March 2008, Vol 1, No 2 by Dalia Buffery

THE PEER-REVIEWED STAKEHOLDERS’ FORUM FOR DRUG BENEFIT DESIGN™ MARCH 2008

VOLUME 1, NUMBER 2

EDITORIAL

Risk Factors, Subjectivity, and Truth in Healthcare Robert Emmett Henry

Stop the War on Drugs Scott Gottlieb, MD REGULATORY

™

Patent Reform Proposals Raise the Stakes for Researchers, Manufacturers of Biologics Shayna B. Kravetz, BSc, Rosemary Frei, MSc BUSINESS

The Value of Biologics Gary M. Owens, MD CLINICAL

When Novelty Is Not Enough Michael F. Murphy, MD, PhD

Asthma—The National Surveillance Data and the National Asthma Education and Prevention Program’s Expert Panel Report 3 Thomas McCarter, MD, FACP COLUMNS

- FDA Watch - Industry Trends

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)

Printed in U.S.A.

(10/07)

MC48827

More than 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.

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(10/07)

MC48828

MARCH 2008

VOLUME 1, NUMBER 2

™

EDITORIAL

Risk Factors, Subjectivity, and Truth in Healthcare Robert Emmett Henry

Publisher Nicholas Englezos

Stop the War on Drugs

Associate Publisher Maurice Nogueira

Scott Gottlieb, MD

Editorial Director Dalia Buffery Managing Editor Sandy Paton

REGULATORY

Patent Reform Proposals Raise the Stakes for Researchers, Manufacturers of Biologics Shayna B. Kravetz, BSc, Rosemary Frei, MSc

Production Manager Alaina Pede Director of Human Resources Blanche Marchitto President Brian F. Tyburski

BUSINESS

Editor-in-Chief Robert Emmett Henry

The Value of Biologics Gary M. Owens, MD

Mission Statement

CLINICAL

When Novelty Is Not Enough Michael F. Murphy, MD, PhD

Asthma—The National Surveillance Data and the National Asthma Education and Prevention Program’s Expert Panel Report 3 Thomas McCarter, MD, FACP

Continued on page 4

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. Drug benefit designs are greatly affected by numerous clinical, business, and policy conditions. This publication will provide drug benefit decision-makers the integrated industry information they require to devise formularies and drug benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For reprints and subscription information and editorial queries, please contact: Robert Henry - rhenry@AHDBonline.com For advertising inquiries, please contact: Nick Englezos - nick@engagehc.com Maurice Nogueira - maurice@engagehc.com Brian Tyburski - brian@engagehc.com

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March 2008

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ÂŠ2008 Abbott Laboratories Abbott Park, IL 60064 306-78502 March 2008 Printed in U.S.A.

MARCH 2008

VOLUME 1, NUMBER 2

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COLUMNS

Unmanaged Moment: Cartoon

Clinical Editor Thomas McCarter, MD, FACP Chief Medical Officer Main Line Health tmccarter@AHDBonline.com

Business/Government Editor

Information for Authors

Executive Summaries

Unmanaged Moment: Cartoon

Kip Piper, MA, CHE President Health Results Group kpiper@AHDBonline.com

Editorial Board

Pharmacy Reimbursement Policy Michael R. Schaffer, PharmD, MBA

FDA Watch Mark Senak, JD

Employers F. Randy Vogenberg, RPh, PhD

Industry Trends

Specialty Pharmacy Rebecca M. Shanahan, Esq. Managed Care Pharmacy Policy Cynthia J. Pigg, RPh, MHA

For editorial queries and submissions, please contact rhenry@AHDBonline.com.

Managed Markets Marketing Jeffrey A. Bourret, RPh, MS, FASHP Charles E. Collins, Jr., MS, MBA Clinical Research: Hypertension and Preventive Cardiology Michael A. Weber, MD Managed Care and Government Affairs Sharad Mansukani, MD Research & Development Michael F. Murphy, MD, PhD Wayne A. Rosenkrans, Jr., PhD Healthcare Outcomes Gary M. Owens, MD

Editorial correspondence should be addressed to Editor-in-Chief, American Health & Drug Benefits, PO Box 432, Long Valley, NJ 07853. E-mail: editorial@AHDBonline.com. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, PO Box 432, Long Valley, NJ 07853. Fax: 732-656-7938. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Engage Healthcare Communications LLC, PO Box 432, Long Valley, NJ 07853. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editor-in-Chief, 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 manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. Please convey any errors to the Editor-in-Chief. ISSN# applied for January 2008. American Health & Drug Benefits is published 9 times a year by Engage Healthcare Communications, LLC, PO Box 432, Long Valley, NJ 07853. Telephone: 732-656-7935. Fax: 732-656-7938. Copyright © 2008 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Stakeholders’ Forum for Drug 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.

AMERICAN HEALTH & DRUG BENEFITS

March 2008

Outcomes Research Gordon M. Cummins, MS Timothy S. Regan, BPharm, RPh Pharmacy & Specialty Products James T. Kenney, RPh, MBA Policy & Public Health Alex Hathaway, MD, MPH, FACPM Actuary David Williams Medical Research Nirav R. Shah, MD

LETTER FROM THE EDITOR

Risk Factors, Subjectivity, and Truth in Healthcare

n a small, intimate room in a tired old mansion serving as a Connecticut prep school in 1966, a gentle giant of learning listened intently to a youth in his class extol Ayn Rand’s theory of Objectivism. It was English class, and Joseph T. Sunega, known time out of mind to the student body as Sunny Joe for his bright eyes drooping at half mast in a perpetual Celtic half dream, dropped a quiet bombshell on the boy and the class. Usually warm and encouraging of students’ ideas, he demonstrated rare form in his dismissal of the author’s philosophical premise: “Truth is not objective,” he stated, “it is subjective.” The young devotee of Ayn Rand, flush with the enthusiasm that attends discovering “The Anthem” and “The Fountainhead,” stood stunned at this unvarnished didactic move. How did he know with such quiet assurance that truth was subjective at its core? Here was a radical proposition indeed. The thought was left on its own, no elaboration offered, to reverberate in the heads of all present. And like all great teachers, he knew that explanation had to come from the subsequent life experiences of those he was teaching that day. Years later, in a small, intimate board room in the New York Academy of Science, a professor of another intellectual discipline repeated the lesson, albeit in different terms and involving different applications. It was John Laragh, co-discoverer of the renin-angiotensin-aldosterone system. He, Michael Weber, and Joel Neutel had called a press conference to criticize the JNC VI guidelines on hypertension. Preceding the critique was an exposition by Dr. Neutel on cardiovascular risk factors. Then came the punch line from Dr. Laragh: “Risk factors are a measure of our ignorance, not our knowledge.” He explained that if we actually knew what was causing the patient’s disease, we would treat that single cause and not multiple risk factors, essentially hedging our bets in the best interests of the patient. But we do rely on risk factors, because we need to. They are often all we know about that patient, and to protect him we must cover all potential bases. The upshot of this is where it gets really interesting. Because we lack a true knowledge of the disease process in each individual patient, he proposed, we must not take the parochial approach of restricting physician

practice to just the official guidelines. Other clinical strategies hold promise, he stated, and the simultaneous pursuit of multiple strategies, even those not fully supported by a robust evidentiary base, is good for medicine. On the other hand, slapping physicians on the wrist for straying from official guidelines will ensure clinical atrophy and an end to scientific discovery. Guidelines, in short, should remain guidelines, not demands for conformity. Enter managed care, value-based benefit designs, evidence-based medicine, comparative effectiveness research, step therapy, copay incentives, pay-for-performance, and a legion of cost-management techniques “assisting” physicians—or is that just payors and purchasers?—in their unending quest for best practices. Enter too population-based research and its arch rival— or is that its perfect complement?—personalized medicine. What’s a payor, or a physician, to do? How do the multiple stakeholders to the process of care dance around the inherently subjective aspect of patient care—where the individual clinician must take into account the massive body of population-based (objective) research data and then subject it to personalized (subjective) application for each individual patient? There are genuine pressures aplenty impelling the healthcare community to adopt inflexible, absolute compliance with guidelines. But de facto patient care answers remain elusive and subjective, requiring, inconveniently, the art of the physician as healer—and let no one pretend that committees ever heal anyone. It is the individual provider who performs this service, no matter how sophisticated the evidence-based medicine techniques are devised. Individual discretion therefore fights with the real need for oversight and compliance with evidentiary standards. It is a good fight and defies oversimplification. The excellent paradox is that objective, scientific knowledge must continue to inform the subjective application of same in the best practice of medicine. So, may the healthcare debate continue in good faith between the exponents of objective evidencebased medicine and the healer practicing personalized medicine. Hopefully objectivity is the servant of the healer, not its master. The answers will ever evade total

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LETTER FROM THE EDITOR

codification, and this is perhaps the greatest challenge to healthcare as it undergoes its transformation to a value-based system. To remain true to its mission, healthcare must guide facts with subjective insight, giving essential latitude to practitioners even while educating them on the massive objective body of data that informs them on risk factors—often all we will ever know about a disease and its propensity to strike down the vulnerable human host, whom all stakeholders are desperately trying to save. It is, in the final analysis, unique individuals we love whom we seek to cure, and their inestimable worth makes the struggle to reconcile the objective and the subjective quite worth the effort.

To both of these professors, and to my beloved brother who recently fell before the onslaught of his own risk factors, I dedicate this small footnote to the passionate pursuit of the truth of medical excellence.

Robert Emmett Henry Editor-in-Chief For editorial queries and submissions, please contact rhenry@AHDBonline.com.

Unmanaged Moment

Call for Papers The editors of American Health & Drug Benefits™ (AHDB) are pleased to invite readers to submit articles for publication on topics examining advances in clinical, business, and regulatory developments relevant to attaining value—a balance of cost, quality, and access—in formulary and benefit design strategies. AHDB offers an open forum for all healthcare stakeholders to present their needs, initiatives, and data, with the goal of aligning stakeholder incentives in the development of patient-centered health and drug benefits that meet the needs of all stakeholders—patients, providers, payors, purchasers, distributors, regulatory, manufacturers, evaluators, and researchers. Articles should aim to identify key issues that can improve the quality and efficiency of our healthcare delivery system in general and of formulary and drug benefit design strategies in particular. All papers will undergo a peer-review process, and authors will be notified of any changes needed before articles can be accepted for publication. Please submit your article electronically to editorial @AHDBonline.com, or mail to AHDB, PO Box 423, Long Valley, NJ 07853. For complete information on how to submit articles, see Information for Authors, page 12.

AMERICAN HEALTH & DRUG BENEFITS

March 2008

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MANAGING HEALTHCARE COSTS THROUGH TECHNOLOGY

GUEST EDITORIAL

Stop the War on Drugs Scott Gottlieb, MD

n December 2005, Eli Lilly & Co. pled guilty to a criminal indictment from the Bush Justice Department and paid $36 million in fines and “disgorgement” of its ill-gotten gains. The company’s crime was mounting a concerted effort to inform doctors that, according to leading medical authorities, the firm’s estrogen-modulating drug Evista substantially reduced the risk of invasive breast cancer in postmenopausal women. The finding came from a series of landmark national studies, some eventually touted by government research. So why the criminal charge? At the time Eli Lilly was conveying the cancer information to doctors, the U.S. Food and Drug Administration (FDA) had approved Evista for treating osteoporosis, not preventing cancer. Only this past September—8 years after the first significant cancer prevention results were published—did the FDA approve Evista for use against breast cancer, turning Eli Lilly’s speech “crime,” by some measures, into a public service. For patients and doctors who rely on the latest clinical information to make hard decisions, no relevant scientific discovery took place between the medical findings, the legal prosecution, and the FDA’s approval of those same results. In fast-moving fields like cancer, where doctors tailor treatments based on evidence that’s constantly evolving, 2 years can be an eternity of waiting to learn about important science. For some patients, that interval can be fatal. At issue is what’s referred to as “off-label promotion”—allegations that drug companies “encourage” doctors to use medicines for purposes not yet approved by the FDA. These charges are applied even when the information drug firms are sharing is part of educational

Dr. Gottlieb, a practicing physician and resident fellow at the American Enterprise Institute, was deputy commissioner of the FDA from 2005 to 2007. Reprinted with permission from The Wall Street Journal, December 17, 2007, © Dow Jones & Company. All rights reserved.

AMERICAN HEALTH & DRUG BENEFITS

March 2008

meetings, peer-reviewed journal articles, or treatment guidelines issued by medical-specialty societies and government researchers. The prosecutions are aimed at recouping federal money. The argument is that the medical community is goaded by the drug companies into filing “false claims” with the government, where hospitals and health plans charge Medicare and Medicaid for drugs used for unapproved indications. Drug firms tend to settle these cases. Firms have good reason to cut a deal: If they fight and lose in court, they can be banned from doing any business with government programs like Medicare. At one time, prosecutions were aimed at a handful of bad actors who encouraged prescriptions for purposes far outside popular medical practice. But like a lot of government efforts, the scope of these prosecutions expanded to encompass a much broader slice of medical activity. The Justice Department rarely alleges in these cases that the scientific information is false or misleading, only that a firm can be “ahead of the science” in sharing with doctors information about emerging uses of medicines, even when those new uses quickly become the mainstay of care. Underlying this, of course, is a nagging presumption that doctors can’t be trusted to weigh for themselves this sort of medical information, and thus need the FDA’s supervision. This might be more tolerable in a world where the FDA rapidly adjudicates study results to decide what belongs in and out of drug labels. In reality, the FDA reserves 10 months to consider supplemental uses for marketed drugs, and the entire process usually is much longer. In many cases, doctors don’t easily learn about these new drug uses, or get targeted education on prescribing, without the role of the drug firm that is the only deep-pocketed actor with an incentive to share this kind of information. The Philadelphia U.S. Attorney’s Office has waged a multiyear investigation into the biotech company Genentech. They are alleging that meetings the company sponsored for oncologists in the 1990s were ille-

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gal—because Genentech shared information about unapproved uses for its drug Rituxan, used largely in the treatment of lymphoma. Never mind that the forms of lymphoma for which Rituxan was to be used were largely fatal, that some of those uses are now approved by the FDA, or that the education was based on findings from large studies, including one supported by the government. In fact, if you queried the National Cancer Institute’s Website—even at the time when Genentech allegedly engaged in the illegal educational activity—for advice on the best treatments for some of these same forms of lymphoma, the search returned “Rituxan.” “Off label” are now dirty words in conventional lexicon, made synonymous with lawbreaking as a result of these prosecutions, even though these words describe the way more than half of cancer medicine is practiced. It is true that some off-label drug use is based on very unsettled science and has more risks. But medicine— and not just cancer care—involves lots of hard choices. And the more serious the disorder, often the more likely it is that for every right and wrong treatment choice there are many other practical decisions painted in shades of gray. Efforts to confine patients and doctors to FDA-approved uses have their own health consequences, raising the question: Just who is in the best position to make these hard choices? The travails of another Genentech drug, the breastcancer medicine Herceptin, demonstrate the health consequences of these prosecutions. Herceptin was widely used in advanced breast cancers for years, and recently it was found to cut recurrence by about half in some patients with earlier-stage tumors. The results were first published early in 2005, and the new use was approved by the FDA in late 2006. The wider use of Herceptin will save lives, but doctors didn’t embrace it right away. Herceptin prescriptions spiked when the study was first published in the New England Journal of Medicine, only to tail off before spiking again at the time of FDA approval. Those early adopters were probably familiar with the drug and the findings, perhaps through practicing in busy academic centers. Some of the late adopters might have been reluctant to take up the new use without the benefit of targeted education. You can bet that folks at Genentech, living under the thumb of the Philadelphia U.S. attorney, weren’t about to talk up the landmark findings. The use of Herceptin in early-stage breast cancers was roughly half what you’d expect for the almost 2 years between publication of the study’s findings and the FDA nod. It’s hard to deny that some of those

AMERICAN HEALTH & DRUG BENEFITS

March 2008

Herceptin-eligible women who didn’t get the drug are now unnecessarily doomed. Attorney General Michael Mukasey could add to the staff manual for his attorneys a requirement that they merely check with a public health authority like the National Institutes of Health to see if a certain “offlabel” use falls within the scope of appropriate medical care before waging a legal war. Even that may be a hard sell in Washington, where prosecutions are pursued on the basis of how much money they can recoup. This month Rep. Henry Waxman took umbrage at a copy of a draft FDA guidance (he leaked it himself) saying that, as a public health matter, the FDA found it appropriate for drug firms to share study reprints from peer-reviewed medical journals. Drug firms are persona non grata in Washington, a result of the industry’s own excesses, but also of a lot of political targeting. The result is an anything-that-bashes-pharma goes mentality in policy-making. Politicians wage broad wars on medicine to claim thin strips of ideological terrain. This would be good political theater if there weren’t so many human victims.

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Patent Reform Proposals Raise the Stakes for Researchers, Manufacturers of Biologics Shayna B. Kravetz, BSc Rosemary Frei, MSc

When the founding fathers provided for patents in the American Constitution, they could hardly have envisioned the 21stcentury demands the U.S. Patents and Trademarks Office (PTO) face today. The PTO is an institution that is, by definition, concerned with the new—one essential element of a patent is novelty; however, it is also struggling to fit the needs of modern biotech research and development within a framework conceived by the young American government in the 18th century. In their new book Biotechnology and the Patent System (AEI Press, Washington, DC, 2007), Claude Barfield, PhD, and John Calfee, PhD, both Resident Scholars at the American Enterprise Institute, Washington, DC, discuss reforms being considered by legislators, lawyers, and members of the biotechnology industry that could modernize the patent system and make it work for all the stakeholders. The proposed reforms include changing the way patent applications are filed and pursued, limiting encumbrances that slow the application process, providing more funding to the PTO to speed consideration of applications, granting interested parties the right to intervene while a patent application is being considered, and limiting the administrative and economic burdens associated with the mushrooming numbers of patents for each product or process.

he goal of changing the way patent in the timing of patent applications. On applications are filed and pursued is one hand, companies can benefit from filto stop the frenetic dance that ing for and obtaining patents as soon as companies must perform to maximize the they have produced some evidence of a disperiod of patent protection. covery’s utility and novelty, because start-up The first part of the dance has to do with financing frequently relies on patents for laying the claim to originality. Currently, collateral. On the other hand, the period of the claim of originality is awarded by exampatent protection is fixed at 20 years from iners who investigate which applicant actuthe date the patent application is filed— ally invented the product first. Many stakeregardless of when the patent is granted— holders would like this time-consuming and and biologics, unlike most other patentable Rosemary Frei, MSc difficult process to be replaced by a system products, face substantial postapplication in which the claim of originality is simply conferred research and development delays. Safety and effectiveupon whoever reaches the patent office and files the ness studies, for example, are required to gain regulatoapplication first. Detractors observe that the proposed ry clearances from the U.S. Food and Drug Adminisrule would increase the likelihood of “a race to the tration. Thus discoverers who file for patents later in patent office” that could result in the true inventor losthe R&D process are more likely to enjoy longer periing out; however, Drs. Barfield and Calfee report that ods during which they can market their product or many members of the business and legal communities process rather than having to watch the months and believe it would eliminate the ambiguity associated years roll by while they complete the required studies. with having to establish an event that may be associatOn the third hand, applicants who file later face an ed with little objective evidence. increased risk that others may preempt their claim of The second part of the dance relates to a catch-22 novelty by filing for the same patents.

