November/December 2011, Vol 4, No 7

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ NOVEMBER/DECEMBER 2011

VOLUME 4, NUMBER 7

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

CLINICAL

Impact of Treatment by NCQA-Certified Physicians on Diabetes-Related Outcomes Brett Pinsky, MPH; James Harnett, PharmD; Ryne Paulose-Ram, PhD; Jack Mardekian, PhD; Navendu Samant, PhD; Kavita V. Nair, PhD Stakeholder Perspective by Walid F. Gellad, MD, MPH

™

REGULATORY

Are ACOs the Answer to High-Value Healthcare?

Wing Yeung, MA; Harrison Burns, III, BS, PAHM; Deryk Loiacono, PharmD candidate Stakeholder Perspective by F. Randy Vogenberg, RPh, PhD

BUSINESS

Sensitivity of Medication Use to Formulary Controls in Medicare Beneficiaries: A Review of the Literature Rahul Shenolikar, PhD; Amanda Schofield Bruno, PhD, MPH; Michael Eaddy, PharmD, PhD; Christopher Cantrell, PhD Stakeholder Perspective by Gary M. Owens, MD

INDUSTRY TRENDS Back to School: Quality Improvement through Academic Detailing

Drug Shortages the “New” Old Problem: People Are (Finally) Talking

©2011 Engage Healthcare Communications, LLC www.AHDBonline.com

DEXILANT WORKS A

SECOND SHIFT TO HELP SHUT DOWN ACID PUMPS

DEXILANT works to effectively maintain EE healing and heartburn relief Median percentage of 24-hour heartburn-free periods of the maintenance of healed EE study—overall treatment1,2

96%* 29% efficacy endpoint, 0*Secondary20 40 p<0.0025 60

DEXILANT 30 mg (n=132) Placebo 80 (n=141)100

24

HRS

DEXILANT 30 mg provides effective maintenance of EE healing t 66% of patients remained healed over 6 months with DEXILANT 30 mg (n=125) vs 14% with placebo (n=119; p<0.00001).

Study primary endpoint.1,2 Results of a 6-month, multicenter, double-blind, placebo-controlled, randomized study of patients who had successfully completed an EE study and showed endoscopically confirmed healed EE. Based on crude rate estimates, patients who did not have endoscopically documented relapse and prematurely discontinued were considered to have relapsed.

Conclusions of comparative efficacy cannot be drawn from this information.

Indications DEXILANT is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE and relief of heartburn for up to 6 months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

Average patient costs for DEXILANT are less than all other branded Rx PPIs†‡§ †Based on average out-of-pocket costs for commercially insured patients.

Cost comparisons do not imply comparable safety, efficacy, or FDA-approved indications.

Important Safety Information DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.

Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.

Hypomagnesemia has been reported rarely with prolonged treatment with PPls. Most commonly reported adverse reactions were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).

Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations.

Please see adjacent brief summary of prescribing information for DEXILANT. ‡ Wolters Kluwer Pharma Solutions, Dynamic Claims, ≤30 days supply, commercial plans only, September 2010–March 2011. §Average commercial patient cost for a 30-day prescription represents patient out-of-pocket expenses after use of programs such as electronic vouchers and Instant Savings cards.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION DEXILANT (dexlansoprazole) delayed-release capsules for oral use INDICATIONS AND USAGE DEXILANT is indicated for: • the healing of all grades of erosive esophagitis (EE) for up to 8 weeks • maintaining healing of EE and relief of heartburn for up to 6 months • the treatment of heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks.

CONTRAINDICATIONS DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Gastric Malignancy Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.

Bone Fracture Several published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Adverse Reactions].

Hypomagnesemia Hypomagnesemia, symptomatic and asymptomatic, has been reported rarely in patients treated with PPIs for at least three months, in most cases after a year of therapy. Serious adverse events include tetany, arrhythmias, and seizures. In most patients, treatment of hypomagnesemia required magnesium replacement and discontinuation of the PPI. For patients expected to be on prolonged treatment or who take PPIs with medications such as digoxin or drugs that may cause hypomagnesemia (e.g., diuretics), health care professionals may consider monitoring magnesium levels prior to initiation of PPI treatment and periodically [see Adverse Reactions].

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of DEXILANT was evaluated in 4548 patients in controlled and uncontrolled clinical studies, including 863 patients treated for at least 6 months and 203 patients treated for one year. Patients ranged in age from 18 to 90 years (median age 48 years), with 54% female, 85% Caucasian, 8% Black, 4% Asian, and 3% other races. Six randomized controlled clinical trials were conducted for the treatment of EE, maintenance of healed EE, and symptomatic GERD, which included 896 patients on placebo, 455 patients on DEXILANT 30 mg, 2218 patients on DEXILANT 60 mg, and 1363 patients on lansoprazole 30 mg once daily.

Most Commonly Reported Adverse Reactions The most common adverse reactions (≥2%) that occurred at a higher incidence for DEXILANT than placebo in the controlled studies are presented in Table 2.

Table 2: Incidence of Adverse Reactions in Controlled Studies Placebo DEXILANT DEXILANT DEXILANT Lansoprazole 30 mg 60 mg Total 30 mg (N=896) (N=455) (N=2218) (N=2621) (N=1363) Adverse Reaction % % % % % Diarrhea 2.9 5.1 4.7 4.8 3.2 Abdominal Pain 3.5 3.5 4.0 4.0 2.6 Nausea 2.6 3.3 2.8 2.9 1.8 Upper Respiratory 0.8 2.9 1.7 1.9 0.8 Tract Infection Vomiting 0.8 2.2 1.4 1.6 1.1 Flatulence 0.6 2.6 1.4 1.6 1.2 Adverse Reactions Resulting in Discontinuation In controlled clinical studies, the most common adverse reaction leading to discontinuation from DEXILANT therapy was diarrhea (0.7%).

Other Adverse Reactions Other adverse reactions that were reported in controlled studies at an incidence of less than 2% are listed below by body system: Blood and Lymphatic System Disorders: anemia, lymphadenopathy; Cardiac Disorders: angina, arrhythmia, bradycardia, chest pain, edema, myocardial infarction, palpitation, tachycardia; Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo; Endocrine Disorders: goiter; Eye Disorders: eye irritation, eye swelling; Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis,

gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage, retching; General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia; Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly; Immune System Disorders: hypersensitivity; Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvo-vaginal infection; Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains, overdose, procedural pain, sunburn; Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increase; Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia; Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia; Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine, memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia; Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes; Renal and Urinary Disorders: dysuria, micturition urgency; Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder; Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat; Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritis, rash, skin lesion, urticaria; Vascular Disorders: deep vein thrombosis, hot flush, hypertension Additional adverse reactions that were reported in a long-term uncontrolled study and were considered related to DEXILANT by the treating physician included: anaphylaxis, auditory hallucination, B-cell lymphoma, bursitis, central obesity, cholecystitis acute, dehydration, diabetes mellitus, dysphonia, epistaxis, folliculitis, gout, herpes zoster, hyperlipidemia, hypothyroidism, increased neutrophils, MCHC decrease, neutropenia, rectal tenesmus, restless legs syndrome, somnolence, tonsillitis.

Other adverse reactions not observed with DEXILANT, but occurring with the racemate lansoprazole can be found in the lansoprazole prescribing information, ADVERSE REACTIONS section.

Postmarketing Experience The following adverse reactions have been identified during post-approval of DEXILANT. As 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.

Blood and Lymphatic System Disorders: autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura Ear and Labyrinth Disorders: deafness Eye Disorders: blurred vision Gastrointestinal Disorders: oral edema, pancreatitis General Disorders and Administration Site Conditions: facial edema Hepatobiliary Disorders: drug-induced hepatitis Immune System Disorders: anaphylactic shock (requiring emergency intervention), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal) Metabolism and Nutrition Disorders: hypomagnesemia, hyponatremia Musculoskeletal System Disorders: bone fracture Nervous System Disorders: cerebrovascular accident, transient ischemic attack Renal and Urinary Disorders: acute renal failure Respiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightness Skin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitis DRUG INTERACTIONS Drugs with pH-Dependent Absorption Pharmacokinetics DEXILANT causes inhibition of gastric acid secretion. DEXILANT is likely to substantially decrease the systemic concentrations of the HIV protease inhibitor atazanavir, which is dependent upon the presence of gastric acid for absorption, and may result in a loss of therapeutic effect of atazanavir and the development of HIV resistance. Therefore, DEXILANT should not be co-administered with atazanavir.

DEXILANT may interfere with the absorption of other drugs where gastric pH is an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).

Warfarin Co-administration of DEXILANT 90 mg and warfarin 25 mg did not affect the pharmacokinetics of warfarin or INR [see Clinical Pharmacology]. However, there have been reports of increased INR and prothrombin time in patients receiving PPIs and warfarin concomitantly. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Patients treated with DEXILANT and warfarin concomitantly may need to be monitored for increases in INR and prothrombin time.

Tacrolimus Concomitant administration of dexlansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects Pregnancy Category B. There are no adequate and well-controlled studies with dexlansoprazole in pregnant women. There were no adverse fetal effects in animal reproduction studies of dexlansoprazole in rabbits. Because animal reproduction studies are not always predictive of human response, DEXILANT should be used during pregnancy only if clearly needed.

A reproduction study conducted in rabbits at oral dexlansoprazole doses up to approximately 9 times the maximum recommended human dexlansoprazole dose (60 mg per day) revealed no evidence of impaired fertility or harm to the fetus due to dexlansoprazole. In addition, reproduction studies performed in pregnant rats with oral lansoprazole at doses up to 40 times the recommended human lansoprazole dose and in pregnant rabbits at oral lansoprazole doses up to 16 times the recommended human lansoprazole dose revealed no evidence of impaired fertility or harm to the fetus due to lansoprazole [see Nonclinical Toxicology].

Nursing Mothers It is not known whether dexlansoprazole is excreted in human milk. However, lansoprazole and its metabolites are present in rat milk following the administration of lansoprazole. As many drugs are excreted in human milk, and because of the potential for tumorigenicity shown for lansoprazole in rat carcinogenicity studies [see Nonclinical Toxicology], a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use Safety and effectiveness of DEXILANT in pediatric patients (less than 18 years of age) have not been established.

Geriatric Use In clinical studies of DEXILANT, 11% of patients were aged 65 years and over.

No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified significant differences in responses between geriatric and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment No dosage adjustment of DEXILANT is necessary in patients with renal impairment. The pharmacokinetics of dexlansoprazole in patients with renal impairment are not expected to be altered since dexlansoprazole is extensively metabolized in the liver to inactive metabolites, and no parent drug is recovered in the urine following an oral dose of dexlansoprazole.

Hepatic Impairment No dosage adjustment for DEXILANT is necessary for patients with mild hepatic impairment (Child-Pugh Class A). DEXILANT 30 mg should be considered for patients with moderate hepatic impairment (Child-Pugh Class B). No studies have been conducted in patients with severe hepatic impairment (Child-Pugh Class C).

OVERDOSAGE There have been no reports of significant overdose of DEXILANT. Multiple doses of DEXILANT 120 mg and a single dose of DEXILANT 300 mg did not result in death or other severe adverse events. However, serious adverse events of hypertension have been reported in association with twice daily doses of DEXILANT 60 mg. Non-serious adverse reactions observed with twice daily doses of DEXILANT 60 mg include hot flashes, contusion, oropharyngeal pain, and weight loss. Dexlansoprazole is not expected to be removed from the circulation by hemodialysis. If an overdose occurs, treatment should be symptomatic and supportive.

CLINICAL PHARMACOLOGY Pharmacodynamics Serum Gastrin Effects The effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patients for up to 6 to 12 months. The mean fasting gastrin concentrations increased from baseline during treatment with DEXILANT 30 mg and 60 mg doses. In patients treated for more than 6 months, mean serum gastrin levels increased during approximately the first 3 months of treatment and were stable for the remainder of treatment. Mean serum gastrin levels returned to pre-treatment levels within one month of discontinuation of treatment.

Enterochromaffin-Like Cell (ECL) Effects There were no reports of ECL cell hyperplasia in gastric biopsy specimens obtained from 653 patients treated with DEXILANT 30 mg, 60 mg or 90 mg for up to 12 months.

During lifetime exposure of rats dosed daily with up to 150 mg per kg per day of lansoprazole, marked hypergastrinemia was observed followed by ECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology].

Effect on Cardiac Repolarization A study was conducted to assess the potential of DEXILANT to prolong the QT/QTc interval in healthy adult subjects. DEXILANT doses of 90 mg or 300 mg did not delay cardiac repolarization compared to placebo. The positive control (moxifloxacin) produced statistically significantly greater mean maximum and time-averaged QT/QTc intervals compared to placebo.

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2) basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day.

Lansoprazole produced dose-related gastric ECL cell hyperplasia and ECL cell carcinoids in both male and female rats [see Clinical Pharmacology].

In rats, lansoprazole also increased the incidence of intestinal metaplasia of the gastric epithelium in both sexes. In male rats, lansoprazole produced a dose-related increase of testicular interstitial cell adenomas. The incidence of these adenomas in rats receiving doses of 15 to 150 mg per kg per day (4 to 40 times the recommended human lansoprazole dose based on BSA) exceeded the low background incidence (range = 1.4 to 10%) for this strain of rat.

In a 24-month carcinogenicity study, CD-1 mice were treated orally with lansoprazole doses of 15 to 600 mg per kg per day, 2 to 80 times the recommended human lansoprazole dose based on BSA. Lansoprazole produced a dose-related increased incidence of gastric ECL cell hyperplasia. It also produced an increased incidence of liver tumors (hepatocellular adenoma plus carcinoma). The tumor incidences in male mice treated with 300 and 600 mg lansoprazole per kg per day (40 to 80 times the recommended human lansoprazole dose based on BSA) and female mice treated with 150 to 600 mg lansoprazole per kg per day (20 to 80 times the recommended human lansoprazole dose based on BSA) exceeded the ranges of background incidences in historical controls for this strain of mice.

Lansoprazole treatment produced adenoma of rete testis in male mice receiving 75 to 600 mg per kg per day (10 to 80 times the recommended human lansoprazole dose based on BSA).

A 26-week p53 (+/-) transgenic mouse carcinogenicity study of lansoprazole was not positive.

Lansoprazole was positive in the Ames test and the in vitro human lymphocyte chromosomal aberration assay. Lansoprazole was not genotoxic in the ex vivo rat hepatocyte unscheduled DNA synthesis (UDS) test, the in vivo mouse micronucleus test or the rat bone marrow cell chromosomal aberration test.

Dexlansoprazole was positive in the Ames test and in the in vitro chromosome aberration test using Chinese hamster lung cells. Dexlansoprazole was negative in the in vivo mouse micronucleus test.

The potential effects of dexlansoprazole on fertility and reproductive performance were assessed using lansoprazole studies. Lansoprazole at oral doses up to 150 mg per kg per day (40 times the recommended human lansoprazole dose based on BSA) was found to have no effect on fertility and reproductive performance of male and female rats.

PATIENT COUNSELING INFORMATION To ensure the safe and effective use of DEXILANT, this information and instructions provided in the FDA-approved Patient Information Leaflet should be discussed with the patient.

Inform the patient to watch for signs of an allergic reaction as these could be serious and may require that DEXILANT be discontinued.

Advise the patient to immediately report and seek care for any cardiovascular or neurological symptoms including palpitations, dizziness, seizures, and tetany as these may be signs of hypomagnesemia [see Warnings and Precautions].

Advise the patient to tell their health care provider if they take atazanavir, tacrolimus, warfarin and drugs that are affected by gastric pH changes [see Drug Interactions].

Advise the patient to follow the dosing instructions in the Patient Information Leaflet and inform the patient that: • DEXILANT is available as a delayed release capsule.

• DEXILANT may be taken without regard to food.

• DEXILANT should be swallowed whole.

• Alternatively, DEXILANT capsules can be administered as follows: – Open capsule; – Sprinkle intact granules on one tablespoon of applesauce; – Swallow immediately. Granules should not be chewed.

– Do not store for later use.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 DEXILANT is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc. Trademark registered with the U.S. Patent and Trademark office.

All other trademark names are the property of their respective owners. ©2009, 2011 Takeda Pharmaceuticals America, Inc. DEX006 R14_BS Revised: June 2011 L-LPD-0611-2

References: 1. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. 2. Metz DC, Howden CW, Perez MC, et al. Aliment Pharmacol Ther. 2009;29:742-754.

DEXILANT and DEXILANT (with design) are trademarks of Takeda Pharmaceuticals North America, Inc., registered in the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Dual Delayed Release is a trademark of Takeda Pharmaceuticals North America, Inc. and used under license by Takeda Pharmaceuticals America, Inc.

©2011 Takeda Pharmaceuticals North America, Inc. LPD-01866 7/11 Printed in U.S.A.

EDITORIAL BOARD

CLINICAL EDITOR

HEALTH INFORMATION TECHNOLOGY

PHARMACY BENEFIT DESIGN

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

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

Joel V. Brill, MD Chief Medical Officer, Predictive Health, Phoenix, AZ

GOVERNMENT EDITOR

Victor J. Strecher, PhD, MPH Professor and Director, Center for Health Communications Research University of Michigan Schools of Public Health and Medicine, Ann Arbor Founder and Chief Visionary Officer HealthMedia, Johnson & Johnson

William J. Cardarelli, PharmD Director of Pharmacy, Atrius Health Harvard Vanguard Medical Associates

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group Senior Counselor, Fleishman-Hillard Washington, DC ACTUARY

David Williams Milliman Health Consultant Windsor, CT AGING AND WELLNESS

Eric G. Tangalos, MD, FACP, AGSF Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center, Northwestern University Immediate Past President, ACCC Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FACP Professor, Internal Medicine Director, Cancer Center Network Division of Hematology/Oncology Assistant Dean for Research University of Michigan Health Systems CARDIOLOGY RESEARCH

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

Alberto M. Colombi, MD, MPH Corporate Medical Director PPG Industries, Pittsburgh, PA

HEALTH OUTCOMES RESEARCH

Diana Brixner, RPh, PhD Professor and Chair Department of Pharmacotherapy Executive Director, Outcomes Research Center, University of Utah College of Pharmacy, Salt Lake City

Leslie S. Fish, PharmD Senior Director of Pharmacy Services Fallon Community Health Plan, MA Michael S. Jacobs, RPh National Clinical Practice Leader Buck Consultants, Atlanta Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

Kavita V. Nair, PhD Associate Professor, School of Pharmacy University of Colorado at Denver

Paul Anthony Polansky, BSPharm, MBA Senior Field Scientist, Health Outcomes and PharmacoEconomics (HOPE) Endo Pharmaceuticals, Chadds Ford, PA

Gary M. Owens, MD President, Gary Owens Associates Glen Mills, PA

Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System, Danville, PA

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

POLICY & PUBLIC HEALTH

HEALTH & VALUE PROMOTION

Albert Tzeel, MD, MHSA, FACPE National Medical Director HumanaOne, Milwaukee MANAGED CARE & GOVERNMENT AFFAIRS

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

Jeffrey A. Bourret, RPh, MS, FASHP Senior Director, Branded Specialty Pharmacy Programs, US Specialty Customers, Pfizer, Specialty Care Business Unit, PA

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy American Enterprise Institute Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Associate Scientist, RAND Health Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality & biomedical research

Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE

Charles E. Collins, Jr, MS, MBA Vice President, Managed Markets Strategy Fusion Medical Communications

J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago

PATIENT ADVOCACY

RESEARCH & DEVELOPMENT

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL

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

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

F. Randy Vogenberg, RPh, PhD Principal, Institute of Integrated Healthcare, Sharon, MA ENDOCRINOLOGY RESEARCH

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

Joshua N. Liberman, PhD Vice President, Research Operations Center for Health Research Geisinger Health System, Danville, PA

Vol 4, No 7

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PERSONALIZED MEDICINE

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

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

November/December 2011

www.AHDBonline.com

SPECIALTY PHARMACY

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

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VOLUME 4, NUMBER 7

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

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

CLINICAL

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

429 Impact of Treatment by NCQA-Certified Physicians on Diabetes-Related Outcomes Brett Pinsky, MPH; James Harnett, PharmD; Ryne Paulose-Ram, PhD; Jack Mardekian, PhD; Navendu Samant, PhD; Kavita V. Nair, PhD

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

438 Stakeholder Perspective by Walid F. Gellad, MD, MPH

Associate Editors Brett Kaplan Lara J. Lorton 732-992-1892

REGULATORY

441 Are ACOs the Answer to High-Value Healthcare?

Wing Yeung, MA; Harrison Burns, III, BS, PAHM; Deryk Loiacono, PharmD candidate

Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536

450 Stakeholder Perspective by F. Randy Vogenberg, RPh, PhD

Senior Production Manager Lynn Hamilton

BUSINESS

Quality Control Director Barbara Marino

465 Sensitivity of Medication Use to Formulary Controls in Medicare Beneficiaries: A Review of the Literature Rahul Shenolikar, PhD; Amanda Schofield Bruno, PhD, MPH; Michael Eaddy, PharmD, PhD; Christopher Cantrell, PhD

Business Manager Blanche Marchitto Founding Editor-in-Chief Robert E. Henry

473 Stakeholder Perspective by Gary M. Owens, MD

Mission Statement Continued on page 426

American Health & Drug Benefits is included in the following indexing and database services: EMBASE/Elsevier Bibliographic Database SCOPUS/Elsevier Bibliographic Database Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases Standard Periodical Directory MEMBER: Committee on Publication Ethics (COPE) BPA Worldwide membership applied for August 2010.

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American Health & Drug Benefits

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www.AHDBonline.com

American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the improvement of healthcare.

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

Contact Information: For subscription information and editorial queries, please contact: editorial@engagehc.com T: 732-992-1892 F: 732-992-1881

November/December 2011

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Vol 4, No 7

moving millimeters

See how many millimeters you can move with EDARBI EDARBI 80 mg was statistically superior to DIOVAN® 320 mg and BENICAR® 40 mg in reducing 24-hr mean ambulatory and clinic SBP1 REDUCTIONS IN 24-HR MEAN AMBULATORY SBP AT WEEK 61,2 Mean ambulatory baseline: Study 1=144.9 mm Hg

▼ Similar results were observed across two other comparator studies: Study 2 vs BENICAR 40 mg and Study 3 vs DIOVAN 320 mg

STUDY 1

▼ Clinic SBP differences between EDARBI and active comparators were consistent with mean ambulatory results Study 1 Design: A 6-week, randomized, double-blind, placebo-controlled, forced-titration study in patients (N = 1,291) with clinic SBP ≥150 mm Hg and ≤180 mm Hg and 24-hr mean SBP ≥130 mm Hg and ≤170 mm Hg. The primary endpoint was change in 24-hr mean ambulatory SBP. Placebo lowered 24-hr mean ambulatory SBP by 0.3 mm Hg. Data shown are placebo corrected.

IMPORTANT SAFETY INFORMATION WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue EDARBI as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ▼ Avoid fetal or neonatal exposure.

DIOVAN 320 mg

-10.0 mm Hg BENICAR 40 mg

-11.7 mm Hg EDARBI 80 mg

-14.3 mm Hg P<0.001 vs DIOVAN 320 mg P=0.009 vs BENICAR 40 mg References: 1. EDARBI Prescribing Information. 2. White WB, Weber MA, Sica D, et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension.

Hypertension. 2011;57:413-420.

▼ Correct volume or salt depletion prior to administration of EDARBI. ▼ Monitor for worsening renal function in patients with renal impairment. ▼ In patients with an activated renin-angiotensin system, as by volume or salt depletion, reninangiotensin-aldosterone system (RAAS) blockers such as azilsartan medoxomil can cause excessive hypotension. In patients whose renal function may depend on the activity of the reninangiotensin system, e.g., with renal artery stenosis, treatment with RAAS blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. ▼ Monitor renal function periodically in patients receiving EDARBI and NSAIDs who are also elderly, volume-depleted, or who have compromised renal function. ▼ The most common adverse reaction in adults was diarrhea (2%).

For further information, please see adjacent Brief Summary of Prescribing Information.

INDICATIONS AND USAGE EDARBI is an angiotensin II receptor blocker indicated for the treatment of hypertension in adults to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. There are no controlled trials demonstrating risk reduction with EDARBI, but at least one pharmacologically similar drug has demonstrated such benefits.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. EDARBI may be used either alone or in combination with other antihypertensive agents.

EDARBI is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc.

Trademarks are the property of their respective owners. ©2011 Takeda Pharmaceuticals North America, Inc. All rights reserved. LXA-00482 09/11

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for Edarbi (azilsartan medoxomil) tablets WARNING: AVOID USE IN PREGNANCY When pregnancy is detected, discontinue Edarbi as soon as possible.

Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

INDICATIONS AND USAGE Edarbi is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with Edarbi.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Programâ&#x20AC;&#x2122;s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Edarbi may be used alone or in combination with other antihypertensive agents.

CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS 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 during the second and third trimester. When pregnancy is detected, Edarbi 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 Edarbi as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin system is available. In these rare cases, the mother should be apprised of the potential hazards to the fetus and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, Edarbi should be discontinued unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test or biophysical profiling 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 impaired renal function.

Hypotension in Volume- or Salt-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (eg, those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Edarbi.

Correct volume or salt depletion prior to administration of Edarbi, or start treatment at 40 mg. 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.

Impaired Renal Function As a consequence of inhibiting the renin-angiotensin system, changes in renal function may be anticipated in susceptible individuals treated with Edarbi.

In patients whose renal function may depend on the activity of the reninangiotensin system (e.g., patients with severe congestive heart failure, renal artery stenosis, or volume depletion), treatment with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death.

Similar results may be anticipated in patients treated with Edarbi.

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen have been reported. There has been no long-term use of Edarbi in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 4814 patients were evaluated for safety when treated with Edarbi at doses of 20, 40 or 80 mg in clinical trials. This includes 1704 patients treated for at least 6 months; of these, 588 were treated for at least 1 year.

Treatment with Edarbi was well-tolerated with an overall incidence of adverse reactions similar to placebo. The rate of withdrawals due to adverse events in placebo-controlled monotherapy and combination therapy trials was 2.4% (19/801) for placebo, 2.2% (24/1072) for Edarbi 40 mg, and 2.7% (29/1074) for Edarbi 80 mg. The most common adverse event leading to discontinuation, hypotension/orthostatic hypotension, was reported by 0.4% (8/2146) patients randomized to Edarbi 40 mg or 80 mg compared to 0% (0/801) patients randomized to placebo. Generally, adverse reactions were mild, not dose related and similar regardless of age, gender and race.

In placebo controlled monotherapy trials, diarrhea was reported up to 2% in patients treated with Edarbi 80 mg daily compared with 0.5% of patients on placebo.

Other adverse reactions with a plausible relationship to treatment that have been reported with an incidence of â&#x2030;Ľ0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below: Gastrointestinal Disorders: nausea General Disorders and Administration Site Conditions: asthenia, fatigue Musculoskeletal and Connective Tissue Disorders: muscle spasm Nervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: cough Clinical Laboratory Findings In controlled clinical trials, clinically relevant changes in standard laboratory parameters were uncommon with administration of Edarbi.

Serum creatinine: Small reversible increases in serum creatinine are seen in patients receiving 80 mg of Edarbi. The increase may be larger when coadministered with chlorthalidone or hydrochlorothiazide.

In addition, patients taking Edarbi who had moderate to severe renal impairment at baseline or who were >75 years of age were more likely to report serum creatinine increases.

Hemoglobin/Hematocrit: Low hemoglobin, hematocrit, and RBC counts were observed in 0.2%, 0.4%, and 0.3% of Edarbi-treated subjects, respectively.

None of these abnormalities were reported in the placebo group. Low and high markedly abnormal platelet and WBC counts were observed in <0.1% of subjects.

DRUG INTERACTIONS No clinically significant drug interactions have been observed in studies of azilsartan medoxomil or azilsartan given with amlodipine, antacids, chlorthalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin, pioglitazone, and warfarin. Therefore, Edarbi may be used concomitantly with these medications.

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or who have compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including azilsartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving azilsartan and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including azilsartan, may be attenuated by NSAIDs, including selective COX-2 inhibitors.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C (first trimester) and D (second and third trimesters).

There is no clinical experience with the use of Edarbi in pregnant women.

Nursing Mothers It is not known if azilsartan is excreted in human milk, but azilsartan is excreted at low concentrations 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 under 18 years of age have not been established.

Geriatric Use No dose adjustment with Edarbi is necessary in elderly patients. Of the total patients in clinical studies with Edarbi, 26% were elderly (65 years of age and older); 5% were 75 years of age and older. Abnormally high serum creatinine values were more likely to be reported for patients age 75 or older. No other differences in safety or effectiveness were observed between elderly patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Renal Impairment Dose adjustment is not required in patients with mild-to-severe renal impairment or end-stage renal disease. Patients with moderate to severe renal impairment are more likely to report abnormally high serum creatinine values.

Hepatic Impairment No dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Edarbi has not been studied in patients with severe hepatic impairment.

OVERDOSAGE Limited data are available related to overdosage in humans. During controlled clinical trials in healthy subjects, once daily doses up to 320 mg of Edarbi were administered for 7 days and were well tolerated. In the event of an overdose, supportive therapy should be instituted as dictated by the patientâ&#x20AC;&#x2122;s clinical status. Azilsartan is not dialyzable.

CLINICAL PHARMACOLOGY Pharmacokinetics Special Populations The effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference). Effects are modest and do not call for dosage adjustment.

