AHDB February 2015 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN ™ FEBRUARY 2015

VOLUME 8, NUMBER 1

FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

EDITORIAL

N=1 David B. Nash, MD, MBA PERSPECTIVE

Key Strategic Trends that Impact Healthcare Decision-Making and Stakeholder Roles in the New Marketplace By John Santilli, MBA, and F. Randy Vogenberg, PhD, RPh ™

CLINICAL

Is Response-Guided Therapy Being Applied in the Clinical Setting? The Hepatitis C Example Jennifer B. Harris, PharmD; Melea A. Ward, PharmD, PhD, BCPS; Phil Schwab, PhD Stakeholder Perspective: Response-Guided Therapy an Appropriate Tool for Evaluating Treatment Protocols and Costs of Drug Therapies By Jack E. Fincham, PhD

Diagnosis and Treatment of Patients with Thyroid Cancer Quang T. Nguyen, DO, FACP, FACE, FTOS; Eun Joo Lee; Melinda Gingman Huang; Young In Park; Aashish Khullar, MD; Raymond A. Plodkowski, MD Stakeholder Perspective: Predictive Models and Technology Present Opportunities to Support Early Diagnosis, Treatment, and Adherence to Guidelines By Jeffrey A. Bourret, PharmD, MS, BS, RPh, BCPS, FASHP CONTINUING EDUCATION

Optimizing Medication Utilization and Adherence in Patients with Schizophrenia: A Perspective for Managed Care Pharmacists By Robert Navarro, PharmD; Peter J. Weiden, MD; Matthew Mitchell, PharmD, MBA

Industry Trends

www.AHDBonline.com

Consider once-weekly TANZEUM for formulary inclusion

• The lowest Wholesale Acquisition Cost (WAC) in the GLP-1 receptor agonist class1,a — WAC comparison does not imply comparable safety or effectiveness and does not imply identical indications — No Phase III clinical trial data are available comparing the efficacy of TANZEUM to Bydureon® (exenatide extended-release for injectable suspension), Byetta® (exenatide) Injection, or Trulicity™ (dulaglutide) injection, for subcutaneous use. In a head-to-head trial of TANZEUM vs Victoza, TANZEUM provided less HbA1c reduction than Victoza® (liraglutide [rDNA origin] injection), solution for subcutaneous use and the treatment difference was statistically significant • Available in 2 dosage strengths at the same WAC price1,2: 30-mg and 50-mg, single-dose pens • The safety and efficacy for TANZEUM have been evaluated in a clinical trial program comprising 8 Phase III studies and 2365 patients who received TANZEUM2 a

WAC is the listed price to wholesalers and warehousing chains, not including prompt pay, stocking or distribution allowances, or other discounts, rebates, or chargebacks. The listed price may not represent prices charged to other customers, including specialty distributors. WAC does not reflect the price paid by consumers.1

Indications and Usage for TANZEUM TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Limitations of Use: • TANZEUM is not recommended as first-line therapy for patients inadequately controlled on diet and exercise. • TANZEUM has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. • TANZEUM is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. TANZEUM is not a substitute for insulin in these patients. • TANZEUM has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis. The use of TANZEUM is not recommended in patients with pre-existing severe gastrointestinal disease. • TANZEUM has not been studied in combination with prandial insulin.

Important Safety Information for TANZEUM WARNING: RISK OF THYROID C-CELL TUMORS Thyroid C-cell tumors have been observed in rodent studies with glucagon-like peptide-1 (GLP-1) receptor agonists at clinically relevant exposures. It is unknown whether TANZEUM causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans. TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with TANZEUM. Patients should be counseled regarding the risk and symptoms of thyroid tumors.

CONTRAINDICATIONS Hypersensitivity: TANZEUM is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components. Continued on next page

Important Safety Information for TANZEUM (contâ&#x20AC;&#x2122;d) WARNINGS AND PRECAUTIONS Risk of Thyroid C-cell Tumors: Counsel patients regarding the risk for MTC with the use of TANZEUM and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Patients with thyroid nodules noted on physical examination or neck imaging should be referred to an endocrinologist for further evaluation. Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TANZEUM. If serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. Acute Pancreatitis: In clinical trials, acute pancreatitis has been reported in association with TANZEUM. After initiation of TANZEUM, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue TANZEUM. If pancreatitis is confirmed, TANZEUM should not be restarted. TANZEUM has not been studied in patients with a history of pancreatitis to determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when TANZEUM is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting. Hypersensitivity Reactions: Across 8 Phase III clinical trials, a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with TANZEUM. If hypersensitivity reactions occur, discontinue use of TANZEUM; treat promptly per standard of care and monitor until signs and symptoms resolve. Renal Impairment: In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In a trial of TANZEUM in patients with renal impairment, the frequency of such gastrointestinal reactions increased as renal function declined. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TANZEUM in patients with renal impairment. Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. Macrovascular Outcomes: There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug.

ADVERSE REACTIONS The most common adverse reactions, excluding hypoglycemia, reported in â&#x2030;Ľ5% of patients treated with TANZEUM and more commonly than in patients treated with placebo, are: upper respiratory tract infection (14.2 vs 13.0); diarrhea (13.1 vs 10.5); nausea (11.1 vs 9.6); injection site reaction (10.5 vs 2.1); cough (6.9 vs 6.2); back pain (6.7 vs 5.8); arthralgia (6.6 vs 6.4); sinusitis (6.2 vs 5.8); influenza (5.2 vs 3.2).

DRUG INTERACTIONS TANZEUM delays gastric emptying and may impact absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TANZEUM.

USE IN SPECIFIC PATIENT POPULATIONS Pediatric Use: Safety and effectiveness of TANZEUM have not been established in pediatric patients (younger than 18 years). A1C = glycosylated hemoglobin; GLP-1 = glucagon-like peptide-1. References: 1. Data on file. GSK. 2. Prescribing Information for TANZEUM.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for TANZEUM on the following pages. www.GSKSource.com Bydureon and Byetta are registered trademarks of the AstraZeneca group of companies. Trulicity is a trademark of Eli Lilly and Company. Victoza is a registered trademark of Novo Nordisk A/S.

TANZEUM

™

BRIEF SUMMARY

(albiglutide) for injection, for subcutaneous use

The following is a brief summary only; see full prescribing information for complete product information. WARNING: RISK OF THYROID C-CELL TUMORS • Thyroid C-cell tumors have been observed in rodent studies with glucagon-like peptide-1 (GLP-1) receptor agonists at clinically relevant exposures. It is unknown whether TANZEUM™ causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans [see Warnings and Precautions (5.1)]. • TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Routine serum calcitonin or thyroid ultrasound monitoring is of uncertain value in patients treated with TANZEUM. Patients should be counseled regarding the risk and symptoms of thyroid tumors [see Contraindications (4.1), Warnings and Precautions (5.1)]. 1 INDICATIONS AND USAGE TANZEUM is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) of full prescribing information]. Limitations of Use: TANZEUM is not recommended as first-line therapy for patients inadequately controlled on diet and exercise [see Warnings and Precautions (5.1)]. TANZEUM has not been studied in patients with a history of pancreatitis [see Warnings and Precautions (5.2)]. Consider other antidiabetic therapies in patients with a history of pancreatitis. TANZEUM is not indicated in the treatment of patients with type 1 diabetes mellitus or for the treatment of patients with diabetic ketoacidosis. TANZEUM is not a substitute for insulin in these patients. TANZEUM has not been studied in patients with severe gastrointestinal (GI) disease, including severe gastroparesis. The use of TANZEUM is not recommended in patients with pre-existing severe gastrointestinal disease [see Adverse Reactions (6.1)]. TANZEUM has not been studied in combination with prandial insulin. 4 CONTRAINDICATIONS 4.1 Medullary Thyroid Carcinoma: TANZEUM is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions (5.1)]. 4.2 Hypersensitivity: TANZEUM is contraindicated in patients with a prior serious hypersensitivity reaction to albiglutide or to any of the product components [see Warnings and Precautions (5.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Risk of Thyroid C-cell Tumors: Nonclinical studies in rodents of clinically relevant doses of GLP-1 receptor agonists showed dose-related and treatment-duration-dependent increases in the incidence of thyroid C-cell tumors (adenomas and carcinomas). Carcinogenicity studies could not be conducted with TANZEUM because drug-clearing, anti-drug antibodies develop in animals used for these types of studies [see Nonclinical Toxicology (13.1)]. It is unknown whether GLP-1 receptor agonists are associated with thyroid C-cell tumors, including MTC in humans [see Boxed Warning, Contraindications (4.1)]. Across 8 Phase III clinical trials [see Clinical Studies (14) of full prescribing information], MTC was diagnosed in 1 patient receiving TANZEUM and 1 patient receiving placebo. Both patients had markedly elevated serum calcitonin levels at baseline. TANZEUM is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the risk for MTC with the use of TANZEUM and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). The clinical value of routine monitoring of serum calcitonin to diagnose MTC in patients at risk for MTC has not been established. Elevated serum calcitonin is a biological marker of MTC. Patients with MTC usually have calcitonin values >50 ng/L. Patients with thyroid nodules noted on physical examination or neck imaging should be referred to an endocrinologist for further evaluation. Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with TANZEUM. Such monitoring may increase the risk of unnecessary procedures, due to the low specificity of serum calcitonin testing for MTC and a high background incidence of thyroid disease. If serum calcitonin is measured and found to be elevated, the patient should be referred to an endocrinologist for further evaluation. 5.2 Acute Pancreatitis: In clinical trials, acute pancreatitis has been reported in association with TANZEUM. Across 8 Phase III clinical trials [see Clinical Studies (14) of full prescribing information], pancreatitis adjudicated as likely related to therapy occurred more frequently in patients receiving TANZEUM (6 of 2,365 [0.3%]) than in patients receiving placebo (0 of 468 [0%]) or active comparators (2 of 2,065 [0.1%]). After initiation of TANZEUM, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue TANZEUM. If pancreatitis is confirmed, TANZEUM should not be restarted. TANZEUM has not been studied in patients with a history of pancreatitis to

determine whether these patients are at increased risk for pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis. 5.3 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: The risk of hypoglycemia is increased when TANZEUM is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Therefore, patients may require a lower dose of sulfonylurea or insulin to reduce the risk of hypoglycemia in this setting [see Adverse Reactions (6.1)]. 5.4 Hypersensitivity Reactions: Across 8 Phase III clinical trials [see Clinical Studies (14) of full prescribing information], a serious hypersensitivity reaction with pruritus, rash, and dyspnea occurred in a patient treated with TANZEUM. If hypersensitivity reactions occur, discontinue use of TANZEUM; treat promptly per standard of care and monitor until signs and symptoms resolve [see Contraindications (4.2)]. 5.5 Renal Impairment: In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events were reported in patients without known underlying renal disease. A majority of reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. In a trial of TANZEUM in patients with renal impairment [see Clinical Studies (14.3) of full prescribing information], the frequency of such gastrointestinal reactions increased as renal function declined [see Use in Specific Populations (8.6)]. Because these reactions may worsen renal function, use caution when initiating or escalating doses of TANZEUM in patients with renal impairment [see Dosage and Administration (2.3) of full prescribing information, Use in Specific Populations (8.6)]. 5.6 Macrovascular Outcomes: There have been no clinical trials establishing conclusive evidence of macrovascular risk reduction with TANZEUM or any other antidiabetic drug. 6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the labeling: Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)], Acute Pancreatitis [see Warnings and Precautions (5.2)], Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.3)], Hypersensitivity Reactions [see Warnings and Precautions (5.4)], Renal Impairment [see Warnings and Precautions (5.5)]. 6.1 Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials: The data in Table 1 are derived from 4 placebo-controlled trials. TANZEUM was used as monotherapy in 1 trial and as add-on therapy in 3 trials [see Clinical Studies (14) of full prescribing information]. These data reflect exposure of 923 patients to TANZEUM and a mean duration of exposure to TANZEUM of 93 weeks. The mean age of participants was 55 years, 1% of participants were 75 years or older and 53% of participants were male. The population in these studies was 48% white, 13% African/African American, 7% Asian, and 29% Hispanic/Latino. At baseline, the population had diabetes for an average of 7 years and had a mean HbA1c of 8.1%. At baseline, 17% of the population in these studies reported peripheral neuropathy and 4% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 91% of the study population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 9%. Table 1 shows common adverse reactions excluding hypoglycemia associated with the use of TANZEUM in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on TANZEUM than on placebo, and occurred in at least 5% of patients treated with TANZEUM. Table 1. Adverse Reactions in Placebo-controlled Trials Reported in ≥5% of Patients Treated with TANZEUMa Placebo TANZEUM Adverse Reaction (N=468) (N=923) % % Upper respiratory tract infection 13.0 14.2 Diarrhea

10.5

13.1

Nausea

9.6

11.1

Injection site reaction

2.1

10.5

Cough

6.2

6.9

Back pain

5.8

6.7

Arthralgia

6.4

6.6

Sinusitis

5.8

6.2

Influenza

3.2

5.2

Adverse reactions reported includes adverse reactions occurring with the use of glycemic rescue medications which included metformin (17% for placebo and 10% for TANZEUM) and insulin (24% for placebo and 14% for TANZEUM). b See below for other events of injection site reactions reported. a

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Adverse Reactions (cont’d) Gastrointestinal Adverse Reactions: In the pool of placebo-controlled trials, gastrointestinal complaints occurred more frequently among patients receiving TANZEUM (39%) than patients receiving placebo (33%). In addition to diarrhea and nausea (see Table 1), the following gastrointestinal adverse reactions also occurred more frequently in patients receiving TANZEUM: vomiting (2.6% versus 4.2% for placebo versus TANZEUM), gastroesophageal reflux disease (1.9% versus 3.5% for placebo versus TANZEUM), and dyspepsia (2.8% versus 3.4% for placebo versus TANZEUM). Constipation also contributed to the frequently reported reactions. In the group treated with TANZEUM, investigators graded the severity of GI reactions as “mild” in 56% of cases, “moderate” in 37% of cases, and “severe” in 7% of cases. Discontinuation due to GI adverse reactions occurred in 2% of individuals on TANZEUM or placebo. Injection Site Reactions: In the pool of placebo-controlled trials, injection site reactions occurred more frequently on TANZEUM (18%) than on placebo (8%). In addition to the term injection site reaction (see Table 1), the following other types of injection site reactions also occurred more frequently on TANZEUM: injection site hematoma (1.9% versus 2.1% for placebo versus TANZEUM), injection site erythema (0.4% versus 1.7% for placebo versus TANZEUM), injection site rash (0% versus 1.4% for placebo versus TANZEUM), injection site hypersensitivity (0% versus 0.8% versus for placebo versus TANZEUM), and injection site hemorrhage (0.6% versus 0.7% for placebo versus TANZEUM). Injection site pruritus also contributed to the frequently reported reactions. The majority of injection site reactions were judged as “mild” by investigators in both groups (73% for TANZEUM versus 94% for placebo). More patients on TANZEUM than on placebo: discontinued due to an injection site reaction (2% versus 0.2%), experienced more than 2 reactions (38% versus 20%), had a reaction judged by investigators to be “moderate” or “severe” (27% versus 6%) and required local or systemic treatment for the reactions (36% versus 11%). Pool of Placebo- and Active-controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients with type 2 diabetes participating in 7 placebo- and active-controlled trials. These trials evaluated the use of TANZEUM as monotherapy, and as add-on therapy to oral antidiabetic agents, and as add-on therapy to basal insulin [see Clinical Studies (14) of full prescribing information]. In this pool, a total of 2,116 patients with type 2 diabetes were treated with TANZEUM for a mean duration of 75 weeks. The mean age of patients treated with TANZEUM was 55 years, 1.5% of the population in these studies was 75 years or older and 51% of participants were male. Forty-eight percent of patients were white, 15% African/African American, 9% Asian, and 26% were Hispanic/Latino. At baseline, the population had diabetes for an average of 8 years and had a mean HbA1c of 8.2%. At baseline, 21% of the population reported peripheral neuropathy and 5% reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR >60 mL/min/1.73 m2) in 92% of the population and moderately impaired (eGFR 30 to 60 mL/min/1.73 m2) in 8% of the population. In the pool of placebo- and active-controlled trials, the types and frequency of common adverse reactions excluding hypoglycemia were similar to those listed in Table 1. Other Adverse Reactions: Hypoglycemia: The proportion of patients experiencing at least one documented symptomatic hypoglycemic episode on TANZEUM and the proportion of patients experiencing at least one severe hypoglycemic episode on TANZEUM in clinical trials [see Clinical Studies (14) of full prescribing information] is shown in Table 2. Hypoglycemia was more frequent when TANZEUM was added to sulfonylurea or insulin [see Warnings and Precautions (5.3)]. Table 2. Incidence (%) of Hypoglycemia in Clinical Trials of TANZEUMa TANZEUM Monotherapyb Placebo 30 mg Weekly N = 101 (52 Weeks) N = 101 Documented symptomaticc Severed In Combination with Metformin Trial (104 Weeks)e Documented symptomatic Severe In Combination with Pioglitazone ± Metformin (52 Weeks) Documented symptomatic Severe In Combination with Metformin and Sulfonylurea (52 Weeks) Documented symptomatic Severe In Combination with Insulin Glargine (26 Weeks) Documented symptomatic Severe

2% Placebo N = 101 4% Placebo N = 151 1% Placebo N = 115 7% Insulin Lispro N = 281 30% 0.7%

2% TANZEUM N = 302 3% TANZEUM N = 150 3% 1% TANZEUM N = 271 13% 0.4% TANZEUM N = 285 16% -

Table 2. Incidence (%) of Hypoglycemia in Clinical Trials of TANZEUMa (cont’d) Insulin In Combination with TANZEUM Glargine N = 504 Metformin ± Sulfonylurea (52 Weeks) N = 241 Documented symptomatic Severe In Combination with OADs in Renal Impairment (26 Weeks) Documented symptomatic Severe

27% 0.4%

17% 0.4%

Sitagliptin N = 246

TANZEUM N = 249

6% 0.8%

10% -

OAD = Oral antidiabetic agents. Data presented are to the primary endpoint and include only events occurring on-therapy with randomized medications and excludes events occurring after use of glycemic rescue medications (i.e., primarily metformin or insulin). bIn this trial, no documented symptomatic or severe hypoglycemia were reported for TANZEUM 50 mg and these data are omitted from the table. cPlasma glucose concentration ≤70 mg/dL and presence of hypoglycemic symptoms. dEvent requiring another person to administer a resuscitative action. eRate of documented symptomatic hypoglycemia for active controls 18% (glimepiride) and 2% (sitagliptin).

Pneumonia: In the pool of 7 placebo- and active-controlled trials, the adverse reaction of pneumonia was reported more frequently in patients receiving TANZEUM (1.8%) than in patients in the all-comparators group (0.8%). More cases of pneumonia in the group receiving TANZEUM were serious (0.4% for TANZEUM versus 0.1% for all comparators). Atrial Fibrillation/Flutter: In the pool of 7 placebo- and active-controlled trials, adverse reactions of atrial fibrillation (1.0%) and atrial flutter (0.2%) were reported more frequently for TANZEUM than for all comparators (0.5% and 0%, respectively). In both groups, patients with events were generally male, older, and had underlying renal impairment or cardiac disease (e.g., history of arrhythmia, palpitations, congestive heart failure, cardiomyopathy, etc.). Appendicitis: In the pool of placebo- and active-controlled trials, serious events of appendicitis occurred in 0.3% of patients treated with TANZEUM compared with 0% among all comparators. Immunogenicity: In the pool of 7 placebo- and active-controlled trials, 116 (5.5%) of 2,098 patients exposed to TANZEUM tested positive for anti-albiglutide antibodies at any time during the trials. None of these antibodies were shown to neutralize the activity of albiglutide in an in vitro bioassay. Presence of antibody did not correlate with reduced efficacy as measured by HbA1c and fasting plasma glucose or specific adverse reactions. Consistent with the high homology of albiglutide with human GLP-1, the majority of patients (approximately 79%) with anti-albiglutide antibodies also tested positive for anti-GLP-1 antibodies; none were neutralizing. A minority of patients (approximately 17%) who tested positive for anti-albiglutide antibodies also transiently tested positive for antibodies to human albumin. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to albiglutide cannot be directly compared with the incidence of antibodies of other products. Liver Enzyme Abnormalities: In the pool of placebo- and active-controlled trials, a similar proportion of patients experienced at least one event of alanine aminotransferase (ALT) increase of 3-fold or greater above the upper limit of normal (0.9% and 0.9% for all comparators versus TANZEUM). Three subjects on TANZEUM and one subject in the all-comparator group experienced at least one event of ALT increase of 10-fold or greater above the upper limit of normal. In one of the 3 cases an alternate etiology was identified to explain the rise in liver enzyme (acute viral hepatitis). In one case, insufficient information was obtained to establish or refute a drug-related causality. In the third case, elevation in ALT (10 times the upper limit of normal) was accompanied by an increase in total bilirubin (4 times the upper limit of normal) and occurred 8 days after the first dose of TANZEUM. The etiology of hepatocellular injury was possibly related to TANZEUM but direct attribution to TANZEUM was confounded by the presence of gallstone disease diagnosed on ultrasound 3 weeks after the event. Gamma Glutamyltransferase (GGT) Increase: In the pool of placebo-controlled trials, the adverse event of increased GGT occurred more frequently in the group treated with TANZEUM (0.9% and 1.5% for placebo versus TANZEUM). Heart Rate Increase: In the pool of placebo-controlled trials, mean heart rate in patients treated with TANZEUM was higher by an average of 1 to 2 bpm compared with mean heart rate in patients treated with placebo across study visits. The long-term clinical effects of the increase in heart rate have not been established [see Warnings and Precautions (5.6)].

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7 DRUG INTERACTIONS TANZEUM did not affect the absorption of orally administered medications tested in clinical pharmacology studies to any clinically relevant degree [see Clinical Pharmacology (12.3) of full prescribing information]. However, TANZEUM causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with TANZEUM.

