July/August 2008, Vol 1, No 6 by Dalia Buffery

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VOLUME 1, NUMBER 6

EDITORIAL

Contracting for Compliance: Using Adherence as a Patient-Centered Measure of Performance Scott R. Taylor, RPh, MBA; J.B. Jones, MBA; Nirav R. Shah, MD, MPH BUSINESS

Wayward Prescriptions: Costs of Fraud in Payor Plans Thomas Kaye, RPh, MBA CLINICAL ™

Prescribing Warfarin Appropriately to Meet Patient Safety Goals Lekshmi Dharmarajan, MD, FACP, FACC; T.S. Dharmarajan, MD, FACP, AGSF REGULATORY

Treading Water: The No-Growth Investment in Health Services Research Emily J. Holubowich, MPP; Joseph R. Antos, PhD DEPARTMENTS ◆ ◆ ◆ ◆ ◆

Generic Drug Trends FDA Watch ADA Highlights ISPOR Primer ISPOR Highlights

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EDITORIAL

Contracting for Compliance: Using Adherence as a Patient-Centered Measure of Performance Scott R. Taylor, RPh, MBA; J.B. Jones, MBA; Nirav R. Shah, MD, MPH

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

BUSINESS

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

Thomas Kaye, RPh, MBA Stakeholder Perspective by Susan Sarnoff, DSW CLINICAL

Prescribing Warfarin Appropriately to Meet Patient Safety Goals Lekshmi Dharmarajan, MD, FACP, FACC; T.S. Dharmarajan, MD, FACP, AGSF Stakeholder Perspective by Teresa DeLuca, MD, MBA

REGULATORY

Treading Water: The No-Growth Investment in Health Services Research

DEPARTMENTS

ADA MEETING HIGHLIGHTS Bustling Pipeline for Diabetes and Its Metabolic Consequences By Wayne Kuznar

GENERIC DRUG TRENDS FDA Bolsters Its Generic Approval Process: Health Plans Reap the Benefits

FDA WATCH Heparin at the Center of the Storm Mark Senak, JD

Director of Human Resources Blanche Marchitto

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

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

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. At Lilly, helping you manage your patients requires a shared commitment to delivering initiatives, ideas, and positive outcomes. So we keep our focus on those who count on our medicines. From diabetes and mental health education, to patient adherence efforts, to simply offering the best answers we can,

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ISPOR PRIMER The International Society for Pharmacoeconomics and Outcomes Research: Implications for Decision Makers in Healthcare By Gordon M. Cummins, MS

ISPOR MEETING HIGHLIGHTS

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

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American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. Copyright © 2008 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline.com, Telephone: 732-992-1889. Fax: 732-992-1881. American Health & Drug Benefits, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. Fax: 732-992-1881. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD. Permission requests to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Engage Healthcare Communications LLC, 241 Forsgate Drive, Suite 205B, Monroe Township, NJ 08831. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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EDITORIAL

Contracting for Compliance: Using Adherence as a Patient-Centered Measure of Performance Scott R. Taylor, RPh, MBA; J.B. Jones, MBA; Nirav R. Shah, MD, MPH

ith US health spending lization of these agents (eg, quantity limits, expected to reach $3.6 trillion prior authorization, and higher cost-sharing by 2014,1 all stakeholders are [ie, high copays] requirements for more seeking ways to control cost while mainexpensive or novel treatments). These efforts taining quality of and access to care. are all direct or indirect attempts to maximize Experts agree that the US healthcare medication value (ie, cost per outcome). system must address current and emerging One area that holds promise for increasing problems of inefficiency, administrative medication value is improving medication costs, rising prices, and inappropriate compliance. Failure to properly use an appropatient care, as the number of healthcare Scott R. Taylor, RPh, MBA priately prescribed medication translates into consumers continues to rise, with a highsuboptimal patient outcomes, which decreaser disease burden. As a highly visible component of es the value of the medication. The cost of poor healthcare expenditure, pharmaceuticals have been a medication adherence to the US healthcare system is lightning rod for various forms of cost and utilization significant. In 2005, the cost of nonadherence was control. The United States spends more than $200 estimated to be $300 billion annually.4 Improving compliance, although certainly an approbillion ($700 per capita) annually on prescription priate target, is challenging. Measuring patient complidrugs, a figure nearly twice as high as in many other ance in a valid, reliable, and reproducible manner is developed countries.2 Since 2000, national spending on prescription drugs has increased between 8% and 15% one of the key elements for any compliance improvement initiative. However, there are no measures of compliance that meet these objectives; most compliance measures rely on surrogates, such as medication The cost of poor medication adherence to possession ratios. Studies of medication adherence have been hampered by methodological problems. the US healthcare system is significant. In 2005, Many studies rely on patient self-reports of adherence, the cost of nonadherence was estimated to be which are unreliable indicators of actual medication $300 billion annually. use.5 Other studies have used cross-sectional prescription paid claims data to estimate medication possession ratios or other metrics of patient adherence.6 Moreover, many adherence studies were designed to increase annually.2,3 Faced with such rising costs, employers and screening for a condition, or involved modification of health benefit plans have attempted to control drug treatment regimens, hence confounding the associautilization and cost by limiting access to newer, more tion of outcomes with adherence.7,8 At the manufacturer level, the most significant expensive medications and by encouraging appropriate measure of medication utilization throughout the phardrug prescribing. Managed care organizations (MCOs) maceutical marketplace today is market share. In this primarily use management strategies to control the utimodel, manufacturers use trained professionals to communicate, educate, and promote their products to cliMr Taylor is Associate Director, Industry Relations; nicians based on information from distribution chanMr Jones is Research Associate; and Dr Shah is Associate nels (ie, wholesale and retail distribution). Prescriber Investigator, Geisinger Health System, PA. data reported by wholesale and retail distributors are A version of this article appeared in the May 2008 issue matched with zip codes and prescriber identifiers to of the PayerPulse newsletter, produced by Xcenda of pinpoint product use within a selected geographic area. AmerisourceBergen Specialty Group.

AMERICAN HEALTH & DRUG BENEFITS

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Contracting for Compliance

Although this is standard practice among manufacturers, there is no evidence to support a correlation between market share and actual patient compliance; market share metrics are associated with prescribers, not with patients. Pharmaceutical manufacturers that discover and market products for chronic conditions and even for life-threatening cancers are challenged by what the data show about compliance rates or utilization over time. Market share performance continues to be the basis for contractual relations between MCOs and pharmaceutical manufacturers. The model is simple: use more medication against the national market share performance provided by the wholesale distribution report and the MCO’s discount for a product increases. Much of the gap between the promise of evidencebased medicine (EBM) and the reality of improved patient outcomes can be attributed to problems referred to as the “last mile,” “medical moment of truth” (MMOT),9 or patient compliance. Studies have generally shown little relationship between the type of disease and patient adherence to treatment recommendations. Interventions found to be effective have also often been complex, making it difficult to attribute improved patient outcomes to specific elements of interventions.10 Who are the losers in the current market share discount model? As managed care has made its mark on our healthcare system, many payor organizations use strict methods of utilization and cost control to offer reasonable premiums. Employers are demanding ways to reduce their healthcare expenditures and to shift some of the associated costs to the consumers. Pharmaceutical companies are poised to lose the battle on all fronts: government price controls or price negotiations are looming, benefit designs are becoming more restrictive, and historical managed care control mechanisms (eg, prior authorizations, step edits, quantity limits, and National Drug Code blocks) continue to be used in contrast to promoting compliance and access. How do we address the current situation and motivate consumers and payors to “do the right thing?” The market requires a novel, patient-centered compliance metric, with incentives properly aligned for consumers and payors that will optimize the return on investment for pharmaceutical manufacturers who invest billions of dollars to create and bring their treatments to arguably the safest and best healthcare market in the world. The picture is complex, and the evidence that we can improve compliance by increasing access is weak; studies that have successfully linked physician prescrip-

tions to actual claims data suffer from time lag and have not been able to provide adherence data in real-time to allow for prospective or concurrent interventions.11,12 These delays result in a lost opportunity to influence patient behavior during the MMOT. Furthermore, interventions aimed only at the “supply side,” (eg, in doctors’ offices at the time of prescription writing) have failed. Decision support aids, including medication timetables and consumer product information, have not improved compliance.13 Interventions on the “demand side” may improve compliance, provided that physicians can prospectively identify patients who would likely demonstrate poor compliance. Real-time claim-derived data on compliance can give prescribers the information and impetus to provide additional patient education that will motivate patients to adhere to their regimens.14 Taken together, these factors point to a clear need for a novel patient-centered measure of performance that (1) prospectively identifies nonadherent patients in real-time, (2) allows for timely interventions in these patients, and (3) evaluates changes in adherence and clinical end points over time, all of which drive event reduction and improve morbidity and mortality.

The market requires a novel, patient-centered compliance metric, with incentives properly aligned for consumers and payors that will optimize the return on investment for pharmaceutical manufacturers. We propose a new metric that can assess compliance within a pharmaceutical category is needed that will enable payors and manufacturers to calculate baseline compliance rate within that category. With a nationwide emphasis on quality improvement, e-health initiatives, and EBM, the time for change is now. Along with manufacturers, employers, consumers, and governments (state and federal) are beginning to develop compliance patient-centered tools by packaging products and services in ways that enable consumers to succeed with their treatments. Moving beyond a pillbased, product-only approach, disease management organizations, employers, and consumers appear ready and willing to invest in this area with the confidence that better compliance will lead to healthier, more productive employees and consumers. ■ Continued

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EDITORIAL

References 1. Pear R. Health costs will keep rising, US says, along with government share. NY Times. February 24, 2005. http://www.nytimes.com/2005/ 02/24/national/24health.html. Accessed July 17, 2008. 2. Miller DP, Furberg CD, Small RH, et al. Controlling prescription drug expenditures: a report of success. Am J Manag Care. 2007;13:473-480. 3. National Coalition on Health Care. Health insurance costs. www. nchc. org/facts/cost.shtml. Accessed June 17, 2008. 4. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353:487-497. 5. Garber MA, Nau DP, Erickson SR, et al. The concordance of selfreport with other measures of medication adherence: a summary of the literature. Med Care. 2004;42:649-652. 6. Sclar DA, Chin A, Skaer TL, et al. Effect of health education in promoting prescription refill compliance among patients with hypertension. Clin Ther. 1991;13:489-495. 7. Bass MJ, McWhinney IR, Donner A. Do family physicians need medical assistants to detect and manage hypertension? CMAJ. 1986; 134:1247-1255. 8. Jameson J, VanNoord G, Vanderwoud K. The impact of a pharmacotherapy consultation on the cost and outcome of medical therapy. J Fam Pract. 1995;41:469-472.

9. Verispan joins with Marketing Technology Solutions to offer innovative market research integrating primary consumer research with secondary longitudinal data—provides insight into what causes patients to fill, or not fill, prescriptions. http://www.verispan.com/about/press_ release_details.php?id=y8w6h4tryw. Accessed June 17, 2008. 10. Haynes RB, McKibbon KA, Kanani R. Systematic review of randomized trials of interventions to assist patients to follow prescriptions for medications. Lancet. 1996;348:383-386. 11. Grymonpre RE, Didur CD, Montgomery PR, et al. Pill count, selfreport, and pharmacy claims data to measure medication adherence in the elderly. Ann Pharmacother. 1998;32:749-754. 12. Svarstad BL, Shireman TI, Sweeney JK. Using drug claims data to assess the relationship of medication adherence with hospitalization and costs. Psychiatr Serv. 2001;526:805-811. 13. Bennett JW, Glasziou P, Del Mar C, et al. A computerised prescribing decision support system to improve patient adherence with prescribing: a randomised controlled trial. Aust Fam Physician. 2003; 32:667-671. 14. Sherman J, Hutson A, Baumstein S, et al. Telephoning the patient’s pharmacy to assess adherence with asthma medications by measuring refill rate for prescriptions. J Pediatr. 2000;136:532-536.

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AMERICAN HEALTH & DRUG BENEFITS

July/August 2008

VOL. 1

NO. 6

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. ÂŠ2008 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

Wayward Prescriptions: Costs of Fraud in Payor Plans Thomas Kaye, RPh, MBA

The cost of prescription drugs and medical devices has increased dramatically over the past several years. This increase has exceeded the annual average inflation index, making medical products desired sources of ill-gotten financial gains through diversion, theft, fraud, and deceit. With databases often being compromised, personal health information, personal identification, and therapy history are all available to be used by thieves through deception and misrepresentation, and are being traded on clandestine websites. With increasing values of medical services, wanted efforts continue to emerge in profiteering schemes, using illicit deals for financial gains by exploiting what was once perceived as sacred areas of medical care. Estimates of healthcare resource costs in dollars, lives, and products exceed $200 billion. Select examples of fraud in our medical services are presented that expose plan members to the risks of loss and theft that can compromise the privacy of their health records. The author outlines prevention steps for payors to guard against such practices. [AHDB. 2008;1(6):9-16.]

he recent events surrounding the incidences of heparin contamination from China1 that was possibly willful in intent, as well as the dramatic increase in the estimated cases of deaths associated with heparin, point to a very troubling matter of terrorist elements in the medical product chain security.1 Vital records, financial accounts, and personal health records continue to be compromised at the nation’s largest data warehouses.2-6 The massive loss of personal data and customers’ transaction files that have been aligned for marketing purposes poses not only an identity loss risk, but also raises concerns about the healthcare delivery system’s ability to protect personal health information and institute fraud-related prevention activities. In addition, new projects, such as the Medicare Part D program, may feed the opportunity for unwarranted graft and corruption, because of the novelty of the product and the lack of process controls for claim payments needed to establish adequate loss prevention techniques (ie, “audits”). Programs and tools used to audit services were not adopted early in the program by many health plan sponsors and participants in reimbursement projects, because of the novelty of the pro-

Mr Kaye is Senior Pharmacy Director, Passport Health Plan, a Medicaid Managed Program, AmeriHealth Mercy Administrators, Louisville, KY.

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gram, as well as the frequent changes requested by the Centers for Medicare & Medicaid Services. Society must have a baseline degree of trust in its systems to ensure that the identity of the individual requesting medical services is indeed that of the legitimate person who is receiving the service.

Scope of the Problem Data contained in electronic warehouses include all aspects of a person’s life—age, sex, credit, personal shopping habits, financial worth, legal actions, health status, social security numbers, license numbers, educational status, and many other parameters. These data also contain insurance reports, examination results, past medical payments to various healthcare providers, preexisting medical conditions, and possibly the details of current medical benefit coverage. These are all gleaned from multiple sources and are nicely aligned for use in sales prospecting. These data may be sorted, filtered, and aligned to target potential customers with razor-edge accuracy for marketing purposes. These data are for sale to telemarketers, mass mailers and catalog providers, insurance companies, and other prospectors with elements needed to focus success in the sales process. These data are also neatly arranged for marketing and sales purposes to provide new companies the tools to target-market their products.

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KEY POINTS ▲ With escalating medical costs and increasing resistance of

payors to higher premiums, routine fraud cases occurring in payor plans and in supply and manufacturing chains contribute to rising healthcare costs. ▲ Health plans are aware of narcotic diversion but not of

diversion of nonaddictive prescription drugs or that their databases are often compromised. ▲ In a recent survey of 750 physicians, many admitted to “gam-

ing” the system for what they see as the benefit of their patients. And many cases of fraudulent service billings and diversion of provider reimbursements have been documented. ▲ Counterfeit medications are being promoted unknowingly

by the supply chain, with catastrophic results, leading to recalls and FDA alerts. ▲ Implementing the preventive steps outlined in this article

can minimize cost to payors.

The true scope of the data loss (or theft) is far broader than is being reported.7 This situation could become catastrophic in terms of payment for services and the overall integrity of our healthcare delivery process if the current trends of fraud continue. Significant problems can be expected from wrongful details being inserted into a claim history from fraudulent use of personal health services; this may unknowingly occur by the legitimate person for whom the benefits are intended and may continue until the member seeks renewal of benefits or until that member’s policy is being rejected as a result of preexisting stipulations that have entered into the health record from the fraudulent users who have accessed the services. Today’s robust embracement of the electronic world has unwittingly made it easier to perpetrate many of the opportunities for theft, diversion, and fraud. In the years before the widespread electronic medical records (EMRs), automated call centers, and detached services, plans and providers had more live people processing and reviewing claims, but that is rare today. The “tricks,” diversion, and fraud may go unrecognized today because of our sophisticated automated processing methods. Although some may consider this unimportant, or the value of the loss may be seen as unimportant because of the ability to increase premiums to cover the costs of the loss, this is little comfort to the individual whose health records have been compromised. (And yet, individuals who may suffer more than corporations, may at least have legal recourse if the health sponsor failed to protect personal health data.)

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With medical costs now the highest in history and the increasing resistance to higher premium costs from payors, it is only sensible to recognize that fraud is taking place routinely in payor plans, supply chains, and, even in manufacturing processes. This adds to the cost burden of the employer as the payor attempts to maintain financial goals.