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An even worse dilemma of timing can arise in another way. One of the prerequisites for obtaining a patent is proof of utility, or usefulness. But obtaining proof that a biologic does something useful can take years. The result, as Dr. Calfee notes, can be a situation in which the company can neither go forward nor retreat.

Continuations were created to allow patent protection to be extended to developments that were conceived by the discoverers after they had filed their patent application.

“If you don’t have a patent, you may not [be able to obtain the financing to] get any research done—but you may not be able to find [evidence of] utility to establish your right to a patent until you get the research done,” he said.

The Never-ending Story—Continuations To introduce a step they hope will sweep their patent-office dance partners off their feet, some applicants use continuations. These are applications filed with the U.S. Patents and Trademarks Office (PTO) that essentially reset the clock that counts down the 20-year window of patent protection. The clock normally starts when an application is filed. But to the delight of many patent lawyers, the current law also stipulates that the beginning of the 20-year period of patent protection moves forward to the day a continuation is filed. Continuations can be filed even after the original application has been rejected by a patent examiner. There also is no limit to the number of continuations that may be filed. Originally, continuations were created to allow patent protection to be extended to developments that were conceived by the discoverers after they had filed their patent application. It may sound good on paper, but with the current proliferation of continuations— fully 36% of all applications to the PTO in fiscal year 2005 were continuations—some experts believe they are now used primarily to cheat. In their paper, “Ending Abuse of Patent Continuations” (BU L Rev 2004; 84:63-111, available online at http://www.researchon innovation.org/quillen/lemleymoore.pdf), Mark Lemley, JD, the Elizabeth Josslyn Boalt Professor of Law,

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University of California at Berkeley, and Kimberly Moore, JD, Associate Professor of Law, George Mason University, Fairfax, Virginia, call the use of continuations pernicious for increasing delay and uncertainty in the patents system. They also suggest that continuations can wear down an examiner until he or she issues an excessively broad patent “because the examiner has neither incentive [to demand clear proof of the validity of the patent claims in the continuations] nor will to hold out any longer [because of the amount of time he or she has already dedicated to examining previous claims and continuations associated with that patent].” Profs. Lemley and Moore propose that continuations simply be abolished or, failing that, be limited to a certain number per application and restricted to the claims contained in the original application. On the other hand, Drs. Barfield and Calfee report that many members of the biotechnology community defend continuations. They argue that continuations are necessary to accommodate the very rapid pace of biotechnologic research and development within the slower process of patent applications. Although Drs. Barfield and Calfee note that one alternative could be to allow multiple applications to be filed in a series as the innovation and licensing of a product or process move forward; however, they believe this would be an expensive and needlessly complicated process. They report the suggestion of limiting the number of continuations per original application to 10—a number still considerably higher than the PTO’s proposed limit. They also discuss the proposal of other experts that a maximum 8-year period be allowed for the examination of each application, after which the application would be dismissed. And a particularly creative proposal Drs. Calfee and Barfield report is a “rocket docket” that would allow filers to ask for an accelerated examination. “Overall, our main recommendation is to turn the matter over to the National Academy of Sciences,” said Dr. Barfield. “Our argument is that PTO rushed into rule changes without giving the matter serious study.”

Look Out Below!—Submarine Patents One type of continuation is particularly contentious—one that extends claims to cover new processes or products created by the filers or by anyone else after the original application has been filed. This is often called a “submarine patent,” because most such continuations can be filed and pursued in secret for 18 months. Only after this period has elapsed must the applicant bring the continuation to the surface, by pub-

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lishing notice of its having been filed. (Publication of a filing of a claim or a continuation is required in every instance, whether a submarine or an above-board patent.) Meanwhile, the applicant can watch developments unfold among its competitors and redraft the patent claims accordingly. Other applicants who have proceeded to develop and commercialize their discoveries and to apply for the accompanying patents during that 18-month period may find their patent rights—and consequently their financing—have been undermined when a submarine is published. Indeed, they may even find entire avenues of development, manufacturing, or licensing are suddenly closed to them. Profs. Lemley and Moore are adamant that submarining is a completely unproductive practice. They stress that it discourages innovation. They note it can also set up unsuspecting companies for blackmail— those who filed submarine continuations can show up at their door and threaten to sue them for patent infringement. Abolishing continuations would largely eliminate submarining, in the opinion of Profs. Lemley and Moore—but not completely so, unfortunately. It is also possible for companies to produce a form of submarining by simply asking an ally to challenge the application. The resulting hearing would automatically extend the examination period.

Trying to See the Forest Through the Patent Thickets Another often-expressed concern about the current and future state of the biotechnology patent system is the proliferation of patent thickets. Biotechnology researchers anxious to secure patent protection frequently file applications based on intermediate results of animal or human trials. Thus the right to use a single real discovery is quickly scattered among many patents, which form a “patent thicket.” Some industries cope happily with patent thickets. For example, new software products often incorporate hundreds of previously patented technologies. Dr. Barfield noted that biotech products have traditionally been produced using very few patents, and the bureaucratic burden imposed on researchers who seek licenses to products protected by patent thickets may slow or even stop postpatent development. Even more menacingly, the patent thicket is an example of the phenomenon dubbed by Michael Heller, JD, and Rebecca Eisenberg, JD, as anticommons. In their seminal article, “Can Patents Deter Innovation? The

Anticommons in Biomedical Research,” Mr. Heller, the Lawrence A. Wien Professor of Real Estate Law at New York’s Columbia University Law School, and Ms. Eisenberg, Professor of Law, University of Michigan Law School, Ann Arbor, raise the specter of “the anticommons, when multiple owners each have a right to exclude others from a scarce resource and no one has an effective privilege of use” (Science. 1998;280:698-701; available at http://www.sciencemag.org/cgi/reprint/ 280/5364/698.pdf). They predict the result would be the tragic underuse of the resource—in particular, the inability to obtain licensing rights of practical value— owing to the inability or unwillingness of its multiple owners to coordinate their respective rights.

Other applicants who have proceeded to develop and commercialize their discoveries . . . may find their patent rights have been undermined when a submarine is published.

At its worst, argue Profs. Heller and Eisenberg, the anticommons can discourage not only the use of a resource but also further research based on the resource’s possible uses. When no single individual or institution has full ownership rights, but instead those rights are subdivided among a patchwork of part-owners, the selfinterest of each part-owner may militate against cooperation with the rest to develop the resource to everyone’s benefit. As Profs. Heller and Eisenberg put it, “A researcher who may have felt entitlement to coauthorship or a citation in an earlier era may now feel entitled to be a coinventor on a patent or to receive a royalty under a material transfer agreement. The result has been a spiral of overlapping patent claims in the hands of different owners, reaching ever further upstream in the course of biomedical research.” In the end, the prize of patent protection is degraded until it has only negligible value—and thus there is no incentive for anyone to make discoveries and to protect them. Profs. Heller and Eisenberg posit that the anticommons dilemma and the problem of patent thickets can be solved by creating institutions to bundle licensing rights. This would reduce the economic and administrative burden of handling multiple licenses; however, they acknowledge biotechnology firms may be reluctant to

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join the resulting “patent pools” precisely because they would limit the exclusivity that the patent creates. Dr. Barfield told American Health & Drug Benefits there is no proof to back up these concerns about the anticommons. “Despite the claims of Eisenberg and Heller, research by the National Academy of Sciences has failed—with 2 major research efforts—to find evidence that the anticommons is causing the alleged problems,” said Dr. Barfield.

The NIH reserves the right to issue research-only licenses. These allow researchers to proceed with work on new molecules or technologies without having to obtain any other forms of clearance from the commercial licensees.

Mark Rohrbaugh, PhD, Director, Office of Technology Transfer, National Institutes of Health (NIH), Bethesda, Maryland, and his colleagues have come up with a much more practical way to ensure postdiscovery research is never impeded by patent thickets. The NIH reserves the right to issue researchonly licenses. These allow researchers to proceed with work on new molecules or technologies without having to obtain any other forms of clearance from the commercial licensees. “We are not unique. I think some universities do this as well,” said Dr. Rohrbaugh. “Part of the point is that we agree by policy not to enforce our patents against nonprofits. Thus, for them there is no charge and no need to actually take a licence.” Furthermore, the PTO is also starting to demand that companies demonstrate the utility of the product for which they are filing a patent request—something it has always required but has become increasingly lax about enforcing over the last few decades. According to Dr. Calfee, this new examination rigor should go some distance toward thinning the patent thickets, primarily in those comprising patents for intermediate results. “The PTO now requires much more information about utility than formerly,” he said.

The Thin Blue Line—Patent Examiners Every expert interviewed for this review emphasized the importance of a robust patent system that issues good patents; however, as Ashish Arora, PhD, Professor,

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The H. John Heinz III School of Public Policy and Management, Carnegie Mellon University, Pittsburgh, Pennsylvania, put it, “There’s a suspicion that the U.S. patent office is issuing a lot of really bad patents.” Overwhelmed and rushed examiners with inadequate expertise may issue a “bad” patent that is overly broad or that is insufficiently novel and effectively block development in the field. So much damage can result that this scenario is untenable to most observers. “The stakes are pretty big,” said Dr. Calfee. “There’s not much choice [about how to deal with this] other than to spend more money on reviewing patents. If the PTO is functioning poorly, then a lot of harm and big costs can result.” He hopes the current system, in which user fees fund the PTO, can be replaced with a direct appropriation from Congress. Dr. Calfee believes that a sufficiently large appropriation may ensure adequate funding and staffing of the PTO for years to come. Even with better funding and more time to spend on each application, however, patent examiners would face new pressures under a proposed reform that would allow any person or company to intervene in the examination process for 6 months after the publication of notices of patent applications. Currently, the examination takes place in secret between the examiner and the applicant. “The patent office has been overwhelmed with applications, and sometimes it doesn’t get it right. Why not allow people to open up the system?” Dr. Barfield told American Health & Drug Benefits. “This brief administrative window for patent challenges during the examination period would weave a compromise between those who oppose any change and those who want to be able to make administrative challenges for the life of the patent.” Although the proposed reform would slow down the process of issuing patents, Dr. Barfield also argues the result would be a more thorough examination process and hence a less challengeable patent if one is granted. Allowing third-party intervenors also would bolster the limited time and training of the individual examiners, he posits. However, many proponents of this reform support it only if there can be a guarantee that the ability to challenge patents after they have been granted is not expanded. As Drs. Barfield and Calfee write, Congress has “an understandable fear that challengers would game the system and frivolously attempt to block valid patents” if more windows of opportunity for exploitation of the patent-granting process are opened.

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“The most important lesson to be gleaned from earlier attempts to reform the patent system is the danger of unintended negative consequences from proposals advanced in good faith,” conclude Drs. Barfield and Calfee. “Our fundamental principle is ‘First, do no harm.’”

Contacts Ashish Arora, PhD, Professor, The H. John Heinz III School of Public Policy and Management, Carnegie Mellon University, Pittsburgh, PA; 412-268-2191; ashish@andrew.cmu.edu Claude Barfield, PhD, Resident Scholar, American Enterprise Institute, Washington, DC; 202-862-5879; cbarfield@aei.org John Calfee, PhD, Resident Scholar, American Enterprise Institute, Washington, DC; 202-862-7175; jcalfee@aei.org Mark Rohrbaugh, PhD, Director, Office of Technology Transfer, NIH, Bethesda, MD; 301-594-7700; rohrbaugh@nih.gov

For inquiries or comments, please e-mail editorial@AHDBonline.com.

AHDB Stakeholder Perspective The topic of patent protection is of vital importance to the biotechnology industry and to healthcare stakeholders in general. Improvements in healthcare result from innovation. Innovation in medicine and healthcare is risky and expensive and must be funded and rewarded through the marketplace. To maintain a fertile ground to nurture innovation and the future improvements it enables, one must be able to secure the innovation while products are researched, developed, approved, and brought to market. This security must extend long enough to enable the product to generate revenue. The revenue must fund the costs of developing the innovation and also fund the research that did not lead to marketable products, but may have generated knowledge and understanding that may support other innovations. This revenue must fund the navigation through a laborious, expensive, and time-consuming FDA approval process. This revenue must fund the costs of products that are not approved. This revenue must fund future research. This revenue must fund the profits that are necessary to continue to attract companies to the risky business of innovation. Even after an innovation is FDA approved, payment barriers with CMS, insurers, technology review or formulary committees, and fiscal intermediaries must be navigated to secure funding. Few innovations achieve immediate widespread acceptance, so there is further delay as market acceptance occurs— Exubera. Postmarketing storms erupt that may pre-

vent innovative products from achieving financial success—Rezulin, Vioxx, and perhaps Avandia. Although the innovator is managing these challenges, competitors may develop related technologies novel enough to enter competition with the primary product in a limited market. These secondary products may have benefitted from the research supporting the primary innovation, and therefore have lower development costs. They may come to market faster, and therefore have longer protection remaining on their product, than the primary innovation. And these products will parasitize available market share required for the primary innovation to achieve success, as the clock is ticking toward the sunset of protections and further generic competition. Although competition from brand and generic rivals may lower costs, they may also stifle innovation, if protections do not allow innovation to be rewarded. Likewise technology assessment processes and formularies may control costs, but slowing the adoption of life-saving innovations may limit the rewards for innovators and cost patients. Our current marketplace may actually favor secondary products that have less resistance to overcome owing to the work of a true innovator. Our patent protection processes must minimize these disparities to enable innovation to continue in healthcare. All stakeholders must be able to compete effectively and successfully or innovation will cease, and everyone will lose. Thomas McCarter, MD, FACP

continued on page 18 www.AHDBonline.com

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continued from page 17

AHDB Stakeholder Perspective Patent Reform Proposals: More Intervention or Progress? The impact of the current patent reform proposals could either stifle innovation or catapult R&D discovery, especially biologics, to new heights. When you peel back the onion layers of the PTO policies and procedures, it really comes down to loopholes, those legal tactics employed to gain advantage, thwart the competition, game a system, or even confuse patent examiners as to the validity of the patent submission. We see this play out all too often with the latest introduction of the newest “Me-Too drug”; however, for biologics, it is a more stringent path with little room for error. The PTO grants approximately 150,000 patents on an annual basis. The proposed patent reformation should therefore be carefully studied under the microscope. A new theme should emerge: discontinuation of continuations! The original purpose of a continuation appears to have gone to the wayside. If one must keep continuations, capping the number and length of time can only provide a stimulus for novel R&D. On the same path of reformation and in

the spirit of transparency, one word can describe the action needed around submarine patents—torpedo! Progress, the true objective of R&D, can be more effectively realized by complete transparency and public record. Think of all the time, resources, and money saved, not to mention the integrity of the intellectual property preserved by not being sideswiped by a submarine patent. When it comes to patent thickets, one can truly say that the sum of the parts is not greater than the whole. Loss of full ownership or autonomy has never made a great team! The NIH definitely provides the right venue to spawn creativity and novel applications in R&D. A major step for the PTO was the hiring of new patent examiners to handle the influx of patent submissions. Under the proposed reform, another area for scrutiny is allowing a 6-month window for third-party intervention before the patent approval. This action would actually take novel R&D applications down a slippery slope. Let the patent office do what they do best, review patents. There is always plenty of opportunity for patent challenges after the fact. Intervention before patent approval could stall or even deny valid patents having a true impact on the healthcare of our society. Again, the objective here is progress, right? Charles E. Collins, Jr., MS, MBA

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The Value of Biologics Interview with Gary M. Owens, MD American Health & Drug Benefits™ has reached out to a health and drug benefit decision maker to open a dialogue on the benefits coverage implications surrounding the high cost of biologic drugs. We asked Dr. Gary Owens to discuss with us how payors are turning data points, demographic trends, and pharmacologic discoveries into formularies and benefit designs that balance the demands of cost, quality, and access to care. With a decade of experience chairing the Pharmacy & Therapeutics Committee at Independence Blue Cross until 2006 to inform him, Dr. Owens described how benefit design structures are being redesigned to meet these interlocking needs.

obert Henry: By way of introduction, Gary, give us the basic direction that you would like to take on today’s subject—the high costs of biologics—whether your focus is on the benefit design structures that are going to be fashioned in response to the cost of biologics or elsewhere.

Gary Owens: It is not uncommon for new and innovative technologies to be expensive compared with costs for an older technology. Keep in mind that technologies which were considered high in cost 15 years ago, are now considered either average or low cost. If the cost of a new surgical procedure 20 years ago was $10,000, it was considered astronomical. I can remember as a resident in the 1970s how we were admonished for using IV cephalosporin antibiotics, which then cost around $500 for 10 days per day of therapy. However, that was a different era. All things are relative. Now, we are in an ongoing healthcare cost crisis. In 1996, we saw healthcare spending exceed $1 trillion in the United States. By 2005, the $2-trillion spending level had been eclipsed and, slightly after the end of the decade, we will have exceeded $3 trillion in annual healthcare spending, representing more than 18% of the gross domestic output. At that level, healthcare spending certainly gets everyone’s attention for a number of reasons. For one thing, somebody must pay for it. There are only 2 major sources of payment for healthcare in this country—the federal government, including state and local involvement in Medicaid, and private employers. And it is clear that these payors of healthcare are concerned about costs. The federal government is trying to balance the budget, while private employers face having healthcare become a larger and larger portion of their cost of doing business, making it

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more difficult for them to compete. Consequently, they are pushing the people who administer their benefits—eg, health plans, PBMs—to find ways to control costs and keep premiums affordable. In some cases, this has meant changing benefits, implementing utilization controls on certain treatments, and identifying more efficient treatment patterns. We have brought many new ideas into the mix, including case management, disease management, patient education, and physician education. One of the areas that has come squarely into the spotlight is consumerism. The theory behind this is that if consumers have more of a stake in the issue, if consumers have to spend their own healthcare dollars on services, they will become wise purchasers. I am a bit of a skeptic, however. For the most part, consumers do not have the knowledge required to know how to spend their healthcare resources wisely. Even healthcare professionals, such as physicians and managed care executives, do not necessarily have sufficient knowledge to help direct them in how to spend their resources on the most effective treatments. Furthermore, you need to distinguish between 2 kinds of healthcare spending, those being discretionary healthcare spending and necessary healthcare spending. You as a consumer can readily decide when to take care of minor ailments, or when to have somebody look into a rash or check out a painful hip joint that you have been walking around on for the past 5 months, and when you need more aggressive attention than aspirin or another over-the-counter remedy. Then there are life-threatening or chronic conditions that absolutely require care. Sometimes, the treatments for these diseases are exotic and specialized, and therefore, very expensive. Keep in mind, that

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among patients in this category, 10% of the population will typically use 70% of the resources. Robert Henry: Has this statistic increased over the past decade? Gary Owens: When I first started in the business more than 25 years ago, there was the 80/20 rule, that is, 80% of the spending was done by 20% of the people. Today, half the population only spends about 3% of the healthcare dollar: the relatively young and healthy and also the ambulatory unwell who simply do not seek healthcare services for a variety of reasons. So we have 2 competing forces: on one side, half of the population spends almost nothing in healthcare resources, while the other spends a disproportionately large amount. About 10% of the population requires appropriate healthcare because their well-being and their quality of life depend on it. Unfortunately, the one-size-fits-all approach does not work when it comes to managing cost and creating consumer incentives for these very different populations. Each segment of the population has specific requirements because there are very different forces at work on these patients. Employers are looking for ways to control costs, and one of the ways has been to ask consumers to pay more out of pocket. In theory, this works well, but as I have noted, there are populations where this practice can be counterproductive. Many biologic therapies cost between $10,000 and $40,000, and some are as costly as $250,000 per year. If a consumer is asked to pay 20% of a therapy that costs $25,000, that would be $5,000 per year. This often results in having some consumers either forego the treatment altogether or take Draconian steps to afford it. Robert Henry: What disease states are driving this? Will patients with certain disease states receive healthcare benefits that cover the more expensive biologics because their employers have an incentive to get them well and return them to the productive workforce? Are there patterns emerging, or is this still all over the map? Gary Owens: Trends are gradually emerging. Fifteen years ago, there were only a handful of high-cost biologic therapies that were targeted at things such as anemia, growth hormone deficiency, and some of the inborn metabolic errors such as Gaucher’s disease. Since the mid-1990s, we have seen high-cost biologic therapies emerge for rheumatoid arthritis, cirrhosis, and hepatitis C. In these disease instances, patients are often symptomatic, but they are most likely in the

workforce. Hence, the availability of these meds may keep them as productive individuals. Biologic therapy is now emerging for more common diseases such as asthma. Suddenly there is a shift. Highcost biologics are now targeted at a much larger segment of the population than they were 15 years ago. Furthermore, many of these patients are still perfectly capable of maintaining an active and productive lifestyle provided they are able to have access to these therapies. Again, some of the therapies range from $10,000 to $40,000 a year, and if patients do not have adequate coverage, they may find that access to them is limited.

