the local level. In support of this campaign, the Centers for Medicare & Medicaid Services launched a project in late 2006 that leverages local collaboratives as a means to explore a national approach to physician performance measurement. This project, which is known as the Better Quality Information to Improve Care for Medicare Beneficiaries Project, aims to test methods to aggregate Medicare administrative data with data from commercial health plans and, in some cases, Medicaid, in 6 local collaboratives to calculate and report quality measures for physician groups and for some individual physicians. [AHDB. 2008;1(7):22-26.]

O

n August 22, 2006, President Bush issued an Executive Order—Promoting Quality and Efficient Health Care in Federal Government Administered or Sponsored Health Care Programs— calling on all federal agencies and those who do healthcare business with the government to engage in collaborative efforts to incorporate the cornerstones of valuedriven healthcare (Table 1). The 4 cornerstones of value-driven healthcare are1: 1. Interoperable health information technology 2. Measure and publish quality information 3. Measure and publish price information 4. Promote quality and efficiency of care.

Local Collaboration Key to Value-Driven Healthcare Department of Health and Human Services Secretary Michael O. Leavitt has embarked on a campaign to make these 4 cornerstones a reality. A key piece of this campaign, known as the Value-Driven Ms Aucha is a Health Insurance Specialist, Office of Clinical Standards and Quality, Centers for Medicare & Medicaid Services, Baltimore, MD.

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Health Care Initiative, is encouraging the public and private sectors to work collaboratively at the local level. Regional or local public–private collaboration among payers, health plans, providers, and consumers is essential to the success of this initiative.

Healthcare systems are local. The different environments for healthcare delivery differ in the range of populations served, resources available, and in the characteristics of the local marketplace. Thus, broad-based efforts to improve quality of care need to be driven by local leaders who represent the various stakeholders and who are willing to pool their resources toward achieving common goals. In addition, quality initiatives need to allow for local input so that local market conditions can be taken into consideration.

Although fostering the growth of locally led collaboratives is crucial to the success of the Value-Driven Health Care Initiative, national coordination is also needed. Patients should expect and be able to receive good quality care regardless of where they live.

Similarly, all providers should be able to meet certain basic, agreed on standards of care regardless of where they practice. The need for national coordination is

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CMS’s Better Quality Information Initiative

Table 1 The 4 Cornerstones of Value-Driven Healthcare Interoperable HIT • Interoperable HIT is the development and implementation of standards and health information systems that allow various parts of the healthcare delivery system to communicate and exchange data quickly and securely • Interoperable HIT holds the potential to create greater efficiency in the healthcare delivery system Measure and publish quality information • Consumers need quality-of-care information to be able to make confident and informed decisions about their healthcare providers and treatment options • Quality-of-care information is also important for providers to have to be able to improve the quality of care they provide • The quality information consumers and providers receive should be based on measures that are developed through consensus-based processes that involve all stakeholders, such as the processes used by the National Quality Forum, the AQA Alliance, and the Hospital Quality Alliance Measure and publish price information • To be able to make confident and informed decisions about their healthcare providers and treatment options, consumers also need to have price information that is measured and reported in a uniform manner • Efforts are currently under way to develop uniform approaches to measuring and reporting price information, including strategies for measuring the overall cost of services for common episodes of care and the treatment of common chronic diseases Promote quality and efficiency of care • The healthcare delivery system should be structured in a manner to reward those who offer and those who purchase high-quality, cost-effective care • All stakeholders—providers, consumers, health plans, and payers—should participate in arrangements that reward high-quality, cost-effective care HIT indicates health information technology.

Source: Reference 1.

particularly salient for the Medicare program, which provides health insurance coverage for approximately 43.9 million beneficiaries across the United States.2 Because of Medicare’s national scope, the Centers for Medicare & Medicaid Services (CMS) needs to ensure that Medicare beneficiaries residing in Florida can

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KEY POINTS ▲ In 2006, the Department of Health and Human Services

embarked on a campaign to promote the transparency of health information in the United States following the president’s call for value-driven healthcare. ▲ In accordance with this effort, CMS has launched a pilot for

Medicare beneficiaries, known as the Better Quality Information Project. ▲ Because the delivery of care differs by local demographic and

market characteristics, a major concern for CMS is to ensure that Medicare beneficiaries receive comparable information on healthcare quality throughout the country. ▲ The Better Quality Information Project focuses on testing

methods for measuring physician performance using 6 local collaborative efforts. ▲ The lessons collected from this project could offer useful

information for CMS’ future efforts at measuring the performance of physicians who treat Medicare beneficiaries.

receive information on quality of care that is consistent with the quality-of-care information provided to Medicare beneficiaries residing in California.

A National Approach to Physician Performance Measurement A key piece to measuring and reporting quality information is measuring and reporting information on physician performance. Typically, efforts to measure and report on physician performance have been done in a piecemeal manner.3 Physicians, who usually see patients covered by a variety of public and private insurers, often receive information about their performance only as it relates to patients covered by a single insurer. Since physicians typically receive information on only a subpopulation of their entire patient population, physicians typically have no idea how their practice, as a whole, is performing against various quality measures. As a result, consumers looking for information on physician performance to help them select a physician or to review treatment options typically do not have a comprehensive picture of a physician’s performance either.

Often, the insurance plans measure the physicians on a different group of measures as well. For example, a physician could potentially receive a report from one entity that only looked at the preventive services provided by the physician, while a second report from a different entity looked at the services the physician provided to his or her patients with diabetes. Even if the quality measures on the 2 reports appeared to be the

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REGULATORY

Table 2 The 6 BQI Pilot Sites The 6 local collaboratives working with Delmarva are: 1. Arizona State University Center for Health Information & Research, Phoenix, AZ 2. California Cooperative Health Care Reporting Initiative, San Francisco, CA 3. Indiana Health Information Exchange, Indianapolis, IN 4. Massachusetts Health Quality Partners, Watertown, MA 5. MN Community Measurement, Minneapolis/St. Paul, MN 6. Wisconsin Collaborative for Healthcare Quality, Madison, WI

same, it is possible that the methods used by the 2 entities to generate the physician’s performance rate may have differed. For example, a physician receives 2 reports from 2 entities notifying the physician of the percentage of his or her patients with diabetes whose hemoglobin A1C levels are under control. However, the threshold used for determining whether a patient’s hemoglobin A1C level is under control may differ between the 2 entities. Consequently, the information that the physician received from the 2 entities would not be comparable. Since the various reports provide the physician with inconsistent information that may even be conflicting at times, it becomes difficult for the physician to act on the information provided in these various reports to improve the quality of care he or she provides.

CMS’ BQI Project In an attempt to explore how to provide physicians who treat Medicare beneficiaries with more meaningful, comprehensive information of their performance, CMS launched a new project in late 2006. In keeping with the central principles of the Value-Driven Health Care Initiative, this project, known as the Better Quality Information (BQI) to Improve Care for Medicare Beneficiaries Project, also leverages the experience of local multistakeholder collaboratives to explore a national, coordinated approach to physician performance measurement.

CMS contracted with the Delmarva Foundation for Medical Care (CMS’s Quality Improvement Organization for Maryland) to provide overall project administration and management for the BQI Project and to conduct analyses on the Medicare administrative data.

Delmarva awarded subcontracts to 6 local collaboratives, or pilot sites (Table 2), to receive, aggregate, and analyze Medicare administrative data along with their existing datasets. Delmarva and the 6 BQI pilot sites were tasked with testing:

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1. Methods to aggregate Medicare administrative data with data from commercial health plans and, in some cases, Medicaid 2. The use of the aggregated data to calculate and report on quality measures for physician groups and, in some cases, for individual physicians practicing in each of the pilot sites’ local communities.

The BQI Project will be completed at the end of October 2008. The following criteria were used to select the pilot sites: • Strong physician leadership engaged in creating the coalition • Multiple employer participation • Experience in measuring and aggregating physician level data • Experience providing feedback reports to physicians • Presence of a public website for consumers to access relevant information • Demonstrated capacity and interest to accept additional tasks • Willingness to work with a viable health information network if available • Capability and infrastructure to begin data collection within a short time frame.

The 6 local collaboratives selected to participate in the BQI Project each brings a unique set of characteristics and experiences that have resulted in some differences in approach to implementation. One pilot site, for example, receives all payer data (including Medicare and Medicaid) directly from its member physician practices, while another pilot site relies solely on administrative data received from participating health plans.

Similarly, some pilots have access to clinical data, including laboratory results, whereas other pilots only have access to administrative data, such as claims. Some pilots have a wealth of experience in publicly reporting healthcare performance information. Other pilots have no experience with public reporting. Some pilot sites are statewide in terms of population covered and scope, whereas others cover specific areas within the state in which they operate. We believe, however, that the uniqueness of each pilot site will prove beneficial for gathering lessons for the development of a national strategy for physician performance measurement.

Goals for the BQI Project The BQI pilot sites all have had some previous experience linking data from different sources together. In some cases, a pilot site may even have previous experience using the linked, or aggregated, data to produce healthcare performance information on the providers

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in their respective communities. Before their participation in the BQI Project, however, few of the pilot sites had the ability to incorporate Medicare data with the pilot sites’ other data sources. In seeking to test methods for aggregating Medicare administrative data with other data sources to produce a more comprehensive picture of the quality of care provided by physicians to Medicare beneficiaries through the BQI Project, CMS has provided many of the BQI pilot sites the opportunity to incorporate the experiences of Medicare beneficiaries into their local efforts for the first time.

For many BQI pilot sites, the BQI Project represents the first time that Medicare data have been combined with other data sources for the purpose of generating meaningful information on physician performance. In most cases, the addition of Medicare data represents a significant addition of information about a physician’s practice that many of these local collaboratives had been missing. In 2005 alone, approximately 33 million people received a reimbursed service under Medicare fee-for-service, including roughly 32.7 million people who received reimbursable physician services.4 The BQI pilot sites will be working until the end of October 2008 to aggregate Medicare administrative data (eg, Medicare inpatient claims, outpatient claims, carrier claims, enrollment databases, and provider databases) with data from other payers to produce quality measure results. Since the BQI pilot sites will be using data from multiple payers, including Medicare, to produce these measurement results, they will be able to provide a more comprehensive picture of the quality of services being provided by physicians in their communities who treat Medicare beneficiaries. Each BQI pilot site will be reporting on 12 measures. The measures selected by each BQI pilot site are derived from the AQA Alliance (formerly the Ambulatory Care Quality Alliance) starter set of measures for physician performance (Table 3)5 and other quality measures endorsed by the National Quality Forum. In selecting measures for the BQI Project, a number of considerations were taken into account, including the data sources available to each BQI pilot site, to calculate the measure as well as the measure’s relevance to the Medicare population, and the local community.

Methodological Questions Before CMS can develop a strategy for measuring the performance of physicians around the country using Medicare administrative data, a number of methodological questions need to be answered. Each BQI pilot site will be aggregating the Medicare data with their own data sources to generate multipayer physician level

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Table 3 AQA Alliance Measures for Physician Performance Preventive measures 1. Breast cancer screening 2. Colorectal cancer screening 3. Cervical cancer screening 4. Tobacco use 5. Advising smokers to quit 6. Influenza vaccination 7. Pneumonia vaccination Disease-state measures 8. Drug therapy for elevated LDL cholesterol 9. Beta-blocker treatment after heart attack* 10. Beta-blocker therapy post–myocardial infarction* 11. Angiotensin-converting enzyme inhibitor/angiotensin

receptor blocker therapy 12. Left ventricular failure assessment 13. HbA1C management 14. HbA1C management control 15. Blood pressure management 16. Lipid measurement 17. LDL cholesterol level <130 mg/dL 18. Eye examination 19. Use of appropriate medications for people with asthma* 20. Asthma: pharmacologic therapy* 21. Antidepressant medication management (acute phase) 22. Antidepressant medication management (continuation phase) 23. Screening for human immunodeficiency virus 24. Anti-D immune globulin Overuse measures 25. Appropriate treatment for children with upper respiratory

infection 26. Appropriate testing for children with pharyngitis *

Although items 9 and 10, and 19 and 20, appear to be the same, the descriptions that accompany each measure in the actual document are different.

Hb indicates hemoglobin; LDL, low-density lipoprotein.

Source: Reference 5.

and/or physician group level performance measurement results on 12 measures, at least 3 times. During the course of conducting this work, the BQI pilots will be capturing and sharing the lessons learned and challenges around the numerous methodological questions that need to be answered, such as measure selection, methods for assigning accountability for a patient’s care to a physician, or physician attribution, identifying how individual physicians practice as groups, identifying how information about group composition is captured on payers’ administrative data, understanding Medicare data, and the reliability of measure results.

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The BQI project also aims to: 1. Provide beneficiaries in these 6 pilot sites with healthcare performance information on the physicians who treat them to help select physicians and make treatment choices 2. Provide performance information to the physician groups and/or physicians who treat these beneficiaries, which can be used by the physician groups and/or physicians to improve the quality of care they provide.

Thus, the BQI pilot sites will also be capturing and sharing lessons learned around mechanisms for sharing the measurement results with patients as well as their physicians to the extent feasible.

Conclusion The results from CMS’s BQI Project and the shared experiences of the BQI pilot sites could be used to guide future efforts for incorporating Medicare administrative data into the process of measuring the performance of physicians who treat Medicare benefi-

ciaries. Specifically, the lessons learned from the BQI Project could be used to help inform CMS how Medicare administrative data can be aggregated with other sources of data to produce quality measure results that provide a more comprehensive picture of the quality of services being provided by physicians to Medicare beneficiaries across the country. ■ References 1. US Department of Health & Human Services. Value-Driven Health Care. http://www.hhs.gov/valuedriven. Accessed May 2, 2008.

2. US Department of Health & Human Services. Centers for Medicare & Medicaid Services. 2007 CMS Statistics. June 2007. http://www.cms. hhs.gov/CapMarketUpdates/Downloads/2007CMSstat.pdf. Accessed May 5, 2008.

3. AQA Alliance. AQA Pilot Information. Ambulatory Care Quality Alliance Announces Pilot Project: Six Sites Will Combine Public and Private Data on Physician Practice. March 1, 2006. http://www. aqaalliance.org/pilot.htm. Accessed May 30, 2008.

4. US Department of Health & Human Services. 2007 CMS Statistics.

June 2007. http://www.cms.hhs.gov/CapMarketUpdates/Downloads/ 2007CMSstat.pdf. Accessed May 5, 2008.

5. AQA Alliance. Recommended Starter Set of Clinical Measures for Physician Performance. http://www.aqaalliance.org/files/RevisedStarter SetApril2006.doc. Accessed May 12, 2008.