Abuse of Prescription Drug Benefits In 1999, fraud specialist D.M. Disney and associates noted that the amount of dishonesty, fraud, loss, and theft in our healthcare system had reached $100 billion.8 With the healthcare portion of the gross domestic product now exceeding 16%, the next few years will become critical years for prevention efforts to reduce fraud, diversion, and theft, which are drivers of higher healthcare costs. The importance of loss reduction is even more critical with the massive change in Medicare Part D. The 2005 Deficit Reduction Act includes goals to reduce and prevent losses from intentional and erroneous wrongful deeds. Pharmacy and managed care organizations are acutely aware of the existence of narcotic diversion, perpetrated by skilled professionals who use benefits to obtain medications, then resell them on the gray market to unsavory pharmacy dispensers or on the streets for high profits. The acknowledged problem with diversion of narcotics is also a problem for nonnarcotic prescription drugs, because of the high cost of popular prescription medications.9 It has recently been noted that the greatest number of people in the United States are now consuming pharmaceuticals at the highest level ever,10 and the United States is leading the world in consumption of these products. However, nonaddictive drugs are rarely seen as a potential concern for diversion by health plans. This oversight has resulted in many undiscovered diversion issues of medications and devices being sold at flea markets, on eBay, and in the shadow (gray) markets. The term “wayward prescription” was coined to raise awareness to the intentional misuse of prescription drug benefits, using techniques for defrauding health plans, supply chains, or manufacturers. Gaming the system As the cost of prescription drugs rises, so does the ingenuity of perpetrators to convert these opportunities into fast cash. Complicating the issues of overall healthcare fraud and abuse is the admitted participation of some providers in wrongful, even illegal, acts.11 Health plans have recognized that some providers

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admit to intentionally misleading health plans to gain approval of benefits for their patients.11 In a 2000 survey published in the Journal of the American Medical Association, 39% of the 720 responding physicians said they sometimes, often, or very often manipulated reports to their patients’ health plan to help their patients gain coverage for needed medical care.12,13 These “manipulations” consisted of12: 1. Exaggerating the severity of their patients’ conditions 2. Changing the patients’ billing diagnoses 3. Reporting signs or symptoms that the patients did not have. A full 72% of the surveyed physicians admitted to using at least 1 of these 3 tactics in the preceding year. Furthermore, 28.5% of the physicians agreed with the statement, “Today it is necessary to game the system to provide high-quality care.”12 And 15.3% agreed that it is ethical to do so.12 Simply stated, if the benefit terms to the members are less than the actual cost of the services or goods, and if the payment process for medical services continues to be surrounded by lack of consumer knowledge, then the opportunity presents itself for profiteering and diversion.9 As prescription drug costs escalate, the chances of reselling the medications, bartering, or diversion of services for financial gain increase.

Shadow (gray) market activities Today’s injectables may be accessed by using prescription drug benefits; with costs of dosing for injectables often amounting to $1000 per treatment, this creates an incentive for profiteering. And with drug prices exceeding the cost of gold per ounce, the shadow markets for Epogen,14,15 Neupogen,14 growth hormone, and other injectable medications have developed with intensity. In addition to loss, these practices are also contributing to the high costs of the healthcare delivery system overall and possibly for errors in the delivery of care. Counterfeit medications are now being promoted unknowingly by the supply chain, with catastrophic results,15 leading to recalls and alerts from the US Food and Drug Administration. Ironically, with the widespread electronic connectivity, it is not difficult to find willing purchasers of diverted medications or other outlets that participate in shadow market activities. These high-cost medications are easily peddled and are prime targets for profiteering.16 Theft from manufacturing, distribution channels, transportation, prescription drug fraud, or end-users occurs frequently. Because theft from many of these sources is unreported, except for the financial loss,

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it is difficult to assess the magnitude of the problem. The penalties for these diversions and thefts range from none-to-moderate jail time, mostly based on the amount of dollars involved. Enforcement resources for prescription diversion are difficult to obtain because of the demands of competing needs. It is well known that clandestine laboratories making substances for illicit sale often take precedence in resources from law enforcement; legal drugs may seem a minor problem compared with the large dollar amounts needed to deal with illegal drug trade. The resources needed for prosecution of prescription drug crimes are significant as a result of the intertwined police relations, jurisdictional boundaries, and surveillance needs for evidence gathering. Because of the large numbers of participants in illegal behaviors, the combined loss is significant. The variability of the schemes and the diversity of the perpetrators are contributing factors adding to the scope of the problem.

As prescription drug costs escalate, the chances of reselling the medications, bartering, or diversion of services for financial gain increase.

Diversion of prescription drugs Diverting legal prescription medications takes various forms. Prescriptions are gained by multiple presentations of forged documents, the use of prescription drug benefit cards for other than the rightful owner of the benefit, the use of the benefit card to supply medications to a relative, a friend, or to buy favors with. Prescription drugs do not need to have a street value or a narcotic value, but a prescription has a price per unit that makes the resale appealing to the perpetrator. In the prescription drug diversion world, a 100count bottle of the powerful prescription pain medication OxyContin 80 mg has an average street value of about $8000, or $80 per tablet16; the generic, oxycodone, is valued at 50% of this.16 A 500-count bottle of another pain medication, Vicodin, has a value of about $2500, or $5 per tablet17; the generic form, hydrocodone/acetaminophen 5/500, is again valued at 50% of this price.17 Even in a dishonest process, the brand-name drug has a premium price based on the perception of a higher-quality medication.9

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Essential Role for Explanation of Benefits If an explanation of benefits (EOB) is not sent postservice to the legitimate member, the member will remain unaware of any scam or up-coded bills. If the address is changed, this may not be seen until the member calls the payor or until another event alerts the member to the fraud. Members may not pay attention to an EOB because they do not understand them, or they do not care unless they owe a balance. Only when the real member becomes financially responsible for a loss of benefit or a financial loss is that member motivated to act. Most Medicaid providers do not send EOBs. In contrast, Medicare has recognized this risk for many years and provides member payment information after each service encounter. Even with an EOB, the time period of mailings and true member response to customer service regarding errors may be a minimum of 30 to 60 days for prescription drugs and even longer for medical services, because of billing processes. This is much longer than in cases involving financial fraud, such as credit cards, where the credit card companies have a wide range of surveillance tools for alerts that health insurance providers lack. Procurement Once a thief has data elements on hand, it remains a simple task to call the health insurance provider and say that the benefit card has been lost. Most insurers have instituted policies to comply with the Health Insurance Portability and Accountability Act (HIPAA); however, HIPAA requirements may offer a false sense of confidence that the person on the phone is indeed the rightful owner of the identity. By answering a few simple questions for authentication, which may also be in the stolen data, a replacement card is easily obtained from the health plan. Often complicating the issue is that the insurer’s demographic files may be out of date; even if the customer service agent questions the caller stating that this is a different address, the reply is easily covered by the thief by saying, “I’ve moved,” or by making a preliminary call that may be preceded by a call to change the mailing address. Once the health cards are in hand, the opportunities are boundless. Taking this example further, the cards can then be used or sold with additional identification to provide a “package deal,” supporting a “total identity makeover.” Not only are members being targeted, but providers as well are targets for these fraud rings. Many cases of provider identity thefts resulting in fraudulent serv-

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ice billings and diversion of provider reimbursements have been documented. The following examples are ample evidence: On February 10, 2005, a Hunterdon County, New Jersey, healthcare worker pleaded guilty to claim fraud after submitting more than 40 fraudulent health insurance claims totaling $13,900.18 In February 2005, 6 people were arrested in connection with a prescription drug and welfare fraud ring in Boone County, West Virginia. State troopers said a ringleader impersonated her coworkers while working at Madison Healthcare so she could call in false prescriptions for the painkiller hydrocodone.19 Two former employees of major New Jersey pharmaceutical companies were sentenced in February 2005 for the illegal sale of nearly $300,000 in prescription drug samples to pharmacies in New Jersey and Florida, and for a separate scheme to defraud Schering-Plough of more than $500,000, according to US Attorney Christopher J. Christie.20 The Office of the Inspector General reported in January 2005 that scammers were getting identity information so they could file false claims with Medicare.21 Nearly $18 million worth of reduced-price HIV drugs intended for patients in Africa were reported in October 2002 to have been intercepted by profiteers and shipped back to Europe to be sold at marked-up prices.22 Nearly 200,000 tablets of Lipitor, the world’s bestselling cholesterol-lowering medication, “was found to be counterfeit and recalled by a small Missouri wholesaler in May 2004. Some of the pills had already reached Rite Aid and CVS pharmacies”23 by the time the report was issued. Existing laws and regulations present few barriers to entry into the wholesale drug market. It can be harder to become licensed as a beautician than as a pharmaceutical distributor. On October 19, 2003, the Washington Post reported that with a $700 permit fee and a $200 bond, a pair of Florida manicurists got a license to sell intravenous drugs.23 An auto body shop owner in Miami got a license to sell drugs in Maryland.23 Nevada awarded a license to a 23-year-old former restaurant hostess to operate an Internet pharmacy that specialized in narcotics.23 “The problem is, just about anybody can get a license: 50 states, 50 sets of rules, 50 places to venue shop,” said Joe Riley, an FBI agent in Newark, New Jersey, who has investigated pharmaceuticals stolen in cargo heists.23 “And that’s the first thing that’s thrown back once they’re caught with stolen goods or counterfeit drugs: ‘Hey, the guy I bought from faxed me a copy of his license.’”23

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Estimated Cost Burden of Medical Fraud The current number of prescriptions dispensed annually in the United States is estimated to exceed $240 billion in 2008.24 This cost is staggering, but it has been increasing every year, at an average of about 7%. Previous year’s pharmaceutical price increases have raised the ingredient cost of the prescription by a minimum of 5% per year. This makes the present value of nonnarcotic, nonstimulant, and nonhypnotic drugs a significant cost burden. In its 2008 Drug Trend Report, Medco reported that, for the first time ever, more than 50% of Americans are now using prescription drugs.25 This article does not attempt to detail all forms of fraud in our medical services but merely to highlight examples of the exposure of all members—plan participants as well as government agencies—to fraud and theft as a result of EMR, auto-adjudication, and failings of human oversight (Table). Implementing Preventive Steps To prevent or minimize the theft and abuse of prescription drugs described above, health plans should become aware of certain fraud practices and institute mechanisms to detect and prevent it. 1. Managed care plans, both commercial and Medicaid plans, often suffer from not providing tools to their members to assist the managed care organization in detecting fraud. The simple process of providing an EOB to members for prescription encounters greatly reduces prescription-dispensing fraud. Phantom prescriptions are prescriptions adjudicated using a member’s identity at a pharmacy for a member who is unaware that the pharmacy is being paid for the drug as listed on the EOB. Often the driving force in phantom prescriptions presented for plan payment is the belief that the plan is unjust in its reimbursement practices. The issuance of an EOB allows the members to determine if they had an unjustified charge for a prescription they did not pick up; without an EOB, tracking one’s drug charges is a cat and mouse game. 2. Plans often use resources while designing benefits but fail to complete the circle to ensure that if a drug is dispensed, the member receives the drug and the pharmacy is appropriately paid for it. One example is the design to track total out-of-pocket cost. Many plans have the provision for prescriptions to be called in to a pharmacy, and adjudication then takes place before the member picks up the prescription, to minimize the wait time for the member. In this scenario, the claim is processed and member accounting is done on the backside. If the member has a policy that accumulates pay-

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ments to reach a deductible, the practice of calling in prescriptions and not picking them up by the member may add to reaching the deductible. To resolve this problem, if a claim has been voided or reversed, there should be a provision that the claim cost should also be removed from the accumulated totals for that member. The prescription that was not picked up may not be reversed and the dispensed drug returned to stock without a reversal of the paid charges to the dispensing pharmacy, thus allowing it to be placed back into stock. The result is a double gain for the pharmacy, which sells the drug twice. Plans should have auditing systems to look for a percentage of claim reversals and be on the alert for underutilization of a claim reversal feature.

The simple process of providing an EOB to members for prescription encounters greatly reduces prescription-dispensing fraud. Without an EOB, tracking one’s drug charges is a cat and mouse game. 3. Careful oversight should be provided to independent pharmacies that have health contracts with the provider payor. It is much too easy to fill family prescriptions for gain. Because most audits entail looking at the signature log, this can be easily addressed by audits. 4. High-cost injectables are prime targets for fraud, diversion, and theft because of the high drug ingredient cost and the low copayment often in proportion to the drug cost. Medicaid copayment is often less than $5, which buys a month’s supply of growth hormone that costs $1500; a month’s supply of injectable arthritis medication (Enbrel) that costs $1400; and other injectables that cost more than $1000 per month. Organized groups around the country are trying to get as many medications as possible. Medications are often requested for a patient’s disease states but are not being taken by the person for whom they were intended. Instituting prior authorization can prevent this practice. 5. Good accounting practices used by the pharmacy can limit thefts by employees. Purchasing accountability as well as integrated systems for accounting of amounts purchased versus those dispensed in the clinic reduce loss from theft by alerting for misaligned accounting. The awareness of all forms of surveillance is also a significant deterrent to impulsive theft.

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Table Estimated Costs of Fraud and Abuse in US Healthcare Category Medicare (general): Drugs Devices Billing

Typical description, estimated annual costs False claims filed with Medicare for expensive services and devices (durable medical equipment, pharmacy supplies, and phantom drug billings from providers’ offices) Stipulated estimate by the 2005 Deficit Reduction Act for fraud/abuse recovery Law enforcement authorities estimate healthcare fraud costs taxpayers >$60 billion annually1

Studies on the total cost of identity theft: Credit cards Financial Personal assets

Identity theft cost US businesses and consumers $56.6 billion in 20052

Physicians manipulation of reimbursement rules to obtain coverage: Upcoding Unbundling Phantom claims submission

A sizable minority of physicians report manipulating reimbursement rules so patients could receive care that physicians perceive necessary; of those reporting using these tactics, 54% did so more often now than 5 years ago3 Cost estimates vary considerably and cannot be verified

Pharmaceutical prescription fraud: Physicians billing and coding fictitious filings Inflated claims Other types of improper actions

According to some experts, losses from Medicare fraud in 2004 were $20 billion4 Loss from phishing attacks was $137 million in 2004; $2.8 billion in 20065

False Claims Act (qui tam) lawsuits against pharma: Pharmaceutical companies pay federal government and individual states for Medicare and Medicaid False Claims Act (qui tam) lawsuits originating from whistleblowers

Paying $3 billion resulting from False Claims Act (qui tam) lawsuits6 • Paying kickbacks and inducements to physicians, hospitals, and pharmacists to prescribe or otherwise favor their drugs • Off-label marketing practices; misreporting the “best price,” the “federal ceiling price,” or other benchmark prices reported to Medicare and Medicaid programs • Overcharging for “340B” program drugs; manufacturing or diverting substandard or tainted drugs • Providing false data to, or withholding negative data from, the FDA about efficacy of a drug/medical device in clinical trials to get FDA approval for the drug/medical device, including7: Serono S.A. and its US subsidiaries paid $704 million; AstraZeneca paid $355 million; Bayer paid the federal government more than $250 million; GlaxoSmithKline paid $87.6 million; Medtronic Spine paid $75 million; Doctors buying illegally imported cancer drugs paid $275,000

Nearly 600,000 of the nation’s 1.4 million drug-related emergency department visits in 2005 involved prescription drugs9

Drug diversion drains health insurers of $24.9 billion-$72.5 billion annually8; losses include insurance schemes and large hidden costs of treating patients with serious conditions from abusing addictive narcotics they obtained through the swindles

More than 20 million Americans— nearly 7% of the population— abused prescription drugs in 20078 FDA indicates US Food and Drug Administration. 1. Johnson C. Medicare fraud a growing problem: Medicare pays most claims without review. Washington Post. June 13, 2008. http://www.washingtonpost.com/wp-dyn/content/article/2008/06/12/AR2008061203915.html. Accessed June 26, 2008. 2. Identity Theft Resource Center. Facts and Statistics. April 30, 2007. http://www.idtheftcenter.org/artman2/publish/m_facts/Facts_ and_Statistics.shtml. Accessed July 8, 2008. 3. Wynia MK, Cummins DS, VanGeest JB, et al. Physician manipulation of reimbursement rules for patients. JAMA. 2000;283:1858-1865. 4. Prescription fraud patterns. Visual Analytics. 2004. http://support.visualanalytics.com/technicalArticles/vlLinkChart/volume3/ issue3/VLNews.cfm. Accessed June 26, 2008. 5. Identity Theft Resource Center. Find out more about the nation’s fastest growing crime. Identity Theft Resource Center, Facts and Statistics. April 30, 2007. http://www.idtheftcenter.org/artman2/publish/m_facts/Facts_and_Statistics.shtml. Accessed June 26, 2008. 6. Phillips and Cohen LPP. Pharmaceutical sales, qui tam cases and whistleblowers: how drug companies may be liable under the False Claims Act. http://www.phillipsandcohen.com/CM/FalseClaimsAct/FalseClaimsAct344.asp. Accessed June 26, 2008. 7. United States Department of Justice. Various pharmaceutical qui-tam cases. http://searchjustice.usdoj.gov/search?q=pharmaceutical+ recovery&spell=1&access=p&output=xml_no_dtd&site=default_collection&ie=iso-8859-1&client=default_frontend&proxystylesheet= default_frontend. Accessed June 26, 2008. 8. Coalition Against Insurance Fraud. Prescription for Peril: How Insurance Fraud Finances Theft and Abuse of Addictive Prescription Drugs. December 2007. http://www.insurancefraud.org/drugDiversion.htm. Accessed June 26, 2008. 9. SAMHSA news release. Emergency room visits climb for misuse of prescription and over-the-counter drugs. March 13, 2007. http://www.samhsa.gov/newsroom/advisories/0703135521.aspx. Accessed June 26, 2008.