Some of the [high-cost biologic] therapies range from $10,000 to $40,000 a year, and if patients do not have adequate coverage, they may find that access to them is limited.

Robert Henry: It appears to come down to the single issue of access. It strikes me that the high cost of biologics supersedes the ability of the free market system to accommodate the population at large. Because if you are patient A and you have a disease that requires immediate treatment with a biologic that’s going to cost $50,000 to $100,000 a year, and cost sharing is going to be prohibitive, then you’re not going to want to wait around for 7 to 8 years for the market to stabilize, because you won’t be around by then. So, this is the kind of thing that tends to invite government involvement to remedy the situation. This can escalate to a point where the free market system fails and the government steps in to offer a remedy. Do you see this issue being resolved at the policy level? Gary Owens: I think it can be resolved at a number of levels, and you’re absolutely right, the cost of some of these therapies is such that if one doesn’t have thirdparty coverage for all or mostly all of the therapy, you’re just not going to get that therapy; it’s that simple. Or you’re going to mortgage your future in order to get it, and even that can only provide a limited amount of treatment in some instances. The temptation for legislative relief by way of mandates or other actions is always there; although I don’t know in what form that would come. One possibility is a form of price control on some of these therapies, which goes against the capitalistic, free market system.

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It could come in the form of the FDA requiring manufacturers of these new therapies to demonstrate the relative value of the treatments to the system. But one main opportunity exists outside of legislative or regulatory remedy, namely, in benefit design.

The initial temptation to put biologics in a high-cost benefit bucket solved the problem only in the short term, and it may have created access barriers for patients.

Robert Henry: That is clearly the first place to start looking. The role of the payor in throwing a harness around this runaway stallion is still only partially utilized: so much power, so much potency for facilitating the treatment of diseases, so much life-saving potential. Gary Owens: Exactly. Robert Henry: All we have really done here is to run ahead of ourselves financially. The only vice is that science and the corporations funding the science have invented lifesaving remedies that we have not yet figured a way to pay for. It is nothing more or less serious than that. Then frontand-center come the healthcare plan and the actuary models and the overall resource allocation models. Gary Owens: Yes, and up to now, we have figured out a way to pay for them in a straightforward manner: add the cost of the therapy into the benefit program and ultimately charge the consumer, the employer, or the federal government for the costs of these new therapies. Unfortunately, continuing to do that leads to problems. And as you pointed out, the day of reckoning will come, if it has not already. In most health plans, these biologic therapies were not really considered in their existing benefit designs. Benefit programs were often developed several years ago. There were relatively few injectable or infusible medicines, and most health plans offered a benefit that covered injections or infusions when prescribed by a physician in the health planâ&#x20AC;&#x2122;s network. As these treatments began to grow, it was clear that not all health plans were equal, not all of them cost the same, not all of them offered the same benefits to the consumer. Management of these products consisted of

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selecting certain products that could be used for their approved indications, and in some cases, off-label. So traditional medical management programs were put in place. One example of the early management controls imposed involved growth hormones. Treating children with short stature owing to pituitary insufficiency or chronic renal disease was considered appropriate. But it was not necessarily appropriate for the system to pay for growth hormone for somebody who wants to be a bit taller or do body building. Thus, prior authorizations were put in place just to manage usage of these products. This obviously could not be done with every product. In 1990, there were only 20 biologics on the market. Now there are more than 300, and as many as 800 are expected by the end of the decade. So one quick temptation is to allow the problem to self-regulate: Create a unique group of products called the biologics, then create a new tier of benefits for them, allowing access to all the biologics a consumer needed plus a fixed dollar copayment or a percentage from coinsurance. The downside was that 10% of the population have lifethreatening or serious chronic diseases. It is not unheard of for a rheumatoid arthritis patient to have 2 or 3 other chronic diseases and be faced with a 20% coinsurance on a disease-modifying agent. Consequently, they have to turn down the new drugs and opt for traditional therapy because of the out-of-pocket cost. The initial temptation to put biologics in a high-cost benefit bucket solved the problem only in the short term, and it may have created access barriers for patients with resultant decreased quality of life and possibly increased downstream medical costs. Robert Henry: How do healthcare plans avoid the kneejerk reaction to control costs at all costs, falling back on the tired model of cost-minimization when experience has shown that cost-effectiveness is essential to long-term success? Gary Owens: Health plans like to be able to apply cost-effectiveness and cost-utility models and comparative outcomes analyses in developing their coverage policies. That being said, these data are not currently available. In the absence of meaningful comparative outcome studies, health plans have been forced to take some cost-minimization strategies, because those are really the only things on which they have any hard data. It is a stop-gap measure, but it was born of necessity, because the other option is to continue to absorb those costs, which health plans can do; however, when health plans absorb the cost of new therapies, eventually premiums increase in the next underwriting cycle.

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Robert Henry: Yes, the cost point on the cost/quality/ access triangle is out of kilter here. Seven years ago healthcare plan margins were perilously low, and over the past few years they have improved. Has this given plans a cushion to offset the new cost demands of biologics? Gary Owens: That cushion disappears very, very rapidly. In the health plan business, all things are relative. Somewhere between $0.80 and $0.85 of every premium dollar collected goes back out to cover healthcare costs. And $0.10 to $0.12 of every premium dollar goes toward the health plan’s administrative load. What remains is the margin, and, as you can see, that margin is quite small. A small margin on a large number of dollars can still represent some significant amounts of money that can go into a health plan reserve or become profit; but remember, as healthcare cost increases are covered, the amount of money that must be kept in reserve, either from a state regulatory standpoint or insurance department regulatory standpoint, must increase. So health plans must keep some reserve. If they do not, they become financially nonviable and incapable of dealing with downtimes or when their actuarial projections were incorrect. It doesn’t take very long to erode those reserves, and an ultimate outcome of increasing healthcare costs is to increase premiums. As premiums increase, fewer people are insured. Employers have second thoughts about providing healthcare coverage for their employees, especially small to mid-sized employers who may have to determine how to provide healthcare coverage for their employees and still have a sufficient margin to stay in business. Robert Henry: Earlier in our conversation, we discussed the natural course of events attending new technologies, which raises its head here in hopes of offering a natural, unlegislated solution. Over time, these new technologies will decrease in cost, and people have to be patient and allow the market to settle, and the cost of biologic agents to decrease on their own after we have gone through the hurtle of initial high cost associated with discovery and development. Is there a consensus on the part of chief financial officers at healthcare plans as to when such a settling out of costs might occur? Gary Owens: If it were most any other technologydriven business, I would agree that people are probably waiting for the proverbial light at the end of the tunnel. I recently purchased a laptop computer that is much more sophisticated and has more capacity than

my previous laptop did 5 years ago. And it does it for less than half the cost. This is a perfect example of market forces and technology balancing new and improved technology with decreasing costs. Unfortunately, this paradigm does not fit medicine. New medical technology and medications continue to cost more, and as innovation builds upon innovation, the newer innovation tends to cost even more than the technology that is being replaced.

As healthcare cost increases are covered, the amount of money that must be kept in reserve, either from a state regulatory standpoint or insurance department regulatory standpoint, must increase.

Robert Henry: This brings me back to the core mission of American Health & Drug Benefits: the notion of collegiality, that the different stakeholders should combine forces to solve such problems rather than take adversarial, competitive stances toward one another. How can we— meaning we the stakeholders—make this system work to accommodate biologics? It seems to me that this is one of those examples where healthcare really stands to make progress and capitalize on the extraordinary innovations that biologics represent. Sometimes you have to ask for less initially to get more in the long term. Are there examples of the kind of cooperation that I am talking about, that is, enlightened self-interest? Which payors or leaders—either individuals or institutions or private companies—have been the most visionary in this regard? Gary Owens: Frankly, I think we are only on the edge of this ideal at best. All too often what occurs is exactly as you describe: Manufacturers get nervous about dwindling pipelines and having fewer products; payors react to increasing cost trends by deciding to put in management controls such as step therapy, or prior authorizations. Consumers and doctors often react negatively to increased controls, prior authorizations, and benefit designs that require high member out-of-pocket costs. I agree with you that at some point people need to step up and say, “We need to look for a different way of doing this.” Although I have not yet seen it, I would applaud the manufacturer that brings its product to market with outcomes studies and economic data that

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help place their product in the appropriate position in the value equation. Now this, of course, is a double-edged sword, because if you happen to bring a product to market and it does not bring high value according to your studies, then you’re going to have a hard time getting people to pay for it. On the other hand, if you can show significant cost offsets or that the cost of your product produces a value that is unparalleled by the competing products in the same space, you have the opportunity to hit a home run. I think the problem will be getting the parties to sit down and lay down their arms to solve this problem.

I think too many are still protecting their territory and solving their own problems without giving thought to the other stakeholders’ problems.

Robert Henry: Yes. That is what American Health & Drug Benefits is attempting to do—increase dialogue between the sometimes warring factions. Gary Owens: Somebody must take the first step and take a chance that doing the right thing will ultimately be rewarding. Robert Henry: When I attended the Institute of Medicine roundtables on evidence-based medicine this year, there was that sense that people sat down at the table together. The venue had been designed that way so that there was a time for FDA regulatory people to step up and present their ideas for implementing evidence-based medicine standards. There was a chance for industry pharmaceuticals to step up and present their vision. There was a chance for patient advocacy groups or the healthcare plans for the purchasers. And I liked the feeling that was generated there. It seems to be another example of this kind of form building, this bridges-across-the-water process. Are the other examples of this conciliatory approach as opposed to having one sector dominate the healthcare debate and hope to solve the question all by themselves? Gary Owens: I am not sure you have anybody out there looking to solve it all by themselves. I think too many are still protecting their territory and solving

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their own problems without giving thought to the other stakeholders’ problems. The Institute of Medicine and a few places like that provide at least a starting point for problem solving— How can we continue to provide innovation in healthcare, yet provide basic healthcare for everyone? That is the dilemma. We need to get the stakeholders around the table. Who will lead this? I think you might know more about this after the next election. Robert Henry: There has been a lot of movement in the past few years toward empowering the Agency for Healthcare Research and Quality (AHRQ) to become a center for comparative effectiveness, that is, making it the definitive center for evidence-based medicine standards. Do you consider this an example of healthy data clarification, or an attempt by one healthcare stakeholder group to solve the problem once and for all, as opposed to a collegial way of sitting down and sharing information? Do you think this movement by the government to establish an evidence-based center is fraught with peril, as some fear, or can it help contribute to the dialogue that you hope to promote? Gary Owens: If properly done, taking into account the viewpoints of all the stakeholders, including physicians, patients, health plans, employer groups, manufacturers of innovative products, to name only a few, with balanced, scientifically driven opinions, I think you could create a highly effective body. The challenge is to create a body that can simultaneously balance the needs of all those stakeholders. Robert Henry: Yes. This would require approaching it as an art and not solely a science. Gary Owens: True, not all of medicine is scientifically driven. A good physician must balance the scientific, personal, and artistic aspects of medicine to achieve the best outcomes. Robert Henry: Well, this requires a certain amount of lobbying—for want of a better term—by each of the stakeholder groups to make sure that their point of view is heard. That would mean that each of the stakeholder groups would have to have access to a leadership community within AHRQ to make this work. And there remains another aspect to their effectiveness. Will AHRQ have sufficient funds to do this? Gary Owens: Funds for AHRQ might double from 2007 to 2008, which is a good start, but probably only

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5% of what is really needed to get real answers on evidence-based medicine. That of course brings up another related issue: the high cost of biologics. It becomes a lot easier to pay that bill if there is clear and indisputable evidence that biologics produce high-value outcomes. Robert Henry: With so many of these disease states occurring in small populations, you cannot get sufficient numbers of patients to complete a randomized controlled trial to determine the effectiveness, safety, health-related quality of life, and performance perimeters. What trial designs do you look for when you are evaluating biologics to determine if you are getting a sufficient clinical return on investment? And to what extent do medical and pharmacy directors participate in this process? Gary Owens: Medical and pharmacy directors must collaborate in the process of evaluating biologics, because some of these products are covered under the medical benefits and some by the pharmacy benefit. Some plans have crossover coverage. As you pointed out, we need large, longitudinal trials and trials in naturalistic settings to properly determine value. As soon as you introduce patients into a clinical trial, you have already created an artificial setting that does not always resemble the real world and does not always produce outcomes that can be duplicated in the population atlarge. Studying large populations in naturalistic settings is probably the best way to evaluate the economics of these issues. We generally only have the FDA-required studies, which amounts to examining safety and efficacy. Cost-effectiveness is not evaluated; therefore, acquisition cost is all we have to work with. In other words, if the cost is too high, then utilization may need to be managed. We do not have all of the pieces of this puzzle necessary to assign value to biologics. All we have is cost. And if the cost is high, drug utilization management often becomes restrictive. Robert Henry: Permit me to offer an historical analogy. In the New World, pioneers such as Lewis and Clark sought new methods for understanding, exploring, and developing a new country. The same principle should be in place here. We have a new medical world before us in the form of biologics. It stands to reason that some innovators, both individuals and organizations such as healthcare plans, are going to boldly apply different approaches to a new entity, but this time in the form of benefit design methods, which brings me back to an old axiom: when you’ve seen one managed care organization, you’ve seen one managed care organization.

Gary Owens: Which still holds true, by the way. Robert Henry: What then has been your observation industry-wise with regard to payor innovation in this brave new world of biologics? And can innovation occur, given the clamor for conformity to guidelines, especially where the technology is too new to allow for meaningful guidelines?

Medical and pharmacy directors must collaborate in the process of evaluating biologics.

Gary Owens: I think we are still waiting for the leaders to emerge. For the most part, however, most plans are exploring in their own unique ways. This is still a new enough problem that the solution has not yet manifested in an obvious fashion. Because this is a highly competitive business, it is difficult to be an early innovator and risk failure. Look at the incentive of the payor: If a health plan tries something radical and extremely pioneering and falls flat, it may have given away its competitive advantage for a significant period of time. It takes a health plan a long time to recover if it loses significant market share. Robert Henry: Also true if a healthcare plan takes in all the sick patients who show up at their doorstep to get the liberal coverage benefits provided. Gary Owens: However, if they truly come upon something innovative and can actually take care of these people and make a name for themselves, they win big. But it’s a big risk to take. Robert Henry: It certainly is. I wonder if plans can try something on a small scale, so they don’t risk their entire portfolio. Gary Owens: Yes. I think pilot programs are often the way. I think it behooves all of us who are in this business to keep our ears to the ground and continue to follow new trends and emerging ideas. Whenever somebody truly finds a solution in this business, it is quickly emulated. Robert Henry: One of the other considerations is to look at how each medical group expresses its interest in the

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utilization of these products. I think it’s safe to say that cancer and rheumatoid arthritis are the principal disease states affected by expenditures with biologics. Gary Owens: Yes, the biggest growth area is oncology. Nearly half of all the new biologic therapies are targeted at cancer. Another big area is for diseases mediated through the immune system, such as rheumatoid arthritis, lupus, and Crohn’s disease. A host of other illnesses are also targets for biologic development, simply because the underlying disease mechanisms or the pathology is already understood.

Issues often hit the press so quickly that the public is provided with incomplete information. . . . It strikes me that many clinicians may also fall prey to oversimplification of the results of one study.

Robert Henry: How are medical groups such as the American Society of Clinical Oncology and the American Society of Hematology expressing their desire to utilize the biologics? I ask this because we know that each stakeholder group exerts official pressure to increase access to drugs they find advantageous. Both of these societies came out strongly in favor of more liberal coverage than that determined by the Centers for Medicare & Medicaid Services. Gary Owens: Yes. They have certainly made their position statement quite well known. They usually begin with position statements for their membership that outline how they believe the product should be used, followed by guidelines for the specific use of a product. Robert Henry: So it begins with a dynamic tension between the stakeholder groups that tends to result in a given level of coverage. Gary Owens: That is correct. Robert Henry: In all of this, where is the value of patient knowledge in participating in the cost management aspects of this? I ask because we saw what happened in the wake of the article about rosiglitazone in the New England Journal of Medicine and the national furor that ensued

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from a meta-analysis that many regarded as being of less than conclusive worth. It is likely that the principal result was that patients refused to take their drug anymore. If patients are going to participate in the decision-making process, they have to know enough to be able to say this is what I want and this is what I do not want. What are the implications for biologics, which are far more complicated and probably less within the grasp of the lay public? Gary Owens: Well, I think the lay public is very capable of commenting appropriately and intelligently. The problem is that the issues often hit the press so quickly that the public is provided with incomplete information. The public often will act on incomplete data when they appear to be positive for controlling a disease. It strikes me that many clinicians may also fall prey to oversimplification of the results of one study. Robert Henry: Do you see opportunities or incentives for healthcare plans to institute more aggressive patient education programs? Is it worth their while professionally to try to educate the public sufficiently to engage in a dialogue with their payors and doctors about biologics? Gary Owens: Yes, but we do not know who should be responsible for informing the public. Although it’s tempting to put the onus on health plans, they have limited resources and limited ability for outreach. And sometimes communications from the health plan are viewed by the public as self-serving. So they may be viewed with skepticism. Robert Henry: This strikes me as an opportunity for a larger organization such as PhRMA to be a participant in patient education programs with the medical associations. I could see something at the higher levels of each of the stakeholder groups where the dialogue is further extended, for example, to patient advocacy groups and so on. Does that seem to be part of a reasonable patient education process? Gary Owens: If you can create a patient education process that would be viewed as free of inherent bias and one that represents the viewpoint of multiple stakeholders in the process, then it will be thought of as a credible source of information to the public. The key there is that I think we still have to invent it. Robert Henry: We have seen efforts from American Health Insurance Plans (AHIP) with regard to improving quality of care. So there is a desire and a willingness to become proactive on healthcare measures. The climate

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appears to becoming conducive to such a collaborative measure. It just strikes me as one of the possibilities for progress. On another front, AHIP has been lobbying for generic biologics, and it seems to me that this might be one of the answers to the high cost of biologics. What are your thoughts on this? Gary Owens: Well, this is a possibility; however, the cost of new pharmaceuticals continues to be high, so I am not sure I would expect the use of generics to bring down the cost of new biologics. This is only one piece of the equation. This does not answer the question about how to manage costs with emerging technology. Robert Henry: You bring up an important point: Emerging technology needs a lot of upfront funding for 5 to 10 years before a drug is brought to market. And that requires a strong empowered pharma in the stakeholder sector. In fact, no stakeholder group can afford to be weakened as we continue the process of discovering and bringing new biologics to market. Would you say that it is worth the effort to bring these biologics to market? Gary Owens: I think you hit one of the major issues of the dilemma. In our highly competitive business environment, we need to reward those—whether it’s pharma, a health plan, or a hospital—who are willing to take a bold step for innovation. There are many individuals who seek innovation, who want to step out, but who are bound by the constraints of our highly competitive business environment. You know, I don’t have the answer of how you get around that, because this is a highly competitive environment. And it is precisely this type of environment that has made us as successful as we are with breakthrough technologies and innovation. We need to balance rewarding innovation and technology and taking risks with providing a product that the public can afford. And so I think it is going to take some radical change, some radical reform, exactly those things that your journal, American Health & Drug Benefits, is helping to promote, namely, bringing multiple stakeholders to the table and beginning to introduce and promote collaboration. Robert Henry: Many are too often ready to vilify big pharma, despite their having been the source of life-giving medications and therapies and devices for many years. Gary Owens: As well as the source of incredible innovation. We are often too willing to vilify an organization that is successful, concluding that it must be doing something wrong to achieve success.

