JANUARY/FEBRUARY VOLUME 5, NUMBER 1 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ JANUARY/FEBRUARY 2012

VOLUME 5, NUMBER 1

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL

American Health & Drug Benefits: Reflections on the First 5 Years Gary M. Owens, MD

The Business Case for Ending Homelessness: Having a Home Improves Health, Reduces Healthcare Utilization and Costs Daniel G. Garrett, RPh, MS, FASHP

™

BUSINESS

Primary Care Shortages: Strengthening This Sector Is Urgently Needed, Now and in Preparation for Healthcare Reform Sarah Collins, MBA Stakeholder Perspective by Gary M. Owens, MD CLINICAL

Daily Average Consumption of 2 Long-Acting Opioids: An Interrupted Time Series Analysis R. Amy Puenpatom, PhD; Sheryl L. Szeinbach, PhD, MS, BSPharm; Larry Ma, PhD; Rami H. Ben-Joseph, PhD; Kent H. Summers, PhD, BSPharm Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

INDUSTRY TRENDS Employers, Health Plans, and New Drug Benefit Designs: A Shifting Landscape

DEXILANT MAY BE COADMINISTERED WITH PLAVIX (CLOPIDOGREL BISULFATE) DEXILANT had no clinically important impact on the antiplatelet activity of Plavix in healthy volunteers t DEXILANT 60 mg had no clinically important effect on Plavix active metabolite pharmacodynamics, as measured by Inhibition of Platelet Aggregation (IPA) and inhibition of Platelet Reactivity Index (PRI) based on co-primary endpoints of the study1 t DEXILANT minimally reduced the mean AUC of the Plavix active metabolite by 9%2 t No dose adjustment of Plavix is necessary when administered with an approved dose of DEXILANT2 % decrease in IPA* with Plavix and PPI coadministration (day 9)1

DATA PRESENTED AT ACC IN 2011

% decrease in inhibition of PRI with Plavix and PPI coadministration (day 9)1

0.2% 4.7% 22.5% DEXILANT 60 mg (n=40) Positive control (omeprazole 80 mg; n=40)

35.2%

Results from a Phase 1, open-label, multiple-dose, 2-period crossover study (n=160) of CYP2C19 extensive metabolizers receiving once-daily administration of Plavix 75 mg alone or concomitantly with 1 of 4 PPI agents. Co-primary endpoints were the measurement of PRI and Mean Platelet Aggregation (MPA) of Plavix + PPI vs Plavix alone. *ADP 5ÂľM.

Conclusions of comparative efficacy cannot be drawn from this information. The clinical relevance of these data has not been established. Indications for DEXILANT t Healing all grades of erosive esophagitis (EE) for up to 8 weeks t Maintaining healing of EE and relief of heartburn for up to 6 months t Treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for 4 weeks

Important Safety Information t DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. t Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. t 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. t Hypomagnesemia has been reported rarely with prolonged treatment with PPIs. t 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%). t 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 accompanying brief summary for DEXILANT. References: 1. Data on file, Takeda Pharmaceuticals North America, Inc. 2. DEXILANT (dexlansoprazole) package insert, Takeda Pharmaceuticals America, Inc. 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. Plavix is a registered trademark of sanofi-aventis Corp.

ÂŠ2011 Takeda Pharmaceuticals North America, Inc. LPD-01954 11/11 Printed in U.S.A.

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 osteoporosisrelated 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, vulvovaginal 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. Clopidogrel Concomitant administration of dexlansoprazole and clopidogrel in healthy subjects had no clinically important effect on exposure to the active metabolite of clopidogrel-induced platelet inhibition. No dose adjustment of clopidogrel is necessary when administered with an approved dose of DEXILANT. 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, SpragueDawley 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 R15_BS Revised: October 2011 L-LPD-1011-2

Most Read Articles in American Health & Drug Benefits 2008 • Contracting for compliance: using adherence as a patient-centered measure of performance, by SR Taylor, JB Jones, NR Shah • Delaware’s wellness program: motivating employees improves health and saves money, by J “J.J.” Davis • Benchmarking new frontiers in managed care pharmacy, by C Pigg, J Cihak 2009 • Increased patient cost-sharing, weak US economy, and poor health habits: implications for employers and insurers, by MC Haren, K McConnell, AF Shinn • Estimates of commercial population at high risk for cardiovascular events: impact of aggressive cholesterol reduction, by K Fitch, SW Goldberg, K Iwasaki, et al • Lower copay and oral administration: predictors of first-fill adherence to new asthma prescriptions, by Z Berger, W Kimbrough, C Gillespie, et al 2010 • Obesity: effective treatment requires change in payers’ perspective, by R Greenapple, J Ngai • Physicians’ perceptions of reimbursement as a

barrier to comprehensive diabetes care, by A Pozniak, L Olinger, V Shier • Comparing medical costs of care for patients with metastatic breast cancer receiving taxane therapy: claims analysis, by RW Force, BA Pugmire, VL Culbertson • A comparison of drug formularies and the potential for cost-savings, by AL Kjos, JC Schommer, Y Yuan 2011 • The 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, by A Tzeel, V Lawnicki, KR Pemble • Health resource utilization and direct costs associated with angina for patients with coronary artery disease in a US managed care setting, by J Kempf, E Buysman, D Brixner • Atypical antipsychotics and metabolic syndrome in patients with schizophrenia, by HJ Riordan, P Antonini, MF Murphy Read these articles at www.AHDBonline.com.

JANUARY/FEBRUARY 2012

VOLUME 5, NUMBER 1

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS EDITORIAL

American Health & Drug Benefits: Reflections on the First 5 Years Gary M. Owens, MD

The Business Case for Ending Homelessness: Having a Home Improves Health, Reduces Healthcare Utilization and Costs Daniel G. Garrett, RPh, MS, FASHP

BUSINESS

Stakeholder Perspective by Atheer A. Kaddis, PharmD

Founding Editor-in-Chief Robert E. Henry

REGULATORY

Primary Care Shortages: Strengthening This Sector Is Urgently Needed, Now and in Preparation for Healthcare Reform Sarah Collins, MBA Stakeholder Perspective by Gary M. Owens, MD Continued on page 10

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)

American Health & Drug Benefits

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editors Brett Kaplan Lara J. Lorton 732-992-1892 Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Sales Assistant Zach Ceretelle Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto

www.AHDBonline.com

Mission Statement 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

January/February 2012

Vol 5, No 1

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.

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

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. ÂŠ2011 Takeda Pharmaceuticals America, Inc. April 2011 AZL074 R2 L-LXA-0411-4

JANUARY/FEBRUARY 2012

VOLUME 5, NUMBER 1

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™

™

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

TABLE OF CONTENTS

(Continued)

CLINICAL

Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

DEPARTMENTS

INDUSTRY TRENDS Employers, Health Plans, and New Drug Benefit Designs: A Shifting Landscape Mark Zitter, MBA; Michael Snyder OPINION Should Everyone Be Required to Have Health Insurance?

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America. Address all editorial correspondence to: editorial@AHDBonline.com Telephone: 732-992-1892 Fax: 732-992-1881 American Health & Drug Benefits 241 Forsgate Drive, Suite 205A Monroe Township, NJ 08831 The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. For permission to reuse material from American Health & Drug Benefits (ISSN 1942-2962), please access www. copyright.com <http://www.copyright. com/> or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400.

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American Health & Drug Benefits

www.AHDBonline.com

January/February 2012

Vol 5, No 1

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

(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%)

TJ-BS (7-11)

TJ104305PROF

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 Wayne M. Lednar, MD, PhD Global Chief Medical Officer Director, Integrated Health Services DuPont, Wilmington, DE Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, Lake Worth, FL 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 5, No 1

January/February 2012

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

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

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

Alex Hathaway, MD, MPH, FACPM President & Founder, J.D. BioEdge Health quality & biomedical research

PATIENT ADVOCACY

RESEARCH & DEVELOPMENT

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

J. Warren Salmon, PhD Charles E. Collins, Jr, MS, MBA Professor of Health Policy & Administration Executive Vice President, Managing Director School of Public Health Engage Managed Markets University of Illinois at Chicago

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

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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

American Health & Drug Benefits

EDITORIAL

American Health & Drug Benefits : Reflections on the First 5 Years By Gary M. Owens, MD President, Gary Owens Associates, Glen Mills, PA

t is difficult to believe that 5 years have passed since the first issue of American Health & Drug Benefits (AHDB) arrived on my desk in 2008. In February 2008, the United States was on the verge of an economic downturn that had actually begun almost 3 months earlier. The price of oil topped $100 a barrel for the first time, and job losses were just being reported. Although most of us did not know it yet, the United States was entering the worst economic downturn since the Great Depression. The economic woes of the past 5 years have had a profound impact on the healthcare system. Although the recession has ended and economic indicators are improving, healthcare payers are facing significant challenges in the postrecession economy. Some of these challenges include: • The potential for rapid escalation of healthcare cost resulting from the impact of healthcare reform legislation, as 41 million newly insured Americans seek services in 2014 and beyond • Maintaining affordability of health insurance premiums, with reasonable access to care, while healthcare costs spiral upward • Maintaining and growing market share in a difficult economic climate • Working with employers and other customers who are increasingly looking for plans to actively manage medical costs • Dealing with benefit design issues that may potentially increase deductibles and higher out-of-pocket costs for patients • Managing new and expensive specialty pharmaceuticals that must become a critical core competency of health plans. Because of these and other pressing issues in the healthcare arena, all stakeholders need sources of information to help guide our daily activities. AHDB has consistently been one of those sources since its establishment. The first sentence of the mission statement of AHDB caught my attention from the first issue, “American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econometric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and drug benefit designs.”

American Health & Drug Benefits

The concept of balancing cost, quality, and access is a major concern for payers and the many other stakeholders in healthcare. AHDB has provided an open forum for many of the complex issues addressed in the pages of the journal, by promoting stakeholder integration and collaboration toward the mutual goals of improving health outcomes and controlling costs. Since its establishment, AHDB has published many outstanding articles dealing with the regulatory, clinical, and business aspects of healthcare, such as the following few examples: • 2008: Benchmarking New Frontiers in Managed Care Pharmacy • 2009: Increased Patient Cost-Sharing, Weak US Economy, and Poor Health Habits: Implications for Employers and Insurers • 2010: A Comparison of Drug Formularies and the Potential for Cost-Savings • 2011: The Hickory Project: Controlling Healthcare Costs and Improving Outcomes for Diabetes Using the Asheville Project Model • 2012: Beyond the Cost of Biologics—Employer Survey Provides Insights into Benefit Coverage. In addition, special issues, such as “A WellnessBased Healthcare System for Chronic Diseases: Prevention, Intervention, and Innovation” published in 2010, and the special theme issue on “Cardiometabolic Health and Wellness” published in 2011, have provided guidance to AHDB’s readership on major population-based topics of concern. Many changes in healthcare have occurred since the first issue of AHDB was published in 2008, and I am sure that many unanticipated changes will take place over the next 5 years. During the past 5 years, AHDB has established itself as an important forum for addressing critical issues facing the US healthcare system. As an editorial board member of AHDB, I wish to congratulate all my colleagues on the board and all the many other people who have contributed to the excellent and vigorous publication standards established by the journal and help make it a useful resource for decision makers in healthcare. I look forward to the next 5 years of having AHDB as an important resource to help keep me informed on the constantly evolving US healthcare environment. ■

www.AHDBonline.com

January/February 2012

Vol 5, No 1

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.

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). 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 Gradesa 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)], f Herpes Zoster 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.

EDITORIAL

The Business Case for Ending Homelessness: Having a Home Improves Health, Reduces Healthcare Utilization and Costs Daniel G. Garrett, RPh, MS, FASHP

n June 2008, my wife and I moved to downtown Asheville, NC, with our dog, Max. Max and I were out for a walk early every morning and late every evening. When I first started taking Max for walks, I would occasionally notice people who appeared homeless, and I became curious about the causes of homelessness and its solutions. Now, in 2012, I rarely see a homeless person downtown. What has changed? One major change is that Asheville has instituted a viable 10-year plan to end chronic homelessness, and a group of more than 40 agencies are working together in the Asheville Homeless Coalition. I got involved initially by attending the 2008 annual Homeless Initiative Stakeholders meeting in Asheville and the meetings of Asheville Homeless Coalition, because I wanted to be a part of the solution. As current President of the Board of Homeward Bound of Asheville, I have learned that housing ends homelessness. It is that simple. And housing provides the stability that people need to address unemployment, addiction, mental illness, and physical health. If we pair housing with supportive case management, people will be able to stabilize their lives, increase their self-sufficiency, and remain in housing. As of November 2011, Homeward Bound has housed 338 people, reporting an 89% housing retention rate. I have also learned that by housing people, we are saving our community hundreds of thousands of dollars each year in unpaid healthcare costs. In a 2006 article in the New Yorker, Malcolm Gladwell wrote of “MillionDollar Murray,” relating how one person (Murray Barr) living on the streets in Reno, NV, cost that state $1 million in unpaid emergency department and medical costs.1 This $1 million could have been saved if Murray Barr had been supported by housing.1

Mr Garrett is Chief Trailblazer, Blue Ridge Mountain Group, LLC, Asheville, NC; President of the Board, Homeward Bound of Asheville, NC; a member of the Asheville Homeless Initiative Advisory Committee; and President of the Boards of Liberty Corner Enterprises and Health Partners of Asheville and Buncombe County. He facilitated the original Asheville Project.

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January/February 2012

I have learned that homelessness is a problem that can be solved, that housing is the answer, and that moving people from homelessness into housing results in significant improvements in health and access to healthcare. Ending homelessness is not only beneficial to the people who have moved into housing. It is beneficial to the community and to the healthcare system as well.

Healthcare Costs, Utilization As people become stabilized in housing, their dependence on emergency services drops, and their health outcomes improve significantly. Consider the following facts on the cost of healthcare for the homeless: • The majority of homeless people lack health insurance, a public provision for healthcare, or a primary care physician2,3 • Almost 33% of all visits to the emergency department are made by chronically homeless people. Emergency departments are not equipped to meet the psychosocial needs of homeless patients and do not have the capacity to assist them with housing, substance abuse treatment, or mental healthcare2,3 • Homeless people visit the emergency department an average of 5 times annually, and the most frequent users visit them weekly. Each visit costs $3700, amounting to $18,500 spent annually for the average user and up to $44,400 for the most frequent users2,3 • On average, homeless people spend 3 nights per visit in the hospital, which can cost more than $90002 • According to Margot Kushel, MD, Associate Professor of Medicine, University of California, San Francisco, “Homeless people have higher rates of chronic health problems than the general or poverty population. This takes the form of higher rates of illnesses such as high blood pressure, heart disease, diabetes, lung diseases like asthma and chronic bronchitis, and HIV disease”4 • As many as 80% of emergency department visits made by people struggling with homelessness are for illnesses that could have been addressed through preventive care.2 The answer to reducing healthcare costs for people

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American Health & Drug Benefits

EDITORIAL

who are homeless is supportive housing5: • The provision of housing to homeless residents decreases by nearly 61% the number of visits they make to emergency departments • Providing permanent supportive housing to the homeless community saves the taxpayer money: 1. Healthcare costs are reduced by 59% 2. Emergency depatment costs are decreased by 61% 3. The number of general inpatient hospitalizations is decreased by 77% • For members of the community who need assistance resolving their medical and/or psychosocial problems, permanent supportive housing is often the only successful approach to ending homelessness • Safe and permanent housing can give residents the stability they need to organize their lives and maintain their health.

When homeless people are placed in supportive housing, many are qualified for healthcare coverage. More important, people who have housing are less apt to need healthcare services as often as those who have no housing. The National Coalition for the Homeless points out that, “Homelessness and healthcare are intimately interwoven. Poor health is both a cause and a result of homelessness. The National Healthcare for the Homeless Council (2008) estimates that 70% of Healthcare for the Homeless clients do not have health insurance. Moreover, approximately 14% of people treated by homeless healthcare programs are children under the age of 15.”6 When homeless people are placed in supportive housing, many are qualified for healthcare coverage. More important, people who have housing are less apt to need healthcare services as often as those who have no housing, as noted above.5 Recently, the Substance Abuse and Mental Health Services Administration (SAMHSA) announced grants to Asheville and 19 other communities to benefit homeless people.7 The Cooperative Agreements to Benefit Homeless Individuals provide funding to offer support and housing for homeless people and those with mental and substance use disorders.7 Because of their illness, these people have largely been excluded from the current healthcare system and are, therefore, relying on public “safety net” programs. SAMHSA points out that “Last year alone approxi-

American Health & Drug Benefits

mately 20 million people who needed substance abuse treatment did not receive it and an estimated 10.6 million adults reported an unmet need for mental healthcare. As a result the health and wellness of the individual is jeopardized and the unnecessary costs to society ripple across America’s communities, schools, businesses, prisons and jails, and healthcare delivery systems.”8 The expansion of programs being supported by SAMHSA is a key to housing many people who are homeless and to significantly reducing the medical costs of these people to the healthcare system. For people with chronic health conditions, Project IMPACT Diabetes offers an example of how 25 communities nationwide are coming together to improve health outcomes for those with chronic conditions who are homeless and uninsured.9 When I became a downtown property owner, I had some of the misperceptions that many people (including those involved in healthcare) have about people who are homeless.10 Since I have become involved in groups who work to address homelessness, those myths have been dispelled for me, by learning about what causes homelessness, and how we can end it and reduce healthcare utilization and cost. A common myth is that homeless people move to communities such as Asheville and Buncombe County because of our progressive social services. In fact, 71% of the people experiencing homelessness, according to last year’s Point-in-Time Count data in Asheville, said that the last place they had stable housing was in Buncombe County.11 That means that 71% of the people who live here without housing did not come here because they heard about our social programs; rather, they were community members with housing like you and me, but they have since lost their housing.