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6. In almost all these cases, however, unless the medical provider personally knows the member, identity fraud is easy to perpetrate. Without photo identification, clinicians have little to go by to validate the member’s identity. Implementing radio frequency identification, smart cards, or, at the very least, photo enrollment cards, is recommended. 7. Your plan should partner with a claim administrator that can combine medical and pharmacy claims, using analytic tools and programs to statistically review claim encounters: • Evaluate the reversal rate for prescriptions based on regional or state rates; if your plan rate is excessively low, further investigation should be done on individual pharmacies • Use an internal algorithm that looks for prescription claim reversals after 5 days • If the brand or injectable drug cost exceeds the local average, or if the brand or injectable utilization percent is high, this is another clue for fraud • Use appropriate age edits for drug suspensions and liquids for patients younger than 6 years or older than 65 years (especially for antibiotics); look for out-of-the-ordinary refill transactions • Review dental/medical records for duplicate claims; the first alert often comes from dental extractions and procedures (it is unique to have the same tooth pulled more than once) • Evaluate usual distribution of prescriptions from multiple prescribers or provider stores • Require National Drug Code codes for J-coding for billing; the use of “junk” codes allows hiding duplicate medications • Check your crossover claim billings with Medicare and review the process; if the plan is getting many secondary claims with a denial, it may be a case where the provider is driving the denial so that the secondary insurer will pay • Evaluate the matching of the diagnosis and the prescribed drugs; analysis requires blending the medical and pharmacy data.

Conclusion The current evidence of crime using current processes and systems is staggering, with no end in sight. Payors, distributors, end-users, and members all have a part to play in limiting this growth, as well as proactively attempting to reduce the incidence of fraud, diversion, and theft of medical services. Such diversion was often thought of as occurring exclusively with narcotics, but with the current high cost of medications in

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all drug classes, this is a tantalizing chance for high profits by the profiteer at the expense of our healthcare delivery system and patient safety and wellness. Appropriate restrictions, edits, and authorization must

Appropriate restrictions, edits, and authorization must be put in place to deter such risks and prevent continued waste of healthcare dollars. be put in place to deter such risks and prevent continued waste of healthcare dollars. Awareness of the complex nature of these issues can identify and control this waste of healthcare funds. ■ References 1. Mundy A. FDA triples heparin death count to 62. Wall Street Journal. April 9, 2008:A2. 2. Cullen T. A cottage industry blooms to help victims of ID theft. Wall Street Journal. April 21, 2005. http://online.wsj.com/public/article/ SB111399912456311865WX4DmUirv_YRq9HkP7ro4t4dJEA_200505 21.html?mod=tff_main_tff_top. Accessed June 26, 2008. 3. Pringle D, Zimmerman R. Lexis-Nexis uncovers more consumer data breaches. TBRNews.org. April 12, 2005. http://www.tbrnews.org/ Archives/a1528.htm. Accessed June 26, 2008. 4. Tehan R for members and committees of Congress. Data Security Breaches: Context and Incident Summaries. Congressional Research Service Report for Congress. Updated May 7, 2007. http://www.fas.org/ sgp/crs/misc/RL33199.pdf. Accessed June 26, 2008. 5. Hines M. Lap top theft places 98,000 graduate admissions information at risk. CNet News. March 29, 2005. http://news.cnet.com/Laptop-theftputs-data-of-98%2C000-at-risk/2100-1029_3-5645362.html. Accessed June 30, 2008. 6. Gosselin KR. Visa USA: security may have been breached. Hartford Courant. March 4, 2005: A1. 7. Ngan K, Te J. Misuse of data has broad implications for organizations. Computerworld. March 9, 2007. http://computerworld.co.nz/news.nsf/printer/ E68D1B1E89DF2442CC25729200169514. Accessed June 26, 2008. 8. Disney DM and associates. Insurance fraud is more widespread, and more costly, than many people think. DMdisney.com. 1999. http://www.dmdisney.com/fraud_stats.htm. Accessed June 26, 2008. 9. Muha J. Drug diversion: preventing retail pharmacy theft. Loss Prevention. September 1, 2006. http://www.losspreventionmagazine. com/archives_view.html?id=1591. Accessed June 26, 2008. 10. Hitti M. 5-year report shows sharpest increase in type 2 diabetes drugs. May 17, 2007. MedcineNet.com. http://www.medcinenet.com/ script/main/art.asp?articlekey=81184. Accessed June 26, 2008. 11. Hilzenrath DS. For doctors, managed care’s cost controls post moral dilemma. Washington Post. March 15, 1998:H01. http://www.washington post.com/wp-srv/politics/special/healthcare/stories/h031598.htm. Accessed June 26, 2008. 12. Wynia MK, Cummins SD, VanGeest JB, Wilson IB. Physician manipulation of reimbursement rules for patients: between a rock and a hard place. JAMA. 2000;283:1858-1865. 13. Bloeche MG. Fidelity and deceit at the bedside. JAMA. 2000; 283:1881-1884. 14. MedWatch. The FDA Safety Information and Adverse Event Reporting Program. February 13, 2001. http://www.fda.gov/medwatch/ Safety/2002/safety02.htm. Accessed June 26, 2008.

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BUSINESS

15. Amgen. Important drug warning–counterfeiting of Epogen. May 24, 2002. http://www.amgen.com/patients/counterfeits_epogen. html. Accessed June 26, 2008. 16. Coalition Against Insurance Fraud. Prescription drug scams feast on insurance money. Fraud Focus. Spring 2007. http://www.insurance fraud. org/downloads/FF-Spring2007.pdf. Accessed June 26, 2008. 17. Sajan A, Corneil T, Grzybowski S. The street value of prescription drugs. CMAJ. 1998;159:139-142. 18. NJ Attorney General’s Office. Office of Insurance Fraud Prosecutor. Hunterdon county woman pleads guilty to submitting more than $13,900 in fraudulent health insurance claims. NJ Fraud News. February 10, 2005. http://www.njinsurancefraud.org/release/2005/february/severe_ 0210.htm. Accessed June 26, 2008. 19. West Virginia Media. Prescription drug ring broken up. WVNSTV59. February 9, 2005. http:www.wvnstv.com/story.cfm?func =viewstory&storyid=670. Accessed June 26, 2008. 20. Press Release. NJ pharmaceutical company employees sentenced to prison for selling drug samples, defrauding Schering-Plough. February 2,

2005. www.usdoj.gov/usao/nj/press/files/best0202_r.htm. Accessed June 26, 2008. 21. Vogt K. Physicians being targeted in identity theft scheme. American Medical News/AMA. January 31, 2005. http://www.ama-assn.org/ amednews/2005/01/31/bisd0131.htm. Accessed June 26, 2008. 22. HIV drugs for Africa diverted to Europe; probe targets wholesalers. Washington Post. October 3, 2002: A10. 23. Gaul GM, Flaherty MP. US prescription drug system under attack; multibillion-dollar shadow market is growing stronger. Washington Post. October 19, 2003: A1. http://www.washingtonpost. com/ac2/wp-dyn/A44908-2003Oct18?language=printer. Accessed June 26, 2008. 24. National Conference of State Legislature. 2008 Prescription Drug State Legislations. Updated July 1, 2008. http://www.ncsl.org/programs/ health/drugbill08.htm. Accessed July 7, 2008. 25. Medco Health Solutions. Drug Trend Report 2008. 2008. http://medco.mediaroom.com/file.php/162/2008+DRUG+TREND+ REPORT.pdf. Accessed July 5, 2008.

Stakeholder Perspective Procedures Needed to Prevent Prescription Fraud PAYORS: We know that fraud contributes to the high cost of US healthcare, and prescription drugs are no exception. Thomas Kaye exemplifies, however, that the scope of the problem is far greater than most of us imagine. For instance, although the government strictly controls addictive drugs, nonaddictive drugs are not subject to similar oversight; Americans without health insurance sometimes purchase prescription drugs using false identification (ID); and doctors misreport diagnoses to qualify patients for reimbursement. Although healthcare fraud is not new, the online maintenance of medical data makes it easier than ever to obtain prescription drugs fraudulently. Payors and purchasers will do well to implement Kaye’s simple suggestions on how to improve prescription drugs oversight. Mr Kaye’s article could not be more timely. Despite the escalating healthcare costs, little effort is devoted to oversee cost as a way of reducing fraud. In a July 9, 2008, front-page article in the New York Times, titled “Report links dead doctors to payments by Medicare,” Robert Pear cited a congressional investigation that had uncovered that “from 2000 to 2007, Medicare paid 478,500 claims containing identification numbers that were assigned to deceased physicians….The total amount paid for these claims

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is estimated between $60 million and $92 million.” Some 16,548 to 18,240 ID numbers of deceased physicians were involved in these claims; claims made with one ID amounted to nearly $8 million, and some “2,500 doctors who died before 2003 still had active ID numbers” in May 2008, according to the report. When such extreme examples of fraud, waste, and abuse are exposed, the federal government routinely promises to implement procedures to prevent them. Yet such retroactive responses are usually minimal; even when procedures are implemented, rarely is sufficient staff being hired to oversee the changes. Moreover, defrauders are always developing new methods to “beat the system.” Prescription fraud enables other forms of ID theft and healthcare abuse, which cost at minimum tens of billions of dollars annually. With a problem of that magnitude, it is necessary for the government to scale the response to the scope of the problem. Susan Sarnoff, DSW Associate Professor and Chair Ohio University Department of Social Work, Athens, Ohio

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ADA MEETING HIGHLIGHTS

Bustling Pipeline for Diabetes and Its Metabolic Consequences By Wayne Kuznar A number of drugs in late stages of development were featured at the 2008 annual meeting of the American Diabetes Association. SGLT-2 Inhibitors Sodium glucose contransporter type 2 (SGLT-2) inhibitors, which reduce glucose levels by increasing kidney excretion of glucose, is a novel class designed to treat hyperglycemia. Dapagliflozin is the first SGLT-2 inhibitor in a phase 3 clinical trial. In patients with type 2 diabetes, dapagliflozin reduces fasting glucose levels by about 20 mg/dL versus placebo and improves oral glucose tolerance. By 12 weeks, hemoglobin (Hb)A1C levels decline by 0.7% to 0.9% (from a baseline of 7.1% to 8.0%). Patients using dapagliflozin have lost an average of 2.5 to 3.5 kg of body weight. Potential side effects of dapagliflozin include polyuria, recurrent urinary tract infections, salt wasting/dehydration, and electrolyte imbalance/depletion. Exenatide A long-acting once-weekly formulation of exenatide was found in an open-label, 30-week phase 3 trial to significantly improve HbA1C and fasting plasma glucose from baseline. More patients using once-weekly exenatide achieved an HbA1C of )7% than patients using exenatide twice daily (67% vs 61%; P = .004). A second study showed that twice-daily exenatide was effective as monotherapy in reducing HbA1C and causing weight loss. A new drug application (NDA) has been submitted for twice-weekly exenatide as stand-alone therapy (it is currently only indicated for use with oral antidiabetic agents). Liraglutide Liraglutide, a once-daily human glucagon-like peptide-1 analog, significantly reduced HbA1C levels in a 26-week phase 3 trial of 1091 patients with type 2 diabetes previously treated with oral antidiabetic drugs. In contrast to the combination of metformin and glimepiride, liraglutide resulted in weight loss and few episodes of hypoglycemia. More DPP-IV Inhibitors Alogliptin is a highly selective dipeptidyl peptidase-4

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(DPP-IV) inhibitor being developed as a once-daily oral treatment for type 2 diabetes. Several phase 3 trials of alogliptin as monotherapy and in combination with insulin, metformin, sulfonylureas, or pioglitazone showed improvements in glycemic control as monotherapy or as add-on therapy. As monotherapy, alogliptin was superior to placebo in reducing HbA1C levels in a 12-week randomized, double-blind, dose-ranging study of 223 patients with type 2 diabetes. It was not associated with weight gain. When added to insulin, alogliptin significantly improved glycemic control as early as week 4 in a 26-week randomized, placebo-controlled, double-blind phase 3 international trial of 390 patients with type 2 diabetes. Saxagliptin is a reversible inhibitor of DPP-IV with dual routes of clearance that is being studied as oncedaily treatment. In a 24-week placebo-controlled phase 3 study of 401 patients with type 2 diabetes, saxagliptin monotherapy was associated with significant reductions in HbA1C, fasting plasma glucose, and postprandial glucose in treatment-naĂŻve patients. An NDA for saxagliptin was submitted at the end of July.

New Fibrate for Mixed Dyslipidemia When used in combination with rosuvastatin, an investigational fenofibric acid molecule (ABT-335), submitted for approval to the US Food and Drug Administration, treats mixed dyslipidemia in patients with type 2 diabetes better than rosuvastatin alone. The combination of ABT-335 and rosuvastatin was evaluated in 276 patients with type 2 diabetes and mixed dyslipidemia. ABT-335 plus 10 mg rosuvastatin increased high-density cholesterol by 21% compared with a 6.6% increase with 10 mg of rosuvastatin alone (P = .001) and decreased triglycerides by 44.7% compared with 37.1% with 10 mg rosuvastatin monotherapy. ABT-335 plus 20 mg rosuvastatin was also significantly superior to 20 mg rosuvastatin alone. A fixed-dose combination of ABT-335 and rosuvastatin is in development, for which an NDA is expected to be submitted in 2009. â&#x2013;

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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.

800-RX-MYLAN www.mylan.com ÂŠ2008 Mylan Inc.

MYNMKT228

GENERIC DRUG TRENDS

FDA Bolsters Its Generic Approval Process: Health Plans Reap the Benefits

n October 2007, the US Food and Drug Administration (FDA) launched a program to bolster its generic approval process, which now involves 215 full-time staff members.1 The FDA says it applies as rigorous a process to generics as to brand-name drugs to demonstrate that generics are bioequivalent to their branded counterparts.1 The introduction of new generics Table

to the market offers plans a great opportunity to cut costs and potentially pass the savings to their members. Indeed, because they cost but a fraction of the branded prototypes, generics now constitute the majority of prescriptions being filled by plan members, according to Medco Health Solutions.2 In 2007, the FDA approved or gave tentative approval to 682 generics, a record number.1

Examples of First-Time FDA-Approved Generics, 2006-2007

Brand name

Generic

Use

2006 Approvals Actiq lozenge Ditropan XL Flonase nasal spray Lamictal CD chewable Mobic Plavix Pravachol Proscar Toprol-XL 25 mg Wellbutrin XL Zithromax oral suspension Zocor Zofran tablet, oral solution Zoloft Ambien Coreg Duragesic 12 Famvir Inderal LA Lamisil Lotrel Norvasc Omnicef Protonix Toprol-XL

Trileptal

Fentanyl Oxybutynin Fluticasone Lamotrigine Meloxicam Clopidogrel Pravastatin Finasteride Metoprolol Bupropion Azithromycin Simvastatin Ondansetron Sertraline 2007 Approvals Zolpidem Carvedilol Fentanyl transdermal system 12.5 Âľg/hr Famciclovir Propranolol extendedrelease capsules Terbinafine Amlodipine/benazepril Amlodipine besylate Cefdinir capsules, oral suspension Pantoprazole Metoprolol succinate extended-release 50 mg, 100 mg, 200 mg Oxcarbazepine

$ Millions 2005 Sales

Pain Overactive bladder Rhinitis Seizures Arthritis pain Platelet aggregation inhibition Elevated cholesterol Benign prostatic hyperplasia Hypertension, heart failure, angina Depression Bacterial infections Elevated cholesterol Nausea, vomiting Depression Insomnia Hypertension, heart failure Pain Herpes virus infection Hypertension

479 318 1098 1200 992 2659 1395 247 253 1431 368 3393 818 2664 2006 Sales 2180 1283 427 (all strengths) 186 182

Nail fungal infections Hypertension Hypertension Bacterial infection

802 1400 2,331

Gastroesophageal reflux disease, ulcers Hypertension, angina, heart failure

2262 1200

Seizures

601

Adapted with permission from Medco Health Solutions, Inc. 2007 Drug Trend Report, page 8; 2008 Drug Trend Report, page 8.