Stakeholder Perspective Medicare’s Evolution from Passive Payer to Value-Driven Purchaser of Healthcare EMPLOYERS: The Centers for Medicare and Medicaid Services’ (CMS) Better Quality Information (BQI) Project is a shining example of the steady evolution of Medicare from passive payer of provider claims to a value-driven purchaser of healthcare. CMS’s progression has been circumspect, made difficult as much by intense politics of measurement and transparency as by the day-to-day demands of managing the staggeringly complex $436-billion Medicare program.

At first glance, with 6 pilot sites, a limited measurement set, and exclusive focus on physicians, the BQI Project may appear modest, but this is deceiving. The CMS BQI Project’s intellectual and market influence is significant, as is its promise as a platform to test and ultimately build a sustainable—politically and technically—and transparent system of physician performance reporting. With the BQI Project’s emphasis on collaboration across Medicare, commercial health plans, and state

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Medicaid programs, CMS is building the relationships, multipayer data sets, and best practices essential to leveraging market power and expertise. By working with measures vetted through the AQA Alliance and the National Quality Forum, CMS is able to focus on a small but manageable and clinically defensible measure set while deflecting the alltoo-often duplicitous antitransparency efforts of some provider trade organizations.

Kudos to CMS’s Office of Clinical Standards and Quality for the thoughtfulness, savvy, and sheer tenacity necessary to develop and launch the BQI initiative. The lessons learned will be incredibly valuable to Medicare, as well as to the other large purchasers, notably employers and state Medicaid agencies.

Kip Piper, MA, CHE President, Health Results Group, LLC Senior Counselor, Fleishman-Hillard, Inc

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MEDICAL TOURISM

Emerging Trends in Outsourcing Healthcare: Medical Tourism J. Warren Salmon, PhD

T

he terms “health tourism,” “medical tourism,” or “health services outsourcing” are often interchangeably used to describe health service provision in another country. The more encompassing concept—“health tourism”—includes all health-seeking behaviors by consumers into another country. This definition includes getting health services, tourism for indigenous and alternative medical treatments, and any other form of tourism undertaken with the purpose of addressing a health concern, usually motivated by seeking cheaper care.1 The phenomenon of medical tourism has attracted much attention in the lay press across the United States and holds many implications for our own healthcare system.2,3 In June 2007, the American Medical Association issued a report titled, Medical Tourism Outside the U.S., which was intended to “study the trend of ‘outsourcing’ health care overseas,”4 motivated in large part by the concern for postprocedure followup of patients returning to the United States.4 Private sector development in emerging economies—such as India, Thailand, Singapore, and certain Latin American nations—attracts foreign patients for relatively cheaper care: the uninsured, the underinsured, or those who prefer not to wait for treatment under a national health insurance system or under arrangements where an employer or private health insurance schemes are seeking “bargain care” over US healthcare prices.5 Such conditions have fostered a thriving medical tourism industry of late. In addition, other health alternatives—complementary medicines, some uncovered procedures that have not yet been approved in one’s home country, and indigenous treatments—all form part of the lure that is attracting thousands of health tourists globally each year. While the private health sector in developing countries begins to thrive, the public health sectors all remain at a much lower rate of growth amidst mounting unmet health needs.6 This new section of the journal will address the advent of health tourism, its varying impact on certain

Dr Salmon is Professor of Health Policy and Administration, University of Illinois at Chicago, IL.

societies, as well as the implications for patients and payers. Topics to be addressed under this emerging trend will provide a variety of perspectives to different stakeholders about medical tourism, including: • The coverage in US national and local newspapers7-9 • An examination of the costs and quality of various medical procedures in different countries available for “medical tourists”10 • Potential risks and benefits of traveling abroad for medical care11 • Role of middlemen and websites that attract American consumers12,13 • Alternative therapies and spa treatments14 • US insurance companies’ and health plans’ reactions to medical tourism15-19 • Review of specific nations that are creating a market for European and American patients, such as Thailand, Singapore, India, Mexico, Brazil, and Costa Rica.6,20,21 Relevant questions for US health plans regarding medical tourism include: 1. What is known of these various foreign healthcare systems?

2. What about their professional quality?

3. How are their facilities being accredited?

4. What are the medical malpractice and legal frameworks?

Other topics of interest include concerns by consumers and clinical cautions, along with potential repercussions for medical follow-up and benefits coverage for patients returning to the United States after a medical treatment abroad.22,23 The goal is to place the emerging medical tourism in its context of globalization, travel, and the consequences of medical and pharmaceutical outsourcing.6,24-26 ■

References 1. Cooperman S. Patient travelers. Forbes Life. October 29, 2007. http://www.forbes.com/business/fyi/2007/1029/095.htm. Accessed September 3, 2008.

2. Grassi DM. Offshoring U.S. patients no cure for ailing healthcare system. November 18, 2006. http://www.associatedcontent.com/article/ 88262/offshoring_us_patients_no_cure_for.html?cat=37. Accessed September 3, 2008.

3. Newspapers examine growing medical tourism trend. May 8, 2007.

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http://www.kaisernetwork.org/daily_reports/rep_index.cfm?hint=3&DR _ID=44770. Accessed September 3, 2008.

4. American Medical Association. Medical travel outside the U.S. June 2007. http://www.medretreat.com/templates/UserFiles/Files/AMA%20 Report%20June%202007.pdf. Accessed August 19, 2008.

5. Forbes S. Open-heart surgery—90% off! Forbes. August 13, 2007. http://members.forbes.com/forbes/2007/0813/021.html. Accessed September 3, 2008.

6. Aruru M, Salmon JW. Health tourism to India: challenges against resource competition to sustaining viable public health care infrastructure for the local populace. Paper to be presented at the American Public Health Association 136th Annual Meeting and Expo. San Diego, CA; October 27, 2008.

7. Mollman S. Healthy travels. Wall Street Journal. December 2, 2005. http://online.wsj.com/article/SB113348874893512031.html. Accessed September 3, 2008.

8. Davidow J. Cost-saving surgery lures “medical tourists” abroad. Seattle Post-Intelligencer. July 24, 2006. http://seattlepi.nwsource.com/health/ 278630_medtour24.html. Accessed September 3, 2008.

9. Johnson LA. More Americans look near, far to save on health care.

Pittsburgh Tribune-Review. August 3, 2008. http://www.pittsburghlive.com/ x/pittsburghtrib/business/s_580809.html. Accessed September 3, 2008.

10. Gutierrez D. Organ transplants move offshore as patients pursue “transplant tourism.” NaturalNews.com. November 19, 2007. http:// www.naturalnews.com/z022044.html. Accessed September 3, 2008.

11. China issues new restrictions on transplants for foreigners. Wall Street Journal, July 3, 2007.

12. Middlemen take uncertainty out of medical tourism. Fierce Health IT. January 10, 2007. http://www.fiercehealthcare.com/story/middle men-take-uncertainty-out-of-medical-tourism/2007-01-10. Accessed September 3, 2008.

13. Merrill M. Medical tourism conference to address finance problems.

Healthcare Finance News. March 9, 2007. http://www.healthcare finance news.com/story.cms?id=6190. Accessed September 3, 2008.

14. Taylor C. Medical tourism’s popularity on the rise. Financial Times.

June 22, 2007. http://www.ft.com/cms/s/2/98f03b1c-203f-11dc-9eb1000b5df10621.html. Accessed September 3, 2008.

15. Yi D. Overseas surgery a clamp on costs. LA Times. July 30, 2006. http://articles.latimes.com/2006/jul/30/business/fi-outsource30.

Accessed September 3, 2008.

16. Increased popularity of medical tourism affects health provider revenue. KaiserNetwork.org. August 5, 2008. http://www.kaisernetwork.org/ daily_reports/print_report.cfm?DR_ID=53731&dr_cat=3. Accessed September 3, 2008.

17. Higgins LA. Medical tourism takes off, but not without debate.

Managed Care. April 2007. http://www.managedcaremag.com/ archives/0704/0704.travel.html. Accessed September 3, 2008.

18. Bartelme T. Thailand: surgical vacation. Charleston Post and Courier.

May 22, 2007. http://www.charleston.net/news/2007/may/22/thailand_ surgical/. Accessed September 3, 2008.

19. Some companies to market medical tourism services to U.S. employers. KaiserNetwork.org. July 28, 2007. http://www.kaisernetwork.org/ daily_reports/rep_index.cfm?hint=3&DR_ID=38803. Accessed September 3, 2008.

20. Hawley C. Seniors head south to Mexican nursing homes. USA Today. August 16, 2007. http://www.usatoday.com/printedition/news/ 20070816/1a_cover16.art.htm. Accessed September 3, 2008.

21. Mitra S. Medical tourism and the healthcare services industry: a look at Singapore. April 19, 2005. http://www.frost.com/prod/servlet/marketinsight-top.pag?docid=36278775. Accessed September 3, 2008.

22. Karvounis N. Medical tourism is great—for those who can afford it. AlterNet. August 21, 2008. http://www.alternet.org/story/95827/.

Accessed September 3, 2008.

23. Bowe C. US interest in medical tourism rises. Financial Times.

February 20, 2008. http://www.ft.com/cms/s/0/6b656c96-df55-11dc91d4-0000779fd2ac.html. Accessed September 3, 2008.

24. Medical tourism or global health care? Fierce Health IT. August 16, 2006. http://www.fiercehealthcare.com/story/medical-tourism-or-globalhealthcare/2006-08-16. Accessed September 3, 2008.

25. David R. Outsourcing grows up. Forbes. August 1, 2006. http://www.forbes.com/technology/2006/08/01/jobs-outsourcingprofits_cx_rd_0801jobs.html. Accessed September 3, 2008.

26. Milstein A, Smith M. America’s new refugees—seeking affordable surgery offshore. N Engl J Med. 2006;355:1637-1640.

Unmanaged Moment

“What did you say gasoline was selling for?”

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AMERICAN HEALTH & DRUG BENEFITS

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The Better Quality Information to Improve Care

NOT EVERYONE IS CUT OUT FOR THE SAME TREATMENT. 1 in 4 adults suffer from a diagnosable mental disorder in any given year.1

Open Access.

Because different people have different needs.

Open access is especially important in the treatment of mental disorders because the response to therapy can vary greatly from individual to individual and from one medication to the next. Restrictions in the form of prior authorizations and preferred lists may have the unintended consequences of jeopardizing patient health while failing to reduce costs.

Bristol-Myers Squibb supports open and unrestricted access to mental health medications. For people with mental illness, having access to newer and potentially more effective medications can be a crucial component of treatment.

SUPPORT OPEN ACCESS AND GIVE PROVIDERS THE FREEDOM TO FIND THE MOST APPROPRIATE MEDICATION FOR EACH INDIVIDUAL. 1. National Institute of Mental Health. Available at: http://www.nimh.nih.gov/healthinformation/statisticsmenu.cfm. Accessed March 24, 2008.

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D6-K0197C March 2008

FDA WATCH

Potayto—Potahto? The Meaning of the FDA’s “Complete Response” Letters Mark Senak, JD

O

n August 11, 2008, the Centers for Drug Evaluation and Research (CDER) of the US Food and Drug Administration (FDA) officially changed the way the division is responding to new drug applications (NDAs), raising mild alarm in some circles by stating that in the future, rather than respond with “approvable” letters or “not approvable” letters, the division would be responding with “complete response” letters.

This led many observers to wonder what this switch would mean for stakeholders in the process. Others have asked whether the move clouds rather than supports the goal of transparency in the approval of new drugs, while still others yawn and wonder if this switch means anything substantive at all. After all, the Center for Biologics Evaluation and Research (CBER) has been sending out complete response letters for 11 years now. Has the approval of biologics been impaired as a result compared with the track record of small-molecule drugs?

Eleven years is a long time to change a procedure, leading one to wonder if the approvable letter system did not offer CDER some sort of advantage.

Before CDER’s announcement on July 9, 2008,1 about the switch (which became effective on August 11), there were a few outcomes possible in response to the NDA: first and best was an approval letter. Second, was the far-less welcomed approvable letter, which although it was not an approval, did signal that the company had made a good effort and that the FDA might approve the compound if the drug sponsor met some particular goals. Finally, of course, was the dreaded not approvable letter, which almost always meant what it said—that an NDA could not be approved as submitted, causing the sponsoring companies’ investors to lose heart in many cases.

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Now, with the switch to “approvable” or “complete response” letter, there are only 2 scenarios for which all stakeholders—the company, the physician community, the patient, and the investors—need to prepare.

What prompted this change? According to the announcement by the FDA, “These new regulations will help the FDA adopt a more consistent and neutral way of conveying information to a company when we cannot approve a drug application in its present form,”1 said Janet Woodcock, MD, director of the agency’s CDER. “Thorough and timely review of drug applications is a priority of the FDA, and these new processes will make our communications with sponsors of applications more consistent.”1 From a communications perspective, this is an interesting comment, given that Dr Woodcock uses 2 sentences to announce that this is an effort to be consistent, and uses the word twice, without explaining with what the division is seeking consistency.

The answer is that CDER is moving to be consistent with CBER. The question that follows is: Why did it take CDER 11 years to make the switch that CBER made in no time at all? The agency first made the commitment regarding complete response letters as part of the user-fee performance goals established in conjunction with the enactment of the FDA Modernization Act of 1997 (Public Law 105-115) (the user-fee provisions of this act are known as “PDUFA II”), and this commitment was repeated in conjunction with the enactment of the Prescription Drug User Fee Act of 2002.

Eleven years is a long time to change a procedure, leading one to wonder if the approvable letter system did not offer CDER some sort of advantage.

In any case, the rule has been finalized and is now in use. The rule includes: 1. Additional regulations regarding changes to the FDA’s ability to defer the review of amendments 2. Extensions of the review cycle due to the submission of a major amendment 3. Classification of responses to a complete response letter (ie, class 1 and class 2 resubmissions) 4. Timelines for submitting a response to a complete response letter and administrative actions for failure to respond

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FDA WATCH

5. The definition of an efficacy supplement.

Under the old system, an approvable letter stated that an NDA was basically approvable if certain issues were resolved, indicating that the NDA substantially meets regulatory requirements and the FDA could approve if the applicant submits additional information or agrees to specific conditions. A not approvable letter meant that the application could not be approved and might describe deficiencies.

A complete response letter will state that the FDA cannot approve an NDA in its current form, and will describe specific deficiencies in the application. The deficiencies described therein can be minor (labeling) or major (new clinical trials). When possible, CDER recommends actions that might be taken to place the application in an approval standing.

So what is the difference? For many, this boils down to a matter of transparency. The contents of an approvable letter and a complete response letter are considered proprietary, and the FDA does not divulge the contents of such letters, nor does it issue a press release.

Rather, it is in the purview of the sponsoring drug company to release as much information as it wants, with as much specificity as it wishes.

Under the old system, when a company received an approvable letter, although the company might not have said much about the contents, the fact that an approvable letter was received instead of a not approvable letter signaled that the NDA at least had some merit, and that if the company was willing to fulfill certain tasks, the application would likely be approved.

