january/february volume 5, number 1

EDITORIAL

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

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

BUSINESS

Beyond the Cost of Biologics: Employer Survey Reveals Gap inUnderstanding Role of Specialty Pharmacy and Benefit DesignF. Randy Vogenberg, RPh, PhD; Cheryl Larson, BA; Margaret Rehayem, MA; Larry Boress, MPA

Stakeholder Perspective by Atheer A. Kaddis, PharmD

REGULATORY

Primary Care Shortages: Strengthening This Sector Is Urgently Needed, Nowand 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 TimeSeries AnalysisR. 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

™

©2012 Engage Healthcare Communications, LLCwww.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

DEXILANT MAY BE COADMINISTERED WITH PLAVIX (CLOPIDOGREL BISULFATE)

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.

©2011 Takeda Pharmaceuticals North America, Inc. LPD-01954 11/11 Printed in U.S.A.

DEXILANT had no clinically important impact on the antiplatelet activity of Plavix in healthy volunteersDEXILANT 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

DEXILANT minimally reduced the mean AUC of the Plavix active metabolite by 9%2

No dose adjustment of Plavix is necessary when administered with an approved dose of DEXILANT2

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

4.7%

35.2%

0.2%

22.5%

DEXILANT 60 mg (n=40)

Positive control (omeprazole 80 mg; n=40)

% decrease in IPA* with Plavixand PPI coadministration (day 9)1

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 5µM.

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

Important Safety InformationDEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use.Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy.Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated.Hypomagnesemia has been reported rarely with prolonged treatment with PPIs.Most commonly reported adverse reactions were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%).Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations.

Please see accompanying brief summary for DEXILANT.

DATA PRESENTED AT ACC IN 2011

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONDEXILANT (dexlansoprazole) delayed-release capsules for oral useINDICATIONS AND USAGEDEXILANT 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 PRECAUTIONSGastric MalignancySymptomatic response with DEXILANT does not preclude the presence of gastric malignancy.Bone FractureSeveral published observational studies suggest that proton pump inhibitor (PPI) therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist or spine. The risk of fracture was increased in patients who received high-dose, defined as multiple daily doses, and long-term PPI therapy (a year or longer). Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Patients at risk for osteoporosis-related fractures should be managed according to established treatment guidelines [see Adverse Reactions].HypomagnesemiaHypomagnesemia, 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 REACTIONSClinical Trials ExperienceBecause 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 least6 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 ReactionsThe 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

Adverse Reaction

Placebo

(N=896)%

DEXILANT30 mg

(N=455)%

DEXILANT60 mg

(N=2218)%

DEXILANTTotal

(N=2621)%

Lansoprazole30 mg

(N=1363)%

Diarrhea 2.9 5.1 4.7 4.8 3.2Abdominal Pain 3.5 3.5 4.0 4.0 2.6Nausea 2.6 3.3 2.8 2.9 1.8Upper Respiratory Tract Infection

0.8 2.9 1.7 1.9 0.8

Vomiting 0.8 2.2 1.4 1.6 1.1Flatulence 0.6 2.6 1.4 1.6 1.2

Adverse Reactions Resulting in DiscontinuationIn controlled clinical studies, the most common adverse reaction leading to discontinuation from DEXILANT therapy was diarrhea (0.7%).Other Adverse ReactionsOther adverse reactions that were reported in controlled studies at an incidence of less than 2% are listed below by body system:Blood and Lymphatic System Disorders: anemia, lymphadenopathy; Cardiac Disorders: angina, arrhythmia, bradycardia, chest pain, edema, myocardial

infarction, palpitation, tachycardia; Ear and Labyrinth Disorders: ear pain, tinnitus, vertigo; Endocrine Disorders: goiter; Eye Disorders: eye irritation, eye swelling; Gastrointestinal Disorders: abdominal discomfort, abdominal tenderness, abnormal feces, anal discomfort, Barrett’s esophagus, bezoar, bowel sounds abnormal, breath odor, colitis microscopic, colonic polyp, constipation, dry mouth, duodenitis, dyspepsia, dysphagia, enteritis, eructation, esophagitis, gastric polyp, gastritis, gastroenteritis, gastrointestinal disorders, gastrointestinal hypermotility disorders, GERD, GI ulcers and perforation, hematemesis, hematochezia, hemorrhoids, impaired gastric emptying, irritable bowel syndrome, mucus stools, oral mucosal blistering, painful defecation, proctitis, paresthesia oral, rectal hemorrhage, retching; General Disorders and Administration Site Conditions: adverse drug reaction, asthenia, chest pain, chills, feeling abnormal, inflammation, mucosal inflammation, nodule, pain, pyrexia; Hepatobiliary Disorders: biliary colic, cholelithiasis, hepatomegaly; Immune System Disorders: hypersensitivity; Infections and Infestations: candida infections, influenza, nasopharyngitis, oral herpes, pharyngitis, sinusitis, viral infection, vulvo-vaginal infection; Injury, Poisoning and Procedural Complications: falls, fractures, joint sprains, overdose, procedural pain, sunburn; Laboratory Investigations: ALP increased, ALT increased, AST increased, bilirubin decreased/increased, blood creatinine increased, blood gastrin increased, blood glucose increased, blood potassium increased, liver function test abnormal, platelet count decreased, total protein increased, weight increase; Metabolism and Nutrition Disorders: appetite changes, hypercalcemia, hypokalemia; Musculoskeletal and Connective Tissue Disorders: arthralgia, arthritis, muscle cramps, musculoskeletal pain, myalgia; Nervous System Disorders: altered taste, convulsion, dizziness, headaches, migraine, memory impairment, paresthesia, psychomotor hyperactivity, tremor, trigeminal neuralgia; Psychiatric Disorders: abnormal dreams, anxiety, depression, insomnia, libido changes; Renal and Urinary Disorders: dysuria, micturition urgency; Reproductive System and Breast Disorders: dysmenorrhea, dyspareunia, menorrhagia, menstrual disorder; Respiratory, Thoracic and Mediastinal Disorders: aspiration, asthma, bronchitis, cough, dyspnoea, hiccups, hyperventilation, respiratory tract congestion, sore throat; Skin and Subcutaneous Tissue Disorders: acne, dermatitis, erythema, pruritis, rash, skin lesion, urticaria; Vascular Disorders: deep vein thrombosis, hot flush, hypertensionAdditional 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 ExperienceThe 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 purpuraEar and Labyrinth Disorders: deafnessEye Disorders: blurred visionGastrointestinal Disorders: oral edema, pancreatitisGeneral Disorders and Administration Site Conditions: facial edemaHepatobiliary Disorders: drug-induced hepatitisImmune System Disorders: anaphylactic shock (requiring emergency intervention), exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis (some fatal)Metabolism and Nutrition Disorders: hypomagnesemia, hyponatremiaMusculoskeletal System Disorders: bone fractureNervous System Disorders: cerebrovascular accident, transient ischemic attackRenal and Urinary Disorders: acute renal failureRespiratory, Thoracic and Mediastinal Disorders: pharyngeal edema, throat tightnessSkin and Subcutaneous Tissue Disorders: generalized rash, leucocytoclastic vasculitisDRUG INTERACTIONSDrugs with pH-Dependent Absorption PharmacokineticsDEXILANT 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 pHis an important determinant of oral bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole).WarfarinCo-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.TacrolimusConcomitant administration of dexlansoprazole and tacrolimus may increase whole blood levels of tacrolimus, especially in transplant patients who are intermediate or poor metabolizers of CYP2C19.ClopidogrelConcomitant 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 POPULATIONSPregnancyTeratogenic EffectsPregnancy 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 MothersIt 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 UseSafety and effectiveness of DEXILANT in pediatric patients (less than18 years of age) have not been established.Geriatric UseIn 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 ImpairmentNo 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 ImpairmentNo 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).OVERDOSAGEThere 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 PHARMACOLOGYPharmacodynamicsSerum Gastrin EffectsThe effect of DEXILANT on serum gastrin concentrations was evaluated in approximately 3460 patients in clinical trials up to 8 weeks and in 1023 patientsfor 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) EffectsThere 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 byECL cell proliferation and formation of carcinoid tumors, especially in female rats [see Nonclinical Toxicology].Effect on Cardiac RepolarizationA 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 TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of FertilityThe carcinogenic potential of dexlansoprazole was assessed using lansoprazole studies. In two 24-month carcinogenicity studies, Sprague-Dawley rats were treated orally with lansoprazole at doses of 5 to 150 mg per kg per day, about 1 to 40 times the exposure on a body surface (mg/m2)basis of a 50 kg person of average height [1.46 m2 body surface area (BSA)] given the recommended human dose of lansoprazole 30 mg per day.Lansoprazole produced dose-related gastric ECL cell hyperplasia andECL 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, thein 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 INFORMATIONTo 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 Warningsand 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 byTakeda Pharmaceuticals America, Inc.Deerfield, IL 60015DEXILANT 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

2008• Contracting for compliance: using adherence

as a patient-centered measure of performance,by SR Taylor, JB Jones, NR Shah

• Delaware’s wellness program: motivatingemployees improves health and saves money,by J “J.J.” Davis

• Benchmarking new frontiers in managed carepharmacy, by C Pigg, J Cihak

2009• Increased patient cost-sharing, weak US econo-

my, and poor health habits: implications foremployers and insurers, by MC Haren, KMcConnell, AF Shinn

• Estimates of commercial population at highrisk for cardiovascular events: impact ofaggressive cholesterol reduction, by K Fitch,SW Goldberg, K Iwasaki, et al

• Lower copay and oral administration: predic-tors of first-fill adherence to new asthma pre-scriptions, by Z Berger, W Kimbrough, CGillespie, 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 APozniak, L Olinger, V Shier

• Comparing medical costs of care for patientswith metastatic breast cancer receiving taxanetherapy: claims analysis, by RW Force, BAPugmire, VL Culbertson

• A comparison of drug formularies and thepotential for cost-savings, by AL Kjos, JCSchommer, Y Yuan

2011• The business case for payer support of a com-

munity-based health information exchange: aHumana pilot evaluating its effectiveness incost control for plan members seeking emer-gency department care, by A Tzeel, VLawnicki, KR Pemble

• Health resource utilization and direct costsassociated with angina for patients with coro-nary artery disease in a US managed care set-ting, by J Kempf, E Buysman, D Brixner

• Atypical antipsychotics and metabolic syn-drome in patients with schizophrenia, by HJRiordan, P Antonini, MF Murphy

Read these articles at www.AHDBonline.com.

Most Read Articles in American Health & Drug Benefits

6 l American Health & Drug Benefits l www.AHDBonline.com January/February 2012 l Vol 5, No 1

TABLE OF CONTENTS

Continued on page 10

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EDITORIAL

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

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

BUSINESS

23 Beyond the Cost of Biologics: Employer Survey Reveals Gap in UnderstandingRole of Specialty Pharmacy and Benefit DesignF. Randy Vogenberg, RPh, PhD; Cheryl Larson, BA; Margaret Rehayem, MA; Larry Boress, MPA

30 Stakeholder Perspective by Atheer A. Kaddis, PharmD

REGULATORY

40 Primary Care Shortages: Strengthening This Sector Is Urgently Needed, Nowand in Preparation for Healthcare ReformSarah Collins, MBA

47 Stakeholder Perspective by Gary M. Owens, MD

PublisherNicholas [email protected] PublisherMaurice [email protected] DirectorDalia [email protected] EditorsBrett KaplanLara J. Lorton732-992-1892Editorial AssistantJennifer [email protected] AssistantZach CeretelleSenior Production ManagerLynn HamiltonQuality Control DirectorBarbara MarinoBusiness ManagerBlanche Marchitto

Founding Editor-in-ChiefRobert E. Henry

American Health & Drug Benefits isfounded on the concept that health anddrug benefits have undergone a transfor-mation: the econo metric value of a drugis of equal importance to clinical out-comes as it is to serving as the basis forsecuring coverage in formularies andbenefit designs. Because benefit designsare greatly affected by clinical, business,and policy conditions, this journal offersa forum for stakeholder integration andcollaboration toward the improvementof healthcare.This publication further provides benefitdesign de cision makers the integratedindustry information they require to deviseformularies and benefit designs that standup to today’s special healthcare deliveryand business needs.Contact Information:For subscription information and edi torial queries, please contact: [email protected]: 732-992-1892F: 732-992-1881

Mission Statement

EDARBI 80 mg

-14.3 mm Hg

BENICAR 40 mg

-11.7 mm Hg

DIOVAN 320 mg

-10.0 mm Hg

moving millimeters

EDARBI is a trademark of Takeda Pharmaceutical Company Limited registered with the U.S. Patent and Trademark Office and used under license by Takeda Pharmaceuticals America, Inc. Trademarks are the property of their respective owners. ©2011 Takeda Pharmaceuticals North America, Inc. All rights reserved. LXA-00482 09/11

EDARBI 80 mg was statistically superior to DIOVAN® 320 mg and BENICAR® 40 mg in reducing 24-hr mean ambulatory and clinic SBP1

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

� Clinic SBP differences between EDARBI and active comparators were consistent with mean ambulatory results

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.� 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, renin-

angiotensin-aldosterone system (RAAS) blockers such as azilsartan medoxomil can cause excessive hypotension. In patients whose renal function may depend on the activity of the renin-angiotensin 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 USAGEEDARBI 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.

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.

See how many millimeters you can move with EDARBI

REDUCTIONS IN 24-HR MEAN AMBULATORY SBP AT WEEK 61,2

Mean ambulatory baseline: Study 1=144.9 mm Hg

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.

P<0.001 vs DIOVAN 320 mgP=0.009 vs BENICAR 40 mg

STUDY 1

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 PatientsIn 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 FunctionAs 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 renin-angiotensin 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 REACTIONSClinical Trials ExperienceBecause 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 ≥0.3% and greater than placebo in more than 3300 patients treated with Edarbi in controlled trials are listed below:Gastrointestinal Disorders: nauseaGeneral Disorders and Administration Site Conditions: asthenia, fatigueMusculoskeletal and Connective Tissue Disorders: muscle spasmNervous System Disorders: dizziness, dizziness postural Respiratory, Thoracic and Mediastinal Disorders: coughClinical Laboratory FindingsIn 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 INTERACTIONSNo 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.

BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION for Edarbi (azilsartan medoxomil) tablets

WARNING: AVOID USE IN PREGNANCYWhen 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 USAGEEdarbi 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 Program’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. CONTRAINDICATIONSNoneWARNINGS AND PRECAUTIONSFetal/Neonatal Morbidity and MortalityDrugs 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.

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 PregnancyPregnancy Category C (first trimester) and D (second and third trimesters). There is no clinical experience with the use of Edarbi in pregnant women.Nursing MothersIt 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 UseSafety and effectiveness in pediatric patients under 18 years of age have not been established.Geriatric UseNo 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 ImpairmentDose 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 ImpairmentNo dose adjustment is necessary for subjects with mild or moderate hepatic impairment. Edarbi has not been studied in patients with severe hepatic impairment.OVERDOSAGELimited 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 patient’s clinical status. Azilsartan is not dialyzable.CLINICAL PHARMACOLOGY PharmacokineticsSpecial PopulationsThe effect of demographic and functional factors on the pharmacokinetics of azilsartan was studied in single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of the effect on azilsartan are presented in Figure 1 as change relative to reference (test/reference). Effects are modest and do not call for dosage adjustment.Figure 1 Impact of intrinsic factors on the pharmacokinetics of azilsartan

Population Description PK Fold Change and 90% CI Recommendation

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

No dose adjustment

NO EXPERIENCE

NO EXPERIENCE

0.5 1.0 1.5 2.0 2.5 3.0

Change relative to reference

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

CmaxAUC

AGE

>65y/18-45y

GENDER

Females/Males

RACE

Whites/Blacks

RENAL IMPAIRMENT

Mild/Normal

HEPATIC IMPAIRMENT

Mild/Normal

PEDIATRIC

Moderate/Normal

Severe/Normal

Moderate/Normal

Severe/Normal

ESRD/Normal

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 INFORMATIONSee FDA-approved patient labeling (Patient Information).General InformationPregnancy: 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 byTakeda Pharmaceuticals America, Inc.Deerfield, IL 60015For 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.©2011 Takeda Pharmaceuticals America, Inc.April 2011AZL074 R2 L-LXA-0411-4



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CLINICAL

52 Daily Average Consumption of 2 Long-Acting Opioids: An Interrupted TimeSeries AnalysisR. Amy Puenpatom, PhD; Sheryl L. Szeinbach, PhD, MS, BSPharm; Larry Ma, PhD;Rami H. Ben-Joseph, PhD; Kent H. Summers, PhD, BSPharm

60 Stakeholder Perspective by Matthew Mitchell, PharmD, MBA

DEPARTMENTS

INDUSTRY TRENDS31 Employers, Health Plans, and New Drug Benefit Designs: A Shifting Landscape

Mark Zitter, MBA; Michael Snyder

OPINION62 Should Everyone Be Required to Have Health Insurance?

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

www.tradjenta.comCopyright © 2011, Boehringer Ingelheim Pharmaceuticals, Inc. All rights reserved. (10/11) TJ132005MHC

FOR ADULT PATIENTS WITH TYPE 2 DIABETES MELLITUS

Indication and Important Limitations of UseTRADJENTA 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 InformationCONTRAINDICATIONSTRADJENTA is contraindicated in patients with a history of hypersensitivity reaction to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity.

WARNINGS AND PRECAUTIONSUse With Medications Known To Cause HypoglycemiaInsulin 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 OutcomesThere have been no clinical studies establishing conclusive evidence of macrovascular risk reductionwith TRADJENTA or any other antidiabetic drug.

ADVERSE REACTIONSAdverse 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 INTERACTIONSThe 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 POPULATIONSThere 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

2:52 PM

Tradjenta™ (linagliptin) tablets

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Please see package insert for full Prescribing Information.

INDICATIONS AND USAGETRADJENTA tablets are indicated as an adjunct to diet and exercise to improve gly-cemic 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.

CONTRAINDICATIONSTRADJENTA is contraindicated in patients with a history of a hypersensitivity reac-tion to linagliptin, such as urticaria, angioedema, or bronchial hyperreactivity [seeAdverse Reactions].

WARNINGS AND PRECAUTIONSUse with Medications Known to Cause Hypoglycemia: Insulin secretagogues are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulinsecretagogue (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 hypoglyce-mia when used in combination with TRADJENTA. Macrovascular Outcomes: Therehave been no clinical studies establishing conclusive evidence of macrovascular riskreduction with TRADJENTA tablets or any other antidiabetic drug.