Figure 1 Impact of intrinsic factors on the pharmacokinetics of azilsartan Population Description

PK

Fold Change and 90% CI

Recommendation

AGE

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

No dose adjustment

Severe/Normal

Cmax AUC

No dose adjustment

ESRD/Normal

Cmax AUC

No dose adjustment

Mild/Normal

Cmax AUC

No dose adjustment

Moderate/Normal

Cmax AUC

No dose adjustment

>65y/18-45y GENDER Females/Males RACE Whites/Blacks RENAL IMPAIRMENT

HEPATIC IMPAIRMENT

Severe/Normal

NO EXPERIENCE NO EXPERIENCE

PEDIATRIC

0.5

1.0

1.5

2.0

Change relative to reference

2.5

3.0

NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic (Tg.rasH2) mouse and 2-year rat studies. The highest doses tested (450 mg azilsartan medoxomil/kg/day in the mouse and 600 mg azilsartan medoxomil/kg/day in the rat) produced exposures to azilsartan that are 12 (mice) and 27 (rats) times the average exposure to azilsartan in humans given the maximum recommended human dose (MRHD, 80 mg azilsartan medoxomil/day). M-II was not carcinogenic when assessed in 26-week Tg.rasH2 mouse and 2-year rat studies. The highest doses tested (approximately 8000 mg M-II/kg/day (males) and 11,000 mg M-II/kg/day (females) in the mouse and 1000 mg M-II/kg/day (males) and up to 3000 mg M-II/kg/day (females) in the rat) produced exposures that are, on average, about 30 (mice) and 7 (rats) times the average exposure to M-II in humans at the MRHD. Mutagenesis: Azilsartan medoxomil, azilsartan, and M-II were positive for structural aberrations in the Chinese Hamster Lung Cytogenetic Assay. In this assay, structural chromosomal aberrations were observed with the prodrug, azilsartan medoxomil, without metabolic activation. The active moiety, azilsartan was also positive in this assay both with and without metabolic activation. The major human metabolite, M-II was also positive in this assay during a 24 hr assay without metabolic activation.

Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the Ames reverse mutation assay with Salmonella typhimurium and Escherichia coli, the in vitro Chinese Hamster Ovary Cell forward mutation assay, the in vitro mouse lymphoma (tk) gene mutation test, the ex vivo unscheduled DNA synthesis test, and the in vivo mouse and/or rat bone marrow micronucleus assay.

Impairment of Fertility: There was no effect of azilsartan medoxomil on the fertility of male or female rats at oral doses of up to 1000 mg azilsartan medoxomil/kg/day [6000 mg/m2 (approximately 122 times the MRHD of 80 mg azilsartan medoxomil/60 kg on a mg/m2 basis)]. Fertility of rats also was unaffected at doses of up to 3000 mg M-II/kg/day.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information).

General Information Pregnancy: Female patients of childbearing age should be told that use of drugs like Edarbi that act on the renin-angiotensin system during pregnancy can cause serious problems in the fetus and infant including low blood pressure, poor development of skull bones, kidney failure, and death. These consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Discuss other treatment options with female patients planning to become pregnant. Women using Edarbi who become pregnant should notify their physicians as soon as possible.

Distributed by Takeda Pharmaceuticals America, Inc. Deerfield, IL 60015 For more detailed information, see the full prescribing information for Edarbi at www.edarbi.com or contact Takeda Pharmaceuticals America, Inc. at 1-877-825-3327.

Edarbi is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Š2011 Takeda Pharmaceuticals America, Inc. April 2011 AZL074 R2 L-LXA-0411-4

NOVEMBER/DECEMBER 2011

VOLUME 4, NUMBER 7

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

OPINION

475 The Bush-Obama Rx Shortages: Critical Cancer Drugs Are in Short Supply Thanks to Price Controls

DEPARTMENTS

INDUSTRY TRENDS 455 Back to School: Quality Improvement through Academic Detailing

By Barry Patel, PharmD 483 Drug Shortages the “New” Old Problem: People Are (Finally) Talking

By Caroline Helwick 490 ANNUAL INDEX

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Vol 4, No 7

FOR ADULT PATIENTS WITH TYPE 2 DIABETES MELLITUS

The only DPP-4 inhibitor approved at 1 dose for adult patients with type 2 diabetes No dose adjustment is recommended for patients with hepatic or renal impairment Alone or in combination with metformin, TRADJENTA provided statistically significant improvements in A1C at 24 weeks

−0.7% A1C placebo-adjusted in monotherapy −0.6% A1C placebo-adjusted in combination with metformin

Indication and Important Limitations of Use TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

TRADJENTA has not been studied in combination with insulin.

Important Safety Information CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONS Use With Medications Known To Cause Hypoglycemia Insulin secretagogues (eg, sulfonylurea) are known to cause hypoglycemia. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA or any other antidiabetic drug.

ADVERSE REACTIONS Adverse reactions reported in ≥5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis.

Hypoglycemia was more commonly reported in patients treated with the combination of TRADJENTA and sulfonylurea compared with those treated with the combination of placebo and sulfonylurea. Pancreatitis was reported more often in patients randomized to linagliptin (1 per 538 person-years versus zero in 433 person-years for comparator).

DRUG INTERACTIONS The efficacy of TRADJENTA may be reduced when administered in combination with a strong P-glycoprotein or CYP3A4 inducer (eg, rifampin). Therefore, use of alternative treatments is strongly recommended.

USE IN SPECIFIC POPULATIONS There are no adequate and well-controlled studies in pregnant women. Therefore, TRADJENTA should be used during pregnancy only if clearly needed. It is not known whether linagliptin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Safety and effectiveness of TRADJENTA in patients below the age of 18 have not been established.

Find out more about TRADJENTA and the Savings Card program at www.tradjenta.com

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

www.tradjenta.com Copyright © 2011, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved.

(10/11)

TJ132005MHC

Tradjenta™ (linagliptin) tablets BRIEF SUMMARY OF PRESCRIBING INFORMATION Please see package insert for full Prescribing Information.

INDICATIONS AND USAGE TRADJENTA tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Important Limitations of Use: TRADJENTA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.

TRADJENTA has not been studied in combination with insulin.

CONTRAINDICATIONS TRADJENTA is contraindicated in patients with a history of a hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [see Adverse Reactions].

WARNINGS AND PRECAUTIONS Use with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with a higher rate of hypoglycemia compared with placebo in a clinical trial [see Adverse Reactions]. Therefore, a lower dose of the insulin secretagogue may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with TRADJENTA tablets or any other antidiabetic drug.

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of linagliptin has been evaluated in over 4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlled studies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once daily was studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’ duration. Five placebo-controlled trials investigated linagliptin in combination with other oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treatment duration); one with a sulfonylurea (18 weeks’ treatment duration); one with metformin and sulfonylurea (24 weeks’ treatment duration); and one with pioglitazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adverse reactions that occurred in ≥5% of patients receiving TRADJENTA (n = 2566) and more commonly than in patients given placebo (n = 1183) included nasopharyngitis (5.8% vs 5.5%). Adverse reactions reported in ≥2% of patients treated with TRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfonylurea, or metformin and at least 2-fold more commonly than in patients treated with placebo are shown in Table 1. Following 52 weeks’ treatment in a controlled study comparing linagliptin with glimepiride in which all patients were also receiving metformin, adverse reactions reported in ≥ 5% patients treated with linagliptin (n = 776) and more frequently than in patients treated with a sulfonylurea (n = 775) were arthralgia (5.7% vs 3.5%), back pain (6.4% vs 5.2%), and headache (5.7% vs 4.2%).

Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), and myalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients (4311 patient years of exposure) while being treated with TRADJENTA compared with 0 of 1183 patients (433 patient years of exposure) treated with placebo. Three additional cases of pancreatitis were reported following the last administered dose of linagliptin.

Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566 patients treated with TRADJENTA 5 mg reported hypoglycemia compared to Table 1

49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglycemia was similar to placebo when linagliptin was administered as monotherapy or in combination with metformin, or with pioglitazone. When linagliptin was administered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patients reported hypoglycemia compared with 39 of 263 (14.8%) patients administered placebo in combination with metformin and a sulfonylurea.

Laboratory Tests: Changes in laboratory findings were similar in patients treated with TRADJENTA 5 mg compared to patients treated with placebo. Changes in laboratory values that occurred more frequently in the TRADJENTA group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). No clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA. DRUG INTERACTIONS Inducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptin exposure suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with a P-gp or CYP3A4 inducer.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category B. Reproduction studies have been performed in rats and rabbits. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Linagliptin administered during the period of organogenesis was not teratogenic at doses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49 and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causing maternal toxicity in the rat and the rabbit also caused developmental delays in skeletal ossification and slightly increased embryofetal loss in rat (1000 times the clinical dose) and increased fetal resorptions and visceral and skeletal variations in the rabbit (1943 times the clinical dose). Linagliptin administered to female rats from gestation day 6 to lactation day 21 resulted in decreased body weight and delays in physical and behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductive toxicity was observed in offspring of rats exposed to 49 times the clinical dose. Linagliptin crossed the placenta into the fetus following oral dosing in pregnant rats and rabbits. Nursing Mothers: Available animal data have shown excretion of linagliptin in milk at a milk-to-plasma ratio of 4:1. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TRADJENTA is administered to a nursing woman. Pediatric Use: Safety and effectiveness of TRADJENTA in pediatric patients have not been established. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies of TRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 years and over. No overall differences in safety or effectiveness were observed between patients 65 years and over and younger patients. While this and other reported clinical experience have not identified differences in response between the elderly and younger patients, greater sensitivity of some older individuals cannot be ruled out. No dose adjustment is recommended in this population. Renal Impairment: No dose adjustment is recommended for patients with renal impairment. Hepatic Impairment: No dose adjustment is recommended for patients with hepatic impairment.

OVERDOSAGE During controlled clinical trials in healthy subjects, with single doses of up to 600 mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there were no dose-related clinical adverse drug reactions. There is no experience with doses above 600 mg in humans. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient’s clinical status. Linagliptin is not expected to be eliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis.

Adverse Reactions Reported in ≥2% of Patients Treated with TRADJENTA and at Least 2-Fold Greater than with Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination Therapy Monotherapy* n (%)

Nasopharyngitis Hyperlipidemia Cough Hypertriglyceridemia† Weight increased

Combination with SU n (%)

TRADJENTA Placebo n = 765 n = 458

Combination with Metformin# n (%) TRADJENTA Placebo n = 590 n = 248

– – – – –

– – – – –

7 (4.3) – – 4 (2.4) –

– – – – –

– – – – –

TRADJENTA Placebo n = 161 n = 84 1 (1.2) – – 0 (0.0) –

Combination with Metformin + SU n (%) TRADJENTA Placebo n = 791 n = 263

Combination with Pioglitazone n (%) TRADJENTA Placebo n = 259 n = 130

– – 19 (2.4)

– 7 (2.7) – – 6 (2.3)

–

– – 3 (1.1) – –

– 1 (0.8) – – 1 (0.8)

SU = sulfonylurea *Pooled data from 7 studies #Pooled data from 2 studies †Includes reports of hypertriglyceridemia (n = 2; 1.2%) and blood triglycerides increased (n = 2; 1.2%)

Copyright © 2011 Boehringer Ingelheim Pharmaceuticals, Inc. Revised: July 2011

TJ-BS (7-11)

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ORIGINAL RESEARCH

Impact of Treatment by NCQA-Certified Physicians on Diabetes-Related Outcomes Brett Pinsky, MPH; James Harnett, PharmD; Ryne Paulose-Ram, PhD; Jack Mardekian, PhD; Navendu Samant, PhD; Kavita V. Nair, PhD Background: The National Committee for Quality Assurance supports high-quality care for patients through the Diabetes Recognition Program (DRP). The DRP recognizes physicians and practices that are providing high-quality diabetes care as determined by 10 key measures.

Objective: To examine the impact of treatment by DRP-certified physicians compared with non–DRP-certified physicians on patient outcomes.

Methods: This retrospective claims analysis was conducted from January 1, 2007, through November 30, 2007, using a large US database of approximately 14 million commercially insured members. Physicians with DRP certification (N = 1188) were identified and matched 1:1 to physicians without DRP certification based on physician specialty, location (state) of practice, size of potential patient population, and number of patients with type 2 diabetes treated by the physician. Patients were included if they had type 2 diabetes and had been treated by a physician in the DRP group (N = 3836) or in the comparison group (N = 4175).

Primary outcomes were medication use, medical resource utilization, and expenditures. Perpatient per-year (PPPY) medical and pharmacy utilization measures were analyzed using Poisson regression; PPPY expenditures were estimated using a generalized linear model with gamma distribution.

Results: Multivariate analysis showed that patients treated by DRP-certified physicians had more postindex diabetes-related office visits (mean PPPY, 4.69 vs 4.44, respectively; P <.001) and outpatient visits (mean PPPY, 0.93 vs 0.85, respectively; P <.001) than patients treated by non–DRP-certified physicians, but fewer emergency department visits (mean PPPY, 0.04 vs 0.07, respectively; P <.001) and inpatient visits (mean PPPY, 0.08 vs 0.10, respectively; P = .02). Prescribing rates for oral antihyperglycemic drugs and statins were higher among DRP-certified physicians than non–DRP-certified physicians. Total diabetesrelated healthcare expenditures were lower for patients with type 2 diabetes managed by DRP-certified physicians compared with those managed by non–DRP-certified physicians (mean PPPY, $3424 vs $4097, respectively; P = .03).

Conclusion: Significant differences in oral antihyperglycemic and statin drug use, and diabetes-related emergency department and inpatient visits and expenditures, were observed in this study between DRP-certified and non–DRP-certified physicians, showing overall improved outcomes for patients managed by DRP-certified physicians.

H

ealth plans are increasingly offering payment incentives to motivate providers to strive for improving the quality of patient care based on established criteria such as those set forth by the National Committee for Quality Assurance (NCQA).1,2

Kavita V. Nair

Stakeholder Perspective, page 438

Am Health Drug Benefits.

2011;4(7):429-438 www.AHDBonline.com Disclosures are at end of text

The NCQA accredits healthcare organizations and manages the Health Plan Employer Data and Information Set, a tool for measuring performance in key areas, including diabetes management.3 In partnership with the American Diabetes Association (ADA),4 which has

Mr Pinsky is Senior Researcher and Dr Samant was Research Analyst (at the time this study was conducted), OptumInsight, Eden Prairie, MN; Dr Harnett is Senior Director, US Health Economics and Outcomes Research, Dr Paulose-Ram is Director, US Health Economics and Outcomes Research, and Dr Mardekian is Outcomes Research Statistical Scientist, Pfizer, NY; and Dr Nair is Associate Professor and Director, Graduate Studies, Pharmaceutical and Outcomes Research, University of Colorado Denver. An abstract based on this study was presented at the Association of Managed Care Pharmacy meeting, October 13-15, 2010, in St. Louis, MO.

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KEY POINTS ➤

➤

➤

➤

➤

The national Diabetes Recognition Program (DRP) certifies physicians and practices that provide high-quality diabetes care as determined by 10 key measures.

In this retrospective analysis using a large database with approximately 14 million members, patients with type 2 diabetes who were treated by DRPcertified physicians (N = 3836) had significantly more diabetes-related office visits and outpatient visits than patients treated by non–DRP-certified physicians (N = 4175).

However, those treated by DRP-certified physicians also had significantly fewer emergency department visits and inpatient visits.

Furthermore, prescribing rates for oral antihyperglycemic drugs and statins were higher among DRP-certified physicians than non–DRP-certified physicians.

Total diabetes-related healthcare expenditures were lower for those managed by DRP-certified physicians compared with those managed by non– DRP-certified physicians (mean cost per patient per year, $3424 vs $4097, respectively).

established specific treatment targets for long-term glycemic control in patients with diabetes, the NCQA supports high-quality care for patients through the Diabetes Recognition Program (DRP). The DRP recognizes physicians and practices that are providing highquality diabetes care as determined by 10 key measures, which include hemoglobin (Hb)A1c control, blood pressure (BP) control, low-density lipoprotein cholesterol (LDL-C) control, eye examinations, foot examinations, nephropathy assessment, and smoking cessation advice or treatment.5 For a physician to achieve DRP recognition, ≥40% of patients must meet the recommended HbA1c goal, ≥36% of patients must meet the recommended LDL-C goal, and ≥35% of patients must meet the recommended BP goal.3 Building on previous research,3,6,7 the present study was designed to examine the relationship between treatment by a DRP-certified physician and health-related outcomes for diabetic patients, including prescription utilization, medical resource use, and healthcare expenditures, and to compare the impact of treatment by DRP-certified physicians versus non–DRP-certified physicians on patient outcomes.

Methods This was a retrospective claims-based analysis using

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medical, pharmacy, and enrollment information from a large US database of commercially insured patients. This administrative healthcare claims database included electronic pharmacy and medical claims and enrollment data for commercially insured patients identified between January 1, 2004, and December 31, 2007 (identification period), from a large US managed care provider affiliated with OptumInsight. For 2007, data were available relating to approximately 14 million individuals with medical and pharmacy benefit coverage.

The plan provides fully insured coverage for professional (eg, physician), facility (eg, hospital), and outpatient prescription medication services. Because this study involved analysis of preexisting, deidentified data, it was exempt from Institutional Review Board approval.

Physician Samples All physicians in the database between January 1, 2007, and November 30, 2007, who were treating adult patients with type 2 diabetes (Appendix A, page 437) whose claims data were also included in the database were identified for inclusion in this analysis. Treating physicians included family physicians, internists, and endocrinologists identified from a large and diverse group of physician specialties at the primary, secondary, and tertiary care levels. Our rationale in selecting physicians was based on identifying physician specialties that were most likely to be in charge of managing our targeted patient population. The identification process revealed that the majority of the physicians were either family practice physicians or internists. To be included in the study sample, physicians in the database were required to be either DRP-certified by the NCQA or not DRP-certified by the NCQA in any of the existing recognition programs as of May 2009 (see http://recognition. ncqa.org/index.aspx).

Each of the DRP-certified physicians was matched directly in a 1:1 ratio to a non–DRP-certified physician based on 4 variables: physician specialty, state of physician practice, size of potential patient population (defined as the population density of the postal zip code in which the physician practices), and number of nonpediatric patients with type 2 diabetes (similar number ± 3 patients) in the analytic period.

Patient Samples Study patients were commercial enrollees with evidence of type 2 diabetes treated by a DRP-certified or non–DRP-certified physician identified in the database (8011 patients; 3836 treated by a DRP-certified physician and 4175 treated by a non–DRP-certified physician). The index date was defined as the date of the patient’s first claim for an outpatient diagnosis of dia-

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betes (International Classification of Diseases, Ninth Revision [ICD-9]: 249.xx, 250.xx, 357.2, 362.0x, 366.41, 648.0x, 996.57, V45.85, V53.91, V58.67) by a DRP-certified or non–DRP-certified physician (ie, index physician) during the study period.

Patients were included if they were continuously eligible during the 6-month preindex and 12-month postindex periods. Furthermore, patients could not have had any visits with an index physician or with any DRPcertified physician during the preindex period. Patients with evidence of gestational diabetes or polycystic ovarian syndrome were excluded from the analysis.

Medication Use Medication use was defined as the number of prescriptions per patient for oral antihyperglycemic, statin, or antihypertensive medications. These medication classes were selected because of their impact on the biometric measures that are included in the DRP certification requirements.

Medical Resource Utilization The numbers of diabetes-related office visits, outpatient visits, emergency department visits, and inpatient admissions per patient were calculated. Diabetes-related visits were defined as visits with evidence of diabetes or diabetes-related complications (see Appendix B for ICD-9 codes, www.AHDBonline/node/867.com), such as hypertension, dyslipidemia, ischemic heart disease, atherosclerosis, peripheral vascular disease, aortic aneurysm, congestive heart failure, myocardial infarction, stroke (with and without transient ischemic attack), coronary artery bypass graft surgery, angioplasty, nephropathy, neuropathy, retinopathy, foot ulcers, ketoacidosis, skin infection/skin ulcers, and lower-extremity amputations.

Expenditures Expenditures were defined as combined health plan–paid and patient-paid dollar amounts per patient for medical, pharmacy, ambulatory, emergency, outpatient, and inpatient utilization that were diabetes-related, and all-cause total expenditures. Diabetes-related pharmacy utilization included oral and injectable hypoglycemic drugs. Expenditures (based on annualized US dollar estimates from 2006-2008) were adjusted using the annual medical care component of the Consumer Price Index to adjust for inflation between 2006 and 2008.

Statistical Analyses All study variables, including preindex and postindex utilization, clinical, and expenditure measures, were first analyzed descriptively. Per-patient per-month (PPPM)

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measures were used to assist with the interpretation of within-group utilization and expenditure changes resulting from the difference in follow-up for the preindex (6 months) and postindex (12 months) periods.

Multivariate analyses were performed to compare the impact of specified independent variables between the DRP-certified and non–DRP-certified physician groups on utilization and expenditure measures on a per-patient per-year (PPPY) basis. PPPY was selected because the multivariate analysis focused on the 12-month postindex period only.

Differences in oral antihyperglycemic, antihypertensive, and statin drug use, as well as diabetes-related medical utilization between the DRP-certified and non– DRP-certified physicians were determined using Poisson regression. Predicted means for medication use and healthcare utilization counts were calculated using the parameters from the Poisson model and the mean of the independent variables.

Expenditures were examined using a generalized linear model (GLM) with a gamma distribution, with log link used to assess the incremental costs associated with DRP designation. The gamma distribution and log link account for the skewed distribution of costs. For dichotomous independent variables (eg, preindex hypertension), coefficients from the GLM specification for patients with nonzero costs represent the ratio of expected costs in one cohort versus another. For continuous independent variables (eg, age), coefficients from the GLM specification for patients with nonzero costs represent the ratio of expected costs for each unit increase (ie, per year of age). This method avoids potential difficulties introduced by transformation (eg, calculating the log of the costs) and retransformation of the dependent variable.7 Predicted costs were calculated using the parameters from the GLM model and the mean of the independent variables.

All utilization and expenditure models were adjusted for age, gender, and preindex Deyo-Charlson-Quan comorbidity score.8 Preindex oral and injectable antihyperglycemic agent use, preindex diabetes diagnosis, and preindex all-cause total expenditures were also included in the models for postindex oral antihyperglycemic agent use.

Similar preindex disease-specific covariates and preindex all-cause total expenditures were also added to the models for postindex antihypertensive and statin drug use. Preindex all-cause total healthcare expenditures were also included in the diabetes-related postindex medical utilization models for office visits, outpatient visits, emergency department visits, and inpatient visits. Preindex diabetes-related office visits, emergency department visits, and inpatient visits were also included

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Table 1 Demographic Characteristics Patients managed by Patients treated by DRP-certified non–DRP-certified physicians (N = 3836) physicians (N = 4175) N (%) N (%)

Demographics

Total (N = 8011) N (%)

Male

4283 (53.46)

2046 (53.34)

2237 (53.58)

.83

54.59 (± 11.05)

54.62 (± 11.01)

54.56 (± 11.09)

.80

18-24

34 (0.42)

18 (0.47)

16 (0.38)

.36

25-34

260 (3.25)

132 (3.44)

128 (3.07)

.36

35-44

1087 (13.57)

516 (13.45)

571 (13.68)

.36

45-54

2520 (31.46)

1175 (30.63)

1345 (32.22)

.36

55-64

2915 (36.39)

1440 (37.54)

1475 (35.33)

.36

65-74

816 (10.19)

379 (9.88)

437 (10.47)

.36

≥75

379 (4.73)

176 (4.59)

203 (4.86)

.36

Midwest

3333 (41.61)

1634 (42.6)

1699 (40.69)

.14

South

3518 (43.91)

1633 (42.57)

1885 (45.15)

.14

West

648 (8.09)

318 (8.29)

330 (7.90)

.14

Northeast

512 (6.39)

251 (6.54)

261 (6.25)

.14

Preindex hypertension

3592 (44.8)

1706 (44.5)

1886 (45.2)

.53

Preindex diabetes

3673 (45.9)

1732 (45.2)

1941 (46.5)

.23

Preindex dyslipidemia

3472 (43.3)

1636 (42.7)

1836 (44.0)

.23

0.95 (± 1.31)

0.91 (± 1.24)

0.98 (± 1.36)

.01

Age, yr, mean (± SD)

P value

Age-group, yr

Geographic region

Diabetes-related complication

Deyo-Charlson-Quan comorbidity score, mean (± SD)

DRP indicates Diabetes Recognition Program; SD, standard deviation.

in the diabetes-related expenditure model, whereas preindex oral antihyperglycemic agent use, as well as preindex all-cause office visits, emergency department visits, and inpatient visits were also included in the allcause total expenditure model.

Results Demographic Characteristics The study sample consisted of 8011 patients (3836 treated by a DRP-certified physician and 4175 treated by a non–DRP-certified physician). Most of the patients resided in either the Midwest (44.26%) or South (41.60%). Males outnumbered females (53.5% vs

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46.5%), and the mean (± standard deviation [SD]) age of the study population was 54.6 (± 11.05) years. The prevalence of comorbidities was high: 45% of patients had hypertension; 46% had diabetes (ie, they were newly diagnosed with diabetes at the time of study initiation and had not been diagnosed with diabetes during the preindex period); and 43% had dyslipidemia in the preindex period. The Deyo-Charlson-Quan comorbidity score (mean ± SD) was significantly (P = .01) higher for patients treated by the non–DRP-certified group (0.98 ± 1.36) than for those treated by the DRP-certified group (0.91 ± 1.24; Table 1).

No significant differences existed between patients

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Table 2

Preindex Utilization Per Patient Per Month, Mean (± SD)a Patients managed by Patients managed by DRP-certified non–DRP-certified physicians physicians (N = 3836) (N = 4175)

Total (N = 8011)

P value

Medication use Oral antihyperglycemic useb

0.34 (± 0.56)

0.34 (± 0.56)

0.34 (± 0.55)

.98

Antihypertensive usec

0.60 (± 0.81)

0.60 (± 0.81)

0.61 (± 0.81)

.86

Statin use

0.17 (± 0.31)

0.18 (± 0.31)

0.17 (± 0.30)

.07

Office visits

0.203 (± 0.318)

0.200 (± 0.314)

0.207 (± 0.320)

.33

Outpatient visits

0.058 (± 0.289)

0.055 (± 0.179)

0.061 (± 0.361)

.30

Emergency department visits

0.006 (± 0.035)

0.005 (± 0.033)

0.006 (± 0.037)

.27

Inpatient visits

0.010 (± 0.048)

0.010 (± 0.050)

0.010 (± 0.046)

.64

Diabetes-related total expenditures

$310.89 (± 2405.28)

$307.76 (± 1907.54)

$313.76 (± 2785.50)

.91

All-cause total expenditures

$819.54 (± 2870.95)

$791.74 (± 2325.93)

$845.10 (± 3293.23)

.40

Diabetes-related medical utilization

Expenditures

a

Differences examined using univariate analysis.

Antihyperglycemic agents included SUs, biguanides, TZDs, alpha-glucosidase inhibitors, meglitinide derivatives, DPP-4 inhibitors, SU/metformin, SU/TZD, TZD/metformin, and DPP-4/metformin. c Antihypertensive agents included beta-blockers, calcium channel blockers, agents affecting the renin-angiotensinaldosterone system, alpha-blockers, diuretics, and combination antihypertensives.

DPP-4 indicates dipeptidyl peptidase-4; DRP, Diabetes Recognition Program; SD, standard deviation; SU, sulfonylurea; TZD, thiazolidinedione. b

treated by DRP-certified physicians and those treated by non–DRP-certified physicians with regard to gender, age, geographic distribution, or presence of preindex hypertension, diabetes, or dyslipidemia (Table 1).

Medication Use Although there were no significant differences in preindex use of oral antihyperglycemic agents, antihypertensive agents, and statin medications (Table 2), univariate analysis showed that patients managed by DRPcertified physicians were more likely to receive prescriptions for oral antihyperglycemic agents than those managed by non–DRP-certified physicians (Table 3; mean prescriptions PPPM, 0.49 vs 0.46, respectively; P = .02) and statins (mean PPPM, 0.24 vs 0.22, respectively; P = .005) in the postindex period.

Medical Resource Utilization Univariate analysis showed that the 2 cohorts did not significantly differ with regard to diabetes-related office visits, outpatient visits, emergency department visits, or

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inpatient visits during the preindex period (Table 2).

However, the DRP-certified cohort had fewer emergency department visits (Table 3; mean PPPM, 0.003 vs 0.006, respectively; P <.001) and inpatient visits than the non–DRP-certified cohort (mean PPPM, 0.007 vs 0.008, respectively; P = .008), and greater use of office visits (mean PPPM, 0.388 vs 0.372, respectively; P = .03) during the postindex period.

Expenditures Preindex expenditures did not differ significantly between the 2 cohorts (Table 2), but the postindex diabetes-related expenditures and all-cause total expenditures were significantly higher for the non–DRP-certified cohort (P = .02 and P = .02, respectively; Table 3).

Specifically, diabetes-related expenditures (mean ± SD) were $241.40 ± $960.35 PPPM for the DRP-certified cohort and $315.04 ± $1693.25 PPPM for the non– DRP-certified cohort.

Multivariate analyses (Table 4) showed that patients treated by DRP-certified physicians had greater oral

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Table 3 Postindex Utilization Per Patient Per Month, Mean (± SD)a Total (N = 8011)

Patients managed by DRP-certified physicians

Patients managed by non–DRPcertified physicians

P value

Oral antihyperglycemic

0.47 (± 0.57)

0.49 (± 0.58)

0.46 (± 0.57)

.02

Antihypertensive agent

0.63 (± 0.80)

0.63 (± 0.78)

0.63 (± 0.81)

.89

Statin

0.23 (± 0.32)

0.24 (± 0.33)

0.22 (± 0.32)

.005

Office visits

0.380 (± 0.324)

0.388 (± 0.313)

0.372 (± 0.334)

.03

Outpatient visits

0.074 (± 0.259)

0.076 (± 0.225)

0.073 (± 0.287)

.62

Emergency department visits

0.005 (± 0.027)

0.003 (± 0.019)

0.006 (± 0.033)

<.001

Inpatient visits

0.007 (± 0.031)

0.007 (± 0.029)

0.008 (± 0.032)

.008

Diabetes-related total expenditures

$279.78 (± 1391.75)

$241.40 (± 960.35)

$315.04 (± 1693.25)

.02

All-cause total expenditures

$875.03 (± 1986.84)

$821.77 (± 1620.19)

$923.98 (± 2271.25)

.02

Medication use

Diabetes-related medical utilization

Expenditures

a

Differences examined using univariate analysis.