But under the new system, no such subtle signal is being sent. Especially for investors, that means there is an unprecedented reliance on what the company says, and how it may speak about the complete response letter it has received; reading between the lines of a press release may be very telling, if vague, assuming the company says anything substantive about the release. A statement that the company would be working with the

FDA in the future could signal that there is a pathway set up in the letter for eventual approval, and that the company is going to take it, or it could mean that the company is just going to call the FDA and complain.

So what is the difference? For many, this boils down to a matter of transparency. The contents of an approvable letter and a complete response letter are considered proprietary.

If a press release alludes to a specific issue, such as one of the comparators used in the study, it may signal that more studies are needed. If, however, the matter is simply one of labeling, there might be language in the press release that indicates a short-term fix.

Or, as some are advocating, there could be a push to release the entire contents of complete response letters.

That solution may be one that companies come around to on a voluntary basis, or it is possible that it could be included in what is, no doubt, a substantial amount of FDA and pharmaceutical marketing reforms that are distinct possibilities for Congress during 2009. â&#x2013; Reference 1. US Food and Drug Administration Press Release. FDA Revises Process for Responding to Drug Applications. http://www.fda.gov/bbs/ topics/NEWS/2008/NEW01859.html. Accessed August 26, 2008.

Mr Senak is Senior Vice President at Fleishman-Hillard in Washington, DC, and writes the Eye on FDA blog, www.eyeonfda.com.

Correction In the article â&#x20AC;&#x153;Prescribing warfarin appropriately to meet patients safety goalsâ&#x20AC;? (July/August 2008), the source cited for Table 3 (on page 30) is incorrect. The correct source is Reference 16.

In addition, the type of grant mentioned on page 31 is incorrect. Dr Dharmarajan received a National Grant.

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JOIN AHDB PEER REVIEW American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other experts in benefit design who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal.

You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewers’ names will be published in AHDB at the end of the year.

Reviewers should have at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted for publication in AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to): • Administration/Management • Benefit design • Disease management/state (eg, asthma, infectious diseases, pain management, schizophrenia) • Drug therapy (including biologics, generics) • Drug utilization • Employer benefits • Finance/economics • Health information technology • Health policy/reform • Patient education/initiatives/quality-of-life issues • Pharmacoeconomics: cost-benefit analysis, cost-effectiveness • Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits • Reimbursement: Medicare/Medicaid, health insurance, prior authorization • Research: methods, study design, data collection/analysis

To become a peer reviewer, please complete the form below and fax to: 732-992-1881 or e-mail to editorial@ahdbonline.com Reviewer Information _______________________________________________________________________________________ First Name Last Name Credentials _______________________________________________________________________________________ Title Company _______________________________________________________________________________________ Address _______________________________________________________________________________________ E-mail Phone

SELF-ADMINISTERED V. PROVIDER-ADMINISTERED How route of administration in oncology products affects payer coverage and product strategy Pharmaceutical manufacturers have deployed manufacturing techniques to create self-administered oncology products. As a result, they are changing the treatment paradigm—from one where patients receive treatment in the physician office or healthcare organization setting to one where patients can receive therapies nearly anywhere. This increase in patient convenience comes at a premium price, though, and insurers have taken notice. Public and private payers are rapidly and substantially adapting their coverage policies to manage utilization and control costs. Given the changing oncology landscape, stakeholders in the oncology market seek solid analysis to understand the true impact route of administration has on product success, reimbursement and patient access.

New research from Xcenda provides answers to strategic questions facing the oncology market: > How has drug coverage evolved in the public and private payer markets? > How is reimbursement for self-administered and injectable oncology agents distinguished in the market place? > Are the economic incentives properly aligned to insure access and payment for product and services? > What are the key issues and concerns for providers, payers and patients? > How are managed care organizations evaluating oncology agents for formulary consideration? > How do coverage policies influence treatment preferences of oncologists?

Report Scope This report uses data from historical, primary and secondary sources to explore critical issues related to selfadministered and provider-administered oncology products. Key report features include: > Contrasted stakeholder perspectives: payer, provider and patients > Unique data sets from AmerisourceBergen Specialty Group, including primary market research with: - Commercial medical and pharmacy directors, representing more than 100 million lives (via Xcenda’s Managed Care Network) - Prescribing oncologists (via NMCR Analytics) > Oncology specialties: breast, lung and renal cancers > Supplemental secondary research focusing on: - Evolution of drug coverage for oncology agents in the public and private payer markets - Trends in utilization, cost, formulary status and out-of-pocket requirements

Developed by Xcenda in conjunction with sister company NMCR Analytics, this crucial research is available now. Learn more and download it today.

www.xcenda.com

About Xcenda Xcenda is an integrated d, world-class consulting organizatio on focused on vvalue, alue, integrated, organization reimbursement and pat tient access at discover and patient access.. W Wee provide solutions th that communicate the vvalue aluee of pharmaceuticals and other healt thcare technologi es. healthcare technologies.

info@xcenda.com

CLINICAL REGULARTORY

Chronic Obstructive Pulmonary Disease: An Overview John F. Devine, DO, FACP

Chronic obstructive pulmonary disease is a growing healthcare problem that is expected to worsen as the population ages and the worldwide use of tobacco products increases.

Smoking cessation is the only effective means of prevention. Employers are in a unique position to help employees stop smoking. During the long asymptomatic phase, lung function nevertheless continues to decline; therefore, many patients seek medical attention only when they are at an advanced stage or when they have experienced an acute exacerbation.

To help preserve patientsâ&#x20AC;&#x2122; quality of life and reduce healthcare costs related to this chronic disease, clinicians need to accurately diagnose the condition and appropriately manage patients through the long course of their illness.This article discusses the current approach to patient management. [AHDB. 2008;1(7):34-42.]

34

hronic obstructive pulmonary disease (COPD) is a poorly reversible disease of the lungs that is one of the major causes of morbidity and mortality worldwide. In the United States, it is the fourth leading cause of death after heart disease, cancer, and cerebrovascular disease.1,2 By 2020, it is projected to become the third leading cause of death worldwide.1 Contrary to the trends for other major chronic diseases in the United States, the prevalence of and mortality from COPD have continued to rise3; the death rates doubled between 1970 and 2002,4 and for the first time in 2000, mortality figures for women surpassed those for men.2,5 In the United States, 12 million patients are currently diagnosed with COPD, but there is believed to be at least an equal number of individuals with impaired lung function suggestive of COPD who are undiagnosed.6 Given that the majority of COPD cases are caused by smoking, it is primarily a preventable disease.

Most patients with COPD are middle-aged or elderly. In 2000, 16 million office visits were attributed to COPD-related conditions,7 with the caseload expected to increase with the aging of the population.

There is no cure for COPD. True breakthroughs in treatment, particularly disease-modifying agents, have been elusive. The only strategy known to reduce the

C

incidence of the disease is smoking cessation.

Healthcare costs associated with COPD are approaching $18 billion and $14 billion in direct and indirect costs, respectively.2,8 Hospitalizations, which often result from acute exacerbations, account for approximately 40% of direct costs; prescription drugs account for 20%.7 Emergency department visits for COPD totaled 1.5 million in 2000.2 Inpatient mortality from acute exacerbation is 10% by some estimates,9 and nearly 60% at 1 year for patients older than 65 years of age.10 Despite these disturbing figures, COPD remains largely unrecognized as a public health problem. To increase awareness of COPD, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) was launched in 1997, as a collaboration of the National Heart, Lung, and Blood Institute, the National Institutes of Health, and the World Health Organization, to disseminate information on causes of COPD and issue management guidelines.11 Further multidisciplinary efforts involving government, healthcare workers, and public health officials are needed to reduce the disease burden of COPD, which comprises not only economic and healthcare system costs but also losses to patients and families from progressive disability and impaired quality of life.

Dr Devine is an Emergency Physician, Department of Emergency Medicine, Evangelical Community Hospital, Lewisburg, PA.

Definitions COPD comprises a diverse group of clinical syndromes that share the common feature of limitation of

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expiratory airflow.12 The American Thoracic Society defines COPD in terms of chronic bronchitis and emphysema.13 Chronic bronchitis is characterized by the clinical symptoms of excessive cough and sputum production; emphysema refers to chronic dyspnea, resulting from enlarged air spaces and destruction of lung tissue. The GOLD initiative defines COPD as “a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases.”14 Asthma is also characterized by airflow obstruction and inflammation, but in addition it involves hyperresponsiveness of the airways to stimulus; therefore, the reversibility of functional deficits in asthma differentiates it from COPD.13

Risk Factors Cigarette smoking is the principal risk factor for COPD. However, approximately 1 of 6 Americans with COPD has never smoked.15 Occupational and environmental exposures to chemical fumes, dusts, and other lung irritants account for 10% to 20% of cases.15 Individuals with a history of severe lung infections in childhood are more likely to develop COPD.15 Alpha-1 antitrypsin deficiency is a rare cause of COPD but should be suspected in persons in whom emphysema develops before the age of 40 or those who lack the common risk factors.16 Clinical Course COPD is a slowly progressing disease with a long asymptomatic phase, during which lung function continues to decline. Persistent cough, particularly with mucus production, is a common symptom. Dyspnea, especially with exercise, wheezing, and chest tightness may also be present. Patients often present with the first acute exacerbation of COPD at an advanced stage.

Symptoms do not usually occur until forced expiratory volume in 1 second (FEV1) is approximately 50% of the predicted normal value.17 As the disease progresses, exacerbations may become more frequent and lifethreatening complications may develop. End-stage COPD is characterized by severe airflow limitation, severely limited performance, and systemic complications.18 Patients often succumb to respiratory failure or pulmonary infection. Extrapulmonary effects associated with COPD include weight loss, nutritional abnormalities, and muscle atrophy. Various phenotypes of COPD, with specific prognostic implications, have been identified.19

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KEY POINTS ▲ The prevalence of COPD, characterized by an irreversible

limitation of expiratory airflow, is growing in the United States and worldwide, and no cure is available. ▲ Smoking is the major cause for this disease, thus smoking

cessation in smokers is crucial. Employers are in a unique position to assist employees to stop smoking. ▲ Direct and indirect US healthcare costs for COPD are

estimated at $18 billion and $14 billion, respectively. ▲ Regular use of inhaled bronchodilators to prevent and

relieve symptoms is the mainstay of management. ▲ Short-acting inhalers provide immediate symptom relief,

but long-acting inhaled bronchodilators are more effective and offer greater convenience; thus combining inhalers is often recommended.

Pathogenesis Cigarette smoking or exposure to noxious agents induces an inflammatory process in the lungs and airways of the bronchial tree that leads to small airway disease and parenchymal destruction.20,21 Loss of elasticity of the alveolar attachments, or their destruction, is a hallmark of emphysema. The inability of the lungs to empty results in air trapping and hyperinflation, manifested as dyspnea on exertion.

Over time, this can cause the diaphragm to flatten and the rib cage to enlarge. In the late stages of COPD, hypoxemia develops. Pulmonary hypertension is a consequence of thickening of the intima and vascular smooth muscle and indicates a poor prognosis.

COPD is a slowly progressing disease with a long asymptomatic phase, during which lung function continues to decline.

The net result of the pathophysiologic processes of COPD is increased resistance to airflow and decreased expiratory flow rate. Removing the inflammatory stimulus (eg, stopping smoking) does not diminish the inflammatory process.

The inflammatory process in asthma is markedly different from that in COPD, but since approximately 10% of COPD patients also have asthma, some of the pathologic features may overlap.21

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Table 1 Staging of COPD Stage

Description

Findings (postbronchodilator FEV1)

0

At risk

Risk factors, chronic symptoms, but normal spirometry

1

Mild

FEV1/FVC ratio <70% FEV1 at least 80% of predicted value May have symptoms

2

Moderate

FEV1/FVC ratio <70% FEV1 50% to <80% of predicted value May have chronic symptoms

3

Severe

FEV1/FVC ratio <70% FEV1 30% to <50% of predicted value May have chronic symptoms

4

Very severe

FEV1/FVC ratio <70% FEV1 <30% of predicted value OR FEV1 <50% of predicted value plus severe chronic symptoms

COPD indicates chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

Adapted with permission from Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176:532-555. Am J Respir Crit Care Med is an official publication of the American Thoracic Society.

Comorbid Conditions Clinicians need to be aware of comorbidities in patients with COPD, which can adversely affect health status and complicate management. COPD is associated not only with other respiratory diseases (eg, pneumonia) but also with diseases affecting organ systems, such as the musculoskeletal system (eg, osteoporosis) and the cardiovascular system (eg, angina). A study of comorbidities in COPD shows the following relative risk of COPD patients for pneumonia (16.00), osteoporosis (3.14), respiratory infection (2.24), myocardial infarction (1.75), angina (1.67), fractures (1.58), and glaucoma (1.29).22 The disease has also been associated with depression.23,24 Diagnosis Early symptom detection and evaluation allows for earlier treatment, designed to preserve lung function and slow disease progression. The diagnosis is primarily clinical,25 and most patients are diagnosed by primary care physicians. Suggestive symptoms include chronic cough, excessive sputum production, and dyspnea, especially when any of these symptoms are accompa-

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nied by a history of cigarette smoking or regular exposure to occupational or environmental pollutants or toxins. Close attention is needed to identify patients who have these findings and consider further evaluation earlier than we have in the past.

Screening for the history of smoking, cough, sputum, dyspnea, and exposures should be a routine part of the review of systems, and when present, suggests the need for further evaluation. Spirometry is used to confirm the diagnosis of COPD in suspected cases.