Housing Saves Healthcare Costs I have learned that ending homelessness is a reasonable goal. This does not mean that no one will ever become homeless again; it does mean that if we address the housing needs of the people who are experiencing homelessness now, we will have more resources to prevent homelessness from happening in the future, or to respond quickly and effectively when a person loses his/her housing. Homelessness can be just a brief episode in one’s life; if we use our resources wisely, no one in our community has to experience homelessness for the long-term. Housing ends homelessness and reduces costs. The Homeward Bound of Asheville Housing First program costs about $10,000 per person annually, which is substantially less than it costs our community to maintain homelessness for any individual. We also end it by coor-

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January/February 2012

Vol 5, No 1

EDITORIAL

dinating our efforts and working together. The data confirm that we have had a drop in homelessness in Ashville during a time of budget cuts, high unemployment rates, and declining property values, thanks to the collaboration, accountability, and system efficiency that is emerging from our community-wide homeless initiative.12 The United States is at a national crossroads in terms of rapidly rising healthcare costs, and we need more community-wide leadership, volunteers, and donations to truly impact the way people experience a housing crisis. Homelessness affects the health and well-being of our entire community, and it is within our power to change the way we address it, and even end it. Agencies working on homelessness do a lot with very little, helping hundreds of people to get out of homelessness, and even more people to avoid it completely. If we all—healthcare leaders, businesses, agencies, schools, faith groups, and neighbors—join together, we will see the experience of homelessness in our communities change for everyone. Patient-centered medical homes have been getting much attention in the healthcare industry and in medical journals. An effective way for each of us who is engaged in healthcare to be involved in improving health outcomes and lowering costs is to support the effort to ensure that every American has a home. Housing is healthcare. As we end homelessness one household at a time, we improve the health of our community members, we improve the fiscal well-being of our healthcare systems, and we improve the quality of life for everyone in our community. As the body of evidence supporting the tie between housing and healthcare continues to grow, those of us in the medical world would be wise to seek opportunities to invest in solutions to homelessness. As healthcare professionals and community members, we must recognize our role as stakeholders in ending homelessness and take responsibility as informed leaders who can advocate for housing to end homelessness and improve health. I got involved by walking my dog, and I look forward to the day when every person Max meets on the streets of Asheville has a place to call home and the healthcare benefits he or she needs. You can get involved too. Visit the websites of the United

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January/February 2012

States Interagency Council on Homelessness (www.usich. gov) and the National Alliance to End Homelessness (www.endhomelessness.org/section/solutions/ten_year_plan) to learn about national and local efforts on how to end homelessness. ■

Housing is healthcare. As we end homelessness one household at a time, we improve the health of our community members, we improve the fiscal well-being of our healthcare systems, and we improve the quality of life for everyone in our community. Author Disclosure Statement Mr Garrett has no conflicts of interest to report.

References 1. Gladwell M. Dept. of Social Services. Million-dollar Murray: why problems like homelessness may be easier to solve than to manage. The New Yorker. February 13, 2006. www.gladwell.com/pdf/murray.pdf. Accessed January 5, 2012. 2. Green Doors. The cost of homelessness facts. www.greendoors.org/facts/cost.php. Accessed January 5, 2011. 3. National Alliance to End Homelessness. Cost of homelessness. www.endhomeless ness.org/section/about_homelessness/cost_of_homelessness. Accessed January 5, 2012. 4. Kushel M. Written remarks to the Joint Committee on Homelessness. July 18, 2007. www.housingca.org/site/DocServer/testimony_jointctteonhmlessnss_Kushel. pdf?docID=201. Accessed January 5, 2012. 5. Linkins KW, Brya JJ, Chandler DW. Frequent users of health services initiative: final evaluation report. The California Endowment and the California HealthCare Foundation. August 2008. http://funderstogether.org/files/documents/FUSHI_ evaluation.pdf. Accessed January 5, 2012. 6. National Coalition for the Homeless. Healthcare and homelessness. July 2009. www.nationalhomeless.org/factsheets/health.html. Accessed January 5, 2012. 7. Substance Abuse & Mental Health Services Administration. FY 2011 SAMHSA grant awards. CSAT/TI-11-008: cooperative agreements to benefit homeless individuals (short title: CABHI). Updated October 14, 2011. www.samhsa.gov/grants/ 2011/awards/ti_11_008.aspx. Accessed January 5, 2012. 8. Substance Abuse & Mental Health Services Administration. Agency overview. Updated August 13, 2010. www.samhsa.gov/about/background.aspx. Accessed January 5, 2011. 9. American Pharmacists Association Foundation. APhA Foundation Project IMPACT: diabetes overview. April 9, 2011. www.pharmacist.com/Content/NavigationMenu/ ResearchProjects/ProjectIMPACTDiabetes/Project_IMPACT_ Diabetes_Overview20110409.pdf. Accessed January 5, 2012. 10. Culhane D. Five myths about America’s homeless. The Washington Post. July 11, 2010. www.washingtonpost.com/wp-dyn/content/article/2010/07/09/AR20100709 02357.html. Accessed January 11, 2012. 11. North Carolina Coalition to End Homelessness. Point-in-Time Count Data. January 26, 2011. www.ncceh.org/attachments/contentmanagers/825/Asheville2011_PIT.pdf. Accessed January 5, 2012. 12. Frankel J. Local homelessness counts lower, reflecting national trend. December 14, 2011. www.mountainx.com/article/38403/Local-homeless-counts-lower-reflectingnational-trend. Accessed January 5, 2012.

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

• Adherence Concerns • Benefit Design • Case Studies • Comparative Effectiveness Research • Cost Analyses • Decision-Making Tools • Ethics in Medicine

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

Theme Issue: Cancer Care

Theme Issue: Cardiometabolic Health

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.

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.

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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January/February 2012

Vol 5, No 1

BUSINESS

ORIGINAL RESEARCH

Beyond the Cost of Biologics: Employer Survey Reveals Gap in Understanding Role of Specialty Pharmacy and Benefit Design F. Randy Vogenberg, RPh, PhD; Cheryl Larson, BA; Margaret Rehayem, MA; Larry Boress, MPA Background: Advances in biotechnology have led to the development of many new medical therapies for a variety of diseases. These agents, known as biologics or specialty drugs, represent the fastest-growing segment of pharmaceuticals. They have often proved effective in cases where conventional medications have failed; however, they can cost up to $350,000 per patient annually. Employers sponsor a significant proportion of plans that provide healthcare benefits, but surveys on benefit coverage have neglected to measure employers’ understanding of these drugs or their use. Objective: To establish a baseline understanding of specialty pharmacy drug benefit coverage from the perspective of the employer (ie, commercial benefit plan sponsors). Methods: The Midwest Business Group on Health (MBGH), a Chicago-based, nonprofit coalition of more than 100 large employers, in collaboration with the Institute for Integrated Healthcare, conducted a national web-based survey to determine the extent of employer understanding of specialty pharmacy drug management. MBGH, along with 15 business coalitions nationwide, distributed the survey to their employer members. A total of 120 employers, representing more than 1 million employee lives, completed the survey online. The results were then analyzed by MBGH. Results: Of the 120 employers surveyed, 25% had “little to no understanding” of biologics, and only 53% claimed a “moderate understanding” of these agents. When asked to rank the effectiveness of biologics-related disease management support for their employees, 45% of the participating employers did not know whether productivity had increased, and 43% did not know whether their employees had experienced increased quality of life as a result of taking these drugs. The majority (76%) of employers continued to rely heavily on print medium to communicate with their covered population. Overall, the vast majority of employers (78%) claimed either “little to no understanding” or a “moderate understanding” of specialty pharmacy. Conclusions: That the majority of employers admit they do not understand specialty pharmacy indicates that efforts are needed to fill in this knowledge gap to enable employers to design useful or appropriate drug benefit programs and manage them more effectively to control costs and optimize their employees’ healthcare outcomes. Efforts to educate employers will require continued evaluation to ensure an effective communication between them and their employees while this area of medicine continues to grow.

dvances in biotechnology have led to the development of new medical therapies for a variety of diseases, including many types of cancers and autoimmune diseases (eg, rheumatoid arthritis). Among Dr Vogenberg is Principal, Institute for Integrated Healthcare, Sharon, MA; Ms Larson is Vice President, Ms Rehayem is Director of Member Initiatives, and Mr Boress is President, all at Midwest Business Group on Health, Chicago, IL.

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F. Randy Vogenberg

Stakeholder Perspective, page 30

Am Health Drug Benefits. 2012;5(1):23-30 www.AHDBonline.com Disclosures are at end of text

these agents are biologics, also known as specialty pharmaceuticals. These drugs represent the fastest-growing segment of pharmaceuticals. Employers sponsor a significant proportion of plans that provide healthcare benefits, including biologics. There are currently approximately 750 biologics already approved by the US Food and Drug Administration, and 25% of the drugs that are now in the pipeline are considered specialty pharmaceuticals.1

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KEY POINTS ➤

➤

Employers sponsor a significant proportion of plans that provide healthcare benefits to their employees; however, surveys on benefit coverage of specialty pharmaceuticals, or biologics, have neglected to measure employers’ understanding of these expensive therapies. Specialty pharmaceuticals represent the fastest area of drug growth since 2004, but they can cost up to $350,000 per patient, annually. In the past 5 years, specialty drug plan spending rose by more than 15%, several times higher than the overall drug trend. This first-of-its-kind survey shows that employers are unaware of their spending on biologics and how effective it is. It also shows that employers are unsure of how to design appropriate benefits regarding these high-cost drugs and how to effectively communicate this information to their employees. This survey suggests that employers have not moved away from traditional benefit designs to take advantage of the benefits that specialty pharmacy can provide. These results can suggest to employers the need to fill the gap regarding healthcare benefits coverage, spending, and costs; identify potential improvements to their benefit strategies; and shift their coverage decisions to benefit themselves and their employees.

These drugs are characteristically derived from live organisms, and many require special storage and/or handling. Their administration varies widely, from selfadministration to administration at an infusion center. The cost threshold for each biologic drug also varies widely by health plan. The Medicare threshold is $500 per month,2 whereas on the commercial side, the threshold varies by plan. Coverage and category definitions in this area of pharmaceuticals remain unclear, and this is likely to persist as long as biologics or injectables continue to become available in self-administered formulations (which complicates how best to define biologic products). Specialty drugs are used to treat a variety of diseases; the majority of spending today on these agents is incurred for the treatment of cancer, rheumatoid arthritis and other autoimmune conditions, multiple sclerosis, and anemia.1 Whereas early biologics were solely physician-administered injectables or infusions, advances in medical technology have expanded the formulations to include oral formulations that can be administered by the patient.

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Compounding the complexities of benefit coverage for these treatments is their high cost, accounting for a 17.4% change in prescription spending and the fastest growth of any drug category since 2004.1 In the past 5 years, specialty drug plan spending rose by more than 15%, several times higher than the overall drug trend.1,3 Although specialty drugs account for only 1% of the total prescription claims volume in 2010, 70% of drug cost trend in pharmacy benefit could be attributed to the rising cost of specialty drugs.1 Specialty drugs are expected to represent 21% of all plan drug spending by 2013, and as much as 40% of plan drug spending by the end of 2020. Spending on specialty drugs already accounts for more than 50% of revenues of some specialized medical practices.4 The cost of specialty drugs ranges greatly from $6000 to $350,000 per employee or dependent annually and accounts for major increases in spending growth of prescription benefit plans.5 Among the top contributors to this trend were rheumatoid arthritis and other autoimmune conditions (ie, lupus, Crohn’s disease, ulcerative colitis), accounting for 14.7% of the trend.1 Coverage for specialty pharmaceuticals also varies based on the site of service and the method of contracting. Self-administered drugs are often billed under the pharmacy benefit plan, whereas infused or injected oncology medications and drugs for immune disorders are usually billed under the medical plan. This makes analysis of information on cost and utilization a difficult challenge to buyers or payers in terms of managing coverage, patients, and payments. (Because most employers do not have a retiree program, Medicare coverage was not included in this study.) Impending healthcare reform and a distressed economy introduce yet further complications. The Institute of Medicine recently recommended to the US Department of Health and Human Services that benefits of our finite healthcare resources should be determined not by services but by costs.6 If the current cost growth trend continues, both existing and new biologics will seriously increase the drug cost curve. Drug therapy in oncology alone is expected to increase from $125 billion in 2010 to $207 billion by the end of the decade, in part as a result of the increasing number of cancer survivors.6 In early 2011, the Biologic Finance and Access Council (BFAC) partnered with MediMedia Research to conduct its second annual national survey of healthcare executives. The survey targeted employers that were either affiliated with the Jefferson School of Population Health or were members of BFAC, which includes thought leaders from large employers, pharmacy benefit managers, and national and regional health plans.7 Attention was focused on biologics as the fastest growing cost trend in healthcare. In the BFAC survey, stakehold-

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January/February 2012

Vol 5, No 1

Beyond the Cost of Biologics

ers recognized that specialty pharmacy had an increased effect on benefit cost and patient outcomes, but they were unable to judge trends related to spending and cost management. The outcome measures and value-based assessments were determined to be important issues, but there was a lack of understanding about the value of specialty pharmaceuticals related to these issues or the value of collaborating with other stakeholders to increase patient adherence to treatment regimens. In response to the findings of the BFACâ&#x20AC;&#x2122;s second annual survey, the Midwest Business Group on Health (MBGH), a Chicago-based, nonprofit coalition of more than 100 large private and public employers, in collaboration with the Institute for Integrated Healthcare (IIH), an Employer Project Advisory Council, conducted a web-based survey that was directed solely at employers. Employers are key stakeholders in the specialty pharmacy environment, because they sponsor a significant proportion of plans that provide healthcare benefits for employees and their families. Therefore, it is as important to track employersâ&#x20AC;&#x2122; perceptions and attitudes regarding benefit design, as it is to track changes in access to care and reimbursement concerns. However, benchmark surveys on benefit coverage have neglected to measure employersâ&#x20AC;&#x2122; overall understanding of spending on biologic pharmaceuticals or their use. The present article describes the findings of the survey conducted by MBGH and IIH.

Method and Demographics In the summer of 2011, MBGH and IIH conducted the first national employer-driven survey on specialty pharmacy and the use of specialty pharmaceuticals in an effort to establish a baseline understanding of biologics and specialty drug benefit coverage from the perspective of the employer (ie, commercial benefit plan sponsors). The information gained from this survey will be used to assist employers in understanding the value and benefits of biologics. The survey was the first of a 2-phase effort. Based on the hypothesis that employers did not fully understand pharmaceuticals, the survey was conducted with the hope that it would provide information that will allow the development of various educational initiatives to help employers: (1) better understand specialty pharmacy and specialty pharmaceuticals; (2) manage the challenges posed by specialty pharmaceuticals; (3) manage benefits through plan design innovation by partnering with specialty vendors for contracting and patient management; (4) understand the importance of managing their at-risk population; and (5) more effectively communicate specialty benefits to employees.

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January/February 2012

Top Industries Represented in the Survey, Based on US Table 1 Department of Labor Standard Industry Codes Proportion of employers, %

Industry Manufacturing

Professional scientific, technical services, healthcare, social assistance

Management companies/enterprises

Construction

Finance, insurance

Educational services

In this survey, MBGH collaborated with IIH and 15 other business coalitions across the United States to distribute a web-based questionnaire to their employer members. A total of 120 employers, representing more than 1 million employee lives, completed the survey. The average age of almost half (47%) of employees was between 41 and 45 years. Because this was the first time this type of study was conducted, it was difficult to represent the true demographic region of employers. Therefore, location was determined based on where half of the workforce, for each employer, was located.

Employers are key stakeholders in the specialty pharmacy environment, because they sponsor a significant proportion of plans that provide healthcare benefits for employees and their families. Participating companies represented all US states, with half (50%) of them based in the Midwest, including Illinois, Iowa, Kansas, Michigan, Missouri, North Dakota, and Wisconsin. The type of industry was based on the Standard Industrial Classification as defined by the US Department of Labor. Manufacturing was the largest (36%) industry type represented in this survey (Table 1).

Results All major standard industrial employer categories were represented in the survey, with manufacturing accounting for more than one third (36%) of respondents. Employer funding of health benefits ranged from self-insured (69%) and fully insured (19%) to a combination of both (13%). A total of 60% of employers did not combine more than one type of benefit option for their employees.