DRP indicates Diabetes Recognition Program; SD, standard deviation.

antihyperglycemic agent use (mean prescriptions PPPY, 5.84 vs 5.52, respectively; P <.001), lower antihypertensive agent use (mean PPPY, 7.46 vs 7.60, respectively; P = .02), and greater statin drug use (mean PPPY, 2.81 vs 2.68, respectively; P = .003) compared with the non– DRP-certified group. Patients treated by DRP-certified physicians had more diabetes-related office visits (mean

Oral antihyperglycemic agent use and statin drug use were higher in the DRPcertified group compared with the noncertified group.

PPPY, 4.69 vs 4.44, respectively; P <.001) and outpatient visits (mean PPPY, 0.93 vs 0.85, respectively; P <.001) visits. By contrast, patients treated by noncertified physicians had more diabetes-related emergency department visits (mean PPPY, 0.07 vs 0.04, respectively; P <.001) and inpatient visits (mean PPPY, 0.10 vs 0.08, respectively; P = .02).

Patients managed by non–DRP-certified physicians had greater diabetes-related expenditures than those managed by DRP-certified physicians (mean costs PPPY, $4097 vs $3424, respectively; P = .03). The mean all-

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cause total expenditures for patients treated by DRPcertified physicians was not significantly lower (mean PPPY, $10,627 vs $11,221, respectively; P = .22) than for patients treated by non–DRP-certified physicians.

Discussion Under pay-for-performance models in which financial incentives have been linked to the provision of care, healthcare quality has typically been measured using process-of-care and outcomes-based measures.9 Diabetes has been a target for payment reform models for primary care, because of its high prevalence among primary care patients, the presence of a recognized set of clinical practice guidelines, and the availability of clinical markers used to measure improved glycemic control.

The literature describing the use of retrospective claims analyses to study outcomes of care in pay-forperformance models for diabetes patients is limited.

The goal of this study was to compare outcome measures between DRP-certified physicians and non–DRPcertified physicians.

The study revealed several key findings. First, differences in medication use were found between the DRPcertified and non–DRP-certified groups. Oral antihyperglycemic agent use and statin drug use were higher in the DRP-certified group compared with the noncer-

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Table 4 Multivariate Analyses of Postindex Overall Expected Mean Utilization and Costs Per Patient Per Year, 2006-2008 Patients Patients managed by managed by DRP-certified non–DRPphysicians certified physicians Parameter Unadjusted estimate difference (beta)/cost ratio

95% confidence interval

P value

–0.056

–0.074 - –0.037

<.001

0.028

0.019

0.003 - 0.035

.02

2.68

–0.239

–0.049

–0.076 - –0.023

.003

Expected mean

Expected mean

Oral antihyperglycemic use

5.84

5.52

–0.365

Antihypertensive use

7.46

7.60

Statin use

2.81

Medication use

Diabetes-related medical utilization Office visits

4.69

4.44

–0.189

–0.055

–0.076 - –0.035

<.001

Outpatient visits

0.93

0.85

–0.034

–0.092

–0.139 - –0.046

<.001

Emergency department visits

0.04

0.07

0.041

0.719

0.517 - 0.922

<.001

Inpatient visits

0.08

0.10

0.021

0.176

0.028 - 0.325

.02

$3424

$4097

$883.65

1.20

1.01 - 1.42

.03

$10,627

$11,221

$1226.50

1.06

0.97 - 1.15

.22

Expenditures Diabetes-related total expenditures All-cause total expenditures

DRP indicates Diabetes Recognition Program.

tified group. This finding suggests that DRP-certified physicians prescribe guideline-recommended medications more frequently than non–DRP-certified physicians. However, antihypertensive agent use was lower in the DRP-certified group, suggesting that this is an area where DRP-certified physicians must improve their adherence to ADA standards of care—specifically, the guideline recommending that individuals with diabetes be prescribed angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for their renal protective effects and to treat hypertension.4 Second, the most compelling finding was that medical utilization among patients managed by a DRP-certified physician was lower for emergency department visits and inpatient visits but higher for office and outpatient visits compared with patients managed by non– DRP-certified physicians.

Emergency department and inpatient visits are high cost drivers and have been a primary focus of outcome-

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based measures in pay-for-performance models.9 In a nationwide evaluation of pay-for-performance patientcentered medical home models among UnitedHealthcare members with diabetes and other health conditions, results showed a 29% reduction in emergency department visits, 11% fewer inpatient visits, and 6% fewer office visits at the end of the pilot programs.10 The direction of the results of the present study are similar with regard to emergency department and inpatient visits, and are encouraging. However, the finding that the Deyo-Charlson-Quan comorbidity score was significantly lower for patients managed by the DRP-certified group than for those managed by the non–DRPcertified group may suggest that patients in the latter group had greater severity of illness, which could have accounted for their higher healthcare resource utilization. Although the nature of the reductions in emergency department and inpatient visits is unclear (eg, some of these visits might have been avoided as a result

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of greater primary care intervention), the trends are suggestive of more positive outcomes for DRP-certified physicians with regard to these high cost drivers.

Third, we found that diabetes-related expenditures were lower in the DRP-certified cohort than in the non–DRP-certified cohort. This finding is consistent with the reduction in emergency department and inpa-

Diabetes-related expenditures were lower in the DRP-certified cohort than in the non–DRP-certified cohort. This finding is consistent with the reduction in emergency department and inpatient visits that was observed for the DRP-certified group. tient visits that was observed for the DRP-certified group and appears to provide initial confirmation that DRP-certified physicians could bring about savings in total healthcare expenditures compared with non– DRP-certified physicians.

Limitations Although these results suggest that improvement in healthcare utilization can occur for patients managed by DRP-certified physicians, retrospective analyses are characterized by inherent limitations, namely, the uncontrolled structure of the investigation and the lack of clinical validation. Furthermore, interpretation of these findings must take into account some of the limitations associated with claims data, including coding variation between providers, time lag between receipt of service and claims processing, and missing data—especially in fields not relevant to reimbursement.

Claims are designed for purposes of payment, not research. The degree to which claims data can accurately capture an individual’s medical history is limited.

Furthermore, the data are subject to possible coding errors, coding for the purpose of rule-out rather than actual disease, and undercoding. Although pharmacy claims provide information on prescriptions that were filled, medications may not have been taken as prescribed. Pharmacy claims also do not reflect prescriptions obtained outside of the plan (eg, physician samples).

Most important, patients’ severity of disease and their individual clinical need for tests and treatment cannot be measured using claims data, and therefore, are not taken into account when using performance-based metrics.11 Other limitations specific to this study must also be considered. This study did not match patient for patient between cohorts (only physician cohorts were matched).

Although multivariate analyses were conducted, unob-

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servable confounding factors were not accounted for, such as disease severity and length of time with illness (ie, the longer the duration of illness, the more likely patients are to experience diabetes-related complications, which have an obvious effect on outcomes).

In addition, our physician sample was diverse rather than uniform. The length of time physicians have been in practice could not be assessed from claims data or from the DRP registry; however, because the development of the DRP stemmed from the original Bridges to Excellence 2001 pilot program, there may be a greater likelihood that physicians who have been in practice longer are DRP-certified. Therefore, physician experience may affect outcomes.

It was not discernible from the claims data whether providers in either group used the services of a certified diabetes educator in their practice or whether patients made any visits to certified diabetes educators. Patient consultation with a certified diabetes educator would have had the potential to influence our results. Furthermore, multivariate analyses were not conducted for measures that involved small patient sample sizes.

Other variables that may have been better suited for inclusion than the ones used in this study, such as disease severity and medication adherence, may have offered more insight into the differences between the 2 patient groups. In addition, the data used for this study came from a commercially insured managed care population, and may not be applicable to patients in non–managed care settings or to Medicare and Medicaid populations.

Most important, misclassification of providers in the noncertified cohort may have occurred, because this study relied on matching lists of physicians in the health plan and corresponding NCQA recognition programs. Therefore, the noncertified cohort may have included physicians who were in the process of seeking DRP certification, which may explain some of the comparable clinical and resource use findings— although this would have biased against the significant cost and treatment findings between the groups. This was addressed by selecting physician cohorts in the database with the most recent data (2007-2008) to when the NCQA lists were obtained (beginning of 2009). Furthermore, it was not possible to classify physicians who provided quality care but did not have DRP certification. This would also have biased against demonstrating any differences.

Conclusions This study builds on previous research evaluating the effect of offering incentives to providers—through payments or certified “recognition” of improvements in clinical quality—on patient outcomes. It represents an

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Impact of Treatment by NCQA-Certified Physicians

Appendix A Type 2 Diabetes Mellitus Classification Algorithm Diabetes type (ie, type 1 or type 2) will be determined via a stepwise algorithm using pharmacy and medical claims in the preindex and follow-up periods. Although this algorithm will classify the large majority of patients, a small percentage will not be able to be classified and will be noted as having diabetes of unknown type ➤ If evidence of any oral antihyperglycemic medications, classify patient as type 2 ➤ If no evidence of oral antihyperglycemic medications and no insulin therapy, classify patient as type 2 ➤ If no diagnosis code of 250.xx, classify patient as type 1. If 1 or more diagnosis codes of 250.x but none with a 5th digit specified, classify patient as having diabetes of unknown type ➤ Remaining insulin monotherapy patients, all of whom have at least 1 diagnosis code on a medical claim with a specified 5th digit of 250.xx: • If the 5th digit is always 0 or 2, classify patient as type 2 important contribution to the literature, because it is one of the first studies using claims data from a large US database of commercially insured patients to examine the relationship between treatment by DRP-certified physicians and health-related outcomes for patients with type 2 diabetes. These outcomes include prescription utilization, medical resource use, healthcare expenditures, and clinical markers. Our findings provide insights on how to leverage multiple data sources for optimal provider performance measurement.

An accurate assessment of the impact of provider certification on patient outcomes may require combining the measures derived from claims data sources with more detailed data from electronic medical records to better explain and understand the results. Regardless of the factors that contributed to these study results, these findings suggest a potential advantage in expenditures associated with NCQA recognition of DRP-certified physicians, with room for improvement in medication use among patients managed by both DRP-certified and non–DRPcertified physicians. ■ Acknowledgments The authors acknowledge the contribution of George Goldberg, MD, formerly employed by OptumInsight, who created the type 2 diabetes algorithm depicted in Appendix A. The authors thank Victoria Porter, medical writer at OptumInsight, for her assistance with the preparation of this manuscript.

If the 5th digit is always 1 or 3, classify patient as type 1 ➤ Patients receiving insulin monotherapy who have claims that include a mix of type 1 and type 2 diagnosis codes: • If the patient has <4 claims with a mix of specified 5th digits, then the patient will be classified as having diabetes of unknown type • If the patient has >4 claims with a mix of specified 5th digits and the number of type 1 diagnosis claims exceeds the number with type 2, then the patient will be classified as type 1 • If the patient has >4 claims with a mix of specified 5th digits and the number of type 2 diagnosis claims exceeds the number with type 1, then the patient will be classified as type 2 • If the patient has >4 claims with a mix of specified 5th digit and the numbers of type 1 and type 2 claims are equal, then the patient will be classified as having diabetes of unknown type.

•

Funding Source This study was funded by Pfizer.

Author Disclosure Statement Mr Pinsky and Dr Samant are employees of OptumInsight, the company hired to conduct this study. Dr Harnett, Dr Paulose-Ram, and Dr Mardekian are employees of and own stocks of Pfizer. Dr Nair is a Consultant for Pfizer and Centocor Ortho Biotech and has received research grants from Novartis and Centocor Ortho Biotech.

References 1. National Committee for Quality Assurance. Integrated Healthcare Association California pay for performance program: 2006 P4P guidelines. 2005MY clinical domain. www.allhealth.org/publications/pub_4.pdf. Accessed May 2, 2011.

2. Institute of Medicine of the National Academies. Rewarding provider performance: aligning incentives in Medicare. Washington, DC: National Academies Press; 2007.

3. Ragucci KR, Fermo JD, Wessell AM, Chumney EC. Effectiveness of pharmacistadministered diabetes mellitus education and management services. Pharmacotherapy.

2005;12:1809-1816.

4. American Diabetes Association. Standards of medical care in diabetes—2011.

Diabetes Care. 2011;34(suppl 1):S11-S61.

5. National Committee for Quality Assurance. Diabetes Recognition Program. www. ncqa.org/tabid/139/Default.aspx. Accessed May 2, 2011.

6. Oglesby AK, Secnik K, Barron J, et al. The association between diabetes related medical costs and glycemic control: a retrospective analysis. Cost Eff Resour Alloc. 2006;4:1.

7. Manning WG. The logged dependent variable, heteroscedasticity, and the retransformation problem. J Health Econ. 1998;17:283-295.

8. Quan H, Sundararajan V, Halfon P, et al. Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care. 2005;43:1130-1139.

9. Rosenthal MB. Beyond pay for performance—emerging models for provider-payment reform. N Engl J Med. 2008;59:1197-1200.

10. Ho S. AHRQ 2009 Annual Conference Research to Reform—Achieving Health System Change. Slide presentation from the AHRQ 2009 annual conference. www. ahrq.gov/about/annualconf09/ho.htm. Accessed May 2, 2011.

11. Walter LC, Davidowitz NP, Heineken PA, Covinsky KE. Pitfalls of converting practice guidelines into quality measures: lessons learned from a VA performance measure. JAMA. 2004;291:2466-2470.

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STAKEHOLDER PERSPECTIVE What Certification Really Means for Physician Quality PATIENTS: Consumers are always looking for the best physicians to help manage their health. The problem is how to determine who the best physician really is, whether based on a recommendation from family or friends or based on more public information, including academic credentials, hospital affiliation, or surgical death rates. Newly developed recognition programs such as the National Committee for Quality Assurance (NCQA) Diabetes Recognition Program (DRP)— which, as of April 2011, is managed solely by the NCQA, without American Diabetes Association involvement—provide consumers one way to judge provider competence.

From the patient’s perspective, however, such recognition programs raise 3 important problems: 1. Not all physicians who provide high-quality care will go through the process of obtaining NCQA recognition, since the program is voluntary; therefore, a lack of recognition does not mean poor quality 2. Based on the relatively low bar set by the NCQA, as described in the article by Pinsky and colleagues— 40% or more of patients must meet recommended hemoglobin (Hb)A1c goal, and 35% or more must meet recommended blood pressure goals—recognition does not necessarily ensure high-quality care 3. Finally, as any physician will attest, these quality measures reflect only one kind of quality care; they do not necessarily reflect how well a physician may listen, how astute he or she is in making new diagnoses, or how the physician performs when delivering bad news to a patient.

MEDICAL/PHARMACY DIRECTORS: Payers may have more to learn from these recognition programs than patients do. Although the small differences in medical utilization between DRP-certified and non–DRP-certified physicians shown in this article may not be clinically relevant, the differences in expenditures are quite important and should be of interest to payers. If these recognition programs are a marker of more efficient physicians (those who may obtain similar or better quality measures at lower cost), they are worthy of attention.

The problem for payers and physicians alike is that differences in patient characteristics across physician panels are never adequately adjusted for in these types of measures, as others have demonstrated.1 It is possible, or even likely, that important variables, such as diabetes severity and socioeconomic status, differ across DRP-certified and non–DRP-certified physicians, which in turn affect expenditures.

Payers also need to pay close attention to changing guidelines and research findings when considering these certification programs; as the NCQA is well aware, HbA1c and blood pressure goals that might have been the norm yesterday may not be the norm today.

1. Hong CS, Atlas SJ, Chang Y, et al. Relationship between patient panel characteristics and primary care physician clinical performance rankings. JAMA. 2010;304:1107-1113.

Walid F. Gellad, MD, MPH VA Pittsburgh Healthcare System University of Pittsburgh and RAND Health, PA

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NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK MYELOFIBROSIS

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • It has been observed that patients with platelet counts <200 X 109/L at the start of therapy are more likely to develop thrombocytopenia during treatment.

Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

• •

•

•

•

Dose modifications of Jakafi for patients developing anemia may also be considered Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment [see Dosage and Administration].

Patients should be closely monitored and the dose titrated based on safety and efficacy There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother

Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a trademark of Incyte Corporation. © 2011, Incyte Corporation. All rights reserved.

RUX-1004

11/11

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). a Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its Reactions Grades metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved.

Issued: November 2011 RUX-1040 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

REGULATORY

REVIEW ARTICLE

Are ACOs the Answer to High-Value Healthcare?

Wing Yeung, MA; Harrison Burns, III, BS, PAHM; Deryk Loiacono, PharmD candidate Background: The Patient Protection and Affordable Care Act required the Secretary of the Department of Health and Human Services to establish the Medicare Shared Savings Program (MSSP) by January 1, 2012. The MSSP is intended to encourage physicians, hospitals, and other providers and suppliers to form accountable care organizations (ACOs) to provide cost-effective, coordinated care to Medicare beneficiaries. Under the MSSP, ACOs can qualify for additional payments by meeting specific savings benchmarks and quality measures.

Objectives: To review the anticipated changes in the role and responsibilities of ACOs and to evaluate the challenges and opportunities that various healthcare stakeholders, including patients, providers, and payers, will encounter with the launching of the new MSSP. Discussion: ACOs assume responsibility for overall care, cost, and quality of patient care.

The MSSP will provide ACOs additional payments for meeting cost-savings and quality benchmarks. The extra savings will be shared with participating providers based on different risk-sharing options. As the MSSP and new ACOs launch, stakeholders will be impacted differently. This article is based, in part, on responses of approximately 100 payers to a survey conducted in June 2011 by Xcenda. Each stakeholder group, including providers, payers, patients, and manufacturers, must monitor the reactions and relationships between all players in the care continuum. Providers will have to achieve a greater level of coordination and collaboration than typically exists today. Government and commercial payers will have a role in determining how quickly they will adopt accountable care models. Patients are expected to become more engaged and participatory in their care to achieve optimal outcomes, and manufacturers will be required to prove the value of their products given the clinical value proposition embedded in accountable care models.

Conclusion: Whether ACOs are the answer to providing higher-quality healthcare at lower costs remains unclear. All signs, however, point toward a systemic change in an effort to improve patient care and contain healthcare costs. It will be important for all healthcare stakeholders to understand the roles that ACOs will play in ensuring access to care and quality of care.

S

ection 3022 of the Patient Protection and Affordable Care Act of 2010 (ACA) calls for the Department of Health and Human Services to create the Medicare Shared Savings Program (MSSP) and other pilot programs to reduce healthcare costs while improving the quality of care.1 The ACA requires the Centers for Medicare & Medicaid Services (CMS) to launch the MSSP by January 1, 2012.2 Accountable care organizations (ACOs)—an arrange-

Ms Yeung is a manager at Xcenda, San Bruno, CA; Mr Burns is an analyst at Xcenda, Charlotte, NC; and Mr Loiacono is a pharmacy intern at Xcenda, Tampa, FL. This article is in part based on Xcenda’s white paper “The Drive to High-Value Health: Are ACOs the Answer?”

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ment among healthcare providers “who collectively agree to accept accountability for the cost and quality of care delivered to a specific set of patients”3—were envisioned by the ACA as a vehicle for physicians, hospitals, and other providers to provide cost-effective, coordinated care to Medicare beneficiaries. The MSSP will create for healthcare professionals a framework for sharing risk, which, in turn, will supply financial incentives for integrated care.

CMS released its proposed rule on ACOs and the MSSP on March 31, 2011, and subsequently, the Center for Medicare & Medicaid Innovation (CMMI) announced an alternative, non–MSSP-affiliated pathway to establishing ACOs called the Pioneer ACO Model.4 After the initial proposed rule received strong

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KEY POINTS ➤

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Figure 1 Payers’ Plans to Contract with ACOs

The Medicare Shared Savings Program (MSSP) that will take effect in January 2012 is intended to complement the formation of accountable care organizations (ACOs).

ACOs rely on increased stakeholder collaboration, which should help improve care quality and bring overall costs down.

Based on a June 2011 survey of nearly 100 payer decision makers representing more than 200 million covered members, 61% of payers are already contracting with ACOs or are planning to do so in the near future.

Under the MSSP, providers will continue to receive fee-for-service payments from Medicare, but will have opportunities to get additional payments if their ACO meets savings benchmarks.

Patients will be empowered with access to competitive networks of providers offering quality healthcare at relatively lower costs; this is likely to foster competition among ACOs and drive performance up.

Private payers are expected to test different methods of payments to ACOs and may also join independent, non–MSSP-affiliated ACOs. The first-year costs for starting an ACO are estimated at $1.75 million.

criticism across the healthcare community, CMS released its final ruling on ACOs and the MSSP on October 20, 2011, which included significant changes aimed at making participation in ACOs more attractive to providers.2 Under the MSSP and the Pioneer program, providers in ACOs will continue to receive feefor-service (FFS) payments from Medicare for their individual services.4 However, providers will have the opportunity to receive additional bonus payments if their ACOs meet savings benchmarks and quality measures set by CMS.2 Even before CMS released its final MSSP-related ACO regulation, the move toward accountable and more integrated care—with the concept of shared savings between payers and providers—began gaining momentum. Hospitals, physicians, and health plans have already formed or are contracting with ACOs.5 In June 2011, Xcenda’s payer market research platform, the Managed Care Network (MCN), conducted a survey of its panel members, consisting of nearly 100 payer decision makers representing more than 200 million covered members.5 They were asked to identify whether their organizations were contracting with ACOs, planning to contract, or not planning to contract

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20% 39%

41%

N = 59 Currently contracting with ACOs Planning to contract with ACOs within the next 12 mo Not planning to contract with ACOs within the next 12 mo

ACOs indicates accountable care organizations.

NOTE: These data reflect responses to a June 2011 survey of nearly 100 payers responsible for >200 million covered members.5

ACOs within the next 12 months. Based on the MCN panel responses to this survey, 61% of payers are already contracting with ACOs or are planning to contract with them within the next year (Figure 1).5 With the formation of ACOs, payers and providers are creating a new healthcare delivery model that will test value-based and quality-based reimbursement mechanisms. The growth of ACOs, along with a focus on the delivery of increased quality of care at lower costs, will require each sector of healthcare to understand how ACOs will affect all stakeholders, including patients, providers, payers, and manufacturers. This article focuses on the implications for these stakeholders of implementing ACOs and the imminent launch of the MSSP.

Payment to ACOs Currently, Medicare reimburses covered services based on the FFS structure. This payment approach creates an incentive to provide a high volume of services to receive greater payments. To promote improved quality of care, CMS is introducing new financial incentives that reward the delivery of high-quality care and the management of patient costs.2 To achieve this, collaboration among providers will be necessary to leverage resources and reduce unnecessary and duplicative procedures.

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Table 1 Pioneer ACO Core Payment Arrangement and Alternate Options Payment option

Performance period 1

Performance period 2

Performance periods 3, 4, 5

Core arrangement or

Up to 60% shared savings and shared losses 10% maximum

Up to 70% shared savings and shared losses 15% maximum

Population-based payment, with up to 70% shared savings and shared losses 15% maximum

Option A or

Up to 50% shared savings and shared losses 5% maximum

Up to 60% shared savings and shared losses 10% maximum

Population-based payments as in core arrangement

Option B

Up to 70% shared savings and shared losses 15% maximum

Up to 75% shared savings and shared losses 15% maximum

Population-based payment, with up to 75% shared savings and shared losses 15% maximum

ACO indicates accountable care organization.

Adapted from the Center for Medicare & Medicaid Innovation. Pioneer accountable care organization (ACO) model request for application. May 2011.

Along with FFS payments, ACOs participating in the MSSP that meet savings benchmarks will receive a portion of the savings as an “added bonus.” Under CMS’s final ruling, the benchmark rate will be ACO-specific, calculated based on annual Medicare Part A and Part B FFS claims of beneficiaries who have been assigned to an ACO during the most recent 3-year period before the ACO’s agreement with CMS.2 The Pioneer ACO Model launched by the CMMI allows existing ACOs and integrated-care systems to partner with private payers in a shared-savings program.4 CMMI began accepting applications in June 2011 for Pioneer ACOs to start the first performance period by the end of 2011.6 Applicants are required to participate in the program for a minimum of 3 years.

ACOs that meet program savings and/or performance standards will have the option to extend their agreements for as long as 5 years.6 The aim of the Pioneer ACO Model is to achieve greater savings by transferring ACOs to a populationbased model in the third performance year, given satisfactory performance during the first 2 years of operation. Participating pioneers will be held financially accountable by CMS, and their performance results will be published.6

Distribution of Shared Savings to ACOs CMS’s final ruling on the MSSP-based ACOs contains 2 models for distribution of shared savings: the onesided and two-sided risk-sharing models.2 The one-sided model would allow CMS to share savings (not losses) for an ACO’s first 3-year agreement period with CMS. In

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subsequent agreement periods, however, one-sided ACOs would automatically convert to the two-sided model as a way to encourage participation in the MSSP, without incurring a penalty in the early stages, but then move into a true risk-sharing arrangement.2 The two-sided model allows ACOs to share savings, but ACOs would also bear greater risk and responsibility for incurring any losses annually in the 3-year program if savings benchmarks are not met; however, participating ACOs would also be eligible to receive a higher amount of any shared savings. In both models, saving payments would be paid out to ACOs as a percentage of the difference between the average per-beneficiary expenditure and the expenditure benchmark. ACOs that implement one-sided and two-sided models could receive up to 50% or 60% of shared savings, respectively.2 Under the Pioneer ACO Model, participating ACOs enter an agreement with CMS that differs in its risksharing structure from that of their counterparts under the MSSP. Compared with ACOs participating in the MSSP, eligible Pioneer ACOs may earn a larger proportion of the shared savings with the Pioneer model’s core payment structure.6 At the same time, Pioneer ACOs are also liable for greater shared losses beginning in their first performance period.6 Table 1 summarizes the Pioneer ACO core payment structure and variant arrangements on the core structure.6

Quality Performance and Shared-Savings Payment ACOs under the MSSP will be required to report on 33 quality measures that cover 4 areas: patient–caregiver experience; care coordination/patient safety; preventive

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Table 2 The One-Sided and Two-Sided ACO Models Design element

One-sided model

Two-sided model

Maximum sharing rate

50%

60%

Minimum savings rate

2.0%-3.9%, depending on number of assigned beneficiaries

Flat 2%, regardless of number of beneficiaries

Minimum loss rate

None

Flat 2%, regardless of number of beneficaries

Maximum sharing cap

Payments capped at 10% of ACO’s benchmark

Payments capped at 15% of ACO’s benchmark

Shared savings begin

Once minimum savings rate is exceeded

Once minimum savings rate is exceeded

FQHC or RHC participation incentives

No additional incentives

No additional incentives

ACO indicates accountable care organization; FQHC, federally qualified health center; RHC, rural health clinic.

Source: Reference 2.

health; and at-risk populations.2 In the first year of the 3year agreement period between ACOs and CMS, ACOs that fully capture and report on these quality measures would be eligible for 100% of potential bonuses.2 CMS will set quality performance benchmarks and minimum attainment levels for each quality measure based on these data; the performance benchmarks and minimum attainment levels will be set before each annual cycle.2 For the following years, CMS will use ACO performance data to update benchmark levels, and the shared-savings payout will be based on these new benchmarks.2

would apply threshold percentages to the total savings.

A payment cap would be applied before the ACO distributes payments to its participating providers. Table 2 presents an example of a calculation for a one-sided versus a two-sided model.2 This reimbursement method under the MSSP imposes financial accountability and risk on participating provider organizations. The goal of this model is to avoid reducing costs at the expense of quality care; this will necessarily result in increased coordination among providers as collaboration will likely reduce waste and unnecessary services.

The final ruling by CMS requires providers to notify patients about any affiliation with an ACO. Patients must also be informed that they can seek care from other providers at any time.

Impact on Healthcare Stakeholders The implementation of ACOs in the near future will introduce broad challenges and opportunities for different healthcare stakeholders.

As required by the final ruling on the MSSP-based ACOs, ACOs would be required to repay CMS within 90 days for any shared losses incurred.2 Any ACO that experiences a net loss during the first 3-year agreement period is allowed to reapply to the MSSP, but the ACO must identify in its application the causes for the net loss and must specify what safeguards are in place to enable the ACO to potentially achieve savings in its next agreement period.2

Shared-Savings Calculation Before the shared savings can be calculated, CMS

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Opportunities for Patients Because ACOs are patient-centered, the final ruling

by CMS requires providers to notify patients about any affiliation with an ACO.2 Providers must tell patients that they are eligible for shared savings, because the ACO offers incentives to improve quality of care while reducing costs. Providers must alert patients that the ACO is financially bound to CMS requirements and may have to pay penalties if the ACO fails to provide high-quality and cost-effective care. Patients must also be informed that they can seek care from other providers at any time. Providers are required to notify patients that the ACO may use the patient’s claims data throughout the organization.2 If they prove successful, ACOs should translate to

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Group practice ACO Shared-savings payments

Shared-savings payments ➤

➤

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FFS reimbursement

Shared-savings payments

Hospital

➤

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ACO 3-year agreement ➤

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FFS reimbursement

FFS reimbursement

Specialists

➤

Opportunities for Providers Providers will be impacted the most by the ACO implementation. The goal of ACOs is to coordinate high-quality care across different healthcare settings and reduce costs. The primary objectives of accountable care models is to ensure that patients receive care in the most appropriate and least intensive settings, and that the services delivered are not duplicated or conflicting.

ACO proponents believe that coordinated and enhanced care will reduce the need for high-end proce-

CMS

➤

Challenges for Patients Patients will need to be educated to understand the potential benefits of ACO participation, including the ways by which ACOs can improve care and manage costs.2 They will also need access to the appropriate information that allows them to compare their ACOs’ performance against the performance of other ACOs.2 Because ACOs can receive additional compensation for driving down healthcare costs, they may limit the use of new, more costly drugs and technologies; therefore, patients may need to take precautionary measures to allow themselves access to appropriate therapies as needed.

Figure 2 Physician Group Practice ACO Payment Flow

➤

improved overall healthcare. Patients can choose to be seen by providers who are affiliated with high-performing ACOs. The individual’s ability to select a provider will create competition among ACOs to provide quality care.7 Competition may drive the quality of care up and the cost of care down; some ACOs may also encourage patients’ loyalty to their provider network by ensuring quality care, improving customer experiences, and charging lower copayments.7 Furthermore, patients are also capable of participating in ACOs’ governance, which allows them to advocate for themselves.