However, evidence does not support the use of spirometry for screening purposes in adults who have no respiratory symptoms.26 A high index of suspicion is essential for early diagnosis. Patients whose FEV1 is <80% of predicted value and whose ratio of FEV1 to forced vital capacity (FVC) is <70% after inhalation of a short-acting bronchodilator are considered to have restricted airflow, indicative of COPD. The FEV1/FVC ratio should be compared with age-related norms before the diagnosis is confirmed, since that ratio normally declines with aging. Spirometry is useful in establishing the need for inhaled treatment in adults with COPD symptoms and whose FEV1 is <60% of predicted value.26 Spirometric measurements can be used to classify the severity of COPD, as established by GOLD (Table 1).27 Asthma should be ruled out in the differential diagnosis. Unlike COPD, asthma onset is generally early in life and its symptoms vary from day to day, tending to worsen at night or in the early morning. Asthma is often associated with allergy, rhinitis, or eczema and tends to be present in the family history.27 The degree of reversibility of airflow limitation also differentiates the 2 conditions.25

Treatment of COPD Smoking Cessation The single most important intervention in modifying the course of COPD in patients who smoke is smoking cessation. The Lung Health Study reported a progressive decline in postbronchodilator FEV1 in men and women who continued to smoke over an 11-year period.28 At 11 years, 38% of continuing smokers had an FEV1 <60% of the predicted normal value compared with 10% of sustained quitters.28 Most patients will make several attempts before they succeed in giving up the use of tobacco, but even a 3-minute counseling session has been shown to result in quitting rates of 5% to 10%.29 A number of drugs are effective in promoting smoking cessation, including nicotine replacement products (eg, nicotine gum, patch, inhaler), the anti-

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Table 2 Medications Available for the Treatment of COPD Drug class Brand (generic) Beta2-agonist Short-acting Xopenex (levalbuterol HCL)

Inhaler (µg/use)

ProAir HFA* Proventil HFA* Ventolin HFA* (albuterol) AccuNeb* (albuterol)

90 MDI

Long-acting Foradil Aerolizer (formoterol) Perforomist (formoterol) Serevent Diskus (salmeterol) Brovana (arformoterol)

Solution for NEB (mg/mL) 0.1 0.21 0.42

0.21 0.42 0.83 12 DPI

Maintenance dose

50 DPI

Asthma

Hyperglycemia, hypokalemia, viral infection, headache

$$$$$

2 inhalations every 4-6 hrs prn

COPD, asthma, EIA

Tremor

$$

1.25-5 mg every 4-8 hrs prn

$$

COPD, asthma, EIA

(*5%) Palpitation, nausea, headache, diarrhea, bronchitis; asthma exacerbation (age 5-12)

20 µg bid (AM & PM) 50 µg every 12 hrs

0.0075

Cost of 30-day supply

0.63-1.25 mg every 6-8 hrs prn

12 µg every 12 hrs 0.01

Indications

Side effects (>10%, unless otherwise noted)

15 µg every 12 hrs

Anticholinergics Short-acting Atrovent HFA 17 MDI 2 inhalations (ipratropium) 4 times daily Atrovent* 0.2 500 µg 3-4 times (ipratropium) daily Long-acting Spiriva 18 DPI 18 µg/d (tiotropium) Inhaled corticosteroids 40, 80 MDI 40-320 µg bid QVAR (beclomethasone) Pulmicort 90, 180 DPI 180-720 µg bid Flexhaler (budesonide) Flovent HFA 44, 110, 220 88-440 µg bid (fluticasone) MDI Azmacort 75 MDI 40 150 µg 2-3 times (triamcinolone) daily, or 300 µg bid Combination short-acting beta2-agonist + anticholinergic in 1 inhaler Combivent MDI 103/18 MDI 2 inhalations (albuterol) + 4 times daily ipratropium DuoNeb SOLN* 0.83/0.17 One 3-mL vial (albuterol) + via NEB ipratropium 4 times daily Combination long-acting beta2-agonist + corticosteroid in 1 inhaler Advair Diskus 50 + 100, 250/50 µg bid (salmeterol + 50 + 250, fluticasone) 50 + 500 DPI Symbicort 4.5 + 80, 2 inhalations bid (formoterol + 4.5 + 160 budesonide) DPI Methylxanthines Oral tablets/capsules Many brands* 12 h: 100, 125, Initial >45 kg: (theophylline) 200, 300, 10 mg/kg/d 450 mg titrate to max 24 h: 100, 200, 800 mg/d in divided 300, 400, 600 mg doses every 6-8 hrs Systemic corticosteroids Prednisone* 1, 2.5, 5, 10, 5-60 mg/d single or 20, 50 mg divided dose tablets Prednisolone* 5 mg tablets Medrol* 4, 8, 16, 32 mg 4-48 mg/d in 4 (methyltablets divided doses prednisolone)

$$$$ $$$$

Asthma, COPD, EIA, nocturnal asthma COPD, bronchitis, emphysema

COPD, bronchitis, emphysema

Headache, pharyngitis, URTI

$$$$

(*5%) Chest pain, back pain, headache, diarrhea, sinusitis

$$$$$

Bronchitis, URTI, palpitation, dyspnea $$$$ $$$

COPD, bronchitis, emphysema

Xerostomia, URTI, sinusitis

$$$$

Asthma

Hoarseness, thrush, yeast infection in the mouth

$$$$ $$$$$ $$$$ $$$$

Ipratropium: Bronchitis, URTI

$$$$

Albuterol: Tremor, sinus tachycardia, anxiety

$$$$$

Asthma, COPD

URTI, headache pharyngitis

$$$$

COPD†

Headache, URTI, nasopharyngitis

$$$$

Asthma, COPD, neonatal apnea

Tachycardia, nausea. vomiting, nervousness, restlessness

$$$

COPD acute exacerbations, asthma, many others

Short-term: Insomnia, indigestion, increased appetite, nervousness, Long-term: Cataracts, hypertension, thinning bones, easier bruising, slower wound healing, muscle weakness

$

COPD (for asthma patients requiring a 2nd bronchodilator)

$ $-$$

COPD indicates chronic obstructive pulmonary disease; DPI, dry-powder inhaler; EIA, exercise-induced asthma; HFA, hydrofluoroalkane; MDI, metered-dose inhaler; NEB, nebulizer; URTI, upper respiratory tract infection. *Generic available. †Pending approval.

Cost information ($): $, 0-25; $$, 26-50; $$$, 51-100; $$$$, 101-200; $$$$$, >200.

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Table 3 Stepwise Approach to the Management of COPD 4 Stages of COPD Mild FEV1/FVC <70% FEV1 *80% Moderate FEV1/FVC <70%

Pharmacologic intervention Add a short-acting bronchodilator when needed (anticholinergic or beta2-agonist) Prescribe an annual influenza vaccination

50% FEV1 <80%

Add 1 or more long-acting bronchodilators on a scheduled basis Consider pulmonary rehabilitation

Severe FEV1/FVC <70% 30% FEV1 <50%

Add inhaled glucocorticosteroids if repeated exacerbations occur

Very severe FEV1/FVC <70% FEV1 <30%

Evaluate for adding oxygen Consider surgical options

COPD indicates chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity.

Adapted with permission from Hanania NA, Donohue JF. Pharmacologic interventions in chronic obstructive pulmonary disease: bronchodilators.

Proc Am Thorac Soc. 2007;4:526-534. Proc Am Thorac Soc is an official publication of the American Thoracic Society.

depressant bupropion (Zyban), the drug varenicline (Chantix), in addition to counseling.30,31 Most smokers should be treated with varenicline as a first-line agent.

Smoking-cessation rates are highest when medical management is combined with counseling.

Relapse is common, and patients need to be coached and realize that multiple attempts at quitting are often required before quitting permanently.

Acupuncture and hypnosis are often advertised as smoking cures; however, a meta-analysis of 22 studies comparing acupuncture with sham acupuncture or with other methods of smoking cessation found no differences in outcome.32

Employers as Motivators Employers are in a unique position to educate, counsel, and assist employees who use tobacco. Some are viewing it as an opportunity to keep their employees healthier and reduce healthcare costs. Evangelical Community Hospital in Lewisburg, Pennsylvania, is an example of an organization that has been very proactive with smoking-cessation efforts. Through the respiratory therapy department, they developed a program that offers free nicotine replacement to employees, along with counseling. The program has a good success rate and offers ongoing encouragement

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to those who do not quit. More employees quit smoking when the hospital became tobacco free in November 2007.

Varenicline and nicotine replacement patches were offered to employees and their spouses at no cost since June 2007; 55 employees and 24 spouses have participated so far. This program is an example of the impact an employer can have on the health of employees.

Pharmacotherapy None of the medications currently available for COPD has been shown to alter the progressive deterioration of lung function that characterizes the disease.

Therefore, the goals of treatment are to relieve symptoms, prevent or minimize exacerbations and complications, improve exercise performance, and decrease mortality.27,33 Regular use of inhaled bronchodilators, either alone or in combination, to prevent and relieve symptoms is the mainstay of COPD management. Although shortacting inhaled agents are often used when needed to provide immediate symptom relief, especially in mild COPD, long-acting inhaled bronchodilators are more effective and offer greater convenience.27,33 Use of 2 bronchodilators with different durations and mechanisms of action may produce greater bronchodilation than use of a single agent,27 as well as reduce the potential for adverse effects from increasing the dose of a single agent.33 The bronchodilators most often prescribed are beta2-agonists, anticholinergics, and methylxanthines (Table 2).14 Selecting the right agent mainly depends on the patient’s response.

On May 30, 2008, the US Food and Drug Administration (FDA) issued a public health advisory alerting patients and physicians on the transition from inhalers containing chlorofluorocarbons (CFCs) to ozone-friendly hydrofluoroalkane (HFA) inhalers by December 31, 2008.34 After that date, the CFC inhalers will no longer be available in the United States. These inhalers are being phased out “because they are harmful to the environment,”34 the FDA says. The 3 HFA albuterol inhalers approved by the FDA are ProAir, Proventil, and Ventolin. The fourth HFA inhaler, Xopenex, contains the active medication levalbuterol.34 These 4 inhalers are safe and effective replacements for the CFC inhalers, but they may feel and taste different from the CFC inhalers.34 Review of published randomized controlled trials involving different types of aerosol devices (eg, metered-dose inhalers, dry-powder inhalers, nebulizers) for outpatient management of COPD did not reveal

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any differences in pulmonary function responses between the various delivery devices. Thus, cost, convenience, and the patient’s ability to use the device properly are important considerations in choosing the mode of delivery.35 In patients who have difficulty adequately using inhalers, nebulized medication may result in more reliable drug delivery.

In addition to bronchodilators, inhaled glucocorticosteroids are recommended for the treatment of severe to very severe COPD in patients who have repeated exacerbations.27 The combination of a long-acting beta2-agonist (salmeterol) and an inhaled glucocorticosteroid (fluticasone propionate) was shown in the Towards a Revolution in COPD Health (TORCH) trial to be significantly more effective than either agent alone or placebo in reducing the number of moderate or severe exacerbations and in improving health status over the 3-year study.36 However, the combination regimen did not significantly decrease the risk of death compared with placebo. The investigators say the probable reason was that the study was not sufficiently powered to detect an effect on mortality.36 Table 3 lists the types of pharmacotherapy appropriate at each stage of COPD.33 Choosing a specific medication within the class of short- or long-acting beta2-agonists, inhaled steroids, methylxanthines, or combination agents is a decision that is based on provider preference, local standards of care, and formulary availability. Several novel therapies are being investigated; many of them target inflammatory-signaling pathways.37 Although bacterial lung infections should be treated with appropriate antibiotics, long-term prophylaxis with antibiotics has not been shown to be effective in preventing bacterial infections or COPD exacerbations.31

Managing Exacerbations Exacerbation of COPD is generally defined as an acute increase in symptoms beyond normal day-to-day variation.27 Symptoms of an exacerbation range from increased breathlessness accompanied by cough and sputum production in mild COPD to life-threatening respiratory failure in severe COPD. The frequency and severity of exacerbations correspond to the severity of the patient’s underlying disease.31 Infection, particularly bacterial infection, is frequently implicated in exacerbations. Air pollution can also trigger exacerbations; however, the cause cannot be determined in about one third of severe cases.14 COPD exacerbations can often be managed at home. Strategies include developing a plan and edu-

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cating patients on its implementation during an acute exacerbation. The patient-initiated plan may include increasing the dose and/or frequency of the short-acting bronchodilator (administered by nebulizer, if necessary) and adding an anticholinergic agent. If the patient’s FEV1 is <50% of predicted value, a systemic glucocorticosteroid should also be considered to restore lung function and shorten recovery time.14,31 Antibiotic

Symptoms of an exacerbation range from increased breathlessness accompanied by cough and sputum production in mild COPD to life-threatening respiratory failure in severe COPD. therapy should be started if infection is suspected,31 such as in the case of fever and/or purulent sputum.

Many primary care practices have acute care visits, offering same-day appointments for patients with acute exacerbations of chronic illness. If a same-day appointment with the patient’s primary provider is not offered, urgent care centers may be utilized. For home-bound patients, home health agencies can play a crucial role for expediting appropriate treatment services.

When symptoms are severe, emergency department evaluation is necessary. High-risk patients with comorbid conditions, including pneumonia, arrhythmias, heart failure, diabetes, chronic kidney disease, or liver failure, often require inpatient care. Patients who have worsening hypoxemia or hypercapnea, changes in mental status, or those who have a poor response to initial treatment are among those frequently admitted. Patients who cannot eat, sleep, or care for themselves because of worsening condition often cannot be managed at home.38 For patients who require hospitalization, oxygen therapy is the foundation of treatment. The use of supplemental oxygen should achieve a goal of a hemoglobin saturation of 90% (PaO2 of 60-65 mm Hg).27 Noninvasive intermittent ventilation is preferable in certain presentations of exacerbations. Invasive mechanical ventilation may be necessary if the patient has life-threatening hypoxemia, is in respiratory arrest, or has cardiovascular complications. Drug therapy in the hospital is similar to that for home management of an exacerbation. In addition, a methylxanthine such as theophylline may be warranted when the patient’s response to a short-acting bronchodilator is inadequate.14

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Nonpharmacologic Interventions The foundation of most rehabilitation programs for patients with COPD is endurance exercise to increase work and exercise capacity.26 Meta-analysis of the results of 6 small randomized controlled trials showed that compared with usual care, exercise training reduced the number of unplanned hospital admissions as well as significantly improved the patients’ healthrelated quality of life and capacity for exercise.39 The 6 trials all compared the efficacy of a respiratory rehabilitation program (including physical exercise) with standard care in the management of patients after an acute exacerbation of COPD. Baseline FEV1 was )40% of predicted value for all patients included in these trials.

On the basis of clinical evidence, the American College of Physicians recommends that physicians prescribe oxygen therapy for patients with COPD and resting hypoxemia, which is defined as a PaO2 )55 mm Hg. Supplemental oxygen for at least 15 hours daily has been shown to help increase survival in patients with severe airway obstruction (FEV1 <30% of predicted value) and resting hypoxemia.26 All patients with COPD should receive pneumococcal vaccination. An annual influenza vaccination is advised for all older patients who have COPD.27 Vaccination of persons aged 65 or older can reduce rates of hospitalization and death.40 Surgical Modalities Lung volume reduction surgery (LVRS) has been shown—but only among a small, very selective population of patients—to be superior to medical therapy in increasing survival, exercise capacity, and quality of life in patients who have upper-lobe emphysema and low exercise capacity.41 However, because LVRS is an expensive, palliative procedure, it should be undertaken only in carefully selected patients.27 The multidimensional BODE index was developed to assess the risk of death from COPD in an individual patient.42 The index includes 4 variables: • Body mass index (weight) • Airway Obstruction (FEV1) • Dyspnea • Exercise capacity (6-minute walk distance).

The BODE index can be useful in predicting survival after LVRS. A reduced BODE score index postoperatively has been associated with reduced mortality.43 Lung transplantation to improve quality of life and pulmonary function is sometimes performed in appropriately chosen patients with very advanced COPD. The potential benefits of surgery in patients with

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COPD need to be weighed against its risks, including postoperative complications, such as lung infections and increased airflow obstruction.27

Conclusions COPD will remain a significant healthcare problem for years to come. Early identification of the disease through primary care screening for the common symptoms in smokers or those exposed to air pollutants or toxins will lead to earlier diagnosis and treatment.

