February 2008, Vol 1, No 1

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

VOLUME 1, NUMBER 1

REGULATORY

Creating a 21st-Century Intelligent Health System Newt Gingrich, Nancy Desmond

Interview: The Impact of CMS on Biotech Drug Coverage (Part 1) Joseph Antos BUSINESS

Disruptive Innovation: Value-Based Health Plans ™

F. Randy Vogenberg

Role of NCCN in Integrating Cancer Clinical Practice Guidelines into the Healthcare Debate Al B. Benson, Elizabeth Brown CLINICAL

Measuring the Value of Treatment to Patients: Patient-Reported Outcomes in Drug Development Richard J. Willke EDITORIAL

What Kind of Healthcare Debate Do We Want?

Robert E. Henry COLUMNS

- FDA Watch - Industry Trends

©2008 Engage Healthcare Communications, LLC www.AHDBonline.com

R E I M E E U PR ISS

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

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

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

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

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

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

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

Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day). Genotoxicity assays did not reveal any telmisartanrelated effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test. No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and Mortality. Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients receiving MICARDIS in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

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

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

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

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

Rx only MC-BS (03/07)

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

Printed in U.S.A.

(10/07)

MC48827

1

fi

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.

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

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

Printed in U.S.A.

(10/07)

MC48828

LETTER FROM THE EDITOR

From the Editor

What Kind of Healthcare Debate Do We Want?

The launch of American Health & Drug Benefits™ brings with it the sentinel question: How shall we frame the healthcare debate? The answer we propose involves a vision of how healthcare standards change; who is involved in the process of care; what are their systems, needs, agendas, and incentives; and what are the evidentiary methods proper for determining success or failure.

All the forces involved in healthcare delivery come to bear at the point of formulary and benefit design coverage, ie, the only real healthcare intervention is that which is covered. The managerial competency needed to make good coverage decisions entails a new type, and a blending, of clinical, financial, and regulatory best practices. This journal seeks to provide a forum for understanding the intersection of these forces and how they form the governing dynamics of health and drug benefits coverage. What’s more, we will examine these forces from the different viewpoints of the key stakeholder groups—patients, providers, payors, purchasers, manufacturers, evaluators, distributors, regulators, academia, and investors—with the idea that they are seated at a round table where the idea of hierarchy is subordinate to the pursuit of consensus. The ideas and resources for healthcare progress have never been more sanguine. However, they require a new perspective to master them, a new spirit of cooperation, and a new willingness to try new systems and dispense with traditional prerogatives.

That this new and urgent pursuit of excellence was precipitated principally by cost rather than quality concerns does not detract from its value to the practice of medicine. What has become evident is that healthcare cannot tolerate inefficiency on any level: not clinical, not business systems, not regulations.

There is yet another new shift in the winds that attends this quest for consensus around best practices: reconciling the responsibilities of the disparate stakeholders toward one another. Could this mean interstakeholder cooperation and transparency? The only answer the healthcare system can tolerate—it is increasingly clear—is yes, though it will take years for the adversarial tone of the healthcare debate to be replaced by a sane, professional discourse. This will occur when they share one another’s realities. In short,

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AMERICAN HEALTH & DRUG BENEFITS

February 2008

good communications will make not only good neighbors, but also a system that is not fighting against itself. The healthcare debate need not—indeed should not—take on the characteristics of a series of power plays, any more than the human body’s own organs would compete with one another for “mastery” over the body.

The confluence of stakeholder interests and demands on healthcare delivery constitute a composite picture of the ever-changing healthcare debate. The vast scope of activity may make the prospect of aligning activities seem daunting, but there are few fundamental structural pillars to the process of care, and these form the scope of inquiry of American Health & Drug Benefits™.

The first is value, as reckoned by a balance of Cost, Quality, and Access. The second is the triad of Clinical, Business, and Regulatory forces that determine health and drug benefits. The third is the “college of stakeholders,” each with its own incentives, data, and agendas. The fourth is Culture—healthcare coverage models are products of the culture in which medicine, and the ancillary business and regulatory pillars supporting it, is practiced. The fifth is Evidence—what do we know, what can we measure, about the Clinical, Business, and Regulatory actions we undertake in the name of healthcare?

There are 2 central questions asked by American Health & Drug Benefits™: (1) Will we conduct the healthcare debate among stakeholder groups as adversaries or as colleagues? (2) Is healthcare on the verge of profound success or imminent collapse? The editorial philosophy of American Health & Drug Benefits™ is collegial, positive, and professionally optimistic, ie, the healthcare system paradigm is undergoing its transformation, not its demise. All parties to the process of care hold immense resources and answers for the quest for better healthcare; hence, American Health & Drug Benefits™ gives all full respect and invites them to share their needs, data, systems, and ideas for change.

The positive outlook of American Health & Drug Benefits™ is predicated on the notion that challenges to healthcare are as fixable now as they were when scrubbing before surgery was a new idea. Right now, the looming question is financing for the many healthcare

LETTER FROM THE EDITOR

interventions that have been devised. This is not a cause for pessimism but for innovation: It means only that our ability to discover cures has lately outpaced our systems for paying for them. It would be infinitely more disturbing if the problem were the reverse.

Thus, American Health & Drug Benefits™ offers a fresh look at the forces of change to healthcare benefits and their downstream effects on Cost, Quality, and Access. What will be the impact of value-based benefit designs? What, in fact, does this new term even mean in practical terms? How much regulation is for the good of healthcare innovation, and how can government contribute to an environment wholesome to R&D? How can payor models balance the needs of patients and investors alike? How can quality control standards provide doctors helpful guidelines without taking from them the professional latitude they require to avoid devolving into “healthcare vendors”?

The answer is that there are no simple answers, only lots of them, and they require a healthy, informed, 3dimensional perspective on the part of all parties.

Ultimately, the Great Healthcare Transformation is under way, and the system of care is going to require adept management of overall resource allocation, the Holy Grail of today’s value-based healthcare system. In the following pages and issues of American Health & Drug Benefits™, you will encounter practical solutions and experiences advanced by different sectors. We are providing a repository of ideas for wresting healthcare improvement out of the countless forces and players driving benefits decisions. And we invite you here and now to contribute your articles and bring your vision and its outcomes to the table where all can assess them.

The editorial approach to achieving a managerial perspective in American Health & Drug Benefits™ follows, therefore, a paradox that begins with the Roman Empire’s “divide and conquer” tactic—identify the forces and players and their systems and the measurable effects of same—and then turns on its heel to align these forces and systems. The goal: a realistic unity among stakeholders based on taking the high road in every facet affecting the process of care. This amounts to “divide and reunite,” always keeping the interventions under the magnifying glass to see how adequately they really serve Cost, Quality, and Access to care.

So let the debate continue, in the spirit of good will and common interest: the patient, the patient, the patient. American Health & Drug Benefits™ will endeavor to help chronicle it. By balancing the Clinical, Business, and Regulatory forces in each benefits decision, by respecting and accommodating valid needs of

every stakeholder group, we will continue groping forward in the search of the humane treatment of those who are ill or injured. And that is not a cause for alarm, but for unceasing, united action.

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

Unmanaged Moment

“You’ve got to hand it to Charles – he really thought outside the box on this anesthesia step therapy initiative.”

www.AHDBonline.com

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FEBRUARY 2008

VOLUME 1, NUMBER 1

™

™

REGULATORY

9

Creating a 21st-Century Intelligent Health System

Publisher Nicholas Englezos

Newt Gingrich, Nancy Desmond

Associate Publisher Maurice Nogueira

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Interview: The Impact of CMS on Biotech Drug Coverage (Part 1) Joseph Antos

Editor-in-Chief Robert Emmett Henry Managing Editor Sandy Paton Production Manager Alaina Pede

BUSINESS

22

Disruptive Innovation: Value-Based Health Plans

Director of Human Resources Blanche Marchitto

F. Randy Vogenberg

28

President Brian F. Tyburski

Role of NCCN in Integrating Cancer Clinical Practice Guidelines into the Healthcare Debate Al B. Benson, Elizabeth Brown

Mission Statement CLINICAL

34

Measuring the Value of Treatment to Patients: Patient-Reported Outcomes in Drug Development Richard J. Willke

Continued on page 6

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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February 2008

Coming Soon...

Š2007 Abbott Laboratories Abbott Park, IL 60064 306 60908 December 2007 Printed in USA

FEBRUARY 2008

VOLUME 1, NUMBER 1

™

™

EDITORIAL

2

Letter From the Editor

8

Letter to Readers

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

Business/Government Editor Kip Piper, MA, CHE President Health Results Group kpiper@AHDBonline.com

COLUMNS

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Unmanaged Moment: Cartoon

41

FDA Watch

42

Unmanaged Moment: Cartoon

Employers F. Randy Vogenberg, RPh, PhD

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Industry Trends

Specialty Pharmacy Rebecca M. Shanahan, Esq.

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Executive Summaries

Managed Care Pharmacy Policy Cynthia J. Pigg, RPh, MHA

52

Information for Authors

Managed Markets Marketing Jeffrey A. Bourret, RPh, MS, FASHP Charles E. Collins, Jr., MS, MBA

Editorial Board Pharmacy Reimbursement Policy Michael R. Schaffer, PharmD, MBA

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

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. Rosenkranz, 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.

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Outcomes Research Gordon M. Cummins, MS Pharmacy & Specialty Products James T. Kenney, RPh, MBA Policy & Public Health Alex Hathaway, MD, MPH, FACPM Actuary David Williams

10

550

1

medicines for diabetes and mental health

thousand patients enrolled in pharmacy adherence programs

happier, healthier, more compliant patient

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

At Lilly, helping you manage your patients requires a shared commitment to delivering initiatives, ideas, and positive outcomes. So we keep our focus on those who count on our medicines.

From diabetes and mental health education, to patient adherence efforts, to simply offering the best answers we can,

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

All numbers current as of December 2006. MG45572 COPYRIGHT Š 2007 ELI LILLY AND COMPANY.

LETTER TO READERS

Welcome to our community Election years are always a great time to take our country’s pulse with regard to an issue, and this year healthcare has emerged as the major topic on the nation’s collective mind. We have enjoyed excellent healthcare in the United States for quite some time, yet today the system seems unstable. Record numbers of uninsured patients populate our delivery system during an era in which few would argue that access to insurance coverage is equivalent to access to good healthcare. Within the delivery system in most disease states, disparities exist with regard to access to excellent care and excellent outcomes.

Providers endure the lower ratcheting of revenues and rising overhead costs (especially in the areas of liability insurance and labor costs). Yet in this environment of low margins, expectations are higher than ever, with patients, payors, and employers demanding evidence of quality care, safer care, more customer-focused care, and more efficient care.

Payors are struggling to maintain costs to manage their risks and to limit expenses that are paid by employers or purchasers. Employers again are facing high costs reminiscent of the early 1970s, when cost pressures drove the mainstreaming of managed care delivery systems. Employers also are demanding more from their health and drug benefit programs and designs. They expect excellent care when their employees are ill, but they also want a workforce that feels that the benefit is competitive, and one that is treated fairly and compassionately during a time of illness. Some sophisticated employers will also demand not only treatment of illness, but also prevention of illness and improvements in the overall health and wellbeing of their employees to stimulate a positive workplace culture and to engender a more healthy, efficient, and productive workforce.

Patients demand respect from this faceless system. In times of illness, they want a system they can navigate and that will lead them to the best possible outcomes.

They want a system where prevention of illness and perpetuation of wellness are equally important as the treatment of disease. Out-of-pocket expenses are continuing to rise, and year after year, patients must accept a greater personal risk in managing these healthcare costs.

Our government is facing its own healthcare battles.

As a growing number of baby boomers reach the age of

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AMERICAN HEALTH & DRUG BENEFITS

February 2008

eligibility, will the Centers for Medicare & Medicaid Services (CMS) and Social Security be able to generate the funding necessary to maintain the level of benefits?

Will a Food and Drug Administration criticized a decade ago for being too slow in allowing new agents to come to market— and now criticized for safety flaws allowing unsafe drugs to reach the market—be able to achieve a level of review and safety that does not limit discovery of new agents? As CMS has become a if not the major purchaser of pharmaceuticals in the United States, can we measure a return on investment? Has the cost of providing pharmacy benefits generated reductions in other costs in the program? And will pharma, biotech, and device manufacturers receive clear and unambiguous messaging from all stakeholders to give them the guidance and incentive to produce innovative products that are relevant to pressing disease states and that exceed the expectations of government, payors, providers, and patients—by delivering true value? When they do develop important new medications, will formulary and benefit designs accommodate or inhibit their utilization, and will these utilization parameters be evidence-based decisions or cost-minimization policies at work?

Can we balance Quality, Access, and Cost, so that in the end we will have a system that meets our country’s needs? Can we generate a benefit design that will allow payors, purchasers, patients, and providers to share a WIN? These are some of the questions with which we will wrestle within the pages of American Health & Drug Benefits™. We want you to participate in these discussions and to help shape the present and the future of healthcare. Although I guarantee there will be white water ahead, I also guarantee that it will not get better until the stakeholders engage one another in intelligent discussion and problem solving and begin to chart the course. I look forward to engaging with you—through the pages of our journal—in this vital process.

Thomas McCarter, MD, FACP Clinical Editor American Health & Drug Benefits™ tmccarter@AHDBonline.com

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Creating a 21st-Century Intelligent Health System Newt Gingrich, PhD Nancy Desmond, MEd, EdS

In most areas of life, Americans enjoy the ease and convenience offered by advances in technology, communications, and transportation. Every day we experience the 21st-century model of America, which is one of effectiveness, accuracy, speed, flexibility, efficiency, lower cost, more choices, and greater achievement. We can shop online, compare prices for goods and services, and when decisions need to be made, we have access to a wide array of information sources to assist in making those decisions. In short, Americans enjoy great latitude in our power to determine what is best for us.

This is not, however, the case when it comes to health and healthcare. In our current healthcare system, individuals are dependent on a structure that has resisted the natural progress and modernization achieved by market-oriented, 21st-century industries. The information age has been leaving health behind.

Although it is the nature of a science- and technology-based entrepreneurial free market to provide more choices of higher quality at lower cost, in the healthcare sector, prices continue to rise, quality is inconsistent, and individuals lack the information, incentives, and power to make choices. to a disaster on the scale of Katrina, imagine what would happen if we were required to withstand multiple crises simultaneously—something that we have to accept as a very real possibility in today’s world.

The Urgency of Health Transformation: Not a Choice, but a Necessity

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he area of health and healthcare is one where transformation is not a choice, but a necessity. That reality has been driven home by a number of recent events and ever-growing challenges:

Demographic Changes: The Aging of America Newt Gingrich, PhD

Health and Homeland Security Hurricane Katrina served as a wake-up call. By homeland security standards, it was not an unexpected or exceptionally large event. Yet we witnessed a collapse of the healthcare system in the Gulf in its aftermath.

Millions of paper records were lost at the very time they were most needed. If we were incapable of responding

In 1965, the average life expectancy was 70.2 years.

Today it is older than age 77 and is expected to increase to 78.5 years by 2010. It is a testament to American innovation and values that we are living longer. Our ability to extend life is a great success but presents some enormous challenges. We must face the reality that 76 million baby boomers are nearing retirement and consider how their retirement will affect the future of our health and healthcare system.

Nancy Desmond, MEd, EdS

Medical Errors and Unnecessary Deaths Dr. Gingrich is Founder of the Center for Health Transformation; Ms. Desmond is President and CEO of the Center for Health Transformation, Washington, DC. The two are authors of the book The Art of Transformation, from which they adapted this article.

A 1999 report by the Institute of Medicine revealed that as many as 98,000 people die in our hospitals annually due to medical error.1 That’s the equivalent of a jet crashing and killing 250 Americans every day. We are 2,000 times more likely to die in a hospital from a

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medical error than in a civilian air crash. Furthermore, nonfatal medical errors often lead to illness or disability. In America, statistics like these are simply unacceptable. And, with public awareness increasing, there is a growing demand that our leaders do something to fix our ailing system.

increase in diabetes. The most recent figures from the CDC show that 66% of U.S. adults—or about 130 million people—are either overweight or obese.5 The percentage of overweight young people has more than tripled since 1980. Among children aged 6 to 11 years, 18.8% are overweight; of those aged 12 to 19 years, 17.4% are overweight.

Disparities in Outcomes The increasing evidence of disparities in outcomes is a critical factor that makes a compelling and tragic case for why a new system of health and healthcare is not just a choice but an absolute necessity. At the top of the list are racial disparities. Recent studies have shown that, relative to whites, infant mortality rates are 2.5 times higher for blacks, life expectancy is 10 years less, and blacks have significantly higher mortality rates from heart disease, stroke, and cancer.2 The racial divide when it comes to health and healthcare is a moral issue that simply cannot be dismissed, and a tragic reality that is at the heart of the need for change is our current system.

According to the Institute of Medicine, uninsured adults younger than age 65 have a 25% higher death rate than their insured counterparts.

The Epidemic of Diabetes and Obesity The number of type 2 diabetes cases in the United States has doubled in the past 2 decades to an estimated 20 million (when undiagnosed cases are included).

This makes diabetes the country’s fastest-growing public health problem. Furthermore, the Centers for Disease Control and Prevention (CDC) predicts that 1 in 3 American children born in 2000 will join the ranks of those afflicted with type 2 diabetes.3 Diabetes is the only major disease with a death rate that is still rising—up 22% since 1990. It is also the leading cause of kidney failure, blindness, and nontraumatic amputation, and a major contributing cause of heart disease and stroke. The American Diabetes Association estimates that, when we include both treatment and lost productivity, diabetes costs the U.S. economy about $132 billion per year.4 Obesity, primarily a result of Americans’ eating and exercise habits, is a major contributor to the

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Shortage of Healthcare Workers Our 20th-century system of healthcare has created an environment that has led to a growing and critical shortage of healthcare professionals. The U.S. Department of Labor predicts that the shortfall of nurses, which has existed since 1998, will increase to a shortage of 400,000 to 800,000 by 2014. Meanwhile, the U.S. Council on Graduate Medical Education, Physician Workforce Policy Guidelines for the United States, 2000-2020 projects a shortage of 85,000 physicians by 2020.6

The Uninsured To put it simply, coverage for all Americans is a moral imperative. Access to health insurance is the equivalent of access to healthcare. Eighteen thousand people die every year because they are uninsured.