ACOs may also focus on lifestyle modification programs and interventions that may produce a high return on the investment. Such interventions include8: • Tests focusing on prevention and early diagnosis • Immunizations, weight management programs, and smoking cessation programs • Regular screenings for serious diseases (eg, cancer) • Evidence-based treatment guidelines and shared decision-making tools.

Many of these interventions exist, but a stronger focus on effectiveness and implementation can help reduce costs and hospitalizations. Studies have shown that patient education and access to primary care can reduce the frequency of emergency department visits and hospitalizations in patients with chronic diseases by 20% to 40%.9-11 Insured members should be aware of and engaged with the changes introduced by new ACO entities so that they can continue to drive competition.

Postacute providers

ACO indicates accountable care organization; CMS, Centers for Medicare & Medicaid Services; FFS, fee-for-service.

Adapted with permission from Drinker, Biddle, Reath. The Medicare shared savings program: accountable care organizations. Webinar presented on April 13, 2011. www.drinkerbiddle. com/files/ftpupload/ACO/ACO%20Webinar%20Materials.pdf.

dures, specialist services, and duplicated care.12 By accepting greater responsibility, physicians may experience more opportunities to report quality-of-care achievements and receive financial benefits.12 Providers in ACOs can meet most of the MSSP 33 quality measures set by CMS by establishing and following systems already in place, such as Medicare’s Physician Quality Reporting System, electronic health records (EHRs), and electronic prescribing. Satisfactory performance in these measures, and the delivery of care below the predetermined expenditure benchmark, will likely create opportunities for payers for sharing the ACO’s savings. CMS will continue to reimburse providers based on the FFS method, with the potential shared savings as a supplemental method. Figure 2 illustrates the payment flow from CMS for a physician group practice ACO.13 Shared savings. Providers in ACOs who meet the quality measures and deliver care below the expenditure benchmark are eligible to receive a portion of the savings they helped earn. As previously mentioned, this expenditure benchmark is based on Medicare Part A and B FFS claims data of the ACO’s patient population, to anticipate the ACO’s performance. ACOs can receive

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Table 3 ACO Payment Structure Options Shared-savings bonuses

ACO reserves a percentage of shared-savings payments for bonus payments to affiliated providers Proposed by Medicare Payment Advisory Commission Low risk for providers

Bundled payments

Gives ACO authority to distribute perepisode payments to affiliated providers Proposed by private payers Medium risk level for providers

Capitated payments

Allows ACO to allocate predetermined, per-patient annual payments among affiliated providers Proposed by private payers and state of Massachusetts High risk for providers

ACO indicates accountable care organization.

Source: Reference 14.

from 50% to 60% of the shared savings, depending on which model they select.14 ACOs can then allocate the savings to their affiliated providers following the different payment methods shown in Table 3.14 In addition, under the MSSP-based ACO final rule, Medicare Part D expenditures are not included in CMS’s calculation for setting each ACO’s expenditure benchmark.2 Critics of this provision believe that CMS has

Private payers recognize various benefits in working with ACOs, such as aligning providers’ incentives to offer quality care, reducing administrative burden, and shifting financial risks/liabilities to providers. inadvertently opened a loophole for providers by excluding Medicare Part D expenditures from the benchmark calculation. This exclusion may incentivize ACO providers to prescribe Part D drugs, because the expenditures will not count toward the ACO’s cost of care, thereby leaving more room for shared savings.

Improvement of patient experience and coordination of care. Providers believe that the lack of patient information is a major barrier to improving coordination of care.5,15 The current FFS payment structure creates fragmented care, resulting in disconnected payments. To remedy this problem, CMS has agreed to provide claims

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data for patients across all providers participating in an ACO.15 Depending on the timeliness of these data, providers will be able to see the services that other providers in the ACO are delivering, which will allow primary care physicians to serve as more effective care coordinators. The ACO must notify patients and receive approval before requesting claims information, but the patients will not suffer any repercussions for declining.15 Physician engagement. Successful clinical care will require strong physician relationships within ACOs. Internal inclusivity and cross-functional synergies could lead to valuable input from providers.16 Hospitals can help providers by holding leadership roles in the ACO, offering quality incentives, and seeking provider input on health information technology initiatives. CMS requires providers and other ACO participants to control 75% of the organization’s governing body, meaning that providers carry a strong voice in every ACO.17 Changing role of the pharmacist. Pharmacists can demonstrate great value to their ACOs. Given their medical expertise and experiences coordinating with physicians, nursing staff, and other staff members, pharmacists can support ACOs in determining appropriate and cost-effective therapies to include in their formularies. Collaboration within ACOs between pharmacists and provider staff may help prevent costly expenditures related to patient hospitalizations, comorbidities, adverse events, and more. Pharmacists will continue to play an important coordinator role with other providers in the ACO.18 Pharmacists’ close collaboration with other providers within the ACO will directly contribute to the organization’s quality and cost-saving goals.

Challenges for Providers: Initial Investment Projected first-year costs to start an ACO are $1.75 million.17 Providers must invest in health information technology to track patient outcomes. Implementation of compliance programs, production of marketing materials, fees for consulting attorneys, and restructuring of internal operations for CMS monitoring will also result in high costs for participating providers.19 Opportunities for Private Payers Although Medicare has occupied the spotlight in the discussion and development of ACOs, private payers have also been implementing ACO pilot programs across the nation to expand services to commercially insured patients. Many believe that hospitals and physicians will lead the charge toward high-quality and lowcost care and that private payers will follow.5,20 However, this process could occur in the reverse. Private payers may be able to influence hospitals and physicians by interacting with ACOs and modifying their payment

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methodologies to better suit the needs of policyholders included in the ACO population.20 Figure 3 outlines the benefits of ACO implementation from the payer perspective.5 Private payers recognize various benefits in working with ACOs, such as aligning providers’ incentives to offer quality care, reducing administrative burden (by making a single payment to a provider group for a patient’s care), and shifting financial risks/liabilities to providers.5 However, Figure 3 also shows some barriers payers expect to encounter with ACO implementation, concerns that center mainly on provider incentive issues.5 Some payers are already considering new models that parallel ACO requirements. For example, UnitedHealthcare is testing a model designed to deliver better medical outcomes for cancer treatments by addressing the costs of patients’ cancer care and the portion of chemotherapy drug profits the provider receives.21 Office visits, chemotherapy administration, and lab fees will still be reimbursed on an FFS basis. UnitedHealthcare will disconnect provider income from drug sales revenue by paying the same fee, no matter which drugs are administered.21 Collaboration with ACOs. Private payers will be able to consolidate resources and provider expertise by contracting with ACOs. The ACA has implemented mandates that expand benefits, implement minimum medical-loss ratio requirements, prohibit the preexisting conditions exclusion, and increase pressure to restrain premium increases. By contracting with ACOs that have larger patient populations, some of these added pressures could be shifted to the ACO. In addition, in view of the emerging evidence of success, it is not surprising private payers are showing interest in contracting and encouraging the formation of ACOs. Blue Shield of California, Catholic Healthcare West, and Hill Physicians formed an ACO to cover 40,000 members of California’s Public Employees’ Retirement System.22 The goal was to keep healthcare costs flat in 2010 by merging the existing Blue Shield HMO benefit product with members affiliated with existing primary care physicians from Hill Physicians. As a result, millions of dollars were saved in the first year, and premiums did not increase in 2011.22 Collaboration with providers. Private payers are expected to test different methods of payment to ACOs, leading the charge in this aspect. Private payers may also join independent, non–MSSP-affiliated ACOs by using their own networks of providers or by leveraging their staff-model HMO arrangements. Paul Markovich, Executive Vice President and Chief Operation Officer of Blue Shield of California, has stated that his organization would be “proud to support all of [Blue Shield’s]

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Figure 3 Payers’ Perspectives Regarding Benefits and Challenges of ACO Implementation Benefits

Challenges

1%

1%

4% 11% 19%

29%

23%

12% 13%

18% 29%

23% 17%

Aligned incentives

Aligned incentives

Improved quality of care

Developing payment incentives

Reduced administrative burden

CMS holding ACOs financially liable

Reduced cost

Finding providers to participate

Reduced liability

Patient confusion

Other

a

Determining cost-sharing amounts Other b

a

Includes better quality of care for members, reduced costs, continuity of care, and payment based on reducing overall healthcare costs. b Includes ensuring that all incentives are aligned between payers and providers, adjusting salaries (decreasing salaries of specialists while increasing those of primary care physicians), and implementing the correct payment system.

ACO indicates accountable care organization; CMS, Centers for Medicare & Medicaid Services.

NOTE: These data reflect responses to a June 2011 survey of nearly 100 payers responsible for >200 million covered members.5

grantees as they work to materially improve care and succeed under federal health reform.”23 Insurance exchange population. It has been suggested that providers are forming commercial ACOs to seek private payers whose number of members will increase once state-level insurance exchanges are established in 2014.24 Insurance exchanges are competitive marketplaces in which small businesses and individuals may purchase qualified health benefit plans with various coverage options. Providers can collaborate with private payers to assemble similar organizations to help providers gain additional business from the flood of health insurance exchange beneficiaries.

The Congressional Budget Office predicts that 24 million people will purchase coverage through the exchanges by 2019.25

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Challenges for Private Payers Unintended consequences. Financial incentives and enhanced collaboration between physicians and hospitals may increase the negotiation power of providers, resulting in higher costs for payers.26 ACOs may also indirectly dictate coverage policies and treatment guidelines of private payers, because they must strive to deliver care within quality parameters. ACOs and private payers may also find themselves in disagreement in instances where private payers do not cover a service, but ACOs may need to include that service in their quality-of-care report.

No guarantee ACOs will succeed. CMS can eventually terminate an ACO if it does not meet quality-ofcare requirements. Therefore, this unknown element provides risk to private payers if they collaborate with ACOs, especially because private payers cannot participate in ACOs’ governance. Private payers could take a proactive approach and research the patient satisfaction data of an ACO’s providers before collaborating with it.

Transparency in one sector encourages transparency in affiliated sectors; therefore, manufacturers will likely maintain ongoing relationships with providers by conveying each product’s added value for patients.

Opportunities for Pharmaceutical Manufacturers: Real-World Outcomes Data As purchasers of healthcare services shift from volume-based to quality-based reimbursement mechanisms, drug manufacturers will be expected to provide additional clinical and health economic data to support the use of their pharmaceuticals during interactions with riskbearing providers.

As previously mentioned, ACOs can achieve numerous quality measures by implementing EHRs. EHRs will help demonstrate the real-world impact of healthcare services and pharmaceutical agents and provide an opportunity for manufacturers to distinguish their products from competitors. EHRs allow providers to see and evaluate a patient’s health risks, behaviors, and status before that patient is even physically seen by the provider. Transparency in one sector encourages transparency in affiliated sectors; therefore, manufacturers will likely maintain ongoing relationships with providers by conveying each product’s added value for patients.27 Because many quality measures are based on the use of EHRs, providers are pressured to thoroughly use and adapt their technology during the ACOs’ first few years.

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EHRs will allow providers to track patient outcomes, and EHR-based outcome studies will undoubtedly result in changing treatment behaviors. Manufacturers’ use of these data, along with clinical trial data, will improve the effectiveness of physician details. Once the ACO program becomes fully implemented, manufacturers will be able to leverage a correlation between high-quality outcomes of drugs and provider behaviors.

These economic and outcomes-based data also support quality-measure goals and may improve a manufacturer’s access to formularies and inclusion in clinical guidelines.27 Impactful data are anticipated to include outcomes such as reduced comorbidities, hospital admissions, hospital length of stay, adverse effects, and number of physician administrations.

If ACO providers believe that a manufacturer’s products will support their quality-of-care and cost-saving goals, the organization may offer manufacturer representatives the opportunity to join the ACO in an advisory role.27 Manufacturers and providers may form strong professional relationships by joining services with a collaborative goal of quality improvement. Patients will likely experience the greatest benefits if cost-savings and highquality care remain the primary focus of any stakeholder collaborative.

Challenges for Manufacturers: Exclusion of Medicare Part D Expenditures Because Medicare Part D drug expenditures would be excluded from the ACO’s benchmark calculations, this would incentivize prescription of Part D products, such as oral drugs and other self-administered products.

Manufacturers that only produce physician-administered, Medicare Part B drugs may be held hostage by this impending loophole.

Overall, ACOs will financially incentivize providers to prescribe cost-effective drugs, use formularies, and follow recommended treatment guidelines. With time, patient outcomes and product value are likely to become the predominant topics of conversations between manufacturers and providers.

Conclusions Since the release of CMS’s final ruling on the MSSP and ACOs, the constructs regarding the implementation of the MSSP have become much more concrete.

However, as the MSSP nears launch and newly created ACOs begin to enter the marketplace, their true impact on various stakeholders remains to be seen. Assuming smooth implementation and consistent uptake by healthcare stakeholders, ACOs should be able to meet their goals of streamlining services and reducing overall healthcare costs.

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Within the ACO model, patients will be empowered with access to competitive networks of providers offering quality healthcare at relatively lower costs. As consumers, patients will need to be cognizant of the changes in the healthcare delivery system to better take advantage of competing services. Physician networks and hospitals will need to increase their collaboration to achieve high-quality care and to ensure profitability under the new payment model.

Simultaneously, payers will have to ensure buy-in from the provider community to sustain the sharedsavings model and its goals to bring change to the healthcare delivery system. In view of the new stakeholder roles, manufacturers will also have to prove their products’ value to ACO decision makers to make certain that patient access to the most appropriate therapies will be preserved at all times. As a result, it will be advantageous for all stakeholders to understand the inner workings of the new ACO landscape and play a supportive role with other stakeholders along the care continuum to enhance appropriate access to their services. ■ Author Disclosure Statement Ms Yeung, Mr Burns, and Mr Loiacono reported no conflicts of interest.

References 1. The Patient Protection and Affordable Care Act of 2010, HR 3590, 111th Cong, 2nd Sess (2010). www.gpo.gov/fdsys/pkg/BILLS-111hr3590enr/pdf/BILLS-111hr35 90enr.pdf. Accessed April 6, 2011.

2. Centers for Medicare & Medicaid Services. Medicare program; Medicare shared savings program: accountable care organizations. 42 CFR part 425. October 31, 2011. www.ofr.gov/OFRUpload/OFRData/2011-27461_PI.pdf. Accessed November 2, 2011.

3. Feder J, Cutler D. Achieving accountable and affordable care: key health policy choices to move the health care system forward. Center for American Progress.

December 20, 2010. www.americanprogress.org/issues/2010/12/aco_report.html.

Accessed June 6, 2011.

4. Center for Medicare & Medicaid Innovation. Pioneer Accountable Care Organization Model. May 2011. http://innovations.cms.gov/areas-of-focus/seamlessand-coordinated-care-models/pioneer-aco/. Accessed July 1, 2011.

5. Xcenda. Managed Care Network Survey. June 2011. http://www.xcenda.com/acowhite-paper.asp.

6. Center for Medicare & Medicaid Innovation. Pioneer accountable care organization (ACO) model request for application. http://innovations.cms.gov/wp-content/ uploads/2011/05/Pioneer-ACO-RFA.pdf. Accessed July 1, 2011.

7. Sinaiko A, Rosenthal MB. Patients’ role in accountable care organizations. N Engl J Med. 2010;363:2583-2585.

8. Miller H. How to create accountable care organizations. Center for Healthcare Quality & Payment Reform. September 7, 2009. www.chqpr.org/downloads/Howto CreateAccountableCareOrganizations.pdf. Accessed April 6, 2011.

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Pulmonary Disease axis of the Respiratory Health Network, Fonds de la recherche en santé du Québec (FRSQ). Self-management reduces both short- and long-term hospitalisation in COPD. Eur Respir J. 2005;26:853-857.

10. Bourbeau J, Julien M, Maltais F, et al, for the Chronic Obstructive Pulmonary Disease axis of the Respiratory Network Fonds de la Recherche en Santé du Québec.

Reduction of hospital utilization in patients with chronic obstructive pulmonary disease: a disease-specific self-management intervention. Arch Intern Med. 2003;163: 585-591.

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Am J Cardiol. 1999;84:860-862, A8.

12. Accountable Care Organization Learning Network. ACO Toolkit. January 2011. https://xteam.brookings.edu/bdacoln/Documents/ACO%20Toolkit%20January%2 02011.pdf. Accessed April 7, 2011.

13. Drinker Biddle & Reath. The Medicare shared savings program: accountable care organizations. Webinar presented April 13, 2011. www.drinkerbiddle.com/files/ ftpupload/ACO/ACO%20Webinar%20Materials.pdf. Accessed April 13, 2011.

14. Keckley PH, Hoffman M. Accountable care organizations: a new model for sustainable innovation. Deloitte Center for Health Solutions. 2010. www.deloitte.com/ assets/Dcom-UnitedStates/Local%20Assets/Documents/US_CHS_Accountable CareOrganizations_041910.pdf. Accessed April 9, 2011.

15. Centers for Medicare & Medicaid Services. Fact sheet. What providers need to know: accountable care organizations. March 31, 2011. www.cms.gov/apps/media/ press/factsheet.asp?Counter=3914&intNumPerPage=10&checkDate=&checkKey =&srchType=1&numDays=3500&srchOpt=0&srchData=&keywordType=All&chk NewsType=6&intPage=&showAll=&pYear=&year=&desc=false&cboOrder=date.

Accessed March 31, 2011.

16. Healthcare Financial Management Association. Contemplating the ACO opportunity—an HFM compendium. November 2010. http://hfma.org/WorkArea/ linkit.aspx?LinkIdentifier=id&ItemID=24081. Accessed April 5, 2011.

17. SNR Denton. The ACO regulations are here: are you ready? Webinar presented April 4, 2011. www.snrdenton.com/pdf/PPT.pdf. Accessed April 4, 2011.

18. Daigle L. Pharmacists’ role in accountable care organizations. ASHP policy analysis. January 2011. www.ashp.org/DocLibrary/Advocacy/PolicyAlert/ACOPolicy-Analysis.aspx. Accessed September 20, 2011.

19. Butcher L. CMS’s draft ACO regulations expected any day now. Oncology Times.

January 25, 2011. http://journals.lww.com/oncology-times/Fulltext/2011/01250/ CMS_s_Draft_ACO_Regulations_Expected_Any_Day_Now.2.aspx. Accessed April 8, 2011.

20. Gold J. “Poster boys” take a pass on pioneer ACO program. Kaiser Health News.

September 14, 2011. www.kaiserhealthnews.org/Stories/2011/September/14/ACOPioneers-Medicare-hospitals.aspx. Accessed October 31, 2011.

21. Nucci C. Bundled payments for oncology. HealthLeaders Media. March 16, 2011. www.healthleadersmedia.com/content/MAG-263628/Bundled-Payments-forOncology. Accessed April 5, 2011.

22. McDermott Will & Emery. Accountable care organizations: payor–ACO payment issues. Providing accountable care: strategy & structure. Webcast presented March 29, 2011. www.mwe.com/info/aco/aco0311c.pdf. Accessed March 29, 2011.

23. Helfand D. Southland hospitals to get Blue Shield grants. Los Angeles Times.

October 18, 2011. http://articles.latimes.com/2011/oct/18/business/la-fi-blue-shieldgrants-20111018. Accessed October 31, 2011.

24. McCanne D. HHS/CMS proposed rule for accountable care organizations.

Physicians for a National Health Program. April 4, 2011. http://pnhp.org/blog/2011/ 04/04/hhscms-proposed-rule-for-accountable-care-organizations/. Accessed April 11, 2011.

25. Kaiser Family Foundation. Focus on health reform: a profile of health insurance exchange enrollees. March 2011. www.kff.org/healthreform/upload/8147.pdf.

Accessed April 7, 2011.

26. Devers K, Berenson R. Can accountable care organizations improve the value of health care by solving the cost and quality quandaries? Timely analysis of immediate health policy issues. October 2009. Robert Wood Johnson Foundation–Urban Institute. www.urban.org/uploadedpdf/411975_acountable_care_orgs.pdf. Accessed April 9, 2011.

27. Wokasch M. How accountable care organizations (ACOs) will affect pharmaceutical sales representatives. Pharma Reform. October 19, 2010. http://pharmareform. com/2010/10/19/how-accountable-care-organizations-acos-will-affect-pharmaceuticalsales-representatives/?wpmp_tp=0&wpmp_switcher=mobile. Accessed April 8, 2011.

Stakeholder perspective on page 450

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STAKEHOLDER PERSPECTIVE The ACO Payment Model a Potential “Game Changer,” but Will It Improve Outcomes?

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he accountable care organization (ACO) payment concept is a game changer in terms of moving away from the current cottage-style care delivery system that is focused on a volume-driven business model. The ACO represents a move away from the model of incentives to earn more by doing more toward a more organized and centrally coordinated delivery system that provides incentives to do only what is needed for individual patients. Yeung and colleagues rightly pose the question whether ACOs can solve the issue of high-value healthcare concerns.

A change in payment structure through any program type will necessarily alter the roles and business models of providers in the care delivery system. Clearly, the trend is toward global payments for patient services, but because many options are still being tested (ACO, medical home, or other), the right payment model or models and quality parameters linked to reimbursement have yet to be determined.

PROVIDERS: Physicians will have a positive financial incentive in coordinated care along with achieving outcome goals, but these will be difficult to achieve in the real world. Such an approach is likely to work well in rural areas using a medical home, whereas urban areas are more likely to follow an ACO-style approach. But the ACO strategy changes the physicians’ relationship with their hospital and other clinical partners and could therefore create ill will.

Hospitals and health systems are in a position to coordinate care and provide the administrative structure to ensure quality as envisioned by the ACO concept. Under the global payment options, there is an opportunity to improve care coordination, but at a higher financial risk to hospitals, and with an increased likelihood of straining physician–hospital relationships.

PATIENTS: At first glance, this approach offers opportunity for better care coordination for the same or less amount of out-of-pocket cost. However, whether the promise will result in better care delivery and outcomes remains a concern. Can such an altered reimbursement system deliver the quality promised, while maintaining tight cost controls? And what would be the reality of out-of-pocket costs incurred by the patient?

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PAYERS: Health plans would have the opportunity to share some of the financial risk or shift it down to providers while maintaining administrative and claim management functions that increase the ability to predict the business health of the plans. They can be a big winner in this new payment approach, as they work with providers or patients in managing financial risk.

The payment structure change will challenge and force payers to alter their business model to focus more on information technology and on customer service, which they have developed slowly and promoted directly to the public over the past few years.

As the only stakeholders not taking financial risk, pharmacy benefit managers (PBMs) are at the greatest risk for establishing their future business value with their current model. This is likely to position PBM services, functions, or firms themselves to be subsumed under health plan or health system organizations as a lower-value commodity vendor. This same issue will be a challenge to third-party administrators, who have sought to expand their service lines without taking on financial risk.

For employers, unions, and municipalities looking to cut costs out of the system and improve integrated care delivery, global payment systems provide more fiscal certainty and predictability for plan sponsors contracting with third-party payers. A key question for purchasers of healthcare is whether such an approach can avoid disruptions or unintended consequences from drawbacks in the current models affecting delivery system stakeholders.

The continuing lack of leadership in healthcare reform implementation from Washington, DC, introduces another layer of confusion and concern from all perspectives as we consider payment system change, along with the impact of that change on stakeholders. The next 18 to 24 months will lead us to a new payment vista that is most likely to be global payment oriented, with some measure of patient quality outcome metrics built into the financial reimbursement equation.

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F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare

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

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being, the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest Include: • Adherence Concerns • Benefit Design • Case Studies • Comparative Effectiveness Research • Cost Analyses • Decision-Making Tools • Ethics in Medicine

• Health Economics Research • Health Plan Initiatives • Health Information Technology • Industry Trends • Innovations in Healthcare • Literature Reviews • Medicare/Medicaid

• Patient Advocacy/Patient Care • Pharmacoeconomics • Policy Issues • Prevention Initiatives • Reimbursement Strategies • Survey Results • Wellness Programs

Coming in 2012

Theme Issue: Cardiometabolic Health

Theme Issue: Cancer Care

Heart disease remains the number one killer in the United States, and metabolic conditions such as diabetes and obesity continue to rise. Cardiometabolic disease consists of a constellation of factors associated with cardiovascular disease and the metabolic syndrome, including dyslipidemia, hypertension, insulin resistance, and high abdominal fat.

In practical terms, it is impossible to separate the risk assessment and management of cardiovascular disease from the approach to metabolic syndrome. Readers are invited to submit original research, review articles, and perspectives on issues related to cost comparisons, pharmacoeconomics, benefit design, emerging therapies, and current diagnosis and management practices.

The growing focus on targeted therapies and diagnostics, personalized medicine, and the ever-growing cost of cancer care require an ongoing examination of current and emerging trends in oncology, cost-effectiveness and costbenefit analyses, utilization, and outcomes. While cancer therapies continue to make considerable strides, the cost of care is becoming out of reach for many Americans. We invite you to submit articles that discuss these issues as well as benefit design, comparative effectiveness analyses, and overall initiatives and programs that can help chart new directions for healthcare stakeholders, including providers, medical and pharmacy directors, health plans, employers, and policymakers.

Manuscripts should follow the Manuscript Instructions for Authors (available at www.AHDBonline.com).

Submit articles to editorial@engagehc.com. For more information, call 732-992-1892.

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D di n Follow-u FFollow-up ll upp 55-Y 5-Year YYear Median N New w Data: eear M Media

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma.

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡

VELCADE (Vc) in combination with MP.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall sur survival: vival:

80

556.4 6 .4 vs 443.1 3..1 m months onths

Patients Patients Surviving Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 P<0.05 < 70 60 50 40 30 20

VELCADE+MP VELC ADE+MP (n=344)

10

MP ((n=338) n=338)

0 0

12

24

36

Kaplan-Meier estimate.

48

60

72

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients.

Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADE.com.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

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Back to School: Quality Improvement through Academic Detailing Barry Patel, PharmD President, Total Therapeutic Management, Kennesaw, GA, and Adjunct Clinical Associate Professor, Department of Pharmacy Practice, Mercer University, Atlanta, GA

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ncorporating new research findings into medical practice can take almost 2 decades according to estimates from the Institute of Medicine. Even when new research is published, clinicians tend to apply this knowledge inconsistently. The problem is most common in outpatient settings, particularly when providers are dispersed and have few opportunities to work in organized care teams in which new research may be more readily discussed and disseminated.

The realities of the healthcare marketplace today highlight the reality that physicians clearly need a better way to access, learn about, and sort through the vast array of data already at their disposal. According to a recent article in the Washington Post, the proliferation of data on best practices makes it difficult for physicians to know which approach is optimal for each patient.1 Physicians quoted in that article reported that competing studies reach different conclusions, creating confusion and inconsistency.1

Academic Detailing Can Provide Answers There are also challenges related to the nature of the research that is available. The same article noted that of the 13,000 medical research studies done annually, only about 689 fall into the category of comparative research,1 the kind physicians can use to make better treatment decisions.

Therefore, a better way is needed to provide information about the latest evidence-based methods of delivering care, so that providers can put this information to use in daily clinical practice. One proved way to disseminate evidence-based research is academic detailing, a method of clinician engagement that involves one-on-one, clinician-to-clinician interaction to help providers become better informed and equipped to make clinical decisions.2-4 Academic detailing remains a misunderstood component of physician and provider education initiatives.

Some believe it comes with its own set of biases5; others say it is simply too time-consuming or costly.6 Nevertheless, a wide range of constituents, including pharmaceutical manufacturers, health plans and other

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payers, medical associations, and society as a whole, will need to identify and develop effective educational methodologies for physicians for many reasons. This is primarily because healthcare is becoming more complex every day, and engaging clinicians will be the key to delivering the best care. Fully exploring the structure, nature, and intent of academic detailing, as well as the ongoing evolution in provider education, will help all stakeholders ensure that they develop optimal strategies designed to improve care quality and patient outcomes.

Continuing Medical Education Efforts to provide physicians with educational information and clinical updates outside of medical school take a variety of forms. The goal of such programs is to ensure that physicians are informed about the latest clinical information so they can achieve optimal patient outcomes. This seems simple enough, but finding the right approach to reach physicians is a challenge.

For years, the primary method to drive quality improvement was accredited, continuing medical education (CME). Most states, medical boards, accreditation agencies, hospitals, and other medical institutions require physicians to complete a certain number of CME hours annually to maintain licensure and practice privileges.

In recent years, CME has been delivered in live, didactic lectures given to large audiences. Today, a variety of learning opportunities and settings are used, including lessons for small groups, point-of-practice settings, online education, case-based learning, and performance/quality improvement programs. Among these methods, online-based learning has grown most quickly.

In 2009, nearly 60,000 accredited hours were offered, representing a 2.5-fold increase since 2002.7 A 2008 evaluation of various CME activities showed that8: â&#x20AC;˘ The more interactive the activity, the greater the educational benefit, defined as changing clinician behavior and improving patient outcomes â&#x20AC;˘ Didactic-only programming has little benefit on its own, although outcomes improve when it is combined with interactivity

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KEY POINTS ➤

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The proliferation of clinical data now available to physicians makes it difficult to discern which approach will be optimal for each patient.

Academic detailing is an effective method of faceto-face, physician-to-physician education that can provide the most up-to-date, evidence-based methods of patient care.

With the growing trend of structuring reimbursement based on quality measures rather than services, physicians will need to improve the quality of care they deliver in hospital and office practice settings; academic detailing can help to meet quality targets.

Some challenges of adopting the academicdetailing approach include physician resistance and doubts about the objectivity of the detailers; however, these can be overcome with proper planning and implementation.

• Interactive workshops are beneficial for changing clinical practice; in one study, researchers found that such a seminar helped physicians reduce asthma symptoms in children • It is not clear that using local opinion leaders to provide the education is any more effective than using other educators • Audit and feedback produced small or moderate effects on physician behavior, and the benefit was greatest if adherence to the recommended behavior was low initially.