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BUSINESS

Figure 1A Level of Understanding of Specialty Pharmacy Rank your organization’s level of understanding related to biologics/specialty pharmacy (choose 1)

53% High: we have a high level of understanding of this benefit Medium: we have a moderate understanding of this benefit Low: we have little to no understanding of this benefit

22%

25%

Size of Employer’s Company and Level of Figure 1B Understanding of Specialty Pharmaceuticals

What is the size of your active employee population? (N)

Rank your organization’s level of understanding related to biologics/specialty pharmacy (choose 1) High: we have a high level of understanding of this benefit Medium: we have a moderate understanding of this benefit Low: we have little to no understanding of this benefit Don’t know >25,000

15%

10,000-25,000

38%

19%

5001-10,000 6%

19%

17%

19%

10% 5%

3001-5000

1001-3000 6%

27%

11% 4% 10%

501-1000 <500

78% 0

8% 5% 60

100

Percentage

When asked to rank their organization’s level of understanding of specialty pharmacy and specialty pharmaceuticals, 25% of employers had “little to no understanding” and 53% had only a “moderate understanding” (Figure 1A). The greatest (78%) lack of understanding of specialty pharmaceuticals was seen among employers of companies with a smaller-size (<500) active number of employees (Figure 1B).

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The survey also uncovered a serious lack of knowledge regarding what percentage of specialty pharmaceuticals was paid through the company’s medical benefit versus through pharmacy benefits. Of the respondent employers, 70% reported not knowing what percentage of specialty pharmaceuticals was paid through their medical benefit, and 40% reported not knowing what percentage was paid through their pharmacy benefit. A total of 29% of employers also reported not knowing what percentage of specialty pharmacy claim costs had increased in the pharmacy benefit over the past 3 to 5 years (Figure 2). Nevertheless, 54% of employers required their employees to use a specialty pharmacy to receive coverage. Of these employers, 57% required the mandatory use of a specialty pharmacy vendor for biologics and injectables, 39% required a minimum 30-day fill or a maximum 90-day fill of a prescription for specialty pharmacy injectables, and 29% required mandatory mail order for drugs used long-term for chronic disease (Table 2). As shown in Figure 3, 44% of the specialty drugs plan designs followed the same design as traditional pharmacy, using tiers and copayments. The second most favored design reported by respondents (27%) was a traditional pharmacy design with tiers and coinsurance. Of note, 59% of employers required utilization of a specialty pharmacy, and 59% also required prior approval and/or step therapy edits for claim approvals. In addition, 55% of employers included patient support and care management in their pharmacy plan design. Practically two thirds (66%) of employers valued medication-related cost transparency in their vendor contracts as “very important,” and 27% valued cost transparency as “important” (Figure 4). When asked which entities provided support for specialty product management, employers reported that the health plan provided the majority of support for case management (78%) or disease management (64%). When asked which entities provided support for specialty management, contracting, and benefit design, employers relied most heavily on pharmacy benefit managers (61%) and specialty pharmacies (56%). As shown in Table 3, contracting support was provided in large part by benefits consultants (60%) or was done in house (51%). More than three quarters (79%) of employers did their own benefit design in house, followed by benefits consultants (77%) and health plans (76%). This indicates that employers use more than 1 contractor but have not moved from traditional benefit designs (ie, designs that cover a determined benefit for every patient, with no distinction among the drug covered) to value-based or innovative benefit designs.

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January/February 2012

Vol 5, No 1

Beyond the Cost of Biologics

In addition, employers were asked to rank the effectiveness of case management/disease management support—from “excellent” to “don’t know”—for their covered employee population in 5 areas: 1. Increases in productivity 2. Improvements in treatment compliance 3. Increases in quality of life 4. Better management of related chronic conditions 5. Improvements in medication adherence. A surprising high percentage of employers indicated not knowing whether increases had occurred in productivity (45%) and in quality of life (40%). However, 43% were at least satisfied with improvements they saw in treatment adherence, and 52% were satisfied with the management of related chronic conditions (Table 4). Survey results show that a large percentage (76%) of employers still largely rely on print media (ie, letters, newsletters, print booklets, summary plan documents) to communicate with their covered population. The second most favored (51%) communication method was electronic medium or e-mail, followed by (48%) webbased medium. Telephone messages and personal contacts were still used by 39% of employers. However, when employers were asked to rate the effectiveness of various strategies used to communicate with their employees during the past 3 to 5 years regarding health benefits, most employers said they did not know (Table 5), indicating an amount of distance from the outcomes. To determine the efficacy of communication strategies, it is necessary to have evaluated their effectiveness over time. This finding highlights an underappreciation of the importance of these strategies in disease management and the importance of continually reevaluating messaging and employee responses to it.

Increase of Specialty Drug Total Claims during the Figure 2 Past 3-5 Years On average, what percentage has your biologics/specialty pharmacy total claim costs increased in the pharmacy benefit only over the past 3-5 years? (choose one) 29%

Don’t know 11%-20%

19%

5%-10%

19% 17%

>20%

10%

<5% No increase

5% 0

Percentage

Employer Mandatory Prescription Requirements for Table 2 Employees Do you currently require the mandatory use of:

Yes, %

No, %

Don’t know, %

Mandatory mail order for chronic use medications

A 30-day minimum or 90-day maximum fill of a prescription for biologics or injectables

A specialty pharmacy vendor for biologics and injectables

Figure 3 Specialty Pharmacy Plan Design Indicate the key components that comprise your current biologics/specialty pharmacy plan design (check all that apply)

Indicate which best describes your biologics/specialty pharmacy plan design (check all that apply) Same as traditional design using tiers and copayments

44%

Same as traditional pharmacy design using tiers and coinsurance 13%

Other, please specify

Don’t know

January/February 2012

42% 15%

Other, please specify 20

2% 0

Percentage

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55%

Don’t know

4% 0

59%

Special distribution requirements for products

11%

Special tier with coinsurance

59%

Prior approval and/or step therapy edits for claim approvals Patient support and care management

27%

Special tier with copay

Utilization of a specialty pharmacy

Percentage

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BUSINESS

Figure 4 Importance of Medication-Related Costs How important is medication-related cost transparency in your vendor contracts (choose one)? 66%

Very important Important

27%

Somewhat important

Not important

2% 0

Percentage

Entities That Support Employers in Specialty Table 3 Management, Contracting, and Benefit Design Management entity

Management, Contracting, Benefit design, % % %

Done on own or in house

Benefits consultant

Outside pharmacy

Pharmacy benefits manager

Specialty pharmacy

Health plan

Effectiveness of Case Management and Disease Table 4 Management Support with Covered Population Excellent, Good, Fair, Poor, Don’t % % % % know, %

Results Increases in productivity

Improvements in treatment compliance

Increases in quality of life

Better management of related chronic conditions

Improvements in medication adherence

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Discussion Specialty pharmaceuticals represent the fastest area of drug growth since 2004, and one in which drugs in the pipeline are already being marketed to consumers. However, as this survey shows, neither specialty pharmacy nor specialty drugs are completely understood by employers in their position as health plan sponsors. The MBGH/IIH survey uncovered the following disturbing facts about employers’ perspective on health benefits: • Employers are unaware of how effective their healthcare spending is • They are not sure how to design innovative benefits or manage the costs • They are also not sure of what works or how to effectively communicate information about specialty pharmaceuticals to their employees. Approximately 25% of employers have little or no understanding of specialty pharmaceuticals, and only 53% possess a moderate understanding of these therapies. Most employers are unaware of the amount of money their company has spent or is spending on specialty pharmacy, and 30% have no idea the extent to which costs have increased in the past 3 to 5 years. This finding mirrors those of the BFAC survey, in which 50% of payers and providers did not know the percentage of their organizations’ healthcare spending on biologics.3 Although all employers were aware that expenditures on specialty pharmaceuticals were important, almost none could project their organization’s approximate healthcare spending on diagnostics in combination with drug therapies for 2012.3 Most important, the survey shows that the represented employers have not moved from traditional benefit designs, thus missing potential benefits associated with using a value-based or innovative benefit design when dealing with specialty pharmacy. Furthermore, employers are apparently unaware how these innovative designs could improve efficiency of their specialty pharmaceutical management. Most employers use vendor costs as the determining factor when selecting and contracting with specialty pharmacy vendors (Figure 4). If the gaps in employer knowledge are allowed to continue, problems associated with not addressing the new mainstream use of biologics emerging from the research and development pipeline may remain unresolved. Furthermore, employers will not be able to communicate well with employees about specialty pharmaceuticals to determine whether their employees understood their specialty pharmacy benefits and whether these drugs had any positive effect on their employees’ health. As a result of these findings, MBGH and IIH are planning efforts to help employers: (1) fill in the educational

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Vol 5, No 1

Beyond the Cost of Biologics

Table 5 Effectiveness of Strategies and Employee Communication Efforts during the Past 3-5 Years Very effective, %

Effective, %

Somewhat effective, %

Not effective, %

Don’t know, %

Generic options

Protocols used for prior approval

Cost-sharing incentive

Days supply limited messaging

Communication from pharmacist

Integrated pharmacy network

Inclusion/exclusion criteria

Communication from physician

Health reimbursement account

Formulary explanation

Cost comparison

Audience benefit management communications for employees

Utilization management mailing and phone messages

Benefit/communication strategy

NOTE: Percentages in this table were rounded; therefore, some rows do not total 100%.

gaps related to understanding benefit coverage, spending, and healthcare costs; (2) determine key areas of utilization trends important to their organization; (3) identify short- and long-term opportunities for improving benefit strategies and examine available resources before executing them; (4) determine how to optimize benefit spending based on technology trends; and (5) shift benefit decisions as they gain knowledge in this area.

Conclusions These outcomes have defined the next steps for MBGH. Phase 2 of this initiative project will be completed in 2012, and includes working with an employer advisory council to advise and drive elements of the 2012 survey research, develop a web-based employer educational toolkit resource, and then build on 2 pilot educational outreach programs from late 2011 designed to disseminate research findings. It is hoped that these current and future efforts will help employers develop a better understanding and delivery of effective benefits for biologics. It is time to move beyond the potential and into optimizing healthcare outcomes, reducing employee risk factors and/or the progression of disease, and linking health with wellness along the continuum of care. ■

Acknowledgment The authors wish to acknowledge the editorial assistance of Sandra Paton in the preparation of this article. Study funding This study was funded by the Midwest Business Group on Health, a not-for-profit health research company that receives research support from various pharmaceutical companies. Author Disclosure Statement Dr Vogenberg, Ms Larson, Ms Rehayem, and Mr Boress reported no conflicts of interest.

References 1. Medco 2011 Drug Trend Report. Healthcare 2020. www.drugtrendreport.com/ 2011-report. Accessed November 30, 2011. 2. Centers for Medicare & Medicaid. Medicare Claims Processing Manual: Chapter 17–Drugs and Biologics. August 19, 2011. www.cms.gov/manuals/downloads/clm 104c17.pdf. Accessed November 30, 2011. 3. Nash DB, Toscani M, Vogenberg FR. The Biologic Finance and Access Council 2nd Annual Biologics Healthcare Survey: views from key healthcare stakeholders. Biotechnol Healthc. 2011;8:19-21. 4. Express Scripts. 2007 Drug Trend Report. April 2008. www.express-scripts.com/ research/research/dtr/archive/2007/dtrFinal.pdf. Accessed January 18, 2012. 5. Medco Health Solutions. Medco 2004 Drug Trend Report: Navigating the New Health Economy. May 2004;6(1). http://medco.mediaroom.com/download/2004+ DRUG+TREND+REPORT.pdf. Accessed November 30, 2011. 6. Dalzell MD. How will biologics fit into healthcare reform? Biotechnol Healthc. 2011;8:6-10. 7. Nash DB, Toscani M, Vogenberg FR. The Biologic Finance and Access Council 2nd Annual Biologics Healthcare Survey: view from key healthcare stakeholders, part 2. Biotechnol Healthc. 2011;8:23-25.

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January/February 2012

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BUSINESS

STAKEHOLDER PERSPECTIVE An Educated Consumer Is Our Best Customer EMPLOYERS: I believe that I speak on behalf of most of my colleagues in the specialty pharmacy industry when I ask the following question: “How can any employer responsible for the healthcare benefits of their employees and dependents today not understand specialty pharmacy?” With the impact of specialty pharmaceuticals on overall healthcare spending and trends, the number of specialty pharmaceuticals approved by the US Food and Drug Administration over the past few years, and the rich pipeline of specialty pharmaceuticals, it would seem that the primary focus of payers today would be on specialty pharmacy. The article by Vogenberg and colleagues in this issue of American Health & Drug Benefits highlights the lack of understanding of specialty pharmacy by a large proportion of employers that were surveyed online for this study. Of the 120 employers surveyed, 25% had little to no understanding of biologics, and only 53% claimed a moderate understanding of these medications. This is troubling, considering that specialty pharmaceuticals are expected to represent 21% of drug spending by 2013, and 40% of drug spending by 2020.1 We need to revisit the famous words, “An educated consumer is our best customer,” used by Sy Syms, CEO of the nowdefunct Syms Corporation, to address this conundrum. PHARMACY DIRECTORS: The specialty pharmacy industry must do a better job of educating the consumer, employer groups in this case, of what specialty pharmacy is, and what it means to payers. Even today, there is no consensus on a definition for specialty pharmaceuticals. We have publications that provide the general characteristics of specialty pharmaceuticals,2,3 but no agreed-on definition, which leads to significant confusion by all stakeholders. In addition, specialty pharmacies need to have less of a distribution focus in their discussions with employers and more focus on clinical support and outcomes

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reporting, to highlight the value that these entities provide to payers. The heavy focus on distribution of specialty pharmaceuticals continues to create a commoditization of the industry, with the majority of the weight on contracted discounts on specialty medications. This is leading to eroding margins and further consolidation of the industry. In addition, the lack of focus on clinical support and outcomes reporting is leading to a perception that specialty pharmacies do not provide much value to payers. As recent as 2 years ago, if I met with a potential client and presented to them that we had a patient care software system, I was almost guaranteed that this was a differentiator for our pharmacy. Today, virtually all potential clients who I present to ask for outcomes data and performance guarantees that we are going to improve patient care. The market has changed, but it is not clear that the specialty pharmacy industry has done enough to keep up with the demands from payers. We seem to be concentrating on shrinking margins, but we are not doing enough to change our model to meet the needs of our customers and reverse these shrinking margins. It is clear that we must start by educating the consumer about the value we provide. This will undoubtedly lead to a stronger relationship between the employer and their specialty pharmacy partner. 1. Medco Health. Medco 2011 Drug Trend Report: Healthcare 2020. www.drugtrend report.com/2011-report. Accessed February 2, 2012. 2. EMD Serono. EMD Serono Specialty Digest 2011. http://specialtydigest.emd serono.com/. Accessed February 2, 2012. 3. Blaser DA, Lewtas AJ, Ousterhout MM, et al. How to define specialty pharmaceuticals: a systematic review. Am J Pharm Benefits. 2010;2:371-380.

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Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy

January/February 2012

Vol 5, No 1

INDUSTRY TRENDS

Employers, Health Plans, and New Drug Benefit Designs: A Shifting Landscape Mark Zitter, MBA; Michael Snyder

ayers generally assert that in the face of rising costs they will manage pharmaceuticals more tightly. However, many restrictions that they say they will initiate never become widespread. Why not? Payers may offer a restrictive benefit design, but often employers and other plan sponsors are reluctant to select such designs for their employees. To understand the benefit landscape, we need to look to payers as well as employers. These findings come from the Zitter Group’s Managed Care Benefit Design Index, which surveys approximately 100 top payer decision makers and 100 self-insured employers and employee benefits consultants. This semiannual, multiclient study explores the trends influencing the creation of benefit design policies. This article is based on findings from the spring 2011 survey.

How Payers and Employers Differ There are significant differences between payers and employers with regard to which disease areas receive the greatest priority. Payers place the greatest management emphasis on the high-cost, high-prevalence categories of type 2 diabetes and cancer. Employers also prioritize cancer, but they focus much more than payers on lifestyle categories that can impact worker productivity, such as obesity and smoking cessation. In response to anticipated cost increases resulting from healthcare reform provisions, 55% of payers and 51% of employers planned to increase employee contributions to health insurance premiums for plan year 2011 (Figure 1). However, there was a stark difference between the 2 groups regarding increasing utilization management. A full 59% of payers surveyed reported having plans to increase utilization management, compared with only 15% of employers. Furthermore, although 45% of payers planned to institute a more restrictive formulary, only 13% of employers intended to adopt such a measure. Mr Zitter is Chief Executive Officer and Mr Snyder is Sales & Marketing Analyst, The Zitter Group, San Francisco, CA.

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KEY POINTS ➤

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This article is based on findings from the Managed Care Benefit Design Index and compares payer management priorities and efforts and the priorities of employers regarding benefit design in the face of healthcare reform and shifting market dynamics. Payers are looking to increase utilization management and cost-sharing to combat the cost increases anticipated as a result of the healthcare reform and shifting market dynamics. Employers are similarly concerned with rising costs, but differ from payers in terms of the level of utilization management and increased cost-sharing they are comfortable instituting. Although both stakeholder groups are in alignment regarding cost concerns and certain aspects of benefit design, significant differences are evident between the management priorities of payers and employers. To address rising healthcare costs and successfully create benefit design policies for the long-term, payers and employers will need to better understand each others’ motivations and concerns.