Focusing on smoking cessation will have a great impact on the progression of disease. Advancements in treatment will require translation of a more fundamental understanding of the pathophysiologic pathways involved into disease-modifying interventions. At present, management efforts are directed toward improving patients’ symptoms and functional limitations through carefully selected treatment modalities. ■ References 1. Murray CJ, Lopez AD. Alternative projection of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet.

1997;349:1498-1504.

2. National Heart, Lung, and Blood Institute. Data Fact Sheet: Chronic Obstructive Pulmonary Disease. National Institutes of Health Publication 03-5229. Bethesda, MD: US Department of Health and Human Services; 2003. www.nhlbi.nih.gov/health/public/lung/other/ copd_fact.pdf. Accessed May 5, 2008.

3. Mannino DM. COPD: epidemiology, prevalence, morbidity and mortality, and disease heterogeneity. Chest. 2002;121(5 suppl):121S-126S. 4. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, 1970-2002. JAMA. 2005;294:1255-1259.

5. Centers for Disease Control and Prevention. Facts about chronic obstructive pulmonary disease (COPD). www.cdc.gov/nceh/airpollution/ copd/copdfaq.htm. Accessed April 30, 2008.

6. National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2007 Chart Book on Cardiovascular, Lung, and Blood Diseases.

Bethesda, MD: National Institutes of Health. http://www.nhlbi.nih.gov/ resources/docs/07-chtbk.pdf. Accessed April 30, 2008.

7. National Heart, Lung, and Blood Institute. Morbidity and Mortality: 2002 Chartbook on Cardiovascular, Lung, and Blood Diseases. Bethesda, MD: US Department of Health and Human Services; 2002.

8. Skrepnek GH, Skrepnek SV. Epidemiology, clinical and economic burden, and natural history of chronic obstructive pulmonary disease and asthma. Am J Manag Care. 2004;10(5 suppl):S129-S138.

9. Fabbri LM, Hurd SS; for the GOLD Scientific Committee. Global strategy for the diagnosis, management, and prevention of COPD: 2003 update. Eur Resp J. 2003;22:1-2.

10. Seneff MG, Wagner DP, Wagner RP, et al. Hospital and 1-year survival of patients admitted to intensive care units with acute exacerbation of chronic obstructive pulmonary disease. JAMA. 1995;274:1852-1857.

11. Pauwels RA, Buist AS, Ma P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care. 2001;46:798-825.

12. Barnes PJ. Chronic obstructive pulmonary disease. N Engl J Med. 2000;343:269-280.

13. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. American Thoracic Society. Am J Respir Crit Care Med. 1995;152(5 pt 2):S77-S121.

14. Pauwels RA, Buist AS, Calverley PM, et al. Global strategy for the

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diagnosis, management, and prevention of chronic obstructive pulmonary disease: NHLBI/WHO Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163:1256-1276.

15. National Heart, Lung, and Blood Institute. COPD essentials for health professionals. NIH Publication No. 07-5845. December 2006.

Bethesda, MD. www.nhlbi.nih.gov/health/public/lung/copd/campaignmaterials/pub/provider-card.pdf. Accessed April 30, 2008.

16. Stoller JK, Fromer L, Brantly M, et al. Primary care diagnosis of alpha-1 antitrypsin deficiency: issues and opportunities. Cleve Clin J Med. 2007;74:869-874.

17. Sutherland ER, Cherniack RM. Management of chronic obstructive pulmonary disease. N Engl J Med. 2004;350:2689-2697.

18. Viegi G, Pistelli F, Sherrill DL, et al. Definition, epidemiology, and natural history of COPD. Eur Respir J. 2007;30:993-1013.

19. Friedlander AL, Lynch D, Dyar LA, et al. Phenotypes of chronic obstructive pulmonary disease. COPD. 2007;4:355-384.

20. Barnes PJ. Small airways in COPD. N Engl J Med. 2004;350:2635-2637.

21. Barnes PJ. Mechanisms in COPD: differences from asthma. Chest.

2000;117(2 suppl):10S-14S. 22. Soriano JB, Visick GT, Muellerova H, et al. Patterns of comorbidities in newly diagnosed COPD and asthma in primary care. Chest.

2005;128:2099-2107.

23. Wagena EJ, Huibers MJ, van Schayck CP. Antidepressants in the treatment of patients with COPD: possible associations between smoking cigarettes, COPD and depression. Thorax. 2001;56:587-588.

24. Pace TW, Mletzko TC, Alagbe O, et al. Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. Am J Psychiatry. 2006;163:1630-1633.

25. Lacy P, Lee JL, Vethanayagam D. Sputum analysis in diagnosis and management of obstructive airway diseases. Ther Clin Risk Manag.

2005;1:169-179.

26. Qaseem A, Snow V, Shekelle P, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2007;147:633-638.

27. Rabe KF, Hurd S, Anzueto A, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007; 176:532-555.

28. Anthonisen NR, Connett JE, Murray RP. Smoking and lung function of Lung Health Study participants after 11 years. Am J Respir Crit Care Med. 2002;166:675-679.

29. Wilson DH, Wakefield MA, Steven ID, et al. “Sick of smoking”: evaluation of a targeted minimal smoking cessation intervention in general practice. Med J Aust. 1990;152:518-521.

30. Jorenby DE, Hays JT, Rigotti NA, et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA. 2006;296:56-63.

31. MacNee W, Calverley PM. Chronic obstructive pulmonary disease.

7: management of COPD. Thorax. 2003;58:261-265.

32. White AR, Rampes H, Ernst E. Acupuncture for smoking cessation.

Cochrane Database Syst Rev. 2002;(2):CD000009.

33. Hanania NA, Donohue JF. Pharmacologic interventions in chronic obstructive pulmonary disease: bronchodilators. Proc Am Thorac Soc. 2007;4:526-534.

34. US Food and Drug Administration. FDA advises patients to switch to HFA-propelled albuterol inhalers now: CFC-propelled inhalers no longer available as of Dec. 31, 2008. May 30, 2008. http://www.fda. gov/bbs/topics/NEWS/2008/NEW01842.html. Accessed August 11, 2008.

35. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005;127:335-371.

36. Calverley PM, Anderson JA, Celli B, et al. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789.

37. Barnes PJ, Hansel TT. Prospects for new drugs for chronic obstructive pulmonary disease. Lancet. 2004;364:985-996.

38. Celli BR, MacNee W; for the ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932-946.

39. Puhan MA, Scharplatz M, Troosters T, et al. Respiratory rehabilitation after acute exacerbations of COPD may reduce risk for readmission and mortality—a systematic review. Respir Res. 2005;6:54.

40. Nichol KL, Margolis KL, Wuorenma J, et al. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med. 1994;331:778-784.

41. Naunheim KS, Wood DE, Mohsenifar Z, et al. Long-term follow-up of patients receiving lung-volume-reduction surgery versus medical therapy for severe emphysema by the National Emphysema Treatment Trial Research Group. Ann Thorac Surg. 2006;82:431-443.

42. Celli BR, Cote CG, Marin JM, et al. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med. 2004;350:1005-1012.

43. Imfeld S, Bloch KE, Weder W, et al. The BODE index after lung volume reduction surgery correlates with survival. Chest. 2006;129: 873-878.

Stakeholder Perspective Cost and Quality Issues in COPD Management PATIENTS: Chronic obstructive pulmonary disease (COPD) is a progressive disease of adults that in many cases leads to the total debilitation of patients as they age. This is particularly significant when the patient does not take precautions to reduce the impact of active personal factors, such as smoking or obesity, which could lead to worsening of symptoms.

In addition, COPD is a difficult disease for patients and physicians to manage because many environ-

mental issues can exacerbate COPD episodes, which can lead to deterioration in quality of life over time.

The most effective way for patients with COPD to keep symptoms at a minimum and maintain a high quality of life is to actively manage their prescribed medical and pharmaceutical regimens. Cost can be a significant difficulty for patients if they do not have a prescription insurance benefit, since some of the newer medications are relatively expensive. Another Continued

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CLINICAL

cost issue has arisen as a result of the recent US Food and Drug Administration decision to phase out chlorofluorocarbon propellants for inhalers used to treat COPD. These inhalers, some of which have very inexpensive generics available, are being replaced with significantly more expensive new formulations with other propellants. These issues add difficulties for physicians and payers in addition to patients.

PHYSICIANS: Physicians have to manage patients without the benefit of a long-available medication, becoming familiar with the effectiveness of newer formulations, and fully understanding the additional cost burdens to their patients. The best way to ensure good care for these patients is to manage COPD in all of their patients according to best practice treatment guidelines, considering the cost burden when a patient has no insurance benefit or understanding the formulary issues for the insurance payers of their patients, and most important, knowing how to get exceptions when medically necessary.

PAYERS: Payers have a unique set of issues as well, since the newer inhaler formulations can sig-

nificantly drive up the monthly cost of COPD treatment for patients. Payers have the unique problem of trying to balance good medical care (quality) with the value of the medications they choose for their formulary (cost-effectiveness).

Payers need to drive value-based care by adhering to best practice guidelines, educating physician panels about their guidelines, ensuring that patients that need it have access to additional services—such as educational programs, disease management programs, counselors, and, as appropriate, programs for smoking cessation, obesity, or exercise management—to deliver the highest quality of life to patients. All of this can lead to high and unnecessary costs if not well coordinated with patients and physicians. Care that is not coordinated well can also lead to poor patient compliance, patient and physician satisfaction issues, and less-than-optimal disease management for the patient.

Paul Anthony Polansky, BSPharm, MBA Executive Vice President and Chief Pharmacy Officer, Sanovia Corporation, Philadelphia, PA

Unmanaged Moment

“Profit–loss? No! It’s my ‘chronic stress’ chart.”

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INDUSTRY TRENDS

e-Prescribing: Stakeholders Collaborating to Reduce Medication Errors

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ealth information technology, and in particular electronic prescribing (e-prescribing), is becoming a major player in any attempt to transform the US healthcare system. A lot of effort is being devoted to e-prescribing today, eliciting greater collaboration among stakeholders and charting new directions in healthcare.

This past July, Congress overrode a presidential veto, passing the Medicare Improvements for Patient and Provider Act of 2008 (H.R. 6331). In addition to reversing Medicare pay reductions to physicians, this act strengthens the Centers for Medicare and Medicaid Services (CMS) initiative (issued in April) for the implementation of e-prescribing standards, which aimed at reducing medication errors.1 CMS’s eprescribing initiative, originally intended to be launched on April 1, 2009, has now been enacted into law by Congress, instructing all Medicare prescribers to adopt this technology by 2011. To sweeten the deal, the new act authorizes Medicare to offer—for the first time—incentives for physicians between January 1, 2009, and 2011: • Medicare reimbursement to those using e-prescribing will increase by 2% in 2009 and 2010; by 1% in 2011 and 2012; and by 0.5% in 2013.

• Those who do not adopt e-prescribing will have their reimbursement reduced by 1% in 2011 and by up to 2% in 2013 and thereafter.

In parallel, collaborative efforts in the private sector have led to the launch of the National ePrescribing Patient Safety Initiative (NEPSI) in 2007, reflecting the desire of all healthcare stakeholders to address the problem of preventable medication errors, which was first put on the national stage with the Institute of Medicine’s 1999 famous report, To Err is Human: Building a Safer Health System.2 Responding to the formation of NEPSI, former CMS Administrator Mark B. McClellan, MD, PhD, observed, “NEPSI is the kind of collaboration…that can make such a difference in our healthcare system.

We all know where we need to go. We know we’re going to get to a healthcare system that relies on electronic information and that is much more effective in providing timely and appropriate care. But getting from here to there…is a big challenge.”3 Major obstacles to adopting e-prescribing are obvi-

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ously cost and technical issues. NEPSI was established with the goal of removing these barriers and is the only national organization that offers free e-prescribing software to all those who are licensed to prescribe and dispense medications in the United States. NEPSI offers access to free e-prescribing services via their website (www.natinalerx.com). NEPSI’s goal, as stated on their website, “is to increase patient safety by making ePrescribing accessible—and desirable—to all physicians and medication prescribers by providing it free of charge.”3 The service is offered by the e-prescribing provider Allscripts in collaboration with eRx Network, a retail pharmacy provider of electronic services.4

In 2007, 35 million e-Rx were transmitted.

In 2008, >100 million e-Rx are expected.

On August 21, 2008, the Texas Medical Association became the first state medical association to join “Get Connected”—another program that helps to implement e-prescribing, which is suppored by many national organizations, including the American Academy of Family Physicians.

SureScripts, which operates the national Pharmacy Health Information Exchange, reports that 35 million prescriptions were transmitted electronically in 2007.5 It estimates that this number will exceed 100 million in 2008.5 Given that this estimate predates the new Medicare policies, it is likely that the number of e-prescriptions will grow exponentially in 2009 and beyond. ■ References 1. Centers for Medicare and Medicaid Services. Medicare Information for Pharmacists. April 2, 2008. http://www.cms.hhs.gov/pharmacy/ downloads/update040208.pdf. Accessed August 29, 2008.

2. Institute of Medicine. To Err is Human: Building a Safer Health System.

1999. www.iom.edu/CMS/8089/5575.aspx?. Accessed August 29, 2008.

3. National ePrescribing Patients Safety Initiative. www.natinalerx.com.

Accessed August 29, 2008.

4. eRx Network Joins National ePrescribing Patient Safety Initiative as Connectivity Partner. www.nationalerx.com/media.htm. Accessed August 29, 2008.

5. SureScripts. National Progress Report on E-Prescribing. December 2007. http://www.surescripts.com/pdf/National-Progress-Report-onEPrescribing-1.pdf. Accessed August 29, 2008.

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CE INFORMATION REGULARTORY

The Promise of Evidence-Based Medicine for Clinical Decision-Making Sponsor This activity is sponsored by Medical Learning Institute, Inc., a nonprofit medical accreditation company.

sions, including evidence aggregation and comparative effectiveness research.

5. Apply evidence-based medicine standards for benefit design by balancing cost, quality, and access to create a value-based healthcare environment.

Instructions for Credit To receive credit, participants must read this CE activity in its entirety and complete the evaluation and post-test. The evaluation and post-test can be completed online at http://www.mlicme.org/p08020. html or you may fill out the printed evaluation and post-test and fax or mail the completed form to Medical Learning Institute, Inc., 384 Grandview Road, Skillman, NJ 08558. Fax: 609-333-1694.

Please retain a copy for your records. Certificates will be issued 4-6 weeks following the activity.

For questions regarding the accreditation of this activity, please contact Medical Learning Institute at (609) 333-1693 or cgusack@mlicme.org.

Commercial Support Acknowledgment

Target Audience

Disclosures

This activity was developed for pharmacists, pharmacy directors, and other healthcare professionals interested in benefits design.