Even printed materials can have a positive effect on physician behavior, although whether patient outcomes improve is unclear. In 2007, the federal Agency for Healthcare Research and Quality (AHRQ) evaluated the effect of 136 CME articles and 9 systemic reviews on physician practice and patient care. The conclusion from that evaluation was that, “CME appears to be effective at the acquisition and retention of knowledge, attitudes, skills, behaviors and clinical outcomes.”9 Professional development activities that involve practice-based learning and improvement should be considered in any educational effort for physicians.

Such activities may be part of a CME activity, but they differ from the traditional, didactic concept of CME in several ways. They10: • Involve lifelong versus episodic learning • Are learner-centered rather than teacher-centered • Are comprehensive in scope, encompassing the practice and the clinical domain • Use a variety of learning formats and media • Are conducted in different venues rather than being done primarily in lecture halls.

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Many researchers believe that practice-based learning may be more beneficial in changing physician performance and health outcomes than strictly didactic presentations. As a result, educators are considering other tools for disseminating evidence-based clinical information, including health information technology such as computerized physician order entry and electronic health record systems. In addition, academic detailing is being considered more frequently because it is the only one-on-one method that allows for an objective educational interaction.

In a 2010 article published in Health Affairs, Avorn and Fischer offered the following advantages of academic detailing over traditional educational options11: • Outreach to physicians in their offices ensures better market penetration and audience than centralized CME courses • Communication can be tailored to individual participants, representing a big advantage in adult learning • The opportunities to engage participants in discussion increase the likelihood that the message will lead to changed behavior.

Expanding Academic Detailing to Evidence-Based Clinical Practice Academic detailing is a method of delivering evidence-based findings that involves trained healthcare professionals, such as physicians, pharmacists, and nurses, educating providers face-to-face. The principles of academic detailing and its effect on clinical decisionmaking were first published by Soumerai and Avorn.4 Since then, many private and public organizations, including AHRQ, have developed academic detailing programs to address pharmacy utilization and quality improvement.

Traditionally, academic detailing has focused on changing prescribing patterns for targeted medications, but in recent years it has been expanded to target adherence to evidence-based medicine guidelines.

One example of academic detailing being used to help physicians adhere to clinical-based medicine guidelines involves the Diabetes Physician Recognition Program (DPRP) of the National Committee for Quality Assurance. In this program, a large national health plan identified 40 primary care physician practices in 2 markets (Florida and Philadelphia) that had low performance scores in delivering care to patients with diabetes.

Believing that a pay-for-performance (P4P) program for these physicians would improve their results, the health plan administrators retained a healthcare quality improvement company to work with the 40 practices to help them meet the DPRP goals and gain higher rates of reimbursement. After informing the practices about the

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benefits of DPRP, clinicians conducted 25 chart reviews at each practice, and used this information to apply for DPRP recognition status. Among the 40 practices, only 1 achieved the adequate number of points (75) to be eligible for DPRP status.12 Based on the results of the chart review, a clinical pharmacist conducted academic detailing to educate the providers about the benefits of following evidencebased national guidelines for optimal care of patients with diabetes and suggested the practices apply again in 6 months. Each practice was evaluated on how well it managed patients with diabetes in terms of control of blood glucose, blood pressure, and cholesterol levels; eye exams; nephropathy assessment; smoking status assessment, and giving smoking-cessation advice or treatment.12 Education was implemented with all practices, and 20 chose to conduct chart reviews 6 months later. Of these 20 practices, 17 achieved the 75 points needed for DPRP recognition. These results were significant in that only 1 of 20 (5%) practices achieved a score of 75 before the intervention, and 17 of 20 (85%) achieved a score of 75 after the intervention.12 In addition, the practices showed marked improvement in clinical outcomes from the first chart review to the second (Table).

Focus on Quality Improvement The DPRP example above is instructive in 2 ways.

First, it shows that when academic detailers compare a clinician’s own quality data with national and local benchmarks, performance is likely to improve. Academic detailing is an ideal method of communication to disseminate medical evidence that demonstrates the need to meet quality targets, because it is built on a relationship of trust between the detailer and the provider. The collaborative and supportive one-on-one nature of academic detailing makes this method of communication particularly effective when comparing a clinician’s quality or performance scores with those of his or her peers. In these sessions, clinicians are often more open to discuss their own quality reports and the need to make improvements.

Second, this case example demonstrates that academic detailing can be useful to health plans seeking to improve quality and P4P programs. Considering that healthcare reform is changing the reimbursement environment by making quality improvement an important priority, and by fostering the adoption of P4P programs, health plans are likely to consider academic detailing to promote these endeavors.

Accountable care organizations (ACOs) also represent the potential for a significant change in reimbursement for healthcare providers and, as a result, it is like-

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Table Clinical Outcomes Before and After Academic Detailing in a Diabetes Physician Recognition Program Initial Post review, % education, %

Outcome Documented increase of A1c in previous 6 mo

54

91

Documented increase of A1c of <7% in previous 6 mo

54

65

Documented increase of diabetic foot examination in previous 6 mo

22

33

Documented increase of retinal eye examination in previous 6 mo

11

18

Documented increase of LDL-C in past 12 mo

84

96

Documented increase of LDL-C <100 mg/dL in previous 6 mo

49

63

Documented decrease in uncontrolled blood pressure of >140/90 mm Hg

34

18

A1c indicates glycated hemoglobin; LDL-C, low-density lipoprotein cholesterol.

Source: Total Therapeutic Management, Kennesaw, GA. Used with permission.

ly that quality improvement education could be required of all providers in ACOs. On October 20, 2011, the Centers for Medicare & Medicaid Services (CMS) issued final rules for ACOs that include 33 quality indicators designed to reflect each organization’s quality status and their corresponding payments.

Education regarding these measures, and how providers can improve them, can be achieved effectively through academic detailing.

Considering that healthcare reform is changing the reimbursement environment by making quality improvement an important priority, health plans are likely to consider academic detailing to promote these endeavors.

In their August 2011 commentary in JAMA, health policy experts Singer and Shortell warned that health systems and providers involved in ACOs should not overestimate their ability to implement standardized care-management protocols.13 “The goal of protocols is to eliminate variation and complexity in the care deliv-

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Figure Typical Academic Detailing Program Flow To implement an academic detailing program, follow these steps: work plan development, recruitment and hiring of medical professionals, training in content and communications, deployment, documentation, management, communication, and measurement and evaluation of predetailing and postdetailing metrics.

Project initiation • Protocol development • CRF development • IRB submission

Study population acquisition • Data partner • Client

Database development • Data scrubbing • Analytic database

Data analysis • Database QA • Report preparation • Profiling reports

Data abstraction • Abstraction training • Medical record review/abstraction • Data validation

Medical record acquisition • Record requests • Record storage • Record posting

Remeasurement • Repeat data abstraction, analysis, and reporting

Dissemination of research and evidence via academic detailing

CRF indicates Case Report Form; IRB, Institutional Review Board; QA, quality assurance.

ery process that do not add value,” Singer and Shortell wrote,13 noting that it takes time to implement protocols.13 Academic detailing is well-suited for health systems seeking to implement care-management protocols, because providers can be better engaged regarding evidence-based care management to eliminate care variation, as opposed to a more demanding approach.

Another reason academic detailing will be important in the near future is that CMS is changing the way it pays hospitals, and health plans are likely to do so as well. CMS has stopped paying for so-called never events and is expected to reduce or eliminate payments for hospital-acquired infections and high readmission rates.

When CMS does stop these payments, industry leaders believe that health plans will likely follow suit.14 For this reason alone, physicians will need to improve the quality of care they deliver in hospitals and other settings, and

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again, academic detailing can help physicians and health plans to meet quality targets.

Medicare Advantage Quality Ratings Providers in Medicare Advantage managed care plans could face similar challenges. Medicare Advantage plans are expected to use quality ratings unveiled in October 2011 to attract more business and promote their ratings, given that the federal government will pay bonuses ranging from 3 to 5 percentage points to plans that rate the highest on a new rating scale. The ratings this year will be used to figure bonus payments that Medicare Advantage plans can receive in 2013.15 When it introduced the new “star ratings” program for Medicare Advantage plans, CMS said that 5 stars is the highest rating a plan can get, and starting in 2012, plans can market their ratings to consumers. As a result, there

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is great interest among plans in how they may improve or sustain their star rating. Academic detailing could help health plans increase their ratings by educating physicians about the importance of meeting quality targets.

The following example illustrates the effectiveness of academic detailing in meeting quality goals beyond treatment-based education.

To evaluate the effectiveness of educating primary care physicians in 2 medically underserved communities in New York City, researchers used academic detailing to explain the importance of recommending breast cancer screening to patients with low economic status, African Americans or Hispanics.16 Educators received printed material and had detailing visits lasting an average of 10 minutes per session. They also attended 6 dinner seminars, got a newsletter on the topic, and received officebased breast cancer prevention materials. Compared with a control group in a similar neighborhood that received no intervention, physicians in the intervention group reported increased use of mammography and breast self-examinations among their patients. Physicians in the intervention group also were more likely to use office-based tools and techniques, such as chart stickers, than were physicians in the control group.16

Potential Barriers to Academic Detailing For all the benefits of academic detailing, challenges exist, which can be overcome with appropriate planning (Figure). In a qualitative study of family physicians, researchers found that physicians did not use academic detailing because they did not want to schedule office time for the visit or for educational purposes.17 Of note, some of the physicians also stated that they did not want CME activities that are provided by a nonphysician.17 Other challenges include physician resistance or lack of understanding about evidence-based medicine, doubts about the objectivity of the detailers (including concerns that the information was biased and designed primarily to cut costs), and concerns that the information is not current, or that they had other ways to obtain it.17 All these potential barriers need to be considered when implementing an academic detailing program.

Administrators can take steps to overcome these during the planning phase.

Embracing New Educational Paradigms Despite what in reality often amounts to perceived barriers, healthcare industry leaders seeking to develop new ways to provide medical education are likely to consider the benefits of academic detailing, especially as

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healthcare reform unfolds and health systems begin to work more closely with physicians in ACOs and patientcentered medical homes.

In addition, academic detailing will continue to evolve to address concerns about partiality. New approaches to academic detailing focus on therapeutic categories as opposed to specific brands, helping to alleviate concerns among pharmaceutical manufacturers regarding the potential for bias.

As new reimbursement models are introduced, healthcare leaders will likely discover the value and benefits of academic detailing. The result will be provider education programs that are peer-to-peer focused and tailored to meet the needs and preferences of individual physicians, while ensuring that the decisions physicians make will likely be focused on the evidence designed to provide optimal outcomes for individual patients. ■ Author Disclosure Statement Dr Patel reported no conflicts of interest.

References 1. Brown D. Comparative effectiveness research tackles medicine’s unanswered questions. Washington Post. August 15, 2011. www.washingtonpost.com/national/ health-science/comparative-effectiveness-research-tackles-medicines-unansweredquestions/2011/08/01/gIQA7RJSHJ_story.html. Accessed November 16, 2011.

2. O’Brien MA, Rogers S, Jamtvedt G, et al. Educational outreach visits: effects on professional practice and health care outcomes. Cochrane Database Syst Rev. 2007 (4):CD000409. E-pub October 8, 2008. http://summaries.cochrane.org/CD000409/ educational-outreach-visits-to-change-health-care-professional-care-for-patients.

Accessed November 17, 2011.

3. AARP. Academic detailing in practice: a tale of four states. Rx Watchdog Report.

December 2009. http://assets.aarp.org/www.aarp.org_/cs/health/206907rxwatchdog_ dec_09.pdf. Accessed November 17, 2011.

4. Soumerai SB, Avorn J. Principles of educational outreach (‘academic detailing’) to improve clinical decision making. JAMA. 1990;263:549-556.

5. Mitka M. New physician education initiatives seek to remove the devil from the detailing. JAMA. 2011;306:1187-1188.

6. Smith WR. Evidence for the effectiveness of techniques to change physician behavior. Chest. 2000;118(2 suppl):8S-17S. 7. Accreditation Council for Continuing Medical Education (ACCME). ACCME Annual Report Data, 2010. www.accme.org/dir_docs/doc_upload/e7520312-92c34969-acf0-bdf4c5b8d289_uploaddocument.pdf. Accessed November 16, 2011.

8. Satterlee WG, Eggers RG, Grimes DA. Effective medical education: insights from the Cochrane Library. Obstet Gynecol Surv. 2008;63:329-333.

9. Marinopoulos SS, Dorman T, Ratanawongsa N, et al. Effectiveness of continuing medical education. Evid Rep Technol Assess. 2007;63:1-69.

10. Sachdeva AK. The new paradigm of continuing education in surgery. Arch Surg.

2005;140:264-269.

11. Avorn J, Fischer M. ‘Bench to behavior’: translating comparative effectiveness research into improved clinical practice. Health Aff (Millwood). 2010;29:1891-1900.

12. Kramer M, Perez HE, Stacy T. Diabetes physician recognition in a large health plan. Presented at the 14th International Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research; May 16-20, 2009; Orlando, FL. 13. Singer S, Shortell S. Implementing accountable care organizations. JAMA. 2011;306:758-759.

14. Burns J. At long last…pay for outcomes starts to replace pay for performance.

Manag Care. 2011;20:24-29.

15. Japsen B. Bonuses tied to Medicare’s star system reward insurers. New York Times.

October 12, 2011. http://prescriptions.blogs.nytimes.com/category/health-insurers/ ?scp=5-b&sq=wellpoint&st=nyt. Accessed November 16, 2011.

16. Gorin SS, Ashford AR, Lantigua R, et al. Implementing academic detailing for breast cancer screening in underserved communities. Implement Sci. 2007;2:1-6.

17. Allen M, Ferrier S, O’Connor N, et al. Family physicians’ perceptions of academic detailing: a quantitative and qualitative study. BMC Med Educ. 2007;7:31-39.

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)MPORTANT 3AFETY )NFORMATION WARNINGS AND PRECAUTIONS: s 4REATMENT WITH )34/$!8 HAS BEEN ASSOCIATED WITH THROMBOCYTOPENIA LEUKOPENIA NEUTROPENIA AND LYMPHOPENIA AND ANEMIA THEREFORE MONITOR THESE HEMATOLOGICAL PARAMETERS DURING TREATMENT WITH )34/$!8 AND MODIFY THE DOSE AS NECESSARY s 3ERIOUS AND SOMETIMES FATAL INFECTIONS HAVE BEEN REPORTED DURING TREATMENT AND WITHIN DAYS AFTER TREATMENT WITH )34/$!8 AND THE RISK OF LIFE THREATENING INFECTIONS MAY BE HIGHER IN PATIENTS WITH A HISTORY OF EXTENSIVE OR INTENSIVE CHEMOTHERAPY s %LECTROCARDIOGRAPHIC %#' CHANGES HAVE BEEN OBSERVED WITH )34/$!8 s )N PATIENTS WITH CONGENITAL LONG 14 SYNDROME A HISTORY OF SIGNIlCANT CARDIOVASCULAR DISEASE AND PATIENTS TAKING ANTI ARRHYTHMIC MEDICINES OR MEDICINAL PRODUCTS THAT LEAD TO SIGNIlCANT 14 PROLONGATION APPROPRIATE CARDIOVASCULAR MONITORING PRECAUTIONS SHOULD BE CONSIDERED SUCH AS MONITORING ELECTROLYTES AND %#'S AT BASELINE AND PERIODICALLY DURING TREATMENT s %NSURE THAT POTASSIUM AND MAGNESIUM ARE WITHIN THE NORMAL RANGE BEFORE ADMINISTRATION OF )34/$!8 s 4UMOR LYSIS SYNDROME HAS BEEN REPORTED DURING TREATMENT WITH )34/$!8 0ATIENTS WITH ADVANCED STAGE DISEASE AND OR HIGH TUMOR BURDEN SHOULD BE CLOSELY MONITORED AND APPROPRIATE PRECAUTIONS TAKEN AND TREATMENT SHOULD BE INSTITUTED AS APPROPRIATE s )34/$!8 MAY CAUSE FETAL HARM WHEN ADMINISTERED TO A PREGNANT WOMAN !DVISE WOMEN TO AVOID PREGNANCY WHILE RECEIVING )34/$!8 )F THIS DRUG IS USED DURING PREGNANCY OR IF THE PATIENT BECOMES PREGNANT WHILE TAKING )34/$!8 THE PATIENT SHOULD BE APPRISED OF THE POTENTIAL HAZARD TO THE FETUS 0REGNANCY #ATEGORY $ ADVERSE REACTIONS: 0ERIPHERAL 4 #ELL ,YMPHOMA 4HE MOST COMMON 'RADE ADVERSE REACTIONS REGARDLESS OF CAUSALITY IN 3TUDY N WERE THROMBOCYTOPENIA NEUTROPENIA ANEMIA

ASTHENIA FATIGUE AND LEUKOPENIA AND IN 3TUDY N WERE NEUTROPENIA LEUKOPENIA

THROMBOCYTOPENIA ANEMIA ASTHENIA FATIGUE

PYREXIA VOMITING AND NAUSEA )NFECTIONS WERE THE MOST COMMON TYPE OF SERIOUS ADVERSE EVENT REPORTED IN 3TUDY N AND 3TUDY N )N 3TUDY PATIENTS EXPERIENCED A SERIOUS INFECTION

INCLUDING PATIENTS WITH SERIOUS TREATMENT RELATED INFECTIONS )N 3TUDY PATIENTS EXPERIENCED A SERIOUS INFECTION INCLUDING PATIENTS WITH SERIOUS TREATMENT RELATED INFECTIONS 4HE MOST COMMON ADVERSE REACTIONS REGARDLESS OF CAUSALITY IN 3TUDY N WERE NAUSEA

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LEUKOPENIA ANEMIA ASTHENIA FATIGUE

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VOMITING DERMATITIS EXFOLIATIVE DERMATITIS

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!"#" INHIBITORS s 0HYSICIANS SHOULD CAREFULLY MONITOR PROTHROMBIN TIME 04 AND )NTERNATIONAL .ORMALIZED 2ATIO ).2 IN PATIENTS CONCURRENTLY ADMINISTERED )34/$!8 AND WARFARIN SODIUM DERIVATIVES USE IN SPECIFIC POPULATIONS: s "ECAUSE MANY DRUGS ARE EXCRETED IN HUMAN MILK AND BECAUSE OF THE POTENTIAL FOR SERIOUS ADVERSE REACTIONS IN NURSING INFANTS FROM )34/$!8 A DECISION SHOULD BE MADE WHETHER TO DISCONTINUE NURSING OR DISCONTINUE THE DRUG TAKING INTO ACCOUNT THE IMPORTANCE OF THE DRUG TO THE MOTHER s 0ATIENTS WITH MODERATE AND SEVERE HEPATIC IMPAIRMENT AND OR PATIENTS WITH END STAGE RENAL DISEASE SHOULD BE TREATED WITH CAUTION

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ISTODAX® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation 10/11 IST11038

INDICATIONS THE FIRST AND ONLY s 4REATMENT OF PERIPHERAL 4 CELL LYMPHOMA 04#, IN PATIENTS DRUG APPROVED IN BOTH WHO HAVE RECEIVED AT LEAST ONE PRIOR THERAPY PTCL AND CTCL s 4REATMENT OF CUTANEOUS 4 CELL LYMPHOMA #4#, IN PATIENTS WHO HAVE RECEIVED AT LEAST ONE PRIOR SYSTEMIC THERAPY 4HESE INDICATIONS ARE BASED ON RESPONSE RATE #LINICAL BENEl T SUCH AS IMPROVEMENT IN OVERALL SURVIVAL HAS NOT BEEN DEMONSTRATED

RECHARGE THE POSSIBILITIES

www.istodax.com Please see Important Safety Information on adjacent page.

Please see Brief Summary of full Prescribing Information on following pages.

Only

ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a brief summary only; see full prescribing information for complete product information.

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3E 36H7DE7 D735F;A@E 3D7 ;@5>G676 ;@ +34>7 Table 1. Adverse Reactions Occurring in >20% of Patients in Either CTCL Study (N=185) Study 1 Study 2 (n=102) (n=83) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 @K 36H7DE7 D735F;A@

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Serious Adverse Reactions Infections were the most common type of SAE reported in both studies with 8 patients (8%) in Study 1 and 26 patients (31%) in Study 2 experiencing a serious infection. Serious adverse reactions reported in > 2% of patients in Study 1 were sepsis and pyrexia (3%). In Study 2, serious adverse reactions in > 2% of patients were fatigue (7%), supraventricular arrhythmia, central line infection, neutropenia (6%), hypotension, hyperuricemia, edema (5%), ventricular arrhythmia, thrombocytopenia, nausea, leukopenia, dehydration, pyrexia, aspartate aminotransferase increased, sepsis, catheter related infection, hypophosphatemia and dyspnea (4%).

Most deaths were due to disease progression. In Study 1, there were two deaths due to cardiopulmonary failure and acute renal failure. In Study 2, there were six deaths due to infection (4), myocardial ischemia, and acute respiratory distress syndrome.

Discontinuations Discontinuation due to an adverse event occurred in 21% of patients in Study 1 and 11% in Study 2. Discontinuations occurring in at least 2% of patients in either study included infection, fatigue, dyspnea, QT prolongation, and hypomagnesmia.

Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2.

The mean duration of treatment and number of cycles in these studies were 5.6 months and 6 cycles.

Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2.

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Grade 3 Grade 3 Adverse Reactions n (%) All or 4 All or 4 Any adverse reactions 127 (97) 86 (66) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 13 (10) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 7 (5) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 32 (24) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 13 (10) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 25 patients (19%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (7%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 of patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%).

Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause.

Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%).

6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience.

7 DRUG INTERACTIONS 7.1 Coumadin or Coumadin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and Coumadin or Coumadin derivatives has not been formally studied, physicians should carefully monitor PT and INR in patients concurrently administered ISTODAX and Coumadin or Coumadin derivatives [See Clinical Pharmacology (12.3)].

7.2 Drugs that Inhibit or Induce Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Although there are no formal drug interaction studies for ISTODAX, strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase concentrations of romidepsin. Therefore, co-administration with strong CYP3A4 inhibitors should be avoided if possible. Caution should be exercised with concomitant use of moderate CYP3A4 inhibitors.

Co-administration of potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifampin, rifabutin, rifapentine, phenobarbital) may decrease concentrations of romidepsin and should be avoided if possible. Patients should also refrain from taking St. John’s Wort.

7.3 Drugs that Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [See Warnings and Precautions (5.5)].

There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman.

In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus.

Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures

(AUC) â&#x2030;Ľ0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification.

8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established.

8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were > 65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out.

8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted.

Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution [See Clinical Pharmacology (12.3)].

8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted.

Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution [See Clinical Pharmacology (12.3)].

0 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heart beat, staggering gait, tremor, and tonic convulsions.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required.

There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

3 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been performed with romidepsin.

Romidepsin was not mutagenic in vitro in the bacterial reverse mutation assay (Ames test) or the mouse lymphoma assay. Romidepsin was not clastogenic in an in vivo rat bone marrow micronucleus assay when tested to the maximum tolerated dose (MTD) of 1 mg/kg in males and 3 mg/kg in females (6 and 18 mg/m2 in males and females, respectively).

These doses were up to 1.3-fold the recommended human dose, based on body surface area.

16 HOW SUPPLIED/STORAGE AND HANDLING Keep out of reach of children.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published1-4 [See References (15)].

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling.

17.1 Instructions M %3GE73 3@6 -A?;F;@9 Nausea and vomiting are common following treatment with ISTODAX. Prophylactic antiemetics are recommended to be used in all patients.

Advise patients to report these symptoms so that appropriate treatment can be instituted [See Adverse Reactions (6)].

M #AI >AA6 AG@FE Patients should be informed that treatment with ISTODAX can cause low blood counts and that frequent monitoring of hematologic parameters is required. Patients should be instructed to report fever or other signs of infection, significant fatigue, shortness of breath, or bleeding [See Warnings and Precautions (5.1)].

M @875F;A@E Patients should be informed that infections may occur during treatment with ISTODAX. Patients should be instructed to report fever, cough, shortness of breath with or without chest pain, burning on urination, flu-like symptoms, muscle aches, or worsening skin problems [See Warnings and Precautions (5.2)].

M +G?AD #KE;E *K@6DA?7 Patients at risk of tumor lysis syndrome (i.e, those with advanced stage disease and/or high tumor burden) should be monitored closely for TLS and appropriate measures taken if symptoms are observed [See Warnings and Precautions (5.4)].

M ,E7 ;@ 'D79@3@5K If pregnancy occurs during treatment with ISTODAX, female patients should be advised to seek immediate medical advice and counseling.

[See Warnings and Precautions (5.5)].

M '3F;7@FE E:AG>6 47 ;@EFDG5F76 FA D736 F:7 B3F;7@F ;@E7DF 53D78G>>K Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: 7@ -7@G7 #34AD3FAD;7E @5 Bedford, OH 44146 ISTODAXÂŽ is a registered trademark of Celgene Corporation U.S. Patents: 4,977,138; 7,608,280; 7,611,724 *+ -'

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Based on non-clinical findings, male and female fertility may be compromised by treatment with ISTODAX. In a 26-week toxicology study, romidepsin administration resulted in testicular degeneration in rats at 0.33 mg/kg/dose (2 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were approximately 2% the exposure level in patients receiving the recommended dose of 14 mg/m2/dose. A similar effect was seen in mice after 4 weeks of drug administration at higher doses. Seminal vesicle and prostate organ weights were decreased in a separate study in rats after 4 weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day), approximately 30% the estimated human daily dose based on body surface area. Romidepsin showed high affinity for binding to estrogen receptors in pharmacology studies. In a 26-week toxicology study in rats, atrophy was seen in the ovary, uterus, vagina and mammary gland of females administered doses as low as 0.1 mg/kg/dose (0.6 mg/m2/dose) following the clinical dosing schedule. This dose resulted in AUC0-inf. values that were 0.3% of those in patients receiving the recommended dose of 14 mg/m2/dose. Maturation arrest of ovarian follicles and decreased weight of ovaries were observed in a separate study in rats after four weeks of daily drug administration at 0.1 mg/kg/day (0.6 mg/m2/day). This dose is approximately 30% the estimated human daily dose based on body surface area.

2

BUSINESS

RESEARCH ARTICLE

Sensitivity of Medication Use to Formulary Controls in Medicare Beneficiaries: A Review of the Literature Rahul Shenolikar, PhD; Amanda Schofield Bruno, PhD, MPH; Michael Eaddy, PharmD, PhD; Christopher Cantrell, PhD Background: Several studies have examined the impact of formulary management strategies on medication use in the elderly, but little has been done to synthesize the findings to determine whether the results show consistent trends.

Objective: To summarize the effects of formulary controls (ie, tiered copays, step edits, prior authorization, and generic substitution) on medication use in the Medicare population to inform future Medicare Part D and other coverage decisions.

Methods: This systematic review included research articles (found via PubMed, Google Scholar, and specific scientific journals) that evaluated the impact of drug coverage or costsharing on medication use in elderly (aged â&#x2030;Ľ65 years) Medicare beneficiaries. The impact of drug coverage was assessed by comparing patients with some drug coverage to those with no drug coverage or by comparing varying levels of drug coverage (eg, full coverage vs $1000 coverage or capped benefits vs noncapped benefits). Articles that were published before 1995, were not original empirical research, were published in languages other than English, or focused on populations other than Medicare beneficiaries were excluded. All studies selected were classified as positive, negative, or neutral based on the significance of the relationship (P <.05 or as otherwise specified) between the formulary control mechanism and the medication use, and on the direction of that relationship.

Results: Included were a total of 47 research articles (published between 1995 and 2009) that evaluated the impact of drug coverage or cost-sharing on medication use in Medicare beneficiaries. Overall, 24 studies examined the impact of the level of drug coverage on medication use; of these, 96% (N = 23) supported the association between better drug coverage (ie, branded and generic vs generic-only coverage, capped benefit vs noncapped benefit, supplemental drug insurance vs no supplemental drug insurance) or having some drug coverage and enhanced medication use. Furthermore, 84% (N = 16) of the 19 studies that examined the effect of cost-sharing on medication use demonstrated that decreased costsharing was significantly associated with improved medication use.

Conclusion: Current evidence from the literature suggests that restricting drug coverage or increasing out-of-pocket expenses for Medicare beneficiaries may lead to decreased medication use in the elderly, with all its potential implications.

P

atient access to healthcare resources is an important topic of healthcare discussion, research, and reform in the United States.1,2 Access issues are usu-

Dr Shenolikar is Manager, Applied Outcomes and Analysis, GlaxoSmithKline, Research Triangle Park, NC; Dr Schofield Bruno is Director, Medical Services, Xcenda, Palm Harbor, FL; Dr Eaddy is Vice President, Data Analytics & Trends, Xcenda, Palm Harbor, FL; and Dr Cantrell is Senior Director, GlaxoSmithKline, Research Triangle Park, NC.

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2011;4(7):465-474 www.AHDBonline.com Disclosures are at end of text

ally framed in the context of patients having health insurance, as the quality of health insurance facilitates patient access to necessary medical and pharmaceutical therapies.2 Although patient access to medications is essential, formulary management strategies may introduce barriers aimed at restricting utilization, including curbing patient demand by increasing the cost borne by the patient or providing incentives to select lower-cost alternatives. Examples of these strategies include tiered copays, coinsurance, and benefit caps.3,4

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KEY POINTS ➤

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Many studies have investigated the impact of formulary management (eg, tiered copays, step edits, prior authorization) on medication use (eg, adherence, change in days supply, medication fills) patterns in Medicare beneficiaries, but none has synthesized the findings to arrive at some common trends in this patient population.

The present study reviewed 47 studies that had met the study criteria involving medication use by Medicare beneficiaries between 1995 and 2009.

Among the 24 studies that investigated the impact of drug coverage on medication use, 23 showed that elderly patients with greater drug coverage are more likely to use their medications as prescribed than those with greater coverage restrictions.

Of the 19 studies that examined the effect of costsharing on medication use, 16 demonstrated that decreased patient cost-sharing improved medication use.

Overall, the evidence shows that more restrictive drug coverage is associated with reduced medication use among Medicare beneficiaries, and fewer restrictions encourage enhanced medication use.