Looking at specific utilization management changes, 68% of payers increased the number of drugs subject to prior authorization, prior failure, or step edits, and 49% reduced the range of brand-name drugs covered on their most common formulary. By contrast, a large majority of employers made no changes to their utilization management policies for plan year 2011. Only 21% of employers increased the number of drugs subject to prior authorization, prior failure, or step edits, and 14% decreased the range of brand-name drugs covered on their most common formulary. Some of these differences can be explained by the response samples. Payers represented a cross-section of the market, whereas the employer group was drawn mainly from larger, self-insured employers. Many payers are able to institute more restrictive policies across much

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INDUSTRY TRENDS

Figure 1 Cost Control Responses to Healthcare Reform Please select all actions your organization elected to implement for plan year 2011 to offset anticipated cost increases as a direct result of the aforementioned healthcare reform provisions 59%

Increased utilization management 15%

55%

Increased employee contribution to health insurance premiums

51% 45% Instituted a more restrictive formulary 13% 44%

Increased employee copayments/coinsurance rates for prescription drugs

24% 35%

Increased employee copayments/coinsurance rates for physician visits

28% 35%

Increased employee deductibles

Payers Employers

28%

Payers: N = 75 Employers: N = 75

Respondents

Source: The Zitter Group. Managed Care Benefit Design Index; Spring 2011.

of their populations (including fully insured members) than large employers are willing to accept. Moreover, many employers see their key responsibility as designing and/or selecting the benefit, thereby leaving management to the payer. For example, few employers see themselvesâ&#x20AC;&#x201D;or want others to see themâ&#x20AC;&#x201D;as being involved in utilization management.

Cost-Sharing Although cost-sharing seems to be the most straightforward lever to pull when looking to reduce short-term costs, it is not used as often as might be expected. When payers were asked what factors keep them from increasing cost-sharing, 33% responded that concerns about compliance and healthcare outcomes prevented them from using cost-sharing more liberally. This percentage is double that of employers who share similar concerns. Payers cited a much wider range of cost-sharing structure changes for plan year 2011 than employers

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(Figure 2). Of the payers, 78% planned to increase member contribution to health insurance premiums, and 47% planned to increase cost-sharing for prescription drugs. Increasing member contribution to health insurance premiums was the most frequent selection by employers, although only 39% intended to do so. Despite reported hesitation to increase cost-sharing for physician visits, because of worries that it may have negative ramifications on long-term costs, 30% of payers and 22% of employers still planned to make this change in 2011. For all of these potential interventions, payers said that they were going to be doing more than employers, which emphasizes the increased aggressiveness of payer management relative to what employers indicated they were willing to adopt. Raising premiums can reduce the cost to the payer or to the employer, leaving employees with more of the burden. Increasing cost-sharing can theoretically also drive

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Employers, Health Plans, and New Drug Benefit Designs

Figure 2 Cost-Sharing Structure Changes: Stakeholder Comparison Thinking of your most common commercial plan, please qualify the following possible cost-sharing structure changes with regard to plan year 2011 Member contribution to health insurance premiums

39%

78%

Cost-sharing rates for prescription drugs

47%

HDHP/CDHP/HSA options

44%

Maximum member out-of-pocket responsibility

44%

23% 14% 20% 9%

39%

Cost-sharing spread between tier 2 and tier 3 Cost-sharing rates for inpatient hospital stays

31%

Cost-sharing spread between tier 1 and tier 2

30%

Cost-sharing rates for physician visits

30%

14% 11% 22% Employers

Payers

Payers: N = 101 Employers: N = 101

Respondents

CDHP indicates consumer-directed health plan; HDHP, high-deductible health plan; HSA, health savings account. Source: The Zitter Group. Managed Care Benefit Design Index; Spring 2011.

better health-related behaviors by members, leading them to avoid seeking unnecessary healthcare. The problem with this way of thinking is that research has long shown that increased cost-sharing, although successful in reducing demand for inappropriate care, also tends to reduce the demand for appropriate care.1 By contrast, premium increases do not impact demand for care, because people pay upfront. Unless premiums increase so much that people drop their healthcare coverage entirely, there is no reason to believe there will be any significant difference in utilization. When analyzing the potential risk of enacting measures for short-term savings at the possibility of raising long-term costs, there is an overwhelming difference between payers and employers on a few measures. More than twice as many payers as employers said that increasing the employee copayment for physician visits is a bad idea. Although this will save money in the short-term, people who do not go to the doctor when needed will likely cost more in the long-term. Conversely, employers

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are much more reluctant than payers to increase costs for prescription drugs. These differences in concerns between payers and employers begin to shed light on why employers do not necessarily buy into some of the benefit designs offered by payers.

Benefit Design The most popular pharmacy benefit design today still incorporates a 3-tier formulary. What has been changing over the past 2 or 3 years is the rise of the fourth tier. Of total payer administrator servicesâ&#x20AC;&#x201C;only plans, 23% have 4 tiers on their most representative formulary. However, Medicare Part D plans are now equally likely to have a 3-tier or a 4-tier structure (Figure 3). When seeking to decrease drug costs, payers first look at increasing cost-sharing for prescription drugs and, second, at switching from copayments to coinsurance for drugs. The third option to consider is offering a benefit strategy for specialty biologic drugs that allows claims to

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INDUSTRY TRENDS

Figure 3 Formulary Adoption: Stakeholder Comparison How many tiers are there in your most representative formulary design? 66%

Payers: ASO Payers: full risk Payers: Medicare Part D Employers

63%

Respondents

49%

Payers: N = 101 Employers: N = 101

34%

34% 28% 23%

21% 10%

15%

13% 6%

0% 1 tier/no tier

14%

2 tiers

3 tiers

4 tiers

2% 5 tiers

Formulary design

ASO indicates administrative services only. Source: The Zitter Group. Managed Care Benefit Design Index; Spring 2011.

be managed by pharmacyâ&#x20AC;&#x201D;where payers can exert more controlâ&#x20AC;&#x201D;but is adjudicated back to the medical benefit. However, this cross-benefit management is complex, and many health plans do not have the capability to do so successfully.

One of the most popular future innovation measures that payers intend to use to save on costs is high-deductible benefit design. Although payers and employers are split on the impact of high-deductible benefit design on healthcare outcomes, they agree that there are total pharmacy spending decreases for those commercial lives enrolled in these health plans. Perhaps more important is that approximately 50% of employers do not have the same entity to manage both their medical and pharmacy benefits. Cross-benefit adjudication is not likely to happen when there are different entities managing each benefit.

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With more of the expensive biologic drug categories having multiple drugs with similar safety and efficacy profiles, payers show preference for category management approaches. However, this preference is difficult to achieve if they are only managing one side of that benefit. The plans that cover both benefits are trying to move in the direction of having claims managed by the pharmacy benefit and adjudicated by the medical benefit, but we are a long way from ubiquity.

Looking Ahead One of the most popular future innovation measures that payers intend to use to save on costs is highdeductible benefit design. Although payers and employers are split on the impact of high-deductible benefit design on healthcare outcomes, they agree that there are total pharmacy spending decreases for those commercial lives enrolled in these health plans. Employers are slowly moving in the direction of offering more high-deductible plans. Of the employers who offer preferred provider organization, point of service, and/or HMO plan options, only 11% indicated they plan to offer only high-deductible health plans for the 2012 plan year. However, an additional 23% are actively con-

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Employers, Health Plans, and New Drug Benefit Designs

sidering switching to high-deductible health plans for 2012 and beyond. Value-based benefit design options and adherence programs that include patient–employee communications sound great in theory but have yet to make any substantial impact on cost-savings. All parties involved would like to have improved adherence, but it has not happened significantly in practice. These 2 management techniques have shown success in pilot programs but have failed to scale effectively. When payers are asked to explain why we do not see more of these innovative strategies in widespread practice, aside from cost, they claim that employers are too concerned with employee dissatisfaction. In fact, employers are concerned about employee morale, but not to the degree that payers perceive. When asked to explain why they decline to implement payers’ proposed management strategies, aside from cost, employers most often say that they are just not convinced the proposed benefit will work.

Conclusion Payers and employers have a lot of similarities, but also many differences. The most common lever used in benefit design is cost-sharing. As seen in response to cost increases stemming from healthcare reform, increased cost-sharing is a quick fix for payers and for employers. Although cost-sharing is able to provide some short-term savings, it will not be the answer in the long-term. Therefore, payers and employers need to better understand each other’s motivations and concerns to successfully create benefit design policies that are beneficial to everyone. ■ Author Disclosure Statement Mr Zitter and Mr Snyder reported no conflicts of interest.

Reference 1. Brook RH, Ware JE, Rogers WH, et al. The Effect of Coinsurance on the Health of Adults: Results from the Rand Health Insurance Experiment. RAND Corporation; December 1984. www.rand.org/content/dam/rand/pubs/reports/2006/R3055.pdf. Accessed January 23, 2012.

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

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:

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); PP<0.05 <0.05 < 70 60 50 40 30 20

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

MP ((n=338) n=338)

0 0

Kaplan-Meier estimate.

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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Primary Care Shortages: Strengthening This Sector Is Urgently Needed, Now and in Preparation for Healthcare Reform Sarah Collins, MBA

Stakeholder Perspective, page 47

Am Health Drug Benefits. 2012;5(1):40-47 www.AHDBonline.com Disclosures are at end of text

Background: The United States currently faces great challenges in primary care, particularly when the Patient Protection and Affordable Care Act (ACA) greatly expands the health insurance market. Objectives: To (1) discuss key areas where primary care needs to be strengthened, including advanced models of physician reimbursement, chronic disease management, and improved patient adherence to medications, and (2) to review initiatives applying evidencebased medicine (EBM) where positive changes have in fact occurred. Discussion: This article discusses initiatives that have implemented EBM as their model for change and presents interviews with primary care experts to support the growing need for change in primary care. To improve the quality of care and reduce costs, more needs to be done, particularly by fostering the number of primary care physicians (PCPs) and other healthcare professionals in PCP offices, as well as adjusting payment methods that much more strongly support and reward the primary care and the patient-centered medical home (PCMH) models. An additional area where substantial improvements are needed involves inner-city, rural, and other underserved populations. Provider- and managed care–driven changes are taking place, but much more needs to be done, particularly as a result of the ACA-associated health insurance enrollment expansion. Innovation in payment for PCPs and PCMHs (and corresponding changes in care delivery and improvements in clinically significant outcomes) will be key factors toward the successful implementation of ACA changes. In addition, several examples are discussed, in which the flexibility of managed care and its results-driven orientation are crucial factors for success. Future initiatives that will likely be more challenging and will require significant government funding include the US underserved populations and incentives to encourage medical school students and residents to choose primary care as a specialty. Conclusion: More innovation, particularly related to realignment of financial incentives to strengthen primary care, is needed to meet America’s growing healthcare quality and cost challenges.

ith total health insurance costs at approximately 17% of the US Gross Domestic Product,1 a rapid growth rate, rising rates of chronic diseases, such as diabetes, and an aging population, changing the dynamics—the fundamental drivers—of the US healthcare is key. The 2010 Census estimates 16.3% of Americans do not have health insurance, and that the percentage of people with employment-based health insurance decreased from 56.1% in 2009 to 55.3% in 2010.2 The employment picture is also weak. In 2010, 16.2% Ms Collins is President, America’sHealth, Oak Hill, VA.

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of the US population was either unemployed, had temporarily given up searching for a job, or was working parttime while looking for full-time employment.3 A national survey of employer-based health insurance showed that average premiums for family coverage in 2011 totaled $15,073 (9% higher than in 2010), with employer contributions of $10,944 and employee contributions of $4129.4 In addition, the United States faces strong headwinds from the weakness of the international economy, a financially led downturn that tends to last longer and be deeper than other recessions,5,6 and hyperpartisan politics. The need for accessible, affordable health insurance will be even greater in 2014 than it is now.

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This article reviews the current shortages in primary care physicians (PCPs) and other healthcare professionals that must be greatly ameliorated before the major expansion of the US health insurance system in 2014, when the Patient Protection and Affordable Care Act (ACA) provides health insurance alternatives to individuals and to businesses with 50 or more employees. The article also discusses several examples of transformative initiatives in the US healthcare system that have been shown to improve the quality and lower the cost of care. Figure 1 depicts the key ways in which the US healthcare system may need to move forward to meet these challenges.7-11

The Challenges of the Current PCP Shortages The United States is currently facing shortages in physicians and other healthcare professionals that are needed to provide care in the PCP office setting. A December 2010 Council on Graduate Medical Education report estimated that there were 242,500 PCPs in the United States in 2010, and almost 25% (55,000) of them aged ≥56 years.12 The average compensation for PCPs is approximately only 55% that of other medical specialties, leading to a cumulative lifetime net income gap of approximately $3.5 million for the individual PCP.12 This essentially results from the resource-based relative value system (RBRVS) on which the Medicare fee-for-service (FFS) schedule payments are based. A likely unintended consequence of the RBRVS is a bias toward viewing skill in terms of expertise in conducting a specialized procedure as opposed to professional time, as well as expertise in making a correct diagnosis by differentiating among multiple potential conditions, or improving chronic conditions that are typically associated with increased morbidity and cost. The Medicare FFS schedule is used not only in Medicare; it also influences managed care organization (MCO) and Medicaid physician reimbursement payment amounts. A closely related challenge is the very low percentage of medical school students who are choosing to go into primary care. A related challenge is that approximately 59 million Americans, almost one fifth of the US population, live in areas with health professional shortages.13 Shortages in a number of other primary care healthcare professionals exist, notably with nurses—the single largest provider group in the United States.14,15 A minority of nurses are employed in the ambulatory care and in public and community care settings.14 Many healthcare professional shortage areas in the United States are in rural and inner-city areas, where the population is medically underserved. State-by-state and county data are available on the US Department of Health and Human Services website.16 Rural areas may

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KEY POINTS ➤

➤

The US healthcare system is facing a major expansion in 2014, when the Affordable Care Act is expected to provide insurance alternatives to individuals and businesses with 50 or more employees, which will increase the demand for primary care. The United States is facing shortages in physicians and other professionals who are needed to provide care in the primary care office setting. A key driver of the primary care shortage is relatively low pay and overall lifetime income compared with specialists. The average compensation of primary care physicians (PCPs) is approximately only 55% of that for other clinical specialties, with a cumulative lifetime net income gap of approximately $3.5 million per PCP. Approximately 59 million Americans live in areas with a health professional shortage, primarily in rural and inner-city areas, where the population is medically underserved. The patient-centered medical home is evolving as a key initiative, with the potential to improve the quality and curb the cost escalation of our healthcare. It will require a multidisciplinary team effort that includes PCPs, nurses, and physician assistants, among others, to achieve these goals.

Figure 1 Moving Toward More Effective, Lower-Cost Care

1. Primary care–based care model

2. EBM chronic diseases treatment

3. Patient self-management

EBM indicates evidence-based medicine.

be unable to financially support a PCP’s practice,12 and there may be other practice challenges and lifestyle issues. Solutions may well require innovations in current practices (as discussed below). Inner-city areas present their own challenges, and

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Table 1 Provisions in the Healthcare Reform Law Related to Primary Care Topic

PPACA Provisions

Preventive services

• Provide incentives for Medicare and Medicaid beneficiaries to complete behavior modification programs • Require qualified health plans to cover, without cost-sharing, preventive services rated A or B by the US Preventive Services Task Force

Wellness programs

• Provide grants for up to 5 years to small employers that establish wellness programs • Permit employers to offer employees rewards—premium discounts, cost-sharing waivers, or benefits that would not otherwise have been provided—of up to 30% of the cost of coverage for participating in a wellness program and meeting certain health standards

Workforce

• Establish a multistakeholder workforce advisory committee to develop a national workforce strategy • Increase graduate medical education (GME) training positions, with priority given to primary care and general surgery, and states with the lowest resident physician-topopulation ratios • Increase flexibility in GME funding to promote training in outpatient settings and increase residency programs in rural and underserved areas • Establish federally funded health centers that include primary care residency programs • Increase workforce supply and support healthcare professional training via scholarships and loans • Provide state grants to providers in medically underserved areas • Train and recruit providers to serve in rural areas • Establish a public health workforce loan repayment program • Increase funding for nursing education, training programs, loan repayment and retention grants, and career ladder creation • Provide grants to employ and train family nurse practitioners who provide primary care in federally qualified health centers and nurse-managed clinics • Support development of training programs that focus on primary care models, such as medical homes, team management of chronic disease, and integration of physical and mental health services

PPACA indicates Patient Protection and Affordable Care Act. Source: Henry J. Kaiser Family Foundation. Focus on Health Reform: Summary of New Health Reform Law. April 15, 2011. www.kff.org/healthreform/upload/8061.pdf. Accessed January 12, 2012.

until the ACA’s enactment, Medicaid’s low payment rates may well have created significant disincentives. In a telephone interview on October 8, 2011, with Michael Collins, MD, an internist with 30 years of experience in primarily treating commercial and Medicare patients, as well as inner-city Medicaid patients, he commented on the greater complexity and the number of medical problems his Medicaid beneficiaries have, including an increased incidence of serious mental illness. Transforming the US PCP workforce will require significant changes. The ACA includes a number of measures to support PCPs.17 Table 1 provides a summary of the primary care model as outlined by key ACA provisions.