According to the Institute of Medicine, uninsured adults younger than age 65 have a 25% higher death rate than their insured counterparts.7 The ripple effects of being uninsured and having poor health are felt throughout society. Uninsured children have impaired development and poor school performance. Uninsured adults have more absences from work, more unscheduled sick days, and greater rates of disability. The cost of treating the uninsured is listed as one of the major challenges facing hospitals today.

Unsustainable Increase in Costs The cost of healthcare is going to force us to rethink the entire system. Government healthcare spending alone is currently 6.6% of the gross domestic product7; however, at the current trend, it is predicted to climb to over 32% by 2050!8 Meanwhile, employers are seeing healthcare spending become a major corporate issue. According to General Motors, $1,500 of the cost of every car is a result of the cost of providing healthcare to their employees.9 Small businesses are increasingly making the decision not to insure their workers because the costs of doing so have become unsustainable. And, with more and more of the costs of insurance passed on

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to individuals from their employers, Americans are becoming increasingly aware of the exorbitant cost of the system. Premiums for family coverage in employersponsored health insurance plans have increased by 78% since 2001.10

The Solution: Replacing the Current Healthcare System With a 21st-Century Intelligent Health System That Saves Lives and Saves Money for Every American In a 21st-Century Intelligent Health System, the individual is the center of knowledge, decision-making, and responsibility for his or her own health. Knowledge of health and finances is available in the most accurate, least expensive, and most convenient manner possible.

In a 21st-Century Intelligent Health System, individuals have accurate, timely, personalized knowledge about their health and treatment options, including information about cost and quality. They have the assurance that their treatment is based on the most up-to-date evidence-based medicine, and the focus is on preventive care and early intervention. The system encourages and rewards wise healthcare purchasing decisions and offers more choices of higher quality at lower cost.

A key test for any new system is its ability to provide affordable access to quality care for the poorest and sickest among us. The elimination of health disparities must be a critical goal: No one can be left behind. A 21stCentury Intelligent Health System must provide access to affordable coverage for those currently uninsured.

A 21st-Century Intelligent Health System has 3 essential components.

Component One: Centered on the Individual Putting individuals at the center of the system requires that they be given the incentives, the information, and the power to make wise choices. However, the 20th-century system we inherited is one in which individuals seldom have information about cost or quality, have no financial incentives for wise consumption, and generally have decisions made for them rather than choosing for themselves. Starting with the decision in 1943 to go to a third-party system, we’ve turned healthcare into a rental car. The problem is, almost no one washes a rental car.

Right to Know Allowing individuals to choose will work only if we also provide them with the information needed to make

informed choices. Yet the current healthcare system is absurdly secretive. When it comes to healthcare, Americans typically have no way of comparing the cost and the quality of the various health services, products, or providers they are considering. This situation is tantamount to asking someone to shop for a car when the dealer hides the prices, rolls back the odometers, and does not disclose that the lot is filled with a fleet of rental cars.

In a 21st-Century Intelligent Health System, individuals have certain rights, including the right to know cost and quality information and the right to be assured that their providers are practicing the best standards of care.

Personal Responsibility In a 21st-Century Intelligent Health System, individuals have certain rights, including the right to know cost and quality information and the right to be assured that their providers are practicing the best standards of care. But they also have responsibilities.

First, individuals are expected to be informed and to use that information to make wise decisions. Second, individuals are expected to engage in (and encourage their children or family to engage in) healthy behaviors, related to both nutrition and exercise, that are proven to prevent illnesses and complications. If they develop a chronic illness, they are expected to learn and follow best standards of care to avoid costly complications. Third, individuals are expected to help pay for their care. Everyone should be required to participate in the insurance system. Those whose incomes are too low should receive vouchers or tax credits to help them buy insurance. Those who oppose the concept of insurance should be required to post a bond to cover costs. Allowing individuals to pass their health costs on to others reinforces the attitude that it’s not their problem and adds to the irresponsible, unhealthy behaviors that are bankrupting the current system.

Personalized Health System The 21st-century individual-centered system will be a personalized system of health, resulting in dramatically better health for everyone. Imagine a future where tests will allow us to know exactly what combination of medicines will protect us from the specific diseases or

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conditions to which we are most susceptible, based on our genetics. Consider a world where we know that health and treatment regimens are designed specifically for each individual.

We are already seeing glimmers of how the future of medicine is likely to change as we move toward a more personalized system. Not long ago, the newspapers ran a story about a drug that scientists learned, in reviewing years of data, had a stunning impact on preventing heart attacks in African American males. This was not the original purpose of the drug. Moreover, the drug had no such impact on white males. In a 21st-century, IT-rich, intelligent system, we will be able to recognize these patterns much more quickly and to share them more widely to prevent illnesses, thereby saving lives and money.

Component Two: IT and Quality The personalized system of health we just described cannot be possible without a system that is IT-rich. The system must allow easy but secure sharing, analysis, and usage of information about health and health history and about the cost, quality, and outcomes of treatments we are considering. The difference between health and healthcare and other sectors of society when it comes to IT is dramatic. And it has had a dramatic impact on the lives—and deaths—of the American people.

Paper Kills Paper kills. It is that simple. Instead of saving lives, our current paper system is often taking lives. With as many as 98,000 Americans still dying as a result of medical errors every year, ridding the system of paper-based records and quickly adopting health IT will save lives and money.

Each day that we refuse to move from a paper-based to an electronic system, people are dying needlessly.

This is not just conjecture—health IT’s tremendous potential to saves lives and money is real and is happening in some of the most forward-looking practices and transformational institutions in our country.

Component Three: Health, Not Healthcare: Prevention, Early Detection, Self-Management, and Best Practices The need to transform the current system from an acute care–focused system to one of prevention and early detection is evident.

Heart disease, the leading cause of death for both men and women in the United States, accounted for

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nearly 700,000 deaths in 2002. In 2005, heart disease was projected to cost $393 billion. It is the leading cause of death for American Indians, Alaska Natives, blacks, Hispanics, and whites. More than 300,000 people have bypass surgery in the United States each year, yet heart disease and its complications can often be prevented. Among people with heart disease, studies have shown that lowering cholesterol and high blood pressure can reduce the risk of dying of heart disease, having a nonfatal heart attack, and needing heart bypass surgery or angioplasty. For people without heart disease, studies have shown that lowering high blood cholesterol and high blood pressure can reduce the risk of developing heart disease in the first place.

A system focused on prevention rather than on acute care would provide the incentives and policies to support lifestyle changes needed to control cholesterol and blood pressure. A culture of physical activity and healthy diet choices would replace the current epidemic of inactivity and “fast food.” However, our current system, by providing reimbursement for volume of care rather than outcomes, discourages the type of care that prevents disease, complications, and acute episodes.

The same mindset is evident when it comes to the willingness of the system to pay for technologies and discoveries to keep us healthy. Using diabetes as an example, the current system’s tendency is to pay for dialysis and amputations but to refuse to pay for the education, the tools, or often the medications that can prevent these costly and tragic consequences. A system that takes advantage of 21st-century opportunities will be able to provide us with a whole new range of technologies, tools, and screening mechanisms that will allow us to stay healthier, avoid or delay many illnesses, and manage the illnesses we develop.

Two Futures If Dr. Andy von Eschenbach is right, we may be able to eliminate cancer as a cause of death in the next 10 years. But even if we find the breakthroughs that would allow us to do this, if our current 20th-century system of delivery has not been transformed, it is likely that our own doctor might not adopt the necessary life-saving treatment for 17 years. In those 17 years, how many people will have died needlessly? How many wives or husbands, sisters or brothers, children or grandchildren?

It’s a potential scenario that gives us a startling glimpse into 2 futures: one in which we cling to the sta-

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tus quo (or even magnify it through a single-payor, totally government-run system) and another in which we save countless lives and millions of dollars by replacing the current system with a 21st-Century Intelligent Health System.

The opportunities exist, the choices are clear, and the time for choosing is now. The choice is not just important, it’s a matter of life and death—not only for us but for our children, our children’s children, and Americans everywhere.

References 1. Kohn LT, Corrigan JM, Donaldson MS, eds; Committee on Quality of Health Care in America, Institute of Medicine. To Err is Human: Building a Safer Health System. Washington, DC: The National Academies Press; 1999.

2. Consumer Health: Collection Development Services for Public Libraries. Healthy People 2010. A Systematic Approach to Health Improvement. http://www.healthypeople.gov/Document/html/uih/ uih_2.htm#deter. Accessed January 14, 2008.

3. Centers for Disease Control and Prevention. Number (in Millions) of Persons with Diagnosed Diabetes, United States, 1980-2005. http://

AHDB Stakeholder Perspective The needs and tactical methods behind the transformation of the healthcare system are based on the injury it has inflicted to all 3 points of the value triangle: cost, quality, and access. Transforming the healthcare system involves changes to the categories, number, and function of every stakeholder to the process. Since human nature traditionally shuns radical change for fear of unexpected consequences, there exists considerable clamor by nearly all stakeholder sectors for transformation of the U.S. healthcare system, despite the increased life span in evidence today.

The cause for transformation can be ascribed, in part, to the number of major obstacles threatening healthcare: demographic challenges of the graying baby boomers, medical errors and unnecessary deaths, disparities in outcomes, epidemic of diabetes and obesity, shortage of healthcare workers, the uninsured, and unsustainable increases in costs.

The other reason for support for transformation involves the prospects for success if certain changes can be made: individual-centered medicine; information technology; health promotion; and disease prevention, early detection, self-management, and best practices.

The stakeholders who join the inevitable trend will tend to be winners, since healthcare transforma-

www.cdc.gov/diabetes/statistics/prev/national/figpersons.htm. Accessed January 13, 2008.

4. Centers for Disease Control and Prevention. November is American Diabetes Month. http://www.cdc.gov/Features/LivingWithDiabetes/.

Accessed January 13, 2008.

5. Centers for Disease Control and Prevention. Overweight and Obesity. http://www.cdc.gov/nccdphp/dnpa/obesity/childhood/prevalence.ht m. Accessed January 13, 2008.

6. Cooper RA. Weighing the evidence for expanding physician supply.

Ann Intern Med. 2004;141(9):705-714.

7. Institute of Medicine. Care Without Coverage: Too Little, Too Late.

May 2002. www.iom.edu/CMS/3809/4660/4333.aspx. Accessed January 14, 2008.

8. Hagist C, Kotlikoff LJ. Health Care Spending: What the Future Will Look Like. National Center for Policy Analysis. NCPA Policy Report No. 286, June 2006. http://www.ncpa.org/pub/st/st286. Accessed January 14, 2008.

9. Connolly C. U.S. firms losing health care battle, GM Chairman says.

Washington Post. February 11, 2005:EO1.

10. The Kaiser Family Foundation. Employer Health Benefits 2007 Annual Survey. http://www.kff.org/insurance/7672/index.cfm. Accessed January 14, 2008.

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

tion is now a given, the only question being the details of the next system.

• MANUFACTURERS: Having resisted change to the healthcare system ever since the 1980s, pharma is learning how to adapt by developing new drugs that deliver evidence-based, patient-centered, health improvements.

• PAYORS: No less conservative than pharma during this period, payors have learned that change can be good and have introduced a continuum of member-friendly plans to replace those that greatly limited choices and access. Indispensable players in the transformation process, payor autonomy will continue to erode in favor of increased transparency and collaboration with purchasers.

• PURCHASERS: Health-based medicine strategies are proving their financial worth to large employers, who can exercise control over their costs, while CMS must contend with underfunding. Until CMS receives sufficient government funding to pursue health-based models, cost-minimization remains a priority.

• PROVIDERS: Considerable work needs to be done to motivate recruitment of physicians and nurses. Cost-minimization casualties of payors and purchasers, providers will continue to be in short supply until new reimbursement models are in place.

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We invite you to join us each month at American Health & Drug Benefits™, where you will have a firsthand view of the clinical, business, and regulatory systems driving healthcare resource allocation. Each issue brings the expertise of leading authorities from the many sectors involved in the process of care. Our goal is to help encourage benefit design competency that meets the 3 components of value: cost, quality, and access. We also recognize the need for the alignment of stakeholders, and each issue will bring transparency to their needs, data, and agendas. From R&D to actuarial models, from regulatory trends to value-based benefit designs, from healthcare reform propositions to evidence-based medicine, American Health & Drug Benefits™ will bring you the mosaic that is the healthcare “ecosystem” in motion.

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Medicare Coverage Strategies: Impact of the MMA and PBMs Part 1 of an interview with Joseph Antos, PhD, of the American Enterprise Institute

American Health & Drug BenefitsÛ has been created to act as an ideological melting pot focusing on health and drug benefit decision makers, as well as those who may affect or may be affected by those decisions. By engaging in conversations with payors, regulators, employers, and other stakeholders, our journal hopes to enable decision makers to view the impact of benefit designs from as many perspectives as possible. Through this open dialogue, we hope that better decisions may be made, and that the greater healthcare marketplace will be positively impacted.

In following our editorial mission, American Health & Drug BenefitsÛ has sought thought leaders who have influenced and will continue to influence the healthcare marketplace. During a fall visit to Washington, DC, Dr. Joseph Antos was kind enough to host a visit to the American Enterprise Institute and provide his thoughts to Robert Henry, editor-in-chief, on how the Centers for Medicare & Medicaid Services (CMS) exerts its influence on drug coverage in the wake of the Medicare Modernization Act (MMA) and in the face of evidence-based medicine standards. Following a chronology of CMS’s role from its inception to current events, Dr. Antos offers a lively insight into CMS’s strategy and its tactical effects on the American healthcare system.

R

obert Henry: At a recent Institute of Medicine annual meeting, Elliott Fisher of Dartmouth quoted Uwe Rhinehart referencing something that you had discussed in the book you co-authored with Alice Rivlin, Restoring Fiscal Sanity 2007: The Health Spending Challenge. You make the point that the same level of care or the same procedure provided in 2 different locations in the United States can vary dramatically in price (even twice as much or more). Dr. Fisher quoted Dr. Rhinehart as saying that, “Isn’t it amazing that the best healthcare in the world can cost twice as much as the best healthcare in the world?”

Joseph Antos: Yes, this is a colorful way of making a very important point. Elliott Fisher, Jack Wennberg, Jonathan Skinner, and others have been tracking Medicare data to put this geographical variation into perspective. In Restoring Fiscal Sanity 2007, Alice and I emphasized 3 conclusions from this research into geographical differences in resource utilization. First, variations in resource use are huge—much larger than can be explained by differences in patients or practice traditions. Second, resource consumption follows local

resource supply availability. So geographic areas with large concentrations of a given specialty group will witness higher utilization of that specialty than areas with sparser concentrations. Third, and most surprisingly, higher healthcare expenditures do not necessarily translate into better patient outcomes. And that finding has everyone looking for ways to rein in unnecessary healthcare costs.

Robert Henry: Medicare has undergone a tremendous degree of change since the passage of MMA. Do you see this as a “sea change” in the role of CMS as a purchaser and regulator, especially with regard to pharmaceutical agents?

Joseph Antos: Yes and no. Medicare has always been a regulator, and Medicare has always been a payor.

It started to interact with the drug industry with the introduction of Part B drugs. CMS now has a much greater role as payor and regulator with the addition of the Part D benefit and outpatient drugs.

CMS is well on its way to learning how to deal with the drug industry. They hired hundreds of pharmacists and other experts to help them get the drug benefit

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started and to help them understand formulary issues.

They have also had to deal with the United States Pharmacopeia (USP), but it is not at all clear what use that particular cul-de-sac has been for the past couple of years.

Robert Henry: It didn’t really produce a consensus, did it?

Joseph Antos: It did not produce a consensus. It did not produce a simple, logical, and useful structure for deciding how to create a formulary or what is necessary for a specific group of patients. As far as I can tell, no new information has come out of that process, but USP will continue to refine its model formulary year after year, perhaps indefinitely.

The ESA debate is a microcosm of what is going on in healthcare in general, and points in directions that Medicare could go, but might also point in directions that Medicare should go.

It is difficult to detect any substantial effect of USP on CMS regulation or on the plan sponsors in developing their formularies. However, the USP relationship was necessary politically. Congress needed an external body at the center of the process that was not wholly owned by either the government or by the pharmaceutical industry.

There was confusion and concern about the role that pharmacy benefit managers (PBMs) would play in managing Part D. Congress and other stakeholders were worried that formularies might be biased against sicker beneficiaries. An overall structure imposed by a supposedly neutral third party was the answer to this problem.

The resulting USP guidance was used only to the degree that it made sense. PBMs were already operating in a similar framework, so the net impact was minimal.

The future for CMS’s pharmaceutical regulation and its regulation of coverage and payment for health services more generally is likely to be contentious. That is illustrated to some extent by the ongoing struggle over Medicare coverage of ESAs, the erythropoiesis stimulating agents.

Robert Henry: They would serve as a pretty good poster child.

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Joseph Antos: They are a poster child for the financial pressures in the health system and also serve as a cautionary tale about what could happen in the future.

The current situation points to some deficiencies in knowledge, to some deficiencies in decision-making.

The situation sheds light on major deficiencies in the way drugs are paid for under Part B. In 2007, CMS substantially reduced Medicare coverage of ESAs, narrowing the range of diseases for which payment would be made and, in effect, imposing tighter dosing regimens. The cancer community felt blind-sided by what they said were budget-driven rules that interfere with medical decisions. The uproar over the new rules reached all the way to Congress, but CMS has softened its position only modestly.

The ESA debate is a microcosm of what is going on in healthcare in general, and points in directions that Medicare could go, but might also point in directions that Medicare should go.