Before the activity, all faculty will disclose the existence of any financial interest and/or relationship(s) they might have with the manufacturer(s) of any commercial product(s) to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakersâ&#x20AC;&#x2122; bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions.

The associates of Medical Learning Institute, Inc., have no financial relationships to disclose.

Learning Objectives At the end of this activity, medical directors, pharmacy directors and other healthcare decision makers involved with benefit design should be able to: 1. Discuss the strengths and weaknesses of different types of evidence generation in medicine, such as observational studies, randomized trials, and systematic reviews, and how these relate to clinical decision-making.

2. Define outcomes criteria for clinical decision-making, including efficacy, effectiveness, safety, and quality, and explain their relevance for measuring drug performance in a specified clinical setting.

3. Describe the role of appropriate evidence for clinical decision-making and the potential for patient selection bias in randomized clinical trials, which could lead to faulty evidence and inappropriate coverage decisions.

4. Explain the cutting-edge methods being devised today to attain value in healthcare coverage deci-

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This activity is supported by an educational grant from Eli Lilly and Pfizer.

Pharmacists Designation Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit.

The universal program number for this activity is 468-999-08-010-H04-P.

Faculty Disclosures Dr Nirav R. Shah receives unrestricted research grants from AstraZeneca, Berlex, GlaxoSmithKline, Merck, Novartis, Pfizer, Roche Diagnostics.

Dr Michael Cantor is an employee of Pfizer, Inc. Mr Scott R. Taylor is a consultant for Takeda, Johnson & Johnson.

Disclaimer The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patientâ&#x20AC;&#x2122;s medical condition.

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The Promise of Evidence-Based Medicine for Clinical Decision-Making Nirav R. Shah, MD, MPH The US healthcare system has engendered many attempts at incremental fixes and largescale overhauls. Practitioners of evidence-based medicine have developed the tools that can measure the effects of these attempts on improvement in healthcare by dissecting the strengths and weaknesses of the different means of evidence generation, such as observational studies, randomized trials, and systematic reviews. Randomized clinical trials have emerged as the de facto gold standard for creating medical knowledge; they are used primarily to define whether a drug or intervention is beneficial in an artificially optimized clinical setting, not whether it makes sense for most patients or for a specific patient. Because of the limitations of clinical trials and their exclusionary patient-selection criteria, relying on a single study is likely to lead to an incomplete answer; using a range of randomized and observational studies, or aggregation of studies, is therefore recommended. This article reviews the historical development of evidence creation in medicine, including the strengths and weaknesses of the current state of the science, focusing on outcomes needed for decision-making relevant to the various stakeholders, as well as on the emerging field of comparative effectiveness research. [AHDB. 2008;1(7):45-52.]

A

lthough most stakeholders associated with the US healthcare will likely agree that the system is “broken,” disagreements abound on the specifics of the problem.1 Taken broadly, the arguments on improving healthcare focus on 3 axes— quality, access, and cost2; many solutions have been proposed over the years to address one or more of these areas. Some, such as total quality management3 and a balanced scorecard,4 may simply be the “flavor of the month” of management paradigms applied to medicine. Others, such as disease management5 and the chronic care model,6 evolved within medicine to address specific deficiencies identified in the delivery of care. With all of these proposed solutions, however, the inability to accurately assess results of specific healthcare initiatives (ie, improvements in quality, cost, or access) has led to disappointment.

Recognition of the importance of the metrics of improvement has introduced evidence-based medicine (EBM) as the approach that could help fill the void.

Dr Shah is Assistant Professor of Medicine, New York University School of Medicine, New York, NY, and a member of the Society of General Internal Medicine’s Evidence-Based Medicine Task Force; he is supported by the Sergei S. Zlinkoff Fund for Medical Research and Education.

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EBM is defined as the “conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.”7 This concept was first described in the 1990s7,8 after recognition of widespread unexplainable variation in clinical practice9 and the awareness of a growing disconnect between research and clinical practice.10 After claims that only 10% of all medical care was based on evidence,11 people began to examine what constituted “evidence.” Grading the quality of evidence became in vogue, and scales for assessing randomized clinical trials (RCTs),12,13 observational studies,14 and meta-analyses15,16 arose simultaneously with the widespread promulgation of guidelines by medical societies, patient advocacy groups, and other interested stakeholders. Practitioners of EBM have continued to fill the void and advance the science, incorporating patient preferences and clinical expertise into a broader definition of EBM.17 The purpose of this article is to describe how EBM is addressing the need for high-quality data for the major challenges—cost, quality, and access—facing healthcare today. After describing the evolution of evidence creation in medicine and the current state of EBM, the article highlights results that are of interest to various stakeholders in healthcare and the emerging field of comparative effectiveness research.

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Table 1 Example of Selection Bias in an Observational Study A widely publicized 1981 case-control study (published in the New England Journal of Medicine) found an association between drinking coffee and pancreatic cancer.1 The cases comprised patients diagnosed with the targeted disease— pancreatic cancer. A comparable group of individuals without pancreatic cancer was used as the control.

Both groups were then asked about their previous exposure to several potential causative agents, including coffee.

For an unclear reason, the investigators excluded patients with “diseases known to be associated with smoking”1 from the control group.

Because of the strong association between smoking and coffee drinking, the percent of coffee drinkers among the cases with cancer was much higher than among the controls, which introduced a selection bias.

Hence, the study falsely concluded that drinking coffee led to cancer, whereas the reality was that smoking accounted for that effect; this study would have arrived at this finding had the study been designed more carefully.

1. MacMahon B, Yen S, Trichopoulos D, et al. Coffee and cancer of the pancreas. N Engl J Med. 1981;304:630-633.

Source: Feinstein AR, Horwitz RI, Spitzer WO, Battista RN. Coffee and pancreatic cancer. The problems of etiologic science and epidemiologic case-control research. JAMA. 1981;246:957-961.

The Nature of Medical Evidence Observational Studies and Randomized Controlled Trials Historically, the creation of clinical knowledge began with case reports (ie, individual reports about a patient’s disease course), which then evolved to more sophisticated observational studies (ie, experience with a number of patients with similar findings and diseases), then progressed to controlled trials and, ultimately, to the RCT.

Practical RCTs have been, and most likely will continue to be, used in highly selected populations with a low comorbid disease burden to answer narrowly focused questions.

Early on in the history of medicine, clinical experience sometimes led to dramatic improvements that convinced even the most skeptical observers of a treatment’s benefits: the cause–effect relationship appeared

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obvious. The relative lack of knowledge at the time, the simplicity of the questions being asked, the low expectations of patients, and the high benefit-to-risk ratios justified the use of observational methods as a means of discovery. For example, the dramatic results observed when penicillin was first used in the United States did not require a subsequent randomized trial.18 In the early twentieth century, however, when medical knowledge creation itself emerged as a nascent “industry,” research methods evolved to include more comprehensive observational studies, such as cohort and case-control studies.19 The primary strength of such studies in relatively unselected populations is that the resulting evidence is applicable to a broad spectrum of patients (ie, generalizable). However, conclusions from such studies can be prone to bias (Table 1) and can be confounding.20 The increasing complexity of clinical questions, treatment options, potential clinical outcomes, and their alternative scientific explanations all contributed to a demand for a more rigorous and reliable approach to answering clinical questions, for which the RCT emerged as the gold standard. Today, data from observational studies are often complementary to findings from RCTs. As the dominant method for creating clinical knowledge, the RCT is not typically used to address questions directly relevant to the practice setting for cost and practical and logistic reasons. Instead, RCTs have been, and most likely will continue to be, used in highly selected populations with a low comorbid disease burden to answer narrowly focused questions.21 RCTs are used primarily to define whether a drug or intervention is beneficial in an artificially optimized clinical setting, not whether it makes sense for most patients, or whether it is suitable for one patient subgroup but not for another. Strict selection criteria exclude high-risk patients or those with complex medical needs. Commonly used run-in phases before randomization select for the most adherent patients. And as patient populations have become older, the questions that have to be answered in making clinical decisions have become more intricate.

Consequently for the growing population of patients with multiple comorbidities, medication intolerances, limited cognition, and diverse insurance coverage, the knowledge needed to support objective clinical decision-making is largely nonexistent.22 In addition, an RCT can be easily manipulated to influence what is observed and discoverable.23 Even apparently trivial changes in inclusion criteria, intervention characteristics, or follow-up duration (eg, the publicity over the well-known cut-off date for the

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Vioxx trial’s cardiac events) can lead to different conclusions.24 For example, RCTs on the treatment of mild hypertension and coronary heart disease have alternatively shown both benefit and harm, because of the different patient exclusion criteria in different trials.25 Thus, relying on any single study for a typical clinical decision is likely to lead to an incomplete answer, and examining a range of studies (both randomized and observational) or aggregation of studies (systematic review or meta-analysis) should be considered.26

Evidence Aggregation The logarithmic growth of the medical literature makes keeping up with the primary evidence impossible for primary care physicians. Despite advances in information retrieval and the library sciences, most generalists do not have the time or ability to remain “current,” and they increasingly rely on electronic data aggregators (eg, http://pier.acponline.org; www.tripdata base.com; www.uptodate.com), systematic reviews, meta-analyses, and clinical guidelines (eg, the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure [JNC 7]27).

Meta-analyses are a form of aggregating evidence across similar studies. They are quantitative pooling of data across studies, primarily conducted to increase statistical power (relative to individual studies), improve the precision of estimates of treatment effects, and facilitate the exploration of differences between studies.28 But, as with other research, users of meta-analyses should carefully assess the quality of the pooling by examining the questions asked, the methods used, and conclusions reached—all of which can be confusing.

Guidelines are a form of aggregating a body of evidence across often dissimilar studies that can lead to competing guidelines and add to the confusion. For example, when radiology society–written guidelines recommended mammograms for all women beginning at age 40, and other medical society guidelines recommended the same procedure beginning only at age 50, women and their physicians were rightly indignant and confused.29 Hence, there are now several efforts to compile30,31 and grade32,33 guidelines themselves.

Ideally, guideline recommendations should relate to the size of the net benefit, as well as the certainty surrounding the estimate (Table 2), which is based on the quality of the underlying supporting evidence.33 But questions remain: What happens in the setting of insufficient evidence—does one default to expert recommendations? Also, guidelines often do not (or cannot)

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Table 2 Evaluating Evidence for Guidelines: The US Preventive Services Task Force Consider these questions when assessing the quality of the evidence: 1. Do the studies have the appropriate research design to answer the key question(s)?

2. To what extent are the existing studies of high quality (ie, what is the internal validity)?

3. To what extent are the results of the studies generalizable to the general US primary care population and situation (ie, what is the external validity)?

4. How many studies have been conducted that address the key question(s)? How large are the studies (ie, what is the precision of the evidence)?

5. How consistent are the results of the studies?

6. Are there additional factors that assist us in drawing conclusions (eg, presence or absence of dose–response effects, fit within a biologic model)?

Adapted with permission from Sawaya GF, Guirguis-Blake J, LeFevre M, et al.

Update on the methods of the US Preventive Services Task Force: estimating certainty and magnitude of net benefit. Ann Intern Med. 2007;147:871-875.

extend to include considerations of patient preferences, local values, or even cost.

Evidence on Costs The evolution of our understanding of the cost of healthcare reflects the trends seen with primary medical evidence. In this case, the United States has lagged behind many other industrialized countries, which have more sophisticated approaches.34 For example, in the United Kingdom, the National Institute for Health and Clinical Excellence (NICE; formerly the National Institute for Clinical Excellence), which was established in 1999, publishes critical appraisals of new technologies, medications, and healthcare practices based primarily on their costeffectiveness.35 NICE remains at the forefront of understanding cost implications for various healthcare goods and services. The basic unit of measurement NICE uses is the quality-adjusted life-year (QALY), which is the product of life expectancy and a measure of the quality of the remaining life-years.36 NICE’s approach has led to widespread discussion of what are acceptable cost cut-points for various therapeutic options (eg, $50,000 per QALY), and has strengthened the field of cost-effectiveness analysis. NICE has been lauded as an example of an agency urgently needed in the United States.37

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Table 3 The 4 Categories of Outcome Data for Decision-Making Efficacy Efficacy The impact of an intervention in an ideal setting, such as in a placebo-controlled study. Efficacy data are often thought to overestimate real-world benefits and are most often derived from clinical trials, which preselect patients for adherence, enroll those most likely to benefit from the treatment, and are often compared with placebo as control rather than with “active” comparators, such as other medications.1 Effectiveness The impact of an intervention in real-world situations.

Efficacy is necessary but not sufficient for effectiveness.

Effectiveness data are most often observational, such as from cohort studies, and are therefore viewed with some skepticism by those concerned about bias.

Safety Safety data are generally extrapolated from clinical trials, which are often too “controlled” an environment to unmask fundamental adverse effects seen only after longer follow-up or after use by patients not studied in the original trials (as was the case with, for example, Rezulin, Redux, Baycol, Vioxx, Avandia). The current system of pharmacovigilance has many loopholes, and new safety monitoring requirements are currently in development.

Quality Quality problems in healthcare can be defined as those of overuse of services, underuse of services, and errors. The Institute of Medicine’s report Crossing the Quality Chasm describes how “the nation’s current healthcare system lacks the environment, the processes, and the capabilities needed to ensure that services are safe, effective, patient-centered, timely, efficient, and equitable”2; this report was one of the most important catalysts for the current focus on quality in healthcare.

1. Hayward RA, Kent DM, Vijan S, Hofer TP. Reporting clinical trial results to inform providers, payers, and consumers. Health Aff (Millwood). 2005;24: 1571-1581.

2. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington, DC: National Academies Press; 2001.

Other facets of costs involved in healthcare have emerged as areas of study, examining both patient- and provider-related costs. For example, medication copayments are important levers for cost control, which have resulted in unintended downstream consequences, such as medication noncompliance.38 Value-

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based insurance design, which tries to match patients’ cost-sharing to the value of healthcare services, is but one example of new applications of evidence in EBM.39 In a similar vein, many versions of provider-related cost-incentivization programs have been attempted, with varying degrees of success (eg, pay-for-performance and value-based purchasing).40

Outcomes for Decision-Making: Efficacy, Effectiveness, Safety, Quality EBM researchers have spent much of the past decade explicating the nature of medical evidence and defining boundaries for its subsequent use. As a result, from the 3 axes of quality, cost, and access mentioned earlier, 4 broad categories of the types of data required to make decisions, or “outcomes of interest,” have emerged (Table 3): • Efficacy • Effectiveness • Safety • Quality.

Various stakeholders may have different interests in one or more of these types of outcomes, but by standardizing the vocabulary and making transparent the findings from different types of studies, stakeholders can at least approach different types of evidence with a clear understanding of the limits and possibilities of the evidence. Depending on the question of interest, selecting the appropriate outcome matters. For example, patients may be interested in patient-centered outcomes, such as health-related quality of life, rather than the extra month of survival as a result of using the latest anticancer drug (an efficacy outcome from an RCT).