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The funding levels in the ACA for these priorities— such as $1.5 billion for the National Health Services Corps—are reasonable and in all likelihood may be costsaving, by averting increasing morbidity and hospitalization levels in the United States.17 In 2 separate telephone interviews conducted on September 21, 2011, with Virginia L. Hood, MD, President of the American College of Physicians (ACP), and with Glen R. Stream, MD, MBI, FAAFP, President of the American Academy of Family Physicians, they both expressed strong support for the ACA. Dr Hood and Dr Stream are both concerned that hyperpartisan politics in Washington, DC, as well as concerns about

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the deficit, may derail the funding needed for these key initiatives to support primary care, which are very likely to reduce, or at least restrain, the growth of healthcare costs in the United States. Dr Hood noted that the Workforce Advisory Committee has not yet met, and funding for a number of other initiatives to support a strengthened PCP-based system has either not been provided or has been relatively low. Furthermore, the number of PCP slots at residency programs, which has not changed since 1997, is particularly problematic, according to Dr Hood. And Dr Stream suggested that scholarships are a more powerful incentive than debt forgiveness to draw medical students into primary care. Given the current intense Republican opposition to “Obamacare,” various national polls showing ambivalence toward the ACA, uncertainties related to potential Supreme Court action on the ACA, and the hyperpartisanship in Washington, it may be valuable to bring forth a separate new bill that focuses solely on key primary care–related provisions in the ACA, as identified in Table 1, for which bipartisan support can be expected.

Initiatives to Strengthen Primary Care The politics surrounding Federal Emergency Management Agency (FEMA) expenditures in the wake of multiple unexpected natural disasters, and the passage of a bill to fund FEMA in late September 2011 with bipartisan support, suggests this as a possibility. Strengthening of the PCP model, which is desperately needed, and quickly, is currently being held hostage to politics: there is a strong likelihood that this situation will continue, given the current political environment. Tax Incentives Considering strong negative feelings toward Obamacare and congressional concern about any spending increases, Donald B. Marron, Director of the Urban-Brookings Tax Policy Center, in an interview conducted on September 14, 2011, discussed alternative strategies for providing tax credits for PCPs and training. “People do respond to tax credits,” Mr Marron commented, noting that there would have to be identifiers recognizable by the Internal Revenue Service for program qualification. Increasing the level of tax credit (ie, financial incentives) for PCPs working with identifiable underserved populations may be a successful strategy. To encourage medical school students and residents to join primary care, another strategy could be to have costs associated with medical school training for PCPs depreciated through income tax credits, with the depreciation schedule’s structure developed in such a way that it strongly incentivizes students and residents.

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Particularly because years in residency are rigorous and have low pay, accelerated depreciation could provide a strong incentive to choose primary care. Safeguards, such as a 5-year commitment to work primarily with Medicaid or patients in underserved areas, would of course need to be put into place. These are some strategies that deserve to be further explored in line with Mr Marron’s suggestions.

Patient-Centered Medical Home Among the different ongoing initiatives aimed at improving the quality and reducing the cost of healthcare in the United States, one that stands out is the patient-centered medical home (PCMH). In his interview, Dr Stream commented that various articles published in peer-reviewed journals demonstrate that PCMHs improve the quality of patient care.18-20 Both Dr Stream and Dr Hood discussed the importance of the PCMH as a multidisciplinary team effort that includes not only PCPs but other healthcare providers as well. Dr Stream used the imagery of a football team, where the PCP is the quarterback, but the team as a whole and individual members of the team have considerable flexibility in their activities, always working toward the goals of improved patient care and better outcomes. In different practices, effective models, and which healthcare providers should be involved, vary significantly. Nurses in Primary Care In an interview conducted on September 29, 2011, with Peter McMenamin, PhD, Senior Policy Fellow of the American Nursing Association, Dr McMenamin discussed the value of advanced practice nurses (APNs) and physician assistants (PAs) as physician extenders who can prescribe medications. APNs and PAs receive substantial training related to pharmaceuticals, an important fact because of the importance of drugs and the issue of patient adherence in improving outcomes in chronic diseases. Dr McMenamin pointed out, however, that there is “substantial variation between states in terms of APNs’ scope of practice,” with greater restrictions in Southern states. Many PAs work with surgeons or other specialists; therefore, potentially the growth of this profession may not have as strong an impact on primary care. Additional healthcare professionals that can be valuable in developing the care-provider team include registered nurses, licensed practical nurses (LPNs), case managers, health coaches, and medical assistants. By reviewing multiple cases and coordinating care, case managers can work to ensure delivery of high-quality care and improved outcomes. Health coaches can help to work through particular problems or focus on and achieve specific goals.

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Projected Direct Spending on Diabetes and Figure 2 Complications, 2008-2033 Diagnosed 2029-2033 Diagnosed 2019-2028 Diagnosed 2009-2018 Currently have diabetes ✳ Total spending

350

2007 Dollars, billions

300 250 200 150 100 50

in addition to the approximately 150 PA programs that currently exist, about 40 new programs are preparing for credentialing. According to the 2010 Census, there were more than 83,000 PAs in the United States in 2010.21 Mr Wooten added that PAs can undertake many of the traditional roles of PCPs, which can be particularly valuable in rural and other areas when PCPs are unavailable, or in roles such as case management or professional activities associated with medication management, which is essential for successfully managing patients with chronic conditions. Although the difference in pay is not nearly as monetarily large as between PCPs and specialists, the issue of pay disparities between specialties also affects PAs. However, more than 30% of PAs choose primary care—the largest specialty they select—and they certainly are an important contribution to the primary care workforce.21

0 08 10 12 014 016 018 020 022 024 026 028 030 032 2 2 2 2 2 2 2 2 2 2 20 20 20

Reprinted with permission from Huang E, et al. Diabetes Care. 2009;32:2225-2229.

In his interview, Dr Collins commented that highquality, well-trained medical assistants can be extremely helpful in taking a thorough medical history, which includes understanding patient stress levels. Stress can make medical conditions worse or even lead to the false appearance of a medical condition when the cause is simply very high stress. In addition, he noted that medical assistants’ salaries are significantly lower than those of other healthcare professionals, making it cost-effective for them to spend time with patients. A 2011 Institute of Medicine report highlights the critical need for more nurses.15 Increasing the number of nurses in PCP offices is key to the success of the PCMH model. In his interview, Dr McMenamin noted that there is a shortage of nursing faculty. He also pointed out the issue of faculty aging, which creates additional challenges in educating registered nurses and APNs. He commented that APNs can play multiple roles in the PCMH model, including seeing patients, developing coordinated health plans, and acting as case managers. APNs receive substantial training related to pharmaceuticals and have prescribing authority in all 50 states.

Physician Assistants in Primary Care In an interview conducted on September 9, 2011, with Robert Wooten, PA-C, President of the American Association of Physician Assistants, Mr Wooten said that PAs can play a substantial role in primary care, and

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PCMH’s Success in Managing Chronic Conditions: TEAMcare It is well known that chronic disease is an enormous driver of healthcare costs in the United States.22 Diabetes, which is frequently associated with high blood pressure and/or hypercholesterolemia, is exploding, both in terms of the number and severity of patients with diabetes, as well as treatment costs.22 Figure 2 provides projections about the number of patients with diabetes and the cost burden to the US healthcare in 2033, if, as a society and as individuals, we do not substantially change course. An excellent example of the PCMH in action— albeit within the context of a closed-staff model HMO—is TEAMcare’s work with patients who had depression and diabetes (the majority of patients) and/or cardiovascular disease.7 Table 2 presents 12-month data from the TEAMcare study.7 In a September 9, 2011, discussion with Elizabeth H.B. Lin, MD, MPH, a family physician and researcher with Group Health Research Institute in Seattle, WA, about what can explain why TEAMcare was so successful with such challenging disease states, she noted the importance of identifying and treating depression first, so that patients can become more active as partners in managing their disease. Dr Lin also said that despite the social stigma of depression, there is a very well-validated instrument, the Patient Health Questionnaire (PHQ-9) with which to measure it. Typically, depression in patients with comorbidities has been overlooked to focus on hypoglycemia, systolic blood pressure, or low-density lipoprotein levels. Dr Lin explained that the TEAMcare approach is truly multidisciplinary. Teams include PCPs, nurse case

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managers, and consultant psychiatrists, as needed. The team can be expanded to include PAs, LPNs, medical assistants, and clinical pharmacists. Another notable component of this approach, according to Dr Lin, is the concept of “treat to target,” in which the patient is involved in selecting the target (eg, weight vs exercise) and the specific clinical goal. Creating personal connections between patients and members of their healthcare team is important, and this is potentially one of the factors in TEAMcare’s (and the PCMH’s) success.23

Changing Patient Behavior: The Ochsner Health System Model In a September 12, 2011, telephone interview, with Patrick J. Quinlan, MD, Chief Executive Officer at Ochsner Health System, one of America’s top integrated health systems, Dr Quinlan stressed the importance of not accepting the US current high health burden as inevitable. “The first step is to reduce the disease load to prevent what’s preventable, since about 50% of the disease burden is related to lifestyle factors,” and to moderate what is not, Dr Quinlan said. He noted the importance of caring about one’s own health and taking personal responsibility for it. Dr Quinlan also highlighted the importance of the primary care model and of a team-based strategy, which could potentially include social supports such as family members, groups, or others who could help patients in maintaining healthy choices, such as weight loss, smoking cessation, and exercise. He reinforced the importance of direct personal support, noting that telephonic support alone is a poor substitute. Dr Quinlan further addressed employers’ shared interest in effective wellness programs. When asked what helped motivate people’s behavior the most, Dr Quinlan replied “a pedometer.” Ochsner Health System uses Virgin HealthMiles, an employee wellness program in which employees use a pedometer to record their steps and periodically measure their blood pressure, weight, body fat, and body mass index at kiosks located throughout the 13,000-employee Ochsner system.24 Employees can measure their progress, and data are uploaded to a central system. Dorothy Cain, RN, the system coordinator at Ochsner, commented in a September 28, 2011, interview on the high employee participation rate (87%), adding that daily activity and accountability are important to the program’s success. Successful program participants can significantly reduce their health insurance premiums for the following year, according to Ms Cain. This is logistically easier for Ochsner, and it also benefits employees, because premiums and employer contributions have been rising significantly faster than wages. It also avoids the sales tax that cash or gift card rewards

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Table 2 TEAMcare Select Trial Results at 12 Months TEAMcare group, %

Usual care group, %

Improvement on Patient Global Improvement scale

≥50% decrease in SCL-20 score (depression)

≥1.0% decrease in glycated hemoglobin level from baseline at 12 months (P = .006)

≥10-mm Hg decrease in systolic blood pressure from baseline at 12 months (P = .016)

Satisfaction with care of depression

Satisfaction with care of diabetes, heart disease, or both

Outcome

SCL-20 indicates Symptom Checklist-20. Source: Katon W, et al. N Engl J Med. 2010;363:2611-2620.

incur, she said. Ms Cain discussed the importance of upper-management commitment to wellness, noting that with the unsustainable rise in healthcare costs, this shift is in fact occurring.

Strategies to Strengthen the PCMH Model A number of strategies could help with underserved rural populations. For example, Family Medicine Spokane offers residency and medical school training and participates with other specialties in the Colville, WA (population of approximately 5000 people) rural training track.25 In the interview mentioned earlier with Dr Stream, he said that in very sparsely populated regions in the Northwest, Midwest, and other areas, an APN could schedule clinic visits several days per week and work with a PCMH to deliver the full spectrum of care needed. A central PCMH base and multiple satellites could cover a very wide geographic area. Funding the higher level of care, coordination, and case management required in this type of model requires more than an encounter-based payment schedule. Dr Stream noted that including a care or case management component—a per-member, per-month (PMPM) amount—to pay for the infrastructure needed to establish and operate as a PCMH is important, as is a pay-forperformance component. Dr Stream commented that current payment mechanisms are typically insufficient for the levels and nature of care needed for patients with chronic conditions.

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A number of new healthcare payment models have either been implemented or are being considered. MCOs have greater flexibility in terms of how they pay physicians: a number of MCOs, Medicaid programs, and others are experimenting with new payment systems. In the interview with Dr Hood, she discussed the example of Vermont’s multipayer Blueprint for Health, for which the 2010 annual report demonstrates very favorable results in terms of reduced hospital admissions for Medicaid patients, as well as reduced costs for hospitalizations and overall care.8 Another payment example is the PCMH model created by Community Care of North Carolina (CCNC), which provides care-coordination payments for Medicaid patients. As shown in a study of CCNC’s Medicaid program, which was conducted by Treo Solutions, an independent health analytics company, the program achieved $1.5-billion savings over a 3year period (from 2007 to 2009) for its Medicaid enrollees.26 In an interview conducted on October 5, 2011, with Yul D. Ejnes, MD, FACP, of Coastal Medicine, a primary care practice in Rhode Island that has more than 80 physicians, Dr Ejnes discussed how Blue Cross of Rhode Island—a nonprofit MCO and the state’s largest payer—has contracted with several large practices to develop PCMHs that meet guidelines developed by the ACP several years ago. According to Dr Ejnes, the practice is reimbursed based on a risk-adjusted PMPM payment amount, a slightly enhanced FFS basis, and performance-based criteria, such as following national guidelines for screening and treatment of patients whose disease characteristics place them at particularly high risk for serious medical events. To expand patients’ access, the practice is also open on Saturdays. Dr Ejnes said that the new payment mechanisms helped pay for salaried nurse case managers who provide care coordination and case management. He commented that these changes made the “practice of medicine more fun, and that [his] time was now freed up to interact with patients.” He also noted the reduced time he had to spend on administrative tasks. Finally, the use of H-1B visas, and potentially changing the H-1B program so that PCPs would not need an employer sponsor, could be another way to increase the number of primary care providers in the United States. In addition, other countries, including Canada, Denmark, the Netherlands, and England, have programs to attract designated, highly skilled workers to their countries. A program like this in the United States could potentially be useful in rural areas, because many countries have substantial rural populations.

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Conclusion There is a great deal to be done in a short time to prepare for the changes in the ACA and to reverse the charging and very destructive drivers of America’s growing healthcare costs. This is something that as Americans working in a business environment and as a country, we cannot afford. Dr Stream expressed optimism that we can turn the situation around thanks to the clear understanding of what is needed to be done, the possibility of robust solutions, and the national sense of urgency. More innovation—particularly with regard to realignment of financial incentives to strengthen primary care and increase the number of PCPs and other healthcare providers who choose or move to primary care—is needed to meet America’s growing healthcare quality and cost challenges. ■ Author Disclosure Statement Ms Collins has no conflicts of interest to report.

References 1. Centers for Medicare & Medicaid Services. NHE fact sheet. www.cms.gov/ NationalHealthExpendData/25_NHE_Fact_sheet.asp. Accessed January 12, 2012. 2. US Census Bureau. Health Insurance Highlights: 2010. www.census.gov/hhes/ www/hlthins/data/incpovhlth/2010/highlights.html. Accessed January 12, 2012. 3. Pipes S. The Census, ObamaCare and the Uninsured. Wall Street Journal. September 26, 2011: A17. 4. 2011 Kaiser/HRET Employer Health Benefits Survey. September 2011. http:// ehbs.kff.org/pdf/2011/8225.pdf. Accessed January 12, 2012. 5. Napier R. Anatomy of the Bear: Lessons from Wall Street’s Four Great Bottoms. 2nd ed. Petersfield, UK: Harriman House; 2007. 6. El-Erian M. When Markets Collide. New York, NY: McGraw-Hill; 2008. 7. Katon W, Lin E, Von Korff M, et al. Collaborative care for patients with depression and chronic illnesses. N Engl J Med. 2010;363:2611-2620. 8. Vermont Blueprint for Health 2010 Annual Report. January 2011. http://hcr. vermont.gov/sites/hcr/files/final_annual_report_01_26_11.pdf. Accessed September 12, 2011. 9. Interview with Patrick J. Quinlan, MD, Chief Executive Officer (CEO), Ochsner Health System; September 12, 2011. 10. Stanford Patient Education Research Center. http://patienteducation.stanford. edu/. Accessed November 11, 2011. 11. National Comprehensive Cancer Network. NCCN Guidelines & Clinical Resources. www.nccn.org/professionals/physician_gls/f_guidelines.asp. Accessed November 11, 2011. 12. Council on Graduate Medical Education. Advancing Primary Care Twentieth Report. December 2010. www.aafp.org/online/etc/medialib/aafp_org/documents/ press/2011-match-media-kit/cogme-advancing-primary-care.Par.0001.File.tmp/ COGME-20threport-2011-Exec-Summ.pdf. Accessed January 12, 2012. 13. US Department of Health and Human Services Health Resources, Health Resources and Services Administration. Designated health professional shortage areas (HPSA) statistics. http://ersrs.hrsa.gov/ReportServer?/HGDW_Reports/BCD_ HPSA/ BCD_HPSA_SCR50_Smry&rs:Format=HTML3.2. Accessed January 12, 2012. 14. US Department of Health and Human Services Health Resources, Health Resources and Services Administration. The Registered Nurse Population: Initial Findings from the 2008 National Survey of Registered Nurses (HRSA). http://bhpr. hrsa.gov/healthworkforce/rnsurveys/rnsurveyfinal.pdf. Accessed January 12, 2012. 15. Institute of Medicine. The Future of Nursing: Leading Change, Advancing Health. Washington, DC: National Academies Press; 2011. http://books.nap.edu/openbook. php?record_id=12956. Accessed January 12, 2012. 16. US Department of Health and Human Services, Health Resources and Services Administration. Find Shortage Areas: HPSA by State & County. http://hpsafind. hrsa.gov/. Accessed September 27, 2011. 17. Henry J. Kaiser Family Foundation. Focus on Health Reform: Summary of New Health Reform Law. April 15, 2011. www.kff.org/healthreform/8061.pdf. Accessed January 12, 2012. 18. Reid RJ, Fishman PA, Yu O, et al. Patient-centered medical home demonstration: a prospective, quasi-experimental, before and after evaluation. Am J Manag Care. 2009;15:e71-e87.