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In 2006 and 2007, many branded agents received FDA approval as bioequivalents (Table). And over the next 3 years, according to Drug Trend Report 2008, “drugs with total US sales of nearly $24 billion could lose patent protection.”3 As of June of this year, the FDA approved generic versions of several blockbusters, including Fosamax (alendronate) and Aricept (donepezil), and most recently, on June 30, the popular antipsychotic Risperdal (risperdone); it was approved at varying strengths, leading Gary Brueler, director of the FDA’s Office of Generic Drugs in the Center for Drug Evaluation and Research, to comment, “This generic drug approval is another example of the FDA’s efforts to increase access to safe and effective generic drugs as soon as the law permits.”4 A day after the approval, Teva Pharmaceuticals announced it had begun shipping its generic version of Risperdal.5 Earlier this year, Teva won a dispute with the FDA, claiming it was the first to file the 180-day exclusivity regulation. A new hearing on this is now scheduled for September.5 The generic product will carry the same “black box” warning that appears on the branded Risperdal, but the labeling itself may differ, because “some uses of the drug are protected by patents and exclusivity,”4 according to the FDA. It is therefore not surprising that with increasing numbers of blockbusters coming off patent recently, and many more expected to lose their patent in the next few years, relations between makers of branded agents and makers of their generic equivalents are heating up. The enormous success of new generics is inversely mirrored by the tremendous loss to the makers of branded products (and to a lesser degree to pharmacy benefit managers). For example, in the first month after the introduction of generic products for Zoloft (sertraline) in August 2006, “the brand-name product lost 85% of its overall share market.”2 While branded pharmaceutical companies are trying to defend their return on investment, generic makers are attempting to get into the field early on, often using the 180-day exclusivity rule to gain a financial advantage. In fact, many of the fights between these 2 types of drug makers now involve the 180-day exclusivity (“authorized generics”). While drug-maker feuds can be expected to continue, health plans can continue to garner substantial savings by introducing generics early on to the plan and passing a portion of the savings to their members. Designing drug benefits with low or no copay can potentially boost compliance and further reduce costs to plans and members. ■

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References 1. US Food and Drug Administration. FDA announces initiative to bolster generic drug program. October 4, 2007. www.fda.gov/bbs/topics/ NEWS/2007/NEW01719.html. Accessed June 30, 2008. 2. Medco Health Solutions. 2007 Drug Trend Report. 2007;9:9. 3. Generic Pharmaceutical Association. Authorized generics. http:// www.gphaonline.org/AM/Template.cfm?Section=Federal_Affairs& TEMPLATE=/CM/HTMLDisplay.cfm&CONTENTID=1932. Accessed June 20, 2008. 4. US Food and Drug Administration. FDA approves first generic risperidone to treat psychiatric conditions. June 30, 2008. www.fda. gov/bbs/topics/NEWS/2008/NEW01855.html. Accessed July 1, 2008. 5. Teva Pharmaceutical begins to ship generic schizophrenia drug. Wall Street Journal. July 1, 2008:B4.

Stakeholder Perspective The Value of Generics to Health Plans PAYORS/PATIENTS: As noted in this article, the value of generics for the American public is well recognized. Managed care organizations and pharmacy benefit managers continue to develop strategies to encourage appropriate use of generics within their membership. Such strategies include lowered copayments, generics first step-edits, and generic promotional efforts. These programs— along with the large number of blockbuster drugs that have or will become available as generics between 2006 and 2010—have seen health plan utilization of generics reach unprecedented levels. The value of this to members is obvious—more drugs at lower prices means less out-of-pocket cost. Numerous studies have shown that as out-ofpocket cost rises, the number of medication users and the level of compliance drop. Ultimately, it will need to be shown that enhanced patient compliance and persistency with generic drug use result in improved health outcomes. However, even before that is clearly demonstrated, it makes abundant sense to take advantage of lower-cost medication therapy when it is possible and clinically appropriate. In a time when virtually all services to members and healthcare costs in general are increasing at a rate that is much faster than the rate of inflation, the movement to generics and the associated costsavings are a refreshing change of pace. Gary M. Owens, MD President Gary Owens Associates

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FDA WATCH

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FDA WATCH

Heparin at the Center of the Storm Mark Senak, JD

his past April has seen nothing less than a tug of war between Congress and the US Food and Drug Administration (FDA). During April and May, FDA staffers have been on Capitol Hill to offer testimony to Congress no less than 10 times. During the entire duration of 2006, the FDA only offered 12 testimonies. Congressional scrutiny of the agency has obviously increased in the past 2 years. Although this Capitol Hill activity has involved many issues, the 2 that emerge as the most relevant— safety and funding—are related and were sparked by the problem of contaminated heparin. In fact, during April, matters related to the heparin contamination dominated the attention of Capitol Hill and the FDA. Beginning in February 2008, Baxter Healthcare Corporation initiated a recall of all of its heparin products because of reports of serious adverse events in patients using that drug. It was found that the blood thinner heparin had been contaminated by inferior products that were used by some manufacturers, and the problem was occurring globally. As many as 81 people died after large injections of the product. Heparin was manufactured by multiple suppliers in China, and it is not known where in the supply chain the contamination may have occurred.1 An arch theme is connected with this episode of a contaminated pharmaceutical product. It must be determined how the contamination occurred (and the FDA and Baxter have offered the theory that the contamination was intentional),2 but the bigger issue involves questions related to the safety of the current system of drug manufacturing, and what can be done in today’s real-world system to minimize the risk of drug contamination. On April 29, Dr Woodcock, Director of the Center for Drug Evaluation and Research, told the Subcommittee on Oversight and Investigations Committee on Energy and Commerce, “While the contaminant was first identified in the US, the recall of this product is international in scope. The FDA has notified key regulatory international partners, and we are working closely with our Chinese and European counterparts in the investigation.”2 The events surrounding heparin have raised a host of issues for the FDA and paved the way for realizations about the very global nature of drug manufacturing. The heparin incident has made people realize that the

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components of many—if not most—drugs are produced outside of the United States, where the FDA has a very limited ability to inspect the manufacturing process. This fact further undermines the argument that drugs cannot be imported because of safety concerns, when, in fact, drugs that are manufactured here are found to be unsafe. Perhaps most important to the heparin issue is the means by which we come to understand the weaknesses in the current system, and this is a metaphor for the fact that our ability to regulate safety is far behind the current trends of globalization— whether concerning food or drugs.

The events surrounding heparin have raised a host of issues for the FDA and paved the way for realizations about the very global nature of drug manufacturing.

The heparin incidence has been at least partly responsible for a number of hearings on Capitol Hill. The first focus was on why heparin was contaminated, and whether the FDA was doing its job correctly. The secondary focus became one of how to fix the FDA so that the risk from such occurrences is minimized. This led at one point to a heated exchange between Congressman John Dingell, Chair of the House Committee on Energy and Commerce, and FDA Commissioner Andrew C. von Eshenbach during a recent congressional hearing. The commissioner was repeatedly grilled over whether the agency was doing its job correctly, and, more to the point, what funding measures would be needed to ensure that the FDA is in a stronger position when it comes to the inspection of foreign manufacturers. The fact is, the amount of resources that would be required for the FDA to inspect each and every foreign manufacturer of every component of a medication is quite high. At question—which was unanswered in these hearings and exchanges—is whether it is reasonable to expect the FDA to successfully minimize risk abroad through a program of foreign inspections, or

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FDA WATCH

whether there is a greater role for manufacturers in ensuring quality. In the case of heparin, even if testing had been conducted at the border, it is unlikely that the contamination would have come to light. There is a need for a deeper inspection and analysis of the heparin contamination issue to determine whether funding for a more aggressive inspection program is in fact going to solve the problem that Congress and the FDA are facing. Heparin contamination is the symptom of a larger problem facing all drug manufacturing today, and unless it is addressed with a more comprehensive approach, history may be poised to repeat itself. ■ References 1. FDA media briefing on heparin, April 21, 2008. http://www.fda.gov/bbs/ transcripts/2008/heparin_transcript_042108.pdf. Accessed May 27, 2008.

Unmanaged Moment

“We’ve done it! We’ve invented a new drug. Now we have to find a disease for it.”

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2. Woodcock J. US Food and Drug Administration. Testimonial before Subcommittee on Oversight and Investigations Committee on Energy and Commerce. Ongoing heparin investigation. April 29, 2008. http://www.fda.gov/ola/2008/heparin042908.html. Accessed May 17, 2008.

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

FDA’s “Complete Response” Replaces “Approval/ Nonapproval” Letter Responding to concerns from drug manufacturers, and after several years of deliberations, the US Food and Drug Administration (FDA) announced on July 9, 2008 (www.fda.gov/bbs/ topics/NEWS/2008/NEW01859.html), that starting August 11, 2008, it would no longer be sending an “approvable” or a “nonapprovable” letter to drug sponsors in response to a new drug application. Instead, the FDA’s new wording is a “complete response” letter that is intended to notify the drug maker that the review process has been completed but the drug is not yet ready to be approved, because of “specific deficiencies,” as described by the FDA. When possible, the FDA will also “outline recommended actions the applicant might take to get the application ready for approval.” This last comment appears to imply a change in policy in the form of a more complete explanation of the process than just mere semantics, but this remains to be seen. The FDA noted that complete response letters are already being used for applications for biologic products, and that this change in wording is intended to remove any potential for misinterpretation by different stakeholders as a complete and final rejection of the drug. The use of “approvable” or “nonapprovable” letters was often perceived to imply a “tentative” or “conditional” approval of the drug, when in effect that was not the intent of the FDA, according to John Jenkins, director of the FDA’s Office of New Drugs. Such misinterpretation carried potential clinical and financial ramifications to drug makers, patients, and investors.

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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 August 7, 2006. D6-K0178DD October 2006 AA444681/10-06

CLINICAL

Prescribing Warfarin Appropriately to Meet Patient Safety Goals Lekshmi Dharmarajan, MD, FACP, FACC; T.S. Dharmarajan, MD, FACP, AGSF

The anticoagulant warfarin is increasingly used in a variety of disorders associated with risk of thromboembolism. The drug is undoubtedly effective but is linked to numerous nutrient, disease, and drug interactions; safe use of warfarin therefore necessitates close patient monitoring, using the international normalized ratio. The predominant adverse effect is bleeding, and individuals respond to warfarin in different ways. Both high and subtherapeutic international normalized ratios warrant attention, whereas a high international normalized ratio, with or without bleeding, mandates prompt patient evaluation. The 2008 National Patient Safety Goals require medical institutions to develop processes to ensure the safe use and monitoring of anticoagulant use. Last August, the US Food and Drug Administration revised the prescribing information for warfarin to include genetic testing before initiating therapy, although this is still not covered by most health plans. [AHDB. 2008;1(6):26-32.]

arfarin, which has been in use for more than 50 years, has received considerable attention because of its common use for several indications and the link to adverse events, some lifethreatening, which require close monitoring of the international normalized ratio (INR). The drug is undoubtedly effective, but has a narrow therapeutic index. In a 12-month observational study of 25 nursing homes, one sixth of the approximate 3000 residents received warfarin, which resulted in 720 adverse events1; many of the events were preventable, raising safety concerns.1 Warfarin use is on the increase and with it a higher prevalence of bleeding events, which prompted the addition of a “black box” warning by the US Food and

Dr L. Dharmarajan is Chief, Division of Cardiology, Lincoln Medical and Mental Health Center, Bronx, and Associate Professor of Clinical Medicine, Weill Medical College of Cornell University, NY; Dr T.S. Dharmarajan is Chairman, Department of Medicine, Chief, Division of Geriatrics, and Director, Geriatric Medicine Fellowship Program, Our Lady of Mercy Medical Center, Bronx, and Professor of Medicine, New York Medical College, Valhalla, NY. He is also Chair of Performance Improvement and Patient Safety Committee at Our Lady of Mercy Medical Center.

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Drug Administration (FDA).2 The Joint Commission National Patient Safety Goals requirements for 2008 have stated in goal 3E, “the need to reduce the likelihood of patient harm associated with the use of anticoagulant therapy”3; thus hospitals and long-term care institutions have to develop performance improvement processes to ensure the safe use of warfarin.

Pharmacokinetics and Pharmacodynamics Warfarin is a racemic mixture of 2 isomers, R and S forms, in equal proportion.4 Anticoagulants of the coumarin type, such as warfarin, act by blocking the conversion of inactive vitamin K to the reduced state, a requirement to form procoagulant factors II, VII, IX, and X. Besides vitamin K–dependent clotting factors, warfarin inhibits endogenous anticoagulant proteins C and S.5 Half-lives of clotting factors vary considerably, the shortest being factor VII and the longest being factor II. Warfarin has a narrow therapeutic index, with unpredictable and variable pharmacokinetics influenced by genetic, disease, and environmental factors. It is 99% protein-bound; variations in albumin level, particularly declines after illness, result in lower dose requirements. An exaggerated response in older patients may be caused by reduced clearance of the drug.4 Warfarin has both anticoagulant and antithrombotic effects. Anticoagulant activity results from clear-

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Prescribing Warfarin

ance of clotting factors, the earliest being factor VII (with shortest half-life of 6 hours) manifested in the INR within 24 to 36 hours; antithrombotic effects occur by 5 days of therapy, due to clearance of factor II (prothrombin, half-life 50+ hours) (Table 1).4,5 Bleeding is the well-recognized side effect, with consequences relating to extent of bleed and location. The likelihood of bleeding increases with intensity of anticoagulation. A less-recognized and rare but bothersome side effect is skin necrosis, seen within a few days of therapy. Necrosis occurs in the extremities, penis, or the breasts, and results from a rapid drop in protein C (or with inherited protein C or S deficiency), causing thrombosis of the microvasculature. Rarely encountered is a painful blue discoloration of the toes (purple toe syndrome) attributed to cholesterol emboli from plaques. For decades, anticoagulant effects of warfarin were monitored by measuring prothrombin time (PT) to assess decline in activity of clotting factors II, VII, and X. However, the test was fraught with variations in thromboplastin sensitivities, leading to dosing irregularities and confusion in prescribing warfarin. The introduction of INR as the guide for anticoagulation allows comparison of test results from different laboratories and standardized therapeutic ranges. INR targets are individualized to risk and indication for anticoagulation. However, INR lacks validity during the induction and withdrawal phases of warfarin therapy.4-5 The use of PT is no longer considered safe or acceptable.

Appropriate Dosing The typical initial dose of warfarin is 5 mg, followed by a maintenance dose of 2 to 5 mg/day. In the elderly, it is important to use a low loading dose; the target INR is often achieved with a smaller maintenance dose.6 Prescribers need to resist starting with higher loading doses of warfarin because not all coagulation factors inhibited by warfarin decline at the same time; factor II, with the longest half-life, drops last. Also, during induction, proteins C and S, both with anticoagulant properties, get depressed earlier, resulting in a potentially hypercoagulable situation for a brief period. Hence, heparin is added when immediate anticoagulation is required and the INR is not at therapeutic levels.6,7 Use of higher initial doses of warfarin can lead to bleeding and clotting complications. Typical maintenance is best managed with 1 generic or brand-name preparation; switching from one to the other may lead to variations in bioavailability,

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KEY POINTS ▲ Although warfarin has significant benefits for patients at

risk for thromboembolism, its use is associated with adverse events linked to drug, nutrient, and disease interactions. ▲ The most dangerous side effect of warfarin is bleeding,

which is linked to a high INR, initial dose, age, and certain comorbidities. Monitoring the INR values in a patient taking warfarin is mandatory. ▲ For every bleeding episode, many more stroke events are

prevented. ▲ Nevertheless, anticoagulant therapy is underutilized for stroke

prophylaxis, especially in patients with atrial fibrillation. ▲ Prescribers must resist using a high loading dose, because not

all clotting factors are inhibited by warfarin at the same time. ▲ Genetic testing was added to the prescribing information of

warfarin last August to improve initial dosing variations and reduce the risk of bleeding, but is currently not covered by most insurance plans.