Robert Henry: And it’s the same with government. The FDA can be looked on as oppressively restrictive. Payors can be oppressively restrictive, instead of managers of resources. The purchasers can be looked upon as totally self-interested. The patients can be looked on as naïve and greedy for all the benefits of modern research, but not willing to pay for any of them. All the negative stereotypes could go on. Gary Owens: So, we have to be careful not to vilify any sector. Every sector has valid reasons for doing the things they do. Depersonalizing the dynamic, it becomes a matter of addressing, aligning, and correcting, where necessary, the incentives driving each stakeholder group. These are not good or bad parties, just different participants to the process of care. Robert Henry: I am interested in seeing if an appreciation for the right kind of financial strength of pharma and biotech of the manufacturing sector can emerge, because pharma is a resource that has grown out of a period of economic prosperity in the West over the past few decades to the point where we are able to produce the biologics that we have been covering in today’s conversation. And that resource is finite. If it is hit too hard and treated in a totally adversarial way, it can disappear. And I don’t mean to single out pharma as the sole sector requiring protection. Pharma has to be equitable and balanced and reasonable in its desires for profitability. And it has to be ultimately on fire with a desire to improve patients’ care. And if everybody keeps their eye on that prize—the regulators in government, the payors, the purchasers, the patient advocacy groups—if everyone treats this as Operation Fair Share, then I think we can pursue this new world of biologics with a certain degree of patience, which is really hard to do when there is an immediacy toward patients wanting to get the best care to reverse the progression of their disease. Do you have any final thoughts for payors regarding how they should conduct their affairs strategically in benefit designs for biologics? Gary Owens: Well, I think that has been the essence of this conversation. Ultimately payors will need to examine their benefit designs, how they are paying for value, or how they are assessing value. They are going to have to be willing to reassess their benefits, reassess how those benefits affect certain vulnerable populations and be willing to adjust those benefits as new information emerges. This would help them direct the benefit design in such a way that we are neither wasting healthcare resources on inappropriate spending, and at the same

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time, that we are not depriving patients of vital care. I think such changes will occur as a gradual process. Robert Henry: There is one final question to that, Gary. Do you see an increase of communication within the corporate infrastructure of the average healthcare plan, that is, an increase of communication between the CEO, the medical director, the pharmacy director, and the CFO? Have you seen evidence of an increase in dialogue between these groups to arrive at a corporate consensus that will help them devise benefit designs? Gary Owens: To a great extent, this dialogue has always been there, and we are seeing a continued process, where, in a successful managed care plan, all of the stakeholders in the plan are at the table. This is

AHDB Stakeholder Perspective Value-Based Benefit—A Joint Effort In the era of rising healthcare cost, it is easy for all stakeholders to point fingers at others and assign the “blame” for the high cost of care to any of the other stakeholders. For the system to advance, it will be important for all stakeholders to begin to grasp the complexity of providing healthcare to a growing population, a population that is rapidly aging and to a population that desires the latest and best that medicine has to offer. Simply put, we cannot afford to spend precious healthcare resources unwisely. We must design a system that neither wastes resources on new technology that is unproven, nor deprives patients of access to valuable new technology that has the potential to improve their clinical outcomes or their quality of life. To do this, each of the stakeholders must be prepared to work collaboratively. Patients and providers will need to understand that without proper evidence of effectiveness—and in the future cost-effectiveness—access to some therapies may need to be limited, or simply not available, under insurance benefits. The concept of mandated benefits may need to be reconsidered at the legislative level as in states where

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what makes a health plan successful—having open internal dialogue that flows across various stakeholders in the plan and breaks down the barriers of communication within the plan. Robert Henry: Won’t it be nice when this harmony characterizes the entire stakeholder spectrum. Gary Owens: We’re going to need it if patients are going to receive the awesome potential that biologics offer. This is a case of potentiality versus reality, and we are only just beginning to realize how to reap the harvest made possible through biologics. For inquiries or comments, please e-mail editorial@AHDBonline.com.

there are significant mandates; the cost of health insurance typically exceeds those states where no mandates are available. Insurers will need to be willing to provide new benefit structures that allow relatively open access to treatments—no matter how costly—that are proven to be effective and costeffective for the treatment of chronic illnesses. Manufacturers of these treatments will need to show, by well-designed studies, the comparative efficacy of their newly created therapies relative to existing treatments. They will also need to show cost-effectiveness of their treatments in this new environment. Finally, the purchasers of healthcare, the government, and private employers will need to understand how these new benefit packages are evidence-based, and how the covered therapies are providing value to justify future cost increases. In short, it will be necessary for all involved stakeholders to stop looking to the others to solve the problem and work cooperatively to develop new benefits and products that meet the goal of providing access to timely and effective care, without wasting resources. This is a challenge that readers of American Health & Drug Benefits™ should be willing to embrace, as well as provide the leadership to accomplish it.

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When Novelty Is Not Enough Michael F. Murphy, MD, PhD

Neither orderly nor fully rational, the current healthcare environment is a mosaic of providers, products, services, and intermediaries delivering healthcare, regulatory, and other government institutions, and consumers. The information required for informed healthcare decisions for novel pharmaceutical interventions varies appreciably with the audience, the therapeutic area, and the stage of product development. In this environment, the viability of new product introductions can be heavily influenced by perceived value as well as by mechanistic novelty. Correspondingly, research and development activities can be influenced profoundly by the use of incentive-based formularies, prior authorization requirements, or systems of reimbursement that mandate a stream of evidence confirming clinical utility in the presence of therapeutic uncertainty (eg, Centers for Medicare & Medicaid Services, Coverage with Evidence Development). The economic impact of innovative technology on the healthcare system, as well as the effects on the individual patient, can become a significant variable that influences the extent of research activities from the bench to the physician–patient–payor interface.

he current explosion in the science that supports discovery platforms and clinical development activities places a particular emphasis on the importance of integrating knowledge across a spectrum of interests and perspectives extending from the laboratory to the pharmacy. These efforts are driven by the increases in prevalence of chronic illnesses, the associated direct and indirect costs, and, for some indications, the rapid infusion/diffusion of innovative therapy into practice. Research and development activities, including the hypotheses addressed and the methods used thus become relevant to benefit design decisions. A critical review that separates overly enthusiastic and premature technology endorsements from initiatives that are likely to yield testable novel hypotheses and compounds is warranted. Innovative devices (eg, nanotechnology), routes of administration (eg, oral versus parenteral), and the joint development of diagnostics bundled with treatment (eg, biomarkers permitting disease fractionation and patient segmentation) represent potentially significant effects on the delivery of care in several clinical categories. Changes in regulatory guidance regarding clinical trial design and the art and science of conducting clinical research likewise facilitate an environment of innovation. These changes accelerate the

Dr. Murphy is Chief Medical and Scientific Officer, Worldwide Clinical Trials, Inc., Chadds Ford, PA.

clinical evaluation of compounds that will enhance therapeutic indices, shape longerterm outcomes, and significantly affect the overall cost burden associated with care.

The Discovery–Development Interface Novel Targets Research pipelines in many therapeutic modalities are filled with compounds derived from innovative technology reflecting a scientific environment that has significantly expanded our knowledge of molecular and cellular biology (see commentary, Industry Trends–Clinical, The 2007 Pharmaceutical and Biotech Pipeline Year-End Summary. AHDB. 2008;1[1]:43-45). We now have a vastly better understanding of cellular signals that mediate cellcycle processes in oncology, for example, as well as the critical role that supporting tissue performs in the maintenance of cell growth and viability. A more sophisticated understanding of molecular oncology currently is facilitating significant advancement in the detection, classification, and treatment of clinical conditions.1 Newer, and very specific, medications occasionally offer a compelling rationale for use with, rather than instead of, an established regimen to enhance efficacy or mitigate known toxicity issues—a process that adds to the complexity of evaluating the overall utility of new products entering clinical use. Developments at the interface between devices and

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drugs similarly offer prospects for transforming medical therapies. The advent of nanotechnology, for example, raises the possibility of innovative diagnostics (molecular imaging), or localized cellular reporters of efficacy that can confirm access to the target, and multifunctional therapeutics in which targeting, as well as therapeutic, agents are simultaneously presented.

Innovation in Clinical Methodology In many therapeutic areas, clinical development has been transformed by the research community. As a result, innovative programs yield more data, at more relevant dosing regimens and combinations, in an increasingly segmented but more therapeutically relevant patient population. These initiatives reduce the number of patients exposed unnecessarily to experimental therapy ultimately demonstrated as inferior. They facilitate more extensive exposure to new therapy based upon continually updated efficacy and safety data, and allow clinicians to characterize disease or patient features that will classify and predict response earlier in the drug development process. During this process, the choice of trial end point can materially shape the ability to assess overall value. For example, a composite may facilitate reduction in sample size in aggregate, while obscuring the impact of individual variables, thereby producing a therapeutic profile based on a mosaic of outcomes, none of which individually provides an “index” for response. The choice of a composite facilitates discussion of a net effect but introduces variability into the way in which the value of a therapeutic intervention can be assessed, as a result of the heterogeneity in response or patient importance across components.2 In addition, studies may be truncated based on “proxies” for clinically relevant outcomes, thereby terminating study assessments before the actual measurement of any health outcomes. Further still, quality-of-life assessments may emerge as an indispensable component of an assessment of product attributes, given the needs of clinicians to explain and justify treatment alternatives.3 Each study-design option elected during development dictates the extent and type of data acquired, which either enhances or obscures trial interpretation and utility. Innovative mechanisms of action also invite an exploration of application outside the terms of the product license (ie, off-label use). This activity raises concerns about product safety,4 with attendant uncertainties regarding the rigor of data collection and confounding variables that may cloud interpretation. These studies, in turn, may be accompanied by the rapid dissemination of results that can transform the standard

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of care in a given environment and yield a host of ethical, economic,5 regulatory, legal, and clinical issues. Indeed, enhancements in information technology theoretically enable every physician–patient interaction to become an opportunity for research.6 Such technology can accelerate product diffusion within the community and provide additional opportunities for generating hypotheses that extend potential clinical applications as mono- or adjunctive therapy.

The Development–Commercialization Interface Influencing the Decision Process The increase in the number of drugs aimed at novel targets, as well as the stratification of patients during the development process along genotypic or phenotypic dimensions, will result in psychosocial challenges as significant as technological challenges during the process of commercialization. Segmentation already exists within every disease population. For example, the experience of the illness (as opposed to its diagnosis) fractionates an otherwise homogeneous disease group. At one end of the spectrum are patients who are undiagnosed, unconcerned, and at risk; at the other end are patients who are diagnosed, very motivated, and fully satisfied recipients of care. In the absence of patientspecific outcome measures,7 increasingly technical data may encumber a healthcare decision model in which patients must be active participants. The challenge of creating an information package during development is particularly relevant as diseases are transformed from emergent, life-threatening conditions into chronic illnesses where patients and caregivers cooperatively make choices regarding therapeutic options and resulting quality of life.8 In this therapeutic milieu, the interaction of a healthcare professional with a patient during this decision process provides a key leverage point for the introduction of clinical trial evidence, and qualifying and presenting that information—systematically— becomes an important part of the commercialization process. Potential variables are as intriguing as they are diverse and can include the method of presentation, such as online medical information9 or physician communication behaviors,10 as well as typical demographic, sociologic, and personality characteristics. Physician–patient factors that influence healthcare decisions, including qualitative and quantitative interactions between these factors, are not as frequently evaluated using study designs that are comparable in rigor to the randomized clinical trials used to define efficacy and safety in proto-

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typical registration programs. In an environment where patient copayments and compliance with therapeutic strategies are required, understanding the interplay of physician–patient variables that modify the decision process can be crucial.

Defining the Value Proposition Medical technology assessments provide a conversion point for data formally collected in the preregistration and in the periapproval environment—an evaluation of clinical data from a multidisciplinary perspective, including economic aspects associated with acquiring the intervention.11,12 Weighting methodologic rigor more than funding source, these evaluations identify data considered most relevant clinically and, when fully articulated, can provide direction to a proposed clinical development program that must consider potential reimbursement as a factor in a therapeutic agent’s ultimate commercial success. For example, identifying the population that is most likely to use the product, as opposed to the population where the agent might have been formally evaluated, influences how evidence may be weighted and how processes can be developed to ensure appropriate patient support. Although regulatory acceptance provides a platform for this review, information from peer-reviewed journals can also be considered, and a mix of case series, cohort studies, and registries are complementary to randomized studies if impractical.13 The impact of therapy and alternative interventions, used alone or in combination, on overall health outcomes and the totality of the cost burden associated with a new treatment provides key metrics. It is the impact of a therapeutic modality on the healthcare system rather than an isolated clinical measure that provides focus. Establishing a pathway for actionable information from the clinical development process has a number of generic characteristics that can be monitored during the course of product development and before its commercial introduction. For example, will the clinical development program incorporate hypotheses generated through claims data (laboratory, pharmacy, and administrative), thereby acknowledging and addressing the importance of questions generated within the system of healthcare as well as for the patient in treatment? Will the clinical development program include patients with concurrent illnesses and concomitant medications representative of the community in which the new therapy will be introduced, in addition to the index indication that can significantly modify the overall cost of care? For planned adjunctive therapy in which quality of life is of appreciable importance, will a proposed clinical development

program evaluate patients across a spectrum of disease severity, incorporating patient-specific outcomes contingent upon the severity of illness and facilitating their introduction into clinical research and practice? Bringing the full weight of state-of-the-art technology and trial methodology to address each of these questions will ensure optimal therapy and best choices for patients.

A Redefinition of Translational Research Effective drug benefit design requires sufficient lead time for healthcare providers to assess the implications of innovative technology and its potential impact on a system of healthcare, and to influence the direction of clinical research and development to ensure that questions of relevance are adequately addressed before commercial introduction. Clinical trialists, in contrast, are experts at formulating and addressing testable hypotheses based upon these questions, and are in an optimal position in the discovery/development process to generate information facilitating those assessments. The opportunity for collaborative research at every phase of discovery, development, and commercialization appears to be self-evident based upon the participation of multiple stakeholders in this process. The research and development perspective within this publication operates under the assumption that systematic reviews of new drugs or devices, in discovery or development, by leading experts within the field, will enable informed decisions about health benefits because they can influence the scope and detail of planned clinical research programs. The decision process concerning methods of disease detection, classification and segmentation of affected patients, and treatment will effectively transform the meaning of translational research from its traditional bench-to-bedside venue to a wider spectrum of patient-oriented research. That spectrum will include epidemiologic evaluation, health outcomes research, or educational interventions that are tailored to the needs of a changing and dynamic healthcare environment.

References 1. Varmus H. The new era in cancer research. Science. 2006 May 26;312(5777):1162-1165. 2. Ferreira-González I, Permanyer-Miralda G, Busse JW, et al. Methodologic discussions for using and interpreting composite endpoints are limited, but still identify major concerns. J Clin Epidemiol. 2007 Jul;60(7):651-657; discussion 658-662. 3. Sloan JA, Frost MH, Berzon R, et al, for the Clinical Significance Consensus Meeting Group. The clinical significance of quality of life assessments in oncology: a summary for clinicians. Support Care Cancer. 2006 Oct;14(10):988-998. 4. Neubert A, Dormann H, Weiss J, et al. The impact of unlicensed and

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off-label drug use on adverse drug reactions in paediatric patients. Drug Saf. 2004;27(13):1059-1067. 5. Kocs D, Fendrick AM. Effect of off-label use of oncology drugs on pharmaceutical costs: the rituximab experience. Am J Manag Care. 2003 May;9(5):393-400. 6. Demonaco HJ, Ali A, Hippel E. The major role of clinicians in the discovery of off-label drug therapies. Pharmacotherapy. 2006 Mar;26(3):323-332. 7. Willke RJ, Burke LB, Erickson P. Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved product labels. Control Clin Trials. 2004 Dec;25(6):535552. 8. Watt S. Clinical decision-making in the context of chronic illness. Health Expect. 2000 Mar;3(1):6-16. 9. Gerber BS, Eiser AR. The patient physician relationship in the Internet age: future prospects and the research agenda. J Med Internet Res. 2001 Apr-Jun;3(2):E15. 10. Zachariae R, Pedersen CG, Jensen AB, et al. Association of perceived physician communication style with patient satisfaction, distress, cancer-related self-efficacy, and perceived control over the disease. Br J Cancer. 2003 Mar 10;88(5):658-665. 11. Lehoux P, Blume S. Technology assessment and the sociopolitics of health technologies. J Health Polit Policy Law. 2000 Dec;25(6):10831120. 12. Bozic KJ, Pierce RG, Herndon JH. Health care technology assessment. Basic principles and clinical applications. J Bone Joint Surg Am. 2004 Jun;86-A(6):1305-1314. 13. Institute of Medicine (US), Committee for Evaluating Medical

Technologies and Clinical Use, Division of Health Sciences Policy, Division of Health Promotion and Disease Prevention, Institute of Medicine. Assessing Medical Technologies. Washington, DC: National Academy Press; 1985.

AHDB Stakeholder Perspective Dr. Murphy’s opening statement about the importance of “integrating knowledge across a spectrum of interests and perspectives” to new drug development captures the essence of the challenge to align the interests of manufacturer and customer. Research and development (R&D) represents the capability of science to heal; it is a progressive field. The provider, payor, and regulatory stakeholder sectors are inherently conservative, delaying or outright limiting acceptance of new drug innovation. That is as it should be. The question remains—Are all stakeholders aligning their activities in a way that can be considered progressive and efficient for making available the use of important new therapies?

continued on page 33

It’s About Being Available. 1

Ranked Number One In Building Customer Relationships.

1Based on a survey by Retail Pharmacy Management, 2006.