ADVERSE REACTIONSClinical Trials Experience: Because clinical trials are conducted under widely vary-ing 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 refl ect the rates observed in practice. The safety of linagliptin has been evaluated in over4000 patients with type 2 diabetes in clinical trials, including 12 placebo-controlledstudies and 1 active-controlled study with glimepiride. TRADJENTA 5 mg once dailywas studied as monotherapy in two placebo-controlled trials of 18 and 24 weeks’duration. Five placebo-controlled trials investigated linagliptin in combination withother oral antihyperglycemic agents: two with metformin (12 and 24 weeks’ treat-ment duration); one with a sulfonylurea (18 weeks’ treatment duration); one withmetformin and sulfonylurea (24 weeks’ treatment duration); and one with piogli-tazone (24 weeks’ treatment duration). In placebo-controlled clinical trials, adversereactions that occurred in ≥5% of patients receiving TRADJENTA (n = 2566) andmore commonly than in patients given placebo (n = 1183) included nasopharyn-gitis (5.8% vs 5.5%). Adverse reactions reported in ≥2% of patients treated withTRADJENTA 5 mg daily as monotherapy or in combination with pioglitazone, sulfo-nylurea, or metformin and at least 2-fold more commonly than in patients treatedwith placebo are shown in Table 1. Following 52 weeks’ treatment in a controlledstudy comparing linagliptin with glimepiride in which all patients were also receivingmetformin, adverse reactions reported in ≥ 5% patients treated with linagliptin (n =776) and more frequently than in patients treated with a sulfonylurea (n = 775) werearthralgia (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 TRADJENTAwere hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), andmyalgia. In the clinical trial program, pancreatitis was reported in 8 of 4687 patients(4311 patient years of exposure) while being treated with TRADJENTA comparedwith 0 of 1183 patients (433 patient years of exposure) treated with placebo. Threeadditional cases of pancreatitis were reported following the last administered doseof linagliptin.Hypoglycemia: In the placebo-controlled studies, 195 (7.6%) of the total 2566patients treated with TRADJENTA 5 mg reported hypoglycemia compared to

49 patients (4.1%) of 1183 placebo-treated patients. The incidence of hypoglyce-mia was similar to placebo when linagliptin was administered as monotherapy orin combination with metformin, or with pioglitazone. When linagliptin was adminis-tered in combination with metformin and a sulfonylurea, 181 of 791 (22.9%) patientsreported hypoglycemia compared with 39 of 263 (14.8%) patients administered pla-cebo in combination with metformin and a sulfonylurea.Laboratory Tests: Changes in laboratory findings were similar in patients treated withTRADJENTA 5 mg compared to patients treated with placebo. Changes in labora-tory values that occurred more frequently in the TRADJENTA group and ≥1% morethan 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 INTERACTIONSInducers of P-glycoprotein or CYP3A4 Enzymes: Rifampin decreased linagliptinexposure suggesting that the effi cacy of TRADJENTA may be reduced when admin-istered in combination with a strong P-gp or CYP3A4 inducer. Therefore, use ofalternative treatments is strongly recommended when linagliptin is to be adminis-tered with a P-gp or CYP3A4 inducer.

USE IN SPECIFIC POPULATIONSPregnancy: Pregnancy Category B. Reproduction studies have been performed inrats and rabbits. There are, however, no adequate and well-controlled studies inpregnant women. Because animal reproduction studies are not always predictive ofhuman response, this drug should be used during pregnancy only if clearly needed.Linagliptin administered during the period of organogenesis was not teratogenic atdoses up to 30 mg/kg in the rat and 150 mg/kg in the rabbit, or approximately 49and 1943 times the clinical dose based on AUC exposure. Doses of linagliptin causingmaternal toxicity in the rat and the rabbit also caused developmental delays in skel-etal ossifi cation and slightly increased embryofetal loss in rat (1000 times the clinicaldose) and increased fetal resorptions and visceral and skeletal variations in the rabbit(1943 times the clinical dose). Linagliptin administered to female rats from gestationday 6 to lactation day 21 resulted in decreased body weight and delays in physicaland behavioral development in male and female offspring at maternally toxic doses (exposures >1000 times the clinical dose). No functional, behavioral, or reproductivetoxicity was observed in offspring of rats exposed to 49 times the clinical dose. Lina-gliptin 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 excretedin 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 estab-lished. Geriatric Use: Of the total number of patients (n= 4040) in clinical studies ofTRADJENTA, 1085 patients were 65 years and over, while 131 patients were 75 yearsand over. No overall differences in safety or effectiveness were observed betweenpatients 65 years and over and younger patients. While this and other reportedclinical experience have not identifi ed differences in response between the elderlyand younger patients, greater sensitivity of some older individuals cannot be ruledout. No dose adjustment is recommended in this population. Renal Impairment:No dose adjustment is recommended for patients with renal impairment. HepaticImpairment: No dose adjustment is recommended for patients with hepatic impairment.

OVERDOSAGEDuring controlled clinical trials in healthy subjects, with single doses of up to 600mg of TRADJENTA (equivalent to 120 times the recommended daily dose) there wereno dose-related clinical adverse drug reactions. There is no experience with dosesabove 600 mg in humans. In the event of an overdose, it is reasonable to employ theusual supportive measures, e.g., remove unabsorbed material from the gastrointes-tinal 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 thera-peutically signifi cant degree by hemodialysis or peritoneal dialysis.

Table 1 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 (%)

Combination with Metformin#

n (%)

Combination with SU n (%)

Combination with Metformin + SU n (%)

Combination with Pioglitazone n (%)

TRADJENTAn = 765

Placebon = 458

TRADJENTAn = 590

Placebon = 248

TRADJENTAn = 161

Placebon = 84

TRADJENTAn = 791

Placebon = 263

TRADJENTAn = 259

Placebon = 130

Nasopharyngitis – – – – 7 (4.3) 1 (1.2) – – – –Hyperlipidemia – – – – – – – – 7 (2.7) 1 (0.8)Cough – – – – – – 19 (2.4) 3 (1.1) – –Hypertriglyceridemia† – – – – 4 (2.4) 0 (0.0) – – –Weight increased – – – – – – – – 6 (2.3) 1 (0.8)

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

Copyright © 2011 Boehringer Ingelheim Pharmaceuticals, Inc.

Revised: July 2011 TJ-BS (7-11) TJ104305PROF

2:52 PM

EDITORIAL BOARD

13www.AHDBonline.com l American Health & Drug Benefits lVol 5, No 1 l January/February 2012

CLINICAL EDITOR Thomas G. McCarter, MD, FACPChief Clinical OfficerExecutive Health Resources, PA

GOVERNMENT EDITORKevin B. “Kip” Piper, MA, FACHEPresident, Health Results GroupSenior Counselor, Fleishman-Hillard Washington, DC

ACTUARY David WilliamsMilliman Health ConsultantWindsor, CT

AGING AND WELLNESSEric G. Tangalos, MD, FACP, AGSFProfessor of MedicineMayo Clinic, Rochester, MN

CANCER RESEARCHAl B. Benson, III, MD, FACPProfessor of MedicineAssociate Director for ClinicalInvestigationsRobert H. Lurie Comprehensive CancerCenter, Northwestern UniversityImmediate Past President, ACCCPast Chair, NCCN Board of Directors

Samuel M. Silver, MD, PhD, FACPProfessor, Internal MedicineDirector, Cancer Center NetworkDivision of Hematology/OncologyAssistant Dean for ResearchUniversity of Michigan Health Systems

CARDIOLOGY RESEARCH Michael A. Weber, MDProfessor of MedicineDepartment of Medicine (Cardiology)State University of New York

EMPLOYERSAlberto M. Colombi, MD, MPHCorporate Medical DirectorPPG Industries, Pittsburgh, PA

Wayne M. Lednar, MD, PhDGlobal Chief Medical OfficerDirector, Integrated Health ServicesDuPont, Wilmington, DE

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

F. Randy Vogenberg, RPh, PhDPrincipal, Institute of IntegratedHealthcare, Sharon, MA

ENDOCRINOLOGY RESEARCHJames V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans AffairsMedical Center, Phoenix, AZ

EPIDEMIOLOGY RESEARCHJoshua N. Liberman, PhDVice President, Research OperationsCenter for Health ResearchGeisinger Health System, Danville, PA

HEALTH INFORMATION TECHNOLOGY J. B. Jones, PhD, MBAResearch Associate, Geisinger Health System, Danville, PA

Victor J. Strecher, PhD, MPHProfessor and Director, Center for HealthCommunications ResearchUniversity of Michigan Schools of PublicHealth and Medicine, Ann ArborFounder and Chief Visionary OfficerHealthMedia, Johnson & Johnson

HEALTH OUTCOMES RESEARCH Diana Brixner, RPh, PhDProfessor and ChairDepartment of PharmacotherapyExecutive Director, Outcomes ResearchCenter, University of Utah College ofPharmacy, Salt Lake City

Kavita V. Nair, PhDAssociate Professor, School of PharmacyUniversity of Colorado at Denver

Gary M. Owens, MDPresident, Gary Owens AssociatesGlen Mills, PA

Timothy S. Regan, BPharm, RPhExecutive Director, XcendaPalm Harbor, FL

HEALTH & VALUE PROMOTION Albert Tzeel, MD, MHSA, FACPENational Medical DirectorHumanaOne, Milwaukee

MANAGED CARE & GOVERNMENT AFFAIRSSharad Mansukani, MDChief Strategic Officer, Nations HealthSenior Advisor, Texas Pacific Group, FL

MANAGED MARKETS Jeffrey A. Bourret, RPh, MS, FASHPSenior Director, Branded SpecialtyPharmacy Programs, US SpecialtyCustomers, Pfizer, Specialty Care Business Unit, PA

Charles E. Collins, Jr, MS, MBAExecutive Vice President, Managing DirectorEngage Managed Markets

PATIENT ADVOCACY William E. Fassett, BSPharm, MBA, PhDProfessor of Pharmacy Law & EthicsVice Chair, Dept. of PharmacotherapyCollege of Pharmacy, Washington StateUniversity, Spokane, WA

PERSONALIZED MEDICINE Wayne A. Rosenkrans, Jr, PhDChairman and President, Personalized Medicine Coalition, Distinguished Fellow,MIT Center for Biomedical Innovation

PHARMACOECONOMICSJeff Jianfei Guo, BPharm, MS, PhDAssociate Professor of Pharmacoeconomics& Pharmacoepidemiology, College of Pharmacy, University of Cincinnati Medical Center, OH

PHARMACY BENEFIT DESIGN Joel V. Brill, MDChief Medical Officer, Predictive Health, Phoenix, AZ

William J. Cardarelli, PharmDDirector of Pharmacy, Atrius HealthHarvard Vanguard Medical Associates

Leslie S. Fish, PharmDSenior Director of Pharmacy ServicesFallon Community Health Plan, MA

Michael S. Jacobs, RPhNational Clinical Practice LeaderBuck Consultants, Atlanta

Matthew Mitchell, PharmD, MBAManager, Pharmacy ServicesSelectHealth, Salt Lake City, UT

Paul Anthony Polansky, BSPharm, MBASenior Field Scientist, Health Outcomesand PharmacoEconomics (HOPE) Endo Pharmaceuticals, Chadds Ford, PA

Scott R. Taylor, RPh, MBAAssociate Director, Industry RelationsGeisinger Health System, Danville, PA

POLICY & PUBLIC HEALTH Joseph R. Antos, PhDWilson H. Taylor Scholar in Health CareRetirement PolicyAmerican Enterprise Institute

Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of PharmacyUniversity of Missouri, Kansas City

Walid F. Gellad, MD, MPHAssistant Professor of Medicine, Universityof Pittsburgh, Staff Physician, PittsburghVA Medical Center, Associate Scientist,RAND Health

Alex Hathaway, MD, MPH, FACPMPresident & Founder, J.D. BioEdgeHealth quality & biomedical research

J. Warren Salmon, PhDProfessor of Health Policy & AdministrationSchool of Public HealthUniversity of Illinois at Chicago

RESEARCH & DEVELOPMENT Michael F. Murphy, MD, PhDChief Medical Officer and Scientific Officer Worldwide Clinical TrialsFaculty, Center for Experimental Pharmacology and Therapeutics, Harvard-MIT Division of Health Sciences andTechnology, Cambridge, MA

SPECIALTY PHARMACYAtheer A. Kaddis, PharmDVice President, Managed MarketsDiplomat Specialty Pharmacy Swartz Creek, MI

James T. Kenney, RPh, MBAPharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

It is difficult to believe that 5 years have passed sincethe 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 econom-ic downturn that had actually begun almost 3 monthsearlier. The price of oil topped $100 a barrel for the firsttime, and job losses were just being reported. Althoughmost of us did not know it yet, the United States wasentering the worst economic downturn since the GreatDepression. The economic woes of the past 5 years havehad a profound impact on the healthcare system. Although the recession has ended and economic

indicators are improving, healthcare payers are facingsignificant challenges in the postrecession economy.Some of these challenges include: • The potential for rapid escalation of healthcare costresulting from the impact of healthcare reform legisla-tion, as 41 million newly insured Americans seekservices in 2014 and beyond

• Maintaining affordability of health insurance premi-ums, with reasonable access to care, while healthcarecosts spiral upward

• Maintaining and growing market share in a difficulteconomic climate

• Working with employers and other customers who areincreasingly looking for plans to actively managemedical costs

• Dealing with benefit design issues that may potential-ly increase deductibles and higher out-of-pocket costsfor patients

• Managing new and expensive specialty pharmaceuti-cals that must become a critical core competency ofhealth plans.Because of these and other pressing issues in the

healthcare arena, all stakeholders need sources of infor-mation to help guide our daily activities. AHDB hasconsistently been one of those sources since its establish-ment. The first sentence of the mission statement ofAHDB caught my attention from the first issue,“American Health & Drug Benefits is founded on the con-cept that health and drug benefits have undergone atransformation: the econometric value of a drug is ofequal importance to clinical outcomes as it is to servingas the basis for securing coverage in formularies and drugbenefit designs.”

The concept of balancing cost, quality, and access is amajor concern for payers and the many other stakehold-ers in healthcare. AHDB has provided an open forum formany of the complex issues addressed in the pages of thejournal, by promoting stakeholder integration and col-laboration toward the mutual goals of improving healthoutcomes 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 followingfew examples: • 2008: Benchmarking New Frontiers in Managed CarePharmacy

• 2009: Increased Patient Cost-Sharing, Weak USEconomy, and Poor Health Habits: Implications forEmployers and Insurers

• 2010: A Comparison of Drug Formularies and thePotential for Cost-Savings

• 2011: The Hickory Project: Controlling HealthcareCosts and Improving Outcomes for Diabetes Usingthe Asheville Project Model

• 2012: Beyond the Cost of Biologics—EmployerSurvey Provides Insights into Benefit Coverage.In addition, special issues, such as “A Wellness-

Based Healthcare System for Chronic Diseases: Pre -vention, Intervention, and Innovation” published in2010, and the special theme issue on “CardiometabolicHealth and Wellness” published in 2011, have provid-ed guidance to AHDB’s readership on major popula-tion-based topics of concern.Many changes in healthcare have occurred since the

first issue of AHDB was published in 2008, and I am surethat many unanticipated changes will take place overthe next 5 years. During the past 5 years, AHDB has established itself

as an important forum for addressing critical issues facingthe US healthcare system. As an editorial board memberof AHDB, I wish to congratulate all my colleagues on theboard and all the many other people who have con-tributed to the excellent and vigorous publication stan-dards established by the journal and help make it a usefulresource 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 theconstantly evolving US healthcare environment. �

EDITORIAL


American Health & Drug Benefits:Reflections on the First 5 YearsBy Gary M. Owens, MDPresident, Gary Owens Associates, Glen Mills, PA

Jaka� is a trademark of Incyte Corporation.© 2011, Incyte Corporation. All rights reserved. RUX-1004 11/11

Indications and UsageJaka� is indicated for treatment of patients with intermediate or high-risk myelo� brosis, including primary myelo� brosis, post–polycythemia vera myelo� brosis and post–essential thrombocythemia myelo� brosis.

Important Safety Information• Treatment with Jaka� 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 Jaka� . 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 Jaka� . If clinically indicated, platelet transfusions may be administered

• Patients developing anemia may require blood transfusions.

Dose modi� cations of Jaka� for patients developing anemia may also be considered

• Neutropenia (ANC <0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jaka�

• Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections. Active serious infections should have resolved before starting Jaka� . Physicians should carefully observe patients receiving Jaka� for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly

• A dose modi� cation is recommended when administering Jaka� 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 ef� cacy

• There are no adequate and well-controlled studies of Jaka� in pregnant women. Use of Jaka� during pregnancy is not recommended and should only be used if the potential bene� t justi� es the potential risk to the fetus

• Women taking Jaka� 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.

VISIT WWW.JAKAFI.COM FOR MORE INFORMATION

NOW APPROVED FOR INTERMEDIATE OR HIGH-RISK

MYELOFIBROSIS

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya

Jakafi Placebo (N=155) (N=151)Laboratory All All Parameter Gradesb Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0Anemia 96.1 34.2 11.0 86.8 15.9 3.3Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3

a Presented values are worst Grade values regardless of baselineb National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% ofpatients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine trans-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 treatedwith placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase(AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring orworsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% forJakafi with no Grade 3 or 4 cholesterol elevations.DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinibis predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinibincreased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was alsoprolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamicmarker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent admin-istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction isrecommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should beclosely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors:There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration(10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days,compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3inhibition was consistent with the corresponding exposure information. No dose adjustment is recommendedwhen Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration(50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone inhealthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmaco-dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered witha CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy.USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment withruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses.Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at dosesof 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of terato-genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest andmaternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 timesthe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weightsof approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. Ina pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implan-tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups forfertility indices or for maternal or embryofetal survival, growth and development parameters at the highestdose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily).Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or itsmetabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternalplasma. Because many drugs are excreted in human milk and because of the potential for serious adversereactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinuethe drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effec-tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number ofmyelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differ-ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. RenalImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)],moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8)additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmaco-kinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those withnormal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasingseverity of renal impairment. This was most marked in the subjects with end stage renal disease requiringhemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removalof some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients withmoderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet countbetween 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reductionis recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. HepaticImpairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study inhealthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], orsevere hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28%and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patientswith normal hepatic function. The terminal elimination half-life was prolonged in patients with hepaticimpairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmaco-dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposureexcept in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity wasmore prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) inFull Prescribing Information].