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19. Reinventing Medicaid: state innovations to qualify and pay for patient-centered medical homes show promising results. Health Aff (Millwood). 2011;30:1325-1334. 20. Rosenthal TC. The medical home: growing evidence to support a new approach to primary care. J Am Board Fam Med. 2008;21:427-440. 21. American Academy of Physician Assistants. Physician assistant workforce in the United States reaches record high. Press release; September 8, 2011. www.aapa. org/news_and_publications/news/item.aspx?id=2765. Accessed January 12, 2012. 22. Huang E, Basu A, O’Grady M, Capretta J. Projecting the future diabetes popula-

tion size and related costs for the US. Diabetes Care. 2009;32:2225-2229. 23. Vermeire E, Hearnshaw H, Ratsep A, et al. Obstacles to Adherence in Living with Type-2 Diabetes: an International Qualitative Study Using Meta-Ethnography (EUROBSTACLE). Primary Care Diabetes. 2007;1:25-33. 24. Virgin HealthMiles. www.virginhealthmiles.com. Accessed September 27, 2011. 25. Family Medicine Spokane. http://fammedspokane.org. Accessed September 27, 2011. 26. Community Care of North Carolina. Our results: making headway on cost and quality. www.communitycarenc.org/our-results/. Accessed January 12, 2012.

STAKEHOLDER PERSPECTIVE Primary Care Shortages: It Is All About the Money After All MEDICAL DIRECTORS/POLICYMAKERS: As I sat in the examination room, the doctor looked up at me and sighed, “I don’t know how much longer I can keep doing this.” This is not just any doctor; this is my primary care physician (PCP), whom I have known since our days in medical school and even before. He was among the brightest students in our class, and in the early 1970s, when primary care was undergoing a resurgence, he knew from the first day of medical school that he wanted to do family practice. Never wavering from that goal, he became a dedicated family physician and my own physician. As an aging baby boomer, it is a comforting thought to have one’s medical care in the hands of someone who is not only competent, but who also knows my medical history from experience. He continued, “The demands of primary care have increased, the cost of running my practice is spiraling upward, and the amount of administrative work is huge....and I am making less money than I did 10 years ago.” Although this is just one doctor, his words are symptomatic of the impending crisis in primary care. Those words resonated in my mind when I read Ms Collins’ article in this issue. As Ms Collins notes, almost 25% of the nation’s quarter-million PCPs are aged >55 years. That, coupled with a very low percentage of medical school graduates entering primary care, is a sobering thought. At a time when we have an aging population, when the baby boomers need more care, and when we face the potential for more than 40 million Americans having improved access to care under the Affordable Care Act, we are likely to have a decreasing number of PCPs. This crisis does not have an easy solution. As Ms Collins notes, PCPs tend to earn about half of what other specialties earn, resulting in a more than $3-million gap in lifetime earnings. It is not difficult to under-

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stand that primary care is not a chosen career path by the majority of medical students today. Yet, for the health system to accommodate the growing public care needs, we find ourselves in a dilemma—how do we expand primary care? In this article, Ms Collins explores a number of potential solutions, including adopting the patient-centered medical homes concept, and using nurses and physician assistants to provide primary care. Yet, any solution that does not address the issue of compensation for PCPs is not likely to be successful. As noted in the article, the current reimbursement systems tend to value procedural and technical skills more than cognitive and interpersonal skills—the 2 essential elements of primary care. Although it is tempting to simply increase payments to PCPs, that is not likely to happen in a system that is struggling to manage cost. We ultimately must find a way to redistribute payments to physicians rather than simply increasing overall spending. This is not likely to be a popular concept for those who may stand to lose in the process: we need creative solutions to physician payment. A recent article in the Wall Street Journal discusses large insurers that are beginning to address this issue.1 Aetna, WellPoint, and UnitedHealth are all looking at ways to enhance primary care reimbursement without “breaking the medical bank.” At least this is a start. Meanwhile, my physician’s words are being heard in primary care offices around the country. We must act now to address this impending crisis, before it deepens. 1. Mathews AW. New way to pay doctors: UnitedHealth, nation’s largest insurer, is latest to announce fee overhaul. Wall Street Journal. February 9, 2012.

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

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Implementing the Promise of Personalized Cancer Care

March 9-11, 2012 • The Peabody Orlando • Orlando, Florida 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. 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.

Rüdiger Hehlmann, MD Chief and Professor of Medicine University of Heidelberg Mannheim, Germany

“Managing patients with myeloma means staying current.”

Ira Klein, MD, MBA, FACP Chief of Staff to the Chief Medical Officer Aetna Hartford, CT

Value-Based Care in Myeloma !"'&1"-. "3 '0.&1" &)/"-1&"2. )! +"-.+" /&1". -"' /"! /* *./ ,0 '&/4 )! ".. &..0". +" & ' ." /&*). #*."! '&)& & ). !1 ) "! +- /& " )0-.". )! +% -( &./. 2&'' '.* #* 0. *) /%" 0)&,0" % ''")$". &) /%" ( ) $"(")/ *# (0'/&+'" (4"'*(

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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.

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January/February 2012

Vol 5, No 1

Tell your patients about NovoTwist®, the first and only single-twist needle attachment on the market.

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* 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

Printed in the U.S.A.

0311-00002127-1

April 2011

CLINICAL

ORIGINAL RESEARCH

Stakeholder Perspective, page 60

Am Health Drug Benefits. 2012;5(1):52-60 www.AHDBonline.com Disclosures are at end of text

Background: Oxycodone controlled release (CR) and oxymorphone extended release (ER) are frequently prescribed long-acting opioids, which are approved for twice-daily dosing. The US Food and Drug Administration approved a reformulated crush-resistant version of oxycodone CR in April 2010. Objective: To compare the daily average consumption (DACON) for oxycodone CR and for oxymorphone ER before and after the introduction of the reformulated, crush-resistant version of oxycodone CR. Methods: This was a retrospective claims database analysis using pharmacy claims from the MarketScan database for the period from January 2010 through March 2011. The interrupted time series analysis was used to evaluate the impact of the introduction of reformulated oxycodone CR on the DACON of the 2 drugsâ&#x20AC;&#x201D;oxycodone CR and oxymorphone ER. The source of the databases included private-sector health data from more than 150 medium and large employers. All prescription claims containing oxycodone CR and oxymorphone ER dispensed to members from January 1, 2010, to March 31, 2011, were included in the analysis. Prescription claims containing duplicate National Drug Codes, missing member identification, invalid quantities or inaccurate days supply of either drug, and DACON values of <1 and >500 were removed. Results: The database yielded 483,063 prescription claims for oxycodone CR and oxymorphone ER from January 1, 2010, to March 31, 2011. The final sample consisted of 411,404 oxycodone CR prescriptions (traditional and reformulated) dispensed to 85,150 members and 62,656 oxymorphone ER prescriptions dispensed to 11,931 members. Before the introduction of reformulated oxycodone CR, DACON values for the highest strength available for each of the 2 drugs were 0.51 tablets higher for oxycodone CR than for oxymorphone ER, with mean DACON values of 3.5 for oxycodone CR and 3.0 for oxymorphone ER (P <.001). The differences of mean DACON between the 2 drugs for all lower strengths were 0.46 tablets, with mean DACON values of 2.7 for oxycodone CR and 2.3 for oxymorphone ER (P <.001). After the introduction of the new formulation, the difference in mean DACON between the 2 drugs was slightly lower: 0.45 tablets for the highest-strength and 0.40 tablets for the lower-strength pairs. Regression analyses showed that the immediate and overall impact of the reformulation of oxycodone CR on the DACON of oxycodone CR was minimal, whereas no changes were seen in the DACON of oxymorphone ER. The estimated DACON for oxycodone CR decreased by 0.1 tablets, or 3.7% (P <.001), 6 months after the new formulation was introduced. Conclusion: The mean DACON was 0.4 tablets per day higher for oxycodone CR compared with oxymorphone ER for all dosage strengths for the entire study period. After the introduction of the reformulated oxycodone CR, the DACON for this drug was slightly mitigated; however, there was a minimal impact on the mean differences between oxycodone CR and oxymorphone ER.

Dr Puenpatom is Associate Director of Health Outcomes and Pharmacoeconomics, Endo Pharmaceuticals, Chadds Ford, PA; Dr Szeinbach is Professor, Division of Pharmacy Practice and Administration, College of Pharmacy, Ohio State University, Columbus; Dr Ma is Director, Dr Ben-Joseph is Vice President, and Dr Summers is Senior Director, Health Outcomes and Pharmacoeconomics at Endo Pharmaceuticals, Chadds Ford, PA.

American Health & Drug Benefits

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January/February 2012

Vol 5, No 1

DACON of 2 Long-Acting Opioids

hronic pain is experienced by more than one third of the US population.1 Regardless of disease etiology or individual characteristics, chronic pain is debilitating and has a profound impact on emotional and physical functioning.2,3 For chronic pain, which is characterized as pain lasting 3 or more months,4 opioid analgesics are considered part of a multifaceted strategy to manage moderate-to-severe pain for a number of conditions involving the musculoskeletal system (eg, osteoarthritis, low back pain), neurologic system (eg, diabetic neuropathy, spinal cord pain), and for pain associated with neoplastic disease.5-7 Two long-acting opioid analgesics, oxycodone controlled release (CR; OxyContin) and oxymorphone extended release (ER; Opana), are often prescribed to reduce the intensity of moderate-to-severe noncancer pain.8 However, the usefulness of long-acting opioids in chronic noncancer pain has been scrutinized, because of their adverse effects (eg, nausea and constipation) and the association with illicit drug behaviors, ranging from drug abuse, illegal distribution, and drug product tampering.9,10 In addition, a prospective study confirmed that some patients with chronic pain may require more frequent dosing of sustained-release opioids beyond the doses recommended by the manufacturer.11 Despite concerns over long-term analgesic use, multiple expert panels have concluded that long-term opioid therapy can be effective for carefully selected and monitored patients with chronic noncancer pain.12 To encourage proper use, new drug formulations are designed to improve pharmacotherapy either by reducing the dosing frequency or by hindering potential misuse and abuse. In August 2010, the US Food and Drug Administration (FDA) approved a newly formulated crush-resistant version of oxycodone CR. The recommended dosing regimen for oxycodone CR, oxymorphone ER, and the reformulated oxycodone CR is 2 tablets daily. Besides the need for product formulations that will provide more consistent and sustained levels of analgesia throughout the recommended dosing interval, the crush-resistant form of oxycodone may present an obstacle to some forms of misuse. In making pharmaceutical policy decisions, commercial insurers may need to consider utilization patterns in addition to cost. Daily average consumption (DACON) is a readily available measure that is often used to assess drug utilization. DACON has been used in previous studies to examine medication use in patients with arthritis, diabetes, and hypertension.13-16 With chronic pain, the utilization of opioid analgesics may be of concern to pharmacy benefit managers and third-party payers who design and manage prescription drug benefit plans. To build on previous research,17 we wanted to

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January/February 2012

KEY POINTS ➤

➤

Chronic pain is experienced by at least 38% of the US population. The prevalence of long-term opioid use for noncancer pain in the United States has increased in the past decade. This study compared the overall mean daily average consumption (DACON) for 2 opioids—oxycodone controlled release (CR) and oxymorphone extended release (ER)—after the introduction of the crushresistant formulation of oxycodone CR. Results showed that the overall DACON for oxycodone CR was higher by 0.4 tablets per day for all dosage strengths than for oxymorphone ER, with means of 2.9 and 2.5, respectively. The difference in mean DACON between oxycodone CR and oxymorphone ER was 0.45 tablets per day for the highest-strength pairs and 0.40 tablets per day for the lower-strength pairs after the introduction of reformulated oxycodone CR. After the introduction of the new formulation, the DACON for oxycodone CR was slightly mitigated; however, there was a minimal impact on the mean DACON differences of the 2 drugs. Because changes in opioid utilization may reflect inappropriate drug use, it is essential to follow the guidelines for opioid use to ensure that these drugs are used judiciously in the management of chronic noncancer pain.

know if differences in the DACON for oxycodone CR compared with oxymorphone ER persist in recent data that include utilization of a reformulated version of oxycodone CR. Opportunities to investigate changing patterns of opioid use will allow healthcare benefit managers to monitor opioid use with the goal of maintaining tablet utilization within the expected range of 2 tablets daily. Therefore, the purpose of this study was to evaluate the DACON of oxycodone CR and of oxymorphone ER before and after the introduction of the reformulated oxycodone CR. This study provides some insight into the utilization patterns of 2 branded opioid products used in pain management.

Methods This was a retrospective, interrupted time series analysis of observational data to assess the DACON of oxycodone CR, oxymorphone ER, and reformulated oxycodone CR over time using the prescription claimslevel analysis. Pharmacy claims for the 2 drugs from the MarketScan Commerical database (Thomson Reuters,

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American Health & Drug Benefits

CLINICAL

Ann Arbor, MI) were used to evaluate average monthly and weekly DACON values of oxymorphone ER and oxycodone CR. The database contains individual-level healthcare claims, including enrollment, medical, and prescription (outpatient) records from all providers of care. For the most recent 3 years, data were collected from more than 150 large employers (>200 carriers) and more than 20 regional health plans that provide healthcare coverage for more than 30 million lives annually. The covered lives include active employees, early retirees, COBRA continuees, and their dependents who are insured by large employers and health plans. Insurance coverage was provided under a variety of feefor-service, preferred provider organizations, and capitated and partially captitated health plans. Data were deidentified and used in accordance with the Health Insurance Portability and Accountability Act (HIPAA). Approval by the institutional review board was not required.