This is a classic, big money Washington problem.

Every party has its own particular concerns, and the political and financial incentives are misaligned.

Obviously, the pharmaceutical and biotechnology companies that create these products have money at stake, but there are also concerns about what constitutes good patient care. In addition, there is a new and evolving relationship between the U.S. Food and Drug Administration (FDA) and CMS, as it becomes clear that there is no sharp line separating scientific judgment about safety and effectiveness from business decisions regarding insurance benefits and reimbursement.

CMS itself is in a continuing struggle to limit growth in the costs of the program without seeming to dictate the practice of medicine. One of Medicare’s guiding principles laid out in the Social Security Act is a prohibition against federal interference with medical practice. Now, that is a bit of a façade, because payment does determine to a large extent what doctors will do. Like private health insurers, Medicare establishes in its coverage rules the circumstances under which they are willing to pay for various interventions. If the insurer’s payment rules are clear and known in advance, they certainly influence decisions made by the doctor and the patient regarding the course of treatment.

Robert Henry: In other words, doctors and patients cannot keep demanding unlimited availability of intervention resources while expecting the insurer to find the money to pay for them? Eventually, the insurer or payor is going to step in and practice cost containment.

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Joseph Antos: Well, you could put it that way, but that is more cosmic than what I had in mind. I am talking about the normal business of insurance companies, whose job it is to make payments for a defined set of benefits. Ideally, the criteria for payment should make sense to providers and patients alike and not foreclose necessary treatment.

These benefit and payment decisions should be supported by scientific evidence, but health insurance has been a fairly unscientific business for much of the past 40 or 50 years. That is beginning to change with improvements in our ability to collect and analyze clinical data on treatments and outcomes. Traditionally, Medicare and private insurers based their financial decisions on prevailing medical practice, reasoning that the provider is in the best position to judge what is appropriate for the patient.

Robert Henry: This prevailing view would seem to recognize the reality implementing any new technology where there tends to be innovators, early adapters, late adapters, and traditionalists.

Joseph Antos: It does recognize the way most new technology is adopted in the health system. The innovator tries a new treatment approach. If it offers advantages over conventional methods, a combination of published studies and word of mouth result in adoption by other physicians. However, some new approaches offer minimal benefits to the patient, and insurers (including Medicare) generally pay higher prices for the new technology. Even when an innovation improves patient outcomes or has other clinical value, that does not necessarily mean the additional value is worth the additional cost. Medicare has traditionally left the decision to cover new medical treatments to its carriers, who base their judgments on the prevailing medical practice in their local areas. This was the system Medicare used when the program was created in 1965, and it is largely the system under which Medicare operates today.

This is one of the complications facing Medicare beneficiaries, who are sometimes surprised to find that there are regional differences in what is covered by this national insurance program. Physicians in Boston are likely to have a different therapeutic strategy than physicians in Minneapolis for the same disease, and Medicare is likely to reimburse differently in the 2 cities.

Another factor driving technology adoption is the role of the specialist. Specialists are likely to use more technology, and use it more aggressively, than general-

ists. Medicare pays primary care physicians significantly less than specialists, reflecting a long-standing bias that favors surgery and other interventions over cognitive services. The unmanaged fee-for-service nature of traditional Medicare provides an incentive to expand the use of ancillary services (such as diagnostic tests performed in the physician’s office) and to increase referrals to specialists (which increases a primary care physician’s capacity to see more patients in shorter visits). That drives up Medicare spending but may not improve health outcomes—a point that Jack Wennberg, Elliott Fisher, and their colleagues have been making for sometime.

Over 30 years ago, Wennberg discovered variations in clinical practice that could not be explained on the basis of illness, patient preferences, or scientifically grounded treatment standards. Much of his work has relied on Medicare claims data, which have been the only source of information on health treatment that is national in scope and reasonably complete and accurate. It has taken all of that time for policymakers to realize the serious implications for cost and quality of care of clinical variations, but there is now the technical capability to analyze large databases and a growing political interest in using that analysis to inform Medicare policy.

Medicare has traditionally left the decision to cover new medical treatments to its carriers, who base their judgments on the prevailing medical practice in their local areas.

Robert Henry: Because the data were only slenderly understood, can we say with confidence that the decision to get a handle on practices and to provide more standardization is tied into evidence-based medicine? Is it tied into the fact that new data methodologies are emerging that are permitting people to draw accurate resource allocation conclusions?

Joseph Antos: Absolutely. Jack Wennberg’s work 30 years ago was path-breaking, but the greater availability of billing and clinical data and 3 decades of methods development now make it possible in concept to systematically assess what we are buying in healthcare and how well it works. Of course, there is more to be done

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if we hope to use the information generated by the health system to best advantage, and electronic medical records would improve our data collection capabilities. However, an equally important change is the growing realization that we can and should use evidence to make coverage decisions that previously were based on a consensus of providers rather than systematic analysis of treatments and outcomes. We will see a movement away from local coverage determinations in Medicare toward national decisions as analysis of the data becomes more routine, and those national coverage decisions are likely to become more nuanced as we develop better information on the effects of treatment on specific patient populations.

We will see a movement away from local coverage determinations in Medicare toward national decisions as analysis of the data becomes more routine...

Robert Henry: Medicare has followed an almost intuitive process?

Joseph Antos: Yes. Without an ability to systematically analyze the data, coverage decisions relied on limited information about the effectiveness of new treatments. A treatment that seemed effective based on initial studies and reports from physicians in the local area would be covered. Sometimes, that intuition proved to be wrong. That might have resulted in a formal decision to deny coverage, but the same technology diffusion also works in reverse: Ineffective treatments ultimately fall into disuse, although that could take years unless payments are stopped.

Rising healthcare costs in the early 1990s led to the managed care revolution, as spending was outrunning employers’ and families’ willingness to pay. Vigorous managed care generated a backlash a few years later as a growing economy and tightening labor markets made employers rethink their health benefits. Rather than risk losing good employees disgruntled by a health plan that relied on direct controls on the use of services, employers sought less intrusive cost containment offered by PPOs, or preferred provider organizations.

The managed care revolution took a vacation, at least temporarily. Managed care is not dead because health-

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care costs keep rising. The interest in evidence-based medicine stems from the need to find better ways of delivering the right kind of care, allowing us to continue to provide top-quality healthcare without breaking the bank.

Robert Henry: Let me ask you one question about that point. Shouldn’t the decisions that are made, the formulary decisions and the drug benefit designs, be made ideally to provide the sweet spot of cost, quality, and access, as well as to find and hit the second sweet spot of clinical, business, and regulatory drivers?

Joseph Antos: Correct.

Robert Henry: How adept are the professionals who are making these decisions at the payor and purchaser levels?

Has there, to your observation, been increased acumen?

Joseph Antos: Absolutely. The big PBMs run large, efficient distribution systems to push product to the consumer. But they make their money by designing smart benefits that can lower prescription drug cost for Blue Cross, General Motors, the small employer, and the individual insurance subscriber. PBMs recommend formularies and coverage rules, but ultimately the employer or insurer decides how generous the benefit will be based on what he is willing to pay.

Robert Henry: The purchaser, not the payor.

Joseph Antos: Right.

Robert Henry: And not the PBM. Joseph Antos: Well, let’s be careful, because the purchaser is a lot of people, including me as an individual insurance subscriber, and I am certainly not making a specific decision about what the formulary should be in my health plan—and I probably did not select my plan solely on the basis of the prescription drug benefit. We are really talking about the employer as the decision maker, since the employer selects the plan or plans offered to workers. Insurers offer the employer a variety of insurance products that typically include a pharmacy benefit. That benefit might vary according to the breadth of the formulary, the structure of cost-sharing, the aggressiveness of cost management methods (such as requiring the use of generics where available), and the availability of retail and mail order sales outlets, among other considerations. The employ-

REGULATORY

er decides what he is willing to offer his workers given the total premium cost, the generosity of benefits, the adequacy of the provider network, the reputation of the insurer, and his judgment about employee reaction to any benefit changes.

In Part 2 of our interview, Dr. Antos follows up his observations about Medicare strategy with a discussion of Medicare tactics regarding biologics coverage. He examines the rise of virtual regulations that increasingly determine payment and the interaction of CMS, the FDA, and the biotech industry.

Robert Henry: You are describing this combination of clinical, business, and regulatory.

Joseph Antos: It all has to go together.

Robert Henry: And they are getting better at it.

Joseph Antos: And they are getting better at it, partly because PBMs can use data from their own operations to understand physician prescribing patterns, shifting demands among drug classes, and other factors that determine the cost of pharmacy benefits and the value received by patients. Companies such as Express Scripts, Medco, and Caremark are very large organizations with data on millions of covered lives spanning multiple years, which provide them with the ability to make sensible recommendations about benefit design and the effectiveness of specific drugs for specific diseases. With some modest changes in the information provided on the prescription, particularly the inclusion of the patient’s diagnosis, these databases could even give us systematic information about the effectiveness of drugs in off-label uses. That capability to learn from our own experience will increasingly lead to improvements in patient care and ultimately could lead to verifiable improvements in health status. The PBM industry has the potential to become a major source of sensible advice to the rest of the healthcare industry about coverage, and then through coverage to actual treatment decisions by physicians.

AHDB Stakeholder Perspective CMS and Prescription Drugs: Winners and Losers The Part D outpatient prescription drug benefit has ratcheted up CMS’s direct involvement and influence on every aspect of the pharmaceutical industry, from research and development of new products to pricing and distribution to the end-user. The immediate impact

Dr. Antos is the Wilson H. Taylor Scholar in Health Care and Retirement Policy at American Enterprise Institute (AEI) for Public Policy Research. He is also a Commissioner of the Maryland Health Services Cost Review Commission, and an Adjunct Professor at the School of Public Health of the University of North Carolina at Chapel Hill. Before joining AEI, Dr. Antos was Assistant Director for Health and Human Resources at the Congressional Budget Office, Director of the Office of Research and Demonstrations, and Deputy Director of the Office of the Actuary at the Health Care Financing Administration (currently CMS). He served as Health Financing Consultant to the World Bank and the Organisation for Economic Co-operation and Development, as well as Senior Economic Advisor to the U.S. Agency for International Development. He currently is a member of the Panel of Health Advisors to the Congressional Budget Office, and is Commissioner of the Maryland Health Services Cost Review Commission.

The American Enterprise Institute for Public Policy Research is a private, nonpartisan, nonprofit institution, based in Washington, DC, that is dedicated to research and education on issues of government, politics, economics, and social welfare. Founded in 1943, the institute sponsors research and conferences, and publishes books, monographs, and periodicals. More information may be found at the institute’s Web site, www.aei.org.

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

of Part D has largely been beneficial to manufacturers, distributors, health plans, employers, and Medicare beneficiaries. However, the substantial shift in pharmaceutical spending from private payors and Medicaid to Medicare will focus intense political pressure on every part of the supply chain. More money is at stake, but the risks have also risen sharply. Here is how the winners and losers stack up: • MANUFACTURERS: In the near term, pharmaceutical manufacturers may be the biggest winners.

First, the transfer of Medicare dual eligibles into Part D

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plans shifted a substantial share of the market from the Medicaid “best price” world of mandated rebates into a less regulated market. Second, Part D plans are required to cover essentially all drugs in 6 protected classes, including antidepressants and antipsychotic drugs. That requirement virtually eliminates plan leverage on manufacturers, allowing them to increase their prices and profits. Third, Part D expanded the number of Medicare beneficiaries with drug coverage, bumping up demand for the products. A quarter of Medicare beneficiaries had no prescription drug coverage prior to Part D, and perhaps another quarter had less generous coverage (mainly through Medigap or other private insurance).

That good news for manufacturers is tempered by concerns from Congress that Part D plans may not be getting the best possible prices. Critics have called for direct price negotiation authority for CMS. Such authority might be granted under a Democratic president, possibly focusing negotiation on new innovative drugs that can run tens of thousands of dollars per treatment. In addition, concerns about the effectiveness and safety of pharmaceuticals could cause CMS to expand its “coverage with evidence development” program, slowing the adoption of new products for the elderly. As Part D spending grows, expect greater pressure on manufacturers to prove the effectiveness of their drugs and justify their prices.

• PBMs AND HEALTH PLANS: Concern in Congress that PBMs and private health plans might not be willing to offer drug-only benefits led to provisions that substantially reduced the financial risk of entering this new kind of business. Those provisions, the promise of increasing drug spend fueled by government subsidies, and the demand from many employers for seamless health coverage for their retirees led to an explosion of interest by firms seeing new marketing opportunities. The big players—including Humana, United HealthCare (cobranded with AARP), Caremark, and others—captured the lion’s share of the market. Despite aggressive bidding in a highly competitive market, profitability was good for many plan sponsors and several wrote checks to CMS because their net earnings exceeded the upper limit on the risk corridors. Somewhat surprisingly, there has been no consolidation in the Part D market, which continues to offer most consumers 50 or more plan options.

Medicare Advantage plans also appear to have come out on top, despite the new competition from stand-alone prescription drug plans. During the 1990s, private health plans in Medicare became popular pri-

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marily because they could offer a prescription drug benefit unavailable in traditional Medicare. That advantage is gone with Part D, but the private plans have greater flexibility to offer more comprehensive drug benefits that are coordinated with coverage for inpatient and outpatient services. Some sponsors, including Humana, offered low-premium drug plans in the hope of later shifting those enrollees to their more profitable Medicare Advantage plans.

Many in Congress remain skeptical about a Medicare benefit delivered by competing private plans without a government default plan. Such a plan might be given special authority to negotiate prices, and might be designated the default plan for Medicare beneficiaries who do not explicitly select another option. That could significantly erode the market position of existing Part D plan sponsors. At the extreme, existing risk-bearing Part D plans might be replaced by a few regional drug carriers that administer a benefit dictated by Washington.

• CONSUMERS: Despite the early difficulties some seniors encountered in the enrollment process, most Part D beneficiaries seem satisfied with the benefit. Out-ofpocket costs have been reduced for many, particularly for those who did not previously have drug coverage, and the use of pharmaceuticals is up. Fears that employers would drop their retiree drug benefits have not materialized, partly because employers offering equivalent coverage are eligible for a subsidy. Low-income beneficiaries are eligible for special subsidies and low out-of-pocket costs, but a substantial number of those people have not come forward to claim their subsidy. In addition, beneficiaries who are dually eligible for Medicare and Medicaid may have to shift enrollment to another Part D plan to avoid having to pay premiums. CMS has exercised temporary authority to minimize such disruptions, but this problem has not been permanently resolved.

Consumers face an uncertain future with Part D. CMS will be under growing pressure to contain program costs, and that could translate into higher premiums and cost-sharing requirements for Part D enrollees.

Higher-cost drugs are likely to move to third and fourth (specialty) tiers on plan formularies, and access may be further restricted through the use of prior authorization. Cost cutting could also chill the atmosphere for financially risky drug development.

Seniors have gained a drug benefit, but poorly-targeted policies could reduce their access to the breakthrough drugs and biologics of the future.

Joseph Antos, PhD

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MANAGING HEALTHCARE COSTS THROUGH TECHNOLOGY

BUSINESS

Disruptive Innovation: Value-Based Health Plans F. Randy Vogenberg, RPh, PhD

Value and a Complex Healthcare Market What Is Value to an Employer?

“Worth in usefulness or importance to the possessor; utility or merit.”

American Heritage Dictionary “A principle, standard, or quality considered worthwhile or desirable.”

American Heritage Stedman’s Medical Dictionary “A fair return or equivalent in goods, services, or money for something exchanged.”

Merriam-Webster’s Dictionary of Law

L

ike the everyday person, defining value for a payor of healthcare services varies depending on your perspective and application of the meaning. For a patient or employee, value means there is some worth in the usefulness of the subject or importance to possessing it. To a clinician, value relates to a standard of quality or a principle that is not only worthwhile, but also desirable. For an attorney, value is defined in contractual terms connoting an economic exchange or equivalence in goods or services. Thus, it is important for an employer, as a payor of healthcare services, to define value and its resulting business proposition to the organization’s mission or goals.

Healthcare has traditionally been a contracted services arrangement for employers who “purchase” it through health plans and/or pharmacy benefit managers (PBMs). Costs for these services, however, have grown over time along with continual double-digit increases in the cost associated for a healthcare plan that is pur-

Dr. Vogenberg is Chief Strategic Officer, Employer-based Pharmaceutical Strategies, LLC, Cranston, RI.

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chased (fully insured) or funded through a self-insurance plan. Consequently, there is intense interest in the value associated with a health plan for the business enterprise and its associated value proposition.

Enter the Value-Based Health Plan There are several so-called “early innovating” employers who began looking for alternative healthcare funding or contracting approaches that would address the cost trend and value question to their organization. Today, approximately 100 companies have begun or implemented various aspects of what is known as a value-based health plan, which may use a wide variety of tactical concepts under that umbrella.

The foundation for a value-based health plan starts with identifying the goals. Like any business plan, the employer, through their human resources (HR) team, must determine the organizational goals for their health plan. They should also identify goals that are in alignment with the mission and business goals of their organization.

Next come the objectives for the health plan. Based on the goals in the plan, clear, obtainable, and measur-

BUSINESS

able objectives should be identified for implementation through the health plan. This can be done easier through a self-insured program, but can increasingly be accomplished with fully insured programs as part of a defined incremental strategy over time.

When the goals and objectives have been determined, the next step is to incorporate well-established patient behavior principles to design a health benefit program. This requires measuring and providing feedback, rewarding valuable or desired behaviors, assuring visible senior leadership and environmental supports throughout the organization, and engaging employees to promote their own accountability.

Although Pitney Bowes (PB) is among the most well-known innovative companies in this area, the strategy goes beyond PB value-based benefit design; Asheville, North Carolina, pharmacist interventions of counseling, collaborative care, and proactive medication monitoring; and Marriott or University of Michigan copay reduction and elimination tactics.

There are health plans and PBMs who are talking value-based concepts from coast to coast.