Health plans are facing increasing pressures to implement strategies to control costs, including drug costs; nevertheless, restricting access to necessary medications in the elderly may lead to suboptimal clinical outcomes and potentially greater medical expenditures.

The advent of Medicare Part D in 2006 made the federal government the single largest payer of medications in the country, providing coverage to Medicare beneficiaries and the disabled. Although Part D is sponsored by the Centers for Medicare & Medicaid Services (CMS), it is administered by health plans that have the ability to implement restrictions on medication use in the form of drug benefit. Evidence generated from previous studies demonstrate that formulary controls can impact patients’ medication-taking behavior and, ultimately, patient outcomes.4 However, conclusions drawn from these studies were largely based on populations that included nonelderly, commercial, or non-US populations.4 Elderly people could behave differently from younger people in response to formulary controls, given their increased likelihood of comorbidities and greater need for medications to maintain good health.

No study to date has collated existing data to assess the consistency in the findings regarding the impact of formulary controls on medication use—defined in this current study as adherence, change in days supply, med-

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ication fills, and number of tablets—in the elderly.

Synthesizing evidence from previous studies involving elderly populations may help in assisting Medicare and other health plan benefit design guidelines in the future.

Therefore, the objective of this study was to summarize the effects of formulary controls on the US elderly (ie, Medicare) population based on previously published studies to generate evidence using earlier research that could be used to make future coverage decisions.

Formulary controls included all formulary strategies that use mechanisms such as formulary restrictions and benefit design, including tiered copayments, step edits, prior authorization, and generic substitution.

Methods Study Selection First, a list of search terms was applied to a database of the medical sciences (PubMed, published by the National Library of Medicine), the search engine Google Scholar, and specific scientific journals. Second, articles from certain journals, such as Health Affairs, Medical Care, the American Journal of Geriatric Pharmacotherapy, and the Journal of the American Geriatrics Society, were individually searched. These journals were selected because of their wide readership and focus on healthcare policy studies and research related to clinical care, and because of recent developments in drug therapy in the elderly.

The list of search terms used in step 1 was designed to address the impact of formulary controls on patient medication use. Formulary controls included in this study encompassed all formulary strategies that use formulary restrictions and benefit design mechanisms, as noted above (ie, tiered copayments, step edits, prior authorization, and generic substitution). Some of these strategies are intended to curb patient demand for drug therapies, by increasing the cost borne by the patient or by providing incentives to select lower-cost alternatives.

The set of search terms, therefore, included: Medicare, elderly, older, compliance, adherence, persistence, outcomes, adverse event, utilization, resource use, prescription drug expenditures, cost, cost share, copayment, out of pocket, coinsurance, deductible, pharmacy coverage, step therapy, benefit change, cap, premium, insurance coverage, insurance type, tiered benefit design, formulary, consumer-driven health plans, prescription drugs, generic drug use, branded drugs, access, capitated, fee for service, and retrospective analysis.

More than 500 research articles were obtained that pertained to these search terms. To make the articles applicable to this literature review, certain exclusion criteria were applied (Figure 1). Articles were excluded if they were published before 1995, were not original empirical research, were published in languages other

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Variables Defined by Studies Included in This Table 1 Systematic Review

Figure 1 Article Selection and Identification Criteria

Explanatory variable

Definitiona

Level of drug coverage

Full drug coverage vs $1000 coverage vs no coverage

More than 500 articles identified based on search criteria

Drug coverage (any type) vs no drug coverage Capped benefits vs noncapped benefits

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Branded and generic coverage vs generic coverage Copay (eg, copay index, copay per 30 days, proportion of out-ofpocket cost, level of generosity)

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Medication cost-sharing

Exclusions: • Published before 1995 • Published in language other than English • Not empirical research • Did not study Medicare-eligible beneficiaries

Articles remaining, N = 53

1 tier vs 2 tiers or 2 tiers vs 3 tiers Copay vs no copay Capped prescription benefit reached vs not reached (based on out-of-pocket expenses) Outcome variable

Definitiona

Medication use

Medication persistence

than English, or focused on populations other than Medicare enrollees. These exclusion criteria were used after a review of the title and content of the abstracts. A full article review was conducted in cases where the title and abstract review were inconclusive. There was no restriction on study design.

The third component of the search strategy included an examination of the list of references from all studies selected in steps 1 and 2 to determine whether the studies met the selection criteria.

Medication adherence Continuous measure of medication gaps Mean daily number of essential therapeutic classes Change in medication days supply Number of medications Medication discontinuation Failure to purchase tablets Skipped or reduced dose Per-capita prescription events Number of prescriptions Number of tablets Number of fills Use of select medications Medication change a

The definitions for each variable were extracted from the articles included in this literature review.

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Study Variables Formulary controls are tools used by payers to restrict the number of medications covered for each patient.

Operational definitions of formulary controls evaluated in this study were based on the definitions in the studies that met the selection criteria. Included studies examined a variety of formulary controls—except step therapy and prior authorization—and were classified according to whether the specific control affected either (1) the level of drug coverage or (2) medication cost-sharing (Table 1). The classification of studies into these 2 categories allowed for the assessment of the impact of drug coverage on medication use by comparing, for example, patients with some drug coverage with those with no drug coverage, or by comparing different levels of drug coverage (eg, branded and generic vs genericonly coverage).

The impact of cost-sharing, however, was examined by comparing differences in patient copayment or the coinsurance amount for medications. Medication use—

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Positive Study Classification,a Based on Relationships Figure 2 of Interest Better drug coverageb or Lower medication cost-sharing

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Enhanced medication use

a Drug coverage or lower cost-sharing associated with significantly improved medication use was considered a positive relationship, whereas reduced drug coverage or increased costsharing associated with significantly reduced medication use was considered a negative relationship. Relationships that were not significant were considered neutral. b For example, branded and generic versus generic-only coverage, capped benefit versus noncapped benefit, supplemental drug insurance versus no supplemental drug insurance.

Studiesa with Positive Status: Impact of Coverage Type Table 2 on Medication Use in the Medicare Population Positive status studies,b N (%)

Total studies, N

Impact of drug coverage

23 (96)

24

Impact of medication cost-sharing

16 (84)

19

Total

39 (91)

43

Impact on medication use

a

Excluding descriptive studies. b The “postive” and “negative” categories are not mutually exclusive. A study could be included in multiple categories if it examined more than 1 relationship of interest or if it was classified as a positive and a negative study.

the outcome variable included in the study—was also defined according to the definitions used in the included studies (Table 1), and together these variables were used to represent the variable medication use.

Study Classification into Positive, Negative, or Neutral Categories This literature review included 2 types of studies: 1. Studies that examined the relationship between costsharing/level of drug coverage and medication use, using hypothesis testing 2. Descriptive studies. (Some descriptive studies were not categorized and are described separately in the Results section.)

All other studies were classified as positive, negative, or neutral based on the following 2 criteria. First, we determined whether the relationship between the

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impact of the level of drug coverage or medication costsharing on medication use was statistically significant.

Second, if the relationship was significant, we determined the direction of relationship, that is, whether it was positive or negative based on a predetermined definition of positive relationship, as illustrated in Figure 2.

For example, better drug coverage (eg, branded and generic vs generic-only coverage, capped benefit vs noncapped benefit, supplemental drug insurance vs no supplemental drug insurance) or lower cost-sharing associated with significantly improved medication use was considered a positive relationship, whereas reduced drug coverage or increased cost-sharing associated with significantly reduced medication use was considered a negative relationship. Relationships that were not significant were considered neutral.

In addition, the following decision rule was applied to research articles that examined multiple disease states, outcome measures, therapies, or periods of study. Studies with positive and neutral relationships between the impact of drug coverage level or medication cost-sharing on medication use were classified as positive; studies with negative and neutral relationships were classified as negative; and those with positive and negative relationships were classified as both positive and negative.

Studies that assessed the impact of cost-sharing as well as drug coverage were counted as 2 different studies in the results of this systematic review.

Results A total of 47 research articles met the selection criteria and were included in this systematic review (see Appendix at www.AHDBonline.com/node/868).5-51 Of these studies, 13% (N = 6) were descriptive.46-51 Overall, in the 15-year (1995-2009) time frame, 24 studies examined the impact of level of drug coverage on medication use,5-28 and 19 studies examined the impact of cost-sharing on medication use.8,22,29-45 The majority of these studies were cross-sectional and used the Medicare Current Beneficiary Survey (MCBS, a predesigned survey) or medical and/or pharmacy claims as a data source and were not specific to a particular disease state. Studies that were specific, however, focused on a single disease or on multiple diseases (including cardiovascular conditions, diabetes, arthritis, lung disease, and depression).

The studies by Blustein8 and by Steinman22 were counted twice, because they assessed the level of drug coverage as well as the impact of cost-sharing on medication use.

Of the 24 studies that examined the impact of drug coverage,5-27 96% (N = 23) were positive, indicating that better coverage was associated with increased use of medications (Table 2). Similarly, of the 19 studies that examined the effect of cost-sharing on medication use,

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84% (N = 16) were positive, demonstrating that decreased cost-sharing improved medication use.8,22,29-42

Findings from Descriptive Studies All 6 of the descriptive studies were published before the launch of Medicare Part D.46-51 Their findings are described separately, because those studies did not include hypothesis testing to examine the relationship between formulary control and medication use. They simply described the variation in medication use for different levels of cost-sharing or drug coverage.

The study by Davis and colleagues that used the 1995 MCBS showed that elderly persons with drug coverage averaged 20.3 prescriptions annually, whereas those with no drug coverage averaged 5 (25%) fewer prescriptions annually.46 In addition, patients with dual eligibility for Medicare and Medicaid used about twice as many (102% more) prescriptions, on average, as those in fee-for-service plans with no supplemental insurance (25.6 vs 12.7 prescriptions annually, respectively).46 The US Department of Health and Human Services reported similar findings using 1996 MCBS data,47 and another study examining 2 years of data (1995 and 1996) reported that in 1996, on average, Medicare beneficiaries without drug coverage used 5 (24%) fewer prescriptions than those with drug coverage (16.01 vs 21.14 prescriptions, respectively).48 This finding was supported by a follow-up study using 1998 data that showed even greater differences in medication utilization between Medicare beneficiaries with and without drug coverage.49 Those with drug coverage used almost 8 (46%) more prescriptions annually than those without coverage (24.35 vs 16.65 prescriptions, respectively).49 Another study supporting the relationship between drug coverage and medication use based on the 1996 MCBS data reported that Medicare beneficiaries who were always covered during the year filled 22.4 prescriptions compared with 16.7 prescriptions filled by those with no coverage, a 34% difference; beneficiaries with only partial-year coverage fell in between, filling only 21.8 prescriptions for the year.50 The final descriptive study, which examined 4 years (1996-1999) of MCBS data, revealed little difference between Medicare beneficiaries with and without drug coverage in acquiring prescribed medications.51 Less than 3.5% of beneficiaries in each group (those with and without coverage) reported that they did not acquire a prescribed medicine.51 Selected Study Findings Impact of drug coverage or cost-sharing on medication use. Irrespective of formulary control, the majority

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of the studies included in our analysis supported the hypothesis that more restrictive drug coverage is associated with decreased medication use. From a more granular perspective, studies that empirically examined the relationship between the level of coverage or costsharing and medication use showed that implementing 2 cost-sharing options (ie, full prescription drug coverage vs $1000 maximum annual coverage) increased the overall rates of discontinuation over time.

A study that investigated the use of lipid-lowering agents demonstrated that among elderly patients who were initially prescribed a statin, the 12-month discontinuation rates were 33% for those with full drug benefit coverage and 50% for those with $1000 maximum annual coverage. After 21 months, these rates increased to 60% and 86%, respectively (P = .023).5 In another study, an effective price decrease of 10% for prescription drugs was estimated to increase utilization by 5.4% (P <.05).20 In addition, a separate study showed that the odds of failing to purchase any antihypertensive medications were 40% greater (odds ratio [OR], 1.4; P = .002) for those lacking drug coverage compared with those with drug coverage.8 In the same study, drug coverage significantly increased the number of tablets purchased during the year (from 423 tablets to 460, adjusted for other covariates; P = .02).8 In another study, the risk for delay in filling medications was significantly lower (OR, 0.33; P <.001) among those who had drug coverage compared with those who lacked drug coverage.14 However, in a sample of 310 community-dwelling elderly, those who reported having some drug coverage did not report increased daily use of medications, regardless of their out-of-pocket amount.28 Respondents with Medicaid coverage were 17.24 times more likely (90% confidence interval [CI], 1.24-239) to report using at least 1 medication, and those with a service benefit (2.49; 90% CI, 0.53-11.6) or indemnity coverage (OR, 2.67; 90% CI, 0.58-12.5) were more than twice as likely as those who were uninsured to report using a prescription drug; however, these effects were not significant.28 These neutral findings could have been the result of the small sample size, and warrant additional investigation.

Managed care Medicare beneficiaries who reached their prescription drug capped amount were more likely to engage in behavior to decrease out-of-pocket expenses, including taking fewer medications than prescribed (OR, 2.83; 95% CI, 1.55-5.20) and discontinuing medication use (OR, 3.36; 95% CI, 1.63-6.94).32 A 2004 survey of Medicare+Choice beneficiaries revealed that a higher proportion of patients exceeding their coverage cap reported using fewer prescribed med-

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ications than the controls (18% vs 10%, respectively; P <.001), but similar proportions reported stopping their medications completely (8% for both; P = .86), and those with chronic conditions such as asthma, hyperlipidemia, and hypertension were most responsive to benefit caps.27 These results suggest that formulary controls should perhaps be targeted to avoid affecting the elderly at greatest risk for adverse health outcomes. In addition, 2 studies addressed drug benefit generosity. One study showed that Medicare beneficiaries with the most generous drug coverage (defined as the percentage of annual drug expenditures paid by insurance) were twice as likely (OR, 2.22; 95% CI, 1.80-2.75) to receive cyclooxygenase-2 inhibitors as those with no third-party coverage.33

Evidence suggests that formulary management controls designed to direct patients toward lower-cost therapies or reduce their overall medication use have unintended consequences, often resulting in the underuse or discontinued use of medications.

Another study showed that no drug coverage (no retiree drug benefits or no spending covered by an employer) was associated with lower odds of using essential cardiovascular medications, such as statins (OR, 0.34; 95% CI, 0.21-0.56) for coronary artery disease (CAD) or hyperlipidemia, or angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (OR, 0.35; 95% CI, 0.23-0.55) for congestive heart failure CAD.34 Those with no drug coverage (Medicare fee-for-service only and Medigap without drug coverage) were less likely to receive statins than those with some form of drug coverage (OR, 0.16; 95% CI, 0.05-0.49).11 Although certain drug classes were affected more than others, elderly patients who chose 3-tier drug coverage were more likely overall to experience patterns of medication interruption compared with those who remained on 2-tier coverage. In a study that compared four 3-tier formulary intervention plans with two 2-tier plans, the adjusted probability of nonpersistent drug use among one of the 3-tier intervention plans’ ACE inhibitor users (who switched from a 2-tier formulary) was 18.4% compared with 15.3% (P ≤.01) for the comparison group that stayed with the 2-tier coverage.37 The adjusted probability of discontinuation among ACE inhibitor users in the intervention plan was 4.7% com-

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pared with 3.8% for the comparison group (P = .04).37 Furthermore, beneficiaries with chronic obstructive pulmonary disease who were members of a staff model health maintenance organization with a generic-only benefit (lowest level of coverage) were more likely (OR, 1.70; 95% CI, 1.25-2.31) to report taking less than the prescribed dose and discontinuing regular medications more frequently (OR, 1.77; 95% CI, 1.272.47) than those with 1- or 2-tier coverage.39

Discussion This study intended to summarize published evidence in an effort to inform policies related to medication use, medication access, and drug benefits in Medicare plans.

Based on the available research previously published, this review suggests that more restrictive drug coverage— or formulary strategies that are intended to curb patient demand for drug therapies by increasing the cost borne by the patient or by providing incentives to select lowercost alternatives—in the elderly leads to decreased utilization of drug therapies.

Since 1995, 4 studies reported nonsignificant, neutral relationships. Two of these studies had a relatively low sample size (300-800 patients), and therefore, merit consideration in light of other studies conducted in larger Medicare populations.28,43 One of the benefits of implementing formulary controls is that they can be used as a cost-control mechanism to limit or reduce prescription spending. However, these benefits could be short-term. There is little evidence documenting their long-term impact on healthcare costs and patient quality of care.52,53 Furthermore, even though such strategies help control prescription drug spending, they can have limitations. Evidence suggests that formulary management controls designed to direct patients toward lower-cost therapies or reduce their overall medication use have unintended consequences, often resulting in the underuse or discontinued use of medications.52-55 The evidence is constant in commercial and in privately insured populations as well. In a study of privately insured individuals aged 18 to 64 years, Goldman and colleagues showed that doubling the patient copayment was associated with a significant reduction in the use of anti-ulcer drugs (33% reduction), anti-asthmatic agents (32%), antidepressants (26%), antihypertensives (26%), antihyperlipidemic drugs (34%), antidiabetic drugs (25%), anti-inflammatory drugs (45%), and antihistamines (44%).54 Although price sensitivity is greatest in therapies used to treat the symptoms of disease, there is a fair degree of price elasticity in patient demand for essential therapies that are taken regularly for the treatment of chronic

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and/or serious illnesses.54-56 One study compared employersponsored health plans in which one plan simultaneously switched from a 1-tier to a 3-tier formulary and increased all enrollee copayments for medications. The second employer switched from a 2-tier to a 3-tier formulary, changing only the copayments for tier-3 drugs. Enrollees covered by the employer who implemented more dramatic changes experienced slower growth in the probability of the use of a drug than the comparison group.55 Research shows that reduced medication use can lead to worse health outcomes. Inconsistent use of betablockers after a myocardial infarction has been associated with increased rates of mortality,57,58 suboptimal use of antidepressants has been related to decreased productivity59 and quality of life,60 and intermittent use of inhaled corticosteroids in patients with asthma has been linked to exacerbations requiring visits to the emergency department and hospital admission.61 Although these types of unintended effects are undesirable, they support increased efforts by health policymakers to design formulary controls that aim to improve appropriate use of medications to reduce disease burden and improve the overall health of patient populations.

For this reason, it could be argued that formulary controls should be implemented only after considering the potential unintended consequences, such as discontinuation of needed medications, that could further lead to poor health outcomes and inefficient use of medical resources. Broad population-based controls aimed directly at reducing the total pharmacy budget may therefore be less beneficial than more customized approaches that encourage value-based spending.

As formulary controls are becoming more complex, with 86% of Medicare Part D plans utilizing 4- or 5-tier structures,62 consideration of the unintended consequences of restricted coverage in this population will continue to be important. Since the inception of Part D, elderly beneficiaries have faced less restrictive coverage with more drug options on formulary; however, there is evidence that beneficiaries are not reevaluating available coverage options to best meet their needs.13 In addition, drug prices are often not transparent to patients, who can in some cases pay the full price of brand-name medications under reference-based pricing schedules.63 Furthermore, although subsidies are provided to help low-income elderly patients pay for their drug coverage, the most optimal plan is not always selected, because the set of alternatives is difficult to navigate.64 To compound matters, coverage completion and beneficiary selection of a “best plan” is compromised by the highly variable mix of drug therapies needed by patients over time.65 A recent survey conducted by the AARP showed that nearly 17% of all elderly respondents

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believed they would be unable to afford their medications in the coming year.66 Finally, the recent rise in pharmaceutical drug spending67 and health reform efforts to support the implementation of more comparative effectiveness studies will ensure that increased attention will be paid to the contribution of high-cost drug therapies to healthcare budgets. Payers, in turn, will face greater pressure to implement management strategies that reduce drug costs and drug demand while still providing access to valuable treatments.

Since the inception of Part D, elderly beneficiaries have faced less restrictive coverage with more drug options on formulary; however, there is evidence that beneficiaries are not reevaluating available coverage options to best meet their needs.

The results of this study may therefore inform payer and other stakeholder decisions that affect treatment access in the elderly through the promotion of customized, value-based approaches to curbing drug and overall medical spending.

Limitations This study has several limitations. First, the selection criteria might have excluded some studies with useful results. For example, studies that defined older patients as those aged ≥50 years were excluded, because not all patients in these studies were Medicare enrollees. In addition, Canadian studies conducted in a population aged ≥65 years were excluded, because this review was focused on the US Medicare population.

Second, the internal validity of included studies might have been affected by study design or other components of the methodology, such as the lack of standardized measures to assess patterns of medication use or the use of patient-reported measures of medication use.

Very few studies used widely accepted and validated measures, such as the Medication Possession Ratio and Proportion of Days Covered measure, that use patients’ pharmacy claims, partly because these data were unavailable to the researchers.

This literature review evaluated studies that were conducted after, as well as before, the implementation of Medicare Part D. The reason for evaluating these studies together was that there were few published studies conducted after the implementation of Part D. To gain future insights, other researchers should investigate studies conducted only after the implementation of Part D.

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Finally, the measurement of long-term outcomes is inadequate, because of the lack of large databases with clinical and/or economic information for elderly patients.68 The number of total studies included was low despite the minimally restrictive selection criteria. This low number could be the result of limited access to appropriate data sources, creating a need for greater efforts to be made to release this information to organizations and individuals conducting health services research.

Conclusion As additional studies become available, results should continue to be synthesized for policy recommendations.

CMS has issued a final ruling that permits the use of claims data collected from Medicare Part D beneficiaries for research by external researchers, including other federal agencies such as the US Food and Drug Administration and the Agency for Healthcare Research and Quality, as well as reputable academic centers and thinktank organizations.69 The release of these data may allow the study of the benefits and risks of different formulary controls, which would, in turn, inform benefit design restrictions and the differential impact of certain management strategies on patient subgroups, such as those with specific chronic conditions.70 With such increased research and an active political environment determined to maximize value in the US healthcare system, the results presented here suggest that medication use among the elderly, along with clinical outcomes and economic efficiency, can potentially be improved through carefully crafted policies and drug coverage decisions that account for unintended consequences. ■ Acknowledgment GlaxoSmithKline provided funding for this study; it had no influence over the content.

Author Disclosure Statement Dr Shenolikar and Dr Cantrell are employees of and own shares of GlaxoSmithKline. Dr Schofield Bruno and Dr Eaddy are Consultants for GlaxoSmithKline.

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32. Cox ER, Jernigan C, Coons SJ, Draugalis JL. Medicare beneficiaries’ management of capped prescription benefits. Med Care. 2001;39:296-301.

33. Doshi JA, Brandt N, Stuart B. The impact of drug coverage on COX-2 inhibitor use in Medicare. Health Aff (Millwood). 2004;Suppl Web Exclusives:W4-94–W4-105.

34. Doshi JA, Polsky D. Drug benefit generosity and essential medication use among Medicare-eligible retirees. Am J Manag Care. 2007;13:425-431.

35. Gilman BH, Kautter J. Consumer response to dual incentives under multitiered prescription drug formularies. Am J Manag Care. 2007;13:353-359.

36. Gilman BH, Kautter J. Impact of multitiered copayments on the use and cost of prescription drugs among Medicare beneficiaries. Health Serv Res. 2008;43:478-495.

37. Huskamp HA, Deverka PA, Landrum MB, et al. The effect of three-tier formulary adoption on medication continuation and spending among elderly retirees.

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Health Serv Res. 2007;42:1926-1942.

38. Rector TS, Venus PJ. Do drug benefits help Medicare beneficiaries afford prescribed drugs? Health Aff (Millwood). 2004;23:213-222.

39. Spence MM, Hui R, Chan J. Cost reduction strategies used by elderly patients with chronic obstructive pulmonary disease to cope with a generic-only pharmacy benefit. J Manag Care Pharm. 2006;12:377-382.

40. Stuart B, Zacker C. Who bears the burden of Medicaid drug copayment policies?

Health Aff (Millwood). 1999;18:201-212.

41. Thomas CP, Wallack SS, Lee S, Ritter GA. Impact of health plan design and management on retirees’ prescription drug use and spending. Health Aff (Millwood).

2001;Suppl Web Exclusives:W4-408–W4-419.

42. Wilson IB, Rogers WH, Chang H, Safran DG. Cost-related skipping of medications and other treatments among Medicare beneficiaries between 1998 and 2000.

Results of a national study. J Gen Intern Med. 2005;20:715-720.

43. Cox ER, Henderson R. Prescription use behavior among medicare beneficiaries with capped prescription benefits. J Manag Care Pharm. 2002;8:360-364.

44. Johnson RE, Goodman MJ, Hornbrook MC, Eldredge MB. The effect of increased prescription drug cost-sharing on medical care utilization and expenses of elderly health maintenance organization members. Med Care. 1997;35:1119-1131.

45. Johnson RE, Goodman MJ, Hornbrook MC, Eldredge MB. The impact of increasing patient prescription drug cost-sharing on therapeutic classes of drugs received and on the health status of elderly HMO members. Health Serv Res. 1997; 32:103-121.

46. Davis M, Poisal J, Chulis G, et al. Prescription drug coverage, utilization, and spending among Medicare beneficiaries. Health Aff (Millwood). 1999;18:231-243.

47. US Department of Health & Human Services. Report to the president: prescription drug coverage, spending, utilization, and prices. April 2000. http://aspe.hhs. gov/health/reports/drugstudy/index.htm. Accessed July 28, 2011.

48. Poisal JA, Chulis GS. Medicare beneficiaries and drug coverage. Health Aff (Millwood). 2000;19:248-256.

49. Poisal JA, Murray L. Growing differences between Medicare beneficiaries with and without drug coverage. Health Aff (Millwood). 2001;20:74-85.

50. Stuart B, Shea D, Briesacher B. Prescription drug costs for Medicare beneficiaries: coverage and health status matter. The Commonwealth Fund Issue Brief. January 2000. www.commonwealthfund.org/~/media/Files/Publications/Issue%20Brief/2000/ Jan/Prescription%20Drug%20Costs%20for%20Medicare%20Beneficiaries%20%20 Coverage%20and%20Health%20Status%20Matter/Stuart_prescriptiondrug%20pdf. pdf. Accessed July 28, 2011.

51. Craig BM, Kreling DH, Mott DA. Do seniors get the medicines prescribed for them? Evidence from the 1996-1999 Medicare Current Beneficiary Survey. Health Aff (Millwood). 2003;22:175-182.

52. Motheral BR, Henderson R, Cox ER. Plan-sponsor savings and member experience with point-of-service prescription step therapy. Am J Manag Care. 2004;10: 457-464.

53. Ovsag K, Hydery S, Mousa S. Preferred drug lists: potential impact on healthcare

economics. Vasc Health Risk Manag. 2008;4:403-413.

54. Goldman D, Joyce G, Escarce J, et al. Pharmacy benefits and the use of drugs by the chronically ill. JAMA. 2004;291:2344-2350.

55. Huskamp H, Deverka P, Epstein A, et al. The effect of incentive-based formularies on prescription-drug utilization and spending. N Engl J Med. 2003;349:2224-2232.

56. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med. 2005;353: 487-497.

57. Ho PM, Spertus JA, Masoudi FA, et al. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med. 2006;166:1842-1847.

58. Rasmussen JN, Chong A, Alter DA. Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA. 2007;297:177-186.

59. Mintz J, Mintz LI, Arruda MJ, Hwang SS. Treatments of depression and the functional-capacity to work. Arch Gen Psych. 1992;49:761-768.

60. Heiligenstein JH, Ware JE, Beusterien KM, et al. Acute effects of fluoxetine versus placebo on functional health and well-being in late-life depression. Int Psychogeriatr. 1995;7(suppl):125-137.

61. Williams SG, Schmidt DK, Redd, SC, Storms W, for the National Asthma Education and Prevention Program. Key clinical activities for quality asthma care.

MMWR Recomm Rep. 2003;52(RR-6):1-8.

62. Avalere Health. Avalere Health data finds four-tier system growing among Medicare Part D plans. www.avalerehealth.net/wm/show.php?c=&id=777. Accessed July 28, 2011.

63. Zhang J, Fuhrmans V. Medicare plans draw criticism on drug pricing. The Wall Street Journal. December 16, 2008. http://online.wsj.com/article/SB1229389514 83309103.html#. Accessed July 28, 2011.

64. Flaer PJ, Dondériz A, Younis MZ. Medicare Part D—the sea of choices meets the donut hole. J Health Care Finance. 2007;34:1-7.

65. Domino ME, Stearns SC, Norton EC, Yeh WS. Why using current medications to select a medicare Part D plan may lead to higher out of pocket payments. Med Care Res Rev. 2008;65:114-126.

66. Keenan T. Prescription for the future: medications, Medicare Part D, and managing expenses in a difficult economy—research report. AARP Knowledge Management. December 2008. http://assets.aarp.org/rgcenter/health/rx_future_08.pdf.

Accessed July 28, 2011.

67. Catlin A, Cowan C, Hartman M, et al. National health spending in 2006: a year of change for prescription drugs. Health Aff (Millwood). 2008;27:14-29.

68. Choudhry NK, Brennan T, Toscano M, et al. Rationale and design of the PostMI FREEE trial: a randomized evaluation of first-dollar drug coverage for postmyocardial infarction secondary preventive therapies. Am Heart J. 2008;156:31-36.

69. Centers for Medicare & Medicaid Services (CMS). Medicare program; Medicare Part D claims data [CMS 4119-F]. www.cms.hhs.gov/PrescriptionDrugCovGenIn/ Downloads/PartDDataReg.pdf. Accessed November 5, 2008.

70. Balfour DC 3rd, Evans S, Januska J, et al. Medicare part D—a roundtable discussion of current issues and trends. J Manag Care Pharm. 2009;15:S3-S9.

STAKEHOLDER PERSPECTIVE We Need More Research on True Value-Based Benefit Design that Will Improve Outcomes and Control Costs MEDICAL/PHARMACY DIRECTORS: Managing the Medicare drug benefit is one of the most challenging aspects of a Pharmacy and Therapeutics (P&T) committee’s duties. One of the major charges of a P&T committee is to provide plan members a wide range of drugs for a broad number of clinical indications. This must be done in the context of the overall pharmacy benefit cost. Keeping the benefit plan affordable, while providing adequate coverage for a broad range of medications, is not an easy task. To do this, we

must balance not only the cost of the drugs but also the expected utilization, and one of the drivers of that utilization is plan member cost-sharing.