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AHDB Stakeholder Perspective continued from page 32 R&D are providing important new therapies faster than healthcare plans can pay for them. This is putting pressures on payors and health plan sponsors to impede branded drug utilization. Several financial factors are behind this payor dynamic, and they must be addressed if healthcare is to receive the full potential of innovative research. The first is the demographic/epidemiologic reality of the graying of the baby boom generation, which has resulted in an increase in chronic diseases that, in turn, caused an increase in drug utilization. A second factor is the increased cost of launching a new drug, now approaching an average of $800 million. A third factor is a rise in litigation in the wake of a new drugâ&#x20AC;&#x2122;s side effects. However, payors also have an incentive to take advantage of new drug development if they are at risk for overall healthcare resource allocation and not just the drug benefit. A healed patient is preferable financially to a patient taking inexpensive, older drugs that fail to heal. Meanwhile, the demand for evidence-based formu-

First In Service Because We Put Service First

lary/benefit design models is countered by an incomplete consensus on the ability of different categories of evidence to determine drug safety, efficacy, and above all, value, including randomized controlled trials, observational data, meta-analyses, and adaptive clinical trial designs. In addition, much remains to be understood about the application of population-based research findings in the clinical setting. Pharmaceutical and biotech companies are attempting to collaborate with payors at the early stages of drug development to identify which drugs will resonate with the plan. Much work remains to be done to align interests, as manufacturers still need to protect trade secrets and payors cannot agree to use a drug that will be launched several years hence in a changed market. The advantages of aligning stakeholder interests outweigh the traditional boundaries that historically have kept new drug development the best-kept secret. Cost pressures are too great to expect the stakeholders to resist collaboration.

Coming Soon in

Not Waiting for Godot: The Evolution of Health Promotion at PPG Alberto Colombi, MD, MPH

Managed Care Pharmacy Emerging Trends: Second Annual Survey Cynthia J. Pigg, RPh, MHA

The Role of Meta-Analysis in Comparative Drug Evaluation Nirav R. Shah, MD, MPH

The Impact of CMS on Biotech Drug Coverage, Part 2 Joseph Antos, PhD

ESAs in a Meta-Stable State: Guidelines, Economics, and Policy in Flux Samuel M. Silver, MD, PhD, and F. Randy Vogenberg, RPh, PhD

NCCN Compendium William T. McGivney, PhD

STATE-OF-THE-ART REVIEWS ON: Depression Schizophrenia Hypertension Cholesterol-lowering Diabetes Dementia Infectious Diseases

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Asthma—The National Surveillance Data and the National Asthma Education and Prevention Program’s Expert Panel Report 3 Thomas McCarter, MD, FACP

“The disease often begins in childhood and sometimes lasts until old age. It may follow an attack of whooping cough. One of the most striking peculiarities is the bizarre and extraordinary variety of circumstances, which at times induce a paroxysm. Among these local conditions, climate or atmosphere is most important.” —–William Osler, MD (1905) Asthma was familiar to various Greek and Roman authors; however, the attacks of severe wheezing were confused with dyspnea from other causes.1 By the 1900s many of the key attributes of the disease state were well described, such as spasm of the bronchial muscles, swelling of the bronchial mucous membrane, and the role of inflammation. The disease was recognized to run in families, and to be influenced by provocative stimuli such as odors, flowers, hay, and emanations from animals.2 Today, asthma continues to be recognized as a chronic inflammatory disease of the lungs, which typically presents with intermittent cough, wheezing, shortness of breath or dyspnea, and chest tightness, commonly occurring during the night and early morning. The underlying inflammation leads to airway hyperresponsiveness and obstruction with some degree of reversibility. This inflammatory reaction may result in sudden exacerbations and chronic progressive structural changes within the lung.

Incidence, Prevalence, and Mortality

n October 2007, the Centers for Disease Control and Prevention published National Surveillance for Asthma in the United States for the years 1980-2004.3 Over a 3-year period (2001-2003), an average annual 20 million persons in the United States reported having asthma. Of these, approximately 6.2 million were children (younger than age 18 years), and 13.8 million were adults. The prevalence was higher in children (8.5%) than in adults (6.7%). Rates were higher for male children (9.6%) compared with female children

Dr. McCarter is Senior Vice President, Medical Affairs, Chief Medical Officer, Main Line Health, West Chester, PA.

(7.4%); however, male adults (4.9%) had a lower prevalence than female adults (8.4%). Rates were highest in the Northeast (8.1%) compared with the Midwest (7.5%), South (6.7%), or West (6.8%). More than half of these patients reported experiencing an attack in the previous year. For the 3-year period 2001-2003, asthma patients had an annual average of 12.3 million physician office visits, 1.3 million hospital outpatient visits, 1.8 million emergency department visits, and 504,000 hospital discharges (Figure 1).3 During the same period, there were approximately 4,210 deaths annually from asthma (Figure 2).3 About half of these deaths occurred in persons older than 65 years of age. Approximately 200 were children younger

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es in the annual asthma death rates from 1980 to 1998 and the increasing prevalence for each recent year (2001-2004), the number of asthma deaths was lower than that rate in 2000. Despite these gains, these data show that ethnic and racial disparities in asthma outcomes persist, with greater disease impact within African American and Puerto Rican populations. Socioeconomic disparities also persist, with those below the federal poverty level reporting greater prevalence of asthma (10.3%) than those at (6.4%) or above (7.9%) this level. In August 2007, the National Heart, Lung, and Blood Institute in cooperation with the National Asthma Education and Prevention Program (NAEPP) released Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and Management of Asthma.4 This panel was convened to review new information and to update reports published in 1991,5 1997,6 and 2002.7 In the latest work, the panel reviewed more than 15,000 titles, 2,800 abstracts, and in excess of 2,000 fulltext articles. This article attempts to summarize some of the recommendations from this 440-page report, focusing on patients 12 years of age and older, and on the diagnosis and management of asthma. Readers are encouraged to review the original document for more detailed information, including recommendations for children younger than 12 years of age, as well as excellent tools useful for improving practice.

Figure 1. Rate* of Encounters for Asthma by Site of Encounter, Age, Sex, and Race—United States, 2001-2003

100

Hospital

Outpatient clinic

Emergency department

Physician’s office

Rate

80 60 40 20 0 Child

Adult

Male

Age

Female

White

Sex

Black

Race

*Per 100 persons with current asthma. Moorman et al, 2007.3

Figure 2. Number and Rate* of Asthma Deaths by Year and International Classification of Diseases† (ICD)—United States, 1980-2004

30 6,000

4,500

20 15

3,000

Rate

Number

Pathogenesis

ICD-10

ICD-9

10 1,500

0 1980

1984

1988

1992 Year

1996

2000

2004

National Vital Statistics System, National Center for Health Statistics. *Per million population. Age-adjusted to 2000 U.S. population. † During 1979-1998, ICD-9 was used to classify deaths. In 1999, ICD-10 was implemented. Moorman et al, 2007.3

than 18 years of age. Because of changes in coding practice, it is somewhat difficult to compare rates before and after 1999; however, despite linear increas-

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Although there is no clear etiology of asthma, the key pathologic feature is chronic inflammation involving neutrophils, eosinophils, lymphocytes, macrophages, mast cells, and a vast number of inflammatory mediators.8 This inflammation leads to airway hyperresponsiveness, obstruction, and, in some cases, chronic structural changes to the airway, such as fibrosis, excess mucous production and glandular hyperplasia, hypertrophy of smooth muscle, epithelial cell injury, and new vessel formation.9 The acute symptoms of asthma, and sudden exacerbations, result from airflow limitation, and usually respond to bronchodilator and anti-inflammatory medications. Airflow limitation in asthma is caused by bronchoconstriction or bronchospasm—smooth muscle contraction that narrows the airways. This may occur in response to allergic or irritant stimuli that induce immunoglobulin (Ig)E-dependent release of mediators from mast cells (histamine, tryptase, leukotriene, and prostaglandins) that directly contract airway smooth

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muscle. Similar mediator release may occur from nonIgE–mediated mechanisms, including aspirin and nonsteroidal anti-inflammatory drugs, environmental stimuli (extremes of heat, cold, and humidity), exercise, and emotional stress. Bronchoconstriction in asthma is exaggerated and described as hyperresponsiveness. Anti-inflammatory treatment reduces hyperresponsiveness, thereby reducing the frequency of exacerbations and improving asthma control. With more persistent disease and prolonged inflammation, edema, excess mucous production, and structural changes may further limit airflow.

Risk Factors Asthma has long been recognized to be associated with allergy and atopy. Atopy, an adverse inflammatory immune reaction involving IgE, remains the strongest identifiable risk factor for the development of asthma. Therefore, host factors such as genetic predisposition may interact with environmental stimuli generating an excessive acute and/or chronic inflammatory reaction. Distinct phenotypes of asthma have been described, such as intermittent, persistent, exercise-associated, aspirin-sensitive, and severe asthma. Viral infections also play a role as an important cause of disease exacerbations, and perhaps in the development of asthma. Some studies have shown that children with documented hospitalizations due to infection with respiratory syncytial virus have a higher incidence of asthma in later life, but others have conferred a protective effect of viral infections in early life. Environmental risk factors such as house-dust mite, cockroach, and Alternaria exposures are recognized risk factors for children. Dog and cat dander have been implicated in the past; however, some studies have found early exposure to these allergens to be protective. Tobacco smoke, air pollution, occupational exposures, and diet (low intake of antioxidants and omega-3 fatty acid, as well as obesity in general) have been implicated as risk factors. Although genetic and environmental stimuli may vary considerably, the inflammatory reaction remains consistent. The onset of asthma for most patients occurs early in life and is often associated with a parental history of the disease. In early life, asthma is more prevalent among boys; however, at puberty the ratio shifts, and the prevalence and incidence appear higher in women. Female asthmatics are also more likely to have reported attacks in the preceding year.

Natural History Children in whom the onset of asthma symptoms occur within the first 3 years of life may develop deficits in lung growth associated with asthma occurrence by 6 years of age. When followed through 11 to 16 years of age, these children experience significant reduction in lung function compared with children with no history of symptoms for the first 6 years of life. Children whose symptoms begin after 3 years of age do not experience deficits in lung function. Deficits therefore seem to correlate better with the time of onset than to the duration of the disease. Deficits do not correlate to severity of symptoms or to degree of control. Not all children who wheeze will go on to develop persistent asthma. The following algorithm has been shown useful in identifying those who will:

Children in whom the onset of asthma symptoms occur within the first 3 years of life may develop deficits in lung growth associated with asthma occurrence by 6 years of age.

Children younger than 3 years of age who experienced 4 or more episodes of wheezing in the previous year will develop persistent asthma, if they have 1 of the following: • parental history of asthma • physician diagnosis of atopic dermatitis • evidence of sensitization to aeroallergens or 2 of the following: • evidence of sensitization to foods • peripheral blood eosinophilia greater than or equal to 4% • wheezing apart from colds

Asthma Diagnosis The panel defines 5 terms with regard to asthma assessment and monitoring: • Severity is the intrinsic intensity of the disease process, measured most easily during an initial visit with a patient not receiving long-term control therapy. Severity is a useful guide to making clinical decisions regarding therapy. In patients who are already treated at the time of the initial visit, severity may be

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inferred by the least amount of treatment required to maintain control. • Control is the degree to which the manifestations of asthma (symptoms, functional impairments, and risks of untoward events) are minimized and the goals of therapy are met. After therapy is initiated, the degree of control achieved will determine whether adjustments in therapy are required. • Responsiveness is the ease with which asthma control can be achieved through therapy. • Impairment is a measure of the frequency and intensity of symptoms and functional limitations the

patient is experiencing or has recently experienced. • Risk is the likelihood of either asthma exacerbations, progressive decline in lung function (or for children, reduced lung growth), or adverse effects from therapy. To establish a diagnosis of asthma, the clinician should determine that episodic symptoms of airflow obstruction or airway hyperresponsiveness are present. This airflow obstruction should be at least partially reversible, and alternative diagnoses should be excluded. This determination should be made on the basis of a detailed medical history, a physical examination, and pulmonary function testing (spirometry). The medical history should identify symptoms likeCLASSIFYING INITIATING TREATMENT F I G U R E 4 – 6ASTHMA . C L A SSEVERITY S I F Y I N GAND AST HMA SEV E R I T Y A NIN D INITIATING ly caused by asthma, patterns of YOUTHS AND1 ADULTS T R E A T M12 E NYEARS T I N YOF O UAGE THS 2 YEARS OF AGE AND ADULTS symptoms, family history of asth— Assessing severity and initiating treatment for patients who are not currently taking long-term control ma, or a personal or family histomedications ry of allergies. Classification of Asthma Severity Physical examination may 12 years of age indicate hyperexpansion of the Components of Severity Persistent thorax, accessory muscle use, Intermittent Mild Moderate Severe hunched shoulders, chest defor2 days/week >2 days/week but Daily Throughout the day Symptoms not daily mity, wheezing, prolonged expi2x/month 3 4x/month Nighttime >1x/week but Often 7x/week ration, nasal discharge, congesawakenings not nightly 2 days/week >2 days/week Short-acting Daily Several times tion or polyps, atopic dermatitis, Impairment beta -agonist use for per day but not daily, and symptom control (not not more than eczema, or other allergic skin prevention of EIB) 1x on any day Normal FEV /FVC: Interference with None Minor limitation Some limitation Extremely limited conditions. Pulmonary function 8 19 yr 85% normal activity 20 39 yr 80% testing should be used to deter• Normal FEV 40 59 yr 75% between 60 80 yr 70% exacerbations mine the presence and degree of • FEV <60% • FEV >80% • FEV >80% • FEV >60% but Lung function obstruction, and the degree of predicted predicted <80% predicted predicted • FEV /FVC normal • FEV /FVC normal • FEV /FVC reduced • FEV /FVC reversibility. The expert panel 5% reduced >5% recommends that forced expira0 1/year (see 2/year (see note) note) Exacerbations tory volume in 1 second (FEV1), requiring oral Consider severity and interval since last exacerbation. Risk systemic Frequency and severity may fluctuate over time for patients in any severity category. forced vital capacity (FVC), and corticosteroids Relative annual risk of exacerbations may be related to FEV . the ratio of FEV1/FVC be meaStep 3 Step 4 or 5 Recommended Step sured before and after the patient Step 1 Step 2 and consider short course of for Initiating Treatment oral systemic corticosteroids inhales a short-acting bronchoIn 2 6 weeks, evaluate level of asthma control that is achieved and adjust therapy (See figure 4 5 for treatment steps.) dilator for all patients 5 years of accordingly. — age or older, in whom the diagnoKey: FEV , forced expiratory volume in 1 second; FVC, forced vital capacity; ICU, intensive care unit sis of asthma is being considered. Notes: Spirometry is preferred over The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual patient measurements by a peak flow needs. meter in physicians’ offices. The Level of severity is determined by assessment of both impairment and risk. Assess impairment domain by patient’s/caregiver’s recall of previous 2–4 weeks and spirometry. Assign severity to the most severe category in forced expiratory volume in 6 which any feature occurs. seconds (FEV6) may be a reasonAt present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma severity. In general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, able alternative to the FVC. hospitalization, or ICU admission) indicate greater underlying disease severity. For treatment purposes, patients Airflow obstruction is indicated who had 2 exacerbations requiring oral systemic corticosteroids in the past year may be considered the same as patients who have persistent asthma, even in the absence of impairment levels consistent with persistent asthma. by a reduction in the values for both the FEV1 and the ratio Source: Reference 4. (FEV1/FVC) relative to reference 2

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or predicted values. If FVC is reduced Figure 3. with a normal or increased ratio (FEV1/FVC), this pattern suggests a restrictive defect rather than an SAMPLE F I G U R EASTHMA 3 – 1 0 a . ACTION S A M PPLAN LE ASTHMA ACTION PLAN obstructive defect, making the diagnosis of asthma less likely. Reversibility is indicated by the American Thoracic Society standards as an increase in FEV1 of more than 200 mL and more than 12% from baseline after the inhalation of a short-acting bronchodilator. Some studies also consider an increase greater than or equal to 10% of predicted FEV1 as an indication of reversibility. The degree of reversibility appears to correlate with the degree of airway inflammation, the risk of developing fixed airflow obstruction, and the severity or loss of lung function. Additional studies may be appropriate based on history and physical examination findings to rule out other diagnoses (vocal cord dysfunction, cough variant asthma, allergic bronchopulmonary aspergillosis, and obstructive sleep apnea) or to identify comorbid conditions that could affect asthma control (gastroesophageal reflux disease and chronic obstructive pulmonary disease). Provocative testing with methacholine, histamine, cold air, or exercise challenge may be useful when asthma is suspected and spirometry is normal or near normal. Chest x-ray may be indicated to exclude other diagnoses. Patients with more severe asthma may require more aggressive therapy Source: Adapted and reprinted with permission from the Regional Asthma Management and Prevention (RAMP) Initiative, a program of the Public Health Institute. http://www.calasthma.org/uploads/resources/actionplanpdf.pdf; San Francisco Bay Area Regional Asthma Management Plan, http://www.rampasthma.org to achieve adequate control. Severity and degree of control can usually be determined by taking a carefully directed history, physical examination, and lung funcmore effectively quantify the degree of obstruction. tion measurement. A number of standardized validatSome historical factors may be valuable in assessing ed instruments have been developed to determine the risk, such as emergency department visits, intensive severity of impairment in patients of various ages. care unit admissions, or hospitalizations in the past Some patients may not accurately gauge their degree year. Some patients with few symptoms and little of obstruction (“poor perceivers”). They may have impairment may still be at risk for life-threatening limited their activity to reduce symptoms or may have exacerbations. A number of possible biomarkers are blamed symptoms on other factors such as age, obesiunder study, but none to date have proved to be diagty, or lack of fitness. In these patients, spirometry may nostic or reliable markers of severity or risk.