There are several key messages from PB’s more than 10 years of experience in benefit design evolution (Table 1).

Messages 5 and 6 are perhaps the most important for an employer, because they relate to business strategy.

For most employers who seek to implement a valuebased health plan for their organization, they pursue it through some form of value-based benefit design. That may include some type of enhanced access to medical care or medications by tactics such as reducing the copay amount paid by the patient or pay-for-performance contracting with the provider network. It can also include some form of enhanced access to medications that have been shown to improve health outcomes for patients and that result in value to the employer, not necessarily the health plan, by lowering total healthcare claims cost.

Table 1.

1. Most tools now give you a fine view through your rear window 2. Identify key medical conditions using data 3. Data are valuable even if you have little 4. Benefits designs do drive consumer behavior 5. Wellness/prevention should be redesigned to include care for chronic conditions and member engagement 6. Prescription drugs, routine office visits, and screenings have value in managing chronic care 7. Benefits planning can create a strategic advantage 8. Benefits decision makers can make a difference Mahoney J, Hom D. BeneFIT Design™: Seven Steps to Value-Based Health Benefit Decisions. www.prnewswire.com/cgi-bin/stories.pl?

ACCT=104&STORY=/www/story/04-23-2007/0004571608&E DATE=. Accessed January 7, 2008.

and made Marshall famous for his plan that provided a clear, understandable road map for people to follow.

Just as technology in computing that has advanced through companies such as Microsoft, technological advances also confer benefits by improving health and increasing longevity. These advances coupled with the complexity of healthcare in the United States make it even more difficult for the individual to understand, let alone select, an approach for reforming the healthcare system.

These and other employers have begun to assess their own value proposition regarding medical and pharmaceutical health programs, and what they are willing to pay or share for the cost of those benefits to their employees. A common thread among most of these employers is recognizing in their employee population where there may be an opportunity to contain the cost of their benefit program while achieving the

Complexity and Technological Advances Challenges to moving to a value-based approach relate back to human nature and the difficulty of dealing with complex issues or topics that may not be fully understood. In 1946, George Marshall had to deal with the enormous complexity of postwar Europe. The war and related events in those countries made it difficult for people to understand how they could rebuild their country or implement change. It kept people from acting on an issue, which was the postwar rebuilding effort,

Bill Gates, in a 2007 commencement address at Harvard, described not only the role of financial complexity in Enron that ordinary people could not grasp, but also healthcare itself, which has a complexity similar to postwar Europe. Like the Marshall Plan, the Bill & Melinda Gates Foundation has set out on a clear, understandable effort to make a difference in healthcare that people can comprehend.

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Table 2. Partial List of Employers Known to Be Involved in Value-Based Health or Health Designs

• • • • • • • • • • • • • •

City of Asheville, North Carolina Caterpillar, Illinois State of Colorado, Colorado Dow Chemical, Michigan Florida Power & Light, Florida HEB, Texas Intel, California Marriott, Washington, DC Mohawk Industries, Georgia Pitney Bowes, Connecticut Quad Graphics, Illinois SCANA, South Carolina Sperian Protection, Rhode Island University of Michigan, Michigan

Value-Based Messages: Disruption, Eruption, or a Sustaining Market Trend?

Table 3. Several Key Stakeholders Working on Value-Based Health or Health Designs in the United States

• • • • • • • • •

• •

University of Michigan Schools of Business and Public Health Harvard Medical School/School of Public Health Thomas Jefferson University Medical School, Health Policy Center Rand University of Rhode Island, Health Research & Outcomes Center MedStat, Ingenix, Abacus Health Solutions Cigna, Great West Life Express Scripts, Medco Health National Business Coalition on Health, Washington, DC, and state member groups representing areas such as Kansas City, Honolulu, Chicago Integrated Benefits Institute, California National Business Group on Health, Washington, DC

same or better health outcomes that ultimately keeps benefit costs under control.

For example, Marriott and the University of Michigan followed a similar strategy as PB in looking at disease conditions with their treatments in their population to determine where the best overall results for

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cost and clinical outcomes could occur. For diabetes, it was in the unstable or brittle diabetics where creative benefit designs to lower financial barriers could be established. Such benefit coverage is important to keep their condition managed on an outpatient basis. To do so includes enhanced coverage for testing equipment and supplies along with medications for the primary diabetes condition as well as secondary conditions involving vascular, cardiovascular, and vision that are established co-risk factors.

February 2008

In the past decade, there was an accumulation of experience and general direction toward value-based health plans. A partial list of employers (Table 2) and other key stakeholders (Table 3) in the marketplace provide an example of not only the number involved in these concepts, but also the diversity and significant players who are currently engaged.

Based on the marketplace experience, a logical question for pharmacy-related benefits then would be whether value-based plans have really changed how medications are utilized in plan design(s), and whether we have moved beyond identifying cost alone when speaking of “value” in healthcare.

A conventional health plan program follows the tenets of insurance underwriting that are based on a large enough population sufficient to cover the cost of those few needing health services versus the many who do not, while all are paying insurance premiums based on the general risks in the covered population pool.

The excess dollars paid into premiums are invested for meeting future estimated payments that are based on actuarial tables of morbidity and mortality in populations. This is a reactive strategy to meet the cost demands driven by the healthcare delivery system and innovation with little ability to “manage” populations.

A value-based health plan takes the conventional approach into a proactive scenario to increase the ability to manage a population and engage the patient in both their own health status and use of healthcare services. It is built on a base of clearly established goals for the health plan; objectives determined for their ability to achieve the stated health plan goals; and a behavioral-based benefit design that incorporates incentives and disincentives designed to achieve the health plan goals. Information sharing and feedback to plan members is a critical component to a value-based health plan to achieve a successful behavioral-based benefit strategy.

BUSINESS

Many would argue that the market view of value for pharmaceutical products remains focused on who controls the drug. By extension, who controls the drug relates not only to physical distribution but also to the means by which to pay for the product. Applying the principles of a value-based health plan addresses both views of value for pharmaceutical products. Such an approach would disrupt the current interrelationships and functioning of the healthcare system around pharmaceutical products.

In further considering the concept of healthcare disruption, it is useful to compare the potential for socalled hyperdisruption, similar to what has been experienced by the information technology (IT) market. A disruptive event occurs when a technological advance results in a breakthrough application, such as the recent Apple iPhone that disrupts the normal market pace or movement. The disruption accelerates further market changes in addition to competition, followed by evolution, until the next disruption.

In early 2007, IT market watchers provided insight into what should be anticipated by 2010. By comparison, anticipated changes in 2010 in healthcare are offered in the same 3 categories selected to illustrate this concept for healthcare decision makers. The relationships across similar burgeoning industries are noted in Table 4. IT and healthcare provide understandable examples of change as well as challenges being faced by those inside and out of these industry segments.

Clearly we have seen marketplace “eruption” trends through “early innovating” employers and health plans along with local communities and state governments who are now exploring a value-based approach for employees who are plan members. In the past 10 years, at least a 10-fold increase in known marketplace valuebased benefit coverage strategies has been reported. At national conferences today, many of the presentations cover various applications of a value-based strategy in the implementation of a particular benefit design or health program for employees.

Recent surveys, however, conducted in several cities have indicated a more conservative and incremental strategy that involves a more traditional approach than that represented by a value-based health plan. Survey results from one business group in the Southwestern states noted that familiarity and senior management interest in value-based benefit was high. Upper management interest in a value-based approach linked with how it can track to their organizations’ strategic objectives. HR and user understanding and access to medical and pharmacy claim data was low. How benefit change

Table 4.

The Information Explosion • Information technology will see a 100-fold increase in data • Consumerism in healthcare and knowledge derived from the human genome project will result in a significantly increased number of applications Explosion of Devices Mobile devices available and used in the market will double • Biotechnology product availability and subsequent utilization grows 4-fold •

Transaction Explosion Information technology has moved from concerns around platform stability for connection to concerns around interaction or interactive capabilities for users in multiple applications • Healthcare claims adjudication or simple financial transactions transforming to more real-time, interactive transactions, incorporating components for a value-based health plan •

affected medical and pharmacy utilization was not clear.

Finally, the 2007-2008 trend was thought to reveal “little to no change” for planned benefit design changes.

These results indicate the extent and type of disconnects that currently exist in health benefit plans and decision-making within an organization. HR-managed benefits are not in sync with corporate goals or objectives that may result in lost productivity, job turnover, or recruitment delays. Lack of accessible data and its interpretation limit the ability of HR decision makers to determine if a program is successful, a failure, or needs limited modification to improve on success.

Translating Plan Performance Evidence for the CFO Private sector companies have moved toward a value-based health plan because it offers a more effective way to better manage healthcare costs as well as the health status of their working employees. The private sector is not alone in this debate, and with the intro-

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duction of Medicare Part D, the prescription drug program for seniors, the Centers for Medicare & Medicaid Services (CMS) is on its own search for value. CMS has already moved toward creating a better value proposition with an integrated benefit program administered by the Medicare Advantage and Prescription Drug Programs (MA-PDPs) evolving over PDP stand-alones that represent an old paradigm, a silo cost-management tactic that is not cost-effective for the “ultimate” payor of all healthcare benefits. Value includes the cost of care (purchasing or payment) as well as management of care over time that produces both predictable cost with known outcomes. This view of costs associated with higher level care can have far-reaching implications for the commercial market as CMS continues moving toward a more value-based strategy.

Employers must begin moving beyond PBM/MCO population initiatives to control prescription utilization and cost initiatives that primarily benefit the third-party payor.

This strategy can be further demonstrated by the various payor population-based initiatives by third-party payors that are aimed solely at controlling medication utilization and costs from their perspective and not that of the employer payor. Initiatives are driven through plan design administered by third-party payors (health plans, insurers, and PBMs). Some are linked to a health risk appraisal instrument that could be useful in overall healthcare cost trend management; however, what is generally seen are efforts to maximize generic medication usage, especially through mail order, which benefits PBM stakeholders, and step therapy for the approval of medication usage that incorporates easy edits online during claim adjudication or what is known as a soft prior approval (ie, a paper submission barrier to getting the medication).

Employers must begin moving beyond PBM/MCO population initiatives to control prescription utilization and cost initiatives that primarily benefit the thirdparty payor. Following a value-based approach, the strategy must acknowledge that healthcare costs are largely driven by a small group of patients with chronic illness, representing 5% of patients and 50% of health plan costs. From a management strategy perspective,

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the prudent path is to follow the dollar. One trend that will be uncovered is the rising cost share of the severely ill within a covered health plan population.

Healthcare spending falls into a few key buckets (hospital, medical/physician, pharmacy, and other).

For pharmacy, the cross-bucket effects of more or less spending on medications can be dramatic. Using new biotechnology therapy as one example, the U.S. healthcare dollar can be broken down to show pharmacy representing approximately $0.12, of which $0.10 or less goes for traditional medications and approximately $0.02 for biotechnology products. Typically, the biotechnology category is aggressively managed, resulting in higher out-of-pocket costs and possibly requiring more approvals before or during their use. At the same time, these new technology-driven applications of genome knowledge represent what medical treatment has become. Many times a $0.01 to $0.02 slice of the healthcare cost pie is denied, requiring employers to pay almost another dollar of healthcare—a cost that could be avoided.

Another example lies in the impact resulting from plan design or human behavior barriers to taking medication that had been prescribed for a chronic medical condition. Many studies have documented the nearly $1-trillion impact on the U.S. economy resulting from the cost of lost productivity alone. For a company CEO, improved medication-taking behavior can result in some of the following quantifiable benefits: • Improvement in employee health status and productivity • Reduction in total cost of health • Improved return on health investment for workforce • Reduction in hospital and emergency room use • Reduced short-term disabilities/workers compensation • Employee accountability achievement (the employee no longer feels entitled to dependence on employer/health plan support) and employee self-management behaviors

A Call to Action Many questions remain unanswered: • Is it possible to rearrange the rocks currently arrayed in our health-related benefits, or are these boulders unmovable?

• Do employee wellness programs and retiree health go together for an employer anymore? If so, what is the value proposition?

BUSINESS

• What is the impact of benefits tactics on human capital assets and what is the value proposition?

• Do acute versus chronic episodes of care require different strategies and how are they linked to recruitment/retention?

• What will the role of the employee benefit manager/HR department be in the future? Will that position be considered in or out of healthcare management?

Technological advancements challenge employers in many ways; however, consider that medication and medical technology is advancing patient treatment as well as escalating diagnostic costs today. Cost-sharing burdens from medication formulary management strategies are not always advantageous to an employer and lack a value-based behavioral plan component beneficial for the employer.

Examples discussed in this article on value-based health plans demonstrate that achievement of value is or should be a major part of your business strategy. Data alone are not sufficient. It is important also to know

AHDB Stakeholder Perspective Value-Based Drug Benefit: Implications for Manufacturers The impact of value-based drug benefit designs on manufacturers will depend on how quickly individual firms adapt their business thinking and communications strategies.

Until recently, the path to success for a drug manufacturer was based largely on product novelty, physician-centric marketing, and pricing strategies, balancing the unit prices and concessions against formulary position. To maximize market share and margins in the world of value-based drug benefit designs, manufacturers will need to (1) demonstrate the clinical and economic case for each product and therapeutic class; (2)

how to aggregate data and interpret them. The goal is to change value proposition by truly tying benefit designs for enhanced outcomes performance to behavioral-based health plan goals.

Costs continue to increase while the issues remain the same. There is an employer opportunity to be proactive and “disrupt” the marketplace to its advantage. An employer or health plan sponsor must (1) understand the total cost. This is important for a value determination and represents the shift from traditional silo cost management to a total cost of care model; (2) understand plan members’ behaviors using their own data to create a value proposition that can work; and (3) finally, determine if their healthcare advisor(s) provide innovative strategies and solutions. There must be a positive alignment and direction for the health plan program to your business goals and objectives.

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

build absolute and comparative evidence on a continuous basis; (3) develop new value-based pricing models and market partnerships; and (4) communicate far more effectively with public and private payors.

For many firms, this will require a significant, even scary change in thinking and tactics, payor-centric communications, comfort with a massive increase in transparency, and a greater willingness to partner. Therefore, while the financial risks of moving to a value-based world are daunting, ultimately the greatest challenges are intellectual.

Value-based drug benefit designs will pose the greatest challenges to manufacturers with product lines (or pipelines) dominated by “me too” drugs; rigid, risk-averse organizational silos; and outdated, prescriber-centric communications.

Kip Piper, MA, CHE

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Role of NCCN in Integrating Cancer Clinical Practice Guidelines into the Healthcare Debate Al B. Benson III, MD, FACP Elizabeth Brown, MD

Many new drugs and drugs in the pipeline are referred to as targeted therapy. Targeted therapies have revolutionized the care of certain cancers, such as chronic myelogenous leukemia, but for other common malignancies, such as colon cancer, the impact on survival has been more modest. These seemingly incremental improvements coupled with the high cost of targeted therapy have focused the debate about the cost of healthcare squarely on oncology. Clinical practice guidelines are a common baseline starting point for this debate. Guidelines reflect clinical evidence and expert judgment, which is necessary to fill in the gaps when clinical evidence is not yet available or is evolving quickly. In addition, clinical guidelines inform other key aspects of oncology care, such as establishing a standard of care, which can then be translated into quality measures.

Guidelines can also be reformatted to create an oncology drug compendium or rewritten to provide patient information.

T

he data regarding healthcare costs are clear, persistent, troubling at the least, and truly frightening at worst.

It is estimated that by 2014, nearly 20% of the nation’s economy will be consumed by healthcare, and the growth in healthcare spending will outpace economic growth through the next decade.1 The National Institutes of Health estimated that the overall cost of cancer in 2006 was $206.3 billion. Of this total figure, $78.5 billion represents direct medical costs, including inpatient and outpatient care, drugs, and devices.2

lectively known as targeted therapy, and include such drugs as imatinib (Gleevec®), erlotinib (Tarceva®), rituximab (Rituxan®), bevacizumab (Avastin®), cetuximab (Erbitux®), and trastuzumab (Herceptin®). Many others are in the pipeline. Some of these drugs are targeted to specific proteins only expressed on tumor cells, and thus their application is limited to those tumors expressing these proteins. For example, trastuzumab is targeted to a tyrosine kinase overexpressed in Al B. Benson III, MD, FACP 25% to 30% of early-stage breast cancer cells. As an adjuvant therapy, trastuzumab reduces the risk of recurrence by 50% in women with surgically treated breast cancer. A full course of trastuzumab treatment costs approximately $50,000.3 The Cost of Improving Care Another example is imatinib, a monoclonal antibody The rising cost of cancer care is in part related to directed at another tyrosine kinase, but one specific to many new and expensive antineoplastic drugs that have chronic myelogenous leukemia (CML) and stromal reached the market in the past 7 years, including those tumors of the gastrointestinal (GI) tract. Imatinib has that specifically target tumor cells. These drugs are colrevolutionized the treatment of CML and GI stromal tumors, essentially turning these malignancies into treatable diseases requiring lifelong maintenance imaDr. Benson is Professor of Medicine, Associate Director for tinib therapy. The impact on GI stromal tumors is parClinical Investigations, Robert H. Lurie Comprehensive Cancer ticularly noteworthy, since prior to imatinib, there Center of Northwestern University, Feinberg School of were no effective chemotherapy options. The annual Medicine, Chicago, IL; Dr. Brown is Senior Oncology Scientist, cost for imatinib is in the range of $30,000,4 but the National Comprehensive Cancer Network, Chicago, IL.

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total population of patients who are candidates for imatinib is small compared with the large population of patients with breast cancer.