BRIEF SUMMARY: For Full Prescribing Information, see package insert.INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-riskmyelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essentialthrombocythemia myelofibrosis.CONTRAINDICATIONS None.WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatmentwith 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 andAdministration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/Lat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia wasgenerally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in FullPrescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans-fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia(ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi[see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosingadjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and AdverseReactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac-terial, fungal and viral infections. Active serious infections should have resolved before starting therapy withJakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection andinitiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signsand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see AdverseReactions].ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted underwidely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directlycompared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Thesafety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies,patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% ofpatients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred andeleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. Ina double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. Themost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia,anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactionswere bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless ofcausality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo.Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return topretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon-tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen;however, it has not been established whether discontinuation of therapy contributed to the clinical course inthese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of thedose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information].Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, placebo-controlled study during randomized treatment.Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlledStudy During Randomized Treatment

Jakafi Placebo (N=155) (N=151)Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 (%) (%) (%) (%) (%) (%)Bruisingb 23.2 0.6 0 14.6 0 0Dizzinessc 18.1 0.6 0 7.3 0 0Headache 14.8 0 0 5.3 0 0Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7Weight Gaine 7.1 0.6 0 1.3 0.7 0Flatulence 5.2 0 0 0.7 0 0Herpes Zosterf 1.9 0 0 0.7 0 0

a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site

hematoma, increased tendency to bruise, petechiae, purpurac includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitisd includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria

urine, bacteria urine identified, nitrite urine presente includes weight increased, abnormal weight gainf includes herpes zoster and post-herpetic neuralgiaDescription of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, mediantime to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%)discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobinreached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and thengradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This patternwas observed in patients regardless of whether they had received transfusions during therapy. In therandomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receivingplacebo received red blood cell transfusions during randomized treatment. Among transfused patients, themedian number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia wasgenerally reversible with dose reduction or dose interruption. The median time to recovery of platelet countsabove 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafiand to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo-cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens.Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency ofGrade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5%versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafibecause of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalitiesreported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Jakafi is a trademark of Incyte Corporation. All rights reserved.U.S. Patent No. 7,598,257© 2011 Incyte Corporation. All rights reserved.Issued: November 2011 RUX-1040

In June 2008, my wife and I moved to down-town Asheville, NC, with our dog, Max.Max and I were out for a walk early every

morning and late every evening. When I firststarted taking Max for walks, I would occasion-ally notice people who appeared homeless, andI became curious about the causes of homeless-ness and its solutions. Now, in 2012, I rarely see a homeless person

downtown. What has changed? One major change isthat Asheville has instituted a viable 10-year plan to endchronic homelessness, and a group of more than 40agencies are working together in the Asheville HomelessCoalition. I got involved initially by attending the 2008annual Homeless Initiative Stakeholders meeting inAsheville and the meetings of Asheville HomelessCoalition, 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 endshomelessness. It is that simple. And housing providesthe stability that people need to address unemployment,addiction, mental illness, and physical health. If we pairhousing with supportive case management, people willbe able to stabilize their lives, increase their self-suffi-ciency, and remain in housing. As of November 2011,Homeward Bound has housed 338 people, reporting an89% housing retention rate. I have also learned that by housing people, we are sav-

ing our community hundreds of thousands of dollarseach year in unpaid healthcare costs. In a 2006 article inthe New Yorker, Malcolm Gladwell wrote of “Million-Dollar Murray,” relating how one person (Murray Barr)living on the streets in Reno, NV, cost that state $1 mil-lion in unpaid emergency department and medicalcosts.1 This $1 million could have been saved if MurrayBarr had been supported by housing.1

I have learned that homelessness is a problemthat can be solved, that housing is the answer,and that moving people from homelessness intohousing results in significant improvements inhealth and access to healthcare. Ending home-lessness is not only beneficial to the people whohave moved into housing. It is beneficial to thecommunity and to the healthcare system as well.

Healthcare Costs, UtilizationAs people become stabilized in housing, their depend-

ence on emergency services drops, and their health out-comes improve significantly. Consider the followingfacts on the cost of healthcare for the homeless: • The majority of homeless people lack health insur-ance, a public provision for healthcare, or a primarycare physician2,3

• Almost 33% of all visits to the emergency departmentare made by chronically homeless people. Emergencydepartments are not equipped to meet the psychoso-cial needs of homeless patients and do not have thecapacity to assist them with housing, substance abusetreatment, or mental healthcare2,3

• Homeless people visit the emergency department anaverage of 5 times annually, and the most frequentusers visit them weekly. Each visit costs $3700,amounting to $18,500 spent annually for the averageuser and up to $44,400 for the most frequent users2,3

• On average, homeless people spend 3 nights per visitin the hospital, which can cost more than $90002

• According to Margot Kushel, MD, AssociateProfessor of Medicine, University of California, SanFrancisco, “Homeless people have higher rates ofchronic health problems than the general or povertypopulation. This takes the form of higher rates of ill-nesses such as high blood pressure, heart disease, dia-betes, lung diseases like asthma and chronic bronchi-tis, and HIV disease”4

• As many as 80% of emergency department visitsmade by people struggling with homelessness are forillnesses that could have been addressed throughpreventive care.2The answer to reducing healthcare costs for people

EDITORIAL


The Business Case for EndingHomelessness: Having a Home ImprovesHealth, Reduces Healthcare Utilization and CostsDaniel G. Garrett, RPh, MS, FASHP

Mr Garrett is Chief Trailblazer, Blue Ridge Mountain Group,LLC, Asheville, NC; President of the Board, HomewardBound of Asheville, NC; a member of the Asheville HomelessInitiative Advisory Committee; and President of the Boards ofLiberty Corner Enterprises and Health Partners of Asheville andBuncombe County. He facilitated the original Asheville Project.

who are homeless is supportive housing5:• The provision of housing to homeless residentsdecreases by nearly 61% the number of visits theymake to emergency departments

• Providing permanent supportive housing to thehomeless 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 hospitaliza-

tions is decreased by 77%• For members of the community who need assistanceresolving their medical and/or psychosocial problems,permanent supportive housing is often the only suc-cessful approach to ending homelessness

• Safe and permanent housing can give residents thestability they need to organize their lives and main-tain their health.

The National Coalition for the Homeless points outthat, “Homelessness and healthcare are intimately inter-woven. Poor health is both a cause and a result of home-lessness. The National Healthcare for the HomelessCouncil (2008) estimates that 70% of Healthcare for theHomeless clients do not have health insurance.Moreover, approximately 14% of people treated byhomeless healthcare programs are children under the ageof 15.”6When homeless people are placed in supportive hous-

ing, many are qualified for healthcare coverage. Moreimportant, people who have housing are less apt to needhealthcare services as often as those who have no hous-ing, as noted above.5Recently, the Substance Abuse and Mental Health

Services Administration (SAMHSA) announced grantsto Asheville and 19 other communities to benefit home-less people.7 The Cooperative Agreements to BenefitHomeless Individuals provide funding to offer supportand housing for homeless people and those with mentaland substance use disorders.7 Because of their illness,these people have largely been excluded from the cur-rent healthcare system and are, therefore, relying onpublic “safety net” programs. SAMHSA points out that “Last year alone approxi-

mately 20 million people who needed substance abusetreatment did not receive it and an estimated 10.6 mil-lion adults reported an unmet need for mental health-care. As a result the health and wellness of the individ-ual is jeopardized and the unnecessary costs to societyripple across America’s communities, schools, business-es, prisons and jails, and healthcare delivery systems.”8The expansion of programs being supported by

SAMHSA is a key to housing many people who arehomeless and to significantly reducing the medical costsof these people to the healthcare system. For people with chronic health conditions, Project

IMPACT Diabetes offers an example of how 25 commu-nities nationwide are coming together to improve healthoutcomes for those with chronic conditions who arehomeless and uninsured.9When I became a downtown property owner, I had

some of the misperceptions that many people (includingthose involved in healthcare) have about people whoare homeless.10 Since I have become involved in groupswho work to address homelessness, those myths havebeen dispelled for me, by learning about what causeshomelessness, and how we can end it and reduce health-care utilization and cost. A common myth is that homeless people move to

communities such as Asheville and Buncombe Countybecause of our progressive social services. In fact, 71% ofthe people experiencing homelessness, according to lastyear’s Point-in-Time Count data in Asheville, said thatthe last place they had stable housing was in BuncombeCounty.11 That means that 71% of the people who livehere without housing did not come here because theyheard about our social programs; rather, they were com-munity members with housing like you and me, but theyhave since lost their housing.

Housing Saves Healthcare CostsI have learned that ending homelessness is a reason-

able goal. This does not mean that no one will everbecome homeless again; it does mean that if we addressthe housing needs of the people who are experiencinghomelessness now, we will have more resources to pre-vent homelessness from happening in the future, or torespond quickly and effectively when a person loseshis/her housing. Homelessness can be just a briefepisode in one’s life; if we use our resources wisely, noone in our community has to experience homelessnessfor the long-term.Housing ends homelessness and reduces costs. The

Homeward Bound of Asheville Housing First programcosts about $10,000 per person annually, which is sub-stantially less than it costs our community to maintainhomelessness for any individual. We also end it by coor-

EDITORIAL


When homeless people are placed insupportive housing, many are qualified forhealthcare coverage. More important,people who have housing are less apt toneed healthcare services as often as thosewho have no housing.

dinating our efforts and working together. The data con-firm that we have had a drop in homelessness in Ashvilleduring a time of budget cuts, high unemployment rates,and declining property values, thanks to the collabora-tion, accountability, and system efficiency that is emerg-ing from our community-wide homeless initiative.12The United States is at a national crossroads in terms

of rapidly rising healthcare costs, and we need morecommunity-wide leadership, volunteers, and donationsto truly impact the way people experience a housing cri-sis. Homelessness affects the health and well-being of ourentire community, and it is within our power to changethe 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 homeless-ness, and even more people to avoid it completely. If weall—healthcare leaders, businesses, agencies, schools,faith groups, and neighbors—join together, we will seethe experience of homelessness in our communitieschange for everyone. Patient-centered medical homes have been getting

much attention in the healthcare industry and in med-ical journals. An effective way for each of us who isengaged in healthcare to be involved in improvinghealth outcomes and lowering costs is to support theeffort 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 com-munity members, we improve the fiscal well-being ofour healthcare systems, and we improve the quality oflife for everyone in our community. As the body of evi-dence supporting the tie between housing and health-care continues to grow, those of us in the medical worldwould be wise to seek opportunities to invest in solu-tions to homelessness. As healthcare professionals and community members,

we must recognize our role as stakeholders in endinghomelessness and take responsibility as informed leaderswho can advocate for housing to end homelessness andimprove health. I got involved by walking my dog, and I look forward

to the day when every person Max meets on the streetsof Asheville has a place to call home and the healthcarebenefits he or she needs. You can get involved too. Visit the websites of the United

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 endhomelessness. ■

Author Disclosure Statement Mr Garrett has no conflicts of interest to report.

References1. Gladwell M. Dept. of Social Services. Million-dollar Murray: why problems likehomelessness 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.endhomelessness.org/section/about_homelessness/cost_of_homelessness. Accessed Janu ary 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 HealthCareFoundation. 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 SAMHSAgrant awards. CSAT/TI-11-008: cooperative agreements to benefit homeless individ-uals (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. AccessedJanuary 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_Overview-20110409.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/AR2010070902357.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/Asheville-2011_PIT.pdf. Accessed January 5, 2012.12. Frankel J. Local homelessness counts lower, reflecting national trend. December14, 2011. www.mountainx.com/article/38403/Local-homeless-counts-lower-reflecting-national-trend. Accessed January 5, 2012.

EDITORIAL


Housing is healthcare. As we endhomelessness one household at a time, we improve the health of our communitymembers, we improve the fiscal well-beingof our healthcare systems, and we improvethe quality of life for everyone in our community.


American Health & Drug Benefits offers an open forum for all healthcare participants to exchangeideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit designmodels 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 specificimplications to policymakers, payers, and employers.

Manuscripts should follow the Manuscript Instructions for Authors (available at www.AHDBonline.com).Submit articles to [email protected]. For more information, call 732-992-1892.

Areas of High Interest Include:

• Adherence Concerns

• Benefit Design

• Case Studies

• Comparative Effectiveness Research

• Cost Analyses

• Decision-Making Tools

• Ethics in Medicine

• Health Economics Research

• Health Plan Initiatives

• Health Information Technology

• Industry Trends

• Innovations in Healthcare

• Literature Reviews

• Medicare/Medicaid

• Patient Advocacy/Patient Care

• Pharmacoeconomics

• Policy Issues

• Prevention Initiatives

• Reimbursement Strategies

• Survey Results

• Wellness Programs

CALL FOR PAPERS

Theme Issue: Cancer CareThe growing focus on targeted therapies and diagnostics,personalized medicine, and the ever-growing cost of can-cer care require an ongoing examination of current andemerging trends in oncology, cost-effectiveness and cost-benefit analyses, utilization, and outcomes. While cancertherapies continue to make considerable strides, the costof care is becoming out of reach for many Americans. Weinvite you to submit articles that discuss these issues aswell as benefit design, comparative effectiveness analy-ses, and overall initiatives and programs that can helpchart new directions for healthcare stakeholders, includ-ing providers, medical and pharmacy directors, healthplans, employers, and policymakers.

Theme Issue: Cardiometabolic Health Heart disease remains the number one killer in the UnitedStates, and metabolic conditions such as diabetes and obe-sity continue to rise. Cardiometabolic disease consists of aconstellation of factors associated with cardiovascular dis-ease and the metabolic syndrome, including dyslipidemia,hypertension, insulin resistance, and high abdominal fat.In practical terms, it is impossible to separate the riskassessment and management of cardiovascular diseasefrom the approach to metabolic syndrome. Readers areinvited to submit original research, review articles, andperspectives on issues related to cost comparisons, phar-macoeconomics, benefit design, emerging therapies, andcurrent diagnosis and management practices.

BUSINESS


Advances in biotechnology have led to the devel-opment of new medical therapies for a variety ofdiseases, including many types of cancers and

autoimmune diseases (eg, rheumatoid arthritis). Among

these agents are biologics, also known as specialty phar-maceuticals. These drugs represent the fastest-growingsegment of pharmaceuticals. Employers sponsor a signif-icant proportion of plans that provide healthcare bene-fits, including biologics.There are currently approximately 750 biologics

already approved by the US Food and DrugAdministration, and 25% of the drugs that are now inthe pipeline are considered specialty pharmaceuticals.1

Dr Vogenberg is Principal, Institute for Integrated Healthcare,Sharon, MA; Ms Larson is Vice President, Ms Rehayem isDirector of Member Initiatives, and Mr Boress is President,all at Midwest Business Group on Health, Chicago, IL.

ORIGINAL RESEARCH

Beyond the Cost of Biologics: EmployerSurvey Reveals Gap in Understanding Role ofSpecialty 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 med-ical 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 effectivein 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 pro-vide healthcare benefits, but surveys on benefit coverage have neglected to measureemployers’ understanding of these drugs or their use.Objective: To establish a baseline understanding of specialty pharmacy drug benefit cov-erage from the perspective of the employer (ie, commercial benefit plan sponsors).Methods: The Midwest Business Group on Health (MBGH), a Chicago-based, nonprofitcoalition of more than 100 large employers, in collaboration with the Institute for IntegratedHealthcare, conducted a national web-based survey to determine the extent of employerunderstanding of specialty pharmacy drug management. MBGH, along with 15 businesscoalitions nationwide, distributed the survey to their employer members. A total of 120employers, 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 rankthe effectiveness of biologics-related disease management support for their employees,45% of the participating employers did not know whether productivity had increased, and43% did not know whether their employees had experienced increased quality of life as aresult of taking these drugs. The majority (76%) of employers continued to rely heavily onprint medium to communicate with their covered population. Overall, the vast majority ofemployers (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 phar-macy indicates that efforts are needed to fill in this knowledge gap to enable employers todesign useful or appropriate drug benefit programs and manage them more effectively tocontrol costs and optimize their employees’ healthcare outcomes. Efforts to educateemployers will require continued evaluation to ensure an effective communication betweenthem and their employees while this area of medicine continues to grow.

Am Health Drug Benefits.2012;5(1):23-30www.AHDBonline.com

Disclosures are at end of text

Stakeholder Perspective,page 30

F. Randy Vogenberg

BUSINESS


These drugs are characteristically derived from liveorganisms, and many require special storage and/or han-dling. Their administration varies widely, from self-administration to administration at an infusion center.The cost threshold for each biologic drug also varieswidely by health plan. The Medicare threshold is $500per month,2 whereas on the commercial side, the thresh-old varies by plan. Coverage and category definitions in this area of

pharmaceuticals remain unclear, and this is likely to per-sist as long as biologics or injectables continue tobecome available in self-administered formulations(which complicates how best to define biologic prod-ucts). Specialty drugs are used to treat a variety of dis-eases; the majority of spending today on these agents isincurred for the treatment of cancer, rheumatoid arthri-tis and other autoimmune conditions, multiple sclerosis,and anemia.1 Whereas early biologics were solely physi-cian-administered injectables or infusions, advances inmedical technology have expanded the formulations toinclude oral formulations that can be administered bythe patient.