Table 1 Pharmacology of Warfarin • Derivative of 4-hydroxycoumarin residue (carbon substituent at 3 position) • Water-soluble • Absorbed within 1 hr, impeded by food • Highly protein-bound, 99% to albumin • Actions: o Decreases availability of vitamin K o Decreases production of: Factors II (half-life 50+ hrs), VII (6 hrs), IX (24 hrs), and X (36 hrs); Proteins C (8 hrs) and S (30 hrs) • Metabolized in the liver, excreted renally and hepatically • Half-life: 36-42 hrs • Duration of action: 2-5 d • Response influenced by: genetics, diet, medications, and disease • Side effects: (most common) bleeding; (less common) skin necrosis, purple toe syndrome, alopecia, dermatitis • Risk factors: age >65 years; history of GI bleeding; hematocrit <30; diabetes mellitus; previous stroke; myocardial infarction; left ventricular dysfunction; high-intensity anticoagulation (INR >4) • Contraindications: severe thrombocytopenia, chronic hypertension (>160/90 mm Hg), medication noncompliance, alcoholism, bleeding • Relative contraindications: nonsteroidal anti-inflammatory drugs without cytoprotection, hazardous activities GI indicates gastrointestinal; INR, international normalized ratio.

which requires more frequent monitoring.8 Observations suggest it may be better to use a single tablet strength (eg, 2-mg tablet) and titrate the number of

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Table 2 Herbal and Nutrient Interactions with Warfarin Potentiate warfarin effects (higher INR)

Inhibiting warfarin effects (lower INR)

Drugs Acid-neutralizing agents: cimetidine, omeprazole Analgesics: aspirin, nonsteroidal anti-inflammatory drugs, tramadol, acetaminophen Antibiotics: cephalosporins, macrolides, quinolones, doxycyclines, sulphonamides Antidepressants: serotonin reuptake inhibitors, fluoxetine, sertraline Antifungals: fluconazole Statins: lovastatin, simvastatin* Miscellaneous: allopurinol, amiodarone, tamoxifen

Drugs Antibiotics: dicloxacillin, nafcillin Anti-epileptic: barbiturates, carbamazepine, phenytoin Antipsychotics: clozapine, haloperidol Bile-acid-binding resins Miscellaneous: antacids, sucralfate, ranitidine Steroids, oral contraceptives (estrogen containing)

Nutrients Alcohol Cranberry products Vitamin E

Nutrients Vitamins C, K

Herbals Mistletoe, Coenzyme Q10, ginseng, green tea, St. John’s wort

Herbals Capsicum, cayenne, cloves, danshen, dong auai, garlic, ginkgo biloba, ginseng, mango, papaya, onions, tamarind Note: This is not an exhaustive list. *Data are inconclusive. INR indicates international normalized ratio.

tablets daily or weekly rather than provide new prescriptions for every INR alteration.5

Pharmacogenetics Periodically one encounters hereditary resistance, where patients require large doses of warfarin, up to 20 mg daily, to achieve adequate anticoagulant effect. This is possibly due to a decline in affinity of warfarin to receptors in the liver.4 In contrast, 10% of patients require smaller-than-usual doses and have greater bleeding tendencies; they inherit variant alleles of the cytochrome (CY) P450 system that cause failure of conversion of S warfarin to metabolites.4 Pharmacodynamic effects of warfarin are explained by genetic polymorphisms in the 2C9 isoform of CYP450 (CYP2C9) and vitamin K epoxide reductase (VKORC1); combined with factors such as age, sex, height, weight, and smoking status, they account for more than half the variance in warfarin dose. Pharmacogenetic tests to guide clinical utility can help predict dosing of warfarin,9,10 but are not currently used. Initial variations in the INR with warfarin use

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were more strongly linked to the VKORC1 haplotype than the CYP2C9 genotype.11 However, in a randomized controlled study, pharmacogenetic-guided and standard dosing did not differ for out-of-range INRs in patients initiated with warfarin therapy.12 In August 2007, the FDA revised the prescribing information for warfarin, “to explain that people’s genetic makeup may influence how they respond to the drug.”10 The FDA noted that the variability in a patient’s response to the drug depends on genetic variations, hence the need for genetic testing before the initiation of warfarin therapy. This labeling change, according to the FDA, would allow physicians to ensure that the initial dosing is not too large and therefore does not increase the risk for bleeding.10 Despite the FDA ruling, most health plans still do not cover genetic testing for this purpose. A recent prospective study provides further evidence in favor of genetic testing.9,13

Indications and Contraindications A MEDLINE literature review indicates that physicians’ fears of bleeding from anticoagulants are

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unfounded14; anticoagulant therapy is underused for stroke prophylaxis, especially in patients with atrial fibrillation (AF). Long-term warfarin use for most causes of AF is effective in significantly decreasing stroke risk, and has a low risk of intracranial bleeding.7,15 Between 1995 and 2002, trends in anticoagulation for AF have been on the rise, although many patients at risk for thromboembolic events were not anticoagulated.15,16 Warfarin (or heparin) is indicated as prophylaxis of deep-vein thrombosis in settings of restricted mobility or high-risk situationsâ&#x20AC;&#x201D;the perioperative period (in particular orthopedic knee and hip surgery), heart failure, a history of cerebrovascular event (nonhemorrhagic, unrelated to AF), and any other hypercoagulable state. In such high-risk situations, INR is targeted to the 2 to 3 range. The presence of a mechanical prosthetic valve, depending on the type, location (mitral or aortic), and associated risk factors, will require longterm anticoagulation, with a target INR range of 2 to 3.5; with bioprosthetic valves, the presence of other risk factors dictates long-term use.4 The disadvantages of warfarin therapy include cost of testing, inconvenience from regular INR monitoring, and most important, bleeding complications. Unlike bleeding into the skin or from the gums that may be without consequence, intracranial and gastrointestinal (GI) bleeding can be life-threatening and is a basis for physician reluctance to prescribe longterm anticoagulants.14,16 Risk factors and contraindications are not universally accepted and are well-reviewed in a systematic literature search.14 Predisposition to falls and the presence of dementia are not contraindications; in a study of a longterm care resident with dementia and AF predisposed to falls, most physicians surveyed believed anticoagulation was contraindicated.14,16 Patients with mild-to-moderate dementia can use anticoagulants if supervised. Contraindications include hazardous or sports activities associated with the risk of head trauma, noncompliance and refusal to follow regular monitoring, and excessive alcohol consumption. Current bleeding is a contraindication, but a healed peptic ulcer is not. Control of blood pressure above 160/90 mm Hg is suggested before initiating warfarin therapy.14,17 Past GI bleeding is a risk factor for bleeding with warfarin.17 Concomitant use of nonselective nonsteroidal antiinflammatory drugs (NSAIDs) or selective cyclooxygenase-2 inhibitors incur similar increased risk of hospitalization for upper-GI hemorrhage.18 Increasing age and intensity of anticoagulation (INR >4) are risks. Patient (caregiver) and provider preferences may influ-

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ence decisions on anticoagulation.14,16 Older adults may not need closer monitoring than younger adults.19

Drugâ&#x20AC;&#x201C;Nutrient Interactions Warfarin use is complicated by interactions with drugs, nutrients, and herbals, which potentiate or inhibit the anticoagulant effect. The mechanisms for interaction vary considerably (Table 2). Cephalosporins inhibit cyclic interconversion of vitamin K4; thyroxine enhances metabolism of clotting factors; and the mechanism involving clofibrate is unclear. Aspirin and NSAIDs inhibit platelet function, increase the prothrombin time, and augment the pharmacodynamic effect of warfarin.4,18 Sulfa and several antibiotics deplete the gut of bacterial flora and worsen vitamin K status.20 Amiodarone causes dose- and concentration-dependent inhibition of warfarin elimination.21 Alcohol interactions are variable; acute alcoholism may inhibit warfarin metabolism, increasing

Long-term warfarin use for most causes of AF is effective in significantly decreasing stroke risk, and has a low risk of intracranial bleeding.

the INR; long-term use may induce liver enzymes and lower the INR; further liver disease increases sensitivity to warfarin.5 Adding antiplatelet agents (clopidogrel and acetylsalicylic acid) to warfarin increases GI-bleeding risk beyond the risk with each drug alone.22 Coadministration of warfarin and aspirin increases bleeding risk, but this combination increases the benefits for patients with acute coronary syndrome, a coronary stent, or a mechanical valve.23 Acetaminophen, perceived as the safest analgesic in the elderly, is an underrecognized cause of anticoagulant instability24; it slows the degradation of warfarin through the CYP450 system, increasing the active (free) fraction. Use of complementary and alternative medicine with warfarin risks a supratherapeutic INR and bleeding events25; cranberry juice has low-level interaction potential26; oral corticosteroids can have a significant interaction.27 The effect of statins is inconsistent, requiring further

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Table 3 A Practical Approach to Warfarin Use The basics • Focused history, including cognition, activities, alcoholism, comorbidity • Laboratory: routine, including baseline INR, hemoglobin, platelet count, hepatic, renal, and thyroid function status • Medication reconciliation: review prescribed, herbals, and over the counter • Review typical dietary preferences of the individual • Counsel patient on need to avoid marked variations in diet (particularly vitamin K–containing foods) and to review use of herbals with physician Warfarin initiation, maintenance • Starting dose !5 mg/d in elderly; avoid larger doses • Maintenance, typically 2-5 mg/d; adjust to target INR • May increase dose if overweight and warfarin resistance exists • May lower dose in warfarin sensitivity, concomitant drugs, comorbidity • Monitor INR daily until at target, then monthly • Monitor INR more often in acute illness, diet/medication changes Managing a high INR • INR <5 and no bleeding, withhold 1-2 doses, revise subsequent dosing • INR 5-9, with greater risk of bleeding, do as above; consider oral vitamin K, 1-5 mg • If there is bleeding, with requirement to reverse anticoagulation (high INR), withhold warfarin, consider IV vitamin K (5-10 mg slow IV infusion, 30 min), fresh frozen plasma, and/or prothrombin complex concentrate. Therapy is individualized to clinical situation, risks • Contact health provider to consider hospitalization • Revise medication regimen; is warfarin to be continued in the individual? Perioperative • Withhold warfarin 4-5 d presurgery, but not necessary for minor procedures (consider provider and patient preferences) • High-risk perioperative states (eg, mechanical prosthetic heart valves), may substitute warfarin using “bridge” therapy (unfractionated/low-molecular-weight heparin) • Ensure INR is at acceptable range presurgery INR indicates international normalized ratio; IV, intravenous. Adapted from Reference 14.

evaluation.28 Clinically significant alterations in coagulation have not been observed with the influenza, pneumococcal, or tetanus vaccines.29

Patient Education, Monitoring Every patient (or caregiver if the patient is incapacitated) should be counseled on the proper use of warfarin. Instructions should include an understanding of

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the interactions with warfarin. This can be simplified by the “3 Ds” mnemonic—Diet, Drug, Disease.30 Patients should be instructed to review any drug changes with their primary physician, including herbal and over-the-counter medications. Most dietary supplements affect the INR. Change in health status (even just fever) and hospitalization calls for frequent monitoring; any newly introduced medications (eg, antibiotics and analgesics) will cause changes in the INR. In addition, illness such as liver disease, malabsorption, or thyroid dysfunction cause alterations in requirement of warfarin and INR results.30 The physician should be contacted for any signs of bleeding or before switching from a branded to a generic product, or vice versa. Patients should also minimize hazardous activities prone to injury. It is most important not to tell patients to avoid vitamin K–rich foods (spinach, greens, broccoli, and lettuce) but rather to keep dietary content consistent, avoiding indulgence. When the INR is not at target, management is focused on the INR and potential bleeding. The severity and site of bleeding may demand prompt attention. For high INR, decreasing or skipping 1 or 2 doses will usually suffice and the regimen is reevaluated; increasing the dose may be warranted for subtherapeutic INR. When vitamin K is required to counter warfarin effects, oral formulations are more predictable and effective than subcutaneous31; the intravenous (IV) slow infusion is used in the presence of bleeding relating to high INR. It is also necessary to search for the reason the INR is not at target, such as a compliance issue, an illness, or a change in diet or medication.4,6 Table 3 outlines a practical approach to the use of warfarin.

The Perioperative Period Most patients can undergo dental procedures, cataract surgery, and endoscopy without biopsy, avoiding alterations in the warfarin regimen, although decisions should be individualized.32 For invasive or major procedures, warfarin must be withheld, and a decision must be made on the requirement for “bridging” therapy with IV or subcutaneous unfractionated heparin or low-molecular-weight heparin.4,32 The decision incorporates the indications for anticoagulation, risks and benefits of withholding warfarin, and the surgeon’s preferences as well. In high-risk situations, such as AF in valvular heart disease, previous stroke, or a mechanical prosthetic valve, it is prudent to stop warfarin 4 to 5 days before the procedure and use bridge therapy.4 Bridging antico-

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agulation may be considered for patients at high risk for thromboembolism.33

Conclusions Although pharmacogenetic testing has the potential to allow for safer prescribing of warfarin, the FDA has not provided clear guidelines, which would encourage coverage by health plans. Patient self-testing to monitor the INR or self-management of anticoagulation instead of monitoring in the clinic has the potential to ease the burden on patients, improve control, and cut the costs associated with long-term oral anticoagulation. The 2008 National Patient Safety Goals promote specific improvements in patient safety, such as improving the safety of using medications and reducing the likelihood of harm associated with the use of anticoagulant therapy, including warfarin, by providing healthcare organizations with proved solutions to patient safety problems; these goals apply to more than 15,000 Joint Commission–accredited and certified healthcare organizations and programs. By consistently meeting these goals, healthcare organizations can substantially improve patient safety and quality of care and reduce costs. ■ References 1. Gurwitz JH, Field TS, Radford MKJ, et al. The safety of warfarin therapy in the nursing home setting. Am J Med. 2007;120:539-544. 2. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use. Arch Intern Med. 2007;167:1414-1419. 3. The Joint Commission. Facts about the 2008 National Patient Safety Goals. http://www.jointcommission.org/PatientSafety/NationalPatient SafetyGoals/08_npsg_facts.htm. Accessed July 7, 2008. 4. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/ American College of Cardiology Foundation guide to warfarin therapy. Circulation. 2003;107:1692-1711. 5. Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician. 1999;59:635-646. 6. American Geriatrics Society Clinical Practice Committee. The use of oral anticoagulants (warfarin) in older people. American Geriatrics Society guideline. J Am Geriatr Soc. 2002;50:1439-1445. 7. Fuster V, Cannom DS, Ellenbogen K, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: executive summary. J Am Coll Cardiol. 2006;48:854-906. 8. Wittkowsky AK. Generic warfarin: implications for patient care. Pharmacotherapy. 1997;17:640-643. 9. Wadelius M, Chen LY, Lindh JD, et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood. June 23, 2008 [Epub ahead of print]. 10. US Food and Drug Administration. FDA approves updated warfarin (Coumadin) prescribing information. August 16, 2008. http://www.fda. gov/bbs/topics/NEWS/2007/NEW01684.html. Accessed July 7, 2008. 11. Schwarz UI, Ritchie MD, Bradford Y, et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med. 2008;358:999-1008. 12. Anderson JL, Horne BD, Stevens SM, et al. Randomized trial of genotype-guided and standard dosing in patients initiating oral anticoagulation. Circulation. 2007;116:2563-2570. 13. Flockhart DA, O’Kane D, Williams MS, et al. Pharmacogenetic test-

ing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008;10:139-150. 14. Man-Son-Hing M, Laupacts A. Anticoagulant-related bleeding in older persons with atrial fibrillation. Arch Intern Med. 2003;163:15801586. 15. Rowan SB, Bailey DN, Bublitz CE, et al. Trends in anticoagulation for atrial fibrillation in the U.S. J Am Coll Cardiol. 2007;49:1561-1565. 16. Dharmarajan TS, Varma S, Norkus EP. To anticoagulate or not to anticoagulate? A common dilemma for the provider: physicians’ opinion poll based on a case study of an older long-term care facility resident with dementia and atrial fibrillation. J Am Med Dir Assoc. 2006;7:23-28. 17. Levine MN, Raskon G, Landefeld S, et al. Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1 suppl):108S-121S. 18. Battistella M, Mamdami MM, Juurlink DN, et al. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med. 2005;165:189-192. 19. Abdelhafiz AH, Wheeldon NM. Risk factors for bleeding during anticoagulation of atrial fibrillation in older and younger patients in clinical practice. Am J Geriatr Pharmacother. 2008;6:1-11. 20. Glasheen JJ, Fugit RV, Prochazka AV. The risk of over-anticoagulation with antibiotic use in outpatients on stable warfarin regimens. J Gen Intern Med. 2005;20:653-656. 21. Almog S, Shafran N, Halkin H, et al. Mechanism of warfarin potentiation by amiodarone: dose and concentration dependent inhibition of warfarin elimination. Eur J Clin Pharmacol. 1985;28:257-261. 22. Delaney JA, Opatrny L, Brophy JM, et al. Drug-drug interactions between antithrombotic medications and the risk of gastrointestinal bleeding. CMAJ. 2007;177:347-351. 23. Madhwal S, Lincoff AM, Rolston DDK. Should patients on longterm warfarin take aspirin for heart disease? Clev Clin J Med. 2008;75:206-208. 24. Dharmarajan L, Sajjad W. Potentially lethal acetaminophen-warfarin interaction in an older adult: an under-recognized phenomenon? J Am Med Dir Assoc. 2007;8:545-547. 25. Shalansky S, Lynd L, Richardson K, et al. Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy. 2007;27:1237-1247. 26. Pham DQ, Pham AQ. Interaction potential between cranberry juice and warfarin. Am J Health Syst Pharm. 2007;64:490-494. 27. Hazlewood KA, Fugate SE, Harrison DL. Effect of oral corticosteroids on warfarin therapy. Ann Pharmacother. 2006;40:2101-2106. 28. Douketis JD, Melo M, Bell CM, et al. Does statin therapy decrease the risk for bleeding in patients who are receiving warfarin? Am J Med. 2007;120:369.e9-369.e14. 29. Jackson ML, Nelson JC, Chen RT, et al. Vaccines and changes in coagulation parameters in adults on chronic warfarin therapy: a cohort study. Pharmacoepidemiol Drug Saf. 2007;16:790-796. 30. Beier MT. Warfarin monitoring: consider the three Ds. J Am Med Dir Assoc. 2005;6:76. 31. Crowther MA, Douketis JD, Schnurr T. Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: a randomized controlled trial. Ann Intern Med. 2002;137:251-254. 32. Dunn AS, Turpie AG. Perioperative management of patients receiving oral anticoagulants: a systematic review. Arch Intern Med. 2003;163:901-908. 33. Wysokinski WE, McBane RD, Daniels PR, et al. Peri-procedural anticoagulation management of patients with nonvalvular atrial fibrillation. Mayo Clin Proc. 2008;83:639-645.