Dr Shenolikar and his colleagues have performed a systematic review of the literature for their study. They analyzed the 47 articles that evaluated the impact of drug coverage or cost-sharing on medication use in the Medicare population in the past 15 years (1995-2009).

Their conclusion is not surprising to those involved in benefit design: “Current evidence from the literature Continued

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STAKEHOLDER PERSPECTIVE (Continued) suggests that restricting drug coverage or increasing out-of-pocket expenses for Medicare beneficiaries may lead to decreased medication use in the elderly, with all its potential implications.”

This is an issue that regularly comes up in benefit design discussions, and the P&T committee members are aware that increasing plan member cost may lead to a reduction in the use of essential medications, as well as medications that may not be essential or may even be inappropriate. It is the latter—nonessential and inappropriate medication use—that formularies and benefit designs are intended to address.

We all share the authors’ goal to create benefit designs and formularies that provide access to needed medications, while avoiding the cost associated with inappropriate or more costly medications that have clinically appropriate, lower-cost alternatives.

However, there is no easy solution to this cost versus benefit problem. Although it is tempting to lower member cost-sharing to improve the uptake and use of essential medications, experience tells us that when that is done, the utilization of essential as well as nonessential medications increases. That becomes important, because the result of increased utilization is increased cost to the plan.

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We also know that as plan costs increase, the affordability of the plan drops, and some plan members are forced to drop drug coverage or choose less costly alternative plans that are even more restrictive.

This may ultimately create the unintended consequence of more individuals having no, or only minimal, coverage because of their inability to afford the plan costs.

POLICYMAKERS/RESEARCHERS: I therefore agree with the authors’ conclusion that more research is needed to better understand the best ways to create affordable drug coverage plans. Such research must address how to motivate Medicare beneficiaries and their prescribers to make clinically and cost-effective medication choices, how to create benefit designs that facilitate these choices, and how benefit design and member cost-sharing impact clinical outcomes.

Our work is just starting in this area, and if we are to develop true value-based benefit designs that simultaneously improve outcomes and control cost, we will need much more research to help drive those decisions.

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Gary M. Owens, MD President, Gary Owens Associates Philadelphia, PA

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REGISTER TODAY & SAVE $100

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April 20-22, 2012 • Le Westin Montreal Montreal, QC, Canada CO-CHAIRS

PROGRAM OVERVIEW The goals of this interactive, CME/CE-certified meeting are to update participants on advances in the field of cutaneous malignancies, including biology, pathology, staging, personalized therapy, novel agents, and ongoing research. In addition to didactic lectures, this program will also include debates and discussions of controversial topics, extensive panel discussions with case scenarios, multidisciplinary tumor boards, question-and-answer sessions, poster sessions, as well as workshops focusing on future strategies for the treatment of cutaneous T-cell lymphoma (CTCL), basal cell carcinoma (BCC), and melanoma. This is the inaugural meeting of what is envisioned as an annual global forum to facilitate integration of contemporary and evolving standards of care for the optimal management of patients with cutaneous malignancies into clinical practice for oncologists and dermatologists.

Kim A. Margolin, MD

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as it relates to treatment of CTCL, BCC, or malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

Professor, Department of Medical Oncology University of Washington School of Medicine Seattle Cancer Care Alliance Seattle, Washington

TARGET AUDIENCE This global educational program is directed toward medical and surgical oncologists, dermatologists, and radiation oncologists involved in the treatment of patients with cutaneous malignancies. Fellows, nurse practitioners, nurses, physician assistants, pharmacists, researchers, and other healthcare professionals interested in the treatment of cutaneous malignancies are also invited to attend.

ACCREDITATION INFORMATION SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians.

CORE PRINCIPLE SOLUTIONS, LLC

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12.5 AMA PRA Category 1 Credits™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.

REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.5 contact hours.

REGISTERED PHARMACY DESIGNATION Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.5 contact hours (0.125 CEUs) of continuing education credit.

The universal activity number for this activity is 0468-9999-089-L01-P.

Teresa Petrella, BSc, MD, MSc, FRCPC Medical Oncologist Chair, National Cancer Institute of Canada Melanoma Group Chair, Melanoma Site Group Odette Cancer Centre Assistant Professor, University of Toronto Toronto, Ontario, Canada

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Celgene is now joining the battle against metastatic breast cancer

ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

If you need help accessing ABRAXANE for your patients, please call Celgene Patient Support ® at 800-931-8691 or visit www.abraxane.com.

Please see Important Safety Information on adjacent page.

Please see brief summary of full Prescribing Information on the following pages.

ABRAXANE® is a registered trademark of Celgene Corporation. ©2011 Celgene Corporation

03/11

ABR11012

ABRAXANEÂŽ for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

IMPORTANT SAFETY INFORMATION WARNING ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drugâ&#x20AC;&#x2122;s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. ADDITIONAL WARNINGS s The use of ABRAXANE has not been studied in patients with renal dysfunction.

In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL Pregnancy-Teratogenic Effects: Pregnancy Category D s ABRAXANE can cause fetal harm when administered to a pregnant woman s If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus s Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE Use in Males: s Men should be advised to not father a child while receiving treatment with ABRAXANE Albumin (human): s ABRAXANE contains albumin (human), a derivative of human blood PRECAUTIONS Drug Interactions: s No drug interaction studies have been conducted with ABRAXANE s Caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit or induce either CYP2C8 or CYP3A4 Hematology: s ABRAXANE therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3 s It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE s Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to >100,000 cells/mm3 s In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended Nervous System: s Sensory neuropathy occurs frequently with ABRAXANE s The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification s If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE Hepatic Impairment: s Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution

s The starting dose should be reduced for patients with moderate and severe hepatic impairment Injection Site Reaction: s Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial s Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration Nursing Mothers: s It is not known whether paclitaxel is excreted in human milk s Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE therapy Ability to Drive and Use Machines: s Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines ADVERSE EVENTS s Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial s These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension s Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely s During postmarketing surveillance, rare reports of congestive heart failure and left ventricular dysfunction were observed, primarily among individuals with underlying cardiac history or prior exposure to cardiotoxic drugs In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), nausea (any 30%; severe 3%), diarrhea (any 27%; severe <1%), infections (24%), vomiting (any 18%; severe 4%), and mucositis (any 7%; severe <1%).

Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), renal dysfunction (any 11%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), thrombocytopenia (any 2%; severe <1%), and injection site reactions (<1%). In clinical trials and during postmarketing surveillance, dehydration was common and pyrexia was very common. Rare occurrences of severe hypersensitivity reactions have also been reported during postmarketing surveillance.

Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

Rx Only

(paclitaxel protein-bound particles for injectable suspension) (albumin-bound) Brief Summary of Full Prescribing Information.

WARNING ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available.

ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. INDICATION: ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

CONTRAINDICATIONS: ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3.

WARNINGS: Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be administered to patients with baseline neutrophil counts of < 1,500 cells/mm3. Frequent monitoring of blood counts should be instituted during ABRAXANE treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3.

The use of ABRAXANE has not been studied in patients with renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Pregnancy – Teratogenic Effects: Pregnancy Category D: ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats on gestation days 7 to 17 at doses of 6 mg/m2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis).

There are no adequate and well-controlled studies in pregnant women using ABRAXANE®. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Use in Males Men should be advised to not father a child while receiving treatment with ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability).

Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

PRECAUTIONS: Drug Interactions No drug interaction studies have been conducted with ABRAXANE. The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4 (see CLINICAL PHARMACOLOGY).

Hematology ABRAXANE® therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE AND ADMINISTRATION).

Nervous System Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE AND ADMINISTRATION).

Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate and severe hepatic impairment. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION, Hepatic Impairment) Injection Site Reaction Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of ABRAXANE has not been studied.

Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay.

Administration of paclitaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately

1 to 5% of the daily maximum recommended human exposure on a mg/m2 basis). Testicular atrophy/ degeneration has also been observed in single-dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2 and dogs administered 175 mg/m2 (see WARNINGS).

Pregnancy: Teratogenic Effects: Pregnancy Category D: (See WARNINGS section).

Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE® therapy.

Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated.

Geriatric Use Of the 229 patients in the randomized study who received ABRAXANE, 11% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients who received ABRAXANE. Ability to Drive and Use Machines Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines.

ADVERSE REACTIONS: The following table shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE® or paclitaxel injection for the treatment of metastatic breast cancer.

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE® Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L 80 82 9 22 < 0.5 x 109/L Thrombocytopenia < 100 x 109/L 2 3 < 50 x 109/L <1 <1 Anemia < 11 g/dL 33 25 < 8 g/dL 1 <1 Infections 24 20 Febrile Neutropenia 2 1 Bleeding 2 2 Hypersensitivity Reactione 4 12 All Severef 0 2 Cardiovascular Vital Sign Changesg Bradycardia <1 <1 5 5 Hypotension 4 Severe Cardiovascular Eventsf 3 Abnormal ECG All patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsf 10 2 Myalgia / Arthralgia Any Symptoms 44 49 Severe Symptomsf 8 4 Asthenia Any Symptoms 47 39 Severe Symptomsf 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsf 0 <1 Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsf 3 <1 Vomiting Any symptoms 18 10 Severe Symptomsf 4 1 Diarrhea Any Symptoms 27 15 Severe Symptomsf <1 1 Mucositis Any Symptoms 7 6 Severe Symptomsf <1 0 Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 (continued)

Table 3: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule, Continued Percent of Patients ABRAXANE® Paclitaxel Injection b 260/30min 175/3hc,d (n=229) (n=225) Hepatic (Patients with Normal Baseline) AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade. b ABRAXANE dose in mg/m2/duration in minutes. c paclitaxel injection dose in mg/m2/duration in hours. d paclitaxel injection pts received premedication. e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. f Severe events are defined as at least grade 3 toxicity. g During study drug dosing.

Myelosuppression and sensory neuropathy were dose related.

Adverse Event Experiences by Body System Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metastatic breast cancer treated with single-agent ABRAXANE® in the randomized controlled trial. The frequency and severity of important adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hematologic Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2.

In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm.

Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm.

Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia.

Rare reports of pancytopenia have been observed in clinical trials and during postmarketing surveillance of ABRAXANE. Hypersensitivity Reactions (HSRs) In the randomized controlled metastatic breast cancer study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE® in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied.

During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug.

Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients in the randomized metastatic breast cancer trial. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation.

Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension.

Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely.

Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study.

The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia.

During postmarketing surveillance, rare reports of congestive heart failure and left ventricular dysfunction have been observed among individuals receiving ABRAXANE. Most of the individuals were previously exposed to cardiotoxic drugs, such as anthracyclines, or had underlying cardiac history.

Respiratory Reports of dyspnea (12%) and cough (6%) were reported after treatment with ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy.

Neurologic The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents.

In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE®. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm.

The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy.

No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial.

Cranial nerve palsies and vocal cord paresis have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.

Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety.

Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single arm study who received higher doses than those recommended (300 or 375 mg/m2).

These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage.

Arthralgia/Myalgia Forty-four percent of patients treated in the randomized trial experienced arthralgia/ myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE® administration, and resolved within a few days.

Hepatic Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%,

36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities.

Gastrointestinal (GI) Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%, and 7% of ABRAXANE treated patients in the randomized trial.

Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents.

Injection Site Reaction Injection site reactions have occurred infrequently with ABRAXANE and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported rarely.

Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days.

Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration.

Asthenia Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE® in the randomized trial.

Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise.

Other Clinical Events Rare cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no patients had severe edema. In clinical trials and during postmarketing surveillance of ABRAXANE, dehydration was common and pyrexia was very common.

The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established.

Accidental Exposure No reports of accidental exposure to ABRAXANE® have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness.

OVERDOSAGE: There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis.

DOSAGE AND ADMINISTRATION: After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks.

Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel.

Patients should not receive ABRAXANE if AST > 10 x ULN or bilirubin > 5.0 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 4. The dose of ABRAXANE can be increased up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. Patients should be monitored closely. (See CLINICAL PHARMACOLOGY: Hepatic Impairment and PRECAUTIONS: Hepatic Impairment) Table 4: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Levels Bilirubin Levels ABRAXANE a Mild <10 x ULN >ULN to ≤ 1.25 x ULN 260 mg/m2 Moderate <10 x ULN AND 1.26 to 2.0 x ULN 200 mg/m2 Severe <10 x ULN 2.01 to 5.0 x ULN 130 mg/m2 b > 10 x ULN OR > 5.0 x ULN not eligible a Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. b A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance.

Dose Reduction Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE. HOW SUPPLIED: Product No. 103450 NDC No. 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton.

Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light.

Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

This Brief Summary is based on the ABRAXANE Full Prescribing Information Revised: March 2010

ABRAXANE and Abraxis are registered trademarks of Abraxis BioScience, LLC. ©2010 Abraxis BioScience, LLC. All Rights Reserved.

U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006

2011 PEER REVIEWERS

THANK YOU AHDB PEER REVIEWERS The Editors and Publisher of American Health & Drug Benefits wish to extend a heartfelt thank you to all the people who participated in the Journalâ&#x20AC;&#x2122;s peer-review process during 2011. Your diligence and expert comments help to ensure the continued high quality of articles published in the Journal. We are grateful for all the time and effort you so generously dedicate to the review process by applying your expertise and knowledge in the spirit of true collaboration that typifies the editorial mission of this Journal. We look forward to continued collaboration with all of you in the coming year.

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Bryan Amick, PharmD

Ronald A. Lyons, MS

Carl Asche, PhD, MBA

Ross M. Miller, MD, MPH, FACPE

Joel V. Brill, MD

Matthew Mitchell, PharmD, MBA

William C. Cardarelli, PharmD

Michael F. Murphy, MD, PhD

Eugene (Chip) Prichard Chambers, Jr, MD

Mark A. Newsom, MSc

Charles E. Collins Jr, MS, MBA

Gary M. Owens, MD

James V. Felicetta, MD

Paul Anthony Polansky, BSPharm, MBA

Jack Fincham, PhD, RPh

Michael F. Pollack, MS

Leslie S. Fish, PharmD

Richard F. Radzin, PharmD, RPh

Walid G. Gellad, MD, MPH

Donald Reese, PharmD, MBA, MSIS

Jeff Jianfei Guo, BPharm, MS, PhD

Timothy S. Regan, BPharm, RPh

Michael S. Jacobs, RPh

Jack Warren Salmon, PhD

Jeff Januska, PharmD

Nirav R. Shah, MD, MPH

J.B. Jones, PhD, MBA

Rahul Shenolikar, PhD

Atheer Kaddis, MD

Arthur F. Shinn, PharmD

James T. Kenney, RPh, MBA

Scott Taylor, RPh, MBA

Steven T. Kmucha, MD, JD, FACS

Albert Tzeel, MD, MHSA, FACPE

Wayne M. Lednar, MD, PhD

F. Randy Vogenberg, RPh, PhD

Joshua N. Liberman, PhD

Yu-Ning Wong, MD, MSCE

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INDUSTRY TRENDS

Drug Shortages the “New” Old Problem: People Are (Finally) Talking

By Caroline Helwick, Medical Writer

O

n October 31, 2011, President Obama directed US regulators to take actions that would help ameliorate the ever-critical shortage of drugs.1 Drug shortages exist in several therapeutic areas—most prominently in oncology—and the problem does not appear to be abating on its own. Most shortages involve cancer and leukemia drugs, anti-infectives, anesthetics, emergency medicine drugs, antihypertensives, and electrolytes. The problem has become an increasing concern for all healthcare stakeholders—patients, physicians, pharmacists, payers, and manufacturers.

The number of drugs involved in shortages has nearly tripled in recent years, from 61 in 2005 to 178 in 2010, according to the US Food and Drug Administration (FDA).2 The American Society of Health-System Pharmacists (ASHP) tracked 232 drug shortages throughout 2011 by its drug shortages center, which tracks these developments and provides alternative treatment options.3 In November 2011, IMS Health released its analysis of the current state of drug shortages, based on the list tracked by the FDA and the ASHP as of October 7, 2011.4 More than half of hospitals and medical centers report that drug shortages compromise patient care, as reflected in a recent survey from the ASHP.5 About 97% of the survey respondents said the shortages also drove up costs through purchases from resellers, known as the “gray market.” The national labor cost of pharmacists having to deal with shortages was estimated to be $216 million.5 In addition, a study released in July 2011 by the ASHP shows that “increasing drug shortages are impacting patient care and increasing costs to the nation’s health system.”6 Addressing a group of industry stakeholders on September 26, 2011, during a public workshop on drug shortages convened by the Center for Drug Evaluation and Research (CDER), Douglas Throckmorton, deputy director of FDA’s CDER, said, “Despite the efforts of all the partners in the room, and particularly the FDA, our drug shortages are getting worse and not better.”7 But drug shortages wax and wane with market forces, according to Margaret Hamburg, MD, Commissioner of the FDA, who put the October 31, 2011, count at 84. In its recent directive, the administration encouraged man-

ufacturers to give early notice to the FDA of impending shortages, which should aid in locating alternate sources, increasing production, or bringing new manufacturing plants online.1 The administration is also pushing for legislation to mandate the reporting of drug shortages and is asking the FDA to work with the Justice Department to “examine whether potential shortages have led to illegal price gouging or stockpiling of life-saving medications.”1

In Oncology, Disincentives May Compound the Problem The FDA indicates that sterile injectables account for 80% of the shortages, and most of these products have one manufacturer that produces at least 90% of the drug.

Almost 30% of sterile injectables are cancer drugs.2 In its recent report, IMS Health indicates that 28 cancer drugs are among the 168 drug shortages listed by the FDA and the ASHP; of these, 22 are chemotherapies.4 Discussing the impact of the shortages in oncology, Patrick Cobb, MD, immediate past president of the Community Oncology Alliance (COA) and chairman of COA’s Policy Committee, noted that a series of events, starting with the Medicare Modernization Act of 2003, has altered the oncology environment, creating “unintended consequences” by revisions in public policy, and one of these is a shortage of oncolytics.8 Generic manufacturers, Dr Cobb suggests, feel pricing pressure from the implementation of the ASP (average sales price) system, which dictates that manufacturers compete on actual sales price, not on the margins that were established under the old AWP (average wholesale price) system. Additional pricing pressure has come from an increase in practices that qualify for lower 340B pricing, according to Dr Cobb.8 The result is that many cancer injectable generics are now priced extremely low, which is good for patients and payers, but reduces a manufacturer’s incentive to stay in the market. This situation encourages secondary middlemen (the gray market) to obtain drugs in short supply and resell them at inflated prices.8 The IMS report echoes this analysis, indicating that 83% of the drug shortages are indeed for generics (and most of those are injectables).4 Continued

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Anesthesiology Hard Hit: 2011 ASA Annual Meeting At the 2011 American Society of Anesthesiologists (ASA) annual meeting in October, Arnold J. Berry, MD, MPH, ASA Vice President for Scientific Affairs, said that anesthesiologists are very concerned about the drug shortages, because anesthetic agents are among the main drugs affected. “The bottom line is that without having the drugs we need, it’s hard to safely take care of our patients.”

In its drug shortage survey of 1373 ASA members conducted in April 2011, 90% of respondents reported a shortage of at least 1 drug, and 98% had experienced a shortage during the previous 12 months.9 Gray market resellers obtain the drugs from pharmacies or other resellers and offer them to facilities in need of the drugs. Although this practice may be helpful, it is clearly not economical. A 2011 survey by the Institute for Safe Medication Practices showed that 56% of 549 hospital purchasing agents and pharmacists reported receiving daily solicitations from vendors, and 52% reported buying drugs from gray market suppliers.10 Survey respondents reported markups as much as 1500% for the anesthetic propofol.10 According to Dr Berry, part of the problem is the FDA’s limited ability to control drug shortages. The agency cannot dictate production quantity and must rely on voluntary participation of the industry. Furthermore, the agency at this point is primarily interested in shortages of drugs considered “medically necessary.”

However, in 2010 the FDA prevented 38 shortages, and in 2011 it has already prevented 99, by receiving early notification from the industry of an impending shortage, according to Dr Berry. When notified of a problem, the FDA can encourage other firms to ramp up production, expedite helpful regulatory processes, and allow temporary importation of substitute drugs, as it did, for example, with propofol.

The Industry Perspective Presenting the industry’s perspective at the 2011 ASA annual meeting, Thomas G. Moore, PharmD, President of Hospira USA, said, “This is a multistakeholder issue, and addressing the broader concerns of drug shortages requires a collective effort. Many drug shortages can be prevented, but we need early dialogue.”

Dr Moore acknowledged at the meeting that the pharmaceutical industry “is acutely aware of the distress caused to patients, families, and clinicians by the shortage of medically necessary drugs,” but he said that there are “common misconceptions” that should be corrected.

According to Dr Moore, most drug shortages are not

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caused by a manufacturer’s decision to voluntarily discontinue supplying the product, or to withhold drugs to push prices up.

Rather, the key problem is “regulatory compliance and product quality issues,” which Dr Moore says is the cause for half of all drug shortages. Furthermore, the majority of these cases do not involve any “quality problem per se with a drug”; rather, there is a compliance issue with manufacturing guidelines or an issue that demands regulatory action.

Furthermore, Dr Moore said, “We want to meet the FDA guidelines of good manufacturing practices, but actions taken are a significant cause of drug shortages we see today.” The overall solution, he proposed, “transcends the pharmaceutical industry” and requires the involvement of the following stakeholders: • Active pharmaceutical ingredient suppliers • Component suppliers • Wholesalers and distributors • Group purchasing organizations • Healthcare providers • Regulatory authorities (eg, FDA, Drug Enforcement Administration).

“It’s a complex problem that requires a lot of collaboration and communication. I think we’re finally starting to see some of that occur between the various stakeholders,” Dr Moore observed. ■

References 1. The White House Office of the Press Secretary. We can’t wait: Obama administration takes action to reduce prescription drug shortages, fight price gouging. October 31, 2011. www.whitehouse.gov/the-press-office/2011/10/31/we-can-t-wait-obamaadministration-takes-action-reduce-prescription-drug. Accessed October 31, 2011.

2. US Food and Drug Administration. A review of FDA’s approach to medical product shortages. www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm277744.htm.

Updated November 3, 2011. Accessed November 21, 2011.

3. American Society of Health-System Pharmacists. Drug shortages: current drugs. www.ashp.org/DrugShortages/Current. Accessed November 21, 2011.

4. IMS Institute for Healthcare Informatics. Drug shortages: a closer look at products, suppliers and volume volatility. November 2011. www.imshealth.com/portal/site/ ims/menuitem.edb2b81823f67dab41d84b903208c22a/?vgnextoid=a6fbcc0f68f73310 VgnVCM100000ed152ca2RCRD&vgnextfmt=default. Accessed November 21, 2011.

5. Traynor K. Drug shortage solutions elude stakeholders. Am Soc HealthSyst Pharmacists News. November 15, 2011. www.ashp.org/menu/News/PharmacyNews/ NewsArticle.aspx?id=3626. Accessed November 21, 2011.

6. American Society of Health-System Pharmacists. Drug shortages harm patients, increasing costs to hospitals. July 11, 2011. www.ashp.org/menu/AboutUs/ForPress/ PressReleases/PressRelease.aspx?id=646. Accessed November 27, 2011.

7. Center for Drug Evaluation and Research. Drug shortage workshop. September 26, 2011. www.fda.gov/downloads/Drugs/NewsEvents/UCM275801.pdf. Accessed November 21, 2011.

8. Cobb P, Okon T. What is causing drug shortages? OncologySTAT. October 20, 2011. www.oncologystat.com/viewpoints/cancer-policy-forum/What_is_Causing_ Drug_Shortages.html. Accessed November 21, 2011.

9. American Society of Anesthesiologists. Survey reveals 90 percent of anesthesiologists experience shortages of anesthetics. May 9, 2011. www.asahq.org/For-the-Publicand-Media/Press-Room/ASA-News/Survey-Reveals-90-Percent-of-AnesthesiologistsExperiencing-Drug-Shortages-of-Anesthetics.aspx. Accessed November 14, 2011.

10. Institute for Safe Medication Practices. ISMP survey on drug shortage “gray market” shows widespread impact on hospitals. August 25, 2011. http://ismp.org/pressroom/ PR20110825.pdf. Accessed November 21, 2011.

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New t 55-Year YYear di n Follow-u FFollow-up ll upp wD Data: Median 5-Y eear M Media N

In combination with MP* vs MP alone for previously untreated multiple myeloma

VELCADE DELIVERED 13-MONTH OVERALL SURVIVAL ADVANTAGE At 3-Year Median Follow-up, VELCADE® (bortezomib)+MP Provided an OS Advantage Over MP That Was Not Regained With Subsequent Therapies ▼ Of the 69% of MP patients who received subsequent therapies, 50% received VELCADE or a VELCADE-containing regimen1

VELCADE is indicated for the treatment of patients with multiple myeloma.

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

For Patient Assistance Information or Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE.com *Melphalan+prednisone. †

VISTA: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and OS. At a pre-specified interim analysis (median follow-up 16.3 months), VcMP‡ resulted in significantly superior results for TTP, PFS, OS, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition.

‡

VELCADE (Vc) in combination with MP.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28(13):2259-2266.

UPDATED VISTA† TRIAL ANALYSIS (60.1-MONTH MEDIAN FOLLOW-UP) 100 90

Median overall survival: survival:

80

556.4 6 .4 vs 443.1 3..1 m months onths

Patients Patients Surviving Surviving (%)

HR=0.695 (95% CI, 0.57-0.85); P<0.05 P<0.05 < 70 60 50 40 30 20

VELC VELCADE+MP ADE+MP (n=344)

10

MP ((n=338) n=338)

0 0

12

24

36

Kaplan-Meier estimate.

48

60

72

Months

IMPORTANT SAFETY INFORMATION VELCADE Warnings and Precautions

Adverse Reactions

▼ Women should avoid becoming pregnant while being treated with VELCADE. Pregnant women should be apprised of the potential harm to the fetus ▼ Peripheral neuropathy, including severe cases, may occur— manage with dose modification or discontinuation. Patients with pre-existing severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment ▼ Hypotension can occur. Caution should be used when treating patients receiving antihypertensives, those with a history of syncope, and those who are dehydrated ▼ Patients with risk factors for, or existing heart disease, should be closely monitored ▼ Acute diffuse infiltrative pulmonary disease has been reported ▼ Nausea, diarrhea, constipation, and vomiting have occurred and may require use of antiemetic and antidiarrheal medications or fluid replacement ▼ Thrombocytopenia or neutropenia can occur; complete blood counts should be regularly monitored throughout treatment ▼ Tumor Lysis Syndrome, Reversible Posterior Leukoencephalopathy Syndrome, and Acute Hepatic Failure have been reported

Most commonly reported adverse reactions (incidence ≥30%) in clinical studies include asthenic conditions, diarrhea, nausea, constipation, peripheral neuropathy, vomiting, pyrexia, thrombocytopenia, psychiatric disorders, anorexia and decreased appetite, neutropenia, neuralgia, leukopenia, and anemia. Other adverse reactions, including serious adverse reactions, have been reported Please see Brief Summary for VELCADE on next page.

Brief Summary INDICATIONS:

ADVERSE EVENT DATA:

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma.

VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

WARNINGS AND PRECAUTIONS: VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory.

However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively.

The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances.

Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known.

Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies.

The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/ prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients.

Therefore, patients should be closely monitored when given bortezomib in combination with strong CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s Wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADE.com.

Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities.

Use in Pregnancy: Pregnancy Category D. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2011, Millennium Pharmaceuticals, Inc. All rights reserved.

Printed in USA

V-11-0264

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

You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewersâ&#x20AC;&#x2122; names will be published online at the end of the year.

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

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to) those listed below.

Please mark the categories that apply to your expertise: Administration/management Benefit design Disease management/state (eg, asthma, diabetes, heart disease, infectious diseases, pain management, etc) Drug therapy (including biologics, generics) Drug utilization Employers/health plans Finance/health economics Health information technology Health policy/reform Patient education/initiatives/quality-of-life issues Payer perspectives Pharmacoeconomics analyses Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits Reimbursement: Medicare/Medicaid, health insurance, prior authorization Research: methods, study design, data collection/analysis

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Annual Subject Index 2011 Academic detailing Back to school: quality improvement through academic detailing [Patel B] 7:455 Access to healthcare Recent trends in the dispensing of 90-daysupply prescriptions at retail pharmacies: implications for improved convenience and access [Liberman JN, Girdish C] 2:95 When more is almost always better [Gellad WF] 2:99 Accountable care organizations ACO payment model a potential “game changer,” but will it improve outcomes?