Compounding the complexities of benefit coverage forthese treatments is their high cost, accounting for a17.4% change in prescription spending and the fastestgrowth of any drug category since 2004.1 In the past 5years, specialty drug plan spending rose by more than15%, several times higher than the overall drug trend.1,3Although specialty drugs account for only 1% of the totalprescription claims volume in 2010, 70% of drug costtrend in pharmacy benefit could be attributed to the ris-ing cost of specialty drugs.1 Specialty drugs are expectedto represent 21% of all plan drug spending by 2013, andas 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 prac-tices.4 The cost of specialty drugs ranges greatly from$6000 to $350,000 per employee or dependent annuallyand accounts for major increases in spending growth ofprescription benefit plans.5 Among the top contributorsto this trend were rheumatoid arthritis and other autoim-mune conditions (ie, lupus, Crohn’s disease, ulcerativecolitis), accounting for 14.7% of the trend.1Coverage for specialty pharmaceuticals also varies

based on the site of service and the method of contract-ing. Self-administered drugs are often billed under thepharmacy benefit plan, whereas infused or injectedoncology medications and drugs for immune disordersare usually billed under the medical plan. This makesanalysis of information on cost and utilization a difficultchallenge to buyers or payers in terms of managing cov-erage, patients, and payments. (Because most employersdo not have a retiree program, Medicare coverage wasnot included in this study.)Impending healthcare reform and a distressed econo-

my introduce yet further complications. The Institute ofMedicine recently recommended to the US Departmentof Health and Human Services that benefits of our finitehealthcare resources should be determined not by serv-ices but by costs.6 If the current cost growth trend con-tinues, both existing and new biologics will seriouslyincrease the drug cost curve. Drug therapy in oncologyalone is expected to increase from $125 billion in 2010to $207 billion by the end of the decade, in part as aresult of the increasing number of cancer survivors.6In early 2011, the Biologic Finance and Access

Council (BFAC) partnered with MediMedia Researchto conduct its second annual national survey of health-care executives. The survey targeted employers that wereeither affiliated with the Jefferson School of PopulationHealth or were members of BFAC, which includesthought leaders from large employers, pharmacy benefitmanagers, and national and regional health plans.7Attention was focused on biologics as the fastest growingcost trend in healthcare. In the BFAC survey, stakehold-

KEY POINTS➤ Employers sponsor a significant proportion of plansthat provide healthcare benefits to their employees;however, surveys on benefit coverage of specialtypharmaceuticals, or biologics, have neglected tomeasure employers’ understanding of these expensivetherapies.

➤ Specialty pharmaceuticals represent the fastest areaof drug growth since 2004, but they can cost up to$350,000 per patient, annually.

➤ In the past 5 years, specialty drug plan spending roseby more than 15%, several times higher than theoverall drug trend.

➤ This first-of-its-kind survey shows that employers areunaware of their spending on biologics and howeffective it is.

➤ It also shows that employers are unsure of how todesign appropriate benefits regarding these high-costdrugs and how to effectively communicate thisinformation to their employees.

➤ This survey suggests that employers have not movedaway from traditional benefit designs to takeadvantage of the benefits that specialty pharmacycan provide.

➤ These results can suggest to employers the need tofill the gap regarding healthcare benefits coverage,spending, and costs; identify potential improvementsto their benefit strategies; and shift their coveragedecisions to benefit themselves and their employees.

Beyond the Cost of Biologics


ers recognized that specialty pharmacy had an increasedeffect on benefit cost and patient outcomes, but theywere unable to judge trends related to spending and costmanagement. The outcome measures and value-based assessments

were determined to be important issues, but there was alack of understanding about the value of specialty phar-maceuticals related to these issues or the value of col-laborating with other stakeholders to increase patientadherence to treatment regimens. In response to the findings of the BFAC’s second

annual survey, the Midwest Business Group on Health(MBGH), a Chicago-based, nonprofit coalition of morethan 100 large private and public employers, in collabo-ration with the Institute for Integrated Healthcare (IIH),an Employer Project Advisory Council, conducted aweb-based survey that was directed solely at employers.Employers are key stakeholders in the specialty phar-

macy environment, because they sponsor a significantproportion of plans that provide healthcare benefits foremployees and their families. Therefore, it is as impor-tant to track employers’ perceptions and attitudesregarding benefit design, as it is to track changes inaccess to care and reimbursement concerns. However,benchmark surveys on benefit coverage have neglectedto measure employers’ overall understanding of spendingon biologic pharmaceuticals or their use. The present article describes the findings of the sur-

vey conducted by MBGH and IIH.

Method and Demographics In the summer of 2011, MBGH and IIH conducted

the first national employer-driven survey on specialtypharmacy and the use of specialty pharmaceuticals in aneffort to establish a baseline understanding of biologicsand specialty drug benefit coverage from the perspectiveof the employer (ie, commercial benefit plan sponsors).The information gained from this survey will be used toassist employers in understanding the value and benefitsof biologics. The survey was the first of a 2-phase effort. Based on

the hypothesis that employers did not fully understandpharmaceuticals, the survey was conducted with thehope that it would provide information that will allowthe development of various educational initiatives tohelp employers: (1) better understand specialty pharma-cy and specialty pharmaceuticals; (2) manage the chal-lenges posed by specialty pharmaceuticals; (3) managebenefits through plan design innovation by partneringwith specialty vendors for contracting and patient man-agement; (4) understand the importance of managingtheir at-risk population; and (5) more effectively com-municate specialty benefits to employees.

In this survey, MBGH collaborated with IIH and 15other business coalitions across the United States to dis-tribute a web-based questionnaire to their employermembers. A total of 120 employers, representing morethan 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 firsttime this type of study was conducted, it was difficult torepresent the true demographic region of employers.Therefore, location was determined based on where halfof the workforce, for each employer, was located.

Participating companies represented all US states, withhalf (50%) of them based in the Midwest, includingIllinois, Iowa, Kansas, Michigan, Missouri, North Dakota,and Wisconsin. The type of industry was based on theStandard Industrial Classification as defined by the USDepartment of Labor. Manufacturing was the largest(36%) industry type represented in this survey (Table 1).

ResultsAll major standard industrial employer categories

were represented in the survey, with manufacturingaccounting for more than one third (36%) of respond -ents. Employer funding of health benefits ranged fromself-insured (69%) and fully insured (19%) to a combi-nation of both (13%). A total of 60% of employers didnot combine more than one type of benefit option fortheir employees.

Table 1 Top Industries Represented in the Survey, Based on USDepartment of Labor Standard Industry Codes

IndustryProportion ofemployers, %

Manufacturing 36

Professional scientific, technical services, healthcare, social assistance

12

Management companies/enterprises 12

Construction 7

Finance, insurance 7

Educational services 6

Employers are key stakeholders in thespecialty pharmacy environment, becausethey sponsor a significant proportion ofplans that provide healthcare benefits foremployees and their families.

BUSINESS


When asked to rank their organization’s level ofunderstanding of specialty pharmacy and specialty phar-maceuticals, 25% of employers had “little to no under-standing” and 53% had only a “moderate understanding”(Figure 1A). The greatest (78%) lack of understanding of specialty

pharmaceuticals was seen among employers of compa-nies with a smaller-size (<500) active number of employ-ees (Figure 1B).

The survey also uncovered a serious lack of knowl-edge regarding what percentage of specialty pharmaceu-ticals was paid through the company’s medical benefitversus through pharmacy benefits. Of the respondentemployers, 70% reported not knowing what percentageof specialty pharmaceuticals was paid through their med-ical benefit, and 40% reported not knowing what per-centage was paid through their pharmacy benefit. A total of 29% of employers also reported not know-

ing what percentage of specialty pharmacy claim costshad increased in the pharmacy benefit over the past 3 to5 years (Figure 2). Nevertheless, 54% of employers required their

employees to use a specialty pharmacy to receive cov-erage. Of these employers, 57% required the mandatoryuse of a specialty pharmacy vendor for biologics andinjectables, 39% required a minimum 30-day fill or amaximum 90-day fill of a prescription for specialtypharmacy injectables, and 29% required mandatorymail 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 pharma-cy, using tiers and copayments. The second most favoreddesign reported by respondents (27%) was a traditionalpharmacy design with tiers and coinsurance. Of note,59% of employers required utilization of a specialty phar-macy, and 59% also required prior approval and/or steptherapy edits for claim approvals. In addition, 55% ofemployers included patient support and care manage-ment in their pharmacy plan design.Practically two thirds (66%) of employers valued

medication-related cost transparency in their vendorcontracts as “very important,” and 27% valued costtransparency as “important” (Figure 4). When asked which entities provided support for spe-

cialty product management, employers reported that thehealth plan provided the majority of support for casemanagement (78%) or disease management (64%).When asked which entities provided support for spe-cialty management, contracting, and benefit design,employers relied most heavily on pharmacy benefit man-agers (61%) and specialty pharmacies (56%). As shown in Table 3, contracting support was provid-

ed in large part by benefits consultants (60%) or wasdone in house (51%). More than three quarters (79%) ofemployers did their own benefit design in house, fol-lowed by benefits consultants (77%) and health plans(76%). This indicates that employers use more than 1contractor but have not moved from traditional benefitdesigns (ie, designs that cover a determined benefit forevery patient, with no distinction among the drug cov-ered) to value-based or innovative benefit designs.

High: we have a high level ofunderstanding of this benefit

Medium: we have a moderateunderstanding of this benefit

Low: we have little to nounderstanding of this benefit

Rank your organization’s level of understanding related to biologics/specialty pharmacy (choose 1)

Figure 1A Level of Understanding of Specialty Pharmacy

53%

22%25%

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

High: we have a high level of understanding of this benefitMedium: we have a moderate understanding of this benefitLow: we have little to no understanding of this benefit

Rank your organization’s level of understanding related to biologics/specialty pharmacy (choose 1)

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

15% 38%

19% 19%

6% 17% 19%

10% 5%

6% 27% 5%

11% 4% 10%

78% 8% 5%

Don’t know

>25,000

10,000-25,000

5001-10,000

3001-5000

1001-3000

501-1000

<500

0 20 40 60 80 100

Percentage



In addition, employers were asked to rank the effec-tiveness of case management/disease management sup-port—from “excellent” to “don’t know”—for their cov-ered employee population in 5 areas:1. Increases in productivity2. Improvements in treatment compliance3. Increases in quality of life4. Better management of related chronic conditions5. Improvements in medication adherence. A surprising high percentage of employers indicated

not knowing whether increases had occurred in produc-tivity (45%) and in quality of life (40%). However, 43%were at least satisfied with improvements they saw intreatment adherence, and 52% were satisfied with themanagement 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) tocommunicate with their covered population. The sec-ond most favored (51%) communication method waselectronic medium or e-mail, followed by (48%) web-based medium. Telephone messages and personal con-tacts were still used by 39% of employers. However, when employers were asked to rate the

effectiveness of various strategies used to communicatewith their employees during the past 3 to 5 years regard-ing health benefits, most employers said they did notknow (Table 5), indicating an amount of distance fromthe outcomes. To determine the efficacy of communica-tion strategies, it is necessary to have evaluated theireffectiveness over time. This finding highlights an under-appreciation of the importance of these strategies in dis-ease management and the importance of continuallyreevaluating messaging and employee responses to it.

Don’t know

11%-20%

5%-10%

>20%

<5%

No increase

0 5 10 15 20 25 30

On average, what percentage has your biologics/specialty pharmacy total claim costs increased in the pharmacy benefitonly over the past 3-5 years? (choose one)

Figure 2 Increase of Specialty Drug Total Claims during the Past 3-5 Years

Table 2 Employer Mandatory Prescription Requirements forEmployees

Do you currently require the mandatory use of: Yes, % No, %

Don’tknow, %

Mandatory mail order for chronic use medications

29 69 2

A 30-day minimum or 90-daymaximum fill of a prescriptionfor biologics or injectables

39 48 13

A specialty pharmacy vendor for biologics and injectables

57 38 5

Same as traditional design usingtiers and copayments

Same as traditional pharmacydesign using tiers and coinsurance

Special tier with copay

Special tier with coinsurance

Other, please specify

Don’t know

Utilization of a specialty pharmacy

Prior approval and/or step therapyedits for claim approvals

Patient support and care management

Special distribution requirementsfor products

Don’t know

Other, please specify

Indicate which best describes your biologics/specialty pharmacy plan design (check all that apply)

Indicate the key components that comprise your current biologics/specialty pharmacy plan design (check all that apply)

Figure 3 Specialty Pharmacy Plan Design

0 10 20 30 40 50 0 10 20 30 40 50

29%

19%

19%

17%

10%

5%

Percentage

59%

59%

55%

42%

15%

2%

44%

27%

13%

11%

7%

4%

Percentage Percentage

BUSINESS


DiscussionSpecialty pharmaceuticals represent the fastest area of

drug growth since 2004, and one in which drugs in thepipeline are already being marketed to consumers.However, as this survey shows, neither specialty pharma-cy nor specialty drugs are completely understood byemployers in their position as health plan sponsors. TheMBGH/IIH survey uncovered the following disturbingfacts about employers’ perspective on health benefits:• Employers are unaware of how effective their health-care spending is

• They are not sure how to design innovative benefitsor manage the costs

• They are also not sure of what works or how to effec-tively communicate information about specialty phar-maceuticals to their employees.Approximately 25% of employers have little or no

understanding of specialty pharmaceuticals, and only53% possess a moderate understanding of these thera-pies. Most employers are unaware of the amount ofmoney their company has spent or is spending on spe-cialty pharmacy, and 30% have no idea the extent towhich costs have increased in the past 3 to 5 years. Thisfinding mirrors those of the BFAC survey, in which50% of payers and providers did not know the percent-age of their organizations’ healthcare spending on bio-logics.3 Although all employers were aware that expen-ditures on specialty pharmaceuticals were important,almost none could project their organization’s approxi-mate healthcare spending on diagnostics in combina-tion with drug therapies for 2012.3Most important, the survey shows that the represent-

ed employers have not moved from traditional benefitdesigns, thus missing potential benefits associated withusing a value-based or innovative benefit design whendealing with specialty pharmacy. Furthermore, employ-ers are apparently unaware how these innovative designscould improve efficiency of their specialty pharmaceuti-cal management.Most employers use vendor costs as the determining

factor when selecting and contracting with specialtypharmacy vendors (Figure 4). If the gaps in employer knowledge are allowed to con-

tinue, problems associated with not addressing the newmainstream use of biologics emerging from the researchand development pipeline may remain unresolved.Furthermore, employers will not be able to communicatewell with employees about specialty pharmaceuticals todetermine whether their employees understood theirspecialty pharmacy benefits and whether these drugs hadany positive effect on their employees’ health. As a result of these findings, MBGH and IIH are plan-

ning efforts to help employers: (1) fill in the educational

Very important

Important

Somewhat important

Not important

How important is medication-related cost transparency in yourvendor contracts (choose one)?

Figure 4 Importance of Medication-Related Costs

0 20 40 60 80

Table 3 Entities That Support Employers in SpecialtyManagement, Contracting, and Benefit Design

Management entity

Management,%

Contracting,%

Benefit design,%

Done on own or in house

36 51 79

Benefits consultant 21 60 77

Outside pharmacy 38 44 74

Pharmacy benefitsmanager

61 41 70

Specialty pharmacy 56 29 54

Health plan 46 42 76

Table 4 Effectiveness of Case Management and DiseaseManagement Support with Covered Population

ResultsExcellent,

%Good,%

Fair,%

Poor,%

Don’tknow, %

Increases in productivity

1 27 23 4 45

Improvements intreatment compliance

2 43 27 4 24

Increases in quality of life

4 33 21 2 40

Better managementof related chronicconditions

5 52 21 2 20

Improvements inmedication adherence

7 35 29 3 26

66%

Percentage

27%

5%

2%



gaps related to understanding benefit coverage, spending,and healthcare costs; (2) determine key areas of utiliza-tion trends important to their organization; (3) identifyshort- and long-term opportunities for improving benefitstrategies and examine available resources before execut-ing them; (4) determine how to optimize benefit spend-ing based on technology trends; and (5) shift benefitdecisions as they gain knowledge in this area.

ConclusionsThese outcomes have defined the next steps for

MBGH. Phase 2 of this initiative project will be com-pleted in 2012, and includes working with an employeradvisory council to advise and drive elements of the2012 survey research, develop a web-based employereducational toolkit resource, and then build on 2 piloteducational outreach programs from late 2011 designedto disseminate research findings.It is hoped that these current and future efforts will

help employers develop a better understanding anddelivery of effective benefits for biologics. It is time tomove beyond the potential and into optimizing health-care outcomes, reducing employee risk factors and/or theprogression of disease, and linking health with wellnessalong the continuum of care. ■

AcknowledgmentThe authors wish to acknowledge the editorial assis-

tance of Sandra Paton in the preparation of this article.

Study fundingThis study was funded by the Midwest Business Group on

Health, a not-for-profit health research company that receivesresearch support from various pharmaceutical companies.

Author Disclosure StatementDr Vogenberg, Ms Larson, Ms Rehayem, and Mr Boress

reported no conflicts of interest.

References1. 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: Chapter17–Drugs and Biologics. August 19, 2011. www.cms.gov/manuals/downloads/clm104c17.pdf. Accessed November 30, 2011.3. Nash DB, Toscani M, Vogenberg FR. The Biologic Finance and Access Council2nd 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 NewHealth 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 Council2nd Annual Biologics Healthcare Survey: view from key healthcare stakeholders,part 2. Biotechnol Healthc. 2011;8:23-25.

Table 5 Effectiveness of Strategies and Employee Communication Efforts during the Past 3-5 Years

Benefit/communication strategyVery

effective, % Effective, %Somewhateffective, %

Not effective, %

Don’t know, %

Generic options 22 32 12 4 31

Protocols used for prior approval 20 24 22 0 34

Cost-sharing incentive 11 20 22 10 38

Days supply limited messaging 10 27 25 4 34

Communication from pharmacist 10 17 22 3 48

Integrated pharmacy network 10 21 18 3 49

Inclusion/exclusion criteria 9 17 22 4 47

Communication from physician 8 14 21 3 55

Health reimbursement account 5 16 26 16 36

Formulary explanation 5 24 32 7 31

Cost comparison 5 15 29 9 41

Audience benefit management communications for employees

3 22 22 4 49

Utilization management mailing and phone messages

3 18 28 9 42

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

Stakeholder Perspective on page 30

BUSINESS


An Educated Consumer Is Our Best Customer

EMPLOYERS: I believe that I speak on behalf ofmost of my colleagues in the specialty pharmacy indus-try when I ask the following question: “How can anyemployer responsible for the healthcare benefits oftheir employees and dependents today not understandspecialty pharmacy?” With the impact of specialtypharmaceuticals on overall healthcare spending andtrends, the number of specialty pharmaceuticalsapproved by the US Food and Drug Administrationover the past few years, and the rich pipeline of special-ty pharmaceuticals, it would seem that the primaryfocus of payers today would be on specialty pharmacy.The article by Vogenberg and colleagues in this issue

of American Health & Drug Benefits highlights the lackof understanding of specialty pharmacy by a large pro-portion of employers that were surveyed online for thisstudy. Of the 120 employers surveyed, 25% had little tono understanding of biologics, and only 53% claimed amoderate understanding of these medications. This istroubling, considering that specialty pharmaceuticalsare expected to represent 21% of drug spending by2013, and 40% of drug spending by 2020.1 We need torevisit the famous words, “An educated consumer is ourbest customer,” used by Sy Syms, CEO of the now-defunct Syms Corporation, to address this conundrum.