Dr T.S. Dharmarajan is on the Speaker’s Bureau of Ortho-Biotech. He received a grant from the National Institutes of Health for implementing processes for the safe use of warfarin at his hospital.

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Stakeholder Perspective Benefits of Genetic Testing in Warfarin Therapy PAYORS: Personalized medicine provides powerful new tools that can help physicians prescribe medications with greater precision. Using advanced genetic and biomarker testing, physicians can more easily predict whether a drug or dosage is likely to be effective—or potentially toxic—for an individual patient. For many drugs, such as warfarin, product labeling already includes information about the possible impact of genetic variations on drug response, but this information is not yet generally used in clinical practice. Widespread use of genetic testing will depend on several factors, including evidence of clinical and economic benefits, easy access to genetic testing, and the integration of this new type of diagnostic testing into health benefits. For drugs like warfarin, determining the appropriate dose early in treatment is crucial. If patients reach therapeutic levels more quickly, hospitalizations due to serious adverse events are less likely. In a recent analysis of patients who were new to warfarin therapy, Medco researchers found that patients who required 2 or more dose adjustments had a significantly higher risk of hospitalization for hemorrhage or thrombosis (30.7%), compared with patients who required 1 or fewer dose adjustments (19.6%). Testing for genetic differences in warfarin metabolism could help clinicians stabilize warfarin doses early in treatment, thereby reducing the costs associated with hospitalization—the most expensive component of the healthcare system. A recent study demonstrates that genotype testing can have a positive impact on warfarin therapy in controlled clinical settings.1 Patients in a genotypeadjusted treatment group achieved therapeutic levels more quickly, spent more time in the therapeutic range, and had fewer minor bleeding events compared with patients in a control group. Many clinicians agree that pharmacogenomic testing is theoretically sound, but they are not yet convinced that its value has been proved in practice. Medco is working on closing the gap between theory and practice by collaborating with the Mayo Clinic on a study to assess the clinical value of genetic testing in warfarin therapy. Patients who are new to warfarin treatment are offered genetic testing to determine

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how sensitive they may be to the drug’s effects on blood clotting. This information is provided to the physician, who can use it to adjust the dose. The objective is to see whether early dose adjustments based on genetic information will result in a lower incidence of complications and hospitalizations. This study will provide the first broad evaluation of personalized medicine in typical community practice settings. If clinical research demonstrates that genetic testing can reduce the risk of serious adverse events in patients using warfarin, the potential savings could be substantial in human and financial terms. The American Enterprise Institute-Brookings Joint Center predicts that using genetic information to prescribe warfarin could save an estimated $1.1 billion in healthcare spending each year, while preventing about 17,000 strokes and 85,000 serious bleeding incidents.2 For health plan sponsors, personalized medicine offers the potential to bring greater precision to medication prescribing. Coverage programs could be more specifically designed based on the genetic profile of the individual patient. For example, medications that work through certain genotypes or biomarkers could be limited to patients who exhibit those targets. Personalized medicine can help ensure that patients receive the correct dose of the right drug at the earliest possible point in their treatment. Precise, individualized prescribing offers significant potential for improving health outcomes and patient safety, while reducing the overall costs of care. 1. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. 2008;8:460-470. 2. McWilliam A, Lutter R, Nardinelli C. Health Care Savings From Personalizing Medicine Using Genetic Testing: The Case of Warfarin. Working Paper 06-23. AEI-Brookings Joint Center for Regulatory Studies; November 2006.

Teresa DeLuca, MD, MBA Vice President, Personalized Medicine Business Solutions Medco Health Solutions, Inc

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Early and intensive treatment can help patients reach their A1C goal Are your plan members not taking their type 2 diabetes medications? s Many patients are not reaching the ADA A1C target goal of <7%, and many are stopping their medications.1,2

Recent data show a drop in the use of oral antidiabetic medications3 2,500

TRx (000s)

2,400 2,300 2,200

OAD TRx 4 week moving avg

Trend (Pre-NEJM)

2,100 2,000 3/16/2007

Days

6/6/2008

The need for early treatment s Because many patients already have chronic complications at the time of diagnosis, treatment plans must be aggressive from the start to optimally manage type 2 diabetes.4 s Long-term beneﬁts of diabetes medications can only be realized if patients adhere to their treatment regimen.2

“Early, intensive intervention has the potential to get patients to glycaemic goals more quickly and be more effective at keeping them at goal...” 5

References: 1. Hoerger TJ, Segel JE, Gregg EW, Saaddine JB. Is glycemic control improving in U.S. adults? Diabetes Care. 2008;31:81-86. 2. Rodgers K. Ensuring compliance in patients with diabetes. In: Diabetes: Disease Management Guide. 4th ed. Montvale, NJ: Thomson PDR; 2004:501-505. 3. Data on ﬁle, Takeda Pharmaceuticals North America, Inc. 4. Cornell SA. Clinical case study: achieving long-term control of insulin resistance. J Manag Care Pharm. 2007;13(suppl B):S11-S15. 5. Goldstein BJ, Gomis R, Lee H-K, Leiter LA, on behalf of the Global Partnership for Effective Diabetes Management. Type 2 diabetes—treat early, treat intensively. Int J Clin Pract. 2007;61(suppl 157):16-21. ©2008 Takeda Pharmaceuticals North America, Inc.

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REGULATORY REGULARTORY

Treading Water: The No-Growth Investment in Health Services Research Emily J. Holubowich, MPP; Joseph R. Antos, PhD

There is a “perfect storm” brewing in the American healthcare system. Healthcare spending has grown faster than our economy for many years and is projected to double in as little as 10 years. In spite of what we spend on healthcare, research tells us that we only receive appropriate care half the time. We are simply not getting what we are paying for. Health services research provides the data and the evidence needed to make better decisions, design healthcare benefits, and develop effective policies to optimize healthcare financing, facilitate access to healthcare services, and improve healthcare outcomes. Despite what we know and what we can learn from health services research, federal funding for this important field continues to erode. This article provides a primer on the federal budget process and summarizes findings from the Federal Funding for Health Services Research 2007. [AHDB. 2008;1(6):34-41.]

ealth services research (HSR) explores healthcare costs, quality, and access and seeks ways to improve healthcare delivery, safety, availability, and affordability. HSR has been defined as a “multidisciplinary field of scientific investigation that studies how social factors, financing systems, organizational structures and processes, health technologies, and personal behaviors affect access to healthcare, the quality and cost of healthcare, and ultimately our health and well-being.”1 In particular, HSR identifies what treatments work best when, for whom, and at what sites of service; it evaluates how best to finance healthcare and control spending; it helps inform healthcare benefit design; it translates the innovations from basic bench science into medical practice, allowing providers, health plans, and patients to make more informed health choices. HSR is the link between research and patient care. Since 2003, the Coalition for Health Services Research (coalition) has been tracking the federal government’s investment in HSR by collecting budgetary data from federal agencies that principally fund HSR.

Ms Holubowich is director of government relations, Coalition for Health Services Research; Dr Antos is Wilson H. Taylor Scholar in Health Care and Retirement Policy, American Enterprise Institute, Washington, DC.

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The coalition has been collecting annual budgetary data from the federal agencies that fund HSR. In the past 5 years, we have found that despite what we can learn from HSR, there has been an erosion of federal funding for this field, in part because of competing federal priorities, a constrained fiscal climate, and polarizing partisan politics. These trends have likely hindered the ability of the researchers to examine the healthcare system and identify innovative and effective solutions. If left unchecked, the declining investment in HSR may have further implications for the study of health and patient care in the future. This article provides a primer on the federal budget process and summarizes findings from Federal Funding for Health Services Research 2007, the fifth annual report of HSR expenditures.2 Federal agencies have not developed or adopted a uniform definition for HSR or standard categories for collecting and reporting data about reimbursement and funding methodologies, health disparities, patient safety, and chronic disease management. Therefore, questions remain about the breadth and scope of activities included in the funding totals presented in this article. Investments in what any one agency has self-reported as “health services research” may not be equivalent to what is reported by another agency. For example, budget numbers can reflect entire agency budgets, including over-

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head costs or a rough estimate of dollars spent on HSR. Nevertheless, our data offer the best available estimate on the federal government’s investment in this area.

Impact of HSR on Healthcare US healthcare has the potential to improve people’s health dramatically but often falls short and costs too much. HSR is used to understand how to better finance the costs of care, measure and improve the quality of care, and facilitate coverage and access to services. HSR is changing the face of healthcare by uncovering critical challenges our healthcare system faces. The 2000 Institute of Medicine report To Err is Human (which in part relied on HSR work) estimated that roughly 98,000 Americans die each year from errors in the hospital.3 HSR uncovered that disparities and lack of access to care in rural and inner cities result in poorer health outcomes. It also found that the rise in obesity in the past 2 decades accounts for 20% of the increase in health spending; obesity-related expenditures were estimated at $78.5 billion in 1998 and $92.6 billion in 2002.4,5 HSR also seeks ways to address healthcare problems. It framed the debate over healthcare reform in Massachusetts—forming the basis for that state’s 2006 health reform legislation—and continues to frame the debate on the national stage.6,7 It offers guidance on implementing health information technology, such as eprescribing, to reduce costs and medical errors. HSR has changed the paradigm of medical practice for cost-effective care, demonstrating that preventive services (eg, mammography) put into practice substantially reduce mortality and morbidity, at reasonable costs.8 And it has provided the leverage needed to make major health system overhauls; a 1988 study showed, based on experiHSR provides the evidence and tools to make healthcare: Affordable, by decreasing cost growth to sustainable levels Efficient, by decreasing waste and monitoring costeffectiveness Safe, by preventing medical errors, monitoring public health, and improving preparedness Effective, by evaluating programs and outcomes and promoting evidence-based innovations Equitable, by eliminating disparities in health and healthcare Accessible, by connecting people with the healthcare they need, when they need it Patient-centered, by increasing patient engagement in, and satisfaction with, the care they receive

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KEY POINTS ▲ Health services research is the link between research and

patient care. It identifies best treatments and how most effectively to finance healthcare and control spending. ▲ Health services research has changed the paradigm for cost-

effective care by demonstrating that preventive services can substantially reduce mortality and morbidity, at reasonable costs. ▲ Nevertheless, in real dollars, the purchasing power of health

services research has declined because this research investment has not kept pace with inflation. ▲ Federal funding is focused on improving quality of care, but

relatively little funding is provided to study what is driving healthcare costs, and how to improve the quality and efficiency of the healthcare system as a whole.

ences of Medicare beneficiaries, that hospital prospective payment systems could lead to shortened lengths of stay, greater efficiency, and no obvious loss of quality.9

The Federal Budget Process The Constitution designates the US Congress as the primary authority in setting taxation and borrowing policies for the federal government and in determining how resources are spent.10 Congress shares this “power of the purse” with the president and the executive branch. The president sets the tone at the beginning of each fiscal year by submitting a budget request to Congress, and has the power to alter congressional action by exerting veto authority over appropriations bills. The federal budget process is prescribed by the Congressional Budget and Impoundment Control Act of 1974 and subsequent legislation.10 Annual budget decisions are made on the basis of a fiscal year beginning October 1 (Table 1). The key stages of the process—formulation of the president’s budget, congressional action, implementation of the budget, and audit and review—typically extend over at least 2.5 years. Federal agencies must deal with 3 different fiscal years at the same time: implementing the budget for the current fiscal year; seeking funds from Congress for the next fiscal year; and planning for the following fiscal year.10 Although the budget timetable is established in statute, Congress generally fails to meet the deadlines. For example, the 1974 Congressional Budget Act provides for the House and Senate to reach a budget resolution (or an agreement by the House and Senate on an overall budget plan and spending cap) by April 15. In recent years, this deadline has rarely been met.

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Table 1 Federal Budget Process Timeline Timeline

Action

First Monday in February

President submits budget to Congress

February 15

Congressional Budget Office submits report on economic and budget outlook to House and Senate Budget Committees

6 weeks after president submits budget

House and Senate committees submit their budget analyses to respective budget committees

April 1

Senate Budget Committee reports budget resolution

April 15

Congress completes action on budget resolution

May 15

House begins action on annual appropriations bills

June 10

House Appropriations Committee reports last appropriations bill

June 30

House completes action on appropriations bills

July 15

President submits midsession review of his budget to Congress

October 1

Fiscal year begins

Adapted with permission from the Congressional Deskbook: The Practical and Comprehensive Guide to Congress. 5th ed. Michael Koempel and Judy Schneider, eds. Copyright 2007 by the TheCapitol.Net. www.Congressional Deskbook.com.

In the past 10 years, the House and Senate failed 4 times to reach agreement on a budget, meeting the April 15 deadline only 3 times (fiscal years 2000, 2001, and 2005).10 Congress often fails to complete the federal budget process before the October 1 start of the new fiscal year. In these situations, 1 or more continuing resolutions may be needed to sustain government operations. A continuing resolution extends federal funding at existing fiscal levels for some period (often weeks, but occasionally the entire fiscal year) if Congress and the president fail to enact spending bills. With the exception of 1989, 1995, and 1997, at least 1 continuing resolution has been enacted for each fiscal year since 1954.11 Since 1996, most continuing resolutions have provided interim funding for short periods of time, but in 2007 funding for many agencies’ spending bills— including those within the US Department of Health and Human Services that fund HSR—extended for the full year, holding agency budgets flat at 2006 levels.11

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In real terms, a yearlong continuing resolution places federal agencies in a holding pattern and budgetary bind, where their operating budgets lose purchasing power as funding levels are not adjusted to account for inflation. In addition, agencies may be unable to implement new initiatives, or if they do, must change funding priorities on a project basis when requested funds are not appropriated. Federal funding for HSR is diffuse, both in terms of who funds it and how it is funded. The Agency for Healthcare Research and Quality (AHRQ) is the lead agency among the principal federal funders of HSR; AHRQ’s core mission is to improve the quality, safety, efficiency, and effectiveness of healthcare through research. AHRQ and other federal agencies use various funding mechanisms to support HSR, which affect the types of research conducted and the degree of autonomy researchers have in their work (Table 2).12-14 For example, when a grant is awarded, “no substantial federal involvement with recipients is anticipated during the performance of a research activity.”12 Conversely, contracts are awarded when an agency’s purpose is to acquire goods or services for the direct benefit or use of the federal government.13 In these circumstances, the government has substantial and direct “hands-on” involvement with the awardees throughout the life of the project. From information provided to the Coalition by the principal federal funders of HSR, we estimate that approximately $1.5 billion was spent on HSR and related activities in fiscal year 2007 (Table 3).2,15 Currently, less than 1 cent of every healthcare dollar is spent on HSR; and only about 4.5% of the federal government’s $33.2 billion health research budget was apportioned to HSR in 2006.16 Within this $1.5 billion investment, the balance of the government’s expenditure on HSR is heavily tilted toward clinical issues. For example, the National Institutes of Health’s HSR budget, which is primarily focused on identifying and overcoming barriers in moving research into practice, constituted roughly 61% of the federal investment in the field in 2007.2 Roughly 53% of the AHRQ’s budget was targeted for research on patient safety and healthcare quality; another 24% was targeted for research on healthcare effectiveness.2 This emphasis on clinical research is aligned with one of the field’s priorities—improving quality of care. But these efforts do not include research on ways to improve the quality and efficiency of the healthcare system as a whole, and relatively little funding is provided to study

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what is driving healthcare costs or how to achieve much-needed improvements in efficiency. Since the coalition first began reporting these data in 2003, federal funding for HSR has remained constant at $1.5 billion. In real dollars, however, the government’s investment in HSR has not kept pace with inflation, and the field’s purchasing power has declined to $1.34 billion as a result (Figure 1).2 This is when spending on healthcare overall has risen faster than the rate of inflation—from $1.4 trillion in 2000 to nearly $2.1 trillion, or $7026 per person, in 2006.16 If this trend continues, federal funding for HSR as a share of national health expenditures will decrease from its 2006 level of 0.07% to 0.04% in 2016.17 How much should the federal government invest in HSR? That depends on the value likely to be gained from additional research funding compared with other uses for the money—a judgment that is difficult to make in advance. To get a better sense of the level of concern about HSR funding, AcademyHealth—the professional society for HSR and health policy—interviewed 38 leaders in HSR and health policy who have served as federal agency executives, as well as members of Congress, senior congressional staff, state officials, employers, health plan executives, and foundation executives.18 The consensus was that federal funding for HSR should be increased from the current level of $1.5 billion to $5 billion. Interviewees recommended, on average, that the HSR funding should constitute 17% of the federal government’s health research budget.18 Rounding down to 15% equals $5 billion of the $33.2-billion research budget in 2006. Experts argued that an increase in HSR funding of this magnitude would ensure that purchasers, health plans, providers, and policymakers could move biomedical and clinical research innovations into practice more efficiently and effectively.