Providers may be interested in how the latest diabetic medication would fare in their particular patient population (effectiveness outcomes), and would look to a cohort study rather than an RTC for such answers. A Pharmacy & Therapeutics Committee may want data on cost-effectiveness before approving the seventh angiotensin receptor blocker that has become available.

An employer may be interested in effects on employee absenteeism for various antimigraine medications when choosing among different coverage plans. The common vocabulary of efficacy, effectiveness, safety, and quality allow the different stakeholders to speak the same language, closing the gaps in communication to better understand what each other values.

Comparative Effectiveness Research Since the Medicare Modernization Act of 2003, there has been renewed interest in cost-effectiveness

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and relative clinical effectiveness of alternative treatments as a means to rein in spending.41 This has made researchers focus their work from an agenda primarily focused on efficacy to another area—comparative effectiveness research.42 Defined as systematic reviews, observational studies, clinical trials, and RCTs—comparative effectiveness research (as its name implies) relies on effectiveness data and refers to the clinical and cost evaluations of specific medical interventions (including medications, devices, and procedures) relative to available alternatives for a given clinical scenario. This includes comparisons of, for example, medications within the same class, but it can also apply to things such as medical versus surgical treatment for cancer. The evidence base for comparative effectiveness research includes the occasional randomized trial43 or indirect comparisons across multiple trials,44 but most often used are observational studies.45,46 At the federal level, Congress is now considering funding an independent, private, nonprofit corporation to study comparative effectiveness. The Comparative Effectiveness Research Act of 2008 authorizes the creation of a Comparative Effectiveness Research Trust Fund and a corporation governed by a multistakeholder Board of Governors, with the authority to contract with federal agencies (including the Agency for Healthcare Research and Quality) and private groups to conduct comparative effectiveness research.47 This group will establish a methodology committee to develop standards for conducting such research and will also examine methods for including cost considerations and health plan benefit design. Priorities for comparative effectiveness research studies will be based on many factors, including disease burden, clinical outcomes, practice variations, utilization, and health expenditures. Within 5 years, the total annual funding for the program is expected to exceed $300 million.

Various healthcare stakeholders view comparative effectiveness research with perspectives that span the full spectrum from trepidation to elation. Manufacturers have to date fared well with a focus on efficacy, obtaining approval for drugs by comparing them to placebo and selling physicians (and patients) on their products’ merits, without reference to data on competitive products. Payers, in contrast, have been the primary proponents of comparative effectiveness research, and finally have gained the clout to demand such information. In the coming years, we can expect a vigorous debate, informed by the evidence, between various stakeholders and their use of EBM.

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Conclusion In the next decade, comparative effectiveness research will likely serve as the foundation for much of the medical decision-making today that is evidence based, by using the best-available data to create knowledge. This research, which spans the spectrum of study types and summaries, will create opportunities for the future—a future where the efficient and effective use of evidence begins to address the current shortcomings of the US healthcare system. ■ References 1. Institute of Medicine. Crossing the Quality Chasm: A New Health System for the 21st Century. National Academies Press; 2001. http://www.iom.edu/?id=12736. Accessed August 1, 2008.

2. Angell M, Kassirer JP. Quality and the medical marketplace—following elephants. N Engl J Med. 1996;335:883-885.

3. Deming WE. Out of the Crisis: Quality, Productivity and Competitive Position. Cambridge, England: Cambridge University Press; 1986.

4. Kaplan RS, Norton DP. Balanced Scorecard: Translating Strategy into Action. Cambridge, MA: Harvard Business School Press; 1996.

5. Ellrodt G, Cook DJ, Lee J, et al. Evidence-based disease management.

JAMA. 1997;278:1687-1692.

6. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic illness. JAMA. 2002;288:1775-1779.

7. Sackett DL, Rosenberg WM, Gray JA, et al. Evidence-based medicine: what it is and what it isn’t. BMJ. 1996;312:71-72.

8. Guyatt G, Cairns J, Churchill D. Evidence-based medicine: a new approach to teaching the practice of medicine. Evidence-Based Medicine Working Group. JAMA. 1992;268:2420-2425.

9. Wennberg JE, Gittelsohn A. Small area variations in healthcare delivery. Science. 1973;82:1102-1108.

10. Eddy DM. Evidence-based medicine: a unified approach. Health Aff (Millwood). 2005;24:9-17.

11. Booth A. What proportion of healthcare is evidence based? Resource Guide. www.shef.ac.uk/scharr/ir/percent.html. Accessed July 20, 2008.

12. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12.

13. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting of randomized controlled trials. The CONSORT statement. JAMA. 1996;276:637-639.

14. von Elm E, Altman DG, Egger M, et al. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol.

2008;61:344-349.

15. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283:2008-2012.

16. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999;354: 1896-1900.

17. Sackett DL, Straus SE, Richardson WS, et al. Evidence-Based Medicine: How to Practice and Teach EBM. 2nd ed. London, England: Churchill Livingstone; 2000.

18. Grossman CM. The first use of penicillin in the United States. Ann Intern Med. 2008;149:135-136.

19. Vandenbroucke JP. A short note on the history of the randomized controlled trial. J Chronic Dis. 1987;40:985-987.

20. Rothman KJ, Greenland S, Lash TL. Modern Epidemiology. 3rd ed.

Philadelphia, PA: Lippincott Williams & Wilkins; 2008.

21. Black N. Why we need observational studies to evaluate the effec-

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tiveness of healthcare. BMJ. 1996;312:1215-1218.

22. Sox H, Blatt MA, Higgins MC, Marton KI. Medical Decision Making.

Philadelphia, PA: American College of Physicians; 2007.

23. Mattocks KM, Horwitz RI. Placebos, active control groups, and the unpredictability paradox. Biol Psychiatry. 2000;47:693-698.

24. Drazen JM. Cox-2 inhibitors—a lesson in unexpected problems. N Engl J Med. 2005;352:1131-1132.

25. MacMahon S, Peto R, Cutler J, et al. Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet. 1990;335:765-774.

26. Shah NR. What is the best evidence for making clinical decisions?

JAMA. 2000;284:3127-3128.

27. Chobanian AV, Bakris GL, Black HR, et al. The Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-2572.

28. Jones JB, Blecker S, Shah NR. Meta-analysis 101: what you want to know in the era of comparative effectiveness. Am Health & Drug Benefits.

2008;1:38-43.

29. Fletcher SW. Whither scientific deliberation in health policy recommendations? Alice in the Wonderland of breast-cancer screening. N Engl J Med. 1997;336:1180-1183.

30. www.guidelines.gov.

31. AGREE Collaboration. Development and validation of an international appraisal instrument for assessing the quality of clinical practice guidelines: the AGREE project. Qual Saf Health Care. 2003;12:18-23.

32. Guyatt GH, Oxman AD, Vist GE, et al, for the GRADE group.

GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924-926.

33. Sawaya GF, Guirguis-Blake J, LeFevre M, et al. Update on the methods of the US Preventive Services Task Force: estimating certainty and magnitude of net benefit. Ann Intern Med. 2007;147:871-875.

34. Anderson G, Hussey PS. Comparing health system performance in OECD countries. Organization for Economic Cooperation and Development. Health Aff (Millwood). 2001;20:219-232.

35. Rawlins M. In pursuit of quality: the National Institute for Clinical Excellence. Lancet. 1999;353:1079-1082.

36. Phillips C, Thompson G. What is a QALY? http://www.evidencebased-medicine.co.uk/ebmfiles/WhatisaQALY.pdf. Accessed August 1, 2008.

37. Roehr B. Consensus emerges on need for US agency similar to NICE. BMJ. 2008;337:a817.

38. Chernew ME, Shah MR, Wegh A, et al. Impact of decreasing copayments on medication adherence within a disease management environment. Health Aff (Millwood). 2008;27:103-112.

39. Fendrick AM, Smith DG, Chernew ME, Shah SN. A benefit-based copay for prescription drugs: patient contribution based on total benefits, not drug acquisition cost. Am J Manag Care. 2001;7:861-867.

40. Rosenthal MB, Frank RG, Li Z, Epstein AM. Early experience with payfor-performance: from concept to practice. JAMA. 2005;294:1788-1793.

41. Wilensky GR. Developing a center for comparative effectiveness information. Health Aff (Millwood). 2006;25:w572-w585.

42. Ellis P. Research on the comparative effectiveness of medical treatments: issues and options for an expanded federal role. Congressional Budget Office, December 2007. http://www.cbo.gov/doc.cfm?index=8891.

Accessed July 21, 2008.

43. Lieberman JA, Stroup TS, McEvoy JP, et al, for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators.

Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.

44. Ioannidis JP. Indirect comparisons: the mesh and mess of clinical trials. Lancet. 2006;368:1470-1472.

45. Rector TS, Anand IS, Nelson DB, Ensrud KE. Carvedilol versus controlled-release metoprolol for elderly veterans with heart failure. J Am Geriatr Soc. 2008;56:1021-1027.

46. Stadhouder A, Buskens E, de Klerk LW, et al. Traumatic thoracic and lumbar spinal fractures: operative or nonoperative treatment: comparison of two treatment strategies by means of surgeon equipoise. Spine.

2008;33:1006-1017.

47. Baucus M. Comparative Effectiveness Research Act of 2008. http://www.capwiz.com/chsr/attachments/Baucus_Conrad_2.pdf.

Accessed August 1, 2008.

Stakeholder Perspectives The Challenges of Evidence-Based Medicine for the Pharmaceutical Industry MANUFACTURERS: The very existence of a pharmaceutical company is based on the strength of the scientific evidence supporting its products, and the industry firmly supports making medical judgments on the basis of the best scientific evidence available. Drug development generally targets areas of unmet medical need, so evaluating the evidence in a particular disease field is important strategically.

Indeed this is what makes drug development in areas such as neuroscience—where the conditions in randomized controlled trials (RCTs) often diverge from patients’ real-world experience (eg, schizophrenia, Alzheimer’s disease)—so challenging.

After a molecule is discovered to have a therapeutic potential, the development process into a viable product consists of increasingly complex phases of

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clinical trials, with at least 2 RCTs required before a new product is approved by the US Food and Drug Administration. As the pharmaceutical marketplace becomes increasingly competitive, scientific support for new medications becomes even more important.

A growing emphasis on “specialty” drugs (ie, those prescribed by specialists rather than those generally used in primary care) requires strong evidence of differentiation and clinical effectiveness from the standard of care for a drug to be adopted into clinical use.

The challenges of applying evidence-based medicine (EBM) in a clinical setting are well-known. The premise of EBM is using the current evidence for making decisions about individual patients. Few patients, however, reflect the carefully selected participants in clinical trials, and clinical decisions by

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their nature are rarely as simple as the concrete questions RCTs are designed to answer. Many patients may fall under existing guidelines, but exceptions certainly exist, which is why integrating clinical expertise is also an important factor in applying EBM. The nature of EBM is likely to change dramatically as medical care becomes more personalized. As more genetic markers that reflect responsiveness to or likely side effects from a particular drug are discovered, the nature of the evidence that clinicians must interpret and that regulators use to measure

effectiveness will also change. This also may lead to a paradigm shift in study design. Targeted medicines will be highly effective in selected populations, making it easier to recruit patients for clinical trials to prove efficacy, and also causing it to be much easier to support generating decisions based on clinical judgment rather than on cost alone.

Michael Cantor, MD Director, Healthcare Informatics Pfizer, Inc

Utilization of Evidence-Based Medicine in Payers’ Decision-Making PAYERS: As indicated in this article, the role of evidence in healthcare decision-making continues to evolve at a rapid pace. The overwhelming need to ensure safety and cost-effectiveness are key drivers in the current payer marketplace. Recently, several national managed care organizations (MCOs) have published their criteria for medication inclusion for formulary or preferred drug list distinction. Specifically, one of the top 5 US plans has also created a scoring system for pharmaceutical evidence that includes comparative effectiveness studies and cost-effectiveness models similar to the United Kingdom’s National Institute for Health and Clinical Excellence criteria (Technology & Medication Evidence Guidelines).

In addition to the increasing burden on manufacturers to create and deliver the most rigorous scientific evidence to support their new product entrants, the criteria discussed in this article support the newest and most important distinction for decision-making; when effectiveness, efficacy, safety, and cost are all evaluated and combined together, we arrive at value.

“Value” is the single most important aspect of bringing a new drug, formulation, indication, device, diagnostic modality, or procedure to the healthcare marketplace. The term is broadly used and is complex to apply. Value includes the quality of evidence (eg, grade of studies included in product dossiers; level of evidence), use of comparators in studies versus traditional placebo-controlled trials still utilized by the US Food and Drug Administration, and the cost-impact or cost-effectiveness of a therapy measured against current agents (branded or generic).

Overall, “value” means the same to all those in managed care, as it relates to investing resources into

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a treatment across an entire population or even a subgroup, but it varies in its operational framework.

For example, a regional MCO may have a uniquely young, healthy population that has little need, and therefore less value, for a medication for Parkinson’s disease. The same medication represents a high value and a greater need for formulary coverage and support in a Medicare population, where the average age is older than 65 years. Some MCOs have begun measuring products’ evidence at an even higher level, in terms of “disease-modifying” and/or “lifesustaining” versus “lifestyle” agents. Disease-modifying agents gain greater support as they are associated with improved outcomes, greater quality-adjusted life-years (QALYs), and reduced costs for morbidity, hospitalizations, and other disease-related events.

Each payer relies on physicians, pharmacists, and clinical experts to evaluate medications and evidence, and link the evidence to their unique population (membership) to assess the overall value to their organization and patient population. The increasing level of evidence required by payers in addition to the rapid increase in generic products (eg, >70% generic products per formulary) leaves US pharmaceutical manufacturers in a difficult situation. Based on several recent product withdrawals and increased safety concerns, manufacturers are beginning to abandon products much sooner, as they struggle to gain traction in a generics-controlled market. MCOs have now organized and aligned their principles for decision-making to serve their patients with cost-effective, safe treatments. The future evidence and value will be even more complex; MCOs have begun to use the same criteria to judge the ability to invest in medications that

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treat life-threatening diseases, such as cancer, with evidence that only adds incremental benefit to an individual’s ability to gain QALYs. Manufacturers are bringing novel biologics into the market that serve subpopulations, have limited clinical benefit, and present tremendous economic burden to payers and employers. What evidence will be needed to justify the addition of a $1-million agent that thousands of patients may ultimately be

prescribed? Have we determined a value threshold?

At what point will an MCO be forced to choose?

What evidence will provide the compelling justification to prove value without a doubt?