PHARMACY DIRECTORS: The specialty phar-macy industry must do a better job of educating theconsumer, employer groups in this case, of what spe-cialty pharmacy is, and what it means to payers. Eventoday, there is no consensus on a definition for special-ty pharmaceuticals. We have publications that providethe general characteristics of specialty pharmaceuti-cals,2,3 but no agreed-on definition, which leads to sig-nificant confusion by all stakeholders. In addition, specialty pharmacies need to have less

of a distribution focus in their discussions with employ-ers and more focus on clinical support and outcomes

reporting, to highlight the value that these entities pro-vide to payers. The heavy focus on distribution of specialty phar-

maceuticals continues to create a commoditization ofthe industry, with the majority of the weight on con-tracted discounts on specialty medications. This isleading to eroding margins and further consolidation ofthe industry. In addition, the lack of focus on clinicalsupport and outcomes reporting is leading to a percep-tion that specialty pharmacies do not provide muchvalue to payers. As recent as 2 years ago, if I met with a potential

client and presented to them that we had a patient caresoftware system, I was almost guaranteed that this wasa differentiator for our pharmacy. Today, virtually allpotential clients who I present to ask for outcomes dataand performance guarantees that we are going toimprove patient care. The market has changed, but it is not clear that the

specialty pharmacy industry has done enough to keepup with the demands from payers. We seem to be con-centrating on shrinking margins, but we are not doingenough to change our model to meet the needs of ourcustomers and reverse these shrinking margins. It is clear that we must start by educating the con-

sumer about the value we provide. This will undoubt-edly lead to a stronger relationship between theemployer and their specialty pharmacy partner.

1. Medco Health. Medco 2011 Drug Trend Report: Healthcare 2020. www.drugtrendreport.com/2011-report. Accessed February 2, 2012.2. EMD Serono. EMD Serono Specialty Digest 2011. http://specialtydigest.emdserono.com/. Accessed February 2, 2012.3. Blaser DA, Lewtas AJ, Ousterhout MM, et al. How to define specialty pharma-ceuticals: a systematic review. Am J Pharm Benefits. 2010;2:371-380.

Atheer A. Kaddis, PharmDVice President, Managed MarketsDiplomat Specialty Pharmacy

STAKEHOLDER PERSPECTIVE

Payers generally assert that in the face of risingcosts they will manage pharmaceuticals moretightly. However, many restrictions that they say

they will initiate never become widespread. Why not?Payers may offer a restrictive benefit design, but oftenemployers and other plan sponsors are reluctant toselect such designs for their employees. To understandthe benefit landscape, we need to look to payers as wellas employers.

These findings come from the Zitter Group’sManaged Care Benefit Design Index, which surveysapproximately 100 top payer decision makers and 100self-insured employers and employee benefits consult-ants. This semiannual, multiclient study explores thetrends influencing the creation of benefit design poli-cies. This article is based on findings from the spring2011 survey.

How Payers and Employers DifferThere are significant differences between payers and

employers with regard to which disease areas receive thegreatest priority. Payers place the greatest managementemphasis on the high-cost, high-prevalence categories oftype 2 diabetes and cancer. Employers also prioritize can-cer, but they focus much more than payers on lifestylecategories that can impact worker productivity, such asobesity and smoking cessation.

In response to anticipated cost increases resultingfrom healthcare reform provisions, 55% of payers and51% of employers planned to increase employee contri-butions to health insurance premiums for plan year2011 (Figure 1). However, there was a stark differencebetween the 2 groups regarding increasing utilizationmanagement. A full 59% of payers surveyed reportedhaving plans to increase utilization management, com-pared with only 15% of employers. Furthermore,although 45% of payers planned to institute a morerestrictive formulary, only 13% of employers intended toadopt such a measure.

Looking at specific utilization management changes,68% of payers increased the number of drugs subject toprior authorization, prior failure, or step edits, and 49%reduced the range of brand-name drugs covered on theirmost common formulary. By contrast, a large majority ofemployers made no changes to their utilization manage-ment policies for plan year 2011. Only 21% of employersincreased the number of drugs subject to prior authoriza-tion, prior failure, or step edits, and 14% decreased therange of brand-name drugs covered on their most com-mon formulary.

Some of these differences can be explained by theresponse samples. Payers represented a cross-section ofthe market, whereas the employer group was drawnmainly from larger, self-insured employers. Many payersare able to institute more restrictive policies across much

INDUSTRY TRENDS


Mr Zitter is Chief Executive Officer and Mr Snyder is Sales &Marketing Analyst, The Zitter Group, San Francisco, CA.

Employers, Health Plans, and NewDrug Benefit Designs: A ShiftingLandscapeMark Zitter, MBA; Michael Snyder

KEY POINTS➤ This article is based on findings from the Managed

Care Benefit Design Index and compares payermanagement priorities and efforts and the prioritiesof employers regarding benefit design in the face ofhealthcare reform and shifting market dynamics.

➤ Payers are looking to increase utilizationmanagement and cost-sharing to combat the costincreases anticipated as a result of the healthcarereform and shifting market dynamics.

➤ Employers are similarly concerned with rising costs,but differ from payers in terms of the level ofutilization management and increased cost-sharingthey are comfortable instituting.

➤ Although both stakeholder groups are in alignmentregarding cost concerns and certain aspects ofbenefit design, significant differences are evidentbetween the management priorities of payers andemployers.

➤ To address rising healthcare costs and successfullycreate benefit design policies for the long-term,payers and employers will need to better understandeach others’ motivations and concerns.

of their populations (including fully insured members)than large employers are willing to accept. Moreover,many employers see their key responsibility as designingand/or selecting the benefit, thereby leaving manage-ment to the payer. For example, few employers see them-selves—or want others to see them—as being involvedin utilization management.

Cost-SharingAlthough cost-sharing seems to be the most straight-

forward lever to pull when looking to reduce short-termcosts, it is not used as often as might be expected. Whenpayers were asked what factors keep them from increas-ing cost-sharing, 33% responded that concerns aboutcompliance and healthcare outcomes prevented themfrom using cost-sharing more liberally. This percentage isdouble that of employers who share similar concerns.

Payers cited a much wider range of cost-sharingstructure changes for plan year 2011 than employers

(Figure 2). Of the payers, 78% planned to increasemember contribution to health insurance premiums,and 47% planned to increase cost-sharing for prescrip-tion drugs.

Increasing member contribution to health insurancepremiums was the most frequent selection by employers,although only 39% intended to do so. Despite reportedhesitation to increase cost-sharing for physician visits,because of worries that it may have negative ramifica-tions on long-term costs, 30% of payers and 22% ofemployers still planned to make this change in 2011. Forall of these potential interventions, payers said that theywere going to be doing more than employers, whichemphasizes the increased aggressiveness of payer man-agement relative to what employers indicated they werewilling to adopt.

Raising premiums can reduce the cost to the payer orto the employer, leaving employees with more of the bur-den. Increasing cost-sharing can theoretically also drive

INDUSTRY TRENDS


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

Increased utilization management

Increased employee contribution to health insurance premiums

Instituted a more restrictive formulary

Increased employee copayments/coinsurance rates for prescription drugs

Increased employee copayments/coinsurance rates for physician visits

Increased employee deductibles

59%

15%

55%

51%

45%

13%

44%

24%

28%

35%

35%

28%

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 increasesas a direct result of the aforementioned healthcare reform provisions

Respondents

Payers

Employers

Payers: N = 75Employers: N = 75

better health-related behaviors by members, leadingthem to avoid seeking unnecessary healthcare. Theproblem with this way of thinking is that research haslong shown that increased cost-sharing, although suc-cessful in reducing demand for inappropriate care, alsotends to reduce the demand for appropriate care.1 Bycontrast, premium increases do not impact demand forcare, because people pay upfront. Unless premiumsincrease so much that people drop their healthcare cov-erage entirely, there is no reason to believe there will beany significant difference in utilization.

When analyzing the potential risk of enacting meas-ures for short-term savings at the possibility of raisinglong-term costs, there is an overwhelming differencebetween payers and employers on a few measures. Morethan twice as many payers as employers said that increas-ing the employee copayment for physician visits is a badidea. Although this will save money in the short-term,people who do not go to the doctor when needed willlikely cost more in the long-term. Conversely, employers

are much more reluctant than payers to increase costs forprescription drugs.

These differences in concerns between payers andemployers begin to shed light on why employers do notnecessarily buy into some of the benefit designs offeredby payers.

Benefit DesignThe most popular pharmacy benefit design today still

incorporates a 3-tier formulary. What has been changingover the past 2 or 3 years is the rise of the fourth tier. Oftotal payer administrator services–only plans, 23% have4 tiers on their most representative formulary. However,Medicare Part D plans are now equally likely to have a3-tier or a 4-tier structure (Figure 3).

When seeking to decrease drug costs, payers first lookat increasing cost-sharing for prescription drugs and, sec-ond, at switching from copayments to coinsurance fordrugs. The third option to consider is offering a benefitstrategy for specialty biologic drugs that allows claims to

Employers, Health Plans, and New Drug Benefit Designs


Member contribution to health insurance premiums

Cost-sharing rates for prescription drugs

HDHP/CDHP/HSA options

Maximum member out-of-pocket responsibility

Cost-sharing spread between tier 2 and tier 3

Cost-sharing rates for inpatient hospital stays

Cost-sharing spread between tier 1 and tier 2

Cost-sharing rates for physician visits

39%

23%

14%

20%

9%

14%

11%

22%

78%

47%

44%

44%

39%

31%

30%

30%

Thinking of your most common commercial plan, please qualify the following possible cost-sharing structure changeswith regard to plan year 2011

Payers EmployersPayers: N = 101Employers: N = 101

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.

Figure 2 Cost-Sharing Structure Changes: Stakeholder Comparison

Respondents

be managed by pharmacy—where payers can exert morecontrol—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 doso successfully.

Perhaps more important is that approximately 50%of employers do not have the same entity to manage boththeir medical and pharmacy benefits. Cross-benefitadjudication is not likely to happen when there are dif-ferent entities managing each benefit.

With more of the expensive biologic drug categorieshaving multiple drugs with similar safety and efficacyprofiles, payers show preference for category manage-ment approaches. However, this preference is difficult toachieve if they are only managing one side of that bene-fit. The plans that cover both benefits are trying to movein the direction of having claims managed by the phar-macy benefit and adjudicated by the medical benefit, butwe are a long way from ubiquity.

Looking AheadOne of the most popular future innovation measures

that payers intend to use to save on costs is high-deductible benefit design. Although payers and employ-ers are split on the impact of high-deductible benefitdesign on healthcare outcomes, they agree that there aretotal pharmacy spending decreases for those commerciallives enrolled in these health plans.

Employers are slowly moving in the direction of offer-ing more high-deductible plans. Of the employers whooffer preferred provider organization, point of service,and/or HMO plan options, only 11% indicated they planto offer only high-deductible health plans for the 2012plan year. However, an additional 23% are actively con-

INDUSTRY TRENDS


0% 0%

10%13%

6% 6% 6%

21%

66%63%

34%

49%

23%28%

34%

15%

4% 2%

14%

3%

Payers: N = 101Employers: N = 101

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

Figure 3 Formulary Adoption: Stakeholder Comparison

How many tiers are there in your most representative formulary design?

Respondents

1 tier/no tier 2 tiers 3 tiers 4 tiers 5 tiers

Payers: ASO

Payers: full risk

Payers: Medicare Part D

Employers

One of the most popular future innovationmeasures that payers intend to use to saveon costs is high-deductible benefit design.Although payers and employers are split on the impact of high-deductible benefitdesign on healthcare outcomes, they agreethat there are total pharmacy spendingdecreases for those commercial livesenrolled in these health plans.

Formulary design

sidering switching to high-deductible health plans for2012 and beyond.

Value-based benefit design options and adherenceprograms that include patient–employee communica-tions sound great in theory but have yet to make anysubstantial impact on cost-savings. All parties involvedwould like to have improved adherence, but it has nothappened significantly in practice.

These 2 management techniques have shown successin pilot programs but have failed to scale effectively.When payers are asked to explain why we do not seemore of these innovative strategies in widespread prac-tice, aside from cost, they claim that employers are tooconcerned with employee dissatisfaction. In fact,employers are concerned about employee morale, butnot to the degree that payers perceive. When asked toexplain why they decline to implement payers’ proposedmanagement strategies, aside from cost, employers mostoften say that they are just not convinced the proposedbenefit will work.

ConclusionPayers and employers have a lot of similarities, but

also many differences. The most common lever used inbenefit design is cost-sharing. As seen in response tocost increases stemming from healthcare reform,increased cost-sharing is a quick fix for payers and foremployers. Although cost-sharing is able to providesome short-term savings, it will not be the answer inthe long-term. Therefore, payers and employers need tobetter understand each other’s motivations and con-cerns to successfully create benefit design policies thatare beneficial to everyone. ■

Author Disclosure Statement Mr Zitter and Mr Snyder reported no conflicts of interest.

Reference1. Brook RH, Ware JE, Rogers WH, et al. The Effect of Coinsurance on the Healthof 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.

Employers, Health Plans, and New Drug Benefit Designs


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Fax to: 732.992.1881

New Data: 5-Year Median Follow-up

W

P

H

P

N

T

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.

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IMPORTANT SAFETY INFORMATIONVELCADE Warnings and Precautions ▼ 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

Adverse Reactions 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.

b

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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

Brief Summary

INDICATIONS:

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.

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 treatment-emergent 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.

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.

ADVERSE EVENT DATA:

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.

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.

V-11-0264 12/11

11:12 AM

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REGULATORY


With total health insurance costs at approxi-mately 17% of the US Gross DomesticProduct,1 a rapid growth rate, rising rates of

chronic diseases, such as diabetes, and an aging popula-tion, changing the dynamics—the fundamental driv-ers—of the US healthcare is key. The 2010 Census esti-mates 16.3% of Americans do not have healthinsurance, and that the percentage of people withemployment-based health insurance decreased from56.1% in 2009 to 55.3% in 2010.2The employment picture is also weak. In 2010, 16.2%

of the US population was either unemployed, had tem-porarily given up searching for a job, or was working part-time while looking for full-time employment.3 A nationalsurvey of employer-based health insurance showed thataverage premiums for family coverage in 2011 totaled$15,073 (9% higher than in 2010), with employer contri-butions of $10,944 and employee contributions of $4129.4In addition, the United States faces strong headwinds

from the weakness of the international economy, a finan-cially led downturn that tends to last longer and be deep-er than other recessions,5,6 and hyperpartisan politics.The need for accessible, affordable health insurance willbe even greater in 2014 than it is now.Ms Collins is President, America’sHealth, Oak Hill, VA.

REVIEW ARTICLE

Primary Care Shortages: StrengtheningThis Sector Is Urgently Needed, Now and inPreparation for Healthcare ReformSarah Collins, MBA

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




Primary Care Shortages


This article reviews the current shortages in primarycare physicians (PCPs) and other healthcare professionalsthat must be greatly ameliorated before the major expan-sion of the US health insurance system in 2014, when thePatient Protection and Affordable Care Act (ACA)provides health insurance alternatives to individuals andto businesses with 50 or more employees. The article alsodiscusses several examples of transformative initiativesin the US healthcare system that have been shown toimprove the quality and lower the cost of care. Figure 1depicts the key ways in which the US healthcare systemmay 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 areneeded to provide care in the PCP office setting. ADecember 2010 Council on Graduate Medical Educa -tion report estimated that there were 242,500 PCPs inthe United States in 2010, and almost 25% (55,000) ofthem aged ≥56 years.12The average compensation for PCPs is approximately

only 55% that of other medical specialties, leading to acumulative lifetime net income gap of approximately$3.5 million for the individual PCP.12 This essentiallyresults 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 con-ducting a specialized procedure as opposed to profession-al time, as well as expertise in making a correct diagnosisby differentiating among multiple potential conditions,or improving chronic conditions that are typically asso-ciated with increased morbidity and cost. The MedicareFFS schedule is used not only in Medicare; it also influ-ences managed care organization (MCO) and Medicaidphysician reimbursement payment amounts. A closely related challenge is the very low percentage

of medical school students who are choosing to go intoprimary care. A related challenge is that approximately59 million Americans, almost one fifth of the US popu-lation, live in areas with health professional shortages.13 Shortages in a number of other primary care health-

care professionals exist, notably with nurses—the singlelargest provider group in the United States.14,15 A minor-ity of nurses are employed in the ambulatory care and inpublic and community care settings.14Many healthcare professional shortage areas in the

United States are in rural and inner-city areas, where thepopulation is medically underserved. State-by-state andcounty data are available on the US Department ofHealth and Human Services website.16 Rural areas may

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

KEY POINTS➤ The US healthcare system is facing a majorexpansion in 2014, when the Affordable Care Act is expected to provide insurance alternatives toindividuals and businesses with 50 or moreemployees, which will increase the demand forprimary care.

➤ The United States is facing shortages in physiciansand other professionals who are needed to providecare in the primary care office setting.

➤ A key driver of the primary care shortage is relativelylow pay and overall lifetime income compared withspecialists.

➤ The average compensation of primary carephysicians (PCPs) is approximately only 55% of thatfor other clinical specialties, with a cumulativelifetime net income gap of approximately $3.5million per PCP.

➤ Approximately 59 million Americans live in areaswith a health professional shortage, primarily in ruraland inner-city areas, where the population ismedically underserved.

➤ The patient-centered medical home is evolving as akey initiative, with the potential to improve thequality and curb the cost escalation of ourhealthcare.

➤ It will require a multidisciplinary team effort thatincludes PCPs, nurses, and physician assistants,among others, to achieve these goals.

1. Primary care–basedcare model

3. Patient self-management

2. EBM chronic diseases treatment

EBM indicates evidence-based medicine.

Figure 1 Moving Toward More Effective, Lower-Cost Care

REGULATORY


until the ACA’s enactment, Medicaid’s low paymentrates may well have created significant disincentives. Ina telephone interview on October 8, 2011, with MichaelCollins, MD, an internist with 30 years of experience inprimarily treating commercial and Medicare patients, aswell as inner-city Medicaid patients, he commented onthe greater complexity and the number of medical prob-lems his Medicaid beneficiaries have, including anincreased incidence of serious mental illness. Transforming the US PCP workforce will require sig-

nificant changes. The ACA includes a number of meas-ures to support PCPs.17Table 1 provides a summary of theprimary care model as outlined by key ACA provisions.