50 mg/kg/day (39 times clinical exposure based on AUC). In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 through 15 (organogenesis), embryo-fetal lethality (post-implantation loss) and bent (wavy) ribs were observed at 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity (body weight loss and reduced food consumption). Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 6 to 17. Offspring of pregnant mice given 50 mg/kg/day (39 times clinical exposure based on AUC), a dose associated with maternal toxicity, had reduced body weight pre-weaning, dehydration and coldness, and a delay in balanopreputial separation. Pregnant mice were given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 15 to lactation day 10. Increased mortality and morbidity were seen at all doses (≥1 mg/kg/ day) in lactating females in mouse pre- and postnatal development studies. Mortalities have not been observed in previous toxicology studies in nonlactating or non-pregnant mice, nor in pregnant mice. These findings are consistent with lactational ileus syndrome which has been previously reported in mice. Since the relative stress of lactation energy demands is lower in humans than mice and humans have large energy reserves, the mortalities observed in lactating mice are of questionable relevance to humans. The offspring had decreased pre-weaning body weight which reversed post-weaning in males but not females at ≥5 mg/kg/day (2.2 times clinical exposure based on AUC) with no other effects on development. Low levels of albiglutide were detected in plasma of offspring. Lactating mice were given SC doses of 1, 5, or 50 mg/kg/day from lactation day 7 to 21 (weaning) under conditions that limit the impact of lactational ileus (increased caloric intake and culling of litters). Doses ≥1 mg/kg/day (exposures below clinical AUC) caused reduced weight gain in the pups during the treatment period.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category C: There are no adequate and wellcontrolled studies of TANZEUM in pregnant women. Nonclinical studies have shown reproductive toxicity, but not teratogenicity, in mice treated with albiglutide at up to 39 times human exposure resulting from the maximum recommended dose of 50 mg/week, based on area under the time-concentration curve (AUC) [see Nonclinical Toxicology (13.1,13.3)]. TANZEUM should not be used during pregnancy unless the expected benefit outweighs the potential risks. Due to the long washout period for TANZEUM, consider stopping TANZEUM at least 1 month before a planned pregnancy. There are no data on the effects of TANZEUM on human fertility. Studies in mice showed no effects on fertility [see Nonclinical Toxicology (13.1)]. The potential risk to human fertility is unknown. 8.3 Nursing Mothers: There are no adequate data to support the use of TANZEUM during lactation in humans. It is not known if TANZEUM is excreted into human milk during lactation. Given that TANZEUM is an albumin-based protein therapeutic, it is likely to be present in human milk. Decreased body weight in offspring was observed in mice treated with TANZEUM during gestation and lactation [see Nonclinical Toxicology (13.3)]. A decision should be made whether to discontinue nursing or to discontinue TANZEUM, taking into account the importance of the drug 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for to the mother and the potential risks to the infant. 8.4 Pediatric Use: Safety Use). The Medication Guide is contained in a separate leaflet that accompanies and effectiveness of TANZEUM have not been established in pediatric patients the product. Inform patients about self-management practices, including the (younger than 18 years). 8.5 Geriatric Use: Of the total number of patients importance of proper storage of TANZEUM, injection technique, timing of dosage (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, 19% (N = of TANZEUM and concomitant oral drugs, and recognition and management of 444) were 65 years and older, and <3% (N = 52) were 75 years and older. hypoglycemia. Inform patients that thyroid C-cell tumors have been observed No overall differences in safety or effectiveness were observed between in rodents treated with some GLP-1 receptor agonists, and the human these patients and younger patients, but greater sensitivity of some older relevance of this finding is unknown. Counsel patients to report symptoms of individuals cannot be ruled out. 8.6 Renal Impairment: Of the total number thyroid tumors to their physician [see Warnings and Precautions (5.1)]. Advise of patients (N = 2,365) in 8 Phase III clinical trials who received TANZEUM, patients that persistent, severe abdominal pain that may radiate to the back 54% (N = 1,267) had mild renal impairment (eGFR 60 to 89 mL/min/1.73 and which may (or may not) be accompanied by vomiting is the hallmark m2), 12% (N = 275) had moderate renal impairment (eGFR 30 to 59 mL/ symptom of acute pancreatitis. Instruct patients to discontinue TANZEUM min/1.73 m2) and 1% (N = 19) had severe renal impairment (eGFR 15 to <30 promptly and to contact their physician if persistent, severe abdominal pain mL/min/1.73 m2). No dosage adjustment is required in patients with mild occurs [see Warnings and Precautions (5.2)]. The risk of hypoglycemia is (eGFR 60 to 89 mL/min/1.73 m2), moderate (eGFR 30 to 59 mL/min/1.73 m2), increased when TANZEUM is used in combination with an agent that induces or severe (eGFR 15 to <30 mL/min/1.73 m2) renal impairment. Efficacy of hypoglycemia, such as sulfonylurea or insulin. Instructions for hypoglycemia TANZEUM in patients with type 2 diabetes and renal impairment is described should be reviewed with patients and reinforced when initiating therapy with elsewhere [see Clinical Studies (14.3) of full prescribing information]. There TANZEUM, particularly when concomitantly administered with a sulfonylurea or is limited clinical experience in patients with severe renal impairment (19 insulin [see Warnings and Precautions (5.3)]. Advise patients on the symptoms subjects). The frequency of GI events increased as renal function declined. of hypersensitivity reactions and instruct them to stop taking TANZEUM and For patients with mild, moderate, or severe impairment, the respective seek medical advice promptly if such symptoms occur [see Warnings and event rates were: diarrhea (6%, 13%, 21%), nausea (3%, 5%,16%), and Precautions (5.4)]. Instruct patients to read the Instructions for Use before vomiting (1%, 2%, 5%). Therefore, caution is recommended when initiating starting therapy. Instruct patients on proper use, storage, and disposal of or escalating doses of TANZEUM in patients with renal impairment [see the pen [see How Supplied/Storage and Handling (16.2) of full prescribing Dosage and Administration (2.3) of full prescribing information, Warnings and information, Patient Instructions for Use of full prescribing information]. Precautions (5.5), Clinical Pharmacology (12.3) of full prescribing information]. Instruct patients to read the Medication Guide before starting TANZEUM and to 10 OVERDOSAGE read again each time the prescription is renewed. Instruct patients to inform No data are available with regard to overdosage in humans. Anticipated their doctor or pharmacist if they develop any unusual symptom, or if any symptoms of an overdose may be severe nausea and vomiting. In the event known symptom persists or worsens. Inform patients not to take an extra of an overdose, appropriate supportive treatment should be initiated as dose of TANZEUM to make up for a missed dose. If a dose is missed, instruct dictated by the patient’s clinical signs and symptoms. A prolonged period of patients to take a dose as soon as possible within 3 days after the missed observation and treatment for these symptoms may be necessary, taking into dose. Instruct patients to then take their next dose at their usual weekly time. account the half-life of TANZEUM (5 days). If it has been longer than 3 days after the missed dose, instruct patients to wait and take TANZEUM at the next usual weekly time. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility: As albiglutide TANZEUM is a trademark of the GSK group of companies. is a recombinant protein, no genotoxicity studies have been conducted. Carcinogenicity studies have not been performed with albiglutide because such studies are not technically feasible due to the rapid development of drug-clearing, anti-drug antibodies in rodents. Thyroid C-cell tumors were observed in 2-year rodent carcinogenicity studies with some GLP-1 receptor agonists. The clinical relevance of rodent thyroid findings observed with GLP-1 Manufactured by GlaxoSmithKline LLC receptor agonists is unknown. In a mouse fertility study, males were treated Wilmington, DE 19808 with subcutaneous (SC) doses of 5, 15, or 50 mg/kg/day for 7 days prior to U.S. Lic. No. 1727 cohabitation with females, and continuing through mating. In a separate fertility Marketed by GlaxoSmithKline study, females were treated with SC doses of 1, 5, or 50 mg/kg/day for 7 days Research Triangle Park, NC 27709 prior to cohabitation with males, and continuing through mating. Reductions ©2014, the GSK group of companies. All rights reserved. in estrous cycles were observed at 50 mg/kg/day, a dose associated with August 2014, TNZ:2BRS maternal toxicity (body weight loss and reduced food consumption). There were no effects on mating or fertility in either sex at doses up to 50 mg/kg/ ©2014 GSK group of companies. day (up to 39 times clinical exposure based on AUC). 13.3 Reproductive All rights reserved. Printed in USA. BIG159R0 November 2014 and Developmental Toxicity: In order to minimize the impact of the drug-clearing, anti-drug antibody response, reproductive and developmental toxicity assessments in the mouse were partitioned to limit the dosing period to no more than approximately 15 days in each study. In pregnant mice given SC doses of 1, 5, or 50 mg/kg/day from gestation Day 1 to 6, there were no adverse effects on early embryonic development through implantation at

EDITORIAL BOARD EDITOR-IN-CHIEF

David B. Nash, MD, MBA Founding Dean, The Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Thomas Jefferson University, Philadelphia, PA DEPUTY EDITORS

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson School of Population Health, Thomas Jefferson University Laura T. Pizzi, PharmD, MPH, RPh Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Thomas Jefferson University AGING AND WELLNESS

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

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Gregory Shaeffer, MBA, RPh, FASHP Vice President, Consulting Pharmacy Healthcare Solutions AmerisourceBurgen, Harrisburg, PA Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY RESEARCH

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA GOVERNMENT

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC HEALTH INFORMATION TECHNOLOGY

Kelly Huang, PhD Operating Partner, Spindletop Capital Austin, TX HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City

Vol 8, No 1

February 2015

Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy University of the Sciences, Philadelphia David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD

Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy Univ. of Cincinnati Medical Center, OH PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Assistant Clinical Professor, Psychiatry, Mount Sinai School of Medicine, New York, NY Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA, FAMCP Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

HEALTH & VALUE PROMOTION

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Byron C. Scott, MD, MBA Medical Director National Clinical Medical Leader Truven Health Analytics, Chicago, IL Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

Jeffrey A. Bourret, PharmD, MS, BCPS, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC PATIENT ADVOCACY

Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy Presbyterian College, Clinton, SC Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA RESEARCH & DEVELOPMENT

PAYER-PROVIDER FINANCES

Bruce Pyenson, FSA, MAAA Principal & Consulting Actuary Milliman, Inc, New York, NY

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA

PERSONALIZED MEDICINE

SPECIALTY PHARMACY

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia

Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

PHARMACOECONOMICS

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc, Norwalk, CT

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American Health & Drug Benefits

FEBRUARY 2015

VOLUME 8, NUMBER 1

THE PEER-REVIEWED FORUM FOR REAL-WORLD EVIDENCE IN BENEFIT DESIGN ™

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TABLE OF CONTENTS EDITORIAL

N=1 David B. Nash, MD, MBA

PERSPECTIVE

15 Key Strategic Trends that Impact Healthcare Decision-Making and Stakeholder Roles in the New Marketplace By John Santilli, MBA, and F. Randy Vogenberg, PhD, RPh CLINICAL

22 Is Response-Guided Therapy Being Applied in the Clinical Setting? The Hepatitis C Example Jennifer B. Harris, PharmD; Melea A. Ward, PharmD, PhD, BCPS; Phil Schwab, PhD 28 Stakeholder Perspective: Response-Guided Therapy an Appropriate Tool for Evaluating Treatment Protocols and Costs of Drug Therapies By Jack E. Fincham, PhD 30 Diagnosis and Treatment of Patients with Thyroid Cancer Quang T. Nguyen, DO, FACP, FACE, FTOS; Eun Joo Lee; Melinda Gingman Huang; Young In Park; Aashish Khullar, MD; Raymond A. Plodkowski, MD 39 Stakeholder Perspective: Predictive Models and Technology Present Opportunities to Support Early Diagnosis, Treatment, and Adherence to Guidelines By Jeffrey A. Bourret, PharmD, MS, BS, RPh, BCPS, FASHP Continued on page 10

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Call for Papers Hematology/Oncology Theme Issue American Health & Drug Benefits is publishing a Theme Issue on Cancer Care in May 2015 Readers are invited to submit original research, cost-effective analyses, evidence-based comprehensive reviews, or industry surveys and trends related to hematology and oncology topics. The growing focus on targeted therapies and diagnostics, and the ever-increasing cost of cancer care, require a thorough examination of current and emerging trends in oncology, focusing on health economics, benefit design and utilization, and health outcomes.

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• Managing toxicities of cancer therapies

• Cost comparisons of cancer therapies

• Pathways and practice guidelines

• Cost considerations in cancer care

• Patient navigation initiatives

• Diagnostic modalities

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Vol 8, No 1

February 2015

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FEBRUARY 2015

VOLUME 8, NUMBER 1

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(Continued)

DEPARTMENT

Industry Trends

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41 The Hospital Is No Place for a Heart Attack: A Group of 12 Institutions Is Working to Improve Survival Rates for In-Hospital Attack Patients By Ron Winslow CONTINUING EDUCATION

44 Optimizing Medication Utilization and Adherence in Patients with Schizophrenia: A Perspective for Managed Care Pharmacists By Robert Navarro, PharmD; Peter J. Weiden, MD; Matthew Mitchell, PharmD, MBA

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RESPIRATORY CARE: RECENT ADVANCES IN ASTHMA a 4-Part SerieS

Faculty Perspectives

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EDITORIAL

N=1 David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits; Founding Dean, J efferson School of Population Health, Philadelphia, PA

he regular readers of this column know that I am a voracious consumer of private sector reports regarding the healthcare industry. Several recent reports and insights gleaned during my travels across the country have led me to think differently about the ways in which we will purchase healthcare services in the future. I have written previously in this space about consumerism in healthcare1 and about public accountability for the outcomes2; this time I would like to focus on the individual consumer of healthcare. At a corporate board briefing dinner several months ago, I had the privilege of listening to business consultant Ram Charan speak in person. Ram is among the best known management consultants and authors in the business world. Despite his age (75 years), he continues to travel the globe, advising corporate leaders. At the briefing, he described the future of healthcare as focused on the “N of 1.” When I first heard this, I was incredulous! What did he mean? How could we really move from our long history of market segmentation, severity of illness adjustment, and related decades of work to a totally disruptive view of the patient? Subsequently, I have read (and thoroughly enjoyed) several recent reports that have helped me connect the dots about the “N of 1” consumer revolution in healthcare. Let me explain. In their recent privately published report, “The Patient-to-Consumer Revolution,” Main and Slywotzky state, “These days, the surest sign that an industry is about to undergo wrenching change is a sudden influx of tech entrepreneurs backed by venture-capital investment….The process has created immense value for consumers but has been brutally hard on the companies that traditionally dominated those sectors— at least those that failed to respond quickly and well.” 3 Main and Slywotzky continue, “And so the tech entrepreneurs are doing what they do best, redefining the rules and tipping value their way, creating magnetic new products and services that eliminate hassles and delight consumers. Some provide general health information (such as Greatist or WebMD), help consumers prepare healthy meals (Zipongo), or even provide live, video-based personal training sessions (Wello). Others drive personalized engagement by aligning consumer

American Health & Drug Benefits

actions and behaviors with incentives and rewards (Welltok), offer primary care based on a whole new model (Iora Health), or enable consumers to find doctors, make appointments, and identify low-cost opportunities (Castlight and ZocDoc).” 3 So, what exactly is going on here? As our readers surely know, there is a huge amount of waste in our healthcare system—waste that has been studied, cataloged, and talked about for nearly 3 decades. Venture capital firms understand that a windfall could be accumulated if they can translate even a small portion of that waste into value for consumers. By honing in on the individual consumer experience, making it as seamless as OpenTable or Uber, healthcare could become very profitable. Recent activity supports this notion. As Main and Slywotzky explain, “Where there is accelerating consumer demand, there is investment. In 2010, the year the Affordable Care Act was signed into law, only 17 healthcare-focused software companies attracted seed or Series A investment of $2 million or more. In 2013, the number was 89, and according to Rock Health, total VC [venture capital] investment in digital health was just under $2 billon, doubling the figure from just two years before.” 3 Who are these new consumers who are open to using web-based applications and receiving their care in nontraditional settings? In a recent study by Estupiñán and colleagues, we learn a lot about exactly who these new consumers are and how they view this new ecosystem.4 Based on their comprehensive national telephone survey, conducted by a company with deep expertise in this arena, Estupiñán and colleagues note that “Consumers, particularly younger ones, increasingly expect healthcare to work the way other digital markets work, with user-friendly interfaces, clearly defined pricing, and a wide selection of product option designed to meet their needs.” 4 What surprised me about the results of this report were their findings that “consumers are getting comfortable with exchanges far more quickly than expected, and they’re highly loyal to the first insurance plan they purchase.” 4 It turns out that more than 50% of consumers say they are very satisfied with the experience of buying health insurance on these new exchanges. In fact, they want more online services. Apparently

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EDITORIAL

80% of the respondents in this survey noted that they would engage with digital services that helped them manage their healthcare, but only 23% said they could currently find appropriate online tools. Talk about a new disruptive industry! Of course, purchasing health insurance online via an exchange, and then Skyping with your primary care doctor is not for every “N = 1.” As Estupiñán and colleagues note, “the elderly and the wealthy are largely unmoved by price variations in various aspects of their care, whereas the young and the healthy consider price to be paramount in their decision-making process, assigning it 20 percent more value than their elderly counterparts do. The key driver of decision-making among respondents older than 65 was the ability to trust their provider’s advice.” 4 Although the elderly may not all engage online, there is no question, according to the best newly available evidence, that “consumers today are savvier and more skeptical, have more options for managing their health, and expect their individual preferences to be met.” 4 Finally, another big surprise for me from the report by Estupiñán and colleagues was the notion that “40% of consumers report that they’d trust large retailers like Walmart or Target to manage their health, compared with 39% and 37% who place that kind of trust in providers and insurers, respectively.” 4 In other words, why not get an inexpensive prescription for generic drugs from WalMart or Target? Why not talk to a nurse practitioner in a “big box” store? If it is convenient and is delivered by a trusted brand, the “N of 1” consumer is comfortable with this choice. In summary, I am convinced that the consumer movement in our industry is a major disruptive change. What I’ve learned in the past few months is how Wall Street views this disruption, and the accumulating recent evidence about the power of the online exchanges.

Ram Charan was right. We better listen up! For provider organizations, the pharmaceutical industry, and payers, we all have to find a way to connect with the healthcare consumer of the future. Our survival is at stake.

More than 50% of consumers say they are very satisfied with the experience of buying health insurance on these new exchanges. In fact, they want more online services. Apparently 80% of the respondents in this survey noted that they would engage with digital services that helped them manage their healthcare. I will continue to track this movement and report back to you periodically. If you’re engaged in disruptive work, connecting consumers to providers, I would like to hear from you. As always, you can reach me at david. nash@jefferson.edu. Appropriate letters will be published in American Health & Drug Benefits, with minimal editing for grammar and length. n

References

1. Nash DB. 2014: the year of the healthcare consumer [Editorial]. Am Health Drug Benefits. 2014;7:198-199. 2. Nash DB. Read all about it [Editorial]. Am Health Drug Benefits. 2014:7:425-426. 3. Main T, Slywotzky A. The patient-to-consumer revolution: how high tech, transparent marketplaces, and consumer power are transforming U.S. healthcare. Oliver Wyman. 2014. www.oliverwyman.com/content/dam/oliver-wyman/global/en/images/ insights/health-life-sciences/2014/October/The-Patient-To-Consumer-Revolution. pdf. Accessed November 30, 2014. 4. Estupiñán J, Fengler K, Kaura A. The birth of the healthcare consumer: growing demands for choice, engagement, and experience. Strategy&, formerly Booz & Company. PwC. 2014. www.strategyand.pwc.com/media/file/The-birth-of-the-healthcareconsumer.pdf. Accessed November 30, 2014.

VISIT OUR ENHANCED USER-FRIENDLY WEBSITE American Health & Drug Benefits is an independent, peer-reviewed journal founded in 2008 Examines drug and other healthcare intervention value for payers, purchasers, providers, patients, manufacturers, regulators, distributors, and evaluators Provides up-to-date information on new drugs approved by the FDA

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American Health & Drug Benefits

Managed Care Payers and Pharmaceutical Oncology Trends

John Fox, MD, MHA Senior Medical Director Associate Vice President Medical Affairs Priority Health

Alex Jung Principal, Global Strategic Advisory Services Ernst & Young LLP

Omni Shoreham Hotel • Washington, DC TH

ANNUAL CONFERENCE

RSARY VE NI

AGENDA

MAY 4, 2015

7:00 am – 8:00 am

Meet the Experts Breakfast

8:00 am – 8:15 am

Introduction to Conference and Opening Remarks John Fox, MD, MHA, Priority Health Alex Jung, Ernst & Young LLP

8:15 am – 9:00 am

Session 1 - The Emerging Role of Personal Medicine – the Business Case Vince Miller, MD, Foundation Medicine

9:00 am – 9:45 am

Session 2 - Pathways versus Personalized Medicine – Never the Twain Shall Meet Michael Kolodziej, MD, Aetna

9:45 am – 10:00 am

Break

10:00 am – 10:45 am

Session 3 - The CMMI Multipayer Oncology Care Model Heidi Schumacher, MD, CMMI

10:45 am – 11:30 am

Session 4 - Practice Accreditation as Oncology Medical Homes Ted Okon, Community Oncology Alliance (Invited) David Eagle, Community Oncology Alliance (Invited)

11:30 am – 12:15 pm

12:15 pm – 1:15 pm

Session 5 - How to Measure Quality in Cancer Michael Kolodziej, MD, Aetna Heidi Schumacher, MD, CMMI David Eagle, Community Oncology Alliance (Invited) Ted Okon, Community Oncology Alliance (Invited) Lunch Presentation - Financial Toxicity Speaker TBD

1:15 pm – 2:00 pm

Session 6 - Keynote Session – IMS Oncology Drug Trends Report Doug Long, IMS Health Inc

2:00 pm – 2:45 pm

Session 7 - Pharma and Defining Value in Cancer Care Sanjeev Wadhwa, Biologist/Life Sciences Consultant for R&D

2:45 pm – 3:30 pm

Session 8 - Comparative Effectiveness and Measuring Value of Drug Therapeutic Options in Cancer Care Robert Bilkovski, MD, Abbott Pharmaceuticals

3:30 pm – 4:15 pm

Session 9 - Perspective on the Future of Oncology Drug and Disease Management Grant Lawless, RPh, MD, FACP, University of Southern California

4:15 pm – 5:00 pm

Session 10 - Limited Distribution Oncology Drug Networks and the Value of Controlled Distribution Alex Jung, Ernst & Young LLP

5:00 pm – 5:45 pm

Session 11 - Specialized Pharmacy and Adding Value of Disease and Patient’s Support in Cancer Care Speaker TBD

5:45 pm – 6:00 pm

Poster Award Q & A

6:00 pm – 6:15 pm

Closing Remarks

6:15 pm – 8:15 pm

Welcome Reception/Exhibit Hall

*Agenda subject to change. AVBCC395_Agenda4Asize021215

AVBCConline.org/conference

PERSPECTIVE

Key Strategic Trends that Impact Healthcare Decision-Making and Stakeholder Roles in the New Marketplace

John Santilli

By John Santilli, MBA, and F. Randy Vogenberg, PhD, RPh

fter the passage of the Affordable Care Act (ACA) in 2010, market changes beyond those already in play began to emerge. Traditional roles, responsibilities, and authority of various healthcare stakeholders could now be tested or altered as a result of some sections of the ACA. One result is that healthcare proÂviders could now share in the savings, take risk, and form relationships that were previously barred or were n Â ebulously forbidden. Among some of the often mentioned trends have been accountable care organizations (ACOs), the formation of large hospital health systems, and the continuation of private insurance coverage by self-funded employers. However, the marketplace had undergone many subtle changes that began before the ACA, which only accelerated after its passage. In fact, one trend is that change has been occurring at a rapid rate throughout the various healthcare stakeholders. Tracking the emerging trends and tracing innovation patterns in the post-ACA marketplace in 2014 has led to the identification of several high-level strategic trends that are or will be increasingly significant. The trends that will increasingly impact multiple healthcare stakeholders over the next few years (through 2018) include: 1. Patients becoming more informed consumers 2. Growth of structured quality measures 3. Revenue-driving consolidation 4. New and alternative provider payment models 5. Specialty drug use driving the cost of care 6. Information technology innovations driving interstakeholder communications. The following discussion details some insights into each of these key market trends that impact multiple healthcare

Mr Santilli is Partner, Access Market Intelligence, Greenville, SC; Dr Vogenberg is Partner, Access Market Intelligence, Greenville, SC, Adjunct Professor of Pharmacy Administration, Presbyterian College School of Pharmacy, Clinton, SC, and Adjunct Instructor, Outcomes and Health Policy, University of Illinois at Chicago College of Pharmacy.