The effectiveness of imatinib has somewhat stifled the debate surrounding its high cost. Other targeted therapies have not been as clearly effective, in part because the multiple biologic pathways underlying other malignancies are not as well defined. For example, many targeted therapies are directed at biologic pathways that may play a part in a wide variety of malignancies, such as epidermal or vascular endothelial growth factors. Elegant preclinical work has defined these pathways, but there are still gaps in understanding how these pathways may interact in individual tumors and individual patients. For common epithelial tumors, such as colon cancer, it is quite likely that effective biologic therapy will require targeting multiple underlying pathways. Further refinement of patient selection criteria will be needed to ensure that these costly drugs are optimally used. This necessary phase of development requires research linking the biologic profile to treatment response. For example, molecular analysis of resected tumor specimens has now been routinely integrated into clinical trial protocols.

Another unique aspect of imatinib is that this drug is effective as a single therapy because the underlying tyrosine kinase target dominates the tumor biology of CML and GI stromal malignancies. In contrast, other targeted therapies are typically used with conventional chemotherapy. For example, in 2006, the U.S. Food and Drug Administration (FDA) approved the drug bevacizumab as an option for second-line therapy of colorectal cancer in 5-FU–based chemotherapy regimens. This FDA approval was based in part on a randomized study comparing the survival outcomes of patients treated with a regimen known as FOLFOX (the combination of oxaliplatin, leucovorin, and 5-FU) with or without additional bevacizumab.5 The median duration of survival for the group treated with FOLFOX and bevacizumab was 12.9 months compared with 10.8 months for the group treated with FOLFOX alone, a statistically significant difference (P = .0011). It is estimated that bevacizumab adds about $10,000 to the FOLFOX regimen per every 8-week cycle.6 Similarly, cetuximab, another monoclonal antibody directed at epithelial growth-factor receptors, has been FDA approved as a second-line therapy for metastatic colon cancer. This approval was based on a randomized trial that showed the combination treatment of cetuximab and irinotecan (Camptosar®) delayed tumor growth by approximately 4.1 months compared to 1.5

months in patients who received cetuximab alone.7 It is estimated that an 8-week course of the irinotecancetuximab combination would cost about $30,790.6

Oncology—Focus of Debate on the Cost of Healthcare These examples of seemingly incremental improvements at high cost have focused the debate about the cost of healthcare squarely on oncology. As Schrag noted, this debate puts individual oncologists caring for individual patients in an increasingly difficult position; the oncologist’s first responsibility is to be an advocate for their patients, and not the arbiter of what is considered cost-effective from a societal perspective.6 During the consultation with the patient, the oncologist must evaluate and recommend those therapies that best meet the patient’s goals, whether it be in terms of cure, survival, or palliation, and dismiss, albeit temporarily, the cost issue.

For common epithelial tumors, such as colon cancer, it is quite likely that effective biologic therapy will require targeting multiple underlying pathways.

Outside the individual physician/patient relationship, the oncology community as a whole takes a leadership role as one of the many stakeholders in the political debate regarding the pricing of drugs and the complex issue of cost-effectiveness and what a society may be willing to pay; however, all stakeholders recognize that the debate must first be grounded in clinical data and expert judgment. From the payor’s perspective, a technology assessment is typically used to analyze the clinical data. These technology assessments are focused on a single technology, such as a new drug, device, or procedure, and their many potential clinical indications.

Although this approach fits the need to develop technology-specific coverage policies, it does not reflect the way cancer care is delivered across a continuum. For example, what the oncologist sees is not that a single drug may add a median of 2 to 6 months of survival, but rather the incremental gains of multiple different drugs and other supportive therapies that can collectively result in a significant impact on the patient’s duration

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and quality of life. Furthermore, a debate that merely focuses on median survival as the key outcome may obscure the fact that some patients respond to novel therapies remarkably well, although others do not, a perspective that only an oncologist can provide.

Clinical Practice Guidelines— Function Before Form Clinical practice guidelines function to review and synthesize the data across the entire continuum of cancer care, and thus are a better reflection of how cancer care is delivered. There is probably no field of medicine that is evolving more rapidly than oncology, thus practicing oncologists must always recommend therapies to their patients in a setting of therapeutic

It is important to clearly define the guideline development process, and to indicate to what extent the guideline recommendations are based on clinical data versus expert judgment.

uncertainty. Although technology assessments typically do not incorporate expert judgment, this is a key element of clinical guidelines necessary for providing real-world and timely guidance to practicing oncologists. Chronic lymphocytic leukemia (CLL) has been traditionally thought of as an indolent disease where the treatment goals are primarily palliative in nature, and thus past research has focused on drug toxicities and quality of life. Management of CLL, however, is rapidly evolving based on 3 converging factors: (1) the availability of specific monoclonal antibodies like rituximab and others in the pipeline; (2) the emergence of novel prognostic factors that will enable risk-adapted therapy; and (3) the ability to more closely monitor the presence of residual disease.

Controlled studies are the basis of many technology assessments, but such studies integrating all of these advancements will always lag behind their clinical availability, particularly given the lengthy natural history of CLL. Clinical practice guidelines integrating both the available clinical data and expert judgment provide a flexible, nonprescriptive approach that best serves the needs of practicing oncologists and their patients.

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Standardizing Care Clinical guidelines can also provide important guidance in standardizing care to ensure that clinical advances that are developed in academic settings will translate to community settings. As previously mentioned, trastuzumab therapy has emerged as a standard adjuvant therapy for early-stage breast cancer that overexpresses a tyrosine kinase protein called human epidermal growth factor receptor 2 (HER-2); however, the effectiveness of this new treatment option is absolutely dependent on the accurate assessment of HER-2 in tumor cells. As the therapy moved from the academic settings to the community setting, it became apparent that different laboratory techniques and interpretations resulted in patients being variably categorized as candidates for trastuzumab therapy depending on where or how their HER-2 status was evaluated. In 2007, the American Society of Clinical Oncologists (ASCO) published clinical guidelines to establish standards for optimal testing performance.8 This example illustrates one of the assumptions underlying the development of clinical guidelines; guidelines have the potential to identify unnecessary tests and services, leading to improved patient quality of care.

Identifying Relevant Outcomes The initial starting point for a clinical guideline is similar to a technology assessment (ie, a review of the available evidence). A key element of this initial step is identification of the most relevant outcomes—the yardsticks by which a therapy will be measured. Although the primary outcome of interest is often overall survival, disease-free survival may be the key outcome in some situations, reflecting the flexible approach of clinical guidelines. Evaluation of diagnostic technologies is often challenging because the final health outcome is based on how the diagnostic information, such as serum tumor markers or prognostic indicators, might influence patient management, which could be many years and many therapeutic interventions down the road. The initial review establishes the state of the evidence, which is then interwoven with expert judgment to address the literature gaps and incorporate real-world clinical experience. Throughout this process, it is important to clearly define the guideline development process, and to indicate to what extent the guideline recommendations are based on clinical data versus expert judgment.

The Development Process A variety of different oncology organizations have developed clinical practice guidelines. In the United

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States the 2 leading organizations are the National Comprehensive Cancer Network (NCCN), a group of 21 preeminent cancer care centers, and ASCO. ASCO has been publishing clinical guidelines since 1994. The guideline process is initiated with a systematic literature review, which is then reviewed by a panel of experts followed by development of specific recommendations. As of January 2007, 33 guidelines had been published by ASCO, of these 19 were considered active, and 14 were considered inactive. In addition, 19 new guidelines or updates to existing guidelines were in progress. ASCO guidelines are specifically focused on emerging technologies, interpretation of major clinical trial results, common clinical management problems, and perceived misuse or overuse of technologies. The guidelines are not designed to address the entire spectrum of cancer care.

In contrast, the NCCN guidelines address the entire continuum of cancer care. The NCCN has developed 110 different guidelines that cover 98% of all cancers.

Additional guidelines focus on screening, early detection, and supportive care. The NCCN process is designed to be both multidisciplinary and comprehensive across all stages of cancer including all modalities of treatment. Guideline development incorporates an evidence-based approach when evidence is available, and evidence-based expert consensus when high-level evidence is lacking.9 The NCCN guidelines are unique in that the recommendations are not presented in a tabular list, but comprise a series of algorithms that address the entire continuum of cancer care, ranging from initial diagnosis to end-of-life care. Extensive footnotes and a manuscript accompany the algorithms, both of which provide supporting references, background information, and discussion of ongoing controversies. A level of evidence/consensus is assigned to each recommendation (Table 1).

It is interesting to note that the majority of recommendations in the NCCN guidelines are considered Category 2A, illustrating that the minority of cancer treatments are based on the results of high-level evidence, such as randomized controlled trials.

Updating Guidelines Every guideline is updated yearly. Before the panel meeting, the existing guidelines are distributed to panel members for broader review in their institutions and for identifying specific areas that require discussion and potential revision. The panel meets face-to-face or by

Table 1. NCCN Levels of Evidence/Consensus

• • •

•

Category 1: Uniform consensus of the NCCN panelists based on high-level evidence Category 2A: Uniform NCCN consensus, based on lower-level evidence Category 2B: Nonuniform NCCN consensus (but no major disagreement), based on lower-level evidence Category 3: Major NCCN disagreement that the recommendation is appropriate

NCCN indicates National Comprehensive Cancer Network.

Table 2. Medicare Coverage Advisory Committee: Desirable Characteristics for a Drug Compendium

• • • • • • • •

• •

Extensive breadth of listing Quick throughput from application for inclusion to listing Detailed description of the evidence reviewed for every individual listing Use of prespecified published criteria for weighing evidence Use of prescribed published process for making recommendations Publicly transparent process for evaluating therapies Explicit “not recommended” listing when validated evidence is appropriate Explicit listing and recommendations regarding therapies, including sequential use or combination in relation to other therapies Explicit “equivocal” listing when validated evidence is equivocal Process for public identification and notification of potential conflicts of interest of the compendia’s parent and sibling organizations, reviewers, and committee members, with an established procedure to manage recognized conflicts

3/30/2006–Compendia for coverage of off-label uses of drugs and biologicals in an anti-cancer chemotherapeutic regimen. http://www.cms.hhs.gov/mcd/viewmcac.asp?where=whatsnew&mid =33#agenda.

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teleconference on alternate years. Each panel member is asked to disclose any potential conflict of interest, which typically consists of pharmaceutical research support or participation in a pharmaceutical advisory board. It should be recognized that most panel members are likely to have conflicts. The conflicts of interest are disclosed in aggregate in every guideline. The guidelines are then discussed at the meeting and revised accordingly.

The NCCN has developed 110 different guidelines that cover 98% of all cancers.

Additional guidelines focus on screening, early detection, and supportive care.

the NCCN guidelines have been reformatted into patient versions for the most common malignancies.

The NCCN has also sought other ways to leverage the clinical guidelines to improve cancer care and quality of care. For example, based on the clinical guidelines for breast cancer, colorectal cancer, and non-Hodgkin’s lymphoma, the NCCN initiated the NCCN Oncology Outcomes Database Project. The project is designed to identify the most efficacious and cost-effective strategies for the management of these common cancers, and monitor and benchmark the member institution’s concordance with the guideline recommendations. The database will be able to describe patterns and outcomes of care, and will serve as the basis of a feedback loop to physicians and their member institutions. Breast cancer was the initial focus of the database project and has now accrued some 30,000 patients.

Drug Compendium One of the strengths of the NCCN guideline process is that the guidelines can also be updated on an ad hoc basis to respond to particularly important trial results or new drug approvals by the FDA. Initial results of influential, high-profile phase 3 studies are often presented at the annual meetings of either ASCO or the American Society of Hematology. The NCCN guidelines can rapidly incorporate these important clinical data into their guidelines, giving it high visibility to both practicing oncologists and payors, who increasingly depend on the NCCN guidelines as a resource for their own coverage policy development process.

Aspects of cancer care that cut across multiple different malignancies are not well addressed by cancer-specific guidelines. These topics have been addressed by separate NCCN task forces that bring together members of different NCCN guideline panels and other experts as necessary. Recent task force reports have included bone health, focusing on the prevention and management of osteoporosis in patients with cancer, PET scans in a variety of malignancies, and oral mucositis as a complication of either chemotherapy and radiation therapy in a variety of malignancies. The multidisciplinary approach is another distinguishing feature of the NCCN guidelines.

Leveraging Guidelines The guidelines and task force reports are publicly available on the NCCN Web site (www.nccn.org), and in collaboration with the American Cancer Society,

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The clinical guidelines have also served as the basis for the development of the NCCN Drugs & Biologics Compendium. Although the parent clinical guidelines look at the treatment of the patient across the continuum of care, the drug compendium reformats this information to list all the indications for a given drug and cancer type in a tabular format. Users seeking additional information are referred to the clinical guidelines. Every NCCN clinical guideline now has a corresponding entry in the NCCN Drugs & Biologics Compendium, and the compendium is revised at the same time as the guidelines. The Medicare Coverage Advisory Committee (MCAC) has evaluated different compendia for cancer care and identified desirable characteristics for an optimal compendium (Table 2).10 The criteria describe a comprehensive compendium based on a well-defined and transparent evidence-based process. Drugs can be categorized as recommended, not recommended, or equivocal, based on the evidence.

The MCAC reviewed and scored 6 different compendia, including NCCN, the American Hospital Formulary Service Drug Information, and the United States Pharmacopeia. The NCCN scored highest of any of the 6 compendia on each criterion. Increasingly, the NCCN clinical guidelines and drug compendium are used by many payors as the basis for their coverage policies. A 2006 survey by the Blue Cross Blue Shield Association of 49 senior medical directors reported that 78% indicated that the NCCN guidelines should be the standard for clinical policy in centers of excellence.11

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The original impetus for the development of oncology clinical guidelines was simple—to provide guidance to practicing oncologists to improve the care of their patients; however, the above examples illustrate that the synthesis of data and expert opinion that is the backbone of clinical guidelines can be leveraged in many ways to inform the larger debate regarding healthcare costs and access to healthcare. From third-party payors’ coverage policies, pharmacy formularies, quality measures, pay for performance, to the debate surrounding the cost of new biologic therapy—all of these initiatives will be grounded in clinical guidelines.

References 1. Borger C, Smith S, Truffer C, et al. Health spending projections through 2015: changes on the horizon. Health Aff (Millwood).

2006;25(2):w61-w75.

2. American Cancer Society. Cancer facts and figures 2006. 2006 update. http://www.cancer.org/download/STT/CAFF2006PW Secured.pdf. Accessed January 7, 2008.

3. Kurian AW, Thompson RN, Gaw AF, et al. A cost-effectiveness analysis of adjuvant trastuzumab regimens in early HER2/neu-positive breast cancer. J Clin Oncol. 2007;25(6):634-641.

4. Goldman G. Is imatinib a cost-effective treatment for newly diag-

nosed chronic myeloid leukemia patients? Nat Clin Prac Oncol.

2005;2(3):126-127.

5. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol.

2007;25(12):1539-1544.

6. Schrag D. The price tag on progress—chemotherapy for colorectal cancer. N Engl J Med. 2004;351(4):317-319.

7. Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med. 2004;351(4):337-345.

8. Wolff AC, Hammond ME, Schwartz JN, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol. 2007;25(1):118-145.

9. Browman GP, Makarski J, Robinson P, et al. Practitioners as experts: the influence of practicing oncologists “in-the-field” on evidencebased guideline development. J Clin Oncol. 2005;23(1):113-119.

10. 3/30/2006–Compendia for coverage of off-label uses of drugs and biologicals in an anti-cancer chemotherapeutic regimen. http://www. cms.hhs.gov/mcd/viewmcac.asp?where=whatsnew&mid=33#ag enda. Accessed January 7, 2008.

11. Blue Cross Blue Shield Association. Oral communication. December 2007.

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

AHDB Stakeholder Perspective Cancer therapy is experiencing an astonishing rate of new breakthrough therapies that succeed in both prolonging life and improving the health-related quality of life. This amounts to a society-wide paradigm shift involving all stakeholders in the process of care. The principal drivers are the high quality of new drugs and the correspondingly high costs, requiring new tactics to balance quality with cost and access to care. The sequence of events is as follows: • Growth in number and quality of new cancer agents = • Increases in healthcare resource consumption ($$) = • Call for new efficiency measures o Preventive medicine o Personalized medicine • STRATEGIES: predetermine responders, eliminate waste usage of expensive biologic drugs • METHODS: molecular mapping and imaging o NCCN guidelines: updated continually, directing providers and payors to best prac-

•

•

• •

tices, especially needed in the complex field of oncology PUBLIC: must decide if it wants the new personalized medicine model and if so, whether they will finance it by paying more of their income into healthcare; this requires a major educational initiative so that lay persons will understand the issues to make an informed strategic public policy shift GOVERNMENT: must find new systems for financing o Coverage for new cancer drugs, molecular mapping, and imaging o Equitable reimbursement models for providers and provide appropriate income and incentives to administer optimal care MANUFACTURERS: must align research closely with provider organizations, FDA, and CMS PAYORS: must pursue efficiency measures appropriate to cancer care, not simplistic costcontainment measures, which have not been shown to reduce costs or otherwise take effective advantage of the new breakthroughs in cancer drug therapy

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Measuring the Value of Treatment to Patients: Patient-Reported Outcomes in Drug Development Richard J. Willke, PhD

Patient-reported outcomes (PROs) can be important measures of the impact and value of new drug treatments to patients.

Recently, both multisector stakeholder groups and the U.S. Food and Drug Administration have carefully considered and issued guidance on best practices for the use of PROs in measuring treatment impact. When best practices are followed and PRO data are appropriately included in drug development strategy and clinical trials, these data can be part of the evidence submitted for drug approval and included in drug labeling. One study showed that PRO data were included in 30% of a sample of new drug labels and were more concentrated in certain therapeutic areas, such as anti-inflammatory agents, vaccines, gastrointestinal agents, and respiratory and urologic agents. PRO data included in labeling, or generated in a similar scientific manner, may often then be used in other communication vehicles, such as formulary submission dossiers, journal or direct-to-consumer advertisements, publications, or continuing medical education. Meaningful and reliable PRO results regarding the effects of new treatments on how patients feel and function provide useful information to those who must make decisions about the availability and utilization of such treatments.

A

lthough improving survival remains a key target for much of drug development, finding new treatments that improve how the patient feels or functions is an increasingly important goal.