The funding levels in the ACA for these priorities—such as $1.5 billion for the National Health ServicesCorps—are reasonable and in all likelihood may be cost-saving, by averting increasing morbidity and hospitaliza-tion levels in the United States.17In 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, Presidentof the American Academy of Family Physicians, theyboth expressed strong support for the ACA. Dr Hoodand Dr Stream are both concerned that hyperpartisanpolitics in Washington, DC, as well as concerns about

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 behaviormodification programs

• Require qualified health plans to cover, without cost-sharing, preventive servicesrated 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-sharingwaivers, or benefits that would not otherwise have been provided—of up to 30% ofthe cost of coverage for participating in a wellness program and meeting certainhealth standards

Workforce • Establish a multistakeholder workforce advisory committee to develop a nationalworkforce strategy

• Increase graduate medical education (GME) training positions, with priority givento primary care and general surgery, and states with the lowest resident physician-to-population ratios

• Increase flexibility in GME funding to promote training in outpatient settings andincrease residency programs in rural and underserved areas

• Establish federally funded health centers that include primary care residencyprograms

• Increase workforce supply and support healthcare professional training viascholarships 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 primarycare in federally qualified health centers and nurse-managed clinics

• Support development of training programs that focus on primary care models, suchas medical homes, team management of chronic disease, and integration of physicaland 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.



the deficit, may derail the funding needed for these keyinitiatives to support primary care, which are very likelyto reduce, or at least restrain, the growth of healthcarecosts in the United States. Dr Hood noted that the Workforce Advisory Com -

mittee has not yet met, and funding for a number ofother initiatives to support a strengthened PCP-basedsystem has either not been provided or has been relative-ly low. Furthermore, the number of PCP slots at residen-cy programs, which has not changed since 1997, is par-ticularly problematic, according to Dr Hood. And DrStream suggested that scholarships are a more powerfulincentive than debt forgiveness to draw medical studentsinto primary care.Given the current intense Republican opposition to

“Obamacare,” various national polls showing ambiva-lence toward the ACA, uncertainties related to poten-tial Supreme Court action on the ACA, and the hyper-partisanship in Washington, it may be valuable to bringforth a separate new bill that focuses solely on key pri-mary care–related provisions in the ACA, as identifiedin Table 1, for which bipartisan support can be expected.

Initiatives to Strengthen Primary CareThe politics surrounding Federal Emergency Man -

agement Agency (FEMA) expenditures in the wake ofmultiple unexpected natural disasters, and the passage ofa bill to fund FEMA in late September 2011 with bipar-tisan support, suggests this as a possibility. Strengtheningof the PCP model, which is desperately needed, andquickly, is currently being held hostage to politics: thereis a strong likelihood that this situation will continue,given the current political environment.

Tax IncentivesConsidering strong negative feelings toward Obamacare

and congressional concern about any spending increases,Donald B. Marron, Director of the Urban-Brookings TaxPolicy Center, in an interview conducted on September14, 2011, discussed alternative strategies for providingtax credits for PCPs and training. “People do respond totax credits,” Mr Marron commented, noting that therewould have to be identifiers recognizable by the InternalRevenue Service for program qualification. Increasing the level of tax credit (ie, financial incen-

tives) for PCPs working with identifiable underservedpopulations may be a successful strategy. To encouragemedical school students and residents to join primarycare, another strategy could be to have costs associatedwith medical school training for PCPs depreciatedthrough income tax credits, with the depreciation sched-ule’s structure developed in such a way that it stronglyincentivizes students and residents.

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

Patient-Centered Medical HomeAmong the different ongoing initiatives aimed at

improving the quality and reducing the cost of health-care in the United States, one that stands out is thepatient-centered medical home (PCMH). In his inter-view, Dr Stream commented that various articles pub-lished in peer-reviewed journals demonstrate thatPCMHs improve the quality of patient care.18-20 Both DrStream and Dr Hood discussed the importance of thePCMH as a multidisciplinary team effort that includesnot 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 andindividual members of the team have considerable flexi-bility in their activities, always working toward the goalsof improved patient care and better outcomes. In differ-ent practices, effective models, and which healthcareproviders should be involved, vary significantly.

Nurses in Primary CareIn an interview conducted on September 29, 2011,

with Peter McMenamin, PhD, Senior Policy Fellow ofthe American Nursing Association, Dr McMenamin dis-cussed the value of advanced practice nurses (APNs) andphysician assistants (PAs) as physician extenders whocan prescribe medications. APNs and PAs receive sub-stantial training related to pharmaceuticals, an importantfact because of the importance of drugs and the issue ofpatient adherence in improving outcomes in chronic dis-eases. Dr McMenamin pointed out, however, that thereis “substantial variation between states in terms of APNs’scope of practice,” with greater restrictions in Southernstates. Many PAs work with surgeons or other specialists;therefore, potentially the growth of this profession maynot have as strong an impact on primary care.Additional healthcare professionals that can be valu-

able in developing the care-provider team include reg-istered nurses, licensed practical nurses (LPNs), casemanagers, health coaches, and medical assistants. Byreviewing multiple cases and coordinating care, casemanagers can work to ensure delivery of high-qualitycare and improved outcomes. Health coaches can helpto work through particular problems or focus on andachieve specific goals.

REGULATORY


In his interview, Dr Collins commented that high-quality, well-trained medical assistants can be extremelyhelpful in taking a thorough medical history, whichincludes understanding patient stress levels. Stress canmake medical conditions worse or even lead to the falseappearance of a medical condition when the cause issimply very high stress. In addition, he noted that med-ical assistants’ salaries are significantly lower than thoseof other healthcare professionals, making it cost-effec-tive for them to spend time with patients.A 2011 Institute of Medicine report highlights the

critical need for more nurses.15 Increasing the number ofnurses in PCP offices is key to the success of the PCMHmodel. In his interview, Dr McMenamin noted thatthere is a shortage of nursing faculty. He also pointed outthe issue of faculty aging, which creates additional chal-lenges in educating registered nurses and APNs. Hecommented that APNs can play multiple roles in thePCMH model, including seeing patients, developingcoordinated health plans, and acting as case managers.APNs receive substantial training related to pharmaceu-ticals and have prescribing authority in all 50 states.

Physician Assistants in Primary CareIn an interview conducted on September 9, 2011,

with Robert Wooten, PA-C, President of the AmericanAssociation of Physician Assistants, Mr Wooten saidthat PAs can play a substantial role in primary care, and

in addition to the approximately 150 PA programs thatcurrently exist, about 40 new programs are preparing forcredentialing. According to the 2010 Census, there weremore than 83,000 PAs in the United States in 2010.21 MrWooten added that PAs can undertake many of the tra-ditional roles of PCPs, which can be particularly valu-able in rural and other areas when PCPs are unavailable,or in roles such as case management or professionalactivities associated with medication management,which is essential for successfully managing patients withchronic conditions. Although the difference in pay is not nearly as mon-

etarily large as between PCPs and specialists, the issueof pay disparities between specialties also affects PAs.However, more than 30% of PAs choose primarycare—the largest specialty they select—and they cer-tainly are an important contribution to the primarycare workforce.21

PCMH’s Success in Managing Chronic Conditions: TEAMcareIt is well known that chronic disease is an enormous

driver of healthcare costs in the United States.22Diabetes, which is frequently associated with high bloodpressure and/or hypercholesterolemia, is exploding, bothin terms of the number and severity of patients with dia-betes, as well as treatment costs.22 Figure 2 provides pro-jections about the number of patients with diabetes andthe cost burden to the US healthcare in 2033, if, as asociety and as individuals, we do not substantiallychange course.An excellent example of the PCMH in action—

albeit within the context of a closed-staff modelHMO—is TEAMcare’s work with patients who haddepression and diabetes (the majority of patients) and/orcardiovascular disease.7 Table 2 presents 12-month datafrom the TEAMcare study.7In a September 9, 2011, discussion with Elizabeth

H.B. Lin, MD, MPH, a family physician and researcherwith Group Health Research Institute in Seattle, WA,about what can explain why TEAMcare was so success-ful with such challenging disease states, she noted theimportance of identifying and treating depression first, sothat patients can become more active as partners inmanaging their disease. Dr Lin also said that despite thesocial stigma of depression, there is a very well-validatedinstrument, the Patient Health Questionnaire (PHQ-9)with which to measure it. Typically, depression inpatients with comorbidities has been overlooked to focuson hypoglycemia, systolic blood pressure, or low-densitylipoprotein levels. Dr Lin explained that the TEAMcare approach is

truly multidisciplinary. Teams include PCPs, nurse case

350

300

250

200

150

100

50

0

20322030

20242028

20262022

20202018

20162014

20122010

2008

Figure 2 Projected Direct Spending on Diabetes andComplications, 2008-2033

Diagnosed 2029-2033Diagnosed 2019-2028Diagnosed 2009-2018Currently have diabetes

Total spending✳

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

2007

Dol

lars

, bill

ions



managers, and consultant psychiatrists, as needed. Theteam can be expanded to include PAs, LPNs, medicalassistants, and clinical pharmacists. Another notablecomponent of this approach, according to Dr Lin, is theconcept of “treat to target,” in which the patient isinvolved in selecting the target (eg, weight vs exercise)and the specific clinical goal. Creating personal connec-tions between patients and members of their healthcareteam is important, and this is potentially one of the fac-tors in TEAMcare’s (and the PCMH’s) success.23

Changing Patient Behavior: The Ochsner Health System ModelIn a September 12, 2011, telephone interview, with

Patrick J. Quinlan, MD, Chief Executive Officer atOchsner Health System, one of America’s top integratedhealth systems, Dr Quinlan stressed the importance ofnot accepting the US current high health burden asinevitable. “The first step is to reduce the disease load toprevent what’s preventable, since about 50% of the dis-ease burden is related to lifestyle factors,” and to moder-ate what is not, Dr Quinlan said. He noted the impor-tance of caring about one’s own health and takingpersonal responsibility for it. Dr Quinlan also highlight-ed the importance of the primary care model and of ateam-based strategy, which could potentially includesocial supports such as family members, groups, or otherswho could help patients in maintaining healthy choices,such as weight loss, smoking cessation, and exercise. Hereinforced the importance of direct personal support,noting that telephonic support alone is a poor substitute.Dr Quinlan further addressed employers’ shared inter-

est in effective wellness programs. When asked whathelped motivate people’s behavior the most, Dr Quinlanreplied “a pedometer.” Ochsner Health System usesVirgin HealthMiles, an employee wellness program inwhich employees use a pedometer to record their stepsand periodically measure their blood pressure, weight,body fat, and body mass index at kiosks located through-out the 13,000-employee Ochsner system.24 Employeescan measure their progress, and data are uploaded to acentral system. Dorothy Cain, RN, the system coordinator at

Ochsner, commented in a September 28, 2011, inter-view on the high employee participation rate (87%),adding that daily activity and accountability are impor-tant to the program’s success. Successful program partic-ipants can significantly reduce their health insurancepremiums for the following year, according to Ms Cain.This is logistically easier for Ochsner, and it also benefitsemployees, because premiums and employer contribu-tions have been rising significantly faster than wages. Italso avoids the sales tax that cash or gift card rewards

incur, she said. Ms Cain discussed the importance ofupper-management commitment to wellness, notingthat with the unsustainable rise in healthcare costs, thisshift is in fact occurring.

Strategies to Strengthen the PCMH ModelA number of strategies could help with underserved

rural populations. For example, Family MedicineSpokane offers residency and medical school trainingand participates with other specialties in the Colville,WA (population of approximately 5000 people) ruraltraining track.25 In the interview mentioned earlier withDr Stream, he said that in very sparsely populatedregions in the Northwest, Midwest, and other areas, anAPN could schedule clinic visits several days per weekand work with a PCMH to deliver the full spectrum ofcare needed. A central PCMH base and multiple satel-lites could cover a very wide geographic area.Funding the higher level of care, coordination, and

case management required in this type of model re -quires more than an encounter-based payment schedule.Dr Stream noted that including a care or case manage-ment component—a per-member, per-month (PMPM)amount—to pay for the infrastructure needed to estab-lish and operate as a PCMH is important, as is a pay-for-performance component. Dr Stream commented thatcurrent payment mechanisms are typically insufficientfor the levels and nature of care needed for patients withchronic conditions.

Table 2 TEAMcare Select Trial Results at 12 Months

OutcomeTEAMcaregroup, %

Usual caregroup, %

Improvement on Patient GlobalImprovement scale

45 18

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

60 30

≥1.0% decrease in glycated hemoglobin level from baseline at12 months (P = .006)

36 19

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

41 25

Satisfaction with care of depression 90 55

Satisfaction with care of diabetes,heart disease, or both

86 70

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

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A number of new healthcare payment models haveeither been implemented or are being considered.MCOs have greater flexibility in terms of how they payphysicians: a number of MCOs, Medicaid programs, andothers 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 veryfavorable results in terms of reduced hospital admis-sions for Medicaid patients, as well as reduced costs forhospitalizations and overall care.8Another payment example is the PCMH model cre-

ated by Community Care of North Carolina (CCNC),which provides care-coordination payments forMedicaid patients. As shown in a study of CCNC’sMedicaid program, which was conducted by TreoSolutions, an independent health analytics company,the program achieved $1.5-billion savings over a 3-year period (from 2007 to 2009) for its Medicaidenrollees.26In an interview conducted on October 5, 2011, with

Yul D. Ejnes, MD, FACP, of Coastal Medicine, a pri-mary care practice in Rhode Island that has more than80 physicians, Dr Ejnes discussed how Blue Cross ofRhode Island—a nonprofit MCO and the state’s largestpayer—has contracted with several large practices todevelop PCMHs that meet guidelines developed by theACP several years ago. According to Dr Ejnes, the practice is reimbursed

based on a risk-adjusted PMPM payment amount, aslightly enhanced FFS basis, and performance-basedcriteria, such as following national guidelines forscreening and treatment of patients whose disease char-acteristics place them at particularly high risk for seri-ous medical events. To expand patients’ access, thepractice is also open on Saturdays. Dr Ejnes said thatthe new payment mechanisms helped pay for salariednurse case managers who provide care coordinationand case management. He commented that thesechanges made the “practice of medicine more fun, andthat [his] time was now freed up to interact withpatients.” He also noted the reduced time he had tospend on administrative tasks. Finally, the use of H-1B visas, and potentially chang-

ing the H-1B program so that PCPs would not need anemployer sponsor, could be another way to increase thenumber of primary care providers in the United States.In addition, other countries, including Canada,Denmark, the Netherlands, and England, have pro-grams to attract designated, highly skilled workers totheir countries. A program like this in the UnitedStates could potentially be useful in rural areas, becausemany countries have substantial rural populations.

ConclusionThere is a great deal to be done in a short time to pre-

pare for the changes in the ACA and to reverse thecharging and very destructive drivers of America’s grow-ing healthcare costs. This is something that asAmericans working in a business environment and as acountry, we cannot afford. Dr Stream expressed opti-mism that we can turn the situation around thanks tothe clear understanding of what is needed to be done,the possibility of robust solutions, and the national senseof urgency. More innovation—particularly with regardto realignment of financial incentives to strengthen pri-mary care and increase the number of PCPs and otherhealthcare providers who choose or move to primarycare—is needed to meet America’s growing healthcarequality and cost challenges. ■

Author Disclosure StatementMs Collins has no conflicts of interest to report.

References1. 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. 2nded. 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 depressionand 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 September12, 2011.9. Interview with Patrick J. Quinlan, MD, Chief Executive Officer (CEO), OchsnerHealth 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 November11, 2011.12. Council on Graduate Medical Education. Advancing Primary Care TwentiethReport. 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, HealthResources 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, HealthResources and Services Administration. The Registered Nurse Population: InitialFindings 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 ServicesAdministration. 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 NewHealth Reform Law. April 15, 2011. www.kff.org/healthreform/8061.pdf. AccessedJanuary 12, 2012.18. Reid RJ, Fishman PA, Yu O, et al. Patient-centered medical home demonstra-tion: a prospective, quasi-experimental, before and after evaluation. Am J Manag Care.2009;15:e71-e87.



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 atme and sighed, “I don’t know how much longer I cankeep doing this.” This is not just any doctor; this is myprimary care physician (PCP), whom I have knownsince our days in medical school and even before. Hewas among the brightest students in our class, and in theearly 1970s, when primary care was undergoing a resur-gence, he knew from the first day of medical school thathe wanted to do family practice. Never wavering fromthat goal, he became a dedicated family physician andmy own physician. As an aging baby boomer, it is acomforting thought to have one’s medical care in thehands of someone who is not only competent, but whoalso knows my medical history from experience. Hecontinued, “The demands of primary care haveincreased, the cost of running my practice is spiralingupward, and the amount of administrative work ishuge....and I am making less money than I did 10 yearsago.” Although this is just one doctor, his words aresymptomatic 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 areaged >55 years. That, coupled with a very low percent-age of medical school graduates entering primary care,is a sobering thought. At a time when we have an agingpopulation, when the baby boomers need more care,and when we face the potential for more than 40 mil-lion Americans having improved access to care underthe Affordable Care Act, we are likely to have adecreasing number of PCPs.This crisis does not have an easy solution. As Ms

Collins notes, PCPs tend to earn about half of whatother specialties earn, resulting in a more than $3-mil-lion gap in lifetime earnings. It is not difficult to under-

stand that primary care is not a chosen career path bythe majority of medical students today. Yet, for thehealth system to accommodate the growing public careneeds, we find ourselves in a dilemma—how do weexpand primary care? In this article, Ms Collinsexplores a number of potential solutions, includingadopting the patient-centered medical homes concept,and using nurses and physician assistants to provideprimary care.Yet, any solution that does not address the issue of

compensation for PCPs is not likely to be successful. Asnoted in the article, the current reimbursement systemstend to value procedural and technical skills more thancognitive and interpersonal skills—the 2 essential ele-ments of primary care. Although it is tempting to sim-ply increase payments to PCPs, that is not likely tohappen in a system that is struggling to manage cost.We ultimately must find a way to redistribute paymentsto physicians rather than simply increasing overallspending. This is not likely to be a popular concept forthose who may stand to lose in the process: we needcreative solutions to physician payment.A recent article in the Wall Street Journal discusses

large insurers that are beginning to address this issue.1Aetna, WellPoint, and UnitedHealth are all looking atways 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 actnow 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.

Gary M. Owens, MDPresident, Gary Owens Associates

Philadelphia, PA


19. Reinventing Medicaid: state innovations to qualify and pay for patient-centeredmedical homes show promising results. Health Aff (Millwood). 2011;30:1325-1334.20. Rosenthal TC. The medical home: growing evidence to support a new approachto primary care. J Am Board Fam Med. 2008;21:427-440.21. American Academy of Physician Assistants. Physician assistant workforce in theUnited 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 Livingwith 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 andquality. www.communitycarenc.org/our-results/. Accessed January 12, 2012.