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stakeholders and will continue to affect decision-making and relationship dynamics.

Patients as Consumers F. Randy Vogenberg Making More Informed Healthcare Choices The old healthcare model of treating acute illnesses is evolving into a model with increasing focus on the patient, disease prevention, and the ongoing management of chronic diseases. Todayâ&#x20AC;&#x2122;s healthcare market allows consumers to take charge of their healthcare in a new way. Readily accessible data and information allow patients to have open dialogues with their doctors about diagnosis and treatment options. Cost estimators increasingly help consumers understand the intersection of cost and quality in assessing their care options. Market exchanges for health insurance let people choose from a large variety of insurance coverage plans and options. A movement toward personalized health treatment is also developing through the advancement of genetic, behavioral, and digital tools that are designed to monitor and manage personal health. Health insurance products and benefit structures that increase consumerism are helping to manage benefit costs. With the increased financial responsibility, consumers are reevaluating how and when to spend on healthcare services. The 2014 Employee Benefit Research Institute/ Greenwald & Associates Consumer Engagement in Health Care Survey found that 26 million individuals with private insurance were enrolled in a consumer-directed health plan (CDHP), a health plan associated with a health savings account (HSA) or health reimbursement arrangement (HRA), or an HSA-eligible health plan.1 This study found evidence that adults in a CDHP and those in a high-deductible health plan were more likely to exhibit cost-conscious behaviors than adults in a traditional plan. Specifically, CDHP members were more likely to say that they had checked whether the plan would cover care, had asked for a generic drug instead of a brand-name drug, had talked to their doctors about pre-

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PERSPECTIVE

scription options and costs, had checked the price of a service before getting care, had asked a doctor to recommend less costly prescriptions, had talked to their doctors about other treatment options and costs, had developed a budget to manage healthcare expenses, and had used an online cost-tracking tool provided by the health plan. Changes in the healthcare marketplace going forward are requiring patients to spend more of their own money on their medications. They are no longer uninvolved players in the selection of treatment and the use of drugs or health services. The pharmaceutical industry is discovering that it is important to understand the behavior of its consumers if it wants to meet sales expectations. Drug manufacturers can no longer expect to have commercial success by simply proving that their drugs meet the established measures of safety and efficacy with traditional clinical customers (ie, providers). Manufacturers must now understand consumer behaviors if they want to meet the increasing demands of patient expectations. One area in particular that already has become more expensive for consumers is specialty medications, which treat complex conditions. It is anticipated that 2014 prescription abandonment rates will continue to rise through 2015, along with the growth of middle-class wage earners who are facing high-deductible plans. Similarly, health systems will continue to struggle with balancing decreasing insurance and/or direct patient-related revenues against the growing cost of diagnostics, drugs, and imaging.

Growth of Quality Measures Increases, Becoming More Structured Reported by many sources since 2010, the United States spends more on healthcare than any other industrialized country; however, the US healthcare system is not better, and its quality is inconsistent. One reason for this is that the healthcare system is primarily fee for service (FFS), in which providers receive payment for each service rendered, leading to incentives to provide more, not better, services. The federal government implemented the National Quality Strategy in March 2011 to increase the quality of healthcare and to decrease its cost. Quality measures are increasingly being used to determine how much providers will be paid. Mounting evidence shows that leadership engagement positively impacts healthcare quality. Several organizations develop and evaluate quality measures, and an even larger number of public- and private-sector organizations use different measures for evaluating and reporting on the performance of providers. Public measure developers include the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality; nonprofit private developers

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include The Joint Commission and the National Committee for Quality Assurance. These organizations use a transparent approach to give the public an opportunity to review and comment on their draft measures, to refuse to use proprietary measures, and to make their measure-scoring mechanisms transparent. Private sectorâ&#x20AC;&#x201C;focused organizations, such as the Leapfrog Group and the National Business Coalition on Health, focus on commercial plan sponsor needs to measure successful plan performance, including quality. Like their public-sector colleagues, these groups operate transparently at the local, regional, and national levels to give real-world data on provider or health plan performance to sponsors and members. These efforts are gaining momentum going into 2015, and have had successes in the market to drive change without publicizing or publishing like public sector agencies. Many health professional societies also develop measures, such as the American Heart Association, the American College of Cardiology, the Society of Thoracic Surgeons, and the American College of Surgeons.2 These societies typically publish and promote their measures along with guidelines through membership and industry supporters. Although there have been successes, failures and lack of significant change have remained issues going back to the use of several preventive measures (eg, the flu vaccine, aspirin, and cardioprotective agents), even in the hospital setting. It is more likely that with shared savings and ACOs in the marketplace, more attention will be placed on compliance with proved clinical solutions or treatment guidelines because of the negative economic implications of not following guidelines. Overall, there is an increasing focus on single measures that are useful across care settings and are more aligned with the entire patient course of disease. Simplifying the large number of similar but different quality measures to more successfully implement change for better clinical and economic outcomes has become a focus going into 2015. The use of quality measures is expanding and increasing the demand for new, innovative care-delivery measures that can deliver desired plan performance by plan sponsors and by patients.

Revenue Pressure Driving Healthcare Stakeholder Consolidation A fundamental shift in healthcare economic risk is taking place, driven by an aging population and the increasing incidence of behaviorally induced chronic conditions. Health systems, which include people, institutions, and resources that deliver healthcare services to meet the health needs of target populations, are evolving with the market and delivery innovations to meet the challenge of managing healthcare risk through a growing

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February 2015

Figure

Self-Funded Commercial Health Plans 60

Proportion of health plans, %

emphasis on primary care, integrated care models, and pay-for-value reimbursement. As operating margins continue to narrow, revenue constraints are becoming a pressing issue for many healthcare organizations. Partially in response, health systems are increasing in scale by engaging in horizontal integration through hospital mergers and acquisitions. Scale could drive more efficiency, could improve the spreading of financial risk across the system, and could reduce operating costs across the enterprise.3 As health systems consolidate and demand bigger price increases, many insurers are under pressure to not increase premiums. A key way for insurers to keep some of the exchange plans affordable is to exclude more expensive doctors and hospitals from the network, so many consumers will have fewer choices when it comes to selecting their doctor or hospital. These narrow networks have become the current response to expensive healthcare, along with forming ACOs or collaborations on sharing risk. Insurers are worried because larger systems have more clout and command higher payments, and they are building alliances of their own. As an example, Memorial Hermann Physician Network and Blue Cross Blue Shield of Texas are developing an ACO for 100,000 patients. Memorial Hermann Health System is hedging its bets, because it also has an ACO relationship with Aetna and a medical home model with Humana. This is happening in other states, as well as with a number of insurers across the country. The good news is that these narrower networks will help keep premiums lower, but the unfortunate side effect may be unintended out-of-network bills for patients. Of plans on the exchange, 70% have narrow or ultranarrow networks, with more than 30% of the hospitals in the US metro areas being out of network.4 This will create an increasing number of access problems for consumers, which is an unintended side effect of the ACA. Hospitals and health systems continue to acquire physicians. They have the ability to immediately escalate physician charges to the higher hospital rate, which will likely trigger a rise in health plan spending in the next fiscal year. Hospitals and health systems are making these purchases to gain local market share and to develop monopolies.5 Although some of these payment dynamics will shift again late in 2015 and 2016, the “too big to fail” scenario may prove a valuable lever to use with politicians, because healthcare still remains a local issue. Employers have been increasingly self-insuring, taking on the claims risk that insurers previously held. Even small employers with as few as 50 to 100 employees are switching to this model in the hopes that they can defray costs and manage their employees’ healthcare spending more effectively on their own. The Kaiser Family Foun-

58 56 54 52 50 48 46 44

2010

2012

2013

2014 estimated

2015 estimated

Source: Access Market Intelligence. Data on file; 2014.

dation and Health Research & Educational Trust’s Employer Health Benefits 2013 Annual Survey and Access Market Intelligence analysis of commercial trends shows that there were 89.1 million fully insured commercial health plan members in 2008, which decreased to 68.8 million members in 2013. At the same time, the number of self-funded commercial health plans increased to nearly 60% of plans (Figure).6

New and Alternative Provider Payment Models New provider payment models are emerging as increased cost pressures are driving payment models away from FFS approaches to those that better align incentives for cost control and high-quality delivery of patient care. In the next 2 to 5 years, the shift from FFS to value- based reimbursement will be even more dramatic. According to a 2013 Wolters Kluwer Health Survey, 9 of 10 physicians cited shifting reimbursement models and the financial management of practices as their top challenges.7 Competition among providers and increasing pressure from public and commercial payers to lower costs and to improve care are driving them away from long-standing volume-based healthcare models and toward value-based care models. These models seek to more fully align payment and objective measures of clinical quality. The concept of pay for performance (P4P) emerged as a more popular tactic for aligning provider payment with value. Under the typical P4P model, financial incentives or disincentives are tied to measured performance; they may also involve performance thresholds, improvement thresholds, or relative performance cutoffs. The bundled payment or episode-of-care model provides a single negotiated payment for all services for a specified procedure or condition, such as pregnancy and birth, knee and hip replacement surgery, and certain cardiac procedures.

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American Health & Drug Benefits

PERSPECTIVE

As a primary care–driven initiative, the medical home focuses on building a team of professionals, such as physicians, registered nurse case managers, medical assistants, and in some cases, pharmacists, that is responsible for coordinating the care of patients across the healthcare continuum. Shared-savings arrangements represent a potentially higher level of reward for providers. Although per-member per-month payments and FFS rate increases generally cover only the added infrastructure and staff resources, shared savings can be an enticing incentive because providers who offer patient-centered medical homes are often challenged to maintain their previous productivity levels.

Only approximately 4% of patients use specialty drugs, but those drugs account for 25% of the total US drug spending. Often combined with FFS, P4P, bundled payments, global payments, or capitation, shared-savings programs reward providers who reduce their total healthcare spending on patients below an expected level set by the payer. The provider is then entitled to a share of the savings. Shared-risk models could be described as the “next level” of risk arrangement that will be seen in the market, under which providers receive performance-based incentives to share cost-savings combined with disincentives to share the excess costs of healthcare delivery. Expect 2015-2017 to be a period of continued risk experimentation, especially in private-sector commercial insurance arrangements. Although these new models have the potential to encourage care coordination, improve quality, and control costs, there are many challenges in implementing them. Many of the new models are being implemented by adjusting the FFS payment rather than replacing it, and their potential to be truly transformative may be limited. The success of new payment models will depend in part on identifying and incorporating lessons learned by early adopters.8

Specialty Drug Use Is Driving the Cost of Care Trend Innovations in biologics and so-called specialty drugs are beginning to enter the market at a more rapid pace as the research pipeline continues to grow. Only approximately 4% of patients use specialty drugs, but those drugs account for 25% of the total US drug spending.9 The current trends in increased utilization and spending for specialty drugs are expected to continue, placing burdens on all healthcare stakeholders. In particular, insurers or other third-party payers and manufacturers will be challenged to develop novel approaches to for-

American Health & Drug Benefits

mulary design and pricing practices that ensure patient access. Diagnostics, drugs, and devices continue to drive the overall care spending. In the short term, in the midst of uncertainty regarding the biosimilars market and the rapid innovation in personalized medicine beyond 2015, plans and pharmacy benefit managers will continue to focus on unit cost-savings. The longer-term impact of the current trends is now being recognized by commercial and self-funded plan sponsors, along with how best to manage the economic risk over time. This issue alone could change the structure of insurance product offerings and consumer coverage by 2017. At the same time, these trends are affecting pharmacy practice. Specialty pharmacy is transforming from a drug distribution model to an integrated system that coordinates many aspects of patient care, enabling health plans to manage populations across all benefits and distribution channels. In parallel, the emergence of personalized medicine is revolutionizing the treatment paradigm for a growing number of disease states. As a result, there is a need for a sophisticated understanding of treatment plans and pathways, a need that can be filled by specialty pharmacy programs. This also changes relationships across stakeholders as roles shift, blend, or change from traditional practices in the next few years. With the increasing availability of tools and mobile applications, new avenues for patient engagement and new healthcare delivery roles are emerging or are rapidly changing. The location of care is shifting from the hospital to the home, and the focus on improving patient health and well-being is increasingly becoming a community-wide effort. Technology and computing trends are quickly embraced by younger consumers, as well as by new-age wellness providers who assist older populations in making decisions about their healthcare options. The improved access to information, including cost, has been identified as a “game changer” that will affect all care provider roles through the end of this decade. Because infused drug therapies can be administered in a hospital, physician’s office, infusion center, or even in the patient’s home, costs related to where the drug is administered can vary significantly. For example, the costs for a standard dose of a treatment for rheumatoid arthritis can vary from $3259 for the drug and $148 for administration when infused at the patient’s home to $5393 for the drug and $425 for administration when infused as an outpatient procedure at a hospital. In fact, the hospital setting is typically the least cost-effective site of care for infusions. According to a recent CVS report, infusions are increasingly being done in a hospital setting, where the costs for the drug and its administration can be the highest of all potential sites of care.10 As previously mentioned, this is

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unlikely to continue in the long-term, and the market will drive other behaviors by providers or systems through altered revenue dynamics. We have already seen this phenomenon with diagnosis-related groups, ambulatory visit groups, and Surgical Care Improvement Project payments to hospitals, to name a few. Newer oral and self-injected drugs will also be changing the costs that are associated with the site of care.

Information Technology Innovations Drive Interstakeholder Communications Innovations in computing and big data services are changing the way health information is recorded and delivered between patients and providers. Electronic health records (EHRs) and electronic medical records (EMRs), clinical documentation tools, and telemedicine devices are changing the way that providers collect and consume health information regarding their patients. US physicians and consumers are increasingly ready to embrace a dramatic expansion of the “high-tech” personal medical kit. Wearable technology, smartphone-linked devices, and mobile applications will become increasingly valuable in the delivery of care. A proliferation of approved and portable medical devices in patients’ homes and on their phones makes diagnosis and treatment more convenient, redoubling the need for strong information security systems.11 Electronic activity monitors (also known as trackers or wearables) are quickly gaining popularity with consumers for tracking physical activity, heart rate, sleep patterns, calorie consumption, and more. Companies such as Nike, Fitbit, Jawbone, and Garmin currently offer a range of wearables, with varying features and price points. The Apple Watch, which is expected to launch in 2015, will include the HealthKit software, which collects data from the user’s health and fitness applications for centralized access to health information. It is estimated that between 10% and 15% of consumers in the United States own wearables, with 61% of those devices being activity trackers.12 Start-up companies that offer applications for iPhones or Android devices are proliferating in healthcare. Providing a new solution or a new approach to managing a disease (eg, diabetes or asthma), and integrating general wellness with the early management of a disease or condition (eg, heart disease, high cholesterol) are primed areas for growth in the next few years. This is a result of the consumer adoption of the technologies, as well as investment in information technology applications for healthcare by angel investors or venture capital groups. Privacy, despite HIPAA/HITEC violation concerns, will lose ground to convenience in 2015, as patients

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adopt digital tools and services that gather and analyze health information. Although numerous positive applications of these electronic activity monitors exist, there is always the possibility for unintended adverse consequences or ethical dilemmas. The potential for the sharing of global positioning system location data and personal health information produces clear privacy concerns. Surveillance of the collected data by healthcare providers may also lead to situations where intervention is deemed ethically necessary. Clear protocols will be necessary to guide provider behavior in such cases and to reduce the risks associated with potential privacy breaches.13 The application of data and analytics to patient care provides novel opportunities for improving care effectiveness and efficiency. Still, the full potential for data-driven insights to revolutionize care is hampered by the current data input and output limitations of medical record systems, the lack of a robust business model for interoperable data exchange across organizations, and broader organizational barriers that require coordinated solutions across stakeholders. Addressing those barriers and alternative revenue for a sustainable solution has become an increased focus of attention for many investors and public health advocates alike. This trend will likely intensify during the next couple of years to be in place when EMR and EHR software selections are finalized.

The application of data and analytics to patient care provides novel opportunities for improving care effectiveness and efficiency. Still, the full potential for data-driven insights to revolutionize care is hampered by the current data input and output limitations of medical record systems. The Medicare and Medicaid Electronic Health Care Record Incentive Programs provide incentive payments to eligible professionals, eligible hospitals, and critical access hospitals as they adopt, implement, upgrade, or demonstrate meaningful use of certified EHR technology. In 2013, 59% of hospitals have adopted at least a basic EHR system. This represents an increase of 34% from 2012 to 2013 and a 5-fold increase since 2008. In 2013, 93% of hospitals possessed certified EHR technology, increasing by 29% since 2011.14 Information technology is an area within healthcare that clearly crosses many disciplines while offering some of the greatest return on investment for healthcare delivery solution implementation. Chief information officers and

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their chief medical officers in systems and plans are very focused on finalizing the implementation of EMRs, at the same time that employer plan sponsors are seeking access to that information in real time. Patients are now jockeying for a seat at the table, because there is a light at the end of the information technology tunnel in this decade. Going forward, new technologies will more quickly empower patients and providers to enhance practices for managing and coordinating healthcare. The effective widespread use of new technology tools may require increased data transparency, patient education, and the coordination of tools across the growing range of technology options.

Personal or business consequences related to these trends will be important for all stakeholders to remain aware of and to prepare for their impact. Individual stakeholders will have to innovate or adapt to these trends, and understand their impact on clinical care decision-making. Conclusion Change and the more rapid, broad-based effect of change have impacted all healthcare stakeholders since 2010 and the passage of healthcare reform in the United States. Although many early changes in the healthcare market have been widely published, trends that are tracing locally early or are still emerging nationally need to be identified to better prepare for success in the healthcare market. High-level trends identified here will impact healthcare roles and decision-making. These trends have the ability to continue the market transformation and to impact relationships among multiple stakeholders. Personal or business consequences related to these trends will be important for all stakeholders to remain aware of and to prepare for their impact. Individual stakeholders will have to innovate or adapt to these trends, and understand their impact on clinical care decision-making. The clinical care decisions that are increasingly shared among the various stakeholders will have to bal-

American Health & Drug Benefits

ance the economic and the clinical consequences among stakeholders. Already occurring in oncology care, this new reality cannot be avoided, and change is difficult. Being aware of tracing early, as well as of emerging trends, can assist each healthcare stakeholder to be better prepared and can drive innovation that could alter an adverse movement of a trend. n Author Disclosure Statement Mr Santilli and Dr Vogenberg reported no conflicts of interest.

References

1. Fronstin P, Elmlinger A. Findings from the 2014 EBRI/Greenwald & Associates Consumer Engagement in Health Care Survey. Employee Benefit Research Institute. December 2014; Issue Brief 407. www.ebri.org/pdf/briefspdf/EBRI_IB_407_Dec14. CEHCS.pdf. Accessed January 29, 2015. 2. Robert Wood Johnson Foundation, Urban Institute. Achieving the potential of health care performance measures. May 2013. www.urban.org/UploadedPDF/412823Achieving-the-Potential-of-Health-Care-Performance-Measures.pdf. Accessed January 29, 2015. 3. Healthcare Financial Management Association. Acquisition and Affiliation Strategies. June 2014. www.hfma.org/WorkArea/DownloadAsset.aspx?id=23451. Accessed January 29, 2015. 4. MDeverywhere. McKinsey: study on the impact of narrow networks on exchange plans. MDe Insights. June 18, 2014. www.mdeverywhere.com/mckinsey-study-onthe-impact-of-narrow-networks-on-exchange-plans/. Accessed February 1, 2015. 5. Evans M. Consolidation creating giant hospital systems. Modern Healthcare. June 21, 2014. www.modernhealthcare.com/article/20140621/MAGAZINE/306219980. Accessed February 1, 2015. 6. Access Market Intelligence. Data on file. 2014. 7. Ritchie A, Marbury D, Verdon DR, et al. Shifting reimbursement models: the risks and rewards for primary care. Medical Economics. April 8, 2014. http://medicaleco nomics.modernmedicine.com/medical-economics/content/tags/aca/shifting-reimburse ment-models-risks-and-rewards-primary-care?page=full. Accessed January 29, 2015. 8. AcademyHealth. Research insights: new models to pay for health care. August 2013. www.academyhealth.org/files/FileDownloads/AH_RI%202013%20New%20 Models.pdf. Accessed January 29, 2015. 9. Health Research Institute. Medical cost trend: behind the numbers 2015. PricewaterhouseCoopers; June 2014. http://pwchealth.com/cgi-local/hregister.cgi/reg/pwchri-medical-cost-trend-2015.pdf. Accessed January 29, 2015. 10. CVS Caremark. Specialty Trend Management: Where to go next. Insights 2013. www.cvshealth.com/sites/default/files/Insights%202013.pdf. Accessed January 29, 2015. 11. Health Research Institute. Top health industry issues of 2015: outlines of a market emerge. PricewaterhouseCoopers. December 2014. www.pwc.com/en_US/us/ health-industries/top-health-industry-issues/assets/pwc-hri-top-healthcare-issues-2015. pdf. Accessed January 29, 2015. 12. Nielsen. Hacking health: how consumers use smartphones and wearable tech to track their health. April 16, 2014. www.nielsen.com/us/en/insights/news/2014/hacking- health-how-consumers-use-smartphones-and-wearable-tech-to-track-their-health.html. Accessed January 29, 2015. 13. Lyons EJ, Lewis ZH, Mayrsohn BG, Rowland JL. Behavior change techniques implemented in electronic lifestyle activity monitors: a systematic content analysis. J Med Internet Res. 2014;16:e192. 14. Office of the National Coordinator for Health Information Technology. Adoption of electronic health record systems among U.S. non-federal acute care hospitals: 2008-2013. Data brief. No.16; May 2014. www.healthit.gov/sites/default/files/oncdata brief16.pdf. Accessed January 29, 2015.