Even treatments that improve survival may be differentiated by how much they improve functionality or health-related quality of life (HRQOL), or may be of limited value if they significantly diminish either one. Thus, these outcomes can be an important gauge of the role of new medicines in the treatment process for many diseases and patients. In such cases, drug development must include appropriate, rigorous measures of such patient outcomes to properly represent and communicate the value of a new medicine when it is introduced to the market.

The science and practice of measuring patient functionality, HRQOL, or any other “subjective” endpoint reported by the patient has been developing rapidly. Indicatively, the term patient-reported out-

Dr. Willke is Senior Director, Global Outcomes Research, Pfizer, Inc., Bridgewater, NJ.

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comes (PROs) has recently come into regular use to encompass the range of endpoints that are based solely on patient responses to questions or instruments.1,2 This range includes patient diary-based data, simple visual analog scores (eg, for pain severity), many symptom measures, questions about activities of daily living, and treatment satisfaction questions, as well as the more complex multi-item, multidomain instruments measuring aspects of HRQOL. HRQOL is a multidimensional measure of the health and treatment experience of the patient, generally involving physical, social, and emotional domains. Thus, “PRO” is a much broader term than “HRQOL,” and the 2 terms are not used interchangeably. For clarity’s sake, it should be noted that “quality of life”—without the “health-related” qualifier—is viewed as including non–health-related, or only indirectly health-related, aspects of well-being (eg, financial status) and is not appropriate for use in the drug development or promotional context.3 Best practices for incorporating PRO measures into drug development and communicating the results will

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be the focus of this paper and go well beyond getting the terminology correct. Key aspects will include: (1) identification of the appropriate role of PROs in drug development and early commercial strategy; (2) establishment of a clear conceptual basis for the PRO instruments to be used; (3) successful implementation of the PRO measures within the clinical trial program; and (4) effective and timely communication of the PRO study objectives and results, both with regulators and other stakeholders. An overview of how PRO results have been used in recent labeling for new drug products approved in the United States, as well as some specific examples, will also be given.

Identifying the Role of PROs in the Drug Development Program As with any other aspect of a drug development program, PRO endpoints should be included only when there is clinical and/or practical medical value to those endpoints. Although clinical and practical medical value are closely related, the clinical value is derived from the information to be gained from PROs about treatment effects on symptoms and physiological measures per se, while the practical medical value is broader and includes the effects of treatment on patient well-being, as well as the relevance of this information to patients, payors, and others involved in decisions about treatment. Since practical medical value contributes to market access and uptake of a product, PRO endpoints are relevant to the early commercial strategy as well.

The value of PROs and their role in clinical trials in particular was outlined by the PRO Harmonization Group, an assemblage of stakeholders from academia, industry, and regulatory agencies, in a series of meetings in 2000-2002.4 The general value of the patient’s perspective was summarized along 4 lines, determined by whether the PRO was: (1) a unique indicator of the impact of disease, (2) essential for evaluating treatment efficacy, (3) useful for interpreting clinical outcomes, and/or (4) a key element in treatment decision-making.4 In other words, the PRO must be important for understanding the benefits of treatment for the patient.

Furthermore, PROs can be “essential endpoints” for clinical trials when: (1) the patient’s self-report is the primary or sole indicator of disease activity; (2) the treatment may have a small impact on survival but may have a significant impact, positive or negative, on HRQOL; (3) the treatment may adversely affect patient functionality or well-being; (4) the treatment

arms offer equal efficacy but differential PRO benefits; or (5) treatment-related decisions are based on a combination of objective and patient-reported subjective parameters.4 These describe the most common situations when PROs complement or replace other clinical endpoints in measuring the treatment benefits (or adverse impact) to the patient. In such situations, PROs can be useful, and perhaps instrumental, to regulators when deciding whether a new treatment should be approved for public use.

As with any other aspect of a drug development program, PRO endpoints should be included only when there is clinical and/or practical medical value to those endpoints.

The role of PROs in decisions about treatments in regular medical practice is the other major consideration in their selection for use in drug development programs. As is well-known, appropriate cancer treatment may be selected based on a tradeoff between likely improvements in survival, sometimes small, versus its impact, sometimes negative, on patient HRQOL. A less critical but nonetheless important example are the choices among the many arthritis treatments available, made in part based on pain relief and the effects on the patient’s ability to perform normal daily activities. An even more common example would be selection of allergy medication, which is often made based on degree of symptom relief versus drowsiness—both PROs. Thus, it is important for providers—physicians, pharmacists, nurses, and others—as well as patients to have meaningful and reliable information about these effects derived from clinical trial data.

PRO data can be useful to managed care decision makers in evaluating the mix of drugs needed on formulary to best suit the variety of their patients’ needs.

In a given category it may be important to have both a drug with maximum efficacy and one that may be not quite as efficacious but more tolerable or “patientfriendly” to encourage adherence and to allow the physician some options in patient treatment (eg, chemotherapy, certain anti-infectives, and pain medications). There is some evidence that payors do use this type of information. In a survey of managed care medical and pharmacy directors, 54% thought

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Figure 1. The Process for Generating PRO Data

Identify concepts & domains that are important to patients.

Determine intended population and research application.

Hypothesize expected relationships among concepts.

i. Identify Concepts & Develop Conceptual Framework ii. Create Instrument iv. Modify Instrument Change concepts measured, populations studied, research application, response options, recall period, or method of administration.

PRO

Generate items.

Choose administration method, recall period & response scales.

Draft instructions.

Format instrument.

Draft procedures for scoring & administration.

Pilot test draft instrument.

Refine instrument & procedures.

iii. Assess Measurement Properties Assess score reliability, validity, and ability to detect change.

Evaluate administrative & respondent burden. Add, delete, or revise items.

Identify meaningful differences in scores. Finalize instrument formats, scoring, procedures & training materials.

FDA, 2007.8

HRQOL information was “important” or “very important,” and 76% felt it would increase in importance.5 A similar survey found that, among factors considered in the drug benefit decision-making process, the HRQOL effects of the drug were more important than physician demand for the drug, rebate arrangements, and consumer demand.6

Developing PRO Claims—Not for Amateurs To provide meaningful and reliable information for regulators, providers, patients, and payors, PRO data must be generated in a scientific way. The scientific process includes appropriate endpoint and instrument (aka, questionnaire) selection—and, when needed, instrument development—as well as data collection, analysis, and interpretation.7 In February 2006, the U.S. Food and Drug Administration (FDA) issued a 36-page draft guidance8—not yet finalized at the time of this writing—that lays out much of the scientific process for generating PRO data, which the FDA expects sponsors to follow before such data can be included in product labeling.

The first step in this process is ensuring that the PRO endpoints used properly capture the aspects of treatment benefit that are most relevant to the patient, an exercise that begins with identifying the specific concepts of patient well-being that are both

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impacted by the disease and likely to be affected by treatment (Figure 1). For example, in the treatment of osteoarthritis, specific concepts considered important often include a “simple” one such as pain, as well as a more complex one such as limitations on activities of daily living. These PRO endpoints generally should be logical counterparts to other clinical or physiological endpoints; the interrelationships of all these endpoints may be described in what is called an “endpoint model.”9 In some cases, however, the PRO measures may be stand-alone primary endpoints if other types don’t apply; for example, migraine treatments rely primarily on PRO endpoints, since making objective measurements of pain and other symptom relief is difficult. When the PRO endpoint is of the more complex variety (ie, consisting of a summary score based on a number of individual questions), it needs to have an underlying “conceptual framework” that relates how the simpler concepts explored in the individual questions (eg, dressing oneself or bathing oneself) combine to form a more complex concept (eg, activities of daily living) represented by the summary score.

Proper delineation of the relationships among concepts and endpoints is important both to good measurement and to clear interpretation and communication of treatment benefit.10 Asking patients about specific concepts relating to how they feel or function is not quite as simple as it may seem. PRO instruments must go through careful development based on input from patients with the relevant condition and characteristics, item (question) selection and testing, piloting, psychometric testing for several aspects of reliability and validity, as well as responsiveness to treatment effects, and then perhaps modification and re-testing. The draft FDA guidance depicts this process in a “wheel and spokes” diagram (Figure 1).8 PRO instrument development can be an expensive and time-consuming process, and sponsors will generally first seek to use existing, well-validated instruments in their programs.11 If no existing instrument applies precisely to the target population or nature of the treatment benefit, the second choice would be to modify an existing instrument, although some additional validation work must then be conducted. As a last resort, a new instrument may need to be developed from scratch—to be validated before phase 3 trials, this development must begin early during human clinical trials. Recently the FDA has been applying increasingly rigorous standards for PRO instruments, such that instruments previously thought to be validated may no longer pass muster. In particu-

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lar, recall periods commonly used in questions (eg, “Over the past week…”) have been a subject of scrutiny. The FDA has shown a strong preference for short recall periods as a guard against recall bias; however, only a limited amount of research has been done on the extent to which recall bias affects the comparative estimates of treatment effect. This regulatory pressure, together with the increasing availability and feasibility of electronic patient diaries, has triggered a new round of development of instruments better suited for use in such circumstances.

Because of the importance of regulatory judgments on the suitability of PRO instruments and results for use in product labeling, regular interaction with the FDA about the PRO strategy and studies during the course of the development program is advisable. This interaction should include discussion of the potential language to be used in the product label if the studies are successful. Whereas the FDA therapeutic area review divisions retain the ultimate authority for the labeling of individual products, the FDA Study Endpoints and Labeling Development Team is the focal point of the agency’s PRO expertise and will often be involved in consultations concerning PRO endpoints. These interactions may start as early as phase 1, when human trials first begin, through phase 3 and the new drug application (NDA), and extend into postmarketing periods. The end-of-phase-2 meeting is generally an important point for the sponsor to review the plans for PRO endpoints in detail with the FDA. At each stage of interaction, including the final NDA submission, the sponsor typically submits a briefing document or dossier with the background on the PRO instruments used and any data available to date; a proposed outline for this dossier is expected to be included with the final FDA PRO guidance.

Diligent implementation of PRO studies in clinical trials is also crucial. Without reasonably complete, properly collected data, even the best PRO instrument cannot yield reliable and meaningful results. Planning the logistics of the data collection during or between patient study visits, training the investigational site staff on administration procedures, early and ongoing communication with sites and monitoring of the success of the data collection, and quick remediation of problems are the hallmarks of successful studies. Even though the inclusion of PRO data in clinical studies has become relatively common, study sites may still consider such data to be of secondary importance and not place sufficient priority on good data collection procedures unless proactively managed by the sponsor.

Inadequate attention to these concerns often results in too much missing or poor quality data and has resulted in the failure of many PRO studies.

Given valid, concept-based instrumentation and complete, high-quality data, the third major step toward a PRO claim is defensible analysis and interpretation of the data.12 Major endpoint hypotheses and analysis methods are declared in the original protocol; a full statistical analysis plan for the PRO data must also be established, preferably at the beginning of the study and absolutely before the data blind is broken.

Key issues to address in this plan typically include, but aren’t limited to, approaches to multiple endpoint testing, missing data (hopefully minimal but rarely zero), and clinically meaningful differences.8 Since different approaches to these issues exist and can yield different results, it is important to prospectively declare the approaches to be used to avoid the appearance, or reality, of data-mining.

Diligent implementation of PRO studies in clinical trials is also crucial. Without reasonably complete, properly collected data, even the best PRO instrument cannot yield reliable and meaningful results.

Assuming successful studies and an approvable drug, the final step is negotiating final PRO label language with the FDA. Although draft language should have been discussed earlier in the development program, the FDA will want to ensure that the final labeling to be used with the general public appropriately communicates the concepts tested and the strength of the data, based on current standards for PROs. Shifting standards can be, and have been, an issue here since PRO study decisions made early in a development program may not yield results for 5 years or more. The issuance of the draft guidance was a big step forward in that it solidified a number of standards that had been evolving for some time. Even though not all current issues are resolved there—the science is always evolving—it gives sponsors a much clearer basis for planning PRO studies during development. Standards for PRO data have essentially become at least equivalent to those applied to more traditional clinical data. These developments should give users of that information—the

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Figure 2. Types of Endpoints in U.S. Product Labels for 215 New Drugs Approved 1997-2002* 30% of new product labels included PRO endpoints

140 120

129 116

100 80

64

60 40 20 0 Lab tests & device measures

Clinician-reported outcomes

Patient-reported outcomes

*Some products have more than one type of endpoint.

Reprinted from Willke R, Burke BL, Erickson P. Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved labels. Control Clin Trials.

2004;25(6):535-552, with permission from Elsevier.

providers, patients, and payors—a greater degree of confidence that PRO claims made for new drugs are meaningful and reliable and represent treatment benefits of value to patients.

Actual PRO Claims PRO data are not new to drug development and labeling. In studies for pain medications, for example, patients have always had to be asked about how much pain or pain relief they experienced, and those results were included in labeling as efficacy measures. (It should be noted that listings of side effects in labeling as evidence regarding safety are often patient-reported but have not been the focus of this discussion.) Broader health status measures also have a long history in both clinical trials and health policy,13 but it was not until about 20 years ago that sponsors began to regularly consider collection of such broader measures in clinical trials and as having potential for labeling claims; the first apparent HRQOL claim appeared in a U.S. label in 1989 (a number of HRQOL endpoints, for erythropoietin alfa).14 Since that time, a variety of simple and more complex PRO claims have been cited in labeling.

In a study of 215 new drugs approved in the United States from 1997 to 2002, we found that 64 of these products (30%) included PRO data in the clinical trials section of the label as a measure of treatment benefit (Figure 2).3 As can be seen in Figure 2, PROs are not as

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commonly used as more traditional clinician-reported outcomes (eg, mortality, fractures, tumor response, the Unified Parkinson’s Disease Rating Scale) or laboratory tests and device measurements (eg, FEV1, HbA1C, blood pressure); however, 23 of these drugs are used only in PRO endpoints as measures of treatment benefit, including antimigraine products and some drugs for pain relief, antiepileptics, antiflu, and 3 drugs for allergic conjunctivitis. Other types of drugs that relied heavily, but not exclusively, on PRO endpoints included anti-inflammatory agents, gastrointestinal agents, vaccines, and respiratory and urologic agents.3 In some cases, these PRO endpoints were relatively simple patient-experienced events (eg, patient recall of angina attacks, partial epileptic seizures, and days with bowel urgency). Also common were symptom ratings— simple questions about influenza symptoms, ocular itching, bloating, headache severity, nausea, and so on—generally in a Likert scale or visual analog scale format. Responses for related symptoms were sometimes combined to get a symptom score, such as in asthma, pruritus, or allergic rhinitis. Such endpoints are not considered HRQOL measures but, given their subjective nature, may be affected by the same validity issues as more complex scales and thus have an important place in the PRO spectrum. More formal, complex PRO scales were represented in 16 of these labels, including both disease-specific scales (eg, Walking Impairment Questionnaire,15 WOMAC Osteoarthritis Index,16 and International Index of Erectile Function17) and more general health status measures (Short Form3618 and Sickness Impact Profile19). The most common scale used in 6 labels of arthritis drugs was the Modified Health Assessment Questionnaire,20,21 a physical function and health perception instrument particularly relevant to that disease.

No comprehensive assessment of PROs in labels since 2002 is available, but an examination of labels of recently approved drugs shows that their use continues.

The label for ciclesonide, a treatment for allergic rhinitis, says that patients treated with it “exhibited statistically significantly greater decreases in total nasal symptom scores than placebo-treated patients.” The label for varenicline, a smoking cessation product, indicates that it “reduced urge to smoke compared to placebo in all studies.” The label for eculizumab, a product for primary nocturnal hemoglobinuria, includes the statement “after 3 weeks … patients reported less fatigue and improved health-related quality of life.” These 3 examples range from a very disease-specific score important to efficacy measurement to a general

CLINICAL

HRQOL claim; the varenicline example is unusual in that “reduced urge to smoke” is related to how the drug helps achieve the ultimate outcome of treatment rather than being the ultimate outcome per se.

Communicating the Value of Treatment-Reported Outcomes The presence of the PRO claim in the approved label is important for 3 reasons: (1) it indicates that the FDA judged the information to be valid, reliable, and worthy of mention; (2) it makes the results widely available in a public document; and (3) it enables further use of the data in a variety of postlaunch communications. Such postlaunch communications are often intended for a variety of stakeholders and may include formulary submission dossiers, journal or direct-to-consumer advertisements, publications, or continuing medical education. They may contain more detail about the PRO results than present in the label per se (eg, results of individual items in a scale), as long as they are consistent with the labeling and are scientifically supportable.

By reaching a wider audience, with more relevant details, the practical medical value of the PRO results can be more completely realized via these communication vehicles than through the label alone.

Under some conditions, PRO data can still be utilized even if it doesn’t appear in the original approved label.

Postlaunch communications about marketed drugs, outside of scientific publications per se, are regulated by the FDA Division of Drug Marketing, Advertising, and Communications (DDMAC). DDMAC may deem that off-label PRO data are appropriate for use in communications if supportive data are brought forward that were not present in the original NDA, such as subsequent validation work, or data from phase 3B or phase 4 trials. In cases where development and validation of a new instrument cannot be completed before the phase 3 trials, or where the phase 3 trials reveal a potential PRO effect that must be confirmed with further trials, DDMACsanctioned use of nonlabel PRO data may be the most feasible route.

For those wishing to obtain more information about PRO results from a drug development program, several options are available. The most direct method is to contact the Medical Information Department of the drug sponsor, which is responsible for responding to external information requests. Many of the results will also be published in the scientific literature, either as conference abstracts or full journal publications. PRO results are also sometimes included in documents post-

ed on ClinicalTrials.gov or ClinicalStudyResults.org.