Consequences of Lost Purchasing Power The plateaued federal investment in HSR and the resulting loss of purchasing power has, at the microlevel, compromised the ability of some federal agencies to fully achieve their missions, and at the macrolevel, hindered progress in generating more and better information about the US healthcare system. Many of the sentinel studies that have changed the face of healthcare in the United States—for example, John E. Wennberg’s Dartmouth Atlas documenting geographic variation in healthcare delivery and outcomes19—are the result of ingenuity on the part of

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Table 2 Examples of Federal Funding Mechanisms for HSR Funding type

Mechanism

Grant

Provides discretionary funds and/or direct assistance to carry out approved research activities Individuals and public and private nonprofit entities eligible to receive grants Minimal federal involvement during performance of the project

R Award

A type of grant to support a discrete, specified research project; may be renewable

K Award

A type of grant to provide a “protected time” for intensive, supervised career development of young researchers

Training and/ dissertation

A type of grant to support dissertation work or by young researchers

Cooperative agreement

A type of research award for nonprofit/forprofit organizations; substantial federal involvement while performing the project

Contract

An agreement initiated by the government and used to acquire an identifiable product or service under specified terms “Hands-on” federal involvement during the performance of the project

Sources: References 12-14.

Table 3 Estimated Funding for HSR, FY 2007 Federal agency Agency for Healthcare Research and Quality Centers for Disease Control and Prevention •National Center for Health Statistics •Public Health Research Centers for Medicare & Medicaid Services Department of Defense Health Services Research Administration Rural Health Research National Institutes of Health Veterans Health Administration Total

$ Millions 319 109 31 58 15* 8.7 921 64 1527

*Department of Defense data represents funding for fiscal year 2004; data were not reported for fiscal years 2005, 2006, and 2007. Sources: References 2, 15.

investigators who believed their ideas had the promise to clarify a phenomenon, improve methods and measurement, or make an otherwise unmanageable policy problem manageable. Yet, the past few years have

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Figure 1 Federal Funding for Health Services Research 1.70 1.65

Dollars (in billions)

1.60 1.55 1.50

Keeping with inflation

1.45

Estimated

1.40

Real dollars

1.35 1.30 1.25 1.20 2003

2004

2005 Fiscal year

2006

2007

Source: Reference 2.

Figure 2 AHRQ’s Research Awards 250

200

Noncompeting

150

New and competing*

100

Training grants 50

0 2003

2004

2005 2006 Fiscal year

2007

2008

*“New and competing” refers to grants that are newly available to researchers in a given fiscal year. “Noncompeting” grants represent multiyear grants already awarded. Source: Reference 2.

Figure 3 Funding for AHRQ’s Research 160

Dollars (in millions)

140 120

Noncompeting grants

100

New and competing

80 Training grants 60

Contracts and inter agency agreements

40 20 0 2003

2004

2005 2006 Fiscal year

2007

2008

Future Trends Show Little Change Although we have not gathered from agencies their

Source: Reference 2.

AMERICAN HEALTH & DRUG BENEFITS

shown a decline in the number of, and funding for, grants that support such investigator innovation. Figure 2 and Figure 3 depict trend data for AHRQ’s research and budget. The number of new and competing grants in fiscal year 2007 jumped 20% compared with 2006, the second highest number of awards in 5 years.2 However, based on 2008 estimates, AHRQ projects that the number of awards will fall from 156 in 2007 to 57 in 2008.2 These projections suggest that AHRQ will fund the fewest number of new and competing awards since we began collecting these data. Not surprisingly, AHRQ’s budget dedicated to funding new and competing grants and training grants also continues to decline; the projected budget may hit a low in 2008— $9.6 million and $8 million, respectively.2 At the same time, funding for contracts has more than doubled at AHRQ, from nearly $68 million in 2003 to roughly $145 million in 2008.2 AHRQ dedicated 54% of its overall budget to contracted work in 2008, but less than 3% was available for new competitive grants.2 Greater funding for contracted work as a proportion of the overall agency budget translates into fewer competitive funding opportunities available to individual researchers, particularly as the agency’s budget remains virtually flat. According to surveys of researchers and analysts conducted by Academy Health, AHRQ grants comprise a smaller proportion of research budgets. In 2003, AHRQ funding averaged 52% of researchers’ external funding; in 2006, the share decreased to 42%.20 The Coalition has not estimated the long-term impact of flat funding on the field or its researchers, but the steady erosion of investment could hinder the development of the next generation of scientists. Trends in educational programs show an increase in the absolute number of researchers graduating from HSR programs.21 These researchers require evidence of independent scholarship to build their careers, including research supported by “R” and “K” awards. Failure to fund such grants adequately may result in losing earlycareer researchers to research fields with more support. If left unchecked, declining federal investments in graduate and postgraduate education could threaten the ability to attract qualified researchers to HSR as a viable career path, and ultimately hinder the capacity to respond to the public and private sector research needs for more and better information.

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Table 4 Estimated Federal Funding for HSR, FY 2008, $ Million

Agency Agency for Healthcare Research and Quality CDC: National Centers for Health Statistics CDC: Public Health Research Centers for Medicare & Medicaid Services Health Services Research Administration: Rural Health Research National Institutes of Health Veterans Health Administration Total

FY 2007 estimated

FY 2008 president request

FY 2008 final

FY 2009 president request

319 109 31 58 8.7

329 110 31 34 8.7

334.6 113.6 31 31 8.6

325.6 124.7 31 31 8.7

921 64 1511

950* 64† 1523

965* 64† 1585

965* 68† 1554

*Expected figures if HSR maintains its current funding proportion of National Institutes of Health funding. †Expected figures if HSR maintains its current proportion of overall VA Medical and Prosthetic Research funding. CDC indicates Centers for Disease Control and Prevention. Sources: References 2, 15, 22.

enacted spending levels for 2008, we can estimate the federal government’s current investment based on the omnibus spending bill signed into law by the president in January 2008. AHRQ and the National Center for Health Statistics received small budget increases in 2008, but the overall investment in HSR remains constant at about $1.5 billion (Table 4).2,15,22 The president’s 2009 budget request cuts most discretionary spending for health and other domestic programs but would hold federal funding for HSR at roughly $1.5 billion, with slight rollbacks in AHRQ’s budget. Under this request, funding for AHRQ’s new and competing grants would further decline to a new low of 23 awards, including only 4 new awards for non–patient-safety-related HSR. And the number of ongoing projects would decline from 144 grants in 2008 to 129 grants in 2009.23 Leadership of the House and Senate Committees on Budget and Committees on Appropriations rejected the president’s budget as “dead on arrival” and at the time of this writing is developing spending bills that would likely increase the investment in health and other domestic programs, if enacted. However, early this year, the president stated that he would veto any spending bills that exceeded the “reasonable and responsible” levels in his request.24 Given that neither the House nor the Senate has the two-thirds majority vote required to override a presidential veto, it is probable that Congress will pass a continuing resolution to sustain government operations at 2008 levels through February or March 2009 and complete its fiscal year

2009 appropriations work after the new administration takes office. For 2010, the Office of Management and Budget— which assists the president in formulating the budget and monitoring the implementation of the enacted budget—has directed executive branch agencies to submit their budget requests after the new administration or a transition team is in place. In the meantime, agencies will complete a technical review of their previous and current year spending to establish baseline estimates for the next administration’s budget planning.25

The overall investment in HSR remains constant at about $1.5 billion.

Conclusions As our healthcare costs continue to rise, chronic diseases become more prevalent, diagnostic and therapeutic technologies proliferate, baby boomers reach Medicare eligibility, the numbers of veterans grow, and more Americans join the ranks of the uninsured, the need for HSR will only increase in the coming years. Yet in the immediate short term, fiscal constraints and competing priorities render dramatic budget increases unlikely, despite the growing awareness that more and better evidence is needed to improve health and healthcare. Continued

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To ultimately reign in costs and get better care at better value, the federal government will eventually need to increase its investment in HSR, the research itself and the researchers who generate it. In addition, federal agencies that fund HSR, and especially AHRQ as the lead agency, will need to reprioritize their research portfolios

by redirecting a significant portion of this increased investment to study healthcare spending, financing, and organization. As we discussed, funding for these research topics in the past decade has lagged behind that of the quality and patient safety agenda. As a result, we remain ill-equipped to fully understand what is driving and derailing the healthcare system and develop evidencebased solutions. A significant and more balanced investment will pay dividends in providing the essential tools to make much needed improvements in our healthcare system and stave off the “perfect storm” that threatens to drown the American economy. Until then, we’ll keep treading water. ■ For agencies’ individual health services research budgets, visit www.chsr.org to download Federal Funding for Health Services Research 2007.

References 1. Lohr KN, Steinwachs DM. Health services research: an evolving definition of the field. Health Serv Res. 2002;37:7-9. 2. Coalition for Health Services Research. Federal Funding for Health Services Research 2007. 2008. http://www.chsr.org/CoalitionFunding Report08.pdf. Accessed May 19, 2008. 3. Kohn LT, Corrigan JM, Donaldson MS, eds. To Err is Human: Building a Safer Health System. Washington, DC: National Academies Press; 2000. 4. Thorpe KE, Florence CS, Howard DH, et al. The impact of obesity in rising medical spending. Health Aff Web Exclusive; October 20, 2004. http://content.healthaffairs.org/cgi/content/abstract/hlthaff.w4.480v1. Accessed July 1, 2008. 5. Finkelstein EA, Fiebelkorn IC, Wang G. National medical spending attributable to overweight and obesity: how much, and who’s paying? Health Aff Web Exclusive; May 14, 2003. http://content.healthaffairs. org/cgi/content/abstract/hlthaff.w3.219v1. Accessed May 19, 2008. 6. Holahan J, Blumberg LJ, Weil A, et al. Roadmap to Coverage: Synthesis

of Findings. Washington, DC: Urban Institute; 2002. http://www.urban. org/url.cfm?ID=411327. Accessed May 19, 2008. 7. Medicare Payment Advisory Commission. Report to Congress: Reforming the Delivery System. 2008. http://www.medpac.gov/documents/ Jun08_EntireReport.pdf. Accessed July 1, 2008. 8. Mandelblatt J, Saha S, Teutsch S, et al. The cost-effectiveness of screening mammography beyond age 65: a systematic review for the US Preventive Services Task Force. Ann Intern Med. 2003;139:835-842. 9. Lui K, Manton KG; US Department of Health and Human Services. Effects of Medicare’s Hospital Prospective Payment System (PPS) on Disabled Medicare Beneficiaries: Final Report. 1988. http://aspe.hhs.gov/ daltcp/reports/pps.pdf. Accessed May 19, 2008. 10. Koempel ML, Schneider J, eds. Congressional Deskbook: The Practical and Comprehensive Guide to Congress. 5th ed. 2007. TheCapitol.Net. www.CongressionalDeskbook.com. Accessed May 19, 2008. 11. Streeter S. CRS Report for Congress. Continuing Resolutions: FY2008 Action and Brief Overview of Recent Practices. Congressional Research Service; 2008. http://www.rules.house.gov/Archives/RL30343.pdf. Accessed May 5, 2008. 12. Agency for Healthcare Research and Quality. AHRQ Funding Opportunities. http://www.ahrq.gov/FUND/funding.htm. Accessed May 19, 2008. 13. AcademyHealth. Historical Analysis of Ownership and Publication Rights in Government Contracts for Health Services Research. 2007. http://www.academyhealth.org/tools/2007historicalanalysis.pdf. Accessed May 19, 2008. 14. Office of Extramural Research, National Institutes of Health. Types of Grant Programs. http://grants.nih.gov/grants/funding/funding_ program.htm. Accessed May 19, 2008. 15. Office of Management and Budget. Budget of the United States Government Fiscal Year 2009. 2008. http://www.whitehouse.gov/omb/ budget/fy2009/. Accessed May 19, 2008. 16. Catlin A, Cowan C, Hartman M, et al. National health spending in 2006: a year of change for prescription drugs. Health Aff (Millwood). 2008;27:14-29. 17. Thornton C, Brown J. The Demand for Health Services Researchers in 2020. Washington, DC: AcademyHealth; 2007. http://www.academy health.org/HSR-Summit-Series/TheDemandforHealthService Researchersin2020.pdf. Accessed May 7, 2008. 18. AcademyHealth. Placement, Coordination, and Funding of Health Services Research within the Federal Government. 2005. http://chsr.org/ placementreport.pdf. Accessed May 19, 2008. 19. The Dartmouth Institute for Health Policy and Clinical Practice. The Dartmouth Atlas of Health Care. http://www.dartmouthatlas.org/. Accessed May 19, 2008. 20. AcademyHealth. AcademyHealth 2006 Member Survey. 2006. http://www.academyhealth.org/membership/membersonly.htm. Accessed May 19, 2008. 21. Ricketts TC; AcademyHealth. Developing the Health Services Research Workforce. 2007. http://www.academyhealth.org/HSRSummit-Series/DevelopingtheHealthServicesResearchWorkforce.pdf. Accessed May 7, 2008. 22. Revised Continuing Appropriations Resolution, 2007 (H. J. Res. 20); Departments of Labor, Health and Human Services, and Education, and Related Agencies Appropriations Act, 2008 (H.R. 3043, S. 1710); Consolidated Appropriations Act, 2008 (H.R. 2764). http://thomas. loc.gov/. Accessed May 19, 2008. 23. Agency for Healthcare Research and Quality. Performance Budget Submission to Department of Health and Human Services, Fiscal Year 2009. 2008. http://www.ahrq.gov/about/cj2009/cj2009.pdf. Accessed May 7, 2008. 24. Nussle J. President’s FY 2009 Budget Committee on Ways and Means, United States House of Representatives [testimony]. 2008. http://www.whitehouse.gov/omb/legislative/testimony/director/nussle_ 021308.html. Accessed May 7, 2008. 25. Nussle J. Requirements for the FY 2010 Budget Process [memorandum]. 2008. http://www.whitehouse.gov/omb/memoranda/fy2008/m08-17.pdf. Accessed May 7, 2008.

Stakeholder Perspective appears on page 42

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Stakeholder Perspective The Golden Age of Health Services Research PAYORS: Our nation’s long-term fiscal outlook is grim. Large and growing structural deficits loom over the federal government, fueled primarily by healthcare spending. The Government Accountability Office notes that these rapidly rising healthcare costs are “our nation’s number one fiscal challenge…not just to the federal government, but to American business and society as a whole.” This is bad news for our nation. But the good news may be that this fiscal crisis and a growing acceptance of its reality and immediacy will bring greater awareness of, and demand for, health services research (HSR). Peter Orszag, Director of the Congressional Budget Office, has reinvigorated interest in HSR on the national stage. Based on work pioneered by Dr Jack Wennberg, Orszag has cited geographic variations in care as evidence of inefficiency and waste in the healthcare system. He has also promoted comparative effectiveness research to move toward better care at better value. Policymakers are listening. Comparative effectiveness research has become a key policy priority for many elected officials, including presidential hopefuls. As David Obey (D-WI), chairman of the House Committee on Appropriations, recently noted, it is “penny wise and pound foolish” to continue to reduce our commitment to HSR when entitlement spending grows unchecked. HSR has been the stepchild of health research, writ large. The “search for the cure” mission of clinical research is compelling to the public and policymakers, who have funded that effort handsomely. In contrast, the potential of HSR to improve healthcare delivery and promote change has been underappreciated. In this new age of enlightenment about our nation’s worsening fiscal well-being, HSR may be on the verge of a renaissance as policymakers, payors, providers, and patients look for answers to hard questions about the availability, quality, and costs of healthcare. The intense political attention focused on comparative effectiveness research has brought new visi-

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bility to a field of scientific study that has long stood in the shadows of clinical research. There is a growing willingness to invest in evidence that will help improve the value we get for our healthcare dollar. However, as important as comparative effectiveness research could be, other areas of research can pay off in terms of improving the performance of the healthcare system. Even with better knowledge about what works for which patients, there remains the challenge of converting that knowledge into effective care that is delivered efficiently. Financing healthcare is another major challenge. HSR can help improve the functioning of the insurance market, finding ways to make affordable coverage available to everyone. POLICYMAKERS: There is a real risk that enthusiasm for comparative effectiveness research could tighten funding for other research areas that could have a more immediate payoff. There is also a real risk of overselling the promise of HSR, as scientific inquiry alone will not fix our healthcare system. Even with the best evidence, political will and public understanding are required to make the necessary, painful changes. As noted in the article, fiscal constraints and competing budget priorities mean that HSR is unlikely to see dramatic budget increases in the near-term. Still, HSR research has led to a paradigm shift in Washington. Policymakers of all political persuasions are now willing to discuss serious health reform. And they appear more open to the idea that increased investment in HSR will pay dividends in the longterm. After nearly 40 years of minimal recognition and limited funding, the Dark Age seems to have passed; the Golden Age is upon HSR. Joseph R. Antos, PhD Wilson H. Taylor Scholar in Healthcare and Retirement Policy American Enterprise Institute

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ISPOR PRIMER

The International Society for Pharmacoeconomics and Outcomes Research: Implications for Decision Makers in Healthcare By Gordon M. Cummins, MS

he day-to-day impact of the economy is felt in all sectors today, with each section reevaluating the best cost-efficiencies for their respective areas. Decision makers in healthcare are facing similar issues: limited budget and increased spending. The International Society for Pharmacoeconomics and Outcomes Research (ISPOR) is the one organization that tries to assist decision makers in healthcare through the application and promotion of pharmacoeconomics and outcomes research—the scientific discipline that evaluates the effect of healthcare interventions on patient well-being, including clinical outcomes, economic outcomes, and patient-reported outcomes. ISPOR facilitates the translation of this research into useful information that can be used by decision makers, in the attempt to ensure that society allocates scarce healthcare resources wisely, fairly, and efficiently. ISPOR serves the public in the following ways: • Provides a forum to facilitate the interchange of scientific knowledge in pharmacoeconomics and patient outcomes • Facilitates and encourages communication in all sectors of society by educating public and private agencies on the utility of research in pharmacoeconomics and in assessing patient outcomes • Acts as a resource for forming public policy relevant to the pharmacoeconomics and healthcare outcomes assessment • Promotes the science of pharmacoeconomics by providing services to advance pharmacoeconomic, outcomes research, and educational activities • Represents the science of pharmacoeconomics and outcomes assessment before public and governmental bodies by: • Making available the results of pharmacoeconomics analyses and healthcare outcomes studies concerning important healthcare interventions • Developing scientifically based input (evidence) for public policy decisions for these areas • Providing evidence and data to governmental bodies and other public entities • Promotes individual achievement and growth in the

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field of pharmacoeconomics and outcomes research. In May 2008, ISPOR gathered in Toronto for its 13th annual international meeting to present research results across multiple therapeutic areas. Two common themes permeated the meeting—(1) the importance and measurement of compliance/adherence/persistence and (2) the structure and impact of health technology assessment (HTA). The following topics presented at the meeting highlight different aspects of these 2 themes.