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February 2015

Vol 8, No 1

Oncology Providers Practice and Personalized Medicine Trends

Barbara L. McAneny, MD Chair, Board of Trustees American Medical Association

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center

Omni Shoreham Hotel • Washington, DC TH

ANNUAL CONFERENCE

RSARY VE NI

AGENDA

MAY 5, 2015

7:00 am – 8:00 am

Meet the Experts Breakfast

8:00 am – 8:15 am

Introduction and Opening Remarks Barbara L. McAneny, MD, American Medical Association Sanjiv S. Agarwala, MD, Temple University School of Medicine

8:15 am – 9:15 am

Session 1 - Win-Win-Win Approaches to Oncology Care: How Providers, Patients, and Payers Can All Benefit from Improving the Way We Pay for Cancer Treatment Harold Miller, Center for Healthcare Quality and Payment Reform

1:15 pm – 2:00 pm

Session 6 - Keynote Session Value-Based Cancer Care: How Do We Get There in the ’Omics Era? Gary Palmer, MD, JD, MBA, MPH, Nanthealth

2:00 pm – 2:45 pm

Session 7 - Can We Afford Personalized Medicine? Michael Kolodziej, MD, Aetna

2:45 pm – 3:30 pm

Session 8 - The Precision Medicine Initiative: Deliverables from Those on the Front Lines of Personalizing Care Harold Varmus, MD, National Cancer Institute (Invited)

3:30 pm – 4:15 pm

Session 9 - Adapting Regulation to Meet the Needs of the Exponential Growth of the Molecular Testing Era Victoria Pratt, MD (Invited)

4:15 pm – 5:00 pm

Session 10 - Role of Pathologist in the Age of Personalized Medicine Pranil Chandra, DO, PathGroup (Invited)

5:00 pm – 5:45 pm

Session 11 - The Role of Immunotherapy in Personalizing Treatment James Allison, PhD, MD Anderson Cancer Center (Invited)

9:15 am – 10:00 am

Session 2 - Pitfalls or Challenges of New Payment Models Bruce Pyenson, Milliman

10:00 am – 10:15 am

Break

10:15 am – 11:00 am

Session 3 - Oncology Medical Home – A Patient-Centric System for Delivering Quality Cancer Care Barbara L. McAneny, MD, American Medical Association

11:00 am – 11:45 am

Session 4 - FDA on Testing and Personalized Medicine Speaker TBD

11:45 am – 12:15 pm

Session 5 - Revamping Research Raju Kucherlapati, PhD, Harvard Medical School

5:45 pm – 6:00 pm

Poster Award Q & A

12:15 pm – 1:15 pm

Networking Lunch in Exhibit Hall or Sponsored Lunch Presentation

6:00 pm – 6:15 pm

Closing Remarks

6:15 pm – 8:15 pm

Reception in Exhibit Hall

*Agenda subject to change.

AVBCC395_Agenda5Asize021215

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CLINICAL

ORIGINAL RESEARCH

Is Response-Guided Therapy Being Applied in the Clinical Setting? The Hepatitis C Example Jennifer B. Harris, PharmD; Melea A. Ward, PharmD, PhD, BCPS; Phil Schwab, PhD

Stakeholder Perspective, page 28

Am Health Drug Benefits. 2015;8(1):22-28 www.AHDBonline.com Received December 9, 2014 Accepted in final form January 14, 2015

Disclosures are at end of text

BACKGROUND: Response-guided therapy (RGT) is a treatment model that bases adjustments to therapeutic regimens on individualized patient physiologic response. This approach is applied to patients with chronic hepatitis C virus (HCV) infection who are treated with a triple therapy regimen of boceprevir or telaprevir in combination with pegylated interferon and ribavirin. As RGT expands in other pharmacologic regimens, including the treatment of breast cancer and acute myeloid leukemia, a measurement of how this approach is applied in clinical practice is important to determine whether the benefits of RGT are being optimized. OBJECTIVE: To measure adherence to the RGT guidelines and to the treatment futility rules based on the drug labeling information for boceprevir and for telaprevir in the treatment of patients with chronic HCV infection. METHODS: A retrospective observational cohort study was conducted using the large Humana research database, which includes pharmacy, medical, and laboratory claims, as well as enrollment data for more than 1.5 million fully insured commercial members, 1.9 million Medicare Advantage members, and 2.4 million Medicare Part D members from all 50 states. The study population included patients aged ≥18 years to <90 years who were fully insured with commercial or Medicare Advantage coverage. A pharmacy claim for boceprevir or telaprevir was used to identify patients receiving triple therapy for HCV infection. Medical, pharmacy, and laboratory claims were reviewed from the date of the first boceprevir or telaprevir pharmacy claim between May 2011 and February 2012 through a 32-week follow-up period, during which patients were required to have continuous health plan enrollment eligibility. This time period allowed for the occurrences of required HCV RNA laboratory monitoring and the assessment of treatment patterns. The use of RGT for boceprevir and telaprevir includes the monitoring of HCV RNA levels at routine intervals to determine how to proceed with therapy. Adherence to HCV RNA monitoring was measured as the proportion of eligible patients who had an HCV RNA assay at each of the recommended time intervals. According to futility rules, patients with greater-than-expected HCV RNA levels are deemed to be nonresponders and should discontinue therapy. Adherence to futility rules was measured as the proportion of patients who stopped therapy among all patients who had an HCV RNA result, which indicated treatment futility at each monitoring interval. RESULTS: A total of 326 patients (65 in the boceprevir group; 261 in the telaprevir group) were eligible for the HCV RNA monitoring analysis, and 134 patients (20 receiving boceprevir and 114 receiving telaprevir) were eligible for the futility rules analysis. There were 1203 HCV RNA assays during the follow-up period. The percentage of patients who were adherent to HCV RNA monitoring during the entire treatment period was 29.2% in the boceprevir group and 32.2% in the telaprevir group. In both treatment groups, adherence to HCV RNA monitoring was highest at the first recommended time interval, followed by a downward trend in the second and third time intervals. Approximately 15% of 134 eligible patients met the futility rules for stopping therapy based on HCV RNA assay results, and 55% of those patients stopped the therapy in accordance with the treatment futility rules. CONCLUSION: The implementation of RGT was suboptimal in this population of patients with chronic HCV infection; adherence to HCV RNA monitoring guidelines was less than 33%, and adherence to treatment futility rules was less than 50%. Managed care pharmacists should identify strategies to increase the adoption of RGT, which may, in turn, improve patient care and reduce unnecessary expenditures. KEY WORDS: response-guided therapy, hepatitis C virus, boceprevir, telaprevir, pegylated interferon, RNA assay

Dr Harris is Clinical Pharmacist, Humana Inc, Louisville, KY; Dr Ward was Clinical Pharmacist, Humana, Inc, Louisville, KY, at the time this work was completed; Dr Schwab is Research Lead, Comprehensive Health Insights, Humana Inc, Louisville, KY.

American Health & Drug Benefits

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February 2015

Vol 8, No 1

Is Response-Guided Therapy Being Applied in the Clinical Setting?

esponse-guided therapy (RGT) is a treatment paradigm that bases adjustments to therapeutic regimens on individualized patient physiologic response. Depending on a patient’s measured response to a drug, dosing may need to be adjusted accordingly or the therapy may need to be stopped altogether if the continuation of that treatment is deemed futile. As personalized medicine and waste reduction become mainstays of drug therapy, RGT is progressively being utilized in pharmacologic regimens for diseases such as breast cancer and acute myeloid leukemia. The implementation of an RGT approach to drug therapy has been used with boceprevir and telaprevir, and is being investigated with simeprevir in the treatment and management of chronic hepatitis C caused by persistent hepatitis C virus (HCV) infection.1 An understanding of how RGT is being applied in clinical practice is paramount for realizing the potential benefits of the approach. In 2011, boceprevir and telaprevir, each in combination with pegylated interferon and ribavirin, became first-line recommended treatments for HCV genotype 1a,2 based on clinical trials demonstrating an increase in sustained virologic response of approximately 40% to 50% with the combination of pegylated interferon and ribavirin,3-5 to upwards of approximately 65% to 75% with the triple therapy regimen.6-9 Sustained virologic response is defined as an undetectable HCV viral load, typically measured 24 weeks after the completion of treatment, an end point that is associated with the longterm clearance of HCV, improved morbidity, and improved mortality.10-12 In late 2013, the US Food and Drug Administration (FDA) approved sofosbuvir and simeprevir for the treatment of patients with HCV.13,14 Clinical trials with sofosbuvir suggested that 80% to 90% of patients should have undetectable virus levels 12 weeks after completing treatment.15 Clinical trials with simeprevir showed similar results, with almost 80% of patients showing undetectable HCV RNA levels after 12 weeks.16 Accordingly, in 2014, the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America released treatment guidelines recommending sofosbuvir for all patients with HCV, except those with severe renal impairment.17 Two additional drugs were approved by the FDA in 2014 for the treatment of HCV infection— the combination of ledipasvir and sofosbuvir, and the combination of ombitasvir, paritaprevir, and ritonavir plus dasabuvir.18,19 In the short term, the utilization of older agents may continue at some level, because of individual patient needs and the cost of newer therapies, among other factors.20 As health plans, pharmacy benefit managers, and other payers continue to define their clinical protocols in the

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February 2015

KEY POINTS Response-guided therapy (RGT) adjusts pharmacologic regimens based on an individual patient’s physiologic response ➤ The benefits of RGT include improved clinical outcomes, reduced unnecessary drug exposure for the patient, and the avoidance of unnecessary costs ➤ This study investigated adherence to HCV RNA monitoring guidelines, using a large database for a commercial- and Medicare-insured population ➤ HCV RNA monitoring guidelines were followed in 1 of 3 patients, and adherence to treatment futility rules was less than 55% in patients with HCV infection ➤ This finding highlights the need for the improved implementation of RGT guidelines, which are increasingly being used in specialty pharmacy therapeutics for different conditions, including breast cancer and acute myeloid leukemia ➤ Strategies that increase the use of RGT may in turn improve patient care and reduce unnecessary healthcare expenditures ➤

rapidly changing environment of hepatitis C, and as RGT is used increasingly in other therapeutic areas, an evaluation of the adherence to RGT in the clinical management of HCV is necessary. This study measured adherence to the RGT guidelines and treatment futility rules for patients with chronic HCV based on the product labeling information for boceprevir and for telaprevir.21,22

Methods Data Source The retrospective observational cohort study was conducted using the Humana research database, which included pharmacy claims, medical claims, laboratory claims, and enrollment data for more than 1.5 million fully insured commercial members, 1.9 million Medicare Advantage members, and 2.4 million Medicare Part D members from all 50 states at the time of the study. The study sample was restricted to members with complete medical and pharmacy claims in the fully insured commercial and Medicare Advantage coverage categories. Pharmacy claims data contained adjudication information for prescription medications, including drug name, dosage, quantity, days’ supply, and date of prescription fill. The medical claims data included up to 9 International Classification of Diseases, Ninth Revision, Clinical Modification codes for all inpatient and outpatient encounters. Medical claims data also included Current Procedural Terminology (CPT) codes, which were used in this study

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American Health & Drug Benefits

CLINICAL

Figure 1 Study Design Enrollment period

Follow-up period

May 1, 2011-February 17, 2012

32 weeks of continuous enrollment

Index date: first pharmacy claim for boceprevir or telaprevir

Figure 2 Sample Selection Patients with ≥1 pharmacy claim for boceprevir (N = 70) or telaprevir (N = 301) Total: 371 patients

HCV RNA monitoring analysis Boceprevir (N = 65) or telaprevir (N = 261) Total: 326 patients

Futility rules analysis Boceprevir (N = 20) or telaprevir (N = 114) Total: 134 patients

— Excluded patients because of age requirement: boceprevir = 0, telaprevir = 0 — Excluded patients because of continuous eligibility requirement: boceprevir = 5, telaprevir = 40

— Excluded patients with no laboratory results data: boceprevir = 26, telaprevir = 87 — Excluded patients whose assays were not in the appropriate time frame: boceprevir = 19, telaprevir = 60

HCV RNA indicates hepatitis C virus ribonucleic acid.

to identify HCV RNA viral load laboratory tests. Data from laboratory results were available for a subset of members and included Logical Observation Identifiers Names and Codes to identify laboratory results. Enrollment data contained information on demographics and coverage start and end dates. The study protocol was approved by Schulman Associates IRB’s Institutional Review Board under a minimal risk review.

Sample Selection Patients aged ≥18 years to <90 years with a pharmacy claim for boceprevir or telaprevir were identified for the study sample. Age was assessed at the date of the first pharmacy claim for boceprevir or telaprevir. A medical diagnosis for hepatitis C was not required for inclusion, because boceprevir and telaprevir have no FDA-approved indications other than for hepatitis C. Patients were required to have 32 weeks of health plan enrollment after the first claim for boceprevir or telaprevir based on

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the recommended duration of therapy (Figure 1). The date of the first pharmacy claim for boceprevir or telaprevir during the enrollment period was defined as the index date. The patients’ claims were observed for the period starting at the index date through 32 weeks after the index date, during which they were required to have continuous eligibility. The 32-week follow-up period allowed for the required HCV RNA laboratory monitoring to occur and for treatment patterns to be assessed.

RGT Outcomes and Analyses RGT with boceprevir and telaprevir includes the monitoring of HCV RNA levels at routine intervals to determine how to proceed with drug therapy. Patients are deemed to be an early responder if their HCV RNA levels, which are measured fairly soon after initiating treatment, are undetectable. Early responders should have a shorter duration of therapy to prevent unnecessary drug exposure. On the contrary, patients with greater-than-expected levels of HCV RNA measured soon after initiating therapy, or later, are deemed to be nonresponders and should discontinue therapy according to the futility rules. Applying the futility rules reduces unnecessary drug exposure and minimizes the development of drug resistance for patients who have little chance of achieving a sustained virologic response. HCV RNA monitoring. Adherence to the recommended HCV RNA monitoring was measured as the proportion of eligible patients who had an HCV RNA assay at each of the recommended time intervals of 8, 12, and 24 weeks for boceprevir, and 4, 12, and 24 weeks for telaprevir. For RGT, because some patients do not complete a full course of therapy, a given patient will require 1, 2, or 3 assays depending on his or her length of treatment. To account for this, adherence was measured as the number of patients who had an assay taken from the number of eligible patients at a given interval, where the number of eligible patients changed at each interval. The number of eligible patients for each interval was determined by using the amount of prescription fills for each medication as a proxy. HCV RNA assays were required to be on the guideline-specified date (based on the index date) or up to 21 days after that date to be classified as adherent. The 21-day buffer allowed for scheduling flexibility encountered in real-world clinical practice. The category I and category II CPT codes that were used to identify the HCV RNA assays included 3220F, 3265F, 87520, 87521, and 87522. Treatment futility rules. An assessment of adherence to the futility rules was conducted among a subset of patients with laboratory results data and whose HCV RNA assays were drawn in the recommended time

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February 2015

Vol 8, No 1

Is Response-Guided Therapy Being Applied in the Clinical Setting?

frames (as defined in the HCV RNA monitoring analysis). Adherence to futility rules was measured as the proportion of patients who correctly stopped therapy among all patients who had an HCV RNA result that indicated treatment futility at each monitoring interval. A patient was determined to have stopped therapy if there were no additional pharmacy claims for HCV therapy after the laboratory date where futility was determined. The Logical Observation Identifiers Names and Codes that were used to identify HCV RNA assay results included 5010-4, 5011-2, 5012-0, 11259-9, 38998-1, 48576-3, 51655-9, 53825-6, and 59052-1.

ample Characteristics of an HCV RNA Monitoring Table 1 S Analysis Population Boceprevir Telaprevir Characteristic N = 65 N = 261

Results Sample Characteristics A total of 326 patients were included in the HCV RNA monitoring analysis, 65 receiving boceprevir and 261 receiving telaprevir; of these, 134 patients were included in the futility rules analysis, including 20 patients in the boceprevir group and 114 in the telaprevir group (Figure 2). The study sample of 326 patients was primarily male (63.2%), insured by Medicare (66.5%), and treated by a gastroenterologist (52.4%). Table 1 lists the characteristics of the study population. These characteristics were similar in patients receiving boceprevir and in patients receiving telaprevir. Patient out-of-pocket (OOP) costs per prescription were higher in the telaprevir treatment group than in the boceprevir treatment group. The range of OOP costs in both groups was wide, because OOP costs vary by plan benefit design. HCV RNA Monitoring There were 1203 HCV RNA assays during the follow-up period among the 326 patients included in the study sample. The mean number of assays was 3.69, with a range of 0 to 26 assays per patient. In the individual patient-level analysis, 19 (29.2%) of the 65 patients in the boceprevir group and 84 (32.2%) of the 261 patients in the telaprevir group were adherent throughout their entire treatment period (data not shown). Adherence to HCV RNA monitoring was highest at the first recommended time interval for the boceprevir (66.2% at 8 weeks) and telaprevir (61.7% at 4 weeks) groups (Table 2). There was a downward trend in adherence at the second and third time intervals in both groups. Treatment Futility Rules Of the 134 patients eligible for this analysis, 20 met the futility rules for stopping therapy based on the HCV RNA assay results. Of those 20 patients, 11 (55%) stopped therapy in accordance with the treatment futility rules (Table 3). Therapy was continued in 9 people,

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February 2015

Male, N (%)

40 (64.5)

166 (63.6)

Mean age, yrs (SD)

57.5 (8.0)

55.9 (7.5)

Insurance type, N (%) Commercial Medicare

21 (32.3) 44 (67.7)

88 (33.7) 173 (66.3)

Patient OOP cost per prescription Mean, $ (SD) Range, $

553 (704) 0-3314

1296 (1336) 0-5073

Provider type, N (%) Gastroenterologist All other physician specialties Nonphysiciana Unknown

31 (47.7) 13 (20.0) 12 (18.5) 9 (13.8)

140 (53.6) 33 (12.6) 59 (22.6) 29 (11.1)

Physicianâ&#x20AC;&#x2122;s assistant, nurse practitioner, or pharmacist. HCV RNA indicates hepatitis C virus ribonucleic acid; OOP, out of pocket; SD, standard deviation.

Table 2 HCV RNA Monitoring Results

Time interval

Eligible patients, N

Assays, N

Eligible patients adherent to HCV RNA monitoring guidelines, %

Boceprevir (N = 65) 8 wks

66.2

12 wks

43.6

24 wks

42.5

4 wks

261

161

61.7

12 wks

205

120

58.5

24 wks

164

41.4

Telaprevir (N = 261)

HCV RNA indicates hepatitis C virus ribonucleic acid.

despite meeting the futility rules. There was a directional trend in improved adherence to treatment futility rules over time.

Discussion In this study, adherence to the RGT guidelines for boceprevir and telaprevir was suboptimal. A breach of these guidelines may contribute to unnecessary drug exposure and to the development of resistant hepatitis C variants. Specifically, we found that adherence to HCV RNA monitoring during the entire treatment period was 29.2% in the boceprevir group and 32.2% in the telapre-

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CLINICAL

Table 3 T reatment Futility Rule Results Patients Met with HCV futility Time RNA rule, interval Futility rule assay, N N (%)

Appropriately stopped therapy, N (%)

Boceprevir (N = 20) 8 wks

No futility rule

12 wks

Stop treatment if HCV RNA is â&#x2030;Ľ100 IU/mL

5 (25.0)

2 (40)

24 wks

Stop treatment if HCV RNA is detectable

1 (8.3)

1 (100)

Telaprevir (N = 114) 4 wks

Stop treatment if HCV RNA is >1000 IU/mL

114

2 (1.7)

0 (0)

12 wks

Stop treatment if HCV RNA is >1000 IU/mL

4 (4.5)

2 (50)

24 wks

Stop treatment if HCV RNA is detectable

8 (15.7)

6 (75)

HCV RNA indicates hepatitis C virus ribonucleic acid.

vir group. There was a mean of 3.69 assays per patient, with a range of 0 to 26, indicating that patients are getting excess assays, and some patients may not be getting them within the recommended time frames. To our knowledge, the clinical implications on sustained virologic response or the financial impact of laboratory tests drawn outside of the recommended time frames have not been reported in the literature. In addition, we identified 134 patients for the futility rules analysis, of which 20 (14.9%) met the stopping criteria based on HCV RNA laboratory values. The treatment failure rate of 14.9% was similar to the rates reported for boceprevir (8%-17%) and telaprevir (8%13%) in clinical trials.6,8 Although the size of the sample in our study was small, 45% of the patients who met the futility rule continued therapy. Continuing treatment when the patient is not clearing the virus not only imparts needless risk to the patient, but it also contributes to an unnecessary cost to the patient and to unjustified costs to the healthcare system. To illustrate this point, if a patient were to fail treatment with boceprevir at week 8, but continue therapy for 36 weeks, at a wholesale acquisition cost of $19.90 per unit,23 the unnecessary costs of boceprevir alone would be nearly $47,000. This example estimate would vary based on a number of factors, including the length of treatment, the contracted drug price, and other treatment-related costs. Adjusting therapy according to response is not a new

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concept; this paradigm has been used for several years in areas including anticoagulation, infectious disease, and heart failure. However, the concern of suboptimal adherence to RGT in clinical practice is increasingly relevant, because this approach is being used for specialty pharmacy therapeutics. For example, a phase 3 trial of response-guided neoadjuvant chemotherapy in early-stage breast cancer found a higher rate of disease-free survival (hazard ratio, 0.78; 95% confidence interval, 0.62-0.97) and an exploratory analysis trended toward improved overall survival compared with conventional therapy.24 Similarly, response-guided induction therapy in pediatric acute myeloid leukemia has been shown to increase remission rates.25 In addition, a randomized phase 3 study showed early response using dose-intensive response-based chemotherapy and radiation in pediatric patients with intermediate-risk Hodgkin lymphoma.26 Stopping therapy appropriately when futility rules are met is also important. Given the adverse clinical risks and economic consequences of extending treatment without a clinical benefit, all stakeholders in the healthcare ecosystem must collaborate to effectively implement RGT. One approach is for payers to modify prior authorization criteria to ensure compliance. Prior authorizations for drug therapy are frequently given for a year of treatment, but a prior authorization requiring documentation of assays and results during the year of treatment could result in better adherence to RGT, reducing drug exposure to the patient and saving costs. Because prior authorizations have time and financial impacts and are onerous on both the physician and the health plan, the administrative burden must be considered in the context of the potential benefit to the patient for any proposed utilization management tactics using RGT.