In summary, PRO endpoints included in drug trials may capture treatment benefits that can only be measured by obtaining patient input. They can translate the effects of a new drug from the very disease-specific, objective clinical measures traditionally used in trials to everyday concepts that are meaningful to patients and those who care for them. They can help make decisions about whether a treatment should be started, or about which treatment should be chosen. Recent regulatory guidance for, and enforcement of, standards for PRO evidence, together with the increased attention by sponsors to well-considered use of PROs in drug development, allows patients, providers, and payors to be confident that PRO data included in product labeling or seen in promotion are meaningful and reliable. When properly communicated, PRO results can help the full value of medical treatments to patients be realized.

Acknowledgments: The thoughts expressed in this paper have benefited from many discussions in recent years with Penny Erickson, Laurie Burke, and several Pfizer employees and other colleagues; however, none of them bear any responsibility for what is written here, nor does it reflect an official position of Pfizer, Inc.

References 1. Burke L. Acceptable evidence for pharmaceutical advertising and labeling. DIA Workshop on Pharmacoeconomic and Quality of Life Labeling and Marketing Claims. October 3, 2000 [presentation].

2. Revicki D. Consistent patient-reported outcomes. Value Health.

2002;5(4):295-296 [editorial].

3. Willke R, Burke LB, Erickson P. Measuring treatment impact: a review of patient-reported outcomes and other efficacy endpoints in approved labels. Control Clin Trials. 2004;25(6):535-552.

4. Acquadro C, Berzon R, Dubois D, et al, for the Harmonization Group. Incorporating the patient’s perspective into drug development and communication: an ad hoc task force report of the PatientReported Outcomes (PRO) Harmonization Group Meeting at the Food and Drug Administration, February 16, 2001. Value Health.

2003;6(5):522-531.

5. Crawford BK, Dukes EM, Evans CJ. The value of providing qualityof-life information to managed care decision makers. Drug Benefit Trends. 2001;13:45-52.

6. Motheral BR, Grizzle AJ, Armstrong EP, et al. Role of pharmacoeconomics on drug benefit decision-making: results of a survey.

Formulary. 2000;35:412-421.

7. Leidy NK, Revicki DA, Geneste B. Recommendations for evaluating the validity of quality of life claims for labeling and promotion. Value Health. 1999;2(2):113-127.

8. U.S. Food and Drug Administration. Guidance for Industry. PatientReported Outcomes Measures: Use in Medical Product Development to Support Labeling Claims. U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research

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(CBER), Center for Devices and Radiological Health (CDRH).

February 2006. www.fda.gov/CDER/guidance/5460dft/pdf. Accessed December 11, 2007.

9. Patrick DL, Burke LB, Powers JH, et al. Patient reported outcomes to support medical product labeling claims. Value Health. 2007;10(suppl 2):S125-S137.

10. Rothman ML, Beltran P, Cappelleri JC, et al. Patient-reported outcomes: conceptual issues. Value Health. 2007;10(suppl 2):S66-S75.

11. Snyder CF, Watson ME, Jackson JD, et al. Patient-reported outcomes: designing a measurement strategy. Value Health. 2007; 10(suppl 2):S76-S85.

12. Sloan JA, Dueck AC, Erickson PA, et al. Analysis and interpretation of results based on patient-reported outcomes. Value Health.

2007;10(suppl 2):S106-S115.

13. Patrick DL, Erickson P. Health Status and Health Policy: Quality of Life in Health Care Evaluation and Resource Allocation. New York, NY: Oxford University Press; 1993.

14. Shah SN, Sesti AM, Copley-Merriman K, et al. Quality of life terminology included in package inserts for US approved medications.

Qual Life Res. 2003;12(8):1107-1117.

15. Regensteiner JG, Steiner JF, Panzer RJ, et al. Evaluation of walking impairment by questionnaire in patients with peripheral arterial disease. J Vasc Med Biol. 1990;2:142-152.

16. Bellamy N, Buchanan W, Watson G, et al. Validation study of

AHDB Stakeholder Perspective When the American public rebelled against managed care in the late 1990s, it was demanding a healthcare delivery system that addressed their specific, or personal, healthcare preferences. Today there is terminology to describe this goal: personalized medicine. The public outcry against managed care is a useful backdrop for examining the phenomenon of patient-reported outcomes (PROs), which can be viewed as a part of personalized medicine.

PROs offer both challenges and opportunities to various stakeholders. Physicians incorporating PROs into their treatment strategies may see improved patient satisfaction, but the benefit comes with some costs: first education on the process, then obtaining PRO data, and finally interpreting it.

However, if PROs put the clinical picture in full relief, it will be attractive to providers and their patients alike. Obviously, physicians must be given incentives to learn PROs, including increased compensation from plans.

If physician interest in PROs is the pursuit of quality, payors have a higher hurdle to climb because they do not practice medicine but manage overall resource allocation. Their concern is the pursuit of value, which is a composite of quality, cost, and

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February 2008

WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol.

1988;15(12):1833-1840.

17. Rosen RC, Riley A, Wagner G, et al. The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Urology. 1997;49(6):822-830.

18. Ware JE Jr, Sherbourne CD. The MOS 36-Item Short-Form Health Survey (SF-36); I. Conceptual framework and item selection. Med Care. 1992;30(6):473-483.

19. Bergner M, Bobbitt RA, Carter WB, et al. The Sickness Impact Profile: development and final revision of a health status measure.

Med Care. 1981;19(8):787-805.

20. Fries JF, Spitz PW, Kraines RG, et al. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23(2):137-145.

21. Pincus T, Summey JA, Soraci SA Jr, et al. Assessment of patient satisfaction in activities of daily living using a modified Stanford Health Assessment Questionnaire. Arthritis Rheum. 1983;26(11): 1346-1353.

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

access. Hence, payors need objective evidence that their professional interests are served in implementing PROs in order to face their more complex learning curve involved in incorporating them into their corporate paradigm: education, implementation, and then interpretation of PRO data.

Large employers and CMS have similar incentives to pursue personalized medicine, as both want healthy patients. But again, they must be able to finance it and establish value. Funding must be secured for CMS to pursue PROs. Manufacturers will pay more to incorporate PRO data into their labeling, but the resulting product will have a more compelling value proposition than traditional safety/efficacy labeling. Demonstrating value of new drugs is essential in today’s climate, and in appropriate disease states PROs can form an important part of the value proposition.

The basic tenet of PROs is that healthcare is a multilateral process, not a unilateral one. It involves really involving the patient into the process. The public has been criticized for not appreciating the value proposition of healthcare intervention.

Perhaps PROs are a means of integrating patients into the decision-making process, and finally achieving that elusive goal of being a responsible healthcare coparticipant.

FDA WATCH

FDA Watch

Approvable Letters in 2007 and the Outlook for 2008 Mark Senak, JD

E

ven the most casual observer of the pharmaceutical and biotechnology industries will have noticed that in 2007, the U.S. Food and Drug Administration (FDA) issued an overwhelming number of approvable letters and a corresponding underwhelming number of approval letters for new product applications. In fact, according to a recent publication

by Sagient Research, the number of approvals fell by 13% from 2006, while the number of approvable letters increased by 40%.

An approvable letter is sometimes also called a Complete Response Letter, and it means that the FDA has cited some conditions that a drug sponsor must attend to before a product will be approved for the market. Sometimes, companies try to spin this as good news, and although it is better than a nonapproval response from the agency, it is still short of an approval.

The conditions on which the FDA demands action may be very easily addressed by the sponsoring company, involving such mundane considerations as label changes or data inclusion or even the development of a risk management plan; however, the conditions may also include new data that necessitate new clinical trials—meaning added expense and time before approval and marketing.

There are many implications related to the issuance of so many approvable letters. The current approval environment represents more than an inconvenience to companies and to patients who are awaiting therapies with serious implications for both, as well as for investors in companies, particularly smaller companies that do not yet have a product on the market. Here are just a few of the effects: • An Erosion of Intellectual Property—When a company files its application with the FDA, its patent has already begun, and the clock is ticking on that patent. The longer the FDA takes to consider and to approve a new compound, the less valuable the compound is when (and if) it is finally approved and enters the marketplace, because there is less time for the drug to have market share and recoup the investment costs represented in its development. That means either (1)

the drug will have to be priced more expensively (which is counter to patient and public interest), or (2) the company may not get back as much funding to reinvest into new research and development (again counter to patient and public interest, as well as those of investors).

• Small Companies Particularly Suffer—In 2007, both small and large companies were well represented among those who received approvable letters; however, if a company with no product yet on the market receives an approvable letter for an investigational compound, it can be devastating to the company. Consider that an approval means that a company wants to move to the market quickly, which requires, among other things, a geared up and trained sales force. An approvable letter necessarily means that a company has to either maintain that force without sales to support it or to lay them off.

Needless to say, the return for investors is not there either. If the FDA is moving the goal posts on approvability, the standards should be clear so that the impact on companies, employees, and investors can be minimized. Otherwise, startup and innovative companies may find it harder to raise the cash needed to produce tomorrow’s miracles today. It is in the public interest to have policies that encourage America’s innovation in creating new compounds, not to hinder it.

Also according to the same Sagient Research report, the average stock price change that was the result of an approvable letter dropped in 2007 to 12.89% from 21.42% in 2006, which would mean that approvable letters are having less of an impact and that perhaps investors are adjusting to this new paradigm.

• Setbacks to the FDA Modernization Act and Prescription Drug User Fee Act—In the 1990s, with the HIV epidemic whirling out of control and no treatments for people diagnosed with AIDS, there was a tremendous public appetite (and hence policymaker action) to get drugs approved more quickly. Consequently, there was policymaker action in response. Hence, FDA reform in the form of 2 pieces of legislation accomplished just that by shortening approval times and allowing for Fast Track and Accelerated Approvals. Now, however, we have a situation where the public priority is focused on risk aversion and safety issues, not quick access to new treatments. That means that policymaker actions are likely to follow public angst about drug safety with additional FDA reforms that direct and scrutinize agency approval actions. Although that is happening, it is highly likely that the agency will continue to operate in a mode of operations that lends itself to caution over speedy drug access and approval.

In short, there is every reason to believe that the

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pharmaceutical, biotech, and even device industries are operating in a new approval environment, whether or not they realize it. Safety signals anywhere along the clinical trial trail or pop meta-analyses conducted on the class or the specific compound can mean serious complications for approval, when just a few years ago, they would not have been of serious concern.

There is no reason to believe that the situation is going to improve in 2008. The FDA reform that began

Upcoming in

in 2007 is likely to continue in 2008 with a great deal of oversight scrutiny by Congress. In the past month, more than one letter has left Congress sent to the FDA to inquire about specific drug approvals and potential conflicts of interest among advisory committee members, the proposed behind-the-counter status of drugs, and whether the system for quicker approval of drugs under Fast Track has been misused. Complicating the situation further will be the election cycle, which has now begun in earnest. It will not only provide a platform for some pharmaceutical industry-bashing, it will also be a showcase for the proposal of further reforms, some of which may be designed to slow down the approval process even more in favor of perceived safety enforcement.

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

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

Unmanaged Moment

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

Patent Reform Proposals to Raise the Stakes for Researchers, Manufacturers of Biologics Rosemary Frei and Shayna Kravetz

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

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

Cost-Containment Strategies for Cancer Drugs Gary M. Owens, MD

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

“My payors don’t understand me.”

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INDUSTRY TRENDS

INDUSTRY TRENDS—CLINICAL

The 2007 Pharmaceutical and Biotech Pipeline Year-End Summary: What it Says About the State of the Art of Discovery & Development Michael F. Murphy, MD, PhD

T

he BioPharm Insight 2007 pipeline data summary (see Tables) accentuates a theme that has been repetitively voiced within the research and clinical development community for a number of years: • Basic science is the engine of innovation in drug discovery • There is a return to “deep science” within the pharmaceutical community with a commitment to characterizing both normal and pathophysiological processes at the molecular level in order to develop potential therapeutics • The more permissive and informative the science the more compounds within discovery that can transition into clinical trials (see cancer, infectious disease, and central nervous system disorders for example) • Drug discovery and early phase clinical development are increasingly enmeshed phases conceptually, with “discovery within development” used as a vehicle to select compounds for registration programs NDA/BLA Filed Phase 3 Phase 2 Phase 1/IND Filed Preclinical/Discovery No. of Products Launched Status Unclear Total

858 1,962 4,231 4,577 11,553 4,017 306 27,504

BLA indicates biologic license application; IND, investigational new drug application; NDA, new drug application.

There is no economy of scale regarding innovation.

Novel therapeutics may be derived from academic institutions, and small and medium-sized pharmaceutical companies, as often as from the larger research organizations. Given an increasingly prolific process, competitive drug discovery demands an ability to eliminate compounds as early in discovery as possible, in a fashion that

does not stifle creativity. Across the industry, “potential hits” are triaged using virtual and actual biodisposition and toxicity paradigms with criteria consistent with potential as a drug candidate. Additionally, enhanced screening is introduced earlier in the discovery/ development algorithm, ie, more upstream (closer) to the primary and secondary biological assays leading to candidate selection for clinical testing. In an entirely analogous fashion, integration of early phase clinical research into the drug discovery process requires an ability to efficiently evaluate different compounds simultaneously, rather than sequentially. The objective of this integrated stratagem is to maximize the value of the early phase portfolio considered in aggregate, rather than the value of individual projects contained within the portfolio, minimizing resource utilization and expenditures until program risk is significantly reduced.

A comparison of the attrition pattern for compounds from preclinical/discovery to registration programs (phase 3) is illustrative. Innovative science permits identification of an increasingly large array of novel new molecular entities. Given the uncertain homology that may exist in some therapeutic areas between animal models and biological effects in man even for basic attributes such as pharmacokinetics and safety, the need to render an early decision about a compound’s potential utility in man, as opposed to extensive testing in animals, is increasingly recognized as key. Therefore, there is an impetus to begin limited human experimental evaluation as expeditiously as possible in phase 1 (including first in man studies) then phase 2 studies (dose ranging, proof of concept trials) placing considerable emphasis upon decision-making paradigms with an efficient allocation of resources. The more compounds within the discovery portfolio (see cancer for example), the more innovative the clinical and biostatistical methodology employed.

This process is accelerating.

For example, no therapeutic area has contributed more to the development of clinical trial methodology, broadly defined, than has oncology. This phenomenon is in part due to an explosion in basic science that has facilitated the identification of very innovative therapeutics for which traditional trial methodology in a “proof of concept” study might be inappropriate. In oncology, and increasingly in other therapeutic areas, an ability to update and modify trial design as new clinical data are accrued, can allow a trialist to “prune” uninformative dosage groups from multi-arm dose-ranging trials prior to trial conclusion, terminate research on a clinical candidate as “futile” within constraints defined at study inception, and continuously update the information supporting the rationale for a study (ie, the hypothesis) as data

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INDUSTRY TRENDS

Therapeutic Area

Total No. of Investigational Drugs

Cancer Infectious Diseases Central Nervous System Cardiovascular Hormonal Systems Miscellaneous Immune System Gastrointestinal Musculoskeletal Pain HIV Infections Respiratory Diagnostic/ Imaging Agents/Delivery Genitourinary Dermatology Hematological Eye and Ear Total

NDA/BLA Filed

Phase 3

Phase 2

Phase 1/IND Filed

Preclinical/ Discovery

No. of Products Launched

Status Unclear

7,020 2,957 2,900 2,135 1,515 1,490 1,434 1,096 1,089 956 874 870

104 89 155 75 72 8 48 48 38 58 17 27

527 196 211 219 124 8 93 98 84 99 43 56

1,540 348 394 300 222 18 126 208 177 172 99 167

1,473 423 397 287 265 168 214 176 161 147 171 163

2,859 1,327 1,217 740 513 1,232 732 347 388 236 454 310

437 542 507 480 309 44 214 212 222 231 70 135

80 32 19 34 10 12 7 7 19 13 20 12

832 670 660 579 427 27,504

17 32 27 24 19 858

23 57 43 39 42 1,962

47 134 140 78 61 4,231

125 90 109 124 84 4,577

508 165 173 198 154 11,553

106 186 151 111 60 4,017

6 6 17 5 7 306

accumulates. Utilization of biomarkers including imaging technology rather than clinical endpoints, and enrolling a highly “leveraged” patient sample (patients with characteristics likely to enhance signal detection based upon genotypic or phenotypic information) additionally maximizes sensitivity in a proof of concept motif. All of these complementary approaches provide a conduit for early phase translational research supporting an active drug discovery process.

Indeed, innovative trial design methodology is facilitated by the existence of relatively new regulatory guidance both in the United States and Europe that will permit compound evaluation in man, with certain restrictions, following submission of a comparatively limited portfolio of preclinical studies. Limited “exploratory IND investigations” in humans can be initiated with less, or different preclinical support than would be required for a traditional application as these studies present fewer potential risks to subjects or patients than traditional trials that specifically look for dose limiting toxicities. An exploratory IND program may permit an understanding of a compound’s mechanism of action relevant to a particular disease state, characterize the pharmacokinetic or biodisposition profile of a candidate drug, or enable the selection of promising lead products from a group of candidates that interact with a therapeutic target in humans.

Should a compound prove “interesting” in small elegant

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clinical trials, traditional safety and toxicological studies in animals that enable large-scale clinical trial testing are completed. This concept is closely related to a “fail fast” thematic that places considerable valence on the elimination of compounds early in development, prior to the allocation of the resources required to obtain regulatory approval. Parenthetically, this strategy is far more appropriately utilized in those pharmaceutical companies with a robust pipeline as opposed to organizations with limited resources and potential therapeutic agents.

The implications for the healthcare environment are considerable.

• First, of necessity, the system continues to place considerable emphasis upon novelty, not potential clinical value during the discovery process and the early phases of clinical research. By definition, it is the chemical and biological novelty of the compound, and a confirmation of activity in man that provides the catalyst for a decision to transition from “discovery in development” to a prototypical development program. For example, it is an unusual company, perhaps only one with a cornucopia of compounds for potential evaluation, that will heavily weight reimbursement decisions late in discovery or very early in clinical research.