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avoid triggers, or if unavoidable, how to adjust their treatment regimen and monitoring in response to triggers. The patient or caregiver must FOR YEARS FSTEPWISE I G U R E 4 APPROACH –5. STEPW I S EMANAGING A P P R O AASTHMA C H F O RINMYOUTHS A N A G I N 12 G A S T H MOF A IAGE N AND ADULTS Y OUT HS 12 YEARS OF AGE AND ADULTS understand and be able to adhere to the treatment plan, including pharPersistent Asthma: Daily Medication macologic administration. AssessIntermittent Consult with asthma specialist if step 4 care or higher is required. Asthma ment of skills as well as education and Consider consultation at step 3. support of self-management techStep 6 Step up if niques must be integrated into all needed Step 5 Preferred: phases of clinical management. (first, check Preferred: High-dose Step 4 ICS + LABA + oral adherence, The initial assessment of severity is High-dose corticosteroid environmental ICS + LABA Preferred: Step 3 made on the basis of current spiromecontrol, and AND Medium-dose ICS AND Preferred: comorbid + LABA try and the patient’s recall of sympStep 2 Low-dose Consider conditions) Consider ICS + LABA Omalizumab for Preferred: Alternative: Omalizumab for toms over the previous 2 to 4 weeks. OR patients who have Low-dose ICS patients who have Medium-dose ICS Medium-dose ICS Step 1 allergies Assess allergies Severity with regard to impairment is Alternative: + either LTRA, Alternative: control Preferred: Theophylline, or Cromolyn, LTRA, Low-dose ICS + assessed via spirometry and review of Zileuton Nedocromil, or either LTRA, SABA PRN Theophylline Theophylline, or symptoms, including nighttime awakZileuton Step down if possible enings; need for short-acting bron(and asthma is chodilators for symptom relief; work Each step: Patient education, environmental control, and management of comorbidities. well controlled at least or school days missed; the ability to Steps 2 4: Consider subcutaneous allergen immunotherapy for patients who have allergic asthma (see notes). 3 months) engage in normal, desired activities; Quick-Relief Medication for All Patients and quality-of-life assessments. Treat• SABA as needed for symptoms. Intensity of treatment depends on severity of symptoms: up to 3 treatments at 20-minute intervals as needed. Short course of oral systemic corticosteroids may be needed. ment decisions for children should be • Use of SABA >2 days a week for symptom relief (not prevention of EIB) generally indicates inadequate control and the need to step up treatment. made on the basis of symptoms with — Key: Alphabetical order is used when more than one treatment option is listed within either preferred or spirometry as an additional guide. alternative therapy. EIB, exercise-induced bronchospasm; ICS, inhaled corticosteroid; LABA, long-acting inhaled beta FEV1 appears to be a useful measure agonist; LTRA, leukotriene receptor antagonist; SABA, inhaled short-acting beta -agonist indicating risk of exacerbations, Notes: The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual patient whereas FEV1/FVC appears to be a needs. more sensitive measure of severity in If alternative treatment is used and response is inadequate, discontinue it and use the preferred treatment before stepping up. the impairment domain. Zileuton is a less desirable alternative due to limited studies as adjunctive therapy and the need to monitor liver function. Theophylline requires monitoring of serum concentration levels. The second dimension of severity In step 6, before oral systemic corticosteroids are introduced, a trial of high-dose ICS + LABA + either LTRA, is the risk of adverse events, includtheophylline, or zileuton may be considered, although this approach has not been studied in clinical trials. Step 1, 2, and 3 preferred therapies are based on Evidence A; step 3 alternative therapy is based on Evidence A for ing exacerbations and death. Patients LTRA, Evidence B for theophylline, and Evidence D for zileuton. Step 4 preferred therapy is based on Evidence B, at increased risk will require close and alternative therapy is based on Evidence B for LTRA and theophylline and Evidence D for zileuton. Step 5 preferred therapy is based on Evidence B. Step 6 preferred therapy is based on (EPR 2 1997) and Evidence B for monitoring and frequent assessment. omalizumab. Immunotherapy for steps 2–4 is based on Evidence B for house-dust mites, animal danders, and pollens; evidence It is important to remember that is weak or lacking for molds and cockroaches. Evidence is strongest for immunotherapy with single allergens. The role of allergy in asthma is greater in children than in adults. patients at any level of severity may Clinicians who administer immunotherapy or omalizumab should be prepared and equipped to identify and treat have severe exacerbations. Predictors anaphylaxis that may occur. of increased risk include severe airflow Source: Reference 4. obstruction as detected by spirometry, especially persistent obstruction; 2 or more emergency department visits or hospitalizations in Management and Self-Management the past year; history of intubation or intensive care Precipitating factors such as inhalant allergen (pets, unit admission, especially in the past 5 years; and a mold, seasonal pollens) exposure at home, work, or reported sense of danger or fear associated with asthma. school; irritants (tobacco smoke, industrial pollutants, Patients who are female, nonwhite, who smoke, who ozone); and viral infections should be identified, as do not use inhaled corticosteroids (ICSs), and who are should comorbid conditions that might aggravate asthdepressed or emotionally stressed are at increased risk ma, such as sinusitis, rhinitis, and gastroesophageal for adverse events. reflux disease. Patients should be educated about how to The first goal of therapy is to achieve adequate con-

Figure 4.

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Table 1. Inhaled Corticosteroids (ICSs) and Linear Growth in Children

• • • • •

•

The potential risks of ICSs are well balanced by their benefits. Growth rates are highly variable in children. Short-term evaluations may not be predictive of final adult height attained. Poorly controlled asthma may delay growth in children. In general, children who have asthma tend to have longer periods of reduced growth rates before puberty (males more than females). The potential for adverse effects on linear growth from ICSs appears to be dose dependent. In treatment of children who have mild or moderate persistent asthma, low- to medium-dose ICS therapy may be associated with a possible, but not predictable, adverse effect on linear growth. The clinical significance of this potential systemic effect has yet to be determined. High doses of ICS have greater potential for growth suppression. Use of high doses of ICS by children who have severe persistent asthma has significantly less potential than use of oral systemic corticosteroids for having an adverse effect on linear growth. Studies in which growth has been carefully monitored suggest the growth-velocity effect of ICS use occurs in the first several months of treatment and is generally small and nonprogressive. In general, the efficacy of ICSs is sufficient to outweigh any concerns about growth or other systemic effects; however, ICSs, as with any medications, should be titrated to as low a dose as needed to maintain good control of the child’s asthma.

Expert Panel Report 3.4

trol by reducing impairment. This may be accomplished by preventing symptoms (specifically daytime symptoms and nighttime awakenings), requiring infrequent use (less than or equal to 2 days per week) of inhaled shortacting bronchodilators, maintaining near-normal pulmonary function and activity levels, and meeting expectations and generating satisfaction with asthma care. The second goal of therapy is to achieve adequate control by reducing risk. This may be accomplished by preventing exacerbations and decreasing the need for emergency department visits and hospitalizations, preventing progressive loss of lung function, and providing optimal pharmacotherapy with minimal adverse effects. Periodic assessments at no greater than 6-month intervals and ongoing monitoring are recommended to determine if goals are being met, or whether adjustments in therapy are required. Follow-up spirometry is recommended at least every 1 to 2 years after treatment has been started and symptoms have stabilized, and more frequently if necessary during periods of progressive or prolonged loss of asthma control. An FEV1 less than 60% of predicted is consistent with “severe asthma,” an FEV1 of 60% to 79% of predicted is consistent with “moderate asthma,” and 80% to 100% with “mild asthma.” All patients should be provided a written asthma action plan based on signs and symptoms or peak expi-

ratory flow (PEF) measurements (Figure 3). Written action plans should contain information specific to daily management and recognition of worsening asthma. Daily management action plans should include names and instructions for the use of daily medications, and actions to take to control environmental triggers. Action plans for worsening symptoms should include signs, symptoms, and peak flow measurements that indicate worsening asthma; medication adjustment to make in response to these signs; symptoms and peak flow measurements indicating the need for urgent medical attention; and emergency contact numbers and instructions for the physician, emergency department, and transport services. Patient self-monitoring of PEF and symptoms are important for the effective management of asthma. Patients should be taught to recognize symptom patterns that indicate poor control and the need for more aggressive therapy. Education and support of self-management should be reinforced in all healthcare settings, including physicians’ offices, pharmacies, emergency departments, schools, community and hospital settings, and in the home. Self-management education has proved both effective and cost-effective for asthma, with increasing benefits in more severe disease. Disease management and intensive case management approaches have also been found to be cost-effective. Providers must under-

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ASSESSING THERAPY F I G U R E 4 –ASTHMA 7 . A S SCONTROL E S S I N G AND A S TADJUSTING HMA CONT R O L A NIN D YOUTHS A D J U S T12 I NYEARS G OF AGE AND T HE RAP Y I ADULTS N YOUTHS 12 YEARS OF AGE AND ADULTS Classification of Asthma Control ( 12 years of age)

Components of Control

Well Controlled Symptoms

2 days/week

>2 days/week

Nighttime awakenings

2x/month

1 3x/week

Interference with normal activity

Impairment

Not Well Controlled

None

Throughout the day 4x/week

Some limitation

2 days/week

Short-acting beta2-agonist use for symptom control (not prevention of EIB) FEV1 or peak flow

Very Poorly Controlled

Extremely limited

>2 days/week

Several times per day

>80% predicted/ personal best

60 80% predicted/ personal best

<60% predicted/ personal best

1–2 1.5 16 19

3–4 N/A 15

Validated questionnaires ATAQ ACQ ACT Exacerbations requiring oral systemic corticosteroids

Risk

0.75* 20 0 1/year

2/year (see note) Consider severity and interval since last exacerbation

Progressive loss of lung function

Evaluation requires long-term followup care

Treatment-related adverse effects

Medication side effects can vary in intensity from none to very troublesome and worrisome. The level of intensity does not correlate to specific levels of control but should be considered in the overall assessment of risk.

Recommended Action for Treatment

• Maintain current step. • Regular followups every 1 6 months to maintain control. • Consider step down if well controlled for at least 3 months.

choscopy. Patients with special needs for education, candidates for immunotherapy, and those in need of evaluation for occupational triggers or mental health conditions should be referred to an appropriate resource.

• Step up 1 step and • Reevaluate in 2 6 weeks. • For side effects, consider alternative treatment options.

• Consider short course of oral systemic corticosteroids, • Step up 1 2 steps, and • Reevaluate in 2 weeks. • For side effects, consider alternative treatment options.

Medication Management The panel categorizes asthma medications in 2 classes: longterm control medications used to achieve and maintain control of asthma, and quick-relief medications used to treat acute symptoms and exacerbations (Figure 4).

Long-Term Control Medications (Controller Medications)

The most effective long-term control medications are those that affect underlying inflamma— *ACQ values of 0.76–1.4 are indeterminate regarding well-controlled asthma. — Key: EIB, exercise-induced bronchospasm; ICU, intensive care unit tion, and these should be taken Notes: daily to achieve and maintain The stepwise approach is meant to assist, not replace, the clinical decisionmaking required to meet individual patient control of persistent asthma. needs. The level of control is based on the most severe impairment or risk category. Assess impairment domain by patient’s recall ICSs are the most potent and of previous 2–4 weeks and by spirometry/or peak flow measures. Symptom assessment for longer periods should reflect a effective anti-inflammatory medglobal assessment, such as inquiring whether the patient’s asthma is better or worse since the last visit. At present, there are inadequate data to correspond frequencies of exacerbations with different levels of asthma control. In ications currently available for general, more frequent and intense exacerbations (e.g., requiring urgent, unscheduled care, hospitalization, or ICU admission) indicate poorer disease control. For treatment purposes, patients who had 2 exacerbations requiring oral the long-term control of asthma. systemic corticosteroids in the past year may be considered the same as patients who have not-well-controlled asthma, even in the absence of impairment levels consistent with not-well-controlled asthma. These agents reduce the severity of Validated Questionnaires for the impairment domain (the questionnaires do not assess lung function or the risk domain) symptoms, improve control, imATAQ = Asthma Therapy Assessment Questionnaire© (See sample in “Component 1: Measures of Asthma Assessment and Monitoring.”) prove spirometry, diminish hyperACQ = Asthma Control Questionnaire© (user package may be obtained at www.qoltech.co.uk or juniper@qoltech.co.uk) responsiveness, and reduce exacACT = Asthma Control Test (See sample in “Component 1: Measures of Asthma Assessment and Monitoring.”) erbations, hospitalizations, and Minimal Important Difference: 1.0 for the ATAQ; 0.5 for the ACQ; not determined for the ACT. Before step up in therapy: death, while improving quality of — Review adherence to medication, inhaler technique, environmental control, and comorbid conditions. life. Short courses of systemic — If an alternative treatment option was used in a step, discontinue and use the preferred treatment for that step. corticosteroids, given orally or Source: Reference 4. intravenously, are often used to gain prompt control of the disease stand and work to eliminate barriers to self-management during exacerbations or when initiating long-term therand participatory care such as poor health literacy, as apy; however, the lower bioavailability of ICSs confers well as cultural and ethnic barriers that might impede lower risks of side effects than systemic corticosteroids. the creation of a true care partnership. Corticosteroid effectiveness is decreased among smokers, Referral to an asthma specialist for consultation of and difficult to control asthma in some African comanagement is recommended when a patient has a American children may be the result of diminished corlife-threatening asthma exacerbation, is not meeting the ticosteroid sensitivity at the cellular level. To reduce the goals of therapy after 3 to 6 months of treatment, has perpotential for adverse effects, ICSs may be used with a sistent atypical signs or comorbid conditions, or has a spacer device (unless breath activated), and patients need for additional testing such as allergy testing or bronmay be instructed to “rinse and spit” after inhalation. (see figure 4 5 for treatment steps)

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Adherence to therapy and technique in using inhalers should be assessed at every opportunity. The lowest dose that achieves control should be used. In some patients, the addition of an adjunct controller medication may allow reduction of inhaled steroid dosage. Monitoring for bone loss, supplemental vitamin D and calcium, or antiresorptive therapy may be indicated in patients with increased risk for osteoporosis. The benefits of ICS use in all age groups outweigh concerns about growth or other systemic effects (Table 1). Cromolyn sodium and nedocromil stabilize mast cells and modulate inflammation by interfering with chloride channel functions. They are not preferred agents but may be used as alternatives in the treatment of mild persistent asthma. They may also have a role in treatment before exercise or unavoidable exposure to other triggers. Immunomodulators, such as omalizumab, a monoclonal antibody that prevents binding of IgE to receptors on mast cells and basophils, may be used as adjunctive therapy for some patients. Clinicians who administer this agent should be prepared to treat anaphylaxis that may occur. Several leukotriene-modifying agents are available for the treatment of asthma. Two of these are leukotriene receptor antagonists (LTRAs), montelukast and zafirlukast. A third agent, zileuton, is a 5-lipoxygenase-pathway inhibitor that requires liver function monitoring and is not approved for use in children. Although these agents are not preferred, they are effective alternative medications for mild persistent asthma or as adjunctive therapy. Long-acting beta2-agonists (LABAs), salmeterol and formoterol, are bronchodilators that have durations of action greater than 12 hours after a single dose. They do not affect the chronic inflammation that is central to the disease process; therefore, they are not recommended for use as monotherapy. They may be used in combination with ICSs for long-term control and prevention of symptoms in moderate or severe persistent asthma. LABAs are the preferred adjunctive therapy in adults and children older than age 12. They may also be used before exercise to prevent exercise-induced bronchospasm (EIB); however, chronic use is discouraged because of the risk of disguising poorly controlled persistent asthma. Use of LABAs for the treatment of acute symptoms or exacerbations is not recommended. Long-term use of LABAs in some studies has been associated with increased mortality, as reflected in the U.S. Food and Drug Administration black box warning on all of these preparations. Methylxanthines, such as sustained-release theo-

Table 2. Risk Factors for Death From Asthma

Asthma history Previous severe exacerbation (eg, intubation or ICU admission for asthma) Two or more hospitalizations for asthma in the past year Three or more ED visits for asthma in the past year Hospitalization or ED visit for asthma in the past month Using >2 canisters of SABA per month Difficulty perceiving asthma symptoms or severity of exacerbations Other risk factors: Lack of a written asthma action plan, sensitivity to Alternaria Social history Low socioeconomic status or inner-city residence Illicit drug use Major psychosocial problems Comorbidities Cardiovascular disease Other chronic lung disease Chronic psychiatric disease ED indicates emergency department; ICU, intensive care unit; SABA, shortacting beta2-agonist. Adapted from Abramson et al, 2001; Greenberger et al, 1993; Hardie et al, 2002; Kallenbach et al, 1993; Kikuchi et al, 1994; Oâ&#x20AC;&#x2122;Hollaren et al, 1991; Rodrigo and Rodrigo, 1993; Strunk and Mrazek, 1986; Suissa et al, 1994.

phylline, are mild to moderate bronchodilators and may have a mild anti-inflammatory effect. Although not preferred, theophylline may be used as an alternative therapy, and although not a preferred adjunct, it may be used in an adjunctive role with ICS. Monitoring of serum theophylline concentrations is essential.

Quick-Relief Medications (Rescue Medications) Anticholinergic medications inhibit muscarinic cholinergic receptors and reduce intrinsic vagal tone in the airway. Ipratropium bromide provides additive benefit to short-acting beta2-agonists (SABAs) in moderate to severe asthma exacerbations, and may be used as an alternative bronchodilator in patients who do not tolerate SABAs. SABAs such as albuterol, levalbuterol, and pirbuterol are bronchodilators that relax smooth muscle. They are the therapy of choice for relief of acute symp-

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toms, exacerbations, and for the prevention of EIB. Oral systemic corticosteroids are used for moderate and severe exacerbations as an adjunct to SABAs to speed recovery and to prevent recurrence of exacerbations. The expert panel has provided specific management recommendations and tools for 3 distinct age groups of patients. Children aged 0 to 4 years comprise one group; children aged 5 to 11 years the second group; and youths older than 12 years of age and adults comprise the third group. For each population, the EPR 3 contains recommendations and specific tools including medications approved, severity classification tools, steptherapy diagrams, as well as dosage and titration recommendation. For this document, agents for “youths greater than 12 years of age and adults” have been included for review and discussion.

Patients who have severe exacerbations and are slow to respond to therapy may benefit from admission to an intensive care unit.