Limitations The study population was derived from only one payerâ&#x20AC;&#x2122;s membership and, although the sample included commercial and Medicare Advantage members from all 50 states, the membership is concentrated in the Southeast and Midwest regions of the United States. Accordingly, our findings may not be reflective of the entire US population. Although the availability of laboratory data in the data set allowed for a sufficient cohort, the sample of patients who could be evaluated for adherence to futility rules was small, and further study should seek to validate the trends that were observed. Although the results of this study are important for understanding adherence to RGT, the treatment landscape for HCV is rapidly evolving with the approval of new drugs and the October 2014 withdrawal of telaprevir from the market. Therefore, these findings have limited applicability in the present HCV practice environment.

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Is Response-Guided Therapy Being Applied in the Clinical Setting?

To measure HCV RNA monitoring, we required that the assay be recorded on day 1 of the recommended time frame or within 21 days after. Our approach may have misclassified some laboratory values as nonadherent if those values occurred earlier than day 1 of the recommended time frame. The guidelines for the management of HCV do not clearly state the RGT criteria, even though the RGT criteria from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America are included in the package inserts of the respective drugs. The lack of specialty society guidelines may contribute to nonadherence with the recommendations. Finally, we used prescription claims data to classify whether a patient had stopped therapy according to the futility rules. Filing a prescription claim does not definitively indicate that a patient consumed the medication, and our results should be interpreted in that context. Conclusion

RGT is a well-established paradigm for drug therapy. In the patients with hepatitis C, however, the implementation of this approach was suboptimal in our study population. Our study is an important contribution to the literature, because there are few data sets containing laboratory results that are large enough to permit an assessment of adherence to futility rules in the management of HCV. Because this approach of guiding drug therapy based on individual patient response is being used increasingly in specialty pharmaceuticals, efforts to improve its uptake may enhance patient care and may also reduce unnecessary expenditures. All members of the patient care team, including payers, are responsible for the optimal implementation of RGT. ■

Author Disclosure Statement Dr Harris and Dr Schwab reported no conflicts of interest; Dr Ward is a former employee of Humana and is currently an employee of GlaxoSmithKline. References

1. MPR. Sustained virologic response with simeprevir for Hepatitis C. May 21, 2013. www.empr.com/sustained-virologic-response-with-simeprevir-for-hepa titis-c/article/294292/. Accessed December 4, 2014. 2. Ghany MG, Nelson DR, Strader DB, et al; for the American Association for the Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444. 3. Manns MP, McHutchison JG, Gordon SC, et al; for the International Hep-

atitis Interventional Therapy Group. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965. 4. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982. 5. Hadziyannis SJ, Sette H Jr, Morgan TR, et al; for the PEGASYS International Study Group. Peginterferon-α2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:346-355. 6. Poordad F, McCone J Jr, Bacon BR, et al; for the SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1195-1206. 7. Bacon BR, Gordon SC, Lawitz E, et al; for the HCV RESPOND-2 Investigators. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364:1207-1217. 8. Jacobson IM, McHutchison JG, Dusheiko G, et al; for the ADVANCE Study Team. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405-2416. 9. Zeuzem S, Andreone P, Pol S, et al; for the REALIZE Study Team. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364:2417-2428. 10. Veldt BJ, Heathcote EJ, Wedemeyer H, et al. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Ann Intern Med. 2007;147:677-684. 11. Bruno S, Crosignani A, Facciotto C, et al. Sustained virologic response prevents the development of esophageal varices in compensated, Child-Pugh class A hepatitis C virus–induced cirrhosis. A 12-year prospective follow-up study. Hepatology. 2010;51:2069-2076. 12. Morgan TR, Ghany MG, Kim H-Y, et al; for the HALT-C Trial Group. Outcome of sustained virological responders with histologically advanced chronic hepatitis C. Hepatology. 2010;52:833-844. 13. Sovaldi (sofosbuvir) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; December 2013. 14. Olysio (simeprevir) capsules [prescribing information]. Titusville, NJ: Janssen Products, LP; November 2013. 15. Lawitz E, Mangia A, Wyles D, et al. Sofosbuvir for previously untreated chronic hepatitis C infection. N Engl J Med. 2013;368:1878-1887. 16. Gurai S. Olysio (simeprevir) price, dosing, side effects, uses. RxEconsult. January 10, 2014. www.rxeconsult.com/healthcare-articles/Olysio-simeprevir- Price-Dosing-Side-Effects-Uses-499/. Accessed August 13, 2014. 17. American Association for the Study of Liver Diseases; Infectious Diseases Society of America; International Antiviral Society–USA. Recommendations for testing, managing, and treating hepatitis C. www.hcvguidelines.org/full- report-view. Accessed January 5, 2014. 18. Harvoni (ledipasvir and sofosbuvir) tablets [prescribing information]. Foster City, CA: Gilead Sciences, Inc; October 2014. 19. Viekira Pak (ombitasvir, paritaprevir, and ritonavir tablets; dasabuvir tablets) [prescribing information]. North Chicago, IL: AbbVie, Inc; December 2014. 20. Leof A, Gerrity M, Thielke A, King V; for the Center for Evidence-based Policy. Sofosbuvir for the treatment of hepatitis C and evaluation of the 2014 American Association for the Study of Liver Diseases treatment guidelines. May 2014. www.ohsu.edu/xd/research/centers-institutes/evidence-based-policycenter/med/upload/Sofosbuvir_for_HepatitisC_FINAL_5_19_2014.pdf. Accessed July 28, 2014. 21. Victrelis (boceprevir) capsules [prescribing information]. Whitehouse Station, NJ: Merck & Co, Inc; April 2014. 22. Incivek (telaprevir) tablets [prescribing information]. Cambridge, MA: Vertex Pharmaceuticals Incorporated; October 2013. 23. RJ Health Systems ReimbursementCodes. Boceprevir pricing tables. http:// reimbursementcodes.com. Accessed January 14, 2015. 24. von Minckwitz G, Blohmer JU, Costa SD, et al. Response-guided neoadjuvant chemotherapy for breast cancer. J Clin Oncol. 2013;31:3623-3630. 25. Abrahamsson J, Forestier E, Heldrup J, et al. Response-guided induction therapy in pediatric acute myeloid leukemia with excellent remission rate. J Clin Oncol. 2011;29:310-315. 26. Friedman DL, Chen L, Wolden S, et al. Dose-intensive response-based chemotherapy and radiation therapy for children and adolescents with newly diagnosed intermediate-risk Hodgkin lymphoma: a report from the Children’s Oncology Group Study AHOD0031. J Clin Oncol. 2014;32:3651-3658.

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STAKEHOLDER PERSPECTIVE

Response-Guided Therapy an Appropriate Tool for Evaluating Treatment Protocols and Costs of Drug Therapies By Jack E. Fincham, PhD Professor of Pharmaceutical and Administrative Sciences, Presbyterian College School of Pharmacy, Clinton, SC

PATIENTS/PROVIDERS: The current estimated number of patients with hepatitis C virus (HCV) infection in the United States ranges from 3 million to 5 million, with an additional total of 185 million patients worldwide.1 In recent years, there has been a dramatic increase in the number of prescriptions for telaprevir and boceprevir, the 2 common anti-HCV agents approved in the past 5 years.1 The increasing cure rates for HCV have resulted in more physicians prescribing these drugs, and these therapies are leading to exceptionally good outcomes. PAYERS: The costs for novel treatments for HCV infection, however, are being perceived as having a potentially dramatic impact on many health insurance plans, including public payers (Medicare and Medicaid) and private health plans.2-5 One component of the Affordable Care Act that has been implemented across the Medicare and Medicaid programs is the pay-for-performance model, which focuses on the outcomes of care as a factor in the reimbursable amounts by Medicare.6 When it comes to therapies for HCV, the costs of the new treatment regimens, even the new therapies approved in 2014, are lower than the total expenses that would be necessary using the older treatment approaches and low cure rates.6 The type of analysis presented in this issue by Harris and colleagues, using response-guided therapy, is precisely what is now being called for to evaluate such expenditures, using HCV therapy as an example.7 According to the authors, the use of response-guided therapy improves

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clinical outcomes, reduces unnecessary drug exposure for the patient, and avoids unnecessary costs. RESEARCHERS: The methods and analyses used by Harris and colleagues in this evaluation of response-guided therapy are exceptionally carried out. The use of this approach as appropriately utilized in this study is precisely the type of clinical tool needed to fully evaluate the treatment protocols and outcomes related to the new therapies for HCV infection.7 The call by Harris and colleagues for the enhanced implementation of response-guided therapy is most appropriate and necessary at this point. Their findings, the authors note, highlight the need for the improved implementation of this approach in other therapeutic areas as well. This study and conclusions should serve as a template for similar studies across various disease states and health insurance companies: this type of study amplifies precisely why this therapeutic tool is needed. ■ 1. Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 2013;57:1333-1342. 2. Brennan T, Shrank W. New expensive treatments for hepatitis C infection. JAMA. 2014;312:593-594. 3. Lopert R, Welch C. Costs of new treatments for hepatitis C infection. JAMA. 2014;312:2168. 4. Blumenthal D, Davis K, Guterman S. Medicare at 50—origins and evolution. N Engl J Med. 2015;372:479-486. 5. Manos MM, Shvachko VA, Murphy RC, et al. Distribution of hepatitis C virus genotypes in a diverse US integrated health care population. J Med Virol. 2012; 84:1744-1750. 6. Damberg CL, Elliott MN, Ewing BA. Pay-for-performance schemes that use patient and provider categories would reduce payment disparities. Health Aff (Millwood). 2015;34:134-142. 7. Harris JB, Ward MA, Schwab P. Is response-guided therapy being applied in the clinical setting? The hepatitis C example. Am Health Drug Benefits. 2015;8:22-28.

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Government and Employer Trends

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, Inc

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

Omni Shoreham Hotel • Washington, DC TH

ANNUAL CONFERENCE

RSARY VE NI

AGENDA

MAY 6, 2015

7:00 am – 8:00 am

Meet the Experts Breakfast

8:00 am – 8:15 am

Introduction and Opening Remarks Jayson Slotnik, JD, MPH, Health Policy Strategies, Inc F. Randy Vogenberg, PhD, RPh, Institute for Integrated Healthcare

8:15 am – 9:00 am

Session 1 - Oncology Bundled Payments Speaker TBD

9:00 am – 9:45 am

Session 2 - Media Coverage Oncology Panel Speaker TBD

9:45 am – 10:00 am

Break

10:00 am – 10:45 am

Session 3 - Actuary View and Future Market Landscape Speaker TBD

10:45 am – 11:30 am

Session 4 - Coverage Parameter Trends in Health Benefits Impacting Oncology Speaker TBD

11:30 am – 12:15 pm

12:15 pm – 1:15 pm

Networking Lunch in Exhibit Hall or Sponsored Lunch Presentation

1:15 pm – 2:00 pm

Session 6 - Private Health Exchanges Laurel Pickering, Northeast Business Group on Health

2:00 pm – 2:45 pm

Session 7 - Onsite and Retail Clinic Services Expansion Larry Boress, Midwest Business Group on Health

2:45 pm – 3:30 pm

Session 8 - Group Health Benefits 2016 and Beyond Brian Klepper, PhD, National Business Coalition on Health

3:30 pm – 4:15 pm

Session 9 - Panel Discussion: Patient Engagement Patrick McKercher, PhD, Patient Assistance Network Foundation

4:15 pm – 4:30 pm

Closing Remarks

*Agenda subject to change.

Session 5 - Keynote Session – 21st-Century Cures Speaker TBD

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AVBCConline.org/conference

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REVIEW ARTICLE

Diagnosis and Treatment of Patients with Thyroid Cancer Quang T. Nguyen, DO, FACP, FACE, FTOS; Eun Joo Lee; Melinda Gingman Huang; Young In Park; Aashish Khullar, MD; Raymond A. Plodkowski, MD

Quang T. Nguyen

Stakeholder Perspective, page 39 Am Health Drug Benefits. 2015;8(1):30-40 www.AHDBonline.com Received December 4, 2014 Accepted in final form January 15, 2015

Disclosures are at end of text

BACKGROUND: Thyroid cancer is the most common malignancy of the endocrine system, representing 3.8% of all new cancer cases in the United States and is the ninth most common cancer overall. The American Cancer Society estimates that 62,450 people in the United States will be diagnosed with thyroid cancer in 2015, and 1950 deaths will result from the disease. OBJECTIVE: To review the current approach to the diagnosis and treatment of patients with thyroid cancer. DISCUSSION: Over the past 3 decades, there has been a dramatic increase in the number of people diagnosed with thyroid cancer, which may be attributable to the wide use of imaging studies, including ultrasounds, computed tomography, magnetic resonance imaging, and positron emission tomography scans that incidentally detect thyroid nodules. Thyroid cancer is divided into several main types, with papillary thyroid cancer being the most common. The treatment options for patients with thyroid cancer include the surgical removal of the entire thyroid gland (total thyroidectomy), radioactive iodine therapy, and molecular-targeted therapies with tyrosine kinase inhibitors. This article summarizes the diagnosis and treatment of thyroid cancer, with recommendations from the American Thyroid Association regarding thyroid nodules and differentiated thyroid cancer. Recently approved drugs and treatment trends are also explored. CONCLUSION: The prognosis and treatment of thyroid cancer depend on the tumor type and its stage at the time of diagnosis. Many thyroid cancers remain stable, microscopic, and indolent. The increasing treatment options for patients with thyroid cancer, including therapies that were recently approved by the US Food and Drug Administration, have kept the mortality rate from this malignancy low, despite the increase in its incidence. Early diagnosis and appropriate treatment can improve prognosis and reduce mortality. KEY WORDS: endocrine system, thyroid cancer, thyroidectomy, tyrosine kinase inhibitors, radioactive iodine, fine-needle aspiration biopsy

he thyroid is an important endocrine gland located at the base of the throat anterior to the trachea. It is composed of 2 wing-shaped lobes and an isthmus that connects them, which normally cannot be palpated through the skin on physical examination. The thyroid uses iodine to secrete hormones that control the heart rate, blood pressure, body temperature, and basal metabolic rate.

Dr Nguyen is Medical Director, Las Vegas Endocrinology; Clinical Associate Professor, Clinical Education, Arizona College of Osteopathic Medicine; Adjunct Associate Professor of Endocrinology, Touro University Nevada; Ms Lee is Osteopathic Medical Student, Touro University Nevada, Henderson; Ms Huang is Osteopathic Medical Student, Touro University Nevada, Henderson; Ms Park is Osteopathic Medical Student, Touro University Nevada, Henderson; Dr Khullar is Medical Resident, University of Nevada, Reno, School of Medicine; Dr Plodkowski is an Endocrinologist, Scripps Green Hospital, San Diego, CA.

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In the past 3 decades, there has been a dramatic increase in the number of people diagnosed with thyroid cancer.1 According to the National Cancer Institute (NCI)â&#x20AC;&#x2122;s Surveillance, Epidemiology, and End Results Program, more than 500,000 people were living with thyroid cancer in the United States in 2011.2 The American Cancer Society has projected more than 62,000 new cases of thyroid cancer and more than 1900 associated deaths in the United States for 2015.3 Based on reports from the NCI, the incidence of thyroid cancer has risen over the past 10 years by an average of 5.5% annually, and the death rate rose by 0.8% annually from 2002 to 2011.2 Most recently, the number of new cases of thyroid cancer is estimated to be 12.9 per 100,000 men and women annually, and the number of associated deaths is estimated to be 0.5 per 100,000 men and women annually.2 Still, the lifetime risk for thyroid cancer is approximately 1.1%, and the 5-year survival rate has risen to 97.8%, because almost 70% of cases are now

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diagnosed at an early stage, when the cancer is localized at the gland.2 The rise in the incidence of thyroid cancers may be attributable to the widespread use of imaging studies, such as ultrasounds, computed tomography, magnetic resonance imaging, and positron emission tomography (PET) scans, that incidentally detect thyroid nodules.4 This article is focused on the diagnostic and treatment approaches used for thyroid nodules and differentiated thyroid cancer (papillary and follicular cancer), which comprise almost 90% of all thyroid cancers, and the increased incidence has been almost entirely attributed to an increase in papillary thyroid cancer.5

Thyroid Nodules Thyroid nodules are very common in the general population, and a great majority of them are benign.4 A thyroid nodule is a growth of cells (a lump) in the thyroid gland, which is located in the anterior neck region. Radiologically, they are lesions within the thyroid gland that are distinct from the surrounding thyroid parenchyma. It is estimated that 3% to 7% of the world’s population have a palpable nodule, and the prevalence may increase to more than 70% if patients are screened by ultrasound.6 Regardless of palpability, approximately 5% of detected thyroid nodules are malignant, with the exception of nodules discovered by PET scans, which have a 33% increased risk for malignancy.5,7 Thus, newly discovered thyroid nodules are clinically important, because of the need to exclude thyroid cancer. Usually, only nodules measuring >1 cm are evaluated, unless there are other risk factors that increase the suspicion for malignancy. Pertinent risk factors include a history of radiation to the head and neck region, a family history of thyroid cancer or thyroid disease, suspicious ultrasound findings, lymphadenopathy, a history of goiter, female sex, and Asian ancestry.1,5 Thyroid cancer occurs more frequently in women than in men, at an approximate ratio of 3:1, and is more prevalent in the white and Asian/Pacific Islander populations than in other populations.2,8 Thyroid cancer can occur in any age-group but more so in adults aged 45 to 54 years, with a mean age of 50 years at diagnosis.2 Along with a thyroid nodule, the symptoms of thyroid cancer include a painless swelling in the front of the neck, difficulty swallowing, difficulty breathing, hoarseness, or a change in voice, among others.9 Diagnostic Workup The initial workup for any newly discovered thyroid nodule should include a serum thyroid-stimulating hormone (TSH) level.5 The TSH is released from the anterior pituitary and signals the thyroid gland to make

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KEY POINTS The incidence of thyroid cancer, the most common endocrine system malignancy, is on the rise, likely because of widespread use of imaging studies ➤ The most common thyroid malignancy (70%80%) and the least aggressive is papillary thyroid carcinoma ➤ The 5-year survival rate for thyroid cancer is 97.8%, thanks to early diagnosis and improved treatments ➤ Treatments vary by the cancer’s stage and type, and include surgery (thyroidectomy), radioactive iodine, tyrosine kinase inhibitors (TKIs), and external beam radiation ➤ Surgery is the first-line therapy for differentiated tumors; total thyroidectomy has been demonstrated to increase survival and to decrease recurrence ➤ For advanced metastatic thyroid cancer, moleculartargeted therapies, including sorafenib, vandetanib, and cabozantinib, control thyroid progression and prolong progression-free survival ➤

thyroid hormone as appropriate. When thyroid hormone levels are low, the TSH rises responsively and vice versa; thus, measuring a TSH level allows differentiation between functional and nonfunctional nodules. This is an important characteristic, because hyperfunctioning nodules are rarely malignant. However, if a TSH is subnormal, indicating a hyperactive gland, a nuclear medicine imaging study (thyroid uptake and scan) should be performed, to document whether the nodule itself is hyperfunctioning (hot), isofunctioning (warm), or nonfunctioning (cold) compared with the surrounding thyroid tissue. If the nodule is hot or warm, no cytologic evaluation is necessary; however, if the patient is symptomatic, additional evaluation is required to rule out other causes, such as Graves’ disease, and to provide adequate treatment. Nonfunctioning nodules will require the use of fine- needle aspiration (FNA) for cytologic evaluation. However, if the TSH is normal or elevated, even within the upper limits of normal, a FNA is recommended, because the rate of malignancy is higher with nonfunctioning nodules and glands affected by Hashimoto’s thyroiditis, a common autoimmune hypothyroid disease.5 Along with serum TSH, a diagnostic neck ultrasound should be performed on all suspected nodules to confirm the existence of a nodule and to check for any suspicious features.5 However, no single ultrasound feature and no combination of ultrasound features is sensitive enough or specific enough to identify malignancy by themselves. Some ultrasound features have greater correlation with

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certain types of cancer, such as microcalcifications with papillary thyroid cancer and its absence in follicular thyroid cancer. Furthermore, certain sonographic features are highly predictive of benign nodules, such as purely cystic nodules and nodules with >50% spongiform appearance (aggregation of multiple microcystic components).5 Of note, routine measurements of serum thyroglobulin and calcitonin for the initial diagnosis of thyroid cancer are not recommended.5