Calculation of Opioid Consumption We evaluated DACON over time for oxycodone CR and oxymorphone ER (traditional and reformulated) from January 2010 to March 2011. All prescription claims containing oxycodone CR and oxymorphone ER dispensed to members aged 18 to 64 years from January 1, 2010, to March 31, 2011, were included in the calculation of DACON. Prescription claims containing duplicate National Drug Codes, missing member identification, invalid quantities or inaccurate days supply for either drug, and DACON of <1 and >500 tablets were removed. The DACON for each prescription was calculated by dividing the total tablets dispensed by days supplied, as reflected by these data fields in each submitted prescription claim. Overall monthly and weekly DACON was calculated for all doses combined, the highest-strengthdosages (80-mg oxycodone CR and 40-mg oxymorphone ER), and for all lower-strength dosages, respectively (ie, oxycodone CR 10, 20, 30, 40, and 60 mg, and oxymorphone ER 5, 7.5, 10, 20, and 30 mg). Statistical Analysis The measurement of DACON over time was interrupted by the introduction of reformulated oxycodone CR. Because the outcome was analyzed with respect to time intervals (ie, weekly), the error terms may be correlated (ie, not independent), thereby violating one of the classic regression assumptions. Therefore, the interrupted time series analysis was used to estimate changes in levels and weekly trends for the mean DACON of oxymorphone ER and oxycodone CR (traditional and reformulated) before and after the introduction of reformulat-

American Health & Drug Benefits

ed oxycodone CR. The model is also often referred to as the segmented regression model, which is used to evaluate longitudinal effects (ie, change in intercept and slopes) of interventions, while relaxing the assumption that observations are independent. The segmented regression model we developed was derived as follows: Yt = ␤0 + ␤1 * timet + ␤2 * interventiont + ␤3 * timet * interventiont + ⑀t • Yt = average DACON in week t • Timet = a continuous variable for time in weeks at time t from the first week of January 2010 • Interventiont = a dummy variable taking the values of 0 in the preintroduction period (before August or week 31) and 1 after introduction • ␤0 estimates the baseline level of outcomes • ␤1 estimates for the baseline slope of the outcomes to control for secular trends before the introduction • ␤2 estimates the intercept change immediately after the introduction • ␤3 estimates the change in slope of mean DACON after the introduction. Autocorrelation in error terms of consecutive observations often exist when time is a predictor in the time series regression analysis. To assess the regression models for serial correlation of the time series data, the DurbinWatson, alternative Durbin-Watson, Breusch-Godfrey LM, and Bartlett’s statistic white noise tests were used.18,19 The Breusch-Pagan test was used to assess heteroscedasticity or the nonconstant variance assumption.19 Serial correlations were adjusted using one of the autoregressive, integrated, moving-average (ARIMA) models. These models are built by finding the best possible weighted average for a single time series, taking into account past observations (autoregressive terms) and past error terms (moving average terms).20 For this study, interrupted time series analysis allowed researchers to control for previous trends in the assessment of DACON and to study the dynamics of change in response to the introduction of reformulated oxycodone CR.21 To ensure a sufficient number of observations for the segmented regression model, we utilized weekly DACON data of 64 weekly intervals in this study: 31 weeks before the intervention and 33 after the intervention, from January 2010 to March 2011. The number of time points in this study exceeds the range of 50 time points suggested in similar segmented regression analyses and achieves an acceptable level of variability of the estimate at each time point.22 Before analysis, outliers were removed using the standard deviation method, such that DACON values whose deviation exceeds 3 standard deviations of the mean were excluded from the analysis.23 A sensitivity analysis was conducted to examine

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January/February 2012

Vol 5, No 1

DACON of 2 Long-Acting Opioids

➤ ➤

Oxycodone CR (all) (412,658 prescriptions)

Oxymorphone ER (62,746 prescriptions) ➤

Oxycodone CR (all) excluding outliers (411,404 prescriptions, 85,150 membersa)

Oxymorphone ER, excluding outliers (62,656 prescriptions, 11,931 members)

➤

January/February 2012

Project-defined prescription cleaning rules (475,404 prescriptions)

➤

Age 18-64 yr (481,913 prescriptions)

➤

Vol 5, No 1

Oxycodone CR (traditional and reformulated) or oxymorphone ER claim (483,063 prescriptions)

➤

Results The MarketScan commercial database yielded 483,063 prescription claims for oxycodone CR and oxymorphone ER from January 1, 2010, to March 31, 2011 (Figure 1). After applying the exclusion criteria for age and high DACON outliers, the final sample consisted of 411,404 oxycodone CR prescriptions (traditional and reformulated) dispensed to 85,150 members and 62,656 oxymorphone ER prescriptions dispensed to 11,931 members. Of the total members, 51% were women with the mean age of 48.5 years. Over the 15-month observation period, the overall mean DACON values for all dosage strengths were approximately 0.4 tablets per day higher for oxycodone CR than for oxymorphone ER, with means of 2.9 for oxycodone CR and 2.5 for oxymorphone ER (Figure 2). Reformulated oxycodone CR accounted for approximately 50% of oxycodone CR tablets dispensed in September 2010, 1 month after its introduction. The proportion of reformulated oxycodone CR relative to all oxycodone CR tablets steadily increased from 50% to 95% by the end of the study period (Figure 3). Overall mean DACON values for the 2 drugs over the observation period were relatively stable, ranging from 2.8 to 2.9 tablets per day for oxycodone CR and 2.4 to 2.5 tablets per day for oxymorphone ER, respectively (Figure 2). During the observation period before the introduction of the new formulation, DACON values for the highest strength were 0.51 tablets higher for oxycodone CR than for oxymorphone ER, with a mean DACON of 3.5 for oxycodone CR and 3.0 for oxymorphone ER (P <.001; Figure 4). After the introduction of the new formulation, the difference in mean DACON values between reformulated oxycodone CR and oxymorphone ER decreased slightly to 0.45 tablets per day for the highest-strength pairs (ie, mean DACON, 3.5 for oxycodone CR vs 3.0 for oxymorphone ER; P <.001). The differences of mean DACON for all lower strengths between oxycodone CR and oxymorphone ER were 0.46 tablets per day before the introduction of the

Sample Selection Process, January 1, 2010Figure 1 March 31, 2011

➤

model stability. The sensitivity analysis used a similar approach to account for the brief transition period after the introduction of reformulated oxycodone CR by excluding the outcome values that occurred during the potential intervention periods of August 2010 and September 2010. Descriptive statistics and overall mean comparison were evaluated using student t-tests. Statistical significance was established for P <.05. SAS version 9.1 (SAS Institute, Inc, Cary, NC) and Stata version 11.2 (StataCorp, College Station, TX) were used for data analysis.

Oxycodone CR (traditional) (250,102 prescriptions, 76,123 members)

Oxycodone CR (reformulated) (161,302 prescriptions, 11,931 members)

The number of members for the traditional and reformulated oxycodone CR do not add up, because members could have had multiple prescriptions across the time horizon and across treatment group. CR indicates controlled release; ER, extended release.

new formulation, with mean DACON values of 2.7 and 2.3 tablets (P <.001) for oxycodone CR and oxymorphone ER, respectively (Figure 4). After the introduction of the new formulation, the difference in mean DACON values between the 2 drugs was 0.40 tablets per day, with a mean DACON of 2.7 for oxycodone CR and 2.3 for oxymorphone ER (P <.001).

Interrupted Time Series Results Figure 2 shows the actual and predicted values of weekly DACON trends for oxycodone CR and oxymorphone ER over time using the interrupted time

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CLINICAL

Actual and Predicted Trend Values of Overall DACON for Oxycodone CR and Oxymorphone ER Figure 2 from the Interrupted Time Series Models, January 2010-March 2011 Oxycodone CR Predicted oxycodone CR Oxymorphone ER Predicted oxycodone ER 4 3.5

DACON, overall

3 2.5 2

After introduction of reformulation 1.5 1 .5 0 Jan 1, 2010

Apr 1, 2010

Jul 1, 2010

Oct 1, 2010

Jan 1, 2011

Apr 1, 2011

Date

CR indicates controlled release; DACON, daily average consumption; ER, extended release.

Tablets per 1000 Beneficiaries of Oxycodone CR and Figure 3 Oxymorphone ER, January 2010-March 2011

Mean DACON by Strength Before and After Introduction Figure 4 of New Formulation of Oxycodone CR

Traditional oxycodone CR Oxymorphone ER Reformulated oxycodone CR

Oxycodone CR Oxymorphone ER 3.5

140 120

95%

100 80

DACON, mean

160

50%

3 2.5 2

∆ = 0.51a

∆ = 0.45a

1.5

∆ = 0.46a

∆ = 0.40a

Before introduction

After introduction

40 1

Before introduction

After introduction

Highest strength

Mar 2011

Feb 2011

Jan 2011

Dec 2010

Nov 2010

Oct 2010

Sep 2010

Aug 2010

Jul 2010

Jun 2010

May 2010

Apr 2010

Mar 2010

Feb 2010

0 Jan 2010

Rate, tablets/1000 beneficiaries

Introduction of new formulation

Lower strengths

CR indicates controlled release; ER, extended release.

American Health & Drug Benefits

Mean differences by each pair were all significant (P <.001). CR indicates controlled release; DACON, daily average consumption; ER, extended release.

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January/February 2012

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DACON of 2 Long-Acting Opioids

Results from the Interrupted Time Series Models: Impact of Introduction of Reformulated Oxycodone CR on Table 1 Each Medication Strength Before introduction Change in DACON each week before the introduction

Medication/ strength

After introduction Change in DACON immediately after the introduction

Change in Change in DACON DACON slope after the slope after the introduction introduction

(␤1 baseline slope) P value (␤2 intercept change) P value

(␤3)

(1 month)

P value

Oxycodone CR All strengths Highest strength

0.00003 –0.002

.956 <.001

0.052

.034

0.0002

.996

–0.003 0.0013

–0.012

<.001

–0.005

.124

0.0002

.658

0.055

<.001

–0.003

–0.011

<.001

All strengths

–0.0001

.878

–0.011

.828

0.001

–0.002

.695

Highest strength

–0.0003

.822

0.041

.518

0.0005

–0.002

.797

.947

0.031

.302

–0.005

.105

Lower strengths Oxymorphone ER

Lower strengths

0.00003

–0.001

CR indicates controlled release; DACON, daily average consumption; ER, extended release.

series models. Before the introduction of reformulated oxycodone CR, there was no significant week-to-week impact in the mean DACON for oxycodone CR and oxymorphone ER (P = .956 and P = .878, respectively; Table 1). Immediately after the introduction of the new formulation, the estimated mean DACON for oxycodone CR dropped slightly, by 0.05 tablets weekly. Throughout the study period, there was neither immediate change nor any weekly change in oxymorphone ER’s DACON as a result of the introduction of oxycodone CR. In terms of changes in trends for the mean DACON after the introduction of oxycodone CR, the weekly trends for oxycodone CR slightly decreased, by 0.003 tablets weekly (0.01 tablets per month). Because the absolute change in weekly DACON was minimal, we compared the overall change by combining the immediate and trend effects for the estimated DACON 6 months after the introduction of the new formulation, with the outcomes as if that introduction had not occurred. The models showed that the average DACON for oxycodone CR decreased by 0.11 tablets or 3.7% (P <.001) 6 months after the new formulation was introduced compared with the DACON level before the introduction (Table 2). When analyzing the data by strength, the average DACON for the 80-mg (highest strength) oxycodone CR 6 months after the introduction increased slightly by 0.07 tablets or 2.1% (P = .003), whereas the DACON

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January/February 2012

for the lower strengths decreased by 0.09 tablets, or 3.4% (P <.001). Sensitivity analyses were conducted by excluding the outcome values that occurred during the potential intervention period of August and September 2010. The results (not shown) indicate that the introduction of reformulated oxycodone CR had a slight, mitigating effect on DACON; however, there was no significant change in DACON over time. In addition, there was no significant change in DACON for oxymorphone ER associated with the introduction of the newly formulated oxycodone CR.

Discussion To evaluate the impact on utilization, differences in DACON were assessed between traditional oxycodone CR and oxymorphone ER before and after the introduction of the reformulated oxycodone CR. Results from the interrupted time series analyses and sensitivity analyses revealed that the impact on DACON associated with the introduction of reformulated oxycodone CR was minimal, whereas there was no impact on oxymorphone ER’s DACON. The models estimated that the average DACON for oxycodone CR decreased by 0.1 tablets, or 3.7%, 6 months after the new formulation was introduced (P <.001). In addition, differences in mean DACON between oxycodone CR and oxymorphone ER were quite stable before and after the introduction of reformulated oxy-

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CLINICAL

Estimated Overall Change of DACON 6 Months after Table 2 Introduction of Reformulated Oxycodone CR from Interrupted Time Series Models Overall change (intercept + slope) 6 months after introduction Change, %

P value

–0.11

–3.7

<.001

Highest strength

0.07

2.1

.003

Lower strengths

–0.09

–3.4

<.001

All strengths

0.02

0.7

.611

Highest strength

0.07

2.3

.236

Lower strengths

–0.03

–1.4

.087

Medication strength

Daily tablets

Oxycodone CR All strengths

Oxymorphone ER

CR indicates controlled release; DACON, daily average consumption; ER, extended release.

codone CR. Throughout the 15-month study period, the overall DACON was higher for oxycodone CR (traditional or reformulated) compared with oxymorphone ER, by 0.4 to 0.5 tablets per day for all dosage strengths. For a subgroup analysis by strength, the differences of mean DACON between oxycodone CR and oxymorphone ER slightly decreased to 0.45 tablets for the highest strength and 0.4 tablets for lower strengths after the introduction of the new formulation.

Findings from this study provide additional information when DACON is considered for oxycodone CR (traditional and reformulated) across all tablet strengths compared with oxymorphone ER. These results are consistent with previous research in this area. For example, there is evidence from other studies to support a higher DACON with oxycodone CR compared with oxymorphone ER. Malkin and colleagues found that the DACON for all strengths of oxycodone CR was 3.4 and that higher strengths were associated with a higher DACON value, ranging from 2.9 for the 10-mg tablets to 5.2 for the 80-mg tablets.24 In another study by Berner and colleagues, a retro-

American Health & Drug Benefits

spective analysis of administrative claims data for commercially insured patients was conducted to compare the DACON of oxycodone CR and oxymorphone ER in patients with low back pain.25 Again, the DACON was higher for the maximum-strength tablets of oxycodone CR 80 mg, which were 3.9 tablets per day and significantly higher than the DACON of 2.9 for an equipotent oxymorphone ER maximum-strength tablet of 40 mg (P <.01).25 The investigators estimated that if oxymorphone ER 40-mg tablets were substituted for oxycodone CR 80-mg tablets in the 688 patients in their analysis of a health plan with 32,325 patients having at least 1 prescription for oxycodone CR or oxymorphone ER, the monthly cost difference would be $217,985 based on the DACON difference, assuming per-tablet wholesale acquisition costs of $10.83 and $10.93, respectively.25 Given the consistent patterns in DACON for these drugs, pharmaceutical policymakers may want to consider these results in related decisions. Findings from this study provide additional information when DACON is considered for oxycodone CR (traditional and reformulated) across all tablet strengths compared with oxymorphone ER. A notable finding is the continued difference in DACON between oxycodone CR and oxymorphone ER, both before and after introduction of the reformulated oxycodone CR. Considering the potential for dose escalation during long-term opioid use,26 the consistent DACON values observed throughout the 15-month study period suggest that current dosing schedules were not altered in response to the introduction of reformulated oxycodone CR. Interrupted time series analysis is useful when changes over time are interrupted by events, such as the introduction of reformulated oxycodone CR in this study. However, longitudinal designs can be influenced by events outside the control of researchers. Therefore, a sensitivity analysis was performed to assess model robustness. The concordance of results through the transition period of reformulated oxycodone CR indicates that our findings will provide decision makers with a valid assessment of the DACON for this population. Although the DACON provides an accurate assessment of drug utilization, with long-term opioid use there may be some members who either fail to achieve adequate analgesic effects despite reaching the maximum tablet strength for frequently prescribed opioids or may experience analgesic tolerance if more frequent dosing is necessary.27 Realizing that it may be difficult to distinguish analgesic tolerance from potential drug abuse, especially if members are requesting traditional oxycodone CR over

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Vol 5, No 1

DACON of 2 Long-Acting Opioids

reformulated oxycodone CR, health professionals should be cognizant of and recognize that changes in utilization may reflect inappropriate drug use. It is, therefore, essential to follow the guidelines for opioid use to ensure that these drugs are used judiciously in the management of chronic noncancer pain, especially for patients who require higher doses of opioids, have issues with drug abuse, or who report numerous comorbid conditions.28,29

Limitations There are certain caveats associated with the use of claims data. First, it was not possible to examine whether patients were actually using the medications examined in this database. Thus, it was not possible to determine if changes in pain intensity required patients to alter the dose or dosing frequency of opioids for medical emergencies or procedures. Second, it was not possible to determine if prescribers changed medications in response to oxycodone CR or to oxymorphone ER failures, or changed the dosing schedule to accommodate other medication use or additional diagnoses. For these reasons, it was not possible to control for patient-initiated self-management of pain. Third, although the calculations of DACON were statistically robust, as observed from sensitivity analyses, additional changes in utilization could occur from inappropriate use of opioids. Fourth, a common limitation about the claims database is that there is no diagnosis code entered on prescription claims; this study was based on prescription claims, not patients. Therefore, information related to diagnosis codes is not provided in this study. Finally, because claims databases do not contain data regarding pain severity, it was not possible to evaluate whether one population suffered from more severe pain. To monitor opioid use, managed care plans often place quantity limits on long-acting opioids. Although the patterns of drug use examined in this study were relatively stable over time, it is important to continue monitoring changes in long-term utilization of these opioids. Conclusion In this study, the introduction of a crush-resistant oxycodone CR very slightly lowered the DACON for that drug; however, the change was minimal. Therefore, this research supports the notion that differences in DACON are more likely a result of differences in the oxycodone and oxymorphone molecules and not the effects of oxycodone CR reformulation. â&#x2013; Acknowledgment The authors would like to thank Robert Garvin, MA, for programming support.

Study Funding This study was supported by funding from Endo Pharmaceuticals. Author Disclosure Statement Drs Puenpatom, Ma, Ben-Joseph, and Summers are employees of and Dr Szeinbach received financial support from Endo Pharmaceuticals.