• Secondly, in the ultimate expression of the art, the clinical trial methodology upon which early development decisions can be based increasingly uses experimental

INDUSTRY TRENDS

paradigms and endpoints that are not transparent to the non-trialist and non-scientist. This process essentially precludes the informed observation and participation of many consumers of this research until peri-approval studies are launched.

• Thirdly, the database that enables health technologies assessments can be increasingly populated by patients and physicians who may not be representative of those ultimately utilizing the product. Although poor “generalizability” has always plagued the drug development process, the current development environment frequently does not encourage evaluation of patients in the “deep end of the swimming pool” until very late in the process; ie, those less than optimal patients from a research perspective with the co-morbidities, diverse concomitant medications, and complicated medical management requirements that ultimately drive healthcare utilization. Given that many discovery programs focus upon indications where “chronicity” is characteristic, where physicians and patients must form a dyadic relationship for healthcare decisions, the inability for many healthcare professionals and patients to participate in the evaluation of a potential therapeutic until its commercialization is notable.

• Finally, given that rare but clinically important safety observations are a reflection of the extent of patient exposure, duration of therapy and disease characteristics, accelerated development efforts particularly for serious or life-threatening illnesses virtually assure the submission of a database with highly circumscribed implications regarding safety and other pragmatic applications in a more relevant healthcare environment.

Accelerated clinical development processes therefore provide an impetus for the initiation of post approval studies (post marketing, phase 4 commitments) that are designed to detect safety signals, characterize optimal use, and generate other hypotheses for definitive prospective testing. An emerging “science of safety” will facilitate an ability to target a specific drug to an appropriate population, maximizing its potential as a therapeutic at every phase of testing. As important as translational medicine has become for first in man investigations, a complementary concept also recognizes that “translational medicine” is mandated at the interface of a development program with its commercial transition.

Data are provided by BioPharm Insight (http:// www.biopharminsight.com); reproduced with permission from Infinata, Inc. All rights reserved.

Dr. Murphy is an Editorial Board member of American Health & Drug Benefits™.

INDUSTRY TRENDS—BUSINESS UNITED HEALTHCARE BECOMES FIRST COMPANY TO BASE CHEMOTHERAPY DRUG COVERAGE ON NATIONAL COMPREHENSIVE CANCER NETWORK COMPENDIUM • NCCN Compendium provides independent source for chemotherapy coverage decisions • Reflects United HealthCare’s commitment to evidence-based medicine by partnering with leading medical societies and physician organizations MINNEAPOLIS—(Jan. 16, 2008)—United HealthCare, a UnitedHealth Group (NYSE: UNH) company, announced that, effective March 15, it will base its benefit coverage for chemotherapy drugs used in outpatient settings on the National Comprehensive Cancer Network (NCCN) Drugs & Biologics Compendium.

The NCCN, an alliance of 21 of the nation’s leading cancer centers, is an authoritative source of information to help patients and health professionals make informed decisions about cancer care. The NCCN’s compendium recommends drugs and biologics for the major types of FDA-approved disease indications and specific NCCN panel recommendations.

The development of NCCN information is based on the independent evaluation of available scientific evidence integrated with the expert judgment of leading clinicians. Compendium recommendations are derived from the NCCN Guidelines™, a widely-used source of information recognized as the standard of care for oncology in the United States.

Bill McGivney, PhD, NCCN CEO, said: “We are pleased that United HealthCare is the first company to choose the NCCN’s compendium as the basis for its guidelines in reimbursing for chemotherapy drugs administered in an outpatient setting. The compendium is developed based on the explicit evaluation of available scientific evidence integrated with the expert judgment of multidisciplinary panels of expert physicians from NCCN member institutions. The breadth and scope of this collaborative effort represents a significant advance beyond any previously developed guidelines. As a result, the NCCN guidelines have become the most widely used in oncology practice.”

Previously, United HealthCare based its chemotherapy-drug policies on a range of medical literature resources, which, according to Lee Newcomer, MD, United HealthCare’s senior vice president, oncology, has been standard in the industry.

The NCCN Drugs & Biologics Compendium guidelines recommend the most appropriate therapy based on clinical

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INDUSTRY TRENDS

INDUSTRY TRENDS—BUSINESS (continued) evidence and the consensus of leading academic cancer centers. They suggest the correct diagnostic evaluation, such as scans, x-rays and lab tests, optimal therapy—drug, x-ray or surgery—as well as appropriate follow-up tests.

“United HealthCare is the first national health plan to incorporate National Comprehensive Cancer Network guidelines into our chemotherapy-drug benefit,” said Dr. Newcomer. “Our collaboration with NCCN reflects United HealthCare’s commitment to partner closely with the nation’s leading independent medical societies and physician organizations in order to ensure our members receive quality, evidence-based care.

“This new policy provides clinicians, patients and our customers with a respected, independent reference

INDUSTRY TRENDS—POLICY

Healthcare Cost Concerns The Kaiser Health Security Watch reports that more Americans are personally worried about healthcare costs than about paying their rent or mortgage, being a victim of a terrorist attack or a violent crime, losing their job, or losing money in the stock market.

Nearly half of adults (46%) say they are very worried about their income not keeping up with rising prices, and nearly as many say the same about having to pay more for their healthcare or health insurance (41%). In our 3 years of tracking, income not keeping up with rising prices and having to pay more for healthcare and insurance have always been the top 2 worries; in some months, the concern about income has been slightly higher, and in others, healthcare cost worries have been slightly higher.

Among other specific healthcare worries, 35% say they are very worried about not being able to afford healthcare services they think they need, and 29% of those with health insurance say they are very worried about losing their health insurance coverage.

Healthcare worries rank ahead of other nonhealth concerns for the public, including not being able to pay their rent or mortgage (27%), losing a job (23% of those who are employed), being the victim of a terrorist attack (22%) or a violent crime (21%), or losing money in the stock market (21%).

Kaiser Health Security Watch—December 2007, The Henry J. Kaiser Family Foundation, December 2007. http://www.kff.org/healthpollreport/ CurrentEdition/security/upload/HSW1207.pdf.

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February 2008

source for use in making chemotherapy coverage decisions,” Dr. Newcomer added. “It is one of several programs launched after United HealthCare established a dedicated oncology team in 2005 to improve the quality of oncology care for our members. NCCN guidelines are a trusted source of treatment recommendations, and we value the fact that they are publicly available for both physicians and patients.”

United HealthCare will update its chemotherapy-drug policies in conjunction with monthly updates made by the NCCN to its compendium. United HealthCare is currently communicating this change in drug policy regarding use of the compendium to its network of physicians.

Complete information is available on the company’s physician portal at www.unitedhealthcareonline.com.

Kaiser Health Tracking Poll: Election 2008 - December 2007 This December 2007 tracking poll finds that Iraq continues to top the list of issues that the public wants to hear presidential candidates talk about, with more than a third (35%) naming the war as one of the top 2 issues in an open-ended question. Healthcare (30%) ranks second, followed by the economy (21%) and immigration (17%).

Healthcare ranks second behind Iraq for Republicans, Democrats, and Independents alike; however, although health ranks clearly ahead of the economy and immigration for Democrats, it is more tightly packed with these issues for Republicans.

When asked about the issues that will affect their vote for president in 2008, the list of issues is similar to those the public wants to hear candidates discuss—Iraq (29%), followed by healthcare and the economy (tied at 21%), with immigration (12%) somewhat further behind. Iraq is the top voting issue for Republicans, Democrats, and Independents alike.

The poll also examines the specific aspects of healthcare that the public wants candidates to address, as well as their perceptions of the presidential candidates on health issues.

This latest Kaiser Health Tracking Poll: Election 2008, the fifth in a series, was designed and analyzed by public opinion researchers at the Kaiser Family Foundation. A nationally representative random sample of 1,221 adults was interviewed by telephone between November 28 and December 9, 2007. The margin of sampling error for the survey is plus or minus 3 percentage points; for results based on subgroups, the sampling error is higher.

INDUSTRY TRENDS

Thinking about the campaign for the presidential election in 2008, what 2 issues would you most like to hear the presidential candidates talk about? (open-ended) Issue Rank

Total

Republicans

Democrats

Independents

1 2 3 4 5 6 7

Iraq (29%) Healthcare (21%) Economy (21%)* Immigration (12%) Frustration w/gov’t (11%) Terrorism (8%) Taxes (6%)

Iraq (25%) Economy (18%) Healthcare (16%) Terrorism (15%) Morality issues (14%) Frustration w/gov’t (14%)* Immigration (13%)

Iraq (35%) Healthcare (28%) Economy (23%) Immigration (10%) Frustration w/gov’t (9%) Gas prices/energy (6%) Education (5%)

Iraq (30%) Economy (22%) Healthcare (20%) Immigration (16%) Frustration w/gov’t (10%) Terrorism (9%) Taxes (9%)*

*Indicates a tie with item directly above.

Kaiser Health Tracking Poll—Election 2008: Key Findings (#7728), The Henry J. Kaiser Family Foundation, December 2007.

healthcare Which ONE of the following health care issues would you most like to hear the presidential candidates talk about? (Dec. 2007) 41% 47% 35% 43%

healthcare Reducing the costs of health care and health insurance

Expanding health insurance coverage for the uninsured

Improving the quality of care and reducing medical errors

Reducing spending on government programs like Medicare and Medicaid

31% 19% 42% 29% 14% 14% 13% 15% 8% 12% 6% 8%

Total Republicans Democrats Independents

Kaiser Health Tracking Poll—Election 2008: Key Findings (#7728), The Henry J. Kaiser Family Foundation, December 2007.

We asked people what concerns them most when thinking about rising healthcare costs. For nearly half the public, their biggest healthcare cost–related concern has to do with increases in the amount people pay out of their own pockets for healthcare and insurance (45%, up from 38% in June, the last time the question was asked). This is true for Republicans, Democrats, and Independents alike.

Behind out-of-pocket costs, smaller shares say they are most concerned about increases in what the nation as a whole spends on health (17%), increased spending on government health insurance programs (13%), and increases in insurance premiums paid by employers (12%).

This information was reprinted with permission from the Henry J. Kaiser Family Foundation. The Kaiser Family 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. http://www.kff.org/healthpollreport/ CurrentEdition/security/upload/HSW1207.pdf.

g , o n p s d r n , e e

healthcare When thinking about rising health care costs, which ONE of the following concerns you most…? (Dec. 2007) 45% 41% 46% 46%

Increases in the amount people pay for their health insurance premiums and other out-of-pocket out of pocket costs

Increases in what the nation as a whole spends on health

Increases in spending on government health insurance programs like Medicare and Medicaid

Increases in the health insurance premiums that employers pay to cover their workers

17% 16% 21% 15% 13% 14% 12% 15% 12% 18% 10% 11%

Total Republicans Democrats Independents

Kaiser Health Tracking Poll—Election 2008: Key Findings3 (#7728), The Henry J. Kaiser Family Foundation, December 2007.

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47

Executive Summaries Creating a 21st-Century Intelligent Health System

By Newt Gingrich, PhD, and Nancy Desmond, MEd, EdS

Authors Newt Gingrich, founder of the Center for Health Transformation, and Nancy Desmond, President and CEO of same, bring their rich experiences with the current healthcare system to this article, which is adapted from their recently published book, The Art of Transformation. They describe the freedom Americans have in shopping online for goods and services as we compare quality and costs. The two have found, however, that the same freedom does not translate to our healthcare system, in which individuals must depend on a structure that has “resisted the natural progress and modernization achieved by market-oriented 21st-century industries.” From the consequences sure to be borne by the steady aging of America, a high national incidence of obesity, a shortage of healthcare workers, and increased medical errors, they describe their solution—replacing the current largely ineffective healthcare system with an intelligent system that will not only save lives but also money.

Every American will have the right to know and the right to choose.

There are caveats, however, such as personal responsibility. Once informed, we need to make the right decisions about our health and health behaviors, including nutri-

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AMERICAN HEALTH & DRUG BENEFITS

tion and exercise, to prevent illness and complications. They further describe “best practices” focusing on prevention rather than acute care.

Making the right choices, they maintain, is a matter of life and death, not only for us, but also for our children. We are urged to make the right choices now.

Medicare Coverage Strategies: Impact of the MMA and PBMs—Part 1 of an interview with Joseph Antos, PhD, of the American Enterprise Institute American Health & Drug BenefitsÛ opens its first conversation with Joseph Antos about the impact of decisions that payors, regulators, employers, and other stakeholders have on our healthcare system.

Robert Henry, editor-in-chief, examines with Antos how the Centers for Medicare & Medicaid Services (CMS) exerts its influence on drug coverage in the wake of the Medicare Modernization Act and in the face of standards set by evidence-based medicine. Dr. Antos offers insight into CMS’s strategy and its effects on the American healthcare system. Dr. Antos paints an optimistic picture of improvements in the treatment of patients, maintaining that continued improvements would ultimately effect positive changes in health status.

February 2008

Disruptive Innovation: Value-Based Health Plans

By F. Randy Vogenberg, RPh, PhD

Continued advances in medicine and medical technology come with a price, and cost-sharing strategies are not always successful for employers and employees. The author offers several examples of value-based health plans that demonstrate achievement of value from the perspective of business strategy, benefit design, and health programs, and translating evidence to enhance plan performance.

Vogenberg notes that data are useless unless one knows how to aggregate and interpret them. He urges changing the value proposition by trying benefit designs (for real) to enhance outcomes and recommends “disrupting” the marketplace for its own good, recognizing the total cost of care (beyond your own silo of interest), understanding plan members’ behavior to put a face on the data, and judging whether plan members’ healthcare advisors are indeed providing workable strategies and solutions. Without positive alignment to business goals and objectives, health plans will be value-less.

Vogenberg also offers a challenge to readers in the form of several unanswered questions related to health-related benefits, wellness and retiree programs, benefits tactics on human capital assets, and strategies surrounding acute versus chronic episodes.

Role of NCCN in Integrating Cancer Clinical Practice Guidelines into the Healthcare Debate

Measuring the Value of Treatment to Patients: PatientReported Outcomes in Drug Development

By Al B. Benson III, MD, FACP, and Elizabeth Brown, MD

By Richard J. Willke, PhD

The debate surrounding the cost of healthcare has landed squarely on oncology owing to the high cost of therapy. The authors note that the overall cost of cancer care in 2006 was $206.3 billion, of which $78.5 billion represents direct medical costs. Many new drugs have been developed and still many more are in the pipeline; however, the application of these drugs is often limited to specific tumors, and a course of treatment is often extremely high. In addition, targeted patient populations are often small. Consequently, the effectiveness of these new agents is continually debated and thus, the increased importance of clinical practice guidelines that provide for “real-world and timely guidance” to practicing oncologists. Clinical guidelines serve several functions: they standardize care, help identify relevant outcomes, and synthesize data and expert opinion to enlighten the continued debate on the cost and therefore value of new biologic therapies.

Dr. Willke leads us through the burgeoning importance of patientreported outcomes (PROs) as they impact drug development. These data, he maintains, can be used as evidence submitted for drug approval

and included in drug labeling. Other applications for PRO data include formulary submissions dossiers, journals, direct-to-consumer advertisements, and continuing medical education. Including PRO endpoints in drug trials may capture treatment benefits that could only have been obtained from patient input. Regulatory guidance for the use and enforcement of PRO standards should increase the acceptance of PROs in drug development, allowing patients, providers, and payors to use PRO data with confidence in product labeling and promotion.

Unmanaged Moment

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SUBMISSION REQUIREMENTS

American Health & Drug Benefits ™ Information for Authors A manuscript submitted for publication in American Health & Drug Benefits™ (AHDB) will be accepted with the understanding that it is an original article and has not been submitted elsewhere or is not being considered by another journal(s). It should also adhere to the style described below; otherwise, it will not be considered for publication.

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TABLES Tables should be created using the Table function in your word-processing software. Please do not use tabs to create a table.

Manuscripts may also be submitted electronically and attached as a Microsoft Word document to editorial@AHDBonline.com.

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GENERAL STYLE AND FORMATTING FOR ALL COPY Please follow the American Medical Association Manual of Style, 10th ed.

• Length = up to 3,500 words, including an abstract of no more than 200 words and a summary of no more than 300 words • Use spellings as provided in Stedman’s Medical Dictionary for all medical terms AUTHORS Provide authors’ highest academic degree and all affiliations.

Provide the name, address, telephone number, e-mail, and fax of the corresponding author.

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• We accept 3 graphic file formats: jpg, tiff, and eps. Please include a color printout of each image.

• Be sure to write your name, the figure number, and orientation indicators on the front of each printout (“front” and “top”).

• Be sure to identify all slides or prints with the name of the author and a number corresponding to their appearance in the article. Please call out the figure in the text. “Figure 1 demonstrates the continually increasing costs associated with chemotherapy”; or “The costs associated with chemotherapy continue to rise (Figure 1).”

• Slides or figures of patients or identifiable body parts must be accompanied by written permission from the subject.

February 2008

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REPRINTS Order forms for reprints may be ordered at a nominal fee by contacting editorial@AHDBonline.com.

Additional Information Please consult the American Medical Association Manual of Style, 10th ed.

New York, NY: Oxford University Press; 2007.

CATEGORIES ACCEPTED Articles—original research, review Interview with AHDB Disease state and drug reviews Commentary Editorial Expert Problem Solving (offer problems or solutions to problems previously published) Profile—KOLs, innovators, agencies, other key organizations Primers—summaries of key concepts or processes, new rules, legislation Reviews—books, government reports, think-tank reports, industry white papers, foundation reports ADDITIONAL REQUIREMENTS Please include the following with your submission: • CV • Photo • Complete affiliations • Financial disclosures Statements of Disclosure Sources of financial support—either directly or through a third party— must be disclosed in the cover letter or in your e-mail along with the submission of your manuscript. Funding by an organization involved in the collection of data must also be disclosed in the Methods section of your submission.

See: AMA Manual of Style. 10th ed. New York, NY: Oxford University Press; 2007.

Managing cost and quality of care can be a balancing act.

Together, we can build a solid foundation for success.

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