Fine-Needle Aspiration Biopsy If the initial workup suggests a nonfunctional nodule with suspicious sonographic features, a FNA biopsy should be performed, because it remains the most accurate, cost-effective, and best diagnostic method for evaluating nodules.5,10 FNA can be performed either with palpation or ultrasound guidance; however, ultrasound-guided FNA is preferred, especially when the nodules have cystic components, are located posteriorly, or are difficult to palpate. Ultrasound-guided FNA also reduces the need for repeat FNA biopsy secondary to inadequate samples.5,10 The goal of the FNA biopsy is to obtain at least 6 follicular cell groups, each containing 10 to 15 cells from at least 2 different aspirates of a nodule for cytologic evaluation.5 In general, routine FNA is not recommended for subcentimeter nodules, unless their sonographic appearance is suspicious, as described earlier. In that case, further assessment of the lateral and central neck lymph nodes by ultrasound would be required.5 If abnormal lymph nodes are detected, a FNA biopsy should be performed on the lymph node in addition to the thyroid nodule. A second exception to not performing a biopsy on a subcentimeter nodule is a patient with a history of high risk for malignancy, which includes irradiation exposure, a family history of thyroid cancer, a previous hemithyroidectomy for thyroid cancer, or having positive nodules as determined by a PET scan.5 When performing a FNA biopsy, some anatomic features may need to be considered for obtaining the best sample. Mixed cystic-solid nodules should be biopsied within the solid component, and cyst drainage may be performed if patients are symptomatic.5 In the case of a multinodular gland that consists of 2 or more nodules measuring >1 cm, the nodule with suspicious sonographic features should be biopsied preferentially.5 However, if none of the nodules is suspicious, only the largest nodule should be aspirated, and the rest should be observed with serial ultrasound examination.5 If nuclear imaging was performed as a result of a low serum TSH, a FNA should be performed on the hypofunctioning nodules, with preference for those with suspicious sonographic features. Therefore, a general rule is to choose the nodule that is

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the least functional, and with the most suspicious features, or the largest if they look benign.5 FNA biopsy results are categorized as nondiagnostic, malignant, suspicious for malignancy (50%-75% risk), indeterminate or suspicious for neoplasm (20%-30% risk), follicular lesion of undetermined significance (5%-10% risk), and benign.5 Nondiagnostic cytology occurs in samples that fail to meet cytologic adequacy, which requires at least 6 follicular-cell groups, each containing 10 to 15 cells from at least 2 different aspirates of a nodule. In such a case, a repeat ultrasound-guided FNA should follow.5 However, 7% of nodules can continue to yield nondiagnostic cytology results that may be malignant, so these nodules should be closely monitored by serial ultrasound or surgery.5 Surgery should be more strongly considered with solid nodules. Indeterminate cytology (suspicious for follicular or H端rthle-cell neoplasm, or follicular lesion of undetermined significance) has an increased risk for malignancy, ranging from 15% to 30%; so, the use of molecular markers can be considered to guide management.5 The American Thyroid Association also recommends thyroid lobectomy for patients with an indeterminate solitary nodule, and total thyroidectomy for large tumors >4 cm and patients who have a high-risk history for malignancy.5 All cytology suggesting malignancy requires surgery with either lobectomy or total thyroidectomy, unless there are contraindications or diffuse metastasis. Finally, if a nodule is benign on cytology, no further immediate workup or treatment is required. Serial ultrasound examinations should be performed every 6 to 18 months to monitor for growth. If there is a more than 50% change in volume or a more than 20% increase in at least 2 dimensions, with a minimal increase of 2 mm in solid nodules, a FNA biopsy should then be repeated.5

Thyroid Cancer and Staging Thyroid cancer is diagnosed histologically via FNA biopsy and is categorized into 4 main types. Representing approximately 70% to 80% of thyroid cancers, papillary thyroid carcinoma is the most common thyroid malignancy.5,8 Papillary thyroid carcinoma is the least aggressive type of cancer, because it tends to grow and metastasize slowly.5,8 It is composed of multifocal papillary and follicular elements forming sites of adenocarcinomas.8 Follicular thyroid carcinoma accounts for approximately 14% of thyroid cancers, is more aggressive than papillary thyroid carcinoma, and may be associated with iodine deficiency.5 H端rthle-cell carcinoma is a variant of follicular carcinoma that is treated the same way as follicular carcinoma. Medullary thyroid carcinoma, a cancer of nonthyroid cells that are normally present in the thyroid

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gland, represents approximately 3% of thyroid cancers and is often associated with multiple endocrine neoplasia 2. Medullary carcinoma produces excess calcitonin, which makes it a useful tumor marker.5,8 Anaplastic thyroid carcinoma represents approximately 2% of thyroid cancers and is the most dangerous form of thyroid cancer, because it metastasizes early to the surrounding lymph nodes and distant sites.11 Other thyroid malignancies, such as lymphoma and variants of the 4 types mentioned above, make up the remaining thyroid cancers. Clinically, thyroid cancer has been divided into 2 categories: (1) well-differentiated, including papillary and follicular cancers, and (2) poorly differentiated, including medullary and anaplastic cancers. After a diagnosis of thyroid cancer, it is important to perform preoperative staging and imaging, because it can alter the patient’s prognosis and treatment course. Up to 50% of patients with differentiated thyroid cancer will have cervical lymph node involvement, despite the primary tumor size.5 Thus, a preoperative neck ultrasound for contralateral lobe and cervical lymph nodes is recommended for all patients undergoing thyroidectomy for malignancy, to help identify possible metastasis; however, neck ultrasounds only identify 50% of the lymph nodes that are found during surgery.5 Lymph node metastasis can be confirmed by ultrasound-guided FNA on abnormal lymph nodes and/or the measurement of thyroglobulin in the needle washout if it would change the disease management.5 These results are then used to stage the extent of the cancer. The American Joint Committee on Cancer (AJCC) has designated thyroid cancer staging by the Tumor, Node, Metastasis (TNM) classification system.8 The AJCC’s TNM classification system is available online (at the AJCC website).8 In addition, thyroid cancer can be stages, using stages I to IV, with the TNM classification system based on the tumor type of thyroid cancer (Table 1).8

Treatment Options Treatment options for thyroid cancer include surgery, radioactive iodine (131I) therapy, and molecular-targeted therapies with several tyrosine kinase inhibitors (TKIs). The standard treatment options vary depending on the type and stage of the cancer. Different guidelines are available from various oncology organizations regarding the treatment options for thyroid cancer. Table 2 (page 34) lists standard treatment options as recommended by the NCI.8 Recommendations from the National Comprehensive Cancer Network are divided by cancer type and are available at www.nccn. org/patients/guidelines/cancers.aspx.

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Table 1 TNM Stages of Thyroid Cancer by Tumor Type Papillary and follicular cancer in patients aged <45 years Stage I: papillary carcinoma is localized to the thyroid gland Stage II: papillary carcinoma that has spread distantly Papillary and follicular cancer in patients aged ≥45 years Stage I: papillary carcinoma is localized to the thyroid gland Stage II: tumor that is >2 cm but ≤4 cm and is limited to the thyroid gland Stage III: tumor that is >4 cm and is limited to the thyroid or with minimal extrathyroid extension or positive lymph nodes limited to the pretracheal, paratracheal, or prelaryngeal/Delphian nodes Stage IV: extension beyond the thyroid capsule to the soft tissues of the neck, cervical lymph node metastases, or distant metastases; the lungs and bone are the most frequent sites of spread Medullary thyroid cancer Stage 0: clinically occult disease detected by provocative biochemical screening Stage I: tumor <2 cm Stage II: tumor >2 cm but ≤4 cm with no metastases or >4 cm with minimal extrathyroid extension Stage III: tumor of any size with metastases limited to the pretracheal, paratracheal, or prelaryngeal/Delphian lymph nodes Stage IVA: moderately advanced with or without lymph node metastases [for T4a], but without distant metastases Stage IVB: very advanced with or without lymph node metastases, but no distant metastases Stage IVC: distant metastases Anaplastic thyroid cancer All patients are considered to have stage IV disease TNM indicates Tumor, Node, Metastasis. Source: National Cancer Institute. Thyroid cancer treatment (PDQ): stage information for thyroid cancer. www.cancer.gov/cancertopics/ pdq/treatment/thyroid/HealthProfessional/page3.

Surgery Surgical options for primary tumors include hemithyroidectomy, with or without isthmusectomy; near-total thyroidectomy (leaving <1 g of thyroid tissue adjacent to the recurrent laryngeal nerve); and total thyroidectomy (removing all visible thyroid tissue).5 Overall, near-total or total thyroidectomy is recommended for the management of thyroid cancer in which the primary tumor measures ≥1.0 cm to 2.0 cm.12 Subtotal lobectomy and unilateral lobectomy used to be performed in the past, but they are now deemed inappropriate for the treatment of patients with thyroid cancer; instead, extracapsular dissection is now recommended.12,13 Because of the high percentage (42.7%) of the multifocal distribution of thyroid cancer, removing the thyroid gland in its entirety reduces the chance for malignancy in the residual parenchyma.14 It also allows for the correct risk assessment of the tumor, which is based on size and extracapsular infiltration.14

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Thyroidectomy is also recommended because 5% to 10% of thyroid cancer recurrences are found in the contralateral lobe.12 The new technologic improvements in devices used for total thyroidectomy, such as the hemostatic vessel-sealing device and nerve monitoring, have increased the safety of the procedure and the efficacy of removing the tissues in patients with malignancy.15 Studies also show the cost-effectiveness of an initial total thyroidectomy for nodules that are suspicious for cancer based on a FNA biopsy versus initial lobectomy and intraoperative frozen section procedure.6,16 Because lymph node metastasis can be present in 20% to 90% of patients with papillary cancer, a therapeutic central compartment neck dissection should be performed along with the total thyroidectomy when lymph nodes are clinically involved.5 Prophylactic central compartment neck dissection is also recommended for T3 or T4 tumors, despite no clinically involved lymph nodes.5 No prophylactic dissection is recomTable 2 NCI Treatment Recommendations for Thyroid Cancer Stage I and II papillary and follicular thyroid cancer • Total thyroidectomy (tumor ≥1 cm) • Lobectomy (tumor <1 cm) Stage III papillary and follicular thyroid cancer • Total thyroidectomy plus removal of involved lymph nodes or other sites of extrathyroid disease • 131 I ablation after total thyroidectomy if the tumor demonstrates uptake of this isotope • External beam radiation therapy if 131I uptake is minimal Stage IV papillary and follicular thyroid cancer • 131I: metastases that demonstrate uptake of this isotope may be ablated by therapeutic doses of 131I • External beam radiation therapy for patients with localized lesions that are unresponsive to 131I • Resection of limited metastases, especially symptomatic metastases, should be considered when the tumor has no uptake of 131I • Thyroid-stimulating hormone suppression with thyroxine is also effective in many lesions that are not sensitive to 131I Medullary thyroid cancer • Localized: total thyroidectomy followed by external beam radiation therapy for recurrent tumors • Metastatic: palliative chemotherapy Anaplastic thyroid cancer • Surgery: tracheostomy if necessary; if confined to local area, total thyroidectomy • External beam radiation therapy if tumor cannot be surgically excised • Chemotherapy: doxorubicin plus cisplatin as radiation sensitizer; not responsive to 131I therapy NCI indicates National Cancer Institute. Source: National Cancer Institute. Thyroid cancer treatment (PDQ). www.cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional.

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mended for smaller T1 or T2 noninvasive tumors.5 Today, thyroidectomy is mostly performed as an outpatient surgery.17 With proper education and counseling, patients are more apt to choose outpatient surgery; however, for the safety of the patient, contraindications need to be considered. The contraindications for outpatient thyroidectomy include noncompensated cardiac and/or respiratory disease, dialysis-dependent renal failure, anticoagulant therapy, seizure disorder, obstructive sleep apnea, mental impairment, pregnancy, unilateral vocal fold paralysis, thyrotoxicosis, and morbid obesity.18 Other factors, such as support from family or friends and emotional stability, are important to the outcome of the outpatient surgery. An analysis of 5121 patients undergoing outpatient thyroidectomy suggested that the morbidity and readmission rates are very low, with 0.92% of patients having perioperative morbidities and 2.17% of patients being readmitted within 30 days of the operation.17 Nevertheless, as with any procedure, complications can arise. The 2 most common early postoperative complications of thyroidectomy are hypocalcemia (20%-30%) and recurrent laryngeal nerve injury (5%-11%).19 The risk for postoperative hypocalcemia is increased by several factors, including the venous drainage of the upper parathyroid glands, the location of the parathyroid glands and difficulty in identifying them, the presence of large goiters, Graves’ disease, thyroid cancer that requires an extensive dissection of lymph nodes, and repeat exploration of the cervical region resulting in adhesions, as well as young age and female sex.19 The risk for injury to the recurrent laryngeal nerve is low, with a rare complication of bilateral recurrent laryngeal nerve palsy. The risk for injury to the nerve is increased by reoperation, the underlying thyroid pathology, the invasion of adjacent structures, and the extent of the resection.19 Another complication is postoperative hemorrhage, the incidence of which rises with increases in the weight and size of the thyroid gland.19 Unilateral lobectomy involves a smaller operative field than total thyroidectomy. Hematomas occur in approximately 1% of patients, with events occurring within the first 6 hours after surgery.19 The early signs of hematoma include pronounced anterior swelling, sensation of tightness, and purple discoloration of the skin. The late signs of hematoma may include respiratory stridor and distress. With early care and patient education about the signs of hematomas, same-day hospital discharge has been shown to be safe.18,19 Although such complications are not completely avoidable, they can be reduced. The incidence of postoperative hypocalcemia can be reduced by starting the patient with oral supplementation of calcium plus vitamin D

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1 week before surgery, and continued for 2 weeks after surgery.19 The calcium and parathyroid hormone levels are obtained between 6 and 24 hours postoperatively.20 In patients with low parathyroid hormone levels, oral calcitriol is also added to increase the absorption of calcium.19 The prevention of recurrent laryngeal nerve injury is dependent on preoperative and intraoperative measures. Preoperatively, patients should be examined for any preexisting laryngeal dysfunctions. Intraoperatively, careful dissection of the nerve, nerve monitoring, and the choice of hemostatic techniques are impor tant.19 Although there is a lack of definitive evidence regarding nerve preservation from nerve monitoring, its use is increasing because it can confirm the functional integrity of the nerve at the end of the thyroidectomy.19 Hemostatic techniques that reduce the operative time as well as intraoperative bleeding include new energy devices, such as ultrasonic dissection and electrothermal bipolar vessel sealing systems. In a study that included 217 patients who had a total thyroidectomy, the treatment of differentiated thyroid cancer with total thyroidectomy alone without 131I ablation showed a low risk (2.3%) for disease recurrence.21 In another study that included 43,227 patients who underwent total thyroidectomy and 8946 patients who underwent lobectomy, for tumors ≥1 cm, the risks for recurrence and death were 15% and 31% higher, respectively, in the lobectomy group (P = .04) than in the total thyroidectomy cohort (P = .009).22

Radioactive Iodine Ablation and Treatment 131 I has had an important role in the treatment and management of thyroid cancer since 1946.23 It is used in coordination with thyroidectomy to completely ablate the thyroid gland and to postoperatively eradicate possible residual cancer.23-25 131I works by entering the thyroid cells via the sodium iodide transporters and emitting short-wavelength beta rays, causing acute cell death. When administered the first time after surgery, it is referred to as ablation, whereas subsequent administrations for residual disease are referred to as treatment.23,26 Removing the remnant tissue serves to decrease the potential for relapse and also to increase the sensitivity of follow-up diagnostic tests (eg, whole-body scintigraphy scans and serum thyroglobulin levels) that facilitate the detection of metastatic or residual disease.23 It is particularly useful for differentiated thyroid cancer, because they account for the majority of thyroid cancers and are associated with a 10-year survival rate of between 90% and 95%. This survival rate suggests a need for long-term surveillance and testing for recurrence.24,27 Although it has mainly been used as an adjuvant therapy, 131I therapy also remains the mainstay treatment for

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nonsurgical and incompletely resectable thyroid tumors, such as microscopic or metastatic disease.26 Several factors should be considered when starting a patient with 131I therapy. The first factor to consider is operability, because surgery is the first-line treatment for differentiated cancers.26,28 In addition, it is impor tant to assess the iodine avidity of the affected tissues, because 131I has to be transported into the tissue to have an effect. PET and posttherapy whole-body scans have been used for confirmation. The disease site and tumor characteristics are important factors to note, because they affect the results of 131I therapy, as is seen by the higher rates of cure with lung and soft-tissue metastases and with well-differentiated tumor histotypes as opposed to brain metastases and poorly differentiated tumors.26,28 In general, guidelines from the American Thyroid Association recommend 131I ablation for known metastases, extrathyroidal extension, and tumor size >4 cm; or smaller tumors with high-risk features, such as vascular invasion and aggressive histologies.28 On the other hand, the guidelines do not recommend ablation for unifocal or multifocal tumors <1 cm without high-risk features.26,28 The patient’s general health status and treatment tolerability are important considerations as well, because side effects are common with 131I therapy and include salivary gland dysfunction (>40%), abnormally dry eyes (25%), transient fertility reduction (20%), transient leukopenia, and thrombocytopenia.29 Finally, and most important, it is pertinent to confirm the absolute contraindications of pregnancy and breastfeeding with 131I, because such treatment can interfere with a fetus’s thyroid gland and cause a severe physical and mental underdevelopment condition known as cretinism.28 Some relative contraindications include bone marrow depression, pulmonary function restriction, salivary gland function restriction, and neurologic symptoms that can be exacerbated with the accumulation of 131I.26,28 In preparation for 131I therapy, patients are initially placed on a low-iodine diet for 4 to 6 weeks before treatment or have 2 weeks of daily intake of <50 μg iodine to avoid competition between 131I and normal iodine.28 Similarly, patients who have high iatrogenic loads of iodine (eg, amiodarone or contrast) cannot receive treatment until their urine iodine level falls to 100 μg per 24 hours.28 Then, patients are placed on a regimen that can sufficiently elevate the serum TSH level to ≥30 mU/L to increase the number of sodium iodide symporters and to optimize the uptake of 131I.26 This is achieved via thyroid hormone withdrawal or the use of the newer recombinant human thyroid stimulating hormone (rhTSH).26 rhTSH was initially intro-

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duced in 1998 for diagnostic purposes30 and was approved for use before treatment with 131I in 2007 by the US Food and Drug Administration (FDA). The main concern with thyroid hormone withdrawal is possible iatrogenic hypothyroidism, which may last several weeks; however, the concern with rhTSH is its efficacy. Recent studies have shown that rhTSH is as effective as thyroid hormone withdrawal with 131I thyroid remnant ablation, with significant benefits to the patient on health-related quality of life, adverse effects during and after ablation, and decreased whole-body radiation exposure.31-33 Once the appropriate TSH level is reached, 131I is administered orally as a capsule at the proper amount of activity. After a single dose of 131I, several tests are performed to verify successful treatment. The 131I uptake is usually confirmed 2 to 8 days after treatment with a whole-body scan, and a follow-up scan is normally performed 6 to 12 months later.28 The stimulated thyroglobulin levels (thyroglobulin levels drawn when TSH is high) and thyroid ultrasounds should also be checked at that time to monitor response; however, “lower risk patients with negative thyroglobulin levels may not require follow-up scanning at all.” 28 A successful treatment is confirmed if there is <0.1% 131I uptake within the thyroid bed on the follow-up scan and a low stimulated thyroglobulin level. A neck ultrasound should reveal an empty thyroid bed, with no new growths or extensions.28

Tyrosine Kinase Inhibitors Radioactive iodine therapy is the staple treatment for recurrent or metastatic thyroid cancers; however, in patients whose cancer no longer takes up iodine, another treatment option is needed. Many genetic alterations have been identified involving tyrosine kinase signaling pathways, including the RET, RAF, or RAS protein kinase genes, which lead to the activation of the tyrosine kinase domain.34 The RET/RAS/RAF pathway is interconnected with the epidermal growth factor receptor–activated cascade, which leads to the syntheses of vascular endothelial growth factor (VEGF) and VEGF receptor.34 Gainof-function mutations in the BRAF oncogene, which confer new or enhanced activity on a protein, are the most frequent genetic alterations found in patients with papillary thyroid cancer, occurring in approximately 45% to 70% of these tumors in adults.35-37 The overexpression of VEGF and other growth factors is frequently found in tumors that originated in the thyroid, particularly in tumors with BRAF mutations.38 Drugs targeting these pathways could play a significant role in controlling the progression of the disease.

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Vandetanib. In 2011, the FDA approved vandeta nib, which targets RET, EGFR, and VEGF receptor for the treatment of patients with symptomatic or progressive, unresectable, locally advanced or metastatic medullary thyroid cancer. The approval of the first drug for this indication was based on data from the phase 3 Zactima Efficacy in Thyroid Cancer Assessment (ZETA) study.39 The study showed a significant prolongation of progression-free survival with vandet anib versus placebo (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.31-0.69; P <.001). The median duration of treatment in the randomized phase was 90.1 weeks for vandetanib and 39.9 weeks for placebo. The ZETA trial included many patients with indolent disease, as is evidenced by the median progression-free survival of 19.3 months in the placebo group (with an estimated progression-free survival of 30 months in the vandetanib group). Adverse events such as diarrhea, rash, nausea, and hypertension occurred in more than 30% of patients receiving vandetanib. A total of 19 (8%) patients developed protocol-defined QTc prolongation, but there were no reports of torsades de pointes.39 Cabozantinib. In 2012, the FDA approved the second TKI, cabozantinib, for the same indication as vandetanib, on the basis of the EXAM (Efficacy of XL184 in Advanced Medullary Thyroid Cancer) trial.40 This drug is a TKI that targets 3 potentially important pathways in medullary thyroid cancer: MET, VEGF receptor 2, and RET.41 The study showed the prolongation of progression-free survival to 11.2 months for cabozantinib versus 4 months for placebo (HR, 0.28; 95% CI, 0.19-0.4; P <.001). Cabozantinib had significant grade 3 or 4 side effects, including diarrhea, hand-foot syndrome, fatigue, and hypertension. In the study, 79% of the patients had dose reductions, of which 16% of patients discontinued their treatment. Grade 5 lethal toxicities occurred in 7% of patients, which included fistula, respiratory failure, sudden death, hemorrhage, and sepsis.41 Vandetanib and cabozantinib have shown significant prolongation of progression-free survival, and calcitonin and carcinoembryonic antigen levels decrease dramatically with these agents; however, no overall survival benefit was seen in these studies so far. These drugs need to be individualized to the patients because of their various side effects; thus, a great deal of clinical judgment is required before treating patients with them. Sorafenib. In 2013, sorafenib, which is a multikinase inhibitor of RET, wild-type and BRAF V600E mutation, VEGF receptors 2 and 3, among others, was the third drug to be approved by the FDA for the treatment of 131I-refractory, locally recurrent or metastatic, progressive, differentiated thyroid cancer.