References 1. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education and Research. Washington, DC: The National Academies Press; 2011. http://books.nap.edu/openbook.php?record_id=13172&page=17. Accessed January 25, 2012. 2. Turk DC, Wilson HD, Cahana A. Treatment of chronic non-cancer pain. Lancet. 2011;377:2226-2235. 3. Annemans L. Pharmacoeconomic impact of adverse events of long-term opioid treatment for the management of persistent pain. Clin Drug Investig. 2011;31:73-86. 4. Portenoy RK, Ugarte C, Fuller I, Haas G. Population-based survey of pain in the United States: differences among white, African American, and Hispanic subjects. J Pain. 2004;5:317-328. 5. Markenson JA, Croft J, Zhang PG, Richards P. Treatment of persistent pain associated with osteoarthritis with controlled-release oxycodone tablets in a randomized controlled clinical trial. Clin J Pain. 2005;21:524-535. 6. Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release oxycodone relieves neuropathic pain: a randomized controlled trial in painful diabetic neuropathy. Pain. 2003;105:71-78. 7. Desandre P, Quest TE. Management of cancer-related pain. Hematol Oncol Clin North Am. 2010;24:643-658. 8. Chou R, Clark E, Helfand M. Comparative efficacy and safety of long-acting oral opioids for chronic non-cancer pain: a systematic review. J Pain Symptom Manag. 2003;26:1026-1048. 9. Leider HL, Dhaliwal J, Davis EJ, et al. Healthcare costs and nonadherence among chronic opioid users. Am J Manag Care. 2011;17:32-40. 10. Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria. J Addict Dis. 2011;30:185-194. 11. Gallagher RM, Welz-Bosna M, Gammaitoni A. Assessment of dosing frequency of sustained-release opioid preparations in patients with chronic nonmalignant pain. Pain Med. 2007;8:71-74. 12. Manchikanti L, Ailinani H, Koyyalagunta D, et al. A systematic review of randomized trials of long-term opioid management for chronic non-cancer pain. Pain Physician. 2011;14:91-121. 13. Schnitzer TJ, Kong SX, Mitchell JH, et al. An observational, retrospective, cohort study of dosing patterns for rofecoxib and celecoxib in the treatment of arthritis. Clin Ther. 2003;25:3162-3172. 14. McAdam-Marx C, Yu J, Bouchard J, et al. Comparison of daily insulin dose and other antidiabetic medications usage for type 2 diabetes patients treated with an analog basal insulin. Curr Med Res Opin. 2010;26:191-201. 15. Borah BJ, Darkow T, Bouchard J, et al. A comparison of insulin use, glycemic control, and health care costs with insulin detemir and insulin glargine in insulinnaĂŻve patients with type 2 diabetes. Clin Ther. 2009;31:623-631. 16. Jan SA, Patel JV, Welz J, Ishak P. A retrospective database analysis of prescribing patterns for specific angiotensin receptor blockers. Drug Benefit Trends. 2005;17:23-29. 17. Rubino M, Summers KH, Puenpatom A, Fu C, Ohsfeldt RL, Ben-Joseph RH. A comparison of daily average consumption (DACON) of oxycodone and oxymorphone long-acting oral tablets. J Manag Care Pharm. 2011;17:367-376. 18. Brockwell PJ, Davis RA. Time Series: Theory and Methods (Springer Series in Statistics). 2nd edition. New York, NY: Springer; 2006. 19. Baltagi BH. Econometrics (Springer Texts in Business and Economics). 5th ed. New York, NY: Springer; 2011. 20. Durbin J. Testing for serial correlation in least squares regressions when some of the regressions are lagged dependent variables. Econometrica. 1970;38:410-421. 21. Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D. Segmented regression analysis of interrupted time series studies in medication use research. J Clin Pharm Ther. 2002;27:299-309. 22. Shardell M, Harris AD, El-Kamary SS, et al. Statistical analysis and application of quasi experiments to antimicrobial resistance intervention studies. Clin Infect Dis. 2007;45:901-907. 23. Maronna RA, Martin DR, Yohai VJ. Robust Statistics: Theory and Methods (Wiley Series in Probability and Statistics). Chichester, England: John Wiley & Sons, Ltd; 2006. 24. Malkin JD, Ackerman SJ, Schein J, et al. Cost and utilization patterns of fentanyl transdermal system and oxycodone hydrochloride controlled-release in a California

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Medicaid population. J Manag Care Pharm. 2002;8:132-140. 25. Berner T, Thomson H, Hartry A, et al. A comparison of daily average consumption of oxycodone controlled release (OxyContin CR) and oxymorphone extended release (Opana ER) in patients with low back pain. PT. 2011;36:139-144. 26. Cifuentes M, Webster B, Genevay S, Pransky G. The course of opioid prescribing for a new episode of disabling low back pain: opioid features and dose escalation. Pain. 2010;151:22-29. 27. Graziottin A, Gardner-Nix J, Stumpf M, Berliner MN. Opioids: how to improve

compliance and adherence. Pain Pract. 2011;11:574-581. 28. Chou R, Ballantyne JC, Fanciullo GJ, et al. Research gaps on use of opioids for chronic noncancer pain: findings from a review of the evidence for an American Pain Society and American Academy of Pain Medicine clinical practice guideline. J Pain. 2009;10:147-159. 29. Chapman CR, Lipschitz DL, Angst MS, et al. Opioid pharmacotherapy for chronic non-cancer pain in the United States: a research guideline for developing an evidence-base. J Pain. 2010;11:807-829.

STAKEHOLDER PERSPECTIVE Daily Average Consumption of 2 Long-Acting Opioids and Coverage Decisions MEDICAL/PHARMACY DIRECTORS: Longacting opioids are continuing to get more attention as a result of several factors. Both long- and short-acting opioids have strong brand recognition among opioid users and nonusers alike. There is no shortage of media coverage around diversion, misuse, and abuse of opioids. Many payers and pharmacy benefit managers have implemented high utilization clinical programs and auditing initiatives specific to this narcotic class. In addition, several opioid manufacturers are modifying existing mechanisms or introducing new release mechanisms to decrease the amount of opioid misuse. Market dynamics have changed within several drug classes over the past couple of years. Several antidepressants and antihypertensives are available as generics. And with the recent introduction of generic atorvastatin, the cholesterol-lowering drug class has also become very accessible in a generic form. During 2012, generics will increase substantially within the atypical antipsychotic class as a result of recent and near-future products losing or about to lose patent protection. Long-acting opioids are moving up the â&#x20AC;&#x153;top paidâ&#x20AC;? list for payers, gaining more attention from large employers as well. This article reviews the daily average consumption (DACON) of 2 long-acting opioids, namely, oxycodone controlled release (CR) and oxymorphone extended release (ER). DACON was analyzed over a 15-month time frame to evaluate if a reformulated oxycodone CR changed the existing variance of the DACON compared with oxymorphone ER. This analysis shows that the reformulation of oxycodone CR

American Health & Drug Benefits

had little impact on the overall DACON of both products, and oxymorphone ER continued to have a similar, but lower, DACON. Several factors are difficult to assess from this review, including the severity of pain within groups, duration of therapy, or previous trials of other long-acting opioids. DACON may correlate with pharmacokinetic differences, pain management needs, or even misaligned prescribing and/or diversion practices. However, these correlations are difficult to ascertain from a retrospective claims analysis. Policymakers and payers need to consider DACON when making coverage decisions, but this is only one piece of the decision-making process. Ingredient cost, utilization patterns, generic availability, and, of course, efficacy and safety need to be evaluated, as well as cost. The long-acting opioid class has a variety of available options, including generic alternatives, and the class is expected to continue to expand with new branded products over the next 18 to 24 months. PATIENTS: Patients now have the opportunity to select from several options, including cost-effective oral and transdermal opioids. No matter the choice, patients must be conscious of adequate pain management needs and out-of-pocket responsibilities. Other concerns need to be considered as well, such as refill requirements and other, less obvious, unintended consequences associated with misuse or theft of medications. Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

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Constipation Dyspepsia

5.3 0.9 1.7 5.2 0.9 2.6 Add-on to Metformin + Glimepiride Placebo + Metformin + Glargine + Metformin Victoza® 1.8 + + Glimepiride Glimepiride Metformin + N = 232 N = 114 Glimepiride N = 230 (%) (%) (%) Adverse Event Term Nausea 13.9 3.5 1.3 Diarrhea 10.0 5.3 1.3 Headache 9.6 7.9 5.6 Dyspepsia 6.5 0.9 1.7 Vomiting 6.5 3.5 0.4 Add-on to Metformin + Rosiglitazone All Victoza® + Metformin + Placebo + Metformin Rosiglitazone N = 355 + Rosiglitazone N = 175 (%) (%) Adverse Event Term Nausea 34.6 8.6 Diarrhea 14.1 6.3 Vomiting 12.4 2.9 Decreased Appetite 9.3 1.1 Anorexia 9.0 0.0 Headache 8.2 4.6 Constipation 5.1 1.1 Fatigue 5.1 1.7 Table 3: Treatment-Emergent Adverse Events in 26 Week Open-Label Trial versus Exenatide (Adverse events with frequency ≥5% and occurring more frequently with Victoza® compared to exenatide are listed) Exenatide 10 mcg twice Victoza® 1.8 mg once daily + metformin and/or daily + metformin and/or sulfonylurea N = 232 sulfonylurea N = 235 (%) (%) Preferred Term Diarrhea 12.3 12.1 Dyspepsia 8.9 4.7 Constipation 5.1 2.6 Gastrointestinal adverse events: In the five clinical trials of 26 weeks duration or longer, gastrointestinal adverse events were reported in 41% of Victoza®-treated patients and were dose-related. Gastrointestinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation. In a 26-week study of Victoza® versus exenatide, both in combination with metformin and/ or sulfonylurea overall gastrointestinal adverse event incidence rates, including nausea, were similar in patients treated with Victoza® and exenatide. In five clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. Approximately 13% of Victoza®treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment. In a 26 week study of Victoza® versus exenatide, both in combination with metformin and/ or sulfonylurea, the proportion of patients with nausea also declined over time. Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza® may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza®treated patients in the five clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these Victoza®-treated patients. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. Crossreacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the Victoza®-treated patients in the 52-week monotherapy trial and in 4.8% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the Victoza®-treated patients in the 52-week monotherapy trial and in 1.0% of the Victoza®-treated patients in the 26-week add-on combination therapy trials. Among Victoza®treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza®-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza®-treated antibody-positive patients; and among 7%, 7% and 5% of antibodynegative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza®-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza®-treated, placebo-treated and active-control-treated patients, respectively. Antibody formation was not associated with reduced efficacy of Victoza® when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with Victoza® treatment. In clinical trials of Victoza®, events from a composite of adverse events potentially related to immunogenicity (e.g. urticaria, angioedema) occurred among 0.8% of Victoza®-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for Victoza®-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies. Injection site reactions: Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of Victoza®-treated patients in the five clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza®-treated patients discontinued due to injection site reactions. Papillary thyroid carcinoma: In clinical trials of Victoza®, there were 6 reported cases of papillary thyroid carcinoma in patients treated with Victoza® and 1 case in a comparator-treated patient (1.9 vs. 0.6 cases per 1000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Hypoglycemia: In the clinical trials of at least 26 weeks

duration, hypoglycemia requiring the assistance of another person for treatment occurred in 7 Victoza®treated patients (2.6 cases per 1000 patient-years) and in two comparator-treated patients. Six of these 7 patients treated with Victoza® were also taking a sulfonylurea. One other patient was taking Victoza® in combination with metformin but had another likely explanation for the hypoglycemia (this event occurred during hospitalization and after insulin infusion) (Table 4). Two additional cases of hypoglycemia requiring the assistance of another person for treatment have subsequently been reported in patients who were not taking a concomitant sulfonylurea. Both patients were receiving Victoza®, one as monotherapy and the other in combination with metformin. Both patients had another likely explanation for the hypoglycemia (one received insulin during a frequently-sampled intravenous glucose tolerance test, and the other had intracranial hemorrhage and uncertain food intake). Table 4: Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials Victoza® Active Placebo Treatment Comparator Comparator Monotherapy Victoza® Glimepiride None (N = 497) (N = 248) Patient not able to self−treat 0 0 — Patient able to self−treat 9.7 (0.24) 25.0 (1.66) — Not classified 1.2 (0.03) 2.4 (0.04) — Placebo + Glimepiride + Add-on to Victoza® + Metformin Metformin Metformin Metformin (N = 121) (N = 242) (N = 724) Patient not able to self−treat 0.1 (0.001) 0 0 Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06) Add-on to Glimepiride Victoza® + Placebo + Rosiglitazone + Glimepiride Glimepiride Glimepiride (N = 114) (N = 231) (N = 695) Patient not able to self−treat 0.1 (0.003) 0 0 Patient able to self−treat 7.5 (0.38) 4.3 (0.12) 2.6 (0.17) Not classified 0.9 (0.05) 0.9 (0.02) 0 Victoza® + Placebo + Add-on to None Metformin + Metformin + Metformin + Rosiglitazone Rosiglitazone Rosiglitazone (N = 175) (N = 355) Patient not able to self−treat 0 — 0 Patient able to self−treat 7.9 (0.49) — 4.6 (0.15) Not classified 0.6 (0.01) — 1.1 (0.03) Placebo + Add-on to Victoza® + Insulin glargine Metformin + Metformin + Glimepiride + Metformin + Metformin + Glimepiride Glimepiride Glimepiride (N = 114) (N = 232) (N = 230) Patient not able to self−treat 2.2 (0.06) 0 0 Patient able to self−treat 27.4 (1.16) 28.9 (1.29) 16.7 (0.95) Not classified 0 1.7 (0.04) 0 In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza®, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza®-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established. Laboratory Tests: In the five clinical trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4.0% of Victoza®-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients. This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Post-Marketing Experience: The following additional adverse reactions have been reported during post-approval use of Victoza®. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: nausea, vomiting and diarrhea sometimes resulting in dehydration [see Warnings and Precautions]. Renal and Urinary Disorders: increased serum creatinine, acute renal failure or worsening of chronic renal failure, which may sometimes require hemodialysis [see Warnings and Precautions]. OVERDOSAGE: In a clinical trial, one patient with type 2 diabetes experienced a single overdose of Victoza® 17.4 mg subcutaneous (10 times the maximum recommended dose). Effects of the overdose included severe nausea and vomiting requiring hospitalization. No hypoglycemia was reported. The patient recovered without complications. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms. More detailed information is available upon request. For information about Victoza® contact: Novo Nordisk Inc., 100 College Road West, Princeton, New Jersey 08540, 1−877-484-2869 Date of Issue: May 18, 2011 Version: 3 Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark Victoza® is a registered trademark of Novo Nordisk A/S. Victoza® is covered by US Patent Nos. 6,268,343; 6,458,924; and 7,235,627 and other patents pending. Victoza® Pen is covered by US Patent Nos. 6,004,297; 6,235,004; 6,582,404 and other patents pending. © 2011 Novo Nordisk 140586-R3 6/2011

Help adult patients with type 2 diabetes gain greater access

Get to know Victoza® on a deeper level. Powerful reductions in A1C from -0.8% to -1.5%*

Low rate of hypoglycemia

Flexible dosing any time of day, independent of meals

May reduce weight

VictozaCare™ helps patients stay on track with ongoing support

—Victoza® is not indicated for the management of obesity, and weight change was a secondary end point in clinical trials

—Patients enrolled in VictozaCare™ were more adherent to Victoza® than those not enrolled†

To see how Victoza® works for your patients, visit VictozaPro.com/GLP1.

Indications and usage Victoza® is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Because of the uncertain relevance of the rodent thyroid C-cell tumor findings to humans, prescribe Victoza® only to patients for whom the potential benefits are considered to outweigh the potential risk. Victoza® is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise. In clinical trials of Victoza®, there were more cases of pancreatitis with Victoza® than with comparators. Victoza® has not been studied sufficiently in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis while using Victoza®. Use with caution in patients with a history of pancreatitis. Victoza® is not a substitute for insulin. Victoza® should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings. ®

The concurrent use of Victoza and insulin has not been studied.

Important safety information Liraglutide causes dose-dependent and treatment-durationdependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza® causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as human relevance could not be ruled out by clinical or nonclinical studies. Victoza® is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Based on the findings in rodents, monitoring with serum calcitonin or thyroid ultrasound was performed during clinical trials, but this may have increased the number of unnecessary thyroid surgeries. It is unknown whether monitoring with serum Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S.

calcitonin or thyroid ultrasound will mitigate human risk of thyroid C-cell tumors. Patients should be counseled regarding the risk and symptoms of thyroid tumors. If pancreatitis is suspected, Victoza® should be discontinued. Victoza® should not be re-initiated if pancreatitis is confirmed. When Victoza® is used with an insulin secretagogue (e.g. a sulfonylurea) serious hypoglycemia can occur. Consider lowering the dose of the insulin secretagogue to reduce the risk of hypoglycemia. Renal impairment has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration, which may sometimes require hemodialysis. Use caution when initiating or escalating doses of Victoza® in patients with renal impairment. There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza® or any other antidiabetic drug. The most common adverse reactions, reported in ≥5% of patients treated with Victoza® and more commonly than in patients treated with placebo, are headache, nausea, diarrhea, and anti-liraglutide antibody formation. Immunogenicity-related events, including urticaria, were more common among Victoza®-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. Victoza® has not been studied in type 2 diabetes patients below 18 years of age and is not recommended for use in pediatric patients. Victoza® should be used with caution in patients with hepatic impairment. Please see brief summary of Prescribing Information on adjacent page. *Victoza® 1.2 mg and 1.8 mg when used alone or in combination with OADs. † Crossix ScoreBoard™ Report, September 2011. Adherence measured by number of actual Victoza® prescriptions filled for existing Victoza® patients enrolled in VictozaCare™ versus a match-pair control group not enrolled in VictozaCare™ through first 8 months of enrollment.

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