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CLINICAL


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 andPharmacoeconomics at Endo Pharmaceuticals, Chadds Ford, PA.

ORIGINAL RESEARCH

Daily Average Consumption of 2 Long-Acting Opioids: An InterruptedTime Series AnalysisR. Amy Puenpatom, PhD; Sheryl L. Szeinbach, PhD, MS, BSPharm; Larry Ma, PhD; Rami H. Ben-Joseph, PhD; Kent H. Summers, PhD, BSPharm

Background: Oxycodone controlled release (CR) and oxymorphone extended release (ER)are frequently prescribed long-acting opioids, which are approved for twice-daily dosing. TheUS Food and Drug Administration approved a reformulated crush-resistant version of oxy-codone CR in April 2010.Objective: To compare the daily average consumption (DACON) for oxycodone CR and foroxymorphone ER before and after the introduction of the reformulated, crush-resistant versionof oxycodone CR.Methods: This was a retrospective claims database analysis using pharmacy claims from theMarketScan database for the period from January 2010 through March 2011. The interruptedtime series analysis was used to evaluate the impact of the introduction of reformulated oxy-codone CR on the DACON of the 2 drugs—oxycodone CR and oxymorphone ER. Thesource of the databases included private-sector health data from more than 150 medium andlarge employers. All prescription claims containing oxycodone CR and oxymorphone ER dis-pensed to members from January 1, 2010, to March 31, 2011, were included in the analysis.Prescrip tion claims containing duplicate National Drug Codes, missing member identification,invalid quantities or inaccurate days supply of either drug, and DACON values of <1 and >500were removed.Results: The database yielded 483,063 prescription claims for oxycodone CR and oxymor-phone ER from January 1, 2010, to March 31, 2011. The final sample consisted of 411,404oxycodone CR prescriptions (traditional and reformulated) dispensed to 85,150 members and62,656 oxymorphone ER prescriptions dispensed to 11,931 members. Before the introductionof reformulated oxycodone CR, DACON values for the highest strength available for each ofthe 2 drugs were 0.51 tablets higher for oxycodone CR than for oxymorphone ER, with meanDACON values of 3.5 for oxycodone CR and 3.0 for oxymorphone ER (P <.001). The differ-ences of mean DACON between the 2 drugs for all lower strengths were 0.46 tablets, withmean DACON values of 2.7 for oxycodone CR and 2.3 for oxymorphone ER (P <.001). Afterthe introduction of the new formulation, the difference in mean DACON between the 2 drugswas slightly lower: 0.45 tablets for the highest-strength and 0.40 tablets for the lower-strengthpairs. Regression analyses showed that the immediate and overall impact of the reformulationof oxycodone CR on the DACON of oxycodone CR was minimal, whereas no changes wereseen in the DACON of oxymorphone ER. The estimated DACON for oxycodone CR decreasedby 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 comparedwith oxymorphone ER for all dosage strengths for the entire study period. After the introduc-tion of the reformulated oxycodone CR, the DACON for this drug was slightly mitigated; how-ever, there was a minimal impact on the mean differences between oxycodone CR and oxy-morphone ER.




DACON of 2 Long-Acting Opioids


Chronic pain is experienced by more than onethird of the US population.1 Regardless of diseaseetiology or individual characteristics, chronic

pain is debilitating and has a profound impact on emo-tional and physical functioning.2,3 For chronic pain,which is characterized as pain lasting 3 or more months,4opioid analgesics are considered part of a multifacetedstrategy to manage moderate-to-severe pain for a num-ber of conditions involving the musculoskeletal system(eg, osteoarthritis, low back pain), neurologic system(eg, diabetic neuropathy, spinal cord pain), and for painassociated with neoplastic disease.5-7

Two long-acting opioid analgesics, oxycodone con-trolled release (CR; OxyContin) and oxymorphoneextended release (ER; Opana), are often prescribed toreduce the intensity of moderate-to-severe noncancerpain.8 However, the usefulness of long-acting opioids inchronic noncancer pain has been scrutinized, because oftheir adverse effects (eg, nausea and constipation) andthe association with illicit drug behaviors, ranging fromdrug abuse, illegal distribution, and drug product tamper-ing.9,10 In addition, a prospective study confirmed thatsome patients with chronic pain may require more fre-quent dosing of sustained-release opioids beyond thedoses recommended by the manufacturer.11 Despite con-cerns over long-term analgesic use, multiple expert pan-els have concluded that long-term opioid therapy can beeffective for carefully selected and monitored patientswith chronic noncancer pain.12

To encourage proper use, new drug formulations aredesigned to improve pharmacotherapy either by reduc-ing the dosing frequency or by hindering potential mis-use and abuse. In August 2010, the US Food and DrugAdministration (FDA) approved a newly formulatedcrush-resistant version of oxycodone CR. The recom-mended dosing regimen for oxycodone CR, oxymor-phone ER, and the reformulated oxycodone CR is 2tablets daily. Besides the need for product formulationsthat will provide more consistent and sustained levels ofanalgesia throughout the recommended dosing interval,the crush-resistant form of oxycodone may present anobstacle to some forms of misuse.

In making pharmaceutical policy decisions, commer-cial insurers may need to consider utilization patterns inaddition to cost. Daily average consumption (DACON)is a readily available measure that is often used to assessdrug utilization. DACON has been used in previousstudies to examine medication use in patients witharthritis, diabetes, and hypertension.13-16 With chronicpain, the utilization of opioid analgesics may be of con-cern to pharmacy benefit managers and third-party pay-ers who design and manage prescription drug benefitplans. To build on previous research,17 we wanted to

know if differences in the DACON for oxycodone CRcompared with oxymorphone ER persist in recent datathat include utilization of a reformulated version of oxy-codone CR.

Opportunities to investigate changing patterns of opi-oid use will allow healthcare benefit managers to moni-tor opioid use with the goal of maintaining tablet utiliza-tion within the expected range of 2 tablets daily.Therefore, the purpose of this study was to evaluate theDACON of oxycodone CR and of oxymorphone ERbefore and after the introduction of the reformulatedoxycodone CR. This study provides some insight intothe utilization patterns of 2 branded opioid products usedin pain management.

MethodsThis was a retrospective, interrupted time series

analysis of observational data to assess the DACON ofoxycodone CR, oxymorphone ER, and reformulatedoxycodone CR over time using the prescription claims-level analysis. Pharmacy claims for the 2 drugs from theMarketScan Commerical database (Thomson Reuters,

KEY POINTS➤ Chronic pain is experienced by at least 38% of the

US population.➤ The prevalence of long-term opioid use for non -

cancer pain in the United States has increased inthe past decade.

➤ This study compared the overall mean daily averageconsumption (DACON) for 2 opioids—oxycodonecontrolled release (CR) and oxymorphone extendedrelease (ER)—after the introduction of the crush-resistant formulation of oxycodone CR.

➤ Results showed that the overall DACON foroxycodone CR was higher by 0.4 tablets per day forall dosage strengths than for oxymorphone ER, withmeans of 2.9 and 2.5, respectively.

➤ The difference in mean DACON betweenoxycodone CR and oxymorphone ER was 0.45tablets per day for the highest-strength pairs and0.40 tablets per day for the lower-strength pairs afterthe introduction of reformulated oxycodone CR.

➤ After the introduction of the new formulation, theDACON for oxycodone CR was slightly mitigated;however, there was a minimal impact on the meanDACON differences of the 2 drugs.

➤ Because changes in opioid utilization may reflectinappropriate drug use, it is essential to follow theguidelines for opioid use to ensure that these drugsare used judiciously in the management of chronicnoncancer pain.

CLINICAL


Ann Arbor, MI) were used to evaluate average monthlyand weekly DACON values of oxymorphone ER andoxycodone CR. The database contains individual-levelhealthcare claims, including enrollment, medical, andprescription (outpatient) records from all providers ofcare. For the most recent 3 years, data were collectedfrom more than 150 large employers (>200 carriers) andmore than 20 regional health plans that provide health-care coverage for more than 30 million lives annually.

The covered lives include active employees, earlyretirees, COBRA continuees, and their dependents whoare insured by large employers and health plans.Insurance coverage was provided under a variety of fee-for-service, preferred provider organizations, and capitat-ed and partially captitated health plans. Data were de-identified and used in accordance with the HealthInsurance Portability and Accountability Act (HIPAA).Approval by the institutional review board was notrequired.

Calculation of Opioid ConsumptionWe evaluated DACON over time for oxycodone CR

and oxymorphone ER (traditional and reformulated)from January 2010 to March 2011. All prescriptionclaims containing oxycodone CR and oxymorphone ERdispensed to members aged 18 to 64 years from January1, 2010, to March 31, 2011, were included in the calcu-lation of DACON. Prescription claims containing dupli-cate National Drug Codes, missing member identifica-tion, invalid quantities or inaccurate days supply foreither drug, and DACON of <1 and >500 tablets wereremoved.

The DACON for each prescription was calculated bydividing the total tablets dispensed by days supplied, asreflected by these data fields in each submitted prescrip-tion claim. Overall monthly and weekly DACON wascalculated for all doses combined, the highest-strength-dosages (80-mg oxycodone CR and 40-mg oxymorphoneER), and for all lower-strength dosages, respectively (ie,oxycodone CR 10, 20, 30, 40, and 60 mg, and oxymor-phone ER 5, 7.5, 10, 20, and 30 mg).

Statistical AnalysisThe measurement of DACON over time was inter-

rupted by the introduction of reformulated oxycodoneCR. Because the outcome was analyzed with respect totime intervals (ie, weekly), the error terms may be corre-lated (ie, not independent), thereby violating one of theclassic regression assumptions. Therefore, the interrupt-ed time series analysis was used to estimate changes inlevels and weekly trends for the mean DACON of oxy-morphone ER and oxycodone CR (traditional and refor-mulated) before and after the introduction of reformulat-

ed oxycodone CR. The model is also often referred to asthe segmented regression model, which is used to evalu-ate longitudinal effects (ie, change in intercept andslopes) of interventions, while relaxing the assumptionthat observations are independent.

The segmented regression model we developed wasderived 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 orweek 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 obser-

vations often exist when time is a predictor in the timeseries regression analysis. To assess the regression modelsfor serial correlation of the time series data, the Durbin-Watson, alternative Durbin-Watson, Breusch-GodfreyLM, and Bartlett’s statistic white noise tests were used.18,19The Breusch-Pagan test was used to assess heteroscedas-ticity or the nonconstant variance assumption.19

Serial correlations were adjusted using one of theautoregressive, integrated, moving-average (ARIMA)models. These models are built by finding the best possi-ble weighted average for a single time series, taking intoaccount past observations (autoregressive terms) andpast error terms (moving average terms).20 For this study,interrupted time series analysis allowed researchers tocontrol for previous trends in the assessment of DACONand to study the dynamics of change in response to theintroduction of reformulated oxycodone CR.21

To ensure a sufficient number of observations for thesegmented regression model, we utilized weekly DACONdata of 64 weekly intervals in this study: 31 weeks beforethe intervention and 33 after the intervention, fromJanuary 2010 to March 2011. The number of time pointsin this study exceeds the range of 50 time points suggest-ed in similar segmented regression analyses and achievesan acceptable level of variability of the estimate at eachtime point.22 Before analysis, outliers were removed usingthe standard deviation method, such that DACON val-ues whose deviation exceeds 3 standard deviations of themean were excluded from the analysis.23

A sensitivity analysis was conducted to examine



model stability. The sensitivity analysis used a similarapproach to account for the brief transition period afterthe introduction of reformulated oxycodone CR byexcluding the outcome values that occurred during thepotential intervention periods of August 2010 andSeptember 2010. Descriptive statistics and overall meancomparison were evaluated using student t-tests.Statistical significance was established for P <.05. SASversion 9.1 (SAS Institute, Inc, Cary, NC) and Stataversion 11.2 (StataCorp, College Station, TX) were usedfor data analysis.

ResultsThe MarketScan commercial database yielded

483,063 prescription claims for oxycodone CR and oxy-morphone ER from January 1, 2010, to March 31, 2011(Figure 1). After applying the exclusion criteria for ageand high DACON outliers, the final sample consisted of411,404 oxycodone CR prescriptions (traditional andreformulated) dispensed to 85,150 members and 62,656oxymorphone ER prescriptions dispensed to 11,931members. Of the total members, 51% were women withthe mean age of 48.5 years.

Over the 15-month observation period, the overallmean DACON values for all dosage strengths wereapproximately 0.4 tablets per day higher for oxycodoneCR than for oxymorphone ER, with means of 2.9 foroxycodone CR and 2.5 for oxymorphone ER (Figure 2).Reformulated oxycodone CR accounted for approxi-mately 50% of oxycodone CR tablets dispensed inSeptember 2010, 1 month after its introduction. Theproportion of reformulated oxycodone CR relative to alloxycodone CR tablets steadily increased from 50% to95% by the end of the study period (Figure 3).

Overall mean DACON values for the 2 drugs overthe observation period were relatively stable, rangingfrom 2.8 to 2.9 tablets per day for oxycodone CR and2.4 to 2.5 tablets per day for oxymorphone ER, respec-tively (Figure 2). During the observation period beforethe introduction of the new formulation, DACON val-ues for the highest strength were 0.51 tablets higher foroxycodone CR than for oxymorphone ER, with a meanDACON of 3.5 for oxycodone CR and 3.0 for oxymor-phone ER (P <.001; Figure 4). After the introductionof the new formulation, the difference in meanDACON values between reformulated oxycodone CRand oxymorphone ER decreased slightly to 0.45 tabletsper day for the highest-strength pairs (ie, meanDACON, 3.5 for oxycodone CR vs 3.0 for oxymor-phone ER; P <.001).

The differences of mean DACON for all lowerstrengths between oxycodone CR and oxymorphone ERwere 0.46 tablets per day before the introduction of the

new formulation, with mean DACON values of 2.7 and2.3 tablets (P <.001) for oxycodone CR and oxymor-phone ER, respectively (Figure 4). After the introduc-tion of the new formulation, the difference in meanDACON values between the 2 drugs was 0.40 tablets perday, with a mean DACON of 2.7 for oxycodone CR and2.3 for oxymorphone ER (P <.001).

Interrupted Time Series ResultsFigure 2 shows the actual and predicted values of

weekly DACON trends for oxycodone CR and oxy-morphone ER over time using the interrupted time

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

Oxycodone CR(reformulated)

(161,302 prescriptions,

11,931 members)

Oxycodone CR (traditional) (250,102

prescriptions,76,123 members)

Oxycodone CR (all) (412,658 prescriptions)

Oxymorphone ER, excluding outliers (62,656 prescriptions,

11,931 members)

Oxymorphone ER (62,746 prescriptions)

Oxycodone CR (all) excludingoutliers (411,404 prescriptions,

85,150 membersa)

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

Age 18-64 yr (481,913 prescriptions)

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

aThe number of members for the traditional and reformulatedoxycodone CR do not add up, because members could havehad multiple prescriptions across the time horizon and acrosstreatment group.CR indicates controlled release; ER, extended release.

➤ ➤

➤➤

➤➤ ➤

➤

CLINICAL


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

4

3.5

3

2.5

2

1.5

1

.5

0

Jan 1, 2010 Apr 1, 2010 Jul 1, 2010 Oct 1, 2010 Jan 1, 2011 Apr 1, 2011

After introduction of reformulation

Oxycodone CRPredicted oxycodone CR

Oxymorphone ERPredicted oxycodone ER

Date

DACO

N, overall

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

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

Introduction of new formulation

Rate, tab

lets/100

0 be

nefic

iarie

s

Jan 20

10

Feb 20

10

Mar 201

0

Apr 2

010

May 201

0

Jun 20

10

Jul 2

010

Aug 20

10

Sep 20

10

Oct 2

010

Nov 20

10

Dec 20

10

Jan 20

11

Feb 20

11

Mar 201

1

CR indicates controlled release; ER, extended release.

Traditional oxycodone CR Oxymorphone ERReformulated oxycodone CR

160

140

120

100

80

60

40

20

0

95%

50%

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

Before introduction

After introduction

Highest strength Lower strengths

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

Oxycodone CROxymorphone ER

3.5

3

2.5

2

1.5

1

∆ = 0.51a ∆ = 0.45a

∆ = 0.46a ∆ = 0.40a

DACO

N, m

ean

Before introduction

After introduction



series models. Before the introduction of reformulatedoxycodone CR, there was no significant week-to-weekimpact in the mean DACON for oxycodone CR andoxymorphone ER (P = .956 and P = .878, respectively;Table 1). Immediately after the introduction of thenew formulation, the estimated mean DACON for oxy-codone CR dropped slightly, by 0.05 tablets weekly.Throughout the study period, there was neither imme-diate change nor any weekly change in oxymorphoneER’s DACON as a result of the introduction of oxy-codone CR.

In terms of changes in trends for the mean DACONafter the introduction of oxycodone CR, the weeklytrends for oxycodone CR slightly decreased, by 0.003tablets weekly (0.01 tablets per month). Because theabsolute change in weekly DACON was minimal, wecompared the overall change by combining the immedi-ate and trend effects for the estimated DACON 6 monthsafter the introduction of the new formulation, with theoutcomes as if that introduction had not occurred.

The models showed that the average DACON foroxycodone CR decreased by 0.11 tablets or 3.7% (P<.001) 6 months after the new formulation was intro-duced compared with the DACON level before theintroduction (Table 2).

When analyzing the data by strength, the averageDACON for the 80-mg (highest strength) oxycodoneCR 6 months after the introduction increased slightlyby 0.07 tablets or 2.1% (P = .003), whereas the DACON

for the lower strengths decreased by 0.09 tablets, or 3.4%(P <.001).

Sensitivity analyses were conducted by excluding theoutcome values that occurred during the potential inter-vention period of August and September 2010. Theresults (not shown) indicate that the introduction ofreformulated oxycodone CR had a slight, mitigatingeffect on DACON; however, there was no significantchange in DACON over time. In addition, there was nosignificant change in DACON for oxymorphone ERassociated with the introduction of the newly formulatedoxycodone CR.

DiscussionTo evaluate the impact on utilization, differences in

DACON were assessed between traditional oxycodoneCR and oxymorphone ER before and after the introduc-tion of the reformulated oxycodone CR. Results from theinterrupted time series analyses and sensitivity analysesrevealed that the impact on DACON associated withthe introduction of reformulated oxycodone CR wasminimal, whereas there was no impact on oxymorphoneER’s DACON. The models estimated that the averageDACON for oxycodone CR decreased by 0.1 tablets, or3.7%, 6 months after the new formulation was intro-duced (P <.001).