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The landmark DECISION study, which led to the FDA’s approval of sorafenib, was a phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial that included patients with locally recurrent or metastatic, progressive differentiated thyroid cancer.42 The major efficacy outcomes measured included progression-free survival, overall survival, tumor response rate, and duration of response. The DECISION study demonstrated a significant prolongation in median progression-free survival of 10.8 months with sorafenib versus 5.8 months with placebo (HR, 0.59; 95% CI, 0.45-0.76; P <.001).42 Adverse events occurred in 204 (98.6%) of 207 patients receiving sorafenib during the double-blind period and in 183 (87.6%) of 209 patients receiving placebo. Most adverse events were grade 1 or 2, with the most frequent treatment-emergent adverse events in the sorafenib group being hand-foot skin reaction (76.3%), diarrhea (68.6%), alopecia (67.1%), and rash or desquamation (50.2%).42 Sorafenib can prolong the QT/corrected QT (QTc) interval and can increase the risk for ventricular arrhythmias.43 Also, sorafenib in combination with carboplatin and paclitaxel is contraindicated in patients with squamous-cell lung cancer.43,44

External Beam Radiation Therapy External beam radiation therapy is only used for palliative treatment of patients with advanced or inoperable thyroid cancer.5 It is usually considered in patients aged >45 years who have grossly visible extrathyroidal extension and a high likelihood of residual disease during surgery.5 It is also reserved for tumors that are unresponsive to therapy with 131I.5 Posttreatment Management TSH suppression therapy is recommended after surgery and after 131I therapy, because differentiated thyroid cancers express TSH receptors that respond to TSH stimulation.5 The cells respond by increasing sodium iodide symporters and thus increasing cell growth. TSH suppression can be achieved by using supraphysiologic doses of levothyroxine to suppress the TSH to <0.1 mU/L or up to 0.5 mU/L for lower-risk patients.5 Serum thyroglobulin should be measured every 6 to 12 months in the same laboratory along with antithyroglobulin antibodies, because 25% of patients with thyroid cancer will produce this antibody, which falsely lowers the level of serum thyroglobulin.5 Periodic neck ultrasound should also be performed in patients with partial thyroidectomy and in patients with total thyroidectomy who have not had 131I ablation to monitor for tissue growth.5

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Approximately 12 months after ablation, a single rhTSH-stimulated serum thyroglobulin measuring <0.5 ng/mL without antithyroglobulin antibody can identify patients who are completely free of tumor.5 A disease-free status is achieved when there is no clinical evidence of tumor, no imaging evidence of tumor (negative whole-body scan), and undetectable serum thyroglobulin level with TSH stimulation in the absence of antibodies.5 Such patients can then be followed up with annual thyroglobulin levels and thyroid hormone replacement.5 If the patient had high-risk disease, TSH should be suppressed to 0.1 to 0.5 mU/L for 5 to 10 years, and patients who had low-risk disease or who have become disease free should maintain a TSH of 0.3 to 2.0 mU/L.5 If a patient is thyroglobulin positive (>10 ng/ mL) and the 131I whole-body scan is negative, a PET scan should be ordered to rule out any metastatic disease that would require further workup.5 In patients with persistent disease, TSH should be maintained to <0.1 mU/L indefinitely.5

Conclusion Thyroid cancer represents 3.8% of all new cases of cancer in the United States.2 The prognosis and treatment of thyroid cancer depend on the type of cancer and the tumor stage at the time of diagnosis. Many thyroid cancers remain stable, microscopic, and indolent. Total thyroidectomy increases survival rates and decreases recurrence rates in patients with thyroid cancer. Treatment with 131I has been an integral adjuvant role in the treatment of thyroid cancer. Molecular- targeted therapies, such as TKIs, have been approved in the past few years for the treatment of patients with advanced thyroid cancer. All of these treatment options have kept the mortality rate for thyroid cancer low, despite the recent increase in its incidence. ■ Author Disclosure Statement Dr Nguyen is on the Speaker’s Bureau for AstraZeneca. Ms Lee, Ms Huang, Ms Park, Dr Khullar, and Dr Plodkowski reported no conflicts of interest.

References

1. National Cancer Institute. A snapshot of thyroid cancer. November 5, 2014. www.cancer.gov/researchandfunding/snapshots/thyroid. Accessed January 12, 2015. 2. National Cancer Institute. SEER stat fact sheets: thyroid cancer. http:// seer.cancer.gov/statfacts/html/thyro.html. Accessed January 12, 2015. 3. American Cancer Society. Thyroid cancer: what are the key statistics about thyroid cancer? Revised January 12, 2015. www.cancer.org/cancer/thyroidcancer/ detailedguide/thyroid-cancer-key-statistics. Accessed January 12, 2015. 4. Knox MA. Thyroid nodules. Am Fam Physician. 2013;88:193-196. 5. Cooper DS, Doherty GM, Haugen BR, et al; for the American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer: the American Thyroid Association (ATA) Guidelines Taskforce on

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Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2009;19:11671214. Errata in: Thyroid. 2010;20:674-675; Thyroid. 2010;20:942. 6. Corso C, Gomez X, Sanabria A, et al. Total thyroidectomy versus hemithyroidectomy for patients with follicular neoplasm. A cost-utility analysis. Int J Surg. 2014;12:837-842. 7. Welker MJ, Orlov D. Thyroid nodules. Am Fam Physician. 2003;67:559-566. 8. National Cancer Institute. Thyroid cancer treatment (PDQ). Updated July 11, 2014. http://cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional. Accessed January 12, 2015. 9. MedlinePlus. Thyroid cancer. Updated March 23, 2014. www.nlm.nih.gov/ medlineplus/ency/article/001213.htm. Accessed January 12, 2015. 10. Nikiforov YE, Yip L, Nikiforova MN. New strategies in diagnosing cancer in thyroid nodules: impact of molecular markers. Clin Cancer Res. 2013;19:2283-2288. 11. Fitzgerald PA. Thyroid cancer. In: Papadakis MA, McPhee SJ, eds. Current Medical Diagnosis & Treatment 2013. 52nd ed. US: McGraw-Hill Companies; 2013:1126-1134. 12. Tuttle RM. Differentiated thyroid cancer: overview of management. UpToDate. www.uptodate.com/contents/differentiated-thyroid-cancer-overviewof-management?source=search_result&search=Differentiated+thyroid+cancer %3A+overview+of+management&selectedTitle=1~150#H27. Accessed January 29, 2015. 13. Nixon IJ, Ganly I, Shah JP. Thyroid cancer: surgery for the primary tumor. Oral Oncol. 2013;49:654-658. 14. Lucchini R, Monacelli M, Santoprete S, et al. Differentiated thyroid tumors: surgical indications. G Chir. 2013;34:153-157. 15. Rudolph N, Dominguez C, Beaulieu A, et al. The morbidity of reoperative surgery for recurrent benign nodular goitre: impact of previous unilateral thyroid lobectomy versus subtotal thyroidectomy. J Thyroid Res. 2014; 2014:231857. 16. Leiker AJ, Yen TW, Cheung K, et al. Cost analysis of thyroid lobectomy and intraoperative frozen section versus total thyroidectomy in patients with a cytologic diagnosis of “suspicious for papillary thyroid cancer.” Surgery. 2013;154:1307-1313; discussion 1313-1314. 17. Khavanin N, Mlodinow A, Kim JYS, et al. Predictors of 30-day readmission after outpatient thyroidectomy: an analysis of the 2011 NSQIP data set. Am J Otolaryngol. 2014;35:332-339. 18. Terris DJ, Snyder S, Carneiro-Pla D, et al; for the American Thyroid Association Surgical Affairs Committee Writing Task Force. American Thyroid Association statement on outpatient thyroidectomy. Thyroid. 2013;23:1193-1202. 19. Christou N, Mathonnet M. Complications after total thyroidectomy. J Visc Surg. 2013;150:249-256. 20. Shore S, Waghorn AJW. Thyroidectomy. Surgery (Oxf). 2011;29:446450. 21. Vaisman F, Shaha A, Fish S, Tuttle RM. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer. Clin Endocrinol (Oxf). 2011;75:112-119. 22. Bilimoria KY, Bentrem DJ, Ko CY, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg. 2007;246:375-381; discussion 381384. 23. Wartofsky L, Van Nostrand D. Radioiodine treatment of well-differentiated thyroid cancer. Endocrine. 2012;42:506-513. 24. Valachis A, Nearchou A. High versus low radioiodine activity in patients with differentiated thyroid cancer: a meta-analysis. Acta Oncol. 2013;52:10551061. 25. Schlumberger M, Catargi B, Borget I, et al; for the Tumeurs de la Thyroïde Refractaires Network for the Essai Stimulation Ablation Equivalence Trial. Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med. 2012;366:1663-1673.

26. Luster M, Clarke SE, Dietlein M, et al; for the European Association of Nuclear Medicine (EANM). Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 2008;35:1941-1959. 27. Mallick U, Harmer C, Yap B, et al. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med. 2012;366:1674-1685. 28. Tuttle RM. Differentiated thyroid cancer: radioiodine treatment. UpToDate. Updated July 15, 2014. www.uptodate.com/contents/differentiated- thyroid-cancer-radioiodine-treatment. Accessed January 12, 2015. 29. Iyer NG, Morris LGT, Tuttle RM, et al. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy. Cancer. 2011;117:4439-4446. 30. Tala H, Robbins R, Fagin JA, et al. Five-year survival is similar in thyroid cancer patients with distant metastases prepared for radioactive iodine therapy with either thyroid hormone withdrawal or recombinant human TSH. J Clin Endocrinol Metab. 2011;96:2105-2111. 31. Grenfell S, Roos D, Rijken J, et al. Comparison of effective I-131 half-life between thyroid hormone withdrawal and recombinant human thyroid- stimulating hormone for thyroid cancer: a retrospective study. J Med Imaging Radiat Oncol. 2014 Oct 6. Epub ahead of print. 32. Pak K, Cheon GJ, Kang KW, et al. The effectiveness of recombinant human thyroid-stimulating hormone versus thyroid hormone withdrawal prior to radioiodine remnant ablation in thyroid cancer: a meta-analysis of randomized controlled trials. J Korean Med Sci. 2014;29:811-817. 33. Tu J, Wang S, Huo Z, et al. Recombinant human thyrotropin-aided versus thyroid hormone withdrawal-aided radioiodine treatment for differentiated thyroid cancer after total thyroidectomy: a meta-analysis. Radiother Oncol. 2014;110:25-30. 34. Smit J. Tyrosine kinase inhibitors in thyroid cancer. Endocr Abstracts. 2010;22. Abstract S5.3. 35. Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003;95:625-627. 36. Henderson YC, Shellenberger TD, Williams MD, et al. High rate of BRAF and RET/PTC dual mutations associated with recurrent papillary thyroid carcinoma. Clin Cancer Res. 2009;15:485-491. 37. Riesco-Eizaguirre G, Gutiérrez-Martínez P, García-Cabezas MA, et al. The oncogene BRAFV600E is associated with a high risk of recurrence and less differentiated papillary thyroid carcinoma due to the impairment of Na+/I– targeting to the membrane. Endocr Relat Cancer. 2006;13:257-269. 38. Cabanillas ME, Waguespack SG, Bronstein Y, et al. Treatment with tyrosine kinase inhibitors for patients with differentiated thyroid cancer: the M.D. Anderson experience. J Clin Endocrinol Metab. 2010;95:2588-2595. 39. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30:134-141. Erratum in: J Clin Oncol. 2013;31:3049. 40. Exelixis. FDA approves Cometriq (cabozantinib) for treatment of progressive, metastatic medullary thyroid cancer. November 29, 2012. http:// exelixis.com/investors-media/press-releases. Accessed January 21, 2015. 41. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639-3646. Erratum in: J Clin Oncol. 2014;32:1864. 42. Brose MS, Nutting CM, Jarzab B, et al; for the DECISION investigators. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384:319-328. 43. Nexavar (sorafenib) tablets [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc; November 2013. 44. Brose MS, Nutting CM, Sherman SI, et al. Rationale and design of DECISION: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer. BMC Cancer. 2011;11:349.

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Diagnosis and Treatment of Patients with Thyroid Cancer

STAKEHOLDER PERSPECTIVE

Predictive Models and Technology Present Opportunities to Support Early Diagnosis, Treatment, and Adherence to Guidelines By Jeffrey A. Bourret, PharmD, MS, BS, RPh, BCPS, FASHP Senior Director, North America Medical Affairs, Pfizer Inc, Collegeville, PA

PATIENTS: Differentiated thyroid cancer, which includes papillary and follicular cancers, represents approximately 90% of all cases of thyroid cancer. In their article in this issue of American Health & Drug Benefits, Nguyen and colleagues report the lifetime risk for thyroid cancer as 1.1% and the 5-year survival rate having risen to 97.8%, which is driven by early diagnosis in almost 70% of patients with localized cancer.1 However, the incidence of thyroid cancer is rising by an average of 5.5% annually.2 Rahib and colleagues project that breast, prostate, and lung cancers will remain the top cancers diagnosed by 2030.2 They also predict that thyroid cancer will replace colorectal cancer as the fourth leading cancer diagnosed by 2030, and that melanoma and uterine cancers will become the fifth and sixth most common cancers, respectively.2 PAYERS: There is concern that the success achieved to date in overall survival in the face of increasing pressures to control costs has resulted in overly conservative treatment strategies.3 To promote high-quality care for patients with differentiated thyroid cancer, payers should focus on ways to support cliniciansâ&#x20AC;&#x2122; adherence to the revised American Thyroid Associationâ&#x20AC;&#x2122;s management guidelines for patients with thyroid nodules and differentiated thyroid cancer.4 Payers should also leverage their access to patient-level data and electronic medical records to develop predictive models that can assist in identifying patients at high risk for thyroid cancer, and provider adherence to treatment guidelines that are focused on early detection and treatment. This will help all stakeholders to maintain the treatment success rates that have been achieved in the past as incidence rates rise with an increasingly aging population. The Medicare population should be of particular relevance to payers; because of their increasing age, Medicare beneficiaries may be at increased risk for thyroid cancer.3 The elderly often present with more aggressive forms of cancer, including metastatic disease, larger tumors, and more extensive local growth.3 Boltz and colleagues conducted a study on the costs attributed to patients with differentiated thyroid cancer

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in the Medicare population using the Surveillance, Epidemiology, and End Results database to establish costs associated with disease stage and treatment options over 5 years.3 The cumulative costs amounted to $17,669 per patient in the first year of treatment and $49,989 per patient by 5 years of treatment. Patients who had regional disease had higher costs at 1 year ($9578) and by 5 years ($8902) of treatment. Patients with distant disease had 1-year costs of $28,447 and 5-year costs of $20,103. Patients undergoing surgery and radiation had a $722 decrease in cost by 5 years of treatment. Boltz and colleagues conclude that differentiated thyroid cancer in the elderly is associated with significant economic burden that is largely attributable to patient demographics, stage of disease, and treatment modalities.3 The standard treatment approach to differentiated thyroid cancer involves multimodal treatment according to the American Thyroid Association management guidelines, yet their economic analysis showed that 55% of patients did not receive radioiodine therapy and 6.5% had additional types of radiation therapy, indicating they had received less aggressive care that is not consistent with current guidelines.3 Unlike the majority of patients with thyroid cancer who have excellent survival rates, patients who have high-risk factors have been identified as having the worst prognosis. Yang and colleagues reported on the development of a nomogram that is designed to help clinicians identify patients at high risk for death from thyroid cancer, which can be used by clinicians to design individualized treatment but can also potentially be used by managed care organizations with predictive modeling capability, where it could be applied across large populations.5 Yildirim conducted a study to determine prognostic factors that could be used to develop a mathematical model for predicting outcomes in patients with differentiated thyroid cancer.6 He determined that age, tumor size, angioinvasion, and distant metastasis were significant predictors of outcomes that allowed for patients to be segmented into very low-risk, low-risk, high-risk, and very high-risk groups using logistic regression. The results of this study could serve as a foundation for a larger-Â

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CLINICAL

STAKEHOLDER PERSPECTIVE Continued scale application of predictive models by managed care analytics departments.6 Health plans face significant challenges in population health management balancing the needs of their clients, while trying to engage their plan members and support the clinicians who deliver and manage their members’ care. Managing the costs and quality of a population has resulted in the development of large, sophisticated databases that provide the potential for harnessing technology to predict which members are at risk and to directly communicate to members and physicians about at-risk patients so that early and aggressive treatment aligned with evidence-based guidelines can be initiated. Thyroid cancer is a common malignancy of the endocrine system, in which early diagnosis and effective treatment can dramatically result in improved outcomes and reduced mortality. Leveraging existing technology, predictive models, electronic medical records, and com-

munication across cross-functional healthcare stakeholders is a promising strategic approach to improve early diagnosis and treatment. ■ 1. Nguyen, QT, Lee EJ, Huang MG, et al. Diagnosis and treatment of patients with thyroid cancer. Am Health Drug Benefits. 2015;8:30-40. 2. Rahib L, Smith BD, Aizenberg R, et al. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74:2913-2921. 3. Boltz MM, Hollenbeak CS, Schaefer E, et al. Attributable costs of differen tiated thyroid cancer in the elderly Medicare population. Surgery. 2013; 154:1363-1369; discussion 1369-1370. 4. Cooper DS, Doherty GM, Haugen BR, et al; for the American Thyroid Association Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009; 19:1167-1214. 5. Yang L, Shen W, Sakamoto N. Population-based study evaluating and predicting the probability of death resulting from thyroid cancer and other causes among patients with thyroid cancer. J Clin Oncol. 2013;31:468-474. 6. Yildirim E. A model for predicting outcomes in patients with differentiated thyroid cancer and model performance in comparison with other classification systems. J Am Coll Surg. 2005;200:378-392.

Call for Papers American Health & Drug Benefits offers an open forum for all healthcare participants to exchange

ideas and present their data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Policymakers, Providers, Purchasers, and Researchers. Topics and type of articles of high interest include:

• Adherence Concerns • Benefit Design • Case Studies • Comorbidities and Cost Issues • Comparative Effectiveness Research • Decision-Making Tools • Ethics in Medicine • Health Economics Outcomes

• Health Information Exchange • Health Plan Initiatives • Innovations in Healthcare • Literature Reviews • Managed Care • Medicare/Medicaid • Patient Outcomes/Advocacy • Pharmacoeconomics

• Pharmacogenomics • Policy Issues • Prevention Initiatives • Real-World Evidence • Reimbursement Strategies • Social Media in Healthcare • Survey Results • Value-Based Healthcare

SUBMIT articles to editorial@engagehc.com or at www.AHDBonline.com Articles must follow the Manuscript Instructions for Authors, available online

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VISIT THE NEW ONLINE RESOURCE FOR THE ENTIRE MULTIPLE MYELOMA CARE TEAM

“Better informed teams provide better care.” Matthew P. Mitchell, PharmD, MBA, FAMCP Director, Pharmacy Services SelectHealth Murray, UT

Value-Based Care IN Myeloma

™

RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues. Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

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Supplement

Optimizing Medication Utilization and Adherence in Patients with Schizophrenia: A Perspective for Managed Care Pharmacists Faculty Peter J. Weiden, MD Director of Psychotic Disorders Program Center for Cognitive Medicine University of Illinois Medical Center Chicago, IL

Robert Navarro, PharmD Clinical Professor Department of Pharmaceutical Outcomes & Policy University of Florida–College of Pharmacy Gainesville, FL

Release date: January 26, 2015 Expiration date: January 31, 2016 Estimated time to complete activity: 1.0 hour Target Audience This activity is directed toward pharmacists who are involved in the management of patients with schizophrenia. Educational Objectives After completing this activity, the participant should be better able to: • List the current management options in schizophrenia, especially in relapsed disease • Describe the significant economic burden associated with medication nonadherence and relapse in patients with schizophrenia • Discuss strategies that can be employed by managed care pharmacists to improve medication utilization and adherence by patients with schizophrenia • Review the relative clinical and economic value of evolving therapies for schizophrenia, particularly involving the use of long-acting injectables • Provide accurate and appropriate counsel as part of the treatment team. Faculty Robert Navarro, PharmD Clinical Professor, Department of Pharmaceutical Outcomes & Policy University of Florida–College of Pharmacy Gainesville, FL

MAC MAC OS X 10.6 or higher Flash Player v10.0 or higher Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

*Required to view printable (PDF) version of the lesson. Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high-quality CME/CE activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest. The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity: Name of Faculty or Presenter

Reported Financial Relationship

Consultant for Alexion, AstraZeneca, Forect Laboratories, Novartis, Pfizer, Purdue, Sunovion, and Valeant; other: Catamaran PBM. Peter J. Weiden, Consultant for Delpor, Forum, Genentech, MD Johnson & Johnson (Janssen Pharmaceuticals), Lundbeck, Novartis, Otsuka, Reckitt Benckiser Pharmaceuticals, Sunovion, and Vanda; has received research support from AbbVie, Alkermes, Forum, Forest Laboratories, Genentech, Johnson & Johnson (Janssen Pharmaceuticals), Neurocrine, Novartis, Otsuka, Reckitt Benckiser Pharmaceuticals, and Takeda; Speaker’s Bureau for Forest Laboratories, Johnson & Johnson (Janssen Pharmaceuticals), Lundbeck, Novartis, Otsuka, and Sunovion; stockholder for Delpor. Matthew Mitchell, Nothing to disclose. PharmD, MBA Robert Navarro, PharmD

Peter J. Weiden, MD Director of Psychotic Disorders Program Center for Cognitive Medicine University of Illinois Medical Center Chicago, IL Matthew Mitchell, PharmD, MBA Pharmacy Director SelectHealth Salt Lake City, UT Pharmacist Continuing Education Accreditation Statement Postgraduate Institute for Medicine is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Credit Designation Postgraduate Institute for Medicine designates this continuing education activity for 1 contact hour(s) (0.1 CEU) of the Accreditation Council for Pharmacy Education. (Universal Activity Number 0809-9999-15-005-H01-P) Type of Activity: Application

System Requirements PC Windows 7 or above Flash Player v10.0 or higher Internet Explorer v9.0 or higher Latest version of Firefox, Google Chrome, or Safari Adobe Acrobat Reader v7.0 or higher*

The following PIM planners and managers—Laura Excell, ND, NP, MS, MA, LPC, NCC; Trace Hutchison, PharmD; Samantha Mattiucci, PharmD, CCMEP; and Jan Schultz, MSN, RN, CCMEP—hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

Matthew Mitchell, PharmD, MBA Pharmacy Director SelectHealth Salt Lake City, UT

Center of Excellence Media, LLC: Susan Berry hereby states that she or her spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Disclosure of Unlabeled Use This educational activity may contain discussion of published and/ or investigational uses of agents that are not indicated by the FDA. Postgraduate Institute for Medicine and Center of Excellence Media, LLC, do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities. Instructions for Credit There is no fee for this activity. To receive credit after reading this CE activity in its entirety, participants must complete the posttest and evaluation. The posttest and evaluation can be completed online at http://ce.lynxcme.com/COE177. Upon completion of the evaluation and scoring 75% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 75% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records. If you have any questions regarding the CE certification for this activity, please contact Postgraduate Institute for Medicine at: information@pimed.com or 303-799-1930. Pharmacists: Upon successfully completing the posttest with a score of 75% or better and the activity evaluation form, transcript information will be sent to the NABP CPE Monitor Service within 4 weeks. Media: Printed report

To obtain a digital version, download a free QR code app on your SmartPhone and then scan this code.