Managing Exacerbations Exacerbations are acute or subacute episodes of progressively worsening asthma symptoms characterized by measurable decreases in expiratory airflow. Milder exacerbations may be managed at home, whereas more serious exacerbations may require an unscheduled visit to the physician’s office, an emergency department visit, or a hospitalization. The most severe exacerbations may require admission to an intensive care unit for optimal monitoring with or without ventilatory support. Patients with well-controlled asthma are less prone to have exacerbations; however, they may occur even in patients with good control. Early treatment of exacerbations is the best strategy for management. Because treatment should start immediately at recognition, patient education that includes a written action plan is essential. Patients must understand the early signs, including peak flow measurements that indicate an exacerbation, and what steps to take to withdraw from environmental triggers, to adjust therapy including initiation of a short course of oral systemic corticosteroids in some cases, and to communicate or seek urgent medical care. The expert panel no longer recommends that patients double their ICS dose when

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managing exacerbations. Patients who are at high risk for asthma-related death, and infants owing to their greater risk for respiratory failure, require special attention (Table 2). The principal goals in treating asthma exacerbations should be correction of hypoxemia, reversal of airflow obstruction, and reduction of the likelihood of relapse. These 3 goals are best achieved through administration of supplemental oxygen or mechanically assisted ventilation when required, repetitive or continuous administration of SABAs, and the administration of a short course of systemic corticosteroids to patients with moderate to severe exacerbations or those who fail to promptly respond to SABAs. Careful assessment and monitoring is necessary to achieve these goals. Monitoring may include serial measurement of lung function through spirometry or PEF, pulse oximetry, and serial assessments of signs and symptoms (several assessment tools are reviewed in EPR 3, and are available in the document). Beginning treatment at home avoids treatment delays, prevents exacerbations from becoming severe, and adds to patients’ sense of control over their asthma. Patients should be taught to recognize symptoms of an exacerbation and to assess severity. When possible, peak flow monitoring may provide an accurate assessment of severity and response to treatment, especially in patients who are “poor perceivers” of their degree of obstruction on the basis of symptoms alone. Patients should increase their frequency of SABA use, initiate oral systemic corticosteroids, continue their dose of ICS (although doubling the dose alone is no longer recommended), and continue this more intensive regimen for several days. The expert panel recommends that personnel involved in prehospital management and transportation begin treatment with oxygen and SABAs, without delaying transport, and that jurisdictions enable these providers to have standing orders for repeated treatments and protocols to allow consideration of anticholinergic and oral corticosteroid administration in situations involving prolonged transportation. In the urgent care setting (emergency department or hospital), treatment should focus on oxygen to relieve hypoxemia, SABAs, and perhaps inhaled anticholinergics to relieve airflow obstruction, and systemic corticosteroids to decrease inflammation in patients who fail to immediately respond to bronchodilators alone. Patients should be evaluated and triaged immediately. Initial assessment that includes a brief history, brief physical examination, and objective measures of lung

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function (FEV1 or PEF) should be performed. Laboratory studies, electrocardiogram, and radiology studies are usually not necessary, unless comorbid conditions are present, or if diagnosis is unclear and these are needed to exclude other conditions. After treatment has been initiated with oxygen, SABAs (3 treatments spaced every 20 to 30 minutes can be given safely to most patients), ipratropium bromide, and systemic corticosteroids, a full history and physical examination may be completed. Because of the risk of cardiotoxicity in high doses, the use of selective SABAs (albuterol, levalbuterol, and pirbuterol) is recommended. These agents may be administered via multidose inhaler with a valved holding chamber, or via nebulizer. The onset of action for SABAs is less than 5 minutes, and repetitive administration pro-

duces incremental bronchodilation. Most patients will have a significant response after the first dose, and 60% to 70% will respond sufficiently to 3 doses to allow discharge. The addition of ipratropium bromide (by metered dose inhaler or nebulizer) to SABAs results in additional bronchodilation in the emergency setting; however, ongoing treatment for patients who require hospitalization is not recommended. Patients with moderate to severe exacerbations who do not respond to initial therapy should be started on a short course of systemic corticosteroids, to speed the resolution of airway obstruction, and to reduce the rate of recurrence. The less invasive use of oral preparations is as effective as intravenous formulations and is therefore preferred. A 5- to 10-day course may prevent early relapse. The expert panel does not recommend methylxanthines,

Managing Exacerbations of Asthma Early treatment of asthma exacerbations is the best strategy for management. Important elements of early treatment at the patient’s home include: • Patient education, including a written asthma action plan to guide patient self-management of exacerbations at home, especially for patients who have moderate or severe persistent asthma and any patient who has a history of severe exacerbations. • A peak-flow–based plan may be particularly useful for patients who have difficulty perceiving airflow obstruction and worsening asthma. o Recognition of early signs of worsening asthma and taking prompt action. o Appropriate intensification of therapy by increasing inhaled SABA and, in some cases, adding a short course of oral systemic corticosteroids. o Removal or withdrawal of the environmental factor contributing to the exacerbation. o Prompt communication between patient and clinician about any serious deterioration in symptoms or peak flow, decreased responsiveness to SABAs, or decreased duration of effect. Management of asthma exacerbations requiring urgent medical care (eg, in the urgent care setting or ED) includes: • Oxygen to relieve hypoxemia in moderate or severe exacerbations (EPR 2, 1997). • SABA to relieve airflow obstruction, with addition of inhaled ipratropium bromide in severe exacerbations. • Systemic corticosteroids to decrease airway inflammation in moderate or severe exacerbations or for patients who fail to respond promptly and completely to a SABA. • Consideration of adjunct treatments, such as intravenous magnesium sulfate or heliox, in severe exacerbations unresponsive to the initial treatments listed above. Monitoring response to therapy with serial measurements of lung function. • Preventing relapse of the exacerbation or recurrence of another exacerbation by providing: referral to follow-up asthma care within 1-4 weeks; an ED asthma discharge plan with instructions for medications prescribed at discharge and for increasing medications or seeking medical care if asthma worsens; review of inhaler techniques whenever possible; and consideration of initiating ICSs. ED indicates emergency department; ICS, inhaled corticosteroids; SABA, short-acting beta2-agonist. Expert Panel Report 3.4

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antibiotics (except as needed for comorbid infections), aggressive hydration, chest physical therapy, mucolytics, or sedation. Serial evaluations of symptoms and lung function are necessary to ensure that patients are responding to therapy and to determine final disposition (see sidebar: Managing Exacerbations of Asthma, p 45).

For patients being discharged from the hospital inpatient setting, medications should be adjusted to the outpatient regimen, and the patient should be monitored for 24 hours to ensure stability.

The response to therapy is a better predictor of the need for hospitalization than is the severity of the exacerbation on presentation. Repeat assessments should be performed after the initial dose of a SABA, and after 3 doses. The patient’s subjective response to therapy, physical findings, FEV1 or PEF, pulse oximetry, and perhaps arterial blood gas should be assessed. The decision for further hospitalization is based on the duration and severity of symptoms, the severity of airflow obstruction, the response to treatment, severity and course of previous exacerbations, medication use at time of exacerbation, access to care and medications, the presence of comorbid conditions that could complicate recovery, and support available to the patient at home. EPR 3 recommends cut points established in 1991 for FEV1 or PEF to determine discharge plans from the emergency setting. The goal for discharge from an emergency setting is an FEV1 or PEF greater than or equal to 70% of predicted or personal best. FEV1 or PEF of 40% to 69% indicates an incomplete response to therapy and possibly a need for continued treatment in a monitored setting. An FEV1 or PEF of less than 40% of predicted indicates a severity level where adjunct therapies may be indicated. These cut points differ from those used to determine long-term control. The panel recognizes the limited value of these measures in young children and in the most severe exacerbations. In severe situations, intravenous magnesium sulfate and heliox may play a role in preventing intubation. Other interventions that may be considered but are supported by less evidence include LTRAs and noninvasive ventilation. The expert panel does not recommend the use of intravenous isoproterenol because of the risk of

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myocardial toxicity. Even without intubation, patients who have severe exacerbations and are slow to respond to therapy may benefit from admission to an intensive care unit, where they can be monitored closely and intubated if necessary. The need for intubation is a determination based on clinical judgment. Intubation should not be delayed after it has been deemed necessary. Because intubation is difficult in asthma patients, semielective intubation performed by a physician with extensive experience in airway management is recommended before respiratory arrest occurs. Worsening airflow obstruction, worsening ventilation or respiratory muscle fatigue, evidenced by the inability to speak, altered mental status, intercostal retraction, or a PCO2 of greater than or equal to 42, may signify impending respiratory failure. The recommended ventilator strategy is that of “permissive hypercapnea” or “controlled hypoventilation,” which provides adequate oxygenation and ventilation while minimizing barotrauma owing to high airway pressures. This strategy may require high FIO2 settings, and treatment of respiratory acidosis with intravenous sodium bicarbonate. Consultation or comanagement by physicians with extensive experience in ventilator management may be indicated. When patients stabilize sufficiently to be discharged from the emergency or hospital setting, medications and education on their use (including inhaler technique), follow-up appointments, a peak flow meter (and instruction on its use), and an emergency discharge plan for recognizing and managing relapse should be provided. Patients who have a rapid response to initial therapy should be observed for 30 to 60 minutes to ensure stability of response before discharge. Discharge is usually appropriate if FEV1 or PEF has returned to greater than or equal to 70% of predicted or personal best, and if symptoms are minimal or absent. Patients who have an incomplete response (FEV1 or PEF 50%-69% of predicted or personal best) and mild symptoms should be individually assessed for discharge readiness. Patients should be prescribed sufficient medications to continue treatment after discharge. Those who receive corticosteroids should continue therapy for 3 to 10 days. For courses less than 10 days, and for patients taking concurrent ICSs, there is no need to taper the dose. ICSs in addition to oral therapy have been shown to reduce risk or relapse. The expert panel recommends that ICS therapy should be initiated at discharge even in patients concurrently receiving a short course of systemic steroids. Follow-up care with the patient’s primary care physician or an asthma specialist within 1 to 4

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weeks should be emphasized and facilitated. Emergency providers should communicate with the patient’s regular provider, and encourage patients to contact their provider during the first 3 to 5 days after discharge. For patients being discharged from the hospital inpatient setting, medications should be adjusted to the outpatient regimen, and the patient should be monitored for 24 hours to ensure stability. Discharge medications, education regarding their use, follow-up appointments, written plan, and a peak flow meter with instructions on its use should be provided as described above for discharges from the emergency setting.

be an indication of poorly controlled asthma in need of treatment adjustments. Pretreatment before exercise with various rescue or controller medications may be effective. SABAs will prevent EIB in more than 80% of patients, and may be helpful for 2 to 3 hours. LABAs can be protective for up to 12 hours; however, daily use is associated with a shortening of the duration of protection, even when used in conjunction with ICSs. Frequent and chronic use of LABAs may disguise poorly controlled persistent asthma, which should be controlled with daily anti-inflammatory medication, and therefore, should be discouraged.

Special Considerations in Management The expert panel identifies and provides specific recommendations for 3 topics identified as “Special Situations.” These include Exercise-Induced Bronchospasm, Asthma in Pregnancy, and Surgery in the Asthma Patient.

It is safer for pregnant women and their infants to be treated with asthma medications than to experience symptoms and exacerbations.

Exercise-Induced Bronchospasm Exercise may be the only precipitant of asthma symptoms in some patients, yet EIB should be anticipated in all asthma patients. EIB is a bronchospastic event that is caused by loss of heat, water, or both from the lung owing to hyperventilation of cool, dry air during exercise. Some studies suggest that inflammatory mediators are involved in the response. EIB usually occurs during or minutes after activity, with symptoms reaching a peak 5 to 10 minutes after stopping the activity, and resolving in another 20 to 30 minutes. Some studies have documented a refractory period of less than 1 hour after EIB, allowing for an asthma-symptom–free interval after warm-up exercises. It is unclear whether a latephase reaction occurs hours after exercise. A history of asthma symptoms or endurance problems during exercise suggests EIB. An exercise challenge resulting in a 15% decrease in PEF or FEV1 (with measurements taken before and after exercise at 5minute intervals) is compatible with EIB. Adequate control should enable the patient to participate in any chosen activity, without experiencing symptoms; therefore, EIB should not limit either participation or success in vigorous activities. Evidence suggests that treatment with anti-inflammatory medications will reduce airway hyperresponsiveness, and the frequency and severity of EIB. Patients should be monitored regularly to ensure that they have no other symptoms of asthma, or reductions in PEF or spirometry in the absence of exercise, because EIB may

LTRAs can attenuate EIB in 50% of patients, but onset of protection generally occurs hours after administration. Cromolyn or nedocromil taken shortly before exercise is a less effective alternative to SABAs. Anticholinergics may also attenuate EIB, but are less effective than SABAs and mast cell stabilizers. A warm-up period or a mask or scarf worn during cold weather may also attenuate EIB. Teachers and coaches should be notified that a child has EIB, and although the child should be able to participate in activities, an inhaled medication before participation may be required. In some competitive athletic arenas, disclosure of the use of medication may be necessary.

Surgery and Asthma Asthma patients may be at an increased risk for some complications during or after surgical procedures. Bronchospasm may be triggered by intubation with subsequent hypoxemia or hypercarbia. Impaired effectiveness of cough may predispose patients to atelectasis and pulmonary infections. Latex and medication sensitivities may be more pronounced in this population. The expert panel recommends that asthma patients should be evaluated prior to surgery with special attention to their recent symptoms, medication use, and measurement of pulmonary function. Attempts should be made to improve lung function preoperatively, with

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a goal toward normalizing FEV1 or PEF to either their predicted values or their personal best level. A short course of oral systemic corticosteroids may be necessary to optimize pulmonary function. Patients who have received oral corticosteroids for longer than 2 weeks in the past 6 months, and some patients on a long-term high dose of corticosteroids may require 100 mg hydrocortisone intravenously (stress dose steroids) every 8 hours during the surgical period to mediate the effects of adrenal suppression. In stable postoperative patients, the dose may be reduced rapidly within 24 hours after surgery.

ICSs, budesonide is preferred because it has the most available safety data in pregnancy, and because the available data are reassuring; however, no data suggest that other ICS preparations are unsafe during pregnancy. Cromolyn has an excellent safety profile, but it has limited effectiveness compared with ICSs. Data on the safety and effectiveness of LTRAs and LABAs in pregnancy are limited. For treatment of associated allergy symptoms, intranasal corticosteroids are recommended and have a low risk of systemic effect, and the current second-generation antihistamines of choice are loratadine and cetirizine.

Public Health Issues The working group encourages monitoring of asthma on a monthly basis during prenatal visits, through symptom reporting and spirometry or peak flows.

Pregnancy and Asthma In 2005, the NAEPP â&#x20AC;&#x153;Working Group Report on Managing Asthma During Pregnancyâ&#x20AC;? released recommendations regarding pharmacologic treatment.10 This report and the expert panel emphasize that maintaining adequate control of asthma during pregnancy is important for the health and well-being of both the mother and her baby. Maternal asthma increases the risk of perinatal mortality, preeclampsia, preterm birth, and low-birth-weight infants. More severe asthma correlates with higher risk, whereas better-controlled asthma correlates with lower risk. It is safer for pregnant women and their infants to be treated with asthma medications than to experience symptoms and exacerbations. Because asthma control may improve, worsen, or remain unchanged over the course of pregnancy, ongoing monitoring and adjustments to the treatment regimen may be required to maintain pulmonary function, blood oxygenation, and oxygen delivery to the developing fetus. The working group encourages monitoring of asthma on a monthly basis during prenatal visits, through symptom reporting and spirometry or peak flows. Albuterol is the preferred SABA because it has an excellent safety profile and it has the most available data related to safety during human pregnancy. ICSs are the preferred long-term control medication. Among

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March 2008

Although influenza vaccination does not improve asthma control or symptoms during an exacerbation, the expert panel recognizes that asthmatic patients have a higher risk of adverse outcome from a severe illness with influenza. Therefore it is recommended that all asthma patients undergo annual influenza vaccination. Home-based allergen-reduction interventions focused on reducing allergens through HEPA-filter vacuum cleaners, washing linens in hot water, mattress covers, and pest control have been associated with improved control. Computer-based education and selfmanagement training programs have also been shown in several studies to improve control. Campaigns to reduce exposure to tobacco smoke, especially for pregnant women and parents, have been shown to affect childhood control and severity, especially in children younger than age 3, in whom severity may compromise lung growth. These results also support public health campaigns to reduce environmental tobacco smoke exposure in all public areas. EPR 3 discusses some of the racial and ethnic disparities as well as the cultural challenges that must be overcome to further improve outcomes. The panel recommends heightened awareness of cultural barriers, as well as modification of educational and communication strategies to eliminate these barriers. Some studies have shown that African American and Hispanic children with more severe asthma than white children used less anti-inflammatory medication. Other studies have shown disparities in patterns of follow-up care after emergency visits. Thus underuse or reduced access to preventive therapy may contribute to some of the outcome disparities. Financial barriers may play a role, as may disparities in health literacy, and provider practice policies (bilingual providers, diversity training, continuity of care, and comanagement practices). A large pro-

CLINICAL

portion of ethnic and racial minorities live in urban areas, where exposure to indoor allergens can be high, and where effective mitigation strategies could significantly reduce symptoms. The degree of interaction between race, ethnicity, and socioeconomic status on asthma morbidity and mortality remains a controversial and active area of exploration. Biologic and pathophysiologic differences between ethnic groups are also more commonly recognized, independent of socioeconomic and educational influences.

Stakeholder Issues The National Surveillance for Asthma and EPR 3 are very important documents to all stakeholders in the healthcare system. They provide guidance with regard to screening, diagnosis, and management of a disease that is both common and increasing in prevalence. With better understanding of pathophysiology and better methods for achieving control, mortality seems to be improving. Patients and providers must work to develop a partnership for comanagement that is based on strong evidence of effectiveness. Payors must ensure that financial barriers to appropriate screening, diagnosis, and monitoring tools, as well as controller and rescue therapies are nonexistent. Regulators and public health authorities must ensure support and funding of school-based and communitybased best practices to continue to erode mortality and morbidity, especially in high-risk populations. We must all continue to correct environmental risk factors that affect this and other populations. The authors encourage all readers to review these documents from the perspective of the role they can play with regard to this condition.

AHDB Stakeholder Perspective Asthma remains a serious health concern today. Affecting people of all ages around the world, uncontrolled asthma leads to a poor quality of life, and may also be fatal. In this issue of AHDB, a focus article reviews highlights of the recommendations made by the Expert Panel of the National Asthma Education and Prevention Program (NAEPP). The author, Dr. McCarter, successfully distills the key points from the comprehensive document and pro-

References 1. Osler W. The Principles and Practice of Medicine. New York, NY: D. Appleton and Company; 1905. 2. Cecil RL, ed. A Textbook of Medicine. Philadelphia, PA: WB Saunders and Company; 1944. 3. Moorman JE, Rudd RA, Johnson CA, et al. National Surveillance for Asthma–United States, 1980-2004. MMWR Surveill Summ. 2007;56:154. http://cdc.gov/mmwr/preview/mmwrhtml/SS5608c1.htm. Accessed December 30, 2007. 4. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma (EPR-3 2007). NIH Publication No. 07-4051. Bethesda, MD: US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; 2007. 5. EPR. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma (EPR 1991). NIH Publication No. 91-3642. Bethesda, MD: US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; 1991. 6. EPR-2. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2 1997). NIH Publication No. 97-4051. Bethesda, MD: US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; 1997. 7. EPR—Update 2002. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics 2002 (EPR— Update 2002). NIH Publication No. 02-5074. Bethesda, MD: US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; June 2003. 8. Busse WW, Lemanske RF. Advances in immunology–asthma. N Engl J Med. 2001;344(5):350-362. 9. Jarjour NN, Kelly EAB. Pathogenesis of asthma. Med Clin North Am. 2002;86(5):925-936. 10. National Asthma Education and Prevention Program (NAEPP). Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment–Update 2004 (NAEPP 2005). NIH Publication No. 05-5236. Rockville, MD: US Department of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute; March 2005. http://www.nhlbi.nih.gov/ health/prof/lung/asthma/astpreg.htm. Accessed December 12, 2007.

For inquiries or comments, please e-mail editorial@AHDBonline.com.

vides information that will help asthma patients to better control their disease. The Expert Panel Report 3 (EPR 3) builds on the key points from its previous reports. In 1991, EPR 1 focused on the treatment of asthma as an inflammatory condition of the lung.1 EPR 2 came 6 years later and emphasized the importance of early diagnosis of asthma in hopes of preventing loss of lung function over time.2 Since the last update from 2002,3 EPR 3 has taken the vast amount of information that has accumulated in the asthma literature to produce a

continued on page 50 www.AHDBonline.com

CLINICAL

AHDB Stakeholder Perspective continued from page 49 scientific document detailing key changes in medical therapy and introducing novel approaches to asthma care management. The new guidelines stress the importance of the longitudinal assessment of asthma, as frequent, close monitoring via spirometry may help reduce the risk of exacerbation. The anticipated outcome from the dissemination of this report is that healthcare providers will be able to manage their asthma patients more effectively, reducing both the economic and social burden of this disease. Indeed, one can project that the many stakeholders intimate to the asthma care delivery system will benefit to some degree. First and foremost, patients with asthma will be assured that the new guidelines incorporate medication safety as well as efficacy in its treatment recommendations. Healthcare providers will be satisfied that the management strategies of the EPR 3 represent evidence-based, consensus-driven decisions derived from current literature. Purchasers of healthcare will gain knowledge that there exists a standard of care in the treatment of asthma and may use the information to critically assess the performances of different health plans in their respective approaches to asthma management. However this important document will

be utilized, it stands clear that its content will help guide the clinical care of asthmatic persons towards the best possible outcome. Joseph G. Dizon, MD Chief, Department of Allergy and Immunology Kaiser Permanente-West Los Angeles

References 1. EPR. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma (EPR 1991). NIH Publication No. 913642. Bethesda, MD: US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; 1991. 2. EPR-2. Expert Panel Report 2: Guidelines for the Diagnosis and Management of Asthma (EPR-2 1997). NIH Publication No. 974051. Bethesda, MD: US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; 1997. 3. EPR-Update 2002. Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma Update on Selected Topics 2002 (EPRâ&#x20AC;&#x201C; Update 2002). NIH Publication No. 02-5074. Bethesda, MD: US Department of Health and Human Services; National Institutes of Health; National Heart, Lung, and Blood Institute; National Asthma Education and Prevention Program; June 2003.