[Vogenberg FR] 7:450 Are ACOs the answer to high-value healthcare? [Yeung W, et al] 7:441 Moving beyond Medicare’s ACOs to accountable care [Karamchedu M, et al] 4:204 We must all engage in the diabetes challenge: a lifelong journey, with no silver bullet [Collins CE] 6:386 Adherence Degree of adherence in chronic diseases inversely correlates with healthcare costs [AMCP highlights] 3:166 When information is insufficient: inspiring patients for medication adherence and the role of social support networking [Hennessey M, Heryer JW] 1:10 Anticoagulation therapy Anticoagulation bridging therapy after total hip or knee replacement: a missed opportunity? [Collins CE] 4:248 Anticoagulation bridging therapy patterns in patients undergoing total hip or total knee replacement in a US health plan: realworld observations and implications [Baser O, et al] 4:240 Antidepressants Comparing treatment persistence, healthcare resource utilization, and costs in adult patients with major depressive disorder treated with escitalopram or citalopram [Wu EQ, et al] 2:78 Efficacy and cost-effectiveness: escitalopram versus citalopram [Mitchell M] 2:87 Antipsychotics Atypical antipsychotics and metabolic syndrome in patients with schizophrenia: risk factors, monitoring, and healthcare implications [Riordan HJ, et al] 5:292 Asthma medications Medicaid spending on asthma medications [Amick B] 3:149 Utilization, spending, and price trends for short- and long-acting beta-agonists and inhaled corticosteroids in the Medicaid program, 1991-2010 [Chiu S, et al] 3:140

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Benefit design Benefit management considerations for BPH medications: single agent or combination therapy? [Mitchell M] 4:161 Business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care [Tzeel A, et al] 4:207 From Asheville to Hickory: transforming our “sick care” system into a true “health care” model [Garrett DG] 6:336 Health resource utilization and direct costs associated with angina for patients with coronary artery disease in a US managed care setting [Kempf J, et al] 6:353 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Impact of value-based insurance design on medication utilization and costs in a large retail employer [AMCP highlights] 3:163 Medical claims data can inform coverage decisions in managed care health plans [Murphy MF] 6:361 Perspectives in value-based insurance design for patients with diabetes: assessment and application [Arevalo JD] 1:27 Re-engineering the healthcare continuum: implementing value-based insurance design to improve diabetes management [Taylor SR] 1:32 Sensitivity of medication use to formulary controls in Medicare beneficiaries: a review of the literature [Shenolikar R, et al] 7:465 Systematic health management: the time has come to do the right thing for each person [Rideout J] 3:152 Benign prostatic hyperplasia medications Benefit management considerations for BPH medications: single agent or combination therapy? [Mitchell M] 4:161 Economic impact of delaying 5-alpha reductase inhibitor therapy in men receiving treatment for symptomatic benign prostatic hyperplasia [Naslund M, et al] 3:155 Cancer care Drug shortages the “new” old problem: people are (finally) talking [Helwick C] 7:483 Era of personalized medicine in oncology: novel biomarkers ushering in new approaches to cancer therapy [Stricker S] 6:387 Cardiometabolic health Atypical antipsychotics and metabolic syndrome in patients with schizophrenia: risk factors, monitoring, and healthcare implications [Riordan HJ, et al] 5:292 Cutting-edge data presented at ADA 2011

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highlight the diabetes–cardiovascular disease link [Kuznar W] 6:412 In search of stakeholder collaboration to stem the cardiometabolic epidemic [Buffery D] 5:270 Lipid management in patients with type 2 diabetes [Daniel MJ] 5:312 Obesity in the workplace: impact on cardiovascular disease, cost, and utilization of care [Colombi AM, Wood GC] 5:271 Time is now to promote aggressive lipid management to prevent macrovascular complications in patients with type 2 diabetes [Owens GM] 5:321 We must all engage in the diabetes challenge: a lifelong journey, with no silver bullet [Collins CE] 6:386 Chronic diseases Atypical antipsychotics and metabolic syndrome in patients with schizophrenia: risk factors, monitoring, and healthcare implications [Riordan HJ, et al] 5:292 Call to action: responding to the future forecasting of chronic disease in America [Page RL, et al] 5:280 Comparing treatment persistence, healthcare resource utilization, and costs in adult patients with major depressive disorder treated with escitalopram or citalopram [Wu EQ, et al] 2:78 Cutting-edge data presented at ADA 2011 highlight the diabetes–cardiovascular disease link [Kuznar W] 6:412 Degree of adherence in chronic diseases inversely correlates with healthcare costs [AMCP highlights] 3:166 Drugs in phase 3 clinical trials for type 2 diabetes [Goodman A] 6:410 Emerging therapies for type 1 and type 2 diabetes [ADA highlights] 4:251 Employers’ obesity initiatives in the workplace: a wakeup call for health plans [Lednar WM] 5:278 Five steps healthcare leaders can take to address childhood obesity [Lovejoy J] 1:50 From Asheville to Hickory: transforming our “sick care” system into a true “health care” model [Garrett DG] 6:336 Health plans must “COPE” with chronic diseases [Owens GM] 1:15 Health resource utilization and direct costs associated with angina for patients with coronary artery disease in a US managed care setting [Kempf J, et al] 6:353 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Lipid management in patients with type 2 diabetes [Daniel MJ] 5:312

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Medicaid spending on asthma medications [Amick B] 3:149 New therapies with novel mechanisms of action are urgently needed for type 2 diabetes [Felicetta JV] 5:311 Obesity in the workplace: impact on cardiovascular disease, cost, and utilization of care [Colombi AM, Wood GC] 5:271 Perspectives in value-based insurance design for patients with diabetes: assessment and application [Arevalo JD] 1:27 Postapproval development options in COPD: a case study in value-based healthcare systems [Murphy MF, et al] 1:19 Potential cost-savings using a treatment algorithm for problem bleeding episodes in patients with hemophilia and inhibitors [Lima HA] 4:228 Prevention efforts before disease strikes the key to a healthy population of young adults [Kenney JT] 5:287 Re-engineering the healthcare continuum: implementing value-based insurance design to improve diabetes management [Taylor SR] 1:32 Review of strategies to enhance outcomes for patients with type 2 diabetes: payers’ perspective [Greenapple R] 6:377 Time is now to promote aggressive lipid management to prevent macrovascular complications in patients with type 2 diabetes [Owens GM] 5:321 We must all engage in the diabetes challenge: a lifelong journey, with no silver bullet [Collins CE] 6:386 Collaborative care Addressing costs and continuity of care through innovative solutions for infused therapies: a collaborative experience with infliximab [Johnson R, Freeman EN] 1:39 Atypical antipsychotics and metabolic syndrome in patients with schizophrenia: risk factors, monitoring, and healthcare implications [Riordan HJ, et al] 5:292 Collaborative approach to drug selection, driven by clinical outcomes excellence [Rangaves D] 3:179 Complexities of treating mental illness [Kaddis AA] 5:301 Economic and clinical value of integrating a clinical pharmacist into the care management team [AMCP highlights] 3:163 From A to Z: medication cost-management strategies for disproportionate share hospitals [Henry A, et al] 3:172 In search of stakeholder collaboration to stem the cardiometabolic epidemic [Buffery D] 5:270 Comparative effectiveness research Anticoagulation bridging therapy after total hip or knee replacement: a missed opportunity? [Collins CE] 4:248 Comparative effectiveness research in the

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United States: a catalyst for innovation [Ali R, et al] 2:68 Compliance See Adherence Coordinated care Systematic health management: the time has come to do the right thing for each person [Rideout J] 3:152 Costs See Health economics Cost-effectiveness Comparing treatment persistence, healthcare resource utilization, and costs in adult patients with major depressive disorder treated with escitalopram or citalopram [Wu EQ, et al] 2:78 Efficacy and cost-effectiveness: escitalopram versus citalopram [Mitchell M] 2:87 Cost trends Addressing costs and continuity of care through innovative solutions for infused therapies: a collaborative experience with infliximab [Johnson R, Freeman EN] 1:39 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Keeping a lid on health plan costs, one patient at a time [Miller R] 6:350 Sensitivity of medication use to formulary controls in Medicare beneficiaries: a review of the literature [Shenolikar R, et al] 7:465 Diabetes management Current therapies and emerging drugs in the pipeline for type 2 diabetes [Nguyen QT, et al] 5:303 Cutting-edge data presented at ADA 2011 highlight the diabetes–cardiovascular disease link [Kuznar W] 6:412 Drugs in phase 3 clinical trials for type 2 diabetes [Goodman A] 6:410 Emerging therapies for type 1 and type 2 diabetes [ADA highlights] 4:251 From Asheville to Hickory: transforming our “sick care” system into a true “health care” model [Garrett DG] 6:336 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Impact of treatment by NCQA-certified physicians on diabetes-related outcomes [Pinsky B, et al] 7:429 Lipid management in patients with type 2 diabetes [Daniel MJ] 5:312 New therapies with novel mechanisms of action are urgently needed for type 2 diabetes [Felicetta JV] 5:311 Perspectives in value-based insurance design for patients with diabetes: assessment and application [Arevalo JD] 1:27 Re-engineering the healthcare continuum: implementing value-based insurance

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design to improve diabetes management [Taylor SR] 1:32 Review of strategies to enhance outcomes for patients with type 2 diabetes: payers’ perspective [Greenapple R] 6:377 Time is now to promote aggressive lipid management to prevent macrovascular complications in patients with type 2 diabetes [Owens GM] 5:321 We must all engage in the diabetes challenge: a lifelong journey, with no silver bullet [Collins CE] 6:386 What certification really means for physician quality [Gellad WF] 7:438 Drug abuse Just say no [Kaddis AA] 2:113 Strategies to prevent opioid misuse, abuse, and diversion that may also reduce the associated costs [Hahn KL] 2:107 Drug development Addressing costs and continuity of care through innovative solutions for infused therapies: a collaborative experience with infliximab [Johnson R, Freeman EN] 1:39 Current therapies and emerging drugs in the pipeline for type 2 diabetes [Nguyen QT, et al] 5:303 Current trends in the pharmaceutical pipeline: key players to watch, few surprises [AMCP highlights] 3:164 Drugs in phase 3 clinical trials for type 2 diabetes [Goodman A] 6:410 Emerging therapies for type 1 and type 2 diabetes [ADA highlights] 4:251 Era of personalized medicine in oncology: novel biomarkers ushering in new approaches to cancer therapy [Stricker S] 6:387 New therapies with novel mechanisms of action are urgently needed for type 2 diabetes [Felicetta JV] 5:311 Postapproval development options in COPD: a case study in value-based healthcare systems [Murphy MF, et al] 1:19 Drug manufacturers Drug shortages the “new” old problem: people are (finally) talking [Helwick C] 7:483 Drug shortages Drug shortages the “new” old problem: people are (finally) talking [Helwick C] 7:483 Employers Employers’ obesity initiatives in the workplace: a wakeup call for health plans [Lednar WM] 5:278 Impact of value-based insurance design on medication utilization and costs in a large retail employer [AMCP highlights] 3:163 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Keeping a lid on health plan costs, one patient at a time [Miller R] 6:350

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Obesity in the workplace: impact on cardiovascular disease, cost, and utilization of care [Colombi AM, Wood GC] 5:271 Formulary Collaborative approach to drug selection, driven by clinical outcomes excellence [Rangaves D] 3:179 Sensitivity of medication use to formulary controls in Medicare beneficiaries: a review of the literature [Shenolikar R, et al] 7:465 Generics First generic ARB approval draws a wave of comparative studies [Buffery D] 1:48 New economic analysis zeroes in on low generic utilization and waste in Medicaid [Buffery D] 2:118 Health economics Addressing costs and continuity of care through innovative solutions for infused therapies: a collaborative experience with infliximab [Johnson R, Freeman EN] 1:39 Building your automated bundled payment for an episode-of-care initiative [Moeller D] 6:403 Business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care [Tzeel A, et al] 4:207 Comparing treatment persistence, healthcare resource utilization, and costs in adult patients with major depressive disorder treated with escitalopram or citalopram [Wu EQ, et al] 2:78 Current therapies and emerging drugs in the pipeline for type 2 diabetes [Nguyen QT, et al] 5:303 Degree of adherence in chronic diseases inversely correlates with healthcare costs [AMCP highlights] 3:166 Economic and clinical value of integrating a clinical pharmacist into the care management team [AMCP highlights] 3:163 Economic impact of delaying 5-alpha reductase inhibitor therapy in men receiving treatment for symptomatic benign prostatic hyperplasia [Naslund M, et al] 3:155 Efficacy and cost-effectiveness: escitalopram versus citalopram [Mitchell M] 2:87 From A to Z: medication cost-management strategies for disproportionate share hospitals [Henry A, et al] 3:172 Health as a sustainability strategy: we need a healthcare system focused on keeping people healthy rather than adding layers to the already too long, fragmented supply chain [Colombi AM] 4:215 Health resource utilization and direct costs associated with angina for patients with coronary artery disease in a US managed care setting [Kempf J, et al] 6:353 Hickory Project: controlling healthcare costs

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and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Impact of value-based insurance design on medication utilization and costs in a large retail employer [AMCP highlights] 3:163 Just say no [Kaddis AA] 2:113 Keeping a lid on health plan costs, one patient at a time [Miller R] 6:350 Managing utilization by exception [Zubiller M] 4:233 Medicaid spending on asthma medications [Amick B] 3:149 Modeling costs and outcomes associated with a treatment algorithm for problem bleeding episodes in patients with severe hemophilia A and high-titer inhibitors [Bonnet P, et al] 4:219 New strategies needed to combat increasing costs and optimize use of infused therapies [Radzin RF] 1:45 Obesity in the workplace: impact on cardiovascular disease, cost, and utilization of care [Colombi AM, Wood GC] 5:271 Potential cost-savings using a treatment algorithm for problem bleeding episodes in patients with hemophilia and inhibitors [Lima HA] 4:228 Strategies to prevent opioid misuse, abuse, and diversion that may also reduce the associated costs [Hahn KL] 2:107 Utilization, spending, and price trends for short- and long-acting beta-agonists and inhaled corticosteroids in the Medicaid program, 1991-2010 [Chiu S, et al] 3:140 We need more research on true value-based benefit design that will improve outcomes and control costs [Owens GM] 7:473 Health information exchange Business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care [Tzeel A, et al] 4:207 Health plans See Payers Healthcare reform ACO payment model a potential “game changer,” but will it improve outcomes?

[Vogenberg FR] 7:450 Adapting to market changes: beyond healthcare reform [Vogenberg FR] 6:368 Are ACOs the answer to high-value healthcare? [Yeung W, et al] 7:441 Business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care [Tzeel A, et al] 4:207 Health as a sustainability strategy: we need a healthcare system focused on keeping people healthy rather than adding layers to the already too long, fragmented supply chain [Colombi AM] 4:215

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Moving beyond Medicare’s ACOs to accountable care [Karamchedu M, et al] 4:204 Patient-centered medical home: an essential destination on the road to reform [Adamson M] 2:122 Systematic health management: the time has come to do the right thing for each person [Rideout J] 3:152 Heart disease Call to action: responding to the future forecasting of chronic disease in America [Page RL, et al] 5:280 Health resource utilization and direct costs associated with angina for patients with coronary artery disease in a US managed care setting [Kempf J, et al] 6:353 Medical claims data can inform coverage decisions in managed care health plans [Murphy MF] 6:361 Obesity in the workplace: impact on cardiovascular disease, cost, and utilization of care [Colombi AM, Wood GC] 5:271 Prevention efforts before disease strikes the key to a healthy population of young adults [Kenney JT] 5:287 Hemophilia Modeling costs and outcomes associated with a treatment algorithm for problem bleeding episodes in patients with severe hemophilia A and high-titer inhibitors [Bonnet P, et al] 4:219 Potential cost-savings using a treatment algorithm for problem bleeding episodes in patients with hemophilia and inhibitors [Lima HA] 4:228 Hickory project From Asheville to Hickory: transforming our “sick care” system into a true “health care” model [Garrett DG] 6:336 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Keeping a lid on health plan costs, one patient at a time [Miller R] 6:350 Hospitals Business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care [Tzeel A, et al] 4:207 From A to Z: medication cost-management strategies for disproportionate share hospitals [Henry A, et al] 3:172 Humana pilot project Business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care [Tzeel A, et al] 4:207 Industry trends ACO payment model a potential “game

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changer,” but will it improve outcomes?

[Vogenberg FR] 7:450 Back to school: quality improvement through academic detailing [Patel B] 7:455 Building your automated bundled payment for an episode-of-care initiative [Moeller D] 6:403 Managing utilization by exception [Zubiller M] 4:233 Drug shortages the “new” old problem: people are (finally) talking [Helwick C] 7:483 Patient-centered medical home: an essential destination on the road to reform [Adamson M] 2:122 Recent trends in the dispensing of 90-daysupply prescriptions at retail pharmacies: implications for improved convenience and access [Liberman JN, Girdish C] 2:95 When more is almost always better [Gellad WF] 2:99 Innovation Addressing costs and continuity of care through innovative solutions for infused therapies: a collaborative experience with infliximab [Johnson R, Freeman EN] 1:39 Building your automated bundled payment for an episode-of-care initiative [Moeller D] 6:403 Comparative effectiveness research in the United States: a catalyst for innovation [Ali R, et al] 2:68 Employers’ obesity initiatives in the workplace: a wakeup call for health plans [Lednar WM] 5:278 From Asheville to Hickory: transforming our “sick care” system into a true “health care” model [Garrett DG] 6:336 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 New strategies needed to combat increasing costs and optimize use of infused therapies [Radzin RF] 1:45 Insurance premiums See Payers Lipid management Lipid management in patients with type 2 diabetes [Daniel MJ] 5:312 Time is now to promote aggressive lipid management to prevent macrovascular complications in patients with type 2 diabetes [Owens GM] 5:321 Medicaid CMS invites feedback on the proposed accountable care organizations rules [Buffery D] 2:120 Do medication therapy management programs achieve their goals? [AMCP highlights] 3:166 Medicaid spending on asthma medications [Amick B] 3:149 New economic analysis zeroes in on low generic utilization and waste in Medicaid [Buffery D] 2:118

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Utilization, spending, and price trends for short- and long-acting beta-agonists and inhaled corticosteroids in the Medicaid program, 1991-2010 [Chiu S, et al] 3:140 Medical education Back to school: quality improvement through academic detailing [Patel B] 7:455 When information is insufficient: inspiring patients for medication adherence and the role of social support networking [Hennessey M, Heryer JW] 1:10 Medical home Patient-centered medical home: an essential destination on the road to reform [Adamson M] 2:122 Systematic health management: the time has come to do the right thing for each person [Rideout J] 3:152 Medicare Are ACOs the answer to high-value healthcare? [Yeung W, et al] 7:441 CMS invites feedback on the proposed accountable care organizations rules [Buffery D] 2:120 Do medication therapy management programs achieve their goals? [AMCP highlights] 3:166 Moving beyond Medicare’s ACOs to accountable care [Karamchedu M, et al] 4:204 Sensitivity of medication use to formulary controls in Medicare beneficiaries: a review of the literature [Shenolikar R, et al] 7:465 Medication cost management From A to Z: medication cost-management strategies for disproportionate share hospitals [Henry A, et al] 3:172 Mental health Atypical antipsychotics and metabolic syndrome in patients with schizophrenia: risk factors, monitoring, and healthcare implications [Riordan HJ, et al] 5:292 Comparing treatment persistence, healthcare resource utilization, and costs in adult patients with major depressive disorder treated with escitalopram or citalopram [Wu EQ, et al] 2:78 Complexities of treating mental illness [Kaddis AA] 5:301 National Committee for Quality Assurance Certification Impact of treatment by NCQA-certified physicians on diabetes-related outcomes [Pinsky B, et al] 7:429 Obesity Employers’ obesity initiatives in the workplace: a wakeup call for health plans [Lednar WM] 5:278 Five steps healthcare leaders can take to address childhood obesity [Lovejoy J] 1:50 Obesity in the workplace: impact on cardiovascular disease, cost, and utilization of care [Colombi AM, Wood GC] 5:271

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Outcomes ACO payment model a potential “game changer,” but will it improve outcomes?

[Vogenberg FR] 7:450 Anticoagulation bridging therapy after total hip or knee replacement: a missed opportunity? [Collins CE] 4:248 Collaborative approach to drug selection, driven by clinical outcomes excellence [Rangaves D] 3:179 From A to Z: medication cost-management strategies for disproportionate share hospitals [Henry A, et al] 3:172 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Impact of treatment by NCQA-certified physicians on diabetes-related outcomes [Pinsky B, et al] 7:429 Modeling costs and outcomes associated with a treatment algorithm for problem bleeding episodes in patients with severe hemophilia A and high-titer inhibitors [Bonnet P, et al] 4:219 Review of strategies to enhance outcomes for patients with type 2 diabetes: payers’ perspective [Greenapple R] 6:377 We need more research on true value-based benefit design that will improve outcomes and control costs [Owens GM] 7:473 Payers ACO payment model a potential “game changer,” but will it improve outcomes?

[Vogenberg FR] 7:450 Anticoagulation bridging therapy patterns in patients undergoing total hip or total knee replacement in a US health plan: realworld observations and implications [Baser O, et al] 4:240 Building your automated bundled payment for an episode-of-care initiative [Moeller D] 6:403 Business case for payer support of a community-based health information exchange: a Humana pilot evaluating its effectiveness in cost control for plan members seeking emergency department care [Tzeel A, et al] 4:207 Collaborative approach to drug selection, driven by clinical outcomes excellence [Rangaves D] 3:179 Employers’ obesity initiatives in the workplace: a wakeup call for health plans [Lednar WM] 5:278 Health plans must “COPE” with chronic diseases [Owens GM] 1:15 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 Keeping a lid on health plan costs, one patient at a time [Miller R] 6:350 Medical claims data can inform coverage

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decisions in managed care health plans [Murphy MF] 6:361 Perspectives in value-based insurance design for patients with diabetes: assessment and application [Arevalo JD] 1:27 Review of strategies to enhance outcomes for patients with type 2 diabetes: payers’ perspective [Greenapple R] 6:377 Systematic health management: the time has come to do the right thing for each person [Rideout J] 3:152 Personalized medicine Era of personalized medicine in oncology: novel biomarkers ushering in new approaches to cancer therapy [Stricker S] 6:387 Pharmacists Drug shortages the “new” old problem: people are (finally) talking [Helwick C] 7:483 Economic and clinical value of integrating a clinical pharmacist into the care management team [AMCP highlights] 3:163 From A to Z: medication cost-management strategies for disproportionate share hospitals [Henry A, et al] 3:172 Recent trends in the dispensing of 90-daysupply prescriptions at retail pharmacies: implications for improved convenience and access [Liberman JN, Girdish C] 2:95 When more is almost always better [Gellad WF] 2:99 Pharmacoeconomics Health resource utilization and direct costs associated with angina for patients with coronary artery disease in a US managed care setting [Kempf J, et al] 6:353 Utilization, spending, and price trends for short- and long-acting beta-agonists and inhaled corticosteroids in the Medicaid program, 1991-2010 [Chiu S, et al] 3:140 Pipeline See Drug development Policy ACO payment model a potential “game changer,” but will it improve outcomes?

[Vogenberg FR] 7:450 Drug shortages the “new” old problem: people are (finally) talking [Helwick C] 7:483 From Asheville to Hickory: transforming our “sick care” system into a true “health care” model [Garrett DG] 6:336 Health as a sustainability strategy: we need a healthcare system focused on keeping people healthy rather than adding layers to the already too long, fragmented supply chain [Colombi AM] 4:215 See also Medicaid; Medicare Postapproval Postapproval development options in COPD:

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a case study in value-based healthcare systems [Murphy MF, et al] 1:19 Prevention Prevention efforts before disease strikes the key to a healthy population of young adults [Kenney JT] 5:287 Providers ACO payment model a potential “game changer,” but will it improve outcomes?

[Vogenberg FR] 7:450 Back to school: quality improvement through academic detailing [Patel B] 7:455 Impact of treatment by NCQA-certified physicians on diabetes-related outcomes [Pinsky B] 7:429 What certification really means for physician quality [Gellad WF] 7:438 Quality of care Back to school: quality improvement through academic detailing [Patel B] 7:455 From Asheville to Hickory: transforming our “sick care” system into a true “health care” model [Garrett DG] 6:336 Hickory Project: controlling healthcare costs and improving outcomes for diabetes using the Asheville Project Model [Bunting BA, et al] 6:343 What certification really means for physician quality [Gellad WF] 7:438 Real-world data Anticoagulation bridging therapy patterns in patients undergoing total hip or total knee replacement in a US health plan: realworld observations and implications [Baser O, et al] 4:240 Research Comparative effectiveness research in the United States: a catalyst for innovation [Ali R, et al] 2:68 Medical claims data can inform coverage decisions in managed care health plans [Murphy MF] 6:361 We need more research on true value-based benefit design that will improve outcomes and control costs [Owens GM] 7:473 Retail pharmacy Recent trends in the dispensing of 90-daysupply prescriptions at retail pharmacies: implications for improved convenience and access [Liberman JN, Girdish C] 2:95 When more is almost always better [Gellad WF] 2:99 Social networking When information is insufficient: inspiring patients for medication adherence and the role of social support networking [Hennessey M, Heryer JW] 1:10

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www.AHDBonline.com

Technology Building your automated bundled payment for an episode-of-care initiative [Moeller D] 6:403 Utilization Comparing treatment persistence, healthcare resource utilization, and costs in adult patients with major depressive disorder treated with escitalopram or citalopram [Wu EQ, et al] 2:78 Health resource utilization and direct costs associated with angina for patients with coronary artery disease in a US managed care setting [Kempf J, et al] 6:353 Impact of value-based insurance design on medication utilization and costs in a large retail employer [AMCP highlights] 3:163 Managing utilization by exception [Zubiller M] 4:233 New economic analysis zeroes in on low generic utilization and waste in Medicaid [Buffery D] 2:118 New strategies needed to combat increasing costs and optimize use of infused therapies [Radzin RF] 1:45 Obesity in the workplace: impact on cardiovascular disease, cost, and utilization of care [Colombi AM, Wood GC] 5:271 Utilization, spending, and price trends for short- and long-acting beta-agonists and inhaled corticosteroids in the Medicaid program, 1991-2010 [Chiu S, et al] 3:140 Value-based healthcare Are ACOs the answer to high-value healthcare? [Yeung W, et al] 7:441 Economic and clinical value of integrating a clinical pharmacist into the care management team [AMCP highlights] 3:163 Impact of a value-based insurance design on medication utilization and costs in a large retail employer [AMCP highlights] 3:163 Managing utilization by exception [Zubiller M] 4:233 Perspectives in value-based insurance design for patients with diabetes: assessment and application [Arevalo JD] 1:27 Postapproval development options in COPD: a case study in value-based healthcare systems [Murphy MF, et al] 1:19 Re-engineering the healthcare continuum: implementing value-based insurance design to improve diabetes management [Taylor SR] 1:32 Systematic health management: the time has come to do the right thing for each person [Rideout J] 3:152 We need more research on true value-based benefit design that will improve outcomes and control costs [Owens GM] 7:473

November/December 2011

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Vol 4, No 7

Tell your patients about NovoTwist®, the first and only single-twist needle attachment on the market.

GOOD DESIGN

The benefits of NovoTwist® are:

Winner of the US Good Design™ award1

• Less time consuming for patients to attach • Features an audible and tactile confirmatory click for correct attachment • Available in 30G (8mm) and 32G Tip (5mm) needles Available for use with FlexPen® and other compatible Novo Nordisk devices.*

For more information, visit myflexpen.com or call 1-800-727-6500

* Designed to be used with Levemir® FlexPen®, NovoLog® FlexPen®, NovoLog® Mix 70/30 FlexPen®, and other compatible Novo Nordisk delivery devices. Please refer to the delivery device user manual to see if NovoTwist® can be used with your device.

Also refer to the user manual for information on assembly and injection.

Needles are sold separately and may require a prescription in some states.

Reference: 1. http://www.chi-athenaeum.org/gdesign/2010/medical/index.html

FlexPen®, Levemir®, NovoLog®, and NovoTwist® are registered trademarks of Novo Nordisk A/S. © 2011 Novo Nordisk

Printed in the U.S.A.

0311-00002127-1

April 2011

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PROGRAM OVERVIEW This is the first global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

CO-CHAIRS

EDUCATIONAL OBJECTIVES After completing this activity, the participants should be better able to: • Assess emerging data and recent advances in the discovery of tumor biomarkers, their impact on the treatment of patients with solid tumors and hematologic malignancies, and how to integrate key findings into clinical practice.

• Discuss the role of tumor biomarkers in designing personalized therapy for patients with cancer, including management of treatment-related adverse events.

TARGET AUDIENCE This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California

ACCREDITATION INFORMATION SPONSORS This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Cincinnati, Medical Learning Institute, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC. The University of Cincinnati is accredited by the ACCME to provide continuing medical education for physicians.

CORE PRINCIPLE SOLUTIONS, LLC

PHYSICIAN CREDIT DESIGNATION The University of Cincinnati designates this live activity for a maximum of 12 AMA PRA Category 1 Credits™. Physicians should only claim the credit commensurate with the extent of their participation in the activity.

Rüdiger Hehlmann, MD Chief and Professor of Medicine University of Heidelberg Mannheim, Germany

REGISTERED NURSE DESIGNATION Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for up to 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION Medical Learning Institute (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for up to 12.0 contact hours (0.12 CEUs) of continuing education credit.

The universal activity number for this activity is 0468-9999-11-088-L01-P. COMMERCIAL SUPPORT ACKNOWLEDGMENT This activity is supported by educational grants from Genentech, Inc. and Millennium Pharmaceuticals, Inc.

Early registration of $425 ends January 13, 2012!

Y DA O T 0 R E T $10 S I E G RE SAV

The One Conference You Can’t AFFORD to Miss!

Second Annual Association for Value-Based Cancer Care Conference Strategies for Optimizing Value in Cancer Care Delivery March 29-31, 2012 • JW Marriott • Houston, Texas

REGISTER TODAY at www.regonline.com/avbcc2012 TARGET AUDIENCE This activity was developed for physicians, nurses, pharmacists, and managed care professionals who are involved in the care of patients with cancer.

CONFERENCE GOAL The Association for Value-Based Cancer Care will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care.

CONFERENCE CO-CHAIRS Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University

EDUCATIONAL OBJECTIVES • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery • Define the barriers associated with cost, quality, and access as it relates to healthcare reform and what solutions are currently being considered • Compare and contrast the different approaches/tools that providers and payers are utilizing to manage and deliver care collaboratively • Examine the current trends in personalized care and companion diagnostics • Analyze the patient issues around cost, quality, and access to care

Gary Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS

DESIGNATION OF CREDIT STATEMENTS

President, CEO OncoMed

Physician Accreditation – Joint Sponsor The Medical Learning Institute, Inc. (MLI) designates this live activity for a maximum of 13.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the Medical Learning Institute, Inc. and the Association for Value-Based Cancer Care, Inc. The Medical Learning Institute, Inc. is accredited by the ACCME to provide continuing medical education for physicians.

Registered Nurse Designation Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5 contact hours.

Registered Pharmacy Designation Medical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit.

This activity is jointly sponsored by Medical Learning Institute, Inc., and the Association for Value-Based Cancer Care

CONFERENCE REGISTRATION

SAVE $100 off full Conference Tuition REGISTER TODAY FOR ONLY $275 at www.regonline.com/avbcc2012 For more information, please visit www.avbcconline.org/2012 or e-mail association@avbcconline.org.