Scott R. Taylor, RPh, MBA Executive Director, Industry Relations, Geisinger Health System, Henry Hood Center for Health Research, Danville, PA

Evidence-Generating in Academic Medical Research RESEARCHERS: Three trends initiated by sponsors of research are changing the way investigators approach and conduct their work, and as a result are influencing the evidence created—a focus on the sustainability of interventions, collaboration, and leveraging scarce funds.

Researchers and academics are often accused of creating interventions that are not applicable to real patients or cannot be sustained beyond the funding of a study. Partly in response to more sophisticated funders, one evidence-based medicine framework that has evolved to calibrate research to these goals is RE-AIM (see www.RE-AIM.org). Its strong emphasis on measurement and tracking spans 5 domains: • Reach—the absolute number, proportion, and representativeness of individuals who participate in a given program • Efficacy/Effectiveness—the impact of an intervention on important outcomes; this includes potential negative effects, quality of life, and costs • Adoption—the absolute number, proportion, and representativeness of settings and staff who are willing to offer a program • Implementation—at the setting level, implementation refers to how closely staff members follow the program that the developers provide. This includes consistency of delivery as intended and the time and cost of the program • Maintenance—the extent to which a program or policy becomes part of the routine organizational practices and policies.

Investigators are frequently using frameworks such as RE-AIM when conducting research, to provide detailed metrics on their program to sponsors throughout their program.

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Hand-in-hand with a careful examination of research “process” measures of success is a requirement by funders that researchers work collaboratively. Evidence of deep partnerships across (historically) siloed fields are now the sine qua non for large National Institutes of Health grants, fundamentally changing the behavior of researchers. The evidence that results is both broader in its applicability and more specific to multiple end-user needs. For example, a current study of smoking cessation involves medical educators who designed a curriculum on tobacco for their trainees, health service educators with expertise in reaching smokers in various settings, health psychologists who tailor the behavioral interventions to patients, and physicians who prescribe nicotine replacement. Such research, thanks to the diversity of the investigators and their various perspectives, is much more patient-centered than more traditional, noncollaborative traditional efforts.

Collaboration has another benefit—it can attract sponsors who normally do not work together to fund different parts of a larger study. Each investigator can bring his or her own funders to the table, thereby creating synergies for sponsors and facilitating “big science” in an era of shrinking budgets.

Collectively, these forces have changed the evidence-generation industry in positive ways. No longer does the traditional view of a researcher hold: a lone scientist holed up in some basement laboratory surrounded by beakers and test tubes. The researchers of tomorrow are reaching into patients’ homes and communities and are reaching out to colleagues in other disciplines, to make the “right intervention for the right patient at the right time.”

Nirav R. Shah, MD, MPH

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CONTINUING EDUCATION

ACPE number: 468-999-08-010-H04-P MLI number: P08020

The Promise of Evidence-Based Medicine for Clinical Decision-Making

Participant Evaluation Form Dear Participant: To receive credit, participants must read this CE activity in its entirety and complete this evaluation form and post-test. The evaluation and post-test can be completed online (www.mclicme.org/p08020.html) or you may print the forms, fill them out, and fax or mail to Medical Learning Institute, Inc., 384 Grandview Road, Skillman, NJ 08558, fax: 609-333-1694. Please retain a copy for your records. Certificates will be issued 4-6 weeks after the activity.

This activity is sponsored by Medical Learning Institute.

Date of Activity: _______ Activity title: The Promise of Evidence-Based Medicine for Clinical Decision-Making E-mail:

Last Name _____________________________ MI _______ First Name _____________________________ Mailing Address ______________________________________________________________________________ ___________________________________________________________________________________________ City State ZIP Phone # ________________________________ Fax # ________________________________

BSPharm MSPharm PharmD RPh Other: _______________ Specialty (check): Medical Director Pharmacy Director P & T Committee Other: ___________

Academic Degree (check one):

Signature: _________________________________ I claim ____ CE credit for participating in this activity and attest that the number of credits claimed is accurate and does not exceed 1.0 credit.

To assist us in evaluating the effectiveness of the CE activity and to make recommendations for future activities, please complete the evaluation form, by circling the appropriate rating using the following scale, as needed: 1. How will you change your practice as a result of participating in this activity? (Check all that apply)

Create/revise protocols, policies, and/or procedures.

Change the management and treatment of my patients.

I will not make any changes to my practice.

Other, please specify _______________________________________________________________________ 2. May we contact you in 3 months to assess the changes to your practice? Yes No 3. Please indicate the barriers that might prevent you from applying the knowledge gained from this activity to your practice. (Check all that apply) Cost Lack of experience Lack of opportunity (patients) Lack of resources (equipment) Lack of time Reimbursement/insurance issues Restrictive practice guidelines/protocols Other, please specify___________________________________ Please continue on next page VOL. 1

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10. Did the activity provide objective, complete, evidence-based information, without expressing a professional preference for any one product or service?

Yes No If no, please explain: ___________________________________________________________________________ ____________________________________________________________________________________________ The purpose of this activity is to provide a review of the historical development of evidence creation in medicine, including the strengths and weaknesses of the current state of the science, by focusing on outcomes needed for decision-making relevant to the various stakeholders, as well as on the emerging field of comparative effectiveness research.

Not at all Low Medium High 11. To what degree did the activity meet the educational purpose?

1 2 3 4 To what degree did this activity prepare you to meet the following educational objectives?

1. Discuss the strengths and weaknesses of different types of evidence generation in medicine, such as observational studies, randomized trials, and systematic reviews, and how these relate to clinical decision-making.

1 2 3 4 2. Define outcomes criteria for clinical decision-making, including efficacy, effectiveness, safety, and quality, and explain their relevance for measuring drug performance in a specified clinical setting.

1 2 3 4 3. Describe the role of appropriate evidence for clinical decision-making and the potential for patient selection bias in randomized clinical trials, which could lead to faulty evidence and inappropriate coverage decisions.

1 2 3 4 4. Explain the cutting-edge methods being devised today to attain value in healthcare coverage decisions, including evidence aggregation and comparative effectiveness research.

1 2 3 4 5. Apply evidence-based medicine standards for benefit design by balancing cost, quality, and access to create a value-based healthcare environment.

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CONTINUING EDUCATION

Posttest Please respond to the following questions based on your learning experience from this activity (please circle your responses).

For each question, select the one statement that provides the best answer.

1. Which one of the following types of data analysis represents an observational study? a. Case-control trial b. Randomized clinical trial c. Meta-analysis d. Clinical guideline

6. What is one unintended consequence of requiring medication copayments? a. Increased utilization b. Improved patient satisfaction c. Medication noncompliance d. Greater QALYs

2. Which is NOT a feature of most randomized clinical trials? a. Efficacy b. Internal validity c. Generalizability d. Protection from selection bias

7. What are the 4 types of “outcomes of interest” for medical decision-making? a. Efficacy, access, cost, quality b. Efficacy, safety, cost, quality c. Efficacy, effectiveness, safety, quality d. Access, cost, quality, effectiveness

3. What percent of medical care is based on evidence? a. 5% b. 10% c. 20% d. 25%

8. All the following sources of evidence are utilized in comparative effectiveness research, except: a. Cohort studies b. Case reports c. Randomized trials d. Meta-analyses

4. Which of the following websites is NOT an example of a “data aggregator?” a. pier.acponline.org b. www.tripdatabase.com c. www.fda.gov d. www.uptodate.com 5. Which of the following definitions applies to quality-adjusted life-years (QALYs)? a. Product of life expectancy and a measure of the quality of the remaining life-years b. Sum total of years of quality life remaining and current age c. Product of the quality of the remaining life-years and current age d. None of the above

9. Which of the following items is NOT a consideration of the US Preventive Services Task Force when evaluating evidence for guidelines? a. Precision of the evidence b. Consistent results c. Quality of the data d. Face validity 10. Efficacy data are most often derived from which one type of the following studies? a. Case reports b. Cohort studies c. Randomized clinical trials d. Meta-analyses

In order to receive credit, participants must read this CE activity in its entirety and complete the evaluation form and post-test. The evaluation and post-test can be completed online (www.mclicme.org/p08020.html) or you may print the forms, fill them out, and fax or mail to Medical Learning Institute, Inc., 384 Grandview Road, Skillman, NJ 08558, fax: 609-333-1694. Please retain a copy for your records. Certificates will be issued 4-6 weeks after the activity.

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EXECUTIVE SUMMARIES

Delaware’s Wellness Program

By Jennifer “J. J.” Davis

With health insurance expenses the fastest growing cost component for employers today, many employers shift some of this cost burden to the employee.

Nationwide, employers are trying to come up with different solutions to the cost escalation of health insurance. Ms Jennifer Davis, Director of the Delaware Office of Management and Budget, and her staff searched for a way to drive down the cost of insurance premiums while encouraging employees to take an active role in their well-being. They tried their original ideas in 2 pilot programs, using financial and healthrelated incentives for employees, as well as motivational techniques such as electronic health risk assessments and educational follow-up in the attempt to empower

employees to take charge of their own health. The results were encouraging, showing a direct link between employees’ improved health status and a reduction in the employer’s overall healthcare costs. In the first pilot, fewer emergency department visits and lower blood pressure levels resulted in >$62,000 savings. In the expanded pilot, significant reductions were seen in blood pressure, body fat, and glucose levels. The overall cost saving was about $450,000. In 2007, the state launched its new wellness program, which encompasses 68,000 state employees and their families. Preliminary results are promising. Such an approach to improving health while reducing insurance costs could potentially be applied to other employer groups.

The Better Quality Information to Improve Care for Medicare Beneficiaries Project

By Aucha Prachanronarong, MHS

Following President Bush’s Executive Order to promote quality and efficiency of healthcare in federally sponsored programs based on the idea of value-driven healthcare, the Centers for Medicare & Medicaid Services (CMS) launched a pilot program for Medicare beneficiaries, known as the Better Quality Information (BQI) Project. Ms Aucha Prachanronarong, Health Insurance Specialist at CMS’s Office of Clinical Standards and Quality, describes the objectives and applications of the BQI pilot, which is testing methods for reporting on physician performance, with the goal of

enhanced transparency in measuring performance and improving the overall quality of healthcare delivery.

CMS has chosen 6 local collaborative centers throughout the country. The lessons learned from this project will be valuable to other large purchasers outside of Medicare, notably commercial employers and state Medicaid agencies. In his stakeholder perspective, Mr Kip Piper notes that CMS’s BQI Project “is a shining example of the steady evolution of Medicare from passive payer of provider claims to a value-driven purchaser of healthcare.”

Chronic Obstructive Pulmonary Disease Overview

By John F. Devine, DO, FACP

The prevalence of chronic obstructive pulmonary disease (COPD), characterized by an irreversible limitation of expiratory airflow and a progressive deterioration of the lungs, is growing in the United States and worldwide.

The economic burden of this disease is staggering, with direct and indirect annual costs estimated at $18 billion and $14 billion, respectively. And although many medications are available to prevent and control symptoms, no cure is yet available for this progressive and irreversible disease. Because smoking is the major cause of COPD, smoking-cessation modalities for smokers are essential preventive measures and must be strongly con-

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sidered by treating physicians, as well as by health plans and benefit design decision makers. Employers are in a unique position to motivate and offer help to employees to stop smoking by offering incentives, educational materials, and support systems. Other health plans can offer incentives designed to motivate smokers to stop.

Inhaled bronchodilators are the mainstay of therapy, with short-acting and long-acting products offering different ways of relieving symptoms and convenience.

Combining inhalers is therefore often recommended to maximize the benefits from the variable mechanisms of action offered by the different medication classes. ■

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Brief Summary of Prescribing Information USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDISÂŽ tablets should be discontinued as soon as possible.

See WARNINGS: Fetal/Neonatal Morbidity and Mortality INDICATIONS MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS MICARDIS (telmisartan) is contraindicated in patients who are hypersensitive to any component of this product.

WARNINGS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, MICARDIS (telmisartan) tablets should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, MICARDIS tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. There is no clinical experience with the use of MICARDIS tablets in pregnant women. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day). Hypotension in Volume-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with MICARDISÂŽ tablets. This condition should be corrected prior to administration of MICARDIS tablets, or treatment should start under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

PRECAUTIONS General. Impaired Hepatic Function: As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. MICARDIS (telmisartan) tablets should be used with caution in these patients. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensinconverting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with MICARDIS tablets. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of MICARDIS tablets in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated. Information for Patients. Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. Drug Interactions.

Digoxin: When telmisartan was coadministered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible overor under-digitalization. Warfarin: Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio (INR).

Other Drugs: Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19.

Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day). Genotoxicity assays did not reveal any telmisartanrelated effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test. No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and Mortality. Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, 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 Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients receiving MICARDIS in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

ADVERSE REACTIONS MICARDIS (telmisartan) has been evaluated for safety in more than 3700 patients, including 1900 treated for

over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160mg) monotherapy for up to 12 weeks, an overall incidence of adverse events similar to that of placebo was observed. Adverse events occurring at an incidence of 1% or more in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented as follows: The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of e1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). In addition to the adverse events, the following events occurred at a rate of 1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea and peripheral edema. Discontinuation of therapy due to adverse events was required in 2.8% of 1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in six placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated with telmisartan). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets.

Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of MICARDIS tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS tablets. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS. OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS (telmisartan) tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis.

DOSAGE AND ADMINISTRATION Dosage must be individualized.The usual starting dose of MICARDIS (telmisartan) tablets is 40 mg once a day. Blood pressure response is dose related over the range of 20-80 mg. Special Populations: Patients with depletion of intravascular volume should have the condition corrected or MICARDIS tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume-Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS, General, Impaired Hepatic Function, and Impaired Renal Function). Most of the antihypertensive effect is apparent within two weeks and maximal reduction is generally attained after four weeks. When additional blood pressure reduction beyond that achieved with 80 mg MICARDIS is required, a diuretic may be added. No initial dosing adjustment is necessary for elderly patients or patients with mild-to-moderate renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored. MICARDIS tablets may be administered with other antihypertensive agents. MICARDIS tablets may be administered with or without food.

Rx only MC-BS (03/07)

Copyright Š 2007, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

(10/07)

MC48827

Get patients with difficult-to-control hypertension to goal1

MICARDIS. More than POWER…

BP PROTECTION in the early morning2

USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS Tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.

MICARDIS is contraindicated in patients who are hypersensitive to any component of this product. The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of e1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%).

Please see Brief Summary of Product Information on adjacent page.

References: 1. Weber MA,White WB,Giles TD,et al.An effectiveness study comparing algorithm-based antihypertensive therapy with previous treatments using conventional and ambulatory blood pressure measurements. J Clin Hypertens.

2006;8:241-250. 2. White WB,Giles T,Bakris GL,et al.Measuring the efficacy of antihypertensive therapy by ambulatory blood pressure monitoring in the primary care setting. Am Heart J. 2006;151:176-184.

Please visit www.micardis.com for more information, including Prescribing Information.

Copyright © 2007, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

Printed in U.S.A.

(10/07)

MC48828