ISPOR is the one organization that tries to assist decision makers in healthcare through the application and promotion of pharmacoeconomics and outcomes research.

An Integrated Pilot Project Utilizing an Internal HTA Process to Set Medical and Payment Policy in a US Commercial Health Plan, presented by John Watkins and colleagues, from Premera Blue Cross, provided an example of how to implement a rigorous, flexible integrated internal process for HTA support for formulary decisions, medical policy development, and payment policy development. Potential benefits of the plan include rapid response to emerging technologies, coordination among internal policy decision makers, and process credibility with the medical community. Premera Blue Cross is a commercial, preferred provider organization health plan with 1.7 million members representing 1.2 million pharmacy lives across 4 states— Washington, Alaska, Oregon, and Arizona. Their project was initiated in the fall of 2005 and is still ongoing. The strategic phase included the development of an internal HTA process; cost-effectiveness analyses; development of or a proactive pipeline surveillance process that integrates all internal stakeholders; clinical review panel consisting of outside experts;

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and integration with existing formulary, actuarial, medical policy, and payment policy processes. The implementation phase includes the development of business cases from pilot project results, using existing resources—staff, Pharmacy & Therapeutics (P&T) Committee members used as an expert clinical review panel—conducting a series of HTA reviews, and selecting technologies that demonstrate various aspects of the review process. A total of 8 new diagnostic and therapeutic technologies were reviewed: • Diagnostic imaging: computer-assisted breast magnetic resonance imaging (MRI); upright MRI • Genetic diagnostics: oncotype diagnosis; Trofile • Other diagnostics: long-term, continuous glucose monitoring • Robotic surgery: robot-assisted laparoscopic prostatectomy • Image-guided radiotherapy: Calypso 4D system; Cyberknife In evaluating the Cyberknife, they looked for evidence for safe and effective extracranial use, as well as published economic evidence. Only small, prospective or retrospective studies were available, with no blinded, randomized clinical trials (because of ethical and logistic reasons). Published studies included patients with liver, lung, renal, or prostate cancers. Findings included severe toxicities or death associated with image-guided radiotherapy; the maximal tolerated radiation dose was not clearly defined. Implementation decisions included coverage for inoperable spinal tumors and refractory tumors. Mr Watkins and colleagues concluded that the overall strength of evidence was poor—the US Food and Drug Administration (FDA) requires only evidence of analytic validity—and they could not demonstrate the cost-effectiveness or identify target populations that would benefit most from this technology. Problems included payor’s complex internal structures with many stakeholders, coding issues that complicated enforcement of decisions, and providers having mixed financial incentives. Additional elements needed to support HTA include better evidence, aligning requirements for registration and payors, dialogue with providers before they buy expensive equipment, and improved Healthcare Common Procedure Coding System and Current Procedural Terminology coding systems and coding accuracy. HTA Trends in the United States, by Sean Tunis, MD, MSc, and colleagues, highlighted recent trends related to HTA, including a backdrop for value-based

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benefit design and evidence development, role of costs and cost-effectiveness analyses, critical knowledge gaps, Medicare coverage with evidence development and its challenges, international classification of diseases registry, and effectiveness guidance documents. A working definition of HTA was developed in 2001, although costs were not initially considered in defining adequate evidence. No statute or regulations address the role of economic factors in the reimbursement process. The Centers for Medicare & Medicaid Services does not explicitly consider costs, whereas payors consider evidence more carefully for higher-cost items. Most of the critical evidence is currently provided by groups such as the National Institutes of Health, the FDA, the Agency for Health Research and Quality, BlueCross association, and Cochrane reviews; decision makers have minimal influence on what evidence is evaluated or developed. Developing and Maintaining a Formulary in a Medicare Plan, by David Yoder, PharmD, MBA, and colleagues, studied the formulary process, including committee development and constraints, monograph presentation, internal resources to support needed activities, and decision criteria. Dr Yoder and colleagues concluded that the smaller the plan, the more demands are placed on the P&T Committee. They found that formulary positioning is very variable between plans, and formularies can be a differentiating factor between plans, which may attract or discourage people from joining a plan. Their findings confirmed that member choice is very important for most plan designs, when building a formulary. Differential Take-Up of the Medicare Part D Prescription Drug Benefit, by G. Caleb Alexander, MD, MS, and colleagues, provided data associated with uptake metrics for Medicare Part D beneficiaries that included a 10% increase in insurance generosity, with a 16% lower likelihood of Part D utilization. The researchers found that 1 standard deviation increase in comorbid disease score translated into 8% greater likelihood of Part D utilization. The results also show that utilization of new insurance is seldom uniform. These results may help inform Part D welfare analyses; estimates are important for assessing Medicare Part D’s impact on processes or outcomes of care. The findings are important to continuing public financing and long-term viability of the program. ■

WEB EXCLUSIVE www.AHDBonline.com Impact of Depression on Absenteeism and Bed Days in Patients with Chronic Disorders

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ISPOR HIGHLIGHTS

Select Topics from ISPOR, May 2008 By Rosemary Frei, MSc

Testing for Diabetes Reduces Healthcare Costs Based on a presentation by Judy Y. Chen, MD, MSHS, and Josh Marehbian, MPH. Dr Chen is Director of Research and Clinical Development, and Mr Marehbian is a consulting manager, Health Benchmarks/IMS Health, Woodland Hills, CA.

team of researchers has created a decision-tree analysis of a pay-for-performance (P4P) program in diabetes care that yields a savings of $25 per patient over 2 years. The total savings for the 25,605 patients from an administrative claims database who were used in the analysis was more than $765,000. The decision-tree model was created by a team at Health Benchmarks, IMS Health, Woodland Hills, California. The model was based on 4 decision points for each diabetic patient, considering the following questions: 1. Was the patient’s health plan using a P4P program? 2. Was the patient’s physician participating in the program? 3. Did the patient receive at least 2 glycosylated hemoglobin (HbA1C) tests and 1 lipid test yearly? 4. Did the patient have to be hospitalized because of complications from the diabetes? The team calculated the probabilities for each of the 2 possible outcomes at each decision point based on data from 25,605 individuals whose healthcare provision was administered by a preferred provider organization in Hawaii between March 31, 2003, and April 21, 2005. The baseline characteristics were similar in patients who were cared for by physicians participating in a P4P

program and those who were not. There was a 91% probability of each patient seeing only program-participating physicians in 2003. Investigators also found, based on multivariate regression analyses, that patients who saw only program-participating physicians had a 61.5% chance of being tested for HbA1C and lipids, whereas those who saw nonparticipating physicians had a 52.7% of receiving the quality care (P <.01). Individuals who received HbA1C and lipid testing had a 31.1% chance of being hospitalized in the subsequent 2 years compared with a 38.8% chance for those who did not. The difference in cost per patient was $2641 versus $2665, respectively, which yielded a total savings of more than $675,000 to the health plan over the 2 years. “We compared the hospitalization rates of diabetic patients who received at least the minimum number of sugar or cholesterol tests recommended by the American Diabetes Association for diabetes patients to those of patients who did not receive the minimum number. Testing is the first step to ensuring that patients have the appropriate blood sugar and cholesterol levels,” noted Judy Y. Chen, MD, MSHS. “And in our analyses, we found that appropriate testing is consistently associated with less hospitalization, and hence with lower healthcare costs.”

Cost-Analysis of Bortezomib Use at M.D. Anderson Cancer Center Based on a presentation by Lincy Lal, PharmD, PhD, and Dwight Kloth, PharmD. Dr Lal is a pharmacoeconomic research specialist, Drug Use Policy and Pharmacoeconomics, M.D. Anderson Cancer Center, Houston, TX, and Dr Kloth is Director of Pharmacy, Fox Chase Cancer Center, Philadelphia, PA.

University of Texas M.D. Anderson Cancer Center analysis of 1 year of bortezomib (Velcade, Millennium Pharmaceuticals) use revealed that the hospital staff treated nearly 6 times as many patients with the monoclonal antibody as they had expected, and spent nearly 3 times as much money as they had planned. The overall reimbursement-to-charge ratio was 53%, slightly lower than the projected 55% ratio. Bortezomib is only the second medication on which

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the team has performed a full budget-impact analysis. The US Food and Drug Administration approved this protease inhibitor in 2003 for the treatment of multiple myeloma in patients who have failed 2 previous drug trials and for mantle-cell lymphoma in 2006. The investigators performed an initial budget analysis in 2003 based on the number of patients they estimated would be given bortezomib. The Pharmacy & Therapeutics Committee at the hospital subsequently

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ISPOR HIGHLIGHTS

added bortezomib to the formulary for the thenapproved indication, noting that physicians should use their clinical discretion for off-label use. A postapproval budget-impact analysis was subsequently performed based on the number of patients treated outside of clinical trials between June 2006 and May 2007. “These analyses did not affect the committee’s decision—we felt it was necessary to add bortezomib to the formulary because all chemotherapy products that show efficacy are included in our formulary, regardless of budget impact,” said coinvestigator Lincy Lal, PharmD, PhD. “This is a difference from other countries, such as the UK, where NICE [National Institute for Health and Clinical Excellence] makes decisions based on both efficacy and cost considerations. However, we are taking the initial steps in including this information in our discussions in the formulary management process.” The M.D. Anderson team had estimated that the hospital would treat 25 patients annually, for a total purchase cost of $414,974 after adjustment to 2007 dol-

lars. However, in the study year, 140 patients were treated at the hospital with bortezomib at a cost of $8,676, for a total cost of $1,214,640. Overall, the reimbursement to charge ratio was 53.3%. Furthermore, 87% of the use (122/140) was for multiple myeloma, and patients received an average of 2 cycles of treatment rather than the 4 cycles recommended by the manufacturer. Dwight Kloth, PharmD, commented that although M.D. Anderson does not yet include cost in its decisions, it is farther along this path than most other centers in the United States. “I applaud M.D. Anderson’s rigorous approach to doing these analyses, because they provide valuable data for the rest of us,” said Dr Kloth. “We don’t have the resources—that is, a pharmacoeconomics study group—to conduct such thorough analyses. In general, what my institution is going to continue to do is follow the available evidence as it evolves, but with an eye on the cost to the healthcare system and to the patients in terms of copays.”

Repeat Testing Needed to Estimate US Health Expenditures Based on a presentation by Aniket Kawatkar, MS, BPharm, and Michael Nichol, PhD. Mr Kawatkar is a MERCK and QSAD Centurion Fellow, and Dr Nichol is QSAD Centurion Professor in Pharmaceutical Sciences and professor of clinical pharmacy, Department of Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, Los Angeles.

ot all econometric models are created equal when it comes to estimating the costs to the American economy of serious medical conditions. A new study shows clear differences between some of the most frequently used econometric models. Aniket Kawatkar, MS, BPharm, and Michael Nichol, PhD, compared the performance of 11 different models in estimating the total direct medical expenditures associated with 7 common and costly diseases—diabetes, arthritis, cardiac disease, asthma, hypertension, stroke, and emphysema. The models included the ordinary least squares (OLS) on logtransformed and raw-scale expenditure, the generalized linear model with log link and 2-part versions of these models. Each model performed better or worse than the others in the tests the investigators subjected them to. “People ignore these considerations and say, ‘Model X is the most popular model in the literature, so that’s the one I’ll use,’” Mr Kawatkar said. “But none of these models dominates the others, so you’ve got to be careful in picking the model to use. You have to go through a series of tests to determine which model is the best

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one for your particular application.” The research team ran each of the models through 4 standard tests for robustness, and each model failed at least 1 of the tests. They then determined how each model dealt with problems, such as skewed distribution of expenditure among the population and people with either zero or very high expenditures. They found that while, for example, the OLS can deal with skewed distribution to some extent, it is not designed to deal with the high proportion of people with zero expenditures, something that is frequently encountered in costdata distribution. “The strong influence of model choice on the total medical expenditure estimate underscores the importance of understanding the data-generation procedure before selection of the appropriate estimator,” concluded Mr Kawatkar. ■

WEB EXCLUSIVE www.AHDBonline.com FDA Increases Efforts to Scrutinize Drug Risks and Benefits

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ISPOR PRIMER

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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EXECUTIVE SUMMARIES

Wayward Prescriptions: Costs of Fraud in Payor Plans By Thomas Kaye, RPh, MBA

One aspect that does not often enter the discussion on the rising costs of medical products is their increased value for perpetrators and their potential for abuse by different elements inside and outside of the healthcare system. Mr Thomas Kaye, senior pharmacy director of Passport Health Plan, a Medicaid managed program, has first-hand understanding of the problem and its potential for harm to payors and patients alike. His article sheds light on the extent of fraud and abuse associated with prescription drugs, which is costing payors millions of dollars each year and can cost patients their privacy, identity, and health benefits. Mr Kaye describes profiteering schemes using illicit deals for financial gains by exploiting what was once perceived as sacred areas of medical care. An unexpected consequence of the easily accessible electronic databases is

their vulnerability to being compromised by illegitimate users, making members’ personal health information, personal identification, and therapy history open to abuse and exploitation. Mr Kaye cites numerous reports of fraud in our medical services, including a recent survey of physicians, many of whom admit to “gaming” the system for what they perceived to be the benefit of their patients, as well as documented cases of fraudulent billings and diversion of provider reimbursements. Mr Kaye, however, does not stop at describing the situation. Drawing on his professional experience, he outlines practical steps payors can take to prevent such cases of fraud, including the simple recommendation to provide an explanation of benefits to all members after any prescription encounter, which can greatly reduce prescription-dispensing fraud.

Prescribing Warfarin Appropriately to Meet Patient Safety Goals By Lekshmi Dharmarajan, MD, FACP, FACC; T.S. Dharmarajan, MD, FACP, AGSF

In this timely discussion of warfarin, Drs L. and T.S. Dharmarajan highlight the importance of close monitoring of the international normalized ratio (INR) to prevent the common but preventable side effect of life-threatening bleeding. Because of inappropriate use and common misunderstandings of this medication, including its many drug and nutrient interactions, the rise in its use has been accompanied by an increased prevalence of bleeding events, which prompted the US Food and Drug Administration (FDA) in 2007 to add a “black box” warning to the label. Nevertheless, these 2 experts say, for every bleeding event in patients using this medication, many more stroke events are prevented, a fact that eludes many

prescribers. Yet careful monitoring of the INR and initiating therapy with a low dose can ensure safe use of this drug in all patients, including the elderly. The importance of the initial dose was emphasized last year by the FDA’s revision of the prescribing information, calling for genetic testing before prescribing warfarin. The FDA noted that genetic differences can influence how people respond to the drug, and this labeling change can prevent physicians from using a too-high initial dose, thus reducing the risk for bleeding. Most health plans still do not cover genetic testing for this purpose, but new, accumulating evidence for the benefits of genetic testing may eventually force health plans to reconsider their reimbursement policies.

Treading Water: The No-Growth Investment in HSR By Emily J. Holubowich, MPP; Joseph R. Antos, PhD

A perfect storm is brewing in the nation’s healthcare system, say Ms Emily J. Holubowich, director of government relations, Coalition for Health Services Research, and Dr Joseph R. Antos, Wilson H. Taylor Scholar in Health Care and Retirement Policy, American Enterprise Institute. One federal sector that is designated to identifying best available treatments and how best to control healthcare spending is health services research (HSR); nevertheless, funding for HSR has been consistently reduced in the past 5 years, thus potentially impeding the efforts to find solutions that could lead to greater

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efficiency of the healthcare system as a whole. For example, the push toward prevention as the best approach to patient care came from HSR, which demonstrated that preventive services can substantially reduce mortality and morbidity and, in turn, reduce overall costs. However, the current focus in federal funding is on improving the quality of care, and relatively little funding is provided to study what is driving healthcare costs, which is crucial to our understanding of how to reduce waste, improve efficiency of the delivery of care, and in turn improve the quality of care, while reducing costs. ■

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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)

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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.

Printed in U.S.A.

(10/07)

MC48828