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March 2008

Executive Summaries Patent Reform Proposals Raise the Stakes for Researchers, Manufacturers of Biologics By Shayna B. Kravetz, BSc, and Rosemary Frei, MSc

Shayna Kravetz and Rosemary Frei provide a thorough review of a new book, Biotechnology and the Patent System, by Drs. Claude Barfield and John Calfee, resident scholars at the American Enterprise Institute in Washington, DC. The book examines reforms being considered by legislators, lawyers, and members of the biotechnology industry that could revolutionize the patent system. Ms. Kravetz and Ms. Frei interview several experts, including Michael Heller, JD, and Rebecca Eisenberg, JD, authors of the article “Can Patents Deter Innovation?” for their take on what would happen if full ownership rights were substituted by shared rights among part-owners. Interviewees offer possible outcomes that

could result from shared ownership and patent pools, including limiting a product’s exclusivity and destroying incentives for making new discoveries and protecting them. Dr. Barfield argues that the proposed reforms may slow the patent process but would provide, in the long run, “less challengeable patents.” Some proponents of the reform are seeking guarantees that the ability to challenge patents after they have been granted is not expanded, fearing a widening of exploitation of the patent-granting process. Drs. Barfield and Calfee urge, “First, do no harm.”

The Value of Biologics American Health & Drug Benefits™ opens a dialogue with Dr. Gary Owens, whose decade of chairing the Pharmacy & Therapeutics Committee at Independence Blue Cross makes him uniquely insightqualified to discuss how benefit design structures are being redesigned in an era of consumerism to accommodate high-cost biologic therapies. Formerly designed only for diseases such as arthritis, cirrhosis, or hepatitis C, biologics are now

AMERICAN

available for more common diseases, such as asthma, thus involving a larger segment of the population. With a biologic therapy costing as much as $100,000 annually, we find ourselves in a unique position: We have developed life-saving remedies but have not yet figured out how to pay for them. Henry and Owens examine the issues surrounding biologics and the ongoing dynamic tension between stakeholder groups, from bias-free patient education to incentives for healthcare plans. It is suggested that “depersonalizing the dynamic” will align the incentives driving each stakeholder group to address their different processes. All stakeholders—from patients to payors—will need to define value, while attempting to avoid inappropriate spending. Reaping the harvest made possible through biologics will be an awesome challenge.

When Novelty Is Not Enough By Michael F. Murphy, MD, PhD

Introducing new medical technology and products in today’s oncology environment is challeng-

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ing because of the myriad influences affecting healthcare decisions. Utilization of new products is influenced by incentive-based formularies, prior authorization requirements, and systems of reimbursement, each of which generates its own evidence for clinical utility. Dr. Murphy makes the case that research and development activities are relevant to benefit-design decisions. He cautions against premature endorsement of technology from these initiatives and encourages changes in regulatory guidance regarding clinical trial design and research. He further reminds us that drug benefit designs require sufficient lead time to assess the implications and impact on medical practices. Choosing the best agents for patients requires examining not only the appropriateness of treatment for a specific patient but also taking into consideration long-term outcomes and costs.

Asthma—The National Surveillance Data and the National Asthma Education and Prevention Program’s Expert Panel Report 3

port 3: Guidelines for the Diagnosis and Management of Asthma, have translated scientific findings into direct recommendations for patient care. Dr. McCarter summarizes the recommendations that result from this collaboration and their implications for physicians as well as for decision makers in managed care. Readers are urged to review the original document in its entirety for more detailed information: National Asthma Education and Prevention Program (NAEPP) Working Group Report on Managing Asthma During Pregnancy: Recommendations for Pharmacologic Treatment—Update 2004 (NAEPP 2005). NIH Publication No. 055236. Rockville, MD, U.S. Department of Health and Human Services, National Institutes of

Health, National Heart, Lung, and Blood Institute, March 2005. http://www.nhlbi.nih.gov/health/pr of/lung/asthma/astpreg.htm. The guidelines were designed not only to ensure access to quality medical care and reduce the national and personal burden of asthma, but also to encourage correction of environmental risk factors that affect this patient population. Patients and providers are encouraged to work as comanagers of asthma; payors are urged to erase financial barriers to screening, diagnosis, monitoring, and use of control and rescue therapies; and regulators and public health authorities are advised to support best practices to erode mortality and morbidity associated with asthma, including environmental risk factors.

Unmanaged Moment

By Thomas McCarter, MD, FACP

Breakthroughs in science continue to generate information to enable patients with asthma to live more active lives. The National Heart, Lung, and Blood Institute, in cooperation with the National Asthma Education and Prevention Program recently released Expert Panel Re-

AMERICAN HEALTH & DRUG BENEFITS

“Concerning the titanium knee implant we’d discussed, Mrs. Cranshaw, our actuaries have really outdone themselves! We’re going to retouch your x-rays first and then see what happens.”

March 2008

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FDA WATCH

FDA Watch

Behind-the-Counter Drug Access Mark Senak, JD

ate in 2007, the U.S. Food and Drug Administration (FDA) held a public meeting chaired by Dr. Randall Lutter, Deputy Commissioner for Policy, and Dr. Douglas Throckmorton, Deputy Director for the Center for Drug Evaluation and Research, to discern the prevailing thought on the possibility of developing a behind-the-counter (BTC) status for drug access in the United States. Similar to over-the-counter (OTC) status, BTC would allow a patient to access medications at the pharmacy without seeing a doctor. Unlike OTC, however, access would not be allowed without the intervention of a learned intermediary. But, unlike a prescription medication, BTC would allow a patient to access drugs after an assessment and decision by a pharmacist. BTC is currently a practice in several European nations, Canada, and Australia. In the United States, there is a limited version of BTC with a very narrow set of drugs, including cold remedies containing pseudoephedrine and Plan B oral (morning after) contraceptives; however, proponents of BTC status are quick to point out that there is a real difference between these types of drugs that involve the pharmacist in a policing action, where the pharmacist’s role is to check age and intention, over a pharmacist’s role as a true learned intermediary where there would be evaluation and counsel. The event of a meeting held by the FDA suggests at least an openness of thought to the concept of BTC status, but the realities, as revealed in the course of the FDA’s meeting, may be far different. It was the third time the FDA has met to discuss BTC, the first time being in the 1970s and the second in 1995. There is ample reason for continued interest in a BTC status for the United States. One driver for drugs to switch from (prescription) Rx to OTC status is naturally that of access. OTC status opens the way for those without traditional access to healthcare channels to be able to access medications that they otherwise might not be able to obtain. Another obvious driver is cost, which also affects access, allowing for many (though not all) patients to access medications for far

AMERICAN HEALTH & DRUG BENEFITS

March 2008

less than they would otherwise pay, unless that access were subsidized by an insurance program. But a cornerstone criterion for the switch is that the patient can self-diagnose and self-treat the condition for which treatment is sought and use the compound safely. Some drugs just miss that call. For example, in 2007 Merck attempted to switch Mevacor, a statin, from Rx to OTC status for the third time and failed. There have been some medical professionals who are such strong advocates of widespread statin use, that they have jokingly made statements that statins, like fluoride, should be in our drinking water. One of the reasons for the statin Rx to OTC switch failure, however, is that because patients cannot selfdiagnose or self-monitor high cholesterol, the drug does not meet switch criteria. But is a physician necessary to assess, diagnose, and monitor the patient? The landscape is further complicated when considering the fact that “ready-clinics”—stripped down instant healthcare available in many retail establishments—are increasingly common and seen as a way to cut costs and improve access. The FDA meeting involved 6 panels designed to represent various stakeholder groups, ranging from pharmacy organizations to educational institutions to consumers, retailers, and manufacturers. Noticeably absent were payors, despite the fact that reimbursement for pharmacists emerged as a major issue that would define the success or failure of a BTC initiative. Of the panelists, the split between those who support a BTC designation and those who opposed was largely predictable, divided along lines of pharmacist groups being in favor of BTC status, and most physician-based groups, such as the American Medical Association, unequivocal in their opposition. Consumer groups and some professional societies fell in between, expressing some limited support for BTC, particularly to save consumers money, but offering caution as well on several points. There have been and remain many barriers to the institution of a BTC class that do not appear poised to be resolved anytime soon, particularly when considering the overwhelming and growing regulatory burden and challenge that the FDA is facing for 2008 and beyond. For example, for a pharmacist’s transformed role, it is clear that there also needs to be a mechanism for reimbursement, which does not exist now. If a pharmacist takes time to evaluate and counsel a patient beyond today’s standards, how will the pharmacist be paid for that service? Currently, there is no mechanism on either the public or private side. Reimbursement

FDA WATCH

would need to address not only the time of the pharmacist, but the increased liability that is being assumed in the role of prescriber. Reimbursement is also a factor when it comes to the patient. How will BTC drugs be reimbursed, if at all? Currently most OTC drugs are not reimbursed, though they may be covered by a patient’s flexible payment system through their employer to use pretax dollars for purchase. Most Rx drugs are reimbursed by public and private plans. And if products are not reimbursed, how does that affect the increased patient access that is one of the primary goals of a BTC system? Where would BTC drugs fit into the reimbursement scheme? There are a myriad of other issues as well, including that most pharmacies are not equipped to provide examinations, blood draws, and room for private, confidential counseling and record-keeping, and would need to be revamped to accommodate a new role for the pharmacist as an evaluator and prescriber. Finally,

although many younger pharmacists may be trained in patient evaluation, many older pharmacists might not be. To bring pharmacists into a new role, there must be a new standard of training and licensing that would require time and money to construct. Although BTC may continue to be an aspiration for some, it became clear in the course of the FDA meeting that any movement to transform the current 2-tier system to a 3-tier system would require significant commitment on the part of many stakeholders to put into place the mechanisms and safeguards that ensure that the existence of a BTC status would in fact reach the goals set for it—to increase patient access and to reduce costs.

Mr. Senak is Sr. Vice President at Fleishman-Hillard in Washington, DC, and author of Eye on FDA, www.eyeonfda.com.

Call for Papers The editors of American Health & Drug Benefits™ (AHDB) are pleased to invite readers to submit articles for publication on topics examining advances in clinical, business, and regulatory developments relevant to attaining value—a balance of cost, quality, and access—in formulary and benefit design strategies. AHDB offers an open forum for all healthcare stakeholders to present their needs, initiatives, and data, with the goal of aligning stakeholder incentives in the development of patient-centered health and drug benefits that meet the needs of all stakeholders—patients, providers, payors, purchasers, distributors, regulatory, manufacturers, evaluators, and researchers. Articles should aim to identify key issues that can improve the quality and efficiency of our healthcare delivery system in general and of formulary and drug benefit design strategies in particular. All papers will undergo a peer-review process, and authors will be notified of any changes needed before articles can be accepted for publication. Please submit your article electronically to editorial@AHDBonline.com, or mail to AHDB, PO Box 423, Long Valley, NJ 07853. For complete information on how to submit articles, see Information for Authors, page 12.

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INDUSTRY TRENDS

INDUSTRY TRENDS—REGULATORY

Kaiser Daily Health Policy Report Capitol Hill Watch | Senate Finance Committee Bans American Medical Association From Medicare Reform Bill Talks The Senate Finance Committee has banned the American Medical Association (AMA) from discussions about an upcoming Medicare package that would stop a 10% cut to physician fees, according to a Democratic aide, CongressDaily reports. The cuts will go into effect on July 1 unless Congress intervenes (Johnson, CongressDaily, 2/15). According to CongressDaily, “AMA lost the trust” of Finance Committee Chair Max Baucus (D-Mont.) “when it broke a confidentiality agreement about Medicare talks last year and informed state affiliates.” In addition, an aide said the Finance Committee criticized AMA for supporting a budget provision in 2006, then complaining about it later, CongressDaily reports. The provision halted the scheduled cuts in exchange for larger cuts in later years. AMA has been pushing the Finance Committee to delay the cuts for 18 months and increase physician payments by 1.5% to cover cost increases. House Ways and Means Health Subcommittee Chair Pete Stark (DCalif.) on Thursday said that he doubts Congress would be able to find the money for a patch and that the cut would go into effect. He also said that he doubts AMA’s request for an 18-month delay would be approved. Stark said, “What we have to write is a complete new payment system. I hope we can talk about it this year and begin to think about what’s needed.” The committee is expected to mark up a Medicare bill in April or May to provide a temporary fix (CongressDaily, 2/15).

Medicare Legislation Outlook Lobbyists and analysts have projected that Congress will only be able to push a slim Medicare legislative package this year “that does little more than protect doctors against payment cuts,” but Baucus and Stark “weren’t talking that way on Thursday,” CQ HealthBeat reports. The lawmakers said that they would like to add mental health parity provisions to Medicare, expand benefits for preventive care, create programs to compare

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March 2008

effectiveness of treatments, and increase access to the Medicare drug benefit. Baucus said that limits on assets for the drug benefit low-income subsidy and the Medicare Savings Programs, which reduce premiums for Medicare Part B, must be increased. He said, “We must raise the asset levels allowed for all of these programs. And we must index them to keep pace with healthcare inflation,” adding, “Seniors should not have to go into poverty to benefit from these Medicare programs.” Baucus also said that he would target Medicare Advantage to find funding to offset the physician payment patch. “Where justified by sound policy, we must find savings within the Medicare outpatient benefit and Medicare Advantage to offset the cost of blocking the scheduled cut in physician payments,” he said. The Medicare Payment Advisory Committee has recommended reducing payments for skilled nursing and home healthcare providers. Baucus said he would be relying on MedPAC for guidance in other areas that could be cut. Baucus said, “With the help of MedPAC and other experts, we must identify areas of overspending. We must see that our Medicare dollars are being used wisely.”

Baucus on Healthcare System Baucus on Thursday also outlined 5 principles to advance healthcare reform: • Providing universal coverage; • Establishing health insurance purchasing pools to combine individuals and small businesses; • Researching comparative effectiveness of treatments and improving quality of care; • Emphasizing preventive care; and • Mandating “shared responsibility” by having business, individuals, government, and other “stakeholders” paying to fund the system. He specifically said that he would introduce legislation that would “create a new entity responsible for the essential work of generating better information on the effectiveness of healthcare treatments,” adding, “We will invest more money in this research” (Reichard, CQ HealthBeat, 2/14).

Reprinted with permission from the Henry J. Kaiser Family Foundation. The Foundation, based in Menlo Park, CA, is a nonprofit, private operating foundation focusing on the major healthcare issues facing the nation and is not associated with Kaiser Permanente or Kaiser Industries. Kaisernetwork.org.

INDUSTRY TRENDS

INDUSTRY TRENDS—BUSINESS

TOTAL ASTHMA ATTACK OR EPISODE PREVALENCE RATE PER 1,000 PERSONS

National Asthma Guidelines Updated The National Asthma Education and Prevention Program (NAEPP) released updated clinical guidelines for the diagnosis and management of asthma on August 29, 2007. These guidelines are the most comprehensive updates in almost a decade and include recommendations for childhood asthma (expanded section), new guidance on medications, patient education in settings beyond the physician’s office, and advice for controlling environmental factors that can cause asthma symptoms.

National Center for Health Statistics, National Health Interview Survey, 1998-2006.

Table. LIFETIME PREVALENCE PER 1,000 PERSONS, EVER TOLD BY A HEALTH PROFESSIONAL THAT THEY HAD ASTHMA

Economic Cost of Asthma, United States, 2007

National Center for Health Statistics, National Health Interview Survey, 1999-2006.

Direct Medical Expenditures Hospital care Physician services Prescription drugs All Direct Expenditures Indirect costs Morbidity Mortality (death) All Indirect Costs All Costs

Costs ($ billions) 4.7 3.8 6.2 14.7 3.1 1.9 5.0 19.7

National Heart, Lung, and Blood Institute Chartbook on Cardiovascular, Lung, and Blood Diseases, 2007. http://www.nhlbi.nih.gov/resources/docs/07chtbk.pdf. ASTHMA – NUMBER OF CONDITIONS AND PREVALENCE RATE PER 1,000 PERSONS (CURRENT PREVALENCE)

National Center for Health Statistics, National Health Interview Survey, 1982-1996, 2001-2006.

Note: Estimates of overall direct and indirect costs were obtained from the NHLBI Chartbook 2007. More specific cost estimates were calculated from applying proportions found in the article with the projected NHLBI 2007 costs. Cost estimates were derived using mortality and health survey data, as well as health expenditure and income data from various sources.

The lifetime prevalence table above indicates an upward trend with 2006 lifetime prevalence of 116 per 1,000 persons. Additionally, the current prevalence of asthma indicates an upward trend with a 2006 current prevalence of 77.9 per 1,000 persons. The guidelines reflect the need to assist in the diagnostic, appropriate treatments, and continued follow-up to monitor asthma patients. After long-term therapy has been initiated following spirometry assessment, the guidelines recommend continued assessment in 2 to 6 weeks based on

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asthma severity. If asthma control is not achieved, step-up therapy, discontinuation, and initiation of new therapy, increasing short-acting beta-agonists, and a short course of oral systemic corticosteroids are all part of the recommendations in the continued assessment for the patient.

With the prevalence of asthma attacks increasing over time (Table) and the economic impact of treating asthma patients, it will be interesting to measure adherence to the new guidelines and evaluate the clinical and economic impact of the guidelines.

INDUSTRY TRENDS—CLINICAL

Table 2. Top Asthma Investigational Drugs

The tables below provide the most recent information regarding investigational drugs for asthma indication. Table 1 shows the majority (~74%) of asthma investigational drugs early in the investigational pipeline (phase 1 or earlier). Table 2 highlights the top 7 mechanisms for asthma investigational drugs, representing more than 40% of all investigational mechanisms.

Anti-inflammatory Hormone (corticosteroid) Arachidonic acid agonist Beta-2-adrenoceptor agonist PDE-4 inhibitor Tryptase inhibitor 5-Lipoxygenase Total

45 23 12 11 8 7 5 275

Table 1. Number of Investigational Drugs NDA/BLA filed Phase 3 Phase 2 Phase 1/IND filed Preclinical/discovery Recent launches Status unclear Total

11 12 73 45 123 54 8 326

Top Asthma Mechanisms Anti-inflammatory 7%

Hormone (corticosteroid) 40%

10%

Arachidonic acid agonist Beta-2-adrenoceptor agonist

11%

PDE-4 inhibitor 21%

Tryptase inhibitor 5-Lipoxygenase

Investigational Drugs—Asthma

2% 3% 4%

PDE indicates phosphodiesterase.

17% 22%

38%

NDA/BLA filed Phase 3 Phase 2 Phase 1/IND filed Preclinical/discovery Recent launches Status unclear

14%

Data are provided by BioPharm Insight (http://www.biopharminsight.com); reproduced with permission from Infinata, Inc. All rights reserved. NDA indicates new drug application; BLA, biologic license application; IND, investigational new drug application.

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