In addition, differences in mean DACON betweenoxycodone CR and oxymorphone ER were quite stablebefore and after the introduction of reformulated oxy-

Table 1 Results from the Interrupted Time Series Models: Impact of Introduction of Reformulated Oxycodone CR onEach Medication Strength

Before introduction After introduction

Medication/strength

Change in DACON eachweek before

the introduction(�1 baseline slope) P value

Change in DACON

immediately afterthe introduction(�2 intercept change) P value

Change in DACON

slope after theintroduction

(�3)

Change in DACON

slope after theintroduction(1 month) P value

Oxycodone CR

All strengths 0.00003 .956 0.052 .034 –0.003 –0.012 <.001

Highest strength –0.002 <.001 0.0002 .996 0.0013 –0.005 .124

Lower strengths 0.0002 .658 0.055 <.001 –0.003 –0.011 <.001

Oxymorphone ER

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

Lower strengths 0.00003 .947 0.031 .302 –0.001 –0.005 .105


CLINICAL


codone CR. Throughout the 15-month study period, theoverall DACON was higher for oxycodone CR (tradi-tional or reformulated) compared with oxymorphoneER, by 0.4 to 0.5 tablets per day for all dosage strengths.For a subgroup analysis by strength, the differences ofmean DACON between oxycodone CR and oxymor-phone ER slightly decreased to 0.45 tablets for the high-est strength and 0.4 tablets for lower strengths after theintroduction of the new formulation.

These results are consistent with previous research inthis area. For example, there is evidence from other stud-ies to support a higher DACON with oxycodone CRcompared with oxymorphone ER. Malkin and colleaguesfound that the DACON for all strengths of oxycodoneCR was 3.4 and that higher strengths were associatedwith a higher DACON value, ranging from 2.9 for the10-mg tablets to 5.2 for the 80-mg tablets.24

In another study by Berner and colleagues, a retro-

spective analysis of administrative claims data for com-mercially insured patients was conducted to comparethe DACON of oxycodone CR and oxymorphone ERin patients with low back pain.25 Again, the DACONwas higher for the maximum-strength tablets of oxy-codone CR 80 mg, which were 3.9 tablets per day andsignificantly higher than the DACON of 2.9 for anequipotent oxymorphone ER maximum-strength tabletof 40 mg (P <.01).25 The investigators estimated that ifoxymorphone ER 40-mg tablets were substituted foroxycodone CR 80-mg tablets in the 688 patients intheir analysis of a health plan with 32,325 patients hav-ing at least 1 prescription for oxycodone CR or oxy-morphone ER, the monthly cost difference would be$217,985 based on the DACON difference, assumingper-tablet wholesale acquisition costs of $10.83 and$10.93, respectively.25

Given the consistent patterns in DACON for thesedrugs, pharmaceutical policymakers may want to consid-er these results in related decisions.

Findings from this study provide additional informa-tion when DACON is considered for oxycodone CR(traditional and reformulated) across all tabletstrengths compared with oxymorphone ER. A notablefinding is the continued difference in DACONbetween oxycodone CR and oxymorphone ER, bothbefore and after introduction of the reformulated oxy-codone CR. Considering the potential for dose escala-tion during long-term opioid use,26 the consistentDACON values observed throughout the 15-monthstudy period suggest that current dosing schedules werenot altered in response to the introduction of reformu-lated oxycodone CR.

Interrupted time series analysis is useful when changesover time are interrupted by events, such as the intro-duction of reformulated oxycodone CR in this study.However, longitudinal designs can be influenced byevents outside the control of researchers. Therefore, asensitivity analysis was performed to assess model robust-ness. The concordance of results through the transitionperiod of reformulated oxycodone CR indicates that ourfindings will provide decision makers with a valid assess-ment of the DACON for this population.

Although the DACON provides an accurate assess-ment of drug utilization, with long-term opioid use theremay be some members who either fail to achieve ade-quate analgesic effects despite reaching the maximumtablet strength for frequently prescribed opioids or mayexperience analgesic tolerance if more frequent dosing isnecessary.27

Realizing that it may be difficult to distinguish anal-gesic tolerance from potential drug abuse, especially ifmembers are requesting traditional oxycodone CR over

Table 2Estimated Overall Change of DACON 6 Months afterIntroduction of Reformulated Oxycodone CR fromInterrupted Time Series Models

Medication strength

Overall change (intercept + slope) 6 months after

introduction

P valueDaily tablets Change, %

Oxycodone CR

All strengths –0.11 –3.7 <.001

Highest strength 0.07 2.1 .003

Lower strengths –0.09 –3.4 <.001

Oxymorphone ER

All strengths 0.02 0.7 .611

Highest strength 0.07 2.3 .236

Lower strengths –0.03 –1.4 .087


Findings from this study provide additionalinformation when DACON is considered foroxycodone CR (traditional and reformulated)across all tablet strengths compared withoxymorphone ER.



reformulated oxycodone CR, health professionals shouldbe cognizant of and recognize that changes in utilizationmay reflect inappropriate drug use. It is, therefore, essen-tial to follow the guidelines for opioid use to ensure thatthese drugs are used judiciously in the management ofchronic noncancer pain, especially for patients whorequire higher doses of opioids, have issues with drugabuse, or who report numerous comorbid conditions.28,29

LimitationsThere are certain caveats associated with the use of

claims data. First, it was not possible to examine whetherpatients were actually using the medications examinedin this database. Thus, it was not possible to determine ifchanges in pain intensity required patients to alter thedose or dosing frequency of opioids for medical emergen-cies or procedures.

Second, it was not possible to determine if prescriberschanged medications in response to oxycodone CR or tooxymorphone ER failures, or changed the dosing sched-ule to accommodate other medication use or additionaldiagnoses. For these reasons, it was not possible to con-trol for patient-initiated self-management of pain.

Third, although the calculations of DACON werestatistically robust, as observed from sensitivity analyses,additional changes in utilization could occur from inap-propriate use of opioids.

Fourth, a common limitation about the claims data-base is that there is no diagnosis code entered on pre-scription claims; this study was based on prescriptionclaims, not patients. Therefore, information related todiagnosis codes is not provided in this study.

Finally, because claims databases do not contain dataregarding pain severity, it was not possible to evaluatewhether one population suffered from more severe pain.To monitor opioid use, managed care plans often placequantity limits on long-acting opioids. Although thepatterns of drug use examined in this study were relative-ly stable over time, it is important to continue monitor-ing changes in long-term utilization of these opioids.

ConclusionIn this study, the introduction of a crush-resistant

oxycodone CR very slightly lowered the DACON forthat drug; however, the change was minimal. Therefore,this research supports the notion that differences inDACON are more likely a result of differences in theoxycodone and oxymorphone molecules and not theeffects of oxycodone CR reformulation. ■

AcknowledgmentThe authors would like to thank Robert Garvin, MA,

for programming support.

Study FundingThis study was supported by funding from Endo

Pharmaceuticals.

Author Disclosure StatementDrs Puenpatom, Ma, Ben-Joseph, and Summers are

employees of and Dr Szeinbach received financial supportfrom Endo Pharmaceuticals.

References1. Institute of Medicine. Relieving Pain in America: A Blueprint for TransformingPrevention, Care, Education and Research. Washington, DC: The National AcademiesPress; 2011. http://books.nap.edu/openbook.php?record_id=13172&page=17. AccessedJanuary 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 opioidtreatment 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 theUnited 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 asso-ciated with osteoarthritis with controlled-release oxycodone tablets in a randomizedcontrolled clinical trial. Clin J Pain. 2005;21:524-535.6. Watson CP, Moulin D, Watt-Watson J, et al. Controlled-release oxycodonerelieves neuropathic pain: a randomized controlled trial in painful diabetic neuropa-thy. Pain. 2003;105:71-78.7. Desandre P, Quest TE. Management of cancer-related pain. Hematol Oncol ClinNorth Am. 2010;24:643-658.8. Chou R, Clark E, Helfand M. Comparative efficacy and safety of long-acting oralopioids 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 amongchronic opioid users. Am J Manag Care. 2011;17:32-40.10. Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opi-oid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4diagnostic criteria. J Addict Dis. 2011;30:185-194.11. Gallagher RM, Welz-Bosna M, Gammaitoni A. Assessment of dosing frequencyof 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 ran-domized trials of long-term opioid management for chronic non-cancer pain. PainPhysician. 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 andother antidiabetic medications usage for type 2 diabetes patients treated with an ana-log basal insulin. Curr Med Res Opin. 2010;26:191-201.15. Borah BJ, Darkow T, Bouchard J, et al. A comparison of insulin use, glycemiccontrol, and health care costs with insulin detemir and insulin glargine in insulin-naïve 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 prescribingpatterns 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. Acomparison of daily average consumption (DACON) of oxycodone and oxymor-phone long-acting oral tablets. J Manag Care Pharm. 2011;17:367-376.18. Brockwell PJ, Davis RA. Time Series: Theory and Methods (Springer Series inStatistics). 2nd edition. New York, NY: Springer; 2006.19. Baltagi BH. Econometrics (Springer Texts in Business and Economics). 5th ed. NewYork, NY: Springer; 2011.20. Durbin J. Testing for serial correlation in least squares regressions when some ofthe regressions are lagged dependent variables. Econometrica. 1970;38:410-421.21. Wagner AK, Soumerai SB, Zhang F, Ross-Degnan D. Segmented regressionanalysis of interrupted time series studies in medication use research. J Clin PharmTher. 2002;27:299-309. 22. Shardell M, Harris AD, El-Kamary SS, et al. Statistical analysis and applicationof 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 (WileySeries 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 fentanyltransdermal system and oxycodone hydrochloride controlled-release in a California

Continued

CLINICAL


Daily Average Consumption of 2 Long-Acting Opioids and Coverage Decisions MEDICAL/PHARMACY DIRECTORS: Long-

acting opioids are continuing to get more attention asa result of several factors. Both long- and short-actingopioids have strong brand recognition among opioidusers and nonusers alike. There is no shortage of mediacoverage around diversion, misuse, and abuse of opi-oids. Many payers and pharmacy benefit managershave implemented high utilization clinical programsand auditing initiatives specific to this narcotic class.In addition, several opioid manufacturers are modifyingexisting mechanisms or introducing new release mech-anisms to decrease the amount of opioid misuse.

Market dynamics have changed within severaldrug classes over the past couple of years. Severalantidepressants and antihypertensives are available asgenerics. And with the recent introduction of genericatorvastatin, the cholesterol-lowering drug class hasalso become very accessible in a generic form. During2012, generics will increase substantially within theatypical antipsychotic class as a result of recent andnear-future products losing or about to lose patentprotection. Long-acting opioids are moving up the“top paid” list for payers, gaining more attention fromlarge employers as well.

This article reviews the daily average consumption(DACON) of 2 long-acting opioids, namely, oxy-codone controlled release (CR) and oxymorphoneextended release (ER). DACON was analyzed over a15-month time frame to evaluate if a reformulated oxy-codone CR changed the existing variance of theDACON compared with oxymorphone ER. Thisanalysis shows that the reformulation of oxycodone CR

had little impact on the overall DACON of both prod-ucts, and oxymorphone ER continued to have a simi-lar, but lower, DACON.

Several factors are difficult to assess from this review,including the severity of pain within groups, durationof therapy, or previous trials of other long-acting opi-oids. DACON may correlate with pharmacokinetic dif-ferences, pain management needs, or even misalignedprescribing and/or diversion practices. However, thesecorrelations are difficult to ascertain from a retrospec-tive claims analysis.

Policymakers and payers need to consider DACONwhen making coverage decisions, but this is only onepiece 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 availableoptions, including generic alternatives, and the class isexpected to continue to expand with new brandedproducts over the next 18 to 24 months.PATIENTS: Patients now have the opportunity to

select from several options, including cost-effectiveoral and transdermal opioids. No matter the choice,patients must be conscious of adequate pain manage-ment needs and out-of-pocket responsibilities.

Other concerns need to be considered as well, suchas refill requirements and other, less obvious, unin-tended consequences associated with misuse or theftof medications.

Matthew Mitchell, PharmD, MBAManager, Pharmacy Services

SelectHealth, Salt Lake City, UT


Medicaid population. J Manag Care Pharm. 2002;8:132-140. 25. Berner T, Thomson H, Hartry A, et al. A comparison of daily average consump-tion of oxycodone controlled release (OxyContin CR) and oxymorphone extendedrelease (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 prescribingfor 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 forchronic noncancer pain: findings from a review of the evidence for an American PainSociety 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 forchronic non-cancer pain in the United States: a research guideline for developing anevidence-base. J Pain. 2010;11:807-829.

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TARGET AUDIENCEThis activity was developed for physicians, nurses, pharmacists, and managed care professionals who areinvolved in the care of patients with cancer.

CONFERENCE GOALThe Association for Value-Based Cancer Care will foster an open dialogue between providers, payers,and/or other members of the oncology team in order for attendees to gain a better understanding ofvarious points of view regarding cost, quality, and access in cancer care.

EDUCATIONAL OBJECTIVES• Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care

delivery• Define the barriers associated with cost, quality, and access as it relates to healthcare reform and

what solutions are currently being considered• Compare and contrast the different approaches/tools that providers and payers are utilizing to

manage and deliver care collaboratively• Examine the current trends in personalized care and companion diagnostics• Analyze the patient issues around cost, quality, and access to care

DESIGNATION OF CREDIT STATEMENTSPhysician Accreditation – Joint SponsorThe Medical Learning Institute, Inc. (MLI) designates this live activity for a maximum of 13.5 AMAPRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent oftheir participation in the activity. This activity has been planned and implemented in accordance withthe Essential Areas and policies of the Accreditation Council for Continuing Medical Education(ACCME) through the joint sponsorship of the Medical Learning Institute, Inc. and the Associationfor Value-Based Cancer Care, Inc. The Medical Learning Institute, Inc. is accredited by the ACCMEto provide continuing medical education for physicians.

Registered Nurse DesignationMedical Learning Institute, Inc. (MLI)Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 13.5contact hours.

Registered Pharmacy DesignationMedical Learning Institute, Inc. (MLI) is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion

of this activity provides for 13.5 contact hours (1.35 CEUs) of continuing education credit.

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Constipation 5.3 0.9 1.7Dyspepsia 5.2 0.9 2.6

Add-on to Metformin + GlimepirideVictoza® 1.8 + Metformin +

Glimepiride N = 230

Placebo + Metformin + Glimepiride

N = 114

Glargine + Metformin + Glimepiride

N = 232Adverse Event Term (%) (%) (%)Nausea 13.9 3.5 1.3Diarrhea 10.0 5.3 1.3Headache 9.6 7.9 5.6Dyspepsia 6.5 0.9 1.7Vomiting 6.5 3.5 0.4

Add-on to Metformin + RosiglitazoneAll Victoza® + Metformin +

Rosiglitazone N = 355Placebo + Metformin

+ Rosiglitazone N = 175Adverse Event Term (%) (%)Nausea 34.6 8.6Diarrhea 14.1 6.3Vomiting 12.4 2.9Decreased Appetite 9.3 1.1Anorexia 9.0 0.0Headache 8.2 4.6Constipation 5.1 1.1Fatigue 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)

Victoza® 1.8 mg once daily + metformin and/or

sulfonylurea N = 235

Exenatide 10 mcg twice daily + metformin and/or

sulfonylurea N = 232Preferred Term (%) (%)Diarrhea 12.3 12.1Dyspepsia 8.9 4.7Constipation 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. Gastroin-testinal adverse events occurred in 17% of comparator-treated patients. Events that occurred more commonly among Victoza®-treated patients included nausea, vomiting, diarrhea, dyspepsia and con-stipation. 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: Con-sistent 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 dilu-tion 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. Cross-reacting 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 antibody-negative 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 associ-ated 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 compos-ite 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 immunogenic-ity 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 screen-ing 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 hypo-glycemia 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® Treatment

Active Comparator

Placebo Comparator

Monotherapy Victoza® (N = 497)

Glimepiride (N = 248)

None

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) —Add-on to Metformin

Victoza® + Metformin (N = 724)

Glimepiride + Metformin (N = 242)

Placebo + Metformin (N = 121)

Patient not able to self−treat 0.1 (0.001) 0 0Patient able to self−treat 3.6 (0.05) 22.3 (0.87) 2.5 (0.06)Add-on to Glimepiride Victoza® +

Glimepiride (N = 695)

Rosiglitazone + Glimepiride

(N = 231)

Placebo + Glimepiride

(N = 114)Patient not able to self−treat 0.1 (0.003) 0 0Patient 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) 0Add-on to Metformin + Rosiglitazone

Victoza® + Metformin +

Rosiglitazone (N = 355)

None

Placebo + Metformin +

Rosiglitazone (N = 175)

Patient not able to self−treat 0 — 0Patient able to self−treat 7.9 (0.49) — 4.6 (0.15)Not classified 0.6 (0.01) — 1.1 (0.03)Add-on to Metformin + Glimepiride

Victoza® + Metformin + Glimepiride

(N = 230)

Insulin glargine + Metformin + Glimepiride

(N = 232)

Placebo + Metformin + Glimepiride

(N = 114)Patient not able to self−treat 2.2 (0.06) 0 0Patient 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 neo-plasms (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 par-ticular 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 refer-ence 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 fol-lowing 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, 1−877-484-2869Date of Issue: May 18, 2011 Version: 3Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, DenmarkVictoza® 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

© 2012 Novo Nordisk 1111-00006045-1 January 2012Victoza® is a registered trademark and VictozaCare™ is a trademark of Novo Nordisk A/S.

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%*

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

Indications and usageVictoza® 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 fi ndings to humans, prescribe Victoza® only to patients for whom the potential benefi ts are considered to outweigh the potential risk. Victoza® is not recommended as fi rst-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 suffi ciently 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 informationLiraglutide causes dose-dependent and treatment-duration-dependent 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 fi ndings 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

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 confi rmed.

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 fi lled for existing Victoza® patients enrolled in VictozaCare™ versus a match-pair control group not enrolled in VictozaCare™ through fi rst 8 months of enrollment.

Low rate ofhypoglycemia

May reduce weight— Victoza® is not indicated

for the management of obesity, and weight change was a secondary end point in clinical trials

Flexible dosing any time of day, independent of meals

VictozaCare™ helps patients stay on track with ongoing support— Patients enrolled in

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

january/february volume 5, number 1

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