This activity is supported by an independent educational grant from Alkermes. Jointly provided by Postgraduate Institute for Medicine and Center of Excellence Media, LLC.

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ntipsychotic medication is the primary intervention for stabilization of acute psychotic episodes and prevention of recurrences and relapses in patients with schizophrenia. However, oral medications may be difficult for patients to maintain on a daily basis. Nonadherence to medication places patients at risk for repeated relapse and rehospitalization and can lead to increased costs for the healthcare system. This educational activity provides highlights of a live symposium from the Academy of Managed Care Pharmacy meeting held in Boston, MA, on October 7-10, 2014, which focused on current treatment options with long-acting injectable (LAI) antipsychotic therapy for relapse prevention, pharmacist-driven strategies for optimal medication utilization and adherence to antipsychotic drugs, and assessment of the clinical and economic value of LAI therapies in the management of schizophrenia.

Risk of Relapse in Schizophrenia and Its Implications Schizophrenia is a chronic, debilitating disorder with a variable pattern affecting the perceptual, cognitive, and emotional aspects of patients, resulting in considerable psychosocial disabilities and social isolation.1,2 Signs and symptoms of schizophrenia include hallucinations, delusions, avolition, movement disorders, and cognitive impairment.1,2 The disorder has a complex etiology with multifactorial genetic, environmental, and psychosocial contributions. Its worldwide prevalence is approximately 1%, with approximately 2.2 million adults currently living with schizophrenia in the United States.1,3 Antipsychotic drugs are the mainstay of treatment for symptom control in patients with schizophrenia. The primary question in the selection of the initial antipsychotic medication or in switching to a new antipsychotic medication typically involves the choice between first-generation antipsychotic agents (referred to as “typical”) and second-generation antipsychotic agents (termed “atypical”). The 2009 Schizophrenia Patient Outcomes Research Team (PORT) guidelines do not provide clear recommendations in this regard because existing evidence shows comparable efficacy and variable side effects of firstand second-generation antipsychotic agents. Therefore, medication choices are commonly based on individual preference and treatment-related factors such as prior treatment response, side effect profile, adherence history, risk factors, and long-term treatment planning.4 First-generation antipsychotic drugs are high-affinity dopamine D2 receptor antagonists associated with high rates of neurologic side effects, such as extrapyramidal symptoms and tardive dyskinesia, whereas second-generation antipsychotic drugs are not associated with these effects but have a propensity to induce weight gain and increased serum prolactin and glycemic levels.2,5-7

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However, results from a meta-analysis indicate that, individually, second-generation antipsychotic drugs were comparable to first-generation antipsychotic drugs in terms of study-defined relapse, overall treatment failure, and hospitalization rate, but that, as a group, second-generation antipsychotic drugs were associated with better outcomes compared with first-generation antipsychotic drugs for these same end points.8 The large, randomized CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) study assessed the relative effectiveness, as measured by treatment discontinuation at 18 months, of several second-generation antipsychotic drugs (olanzapine, quetiapine, risperidone, ziprasidone) versus the first-generation antipsychotic drug perphenazine in patients with schizophrenia.7 The results of this National Institute of Mental Health–sponsored trial showed that, overall, 74% of patients discontinued their antipsychotic therapy, with olanzapine showing the lowest rate of discontinuation (64%). Olanzapine was also the most effective of the antipsychotic drugs, with significantly longer time to discontinuation attributed to all causes versus quetiapine or risperidone, but not perphenazine or ziprasidone.7 Although there were no significant differences in time to discontinuation caused by intolerable side effects among the antipsychotic agents, olanzapine had the highest rate of discontinuation attributed to weight gain or metabolic effects.7

Schizophrenia is a chronic, debilitating disorder with a variable pattern affecting the perceptual, cognitive, and emotional aspects of patients, resulting in considerable psychosocial disabilities and social isolation. Despite treatment with antipsychotic therapy, the majority of patients with schizophrenia experience numerous relapses, alternating with periods of full or partial remission.2,9,10 A prospective and systematic follow-up of patients revealed that the cumulative rate of first relapse following an initial response to treatment of the first episode of schizophrenia was 81.9% over a 5-year period and 53.7% over a 2-year period; the cumulative rate of second and third relapses during the 5-year follow-up was 78% and 86.2%, respectively.10 Moreover, relapses are associated with clinical deterioration, including decreased chances of recovery to previous levels of functioning, worsened disability, decreased responsiveness to treatment, and reduced duration and degree of remission with each subsequent relapse.11,12 In addition to these impacts on clinical outcomes, re-

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curring relapses are associated with increased emergency department visits and hospitalizations. Schizophrenia is associated with hospitalization rates within the same range as those observed with myocardial infarctions (MIs).13 Data from the 2007 National Hospital Discharge Survey of nonfederal, general, and short-stay hospitals in the United States showed that the number of hospitalization discharges was 577,000 for acute MI and 324,000 for schizophrenia.13 These observations gain perspective when one considers that the population at risk for schizophrenia is only 1% of the general population, whereas the percentage of those at risk for acute MI is considerably higher. The risk of relapse may be diminished by maintenance antipsychotic drug treatment. One study reported a nearly 5-fold lower risk of relapse in patients with schizophrenia who were on continuous maintenance treatment versus those who discontinued medications.10 In addition, an analysis of 5 studies that compared continuous versus intermittent maintenance treatment showed that relapse rates after 1 year were higher in the intermittent treatment group. Gains in terms of improved psychosocial adjustment, diminished tardive dyskinesia, or enhanced well-being were also observed in the continuous maintenance group.2 Based on such evidence, the 2009 Schizophrenia PORT guidelines recommended that continuous antipsychotic coverage was needed to maintain symptom relief and to reduce the risk of relapse or worsening of positive symptoms, and discouraged the routine use of targeted, intermittent antipsychotic maintenance strategies.4,14

Medication Nonadherence and Utilization in Schizophrenia Medication nonadherence, which is rampant among patients with schizophrenia, has been significantly correlated with a higher risk of relapse and psychiatric hospitalization. One study reported that approximately 30% of partially or fully nonadherent patients were hospitalized during the 1 year following enrollment compared with 17% of adherent patients, with an average length of hospital stay of 30 days, 18 days, and 9 days for nonadherent, partially adherent, and adherent patients, respectively.15 Moreover, the extent of the medication gap caused by nonadherence has been directly correlated with a higher risk for hospitalization.16 This was shown in a study by Weiden and colleagues that evaluated the relationship between adherence and the risk for hospitalization in a cohort of 4325 California Medicaid patients with schizophrenia who were prescribed antipsychotics between 1999 and 2001 and followed for 1 year. Results of the study showed that the presence of a medication gap as small as 1 to 10 days was associated with an increased risk for hospitalization (odds ratio [OR], 1.9), whereas longer medication gaps were associated with incrementally higher risks

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(11-30 days: OR, 2.81; >30 days: OR, 3.96).16 These results indicate that even short gaps in medication have detrimental effects, thus highlighting the need for continuous, uninterrupted treatment in patients with schizophrenia. Nonadherence to medication is a result of complex patient behaviors and ranges from complete treatment discontinuation to irregular use or partial change of daily medication doses. Partial adherence to medication is at least as frequent as complete nonadherence.17 It is estimated that approximately 20% to 80% of patients with schizophrenia are partially or totally nonadherent to their antipsychotic regimen, the range of nonadherence rates reflecting different assessment methods, observation periods, and definitions of adherence.18 Moreover, assessment of adherence behavior can be challenging in the real-life setting. This is largely because self- and physician-reporting are the most common methods used to assess adherence, and they are often unreliable and overestimate adherence.17 For example, results of the PREFER (Prevent First Episode Relapse) study showed that clinicians missed >50% of nonadherence episodes as defined by a >2-week medication gap among patients on oral therapy compared with adherence episodes identified by All Source Verification, which used multiple sources of adherence information.19

Long-Acting Injectable Antipsychotic Medications in Schizophrenia for Relapse Prevention LAI antipsychotic medications were developed specifically as an intervention to promote treatment adherence.20 The 2009 Schizophrenia PORT guidelines recommend offering LAI therapy as an alternative to oral antipsychotic medication for the maintenance treatment of schizophrenia when there is concern over noncompliance.4 Four US Food and Drug Administration (FDA)approved second-generation LAI antipsychotic agents are currently available in the United States for the treatment of schizophrenia (Table 1).21 There are many potential advantages associated with LAI antipsychotic agents (Table 2). Prominent among these are guaranteed delivery of medication, reliable monitoring of treatment adherence, and knowledge of exact start of nonadherence, which eliminates guessing about adherence status, thus providing an increased opportunity for timely intervention.22 In contrast, gaps in medication may go undetected with oral medications, and given the difficulty in predicting the occurrence of exacerbation, relapses may not be as easily preventable. Another benefit of LAIs is in guiding treatment decision-making, where poor response can be directly correlated to medication efficacy without speculating about the contribution of nonadherence. Moreover, the improved pharmacokinetics of LAIs has provided more reli-

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Table 1 Dose and Administration of FDA-Approved Second-Generation Long-Acting Injectable Antipsychotic Agents for Schizophrenia Available Oral medication Medication dose strength Usual dose Maximum dose Loading dose before initiation Aripiprazole

300 mg (CYP2D6 poor metabolizers) 400 mg

400 mg once monthly

Suggested; overlap with oral antipsychotic drugs for 14 consecutive days

Olanzapine pamoate

210 mg 310 mg 405 mg

150 mg–300 mg every 2 weeks or 405 mg every 4 weeks

300 mg every 2 weeks or 405 mg every 4 weeks

Yes – Varies depending on starting oral olanzapine dose

Suggested; oral olanzapine

Paliperidone palmitate

39 mg 78 mg 117 mg 156 mg 234 mg

117 mg once monthly (39-234 mg)

234 mg once monthly

Yes – 234 mg on day 1, then 156 mg 1 week later

Suggested; overlap with oral paliperidone or oral risperidone

Risperidone microspheres

12.5 mg 25 mg 37.5 mg 50 mg

25 mg–50 mg every 2 weeks

50 mg every 2 weeks

Yes; overlap with oral antipsychotic drugs for 3 weeks

FDA indicates US Food and Drug Administration. Source: Gopalakrishna G, et al. Clin Schizophr Relat Psychoses. 2013;7:87-92.

able drug delivery and reduced differences in peak and trough plasma levels of the drug.22 However, challenges with the use of LAIs include not only fewer drug options compared with oral antipsychotic medications, but also safety concerns, lag time between oral and LAI availability, and pharmacokinetic differences in formulation. The long half-life of LAIs necessitates ensuring safe and effective plasma levels when transitioning from oral to LAI therapy, which may be accomplished by either continuing oral medication until the LAI reaches therapeutic levels or using higher doses of the LAI initially.23 Although safety profiles of second-generation LAI antipsychotic medications have largely been consistent with those of their oral parent formulations, unexpected adverse events of concern have also emerged, which appear to be specific to each second-generation LAI antipsychotic agent and may contribute to nonutilization of therapy.5 For example, postinjection delirium/ sedation syndrome is a potentially serious adverse event that is mostly linked to the routine use of olanzapine-LAI, whereas worsening of psychotic symptoms and depression may be associated with the use of risperidone and paliperidone palmitate LAIs.5 In addition, patient and prescriber attitudes resulting from lack of familiarity with or reluctance to try the LAI formulation have been cited as major obstacles to LAI utilization.24 Despite the availability of LAIs, less than 30% of patients with schizophrenia are prescribed one, as evidenced by preferential endorsement of oral psychotic

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Table 2 Potential Advantages of Using Long-Acting Injectable Antipsychotic Agents Reduces dosage deviations Eliminates guessing about adherence status Shows start date of nonadherence Helps disentangle reasons for poor response to medication Eliminates the need for patients to remember to take oral medications Enables prescribers to avoid first-pass metabolism by using lowest effective dose Results in predictable and stable plasma levels Eliminates abrupt loss of efficacy if dose is missed Many patients prefer them

agents over LAI formulations.20,24 This underutilization may be attributable to physicians’ suboptimal knowledge as well as a mistaken assumption that their patients are more adherent than they actually are.20 Current evidence indicates that patients have less favorable views of LAIs compared with those of psychiatrists or caregivers.24 However, prior experience with LAIs mitigated such negative patient perspectives, as evidenced by data showing that 23% of LAI-naive patients, 45% of patients with previous LAI treatment, and 73% of those currently on LAIs had positive perceptions of these therapies.25 Current evidence regarding LAI therapy appears to be inconsistent, with some studies showing major benefits,

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Figure Managed Care Pharmacist Interventions in Schizophrenia • Initial DUR to identify status • Number and diagnoses of patients • Antipsychotic drug use patterns - Patient–drug utilization - Correlate with care provider (HCP, MHP) • Assess comorbidities and hospitalizations (severity, risk) • Assign care management and program resources • Follow-up program for clinical and economic outcomes

DUR indicates drug utilization review; HCP, healthcare provider; MHP, mental health professional.

and others showing no difference between LAI and oral therapy.23 In a randomized trial of 710 patients with schizophrenia, once-monthly intramuscular aripiprazole-LAI as maintenance therapy following stable disease with oral therapy demonstrated a significant delay in time to impending relapse compared with placebo.26 In a randomized open-label study, olanzapine-LAI and oral olanzapine were found to be similarly effective and well tolerated for up to 2 years of treatment in patients with schizophrenia.27 The median time to all-cause discontinuation, discontinuation rates, and relapse rates were similar between the 2 treatment groups.27 In addition, in a randomized, placebo-controlled study of 652 adults with acutely exacerbated schizophrenia, treatment with paliperidone was shown to result in a significant dose-related and rapid improvement in symptoms (P ≤.034), as measured by the Positive and Negative Syndrome Scale (PANSS).28 The controversy regarding the relative effectiveness of LAI therapy to reduce relapse may be partly explained by the context in which LAI therapy is delivered, primarily on the clinical service platform of the study. In the randomized PROACTIVE relapse prevention study in 305 patients with schizophrenia or schizoaffective disorder at 8 US academic centers, there were no differences in rates of relapse or rehospitalization between risperidone-LAI and physician’s choice of oral second-generation antipsychotic agent.29 In contrast, the 15-month, prospective, randomized, open-label, PRIDE trial, which compared paliperidone palmitate versus oral antipsychotic agents in a real-world setting of patients diagnosed with schizophrenia who had a recent history of incarceration and substance abuse, showed that LAI therapy significantly delayed time to treatment failure (median 416 days vs 226 days; P = .011) compared with oral therapy.30 Time to treatment failure in this study was defined as arrest or incarceration, psychiatric hospitalization, discontinuation of

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treatment, supplementation with another antipsychotic agent, or need for extra services to prevent imminent psychiatric hospitalization; reduction of many or all of these aspects may indirectly impact overall relapse. In the setting of LAI maintenance therapy in early first-episode outpatients, the prospective randomized PREFER study, which evaluated switching to LAI risperidone microspheres or continuing oral antipsychotic treatment for up to 10 weeks, showed that the majority of patients stopped medication within the study period despite an initial adherence benefit.19

Nonpharmacologic Interventions for Improving Medication Adherence The factors most consistently associated with medication nonadherence in patients with schizophrenia are patient-related (eg, sociodemographics, attitude toward illness and treatment, alcohol or substance abuse), illness-related (type and severity of symptoms, poor insight, duration of illness), and treatment-related (eg, length/ complexity of treatment, side effects) variables, as well as environmental factors. Systematic reviews of nonadherence determinants have identified lack of patient insight, unfavorable patient and physician attitudes, distress associated with side effects, inadequate efficacy, misconception that medications are no longer needed, previous nonadherence, substance abuse, shorter illness duration, inadequate discharge planning or aftercare environment, and poor alliance with therapist(s) as contributing factors.17,18 In a study from the Schizophrenia Guidelines Project, the most common patient-reported barriers were related to the stigma of taking medications, adverse drug reactions, forgetfulness, and lack of social support.31 The study also found that patients with high barriers had a significantly greater likelihood of being nonadherent, having alcohol or drug use, and having higher PANSS total scores.31 Identification of these risk factors for nonadherence highlights the need for targeted nonpharmacologic interventional strategies that may broadly be categorized as educational, behavioral, or affective.18 A systematic review of 39 studies found that adherence interventions that focused solely on education without behavioral modifications were usually ineffective; conversely, interventions that focused on nonadherence alone were more likely to be successful than more broadly focused interventions.32 Effective strategies included motivational interviewing, disease education, counseling, reinforcement and rewards skill building, behavioral modeling and contracting, dosage modifications, reminders, computerbased patient interaction, appeal to emotions, as well as family interventions and support.18,33 Successful adherence intervention programs employed individualized combination interventions, with consistent interactions

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and follow-up, followed by assessment and refinement.33 Managed care pharmacists play a unique role in the multidisciplinary team and are often presented interventional opportunities to improve adherence in patients with schizophrenia. For example, they can conduct drug utilization reviews and assess hospitalizations to identify patients who need adherence interventions; implement individualized disease management programs that include motivational interviewing and patient engagement; monitor the impact of interventions; and arrange follow-up programs to reevaluate and personalize programs. This must happen as a cyclical, continual process (Figure). Indeed, multifocal pharmacy-driven interventions have been shown to increase antipsychotic drug adherence among patients with serious mental illnesses. In a study of 118 patients from 7 participating Veterans Affairs facilities who had serious mental illnesses, including schizophrenia, and who were deemed nonadherent to long-term antipsychotic drugs, pharmacy-led interventions significantly improved adherence rates at 6 months (medication possession ratios [MPRs]: 0.91 vs 0.64) compared with usual care that did not include any interventions.34 Moreover, since managed care pharmacists possess a deeper understanding of the relationship between pharmacokinetic, dose-response, and pharmacologic characteristics of medications including LAIs, they are ideally suited to educate and collaborate with mental health professionals to promote appropriate use of LAI therapy options. In essence, they must balance gatekeeper and advocacy roles in medication selection and maintain an administrative perspective on drug utilization.

Value of Long-Acting Injectable Therapies for Schizophrenia Not only is schizophrenia a devastating illness for most individuals who are afflicted, but it is also associated with a significant economic burden. Based on administrative claims data from private and Medicaid insurance plans, the overall 2002 cost of schizophrenia in the United States was estimated to be $62.7 billion.35 Of this, the costs of excess direct healthcare were $22.8 billion (outpatient care, $7.0 billion; medication, $5.0 billion; inpatient care, $2.8 billion; and long-term care, $8.0 billion).35 Annual indirect excess costs were estimated to be $32.4 billion as a result of productivity losses resulting from unemployment, reduced workplace productivity, and diminished family caregiving.35 Importantly, as discussed earlier, nonadherence to antipsychotic medications results in relapse and rehospitalization, which are associated with additional costs.36 In fact, costs incurred for patients with schizophrenia who relapsed were found to be more than 4 times higher than the costs for those who did not relapse.37 In an analysis of

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patients from the Medicaid program who were rehospitalized related to antipsychotic drug nonadherence, the direct healthcare rehospitalization costs ranged from $1392 million to $1826 million in 2005.36 It is also notable that there has been a steady growth in prescription volume of antipsychotic medications (20092011) in the United States, with a 24% increase in expenditures. In 1998, Medicaid antipsychotic medication expenditures totaled $1.3 billion and 51% of the 11 million prescriptions were for atypicals.38 In the same year, prescriptions for antipsychotic medications accounted for 9% of Medicaid pharmaceutical prescriptions and nearly 19% of Medicaid pharmaceutical reimbursements.38 The cost of newer medications has clearly been identified as a key barrier to unrestricted access and utilization of newer antipsychotic agents.38 In this economic context, questions have been raised about the clinical advantages and cost-effectiveness of the currently available atypical antipsychotic agents; clearly, results from such assessments must inform practice of value-based care in patients with schizophrenia to ensure efficient resource use.

Managed care pharmacists play a unique role in the multidisciplinary team and are often presented interventional opportunities to improve adherence in patients with schizophrenia. Findings from the pharmacoeconomic literature conclude that new antipsychotic agents are associated with economic advantages compared with older antipsychotic drugs. An economic model compared the cost-effectiveness and direct treatment cost of olanzapine-LAI versus risperidone-LAI, paliperidone-LAI, haloperidol-LAI, and oral olanzapine, as measured by quality-adjusted life-years in the treatment of nonadherent and partially adherent patients with schizophrenia.39 The findings of the study showed that olanzapine-LAI treatment was more clinically effective and less costly than the LAI antipsychotic agents risperidone, paliperidone, and haloperidol; olanzapine-LAI was also more effective than oral olanzapine, but it was also more costly, with an estimated incremental cost/quality-adjusted life-years of $26,824.39 Moreover, in relapsed patients who are rehospitalized, findings of a retrospective hospital database analysis showed that switching to an LAI versus continuing with an oral antipsychotic drug was associated with a 19% to 12% lower likelihood of rehospitalization, as well as lower emergency department visit rates and fewer days in the hospital, all of which translate into lower costs.40

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Conclusion The substantial clinical and socioeconomic burden of nonadherence in schizophrenia underscores the importance of medication adherence. In this setting, LAI therapy has emerged as an important maintenance treatment option for improving adherence in patients with the disease. In addition to comparable clinical effectiveness, long-acting therapy is associated with lower utilization of health resources compared with oral antipsychotic therapy. In parallel, pharmacy-led nonpharmacologic interventions are also valuable in promoting adherence. Given that nonadherence is a complex, multifaceted issue, multifocal interventions focusing on patients, their families, and their healthcare providers are critical to achieving optimal outcomes in schizophrenia. Acknowledgment Sabeeha Muneer, PhD, contributed to the development of this article. References

1. Andreasen NC. Symptoms, signs, and diagnosis of schizophrenia. Lancet. 1995;346:477-481. 2. Kane JM. Schizophrenia. N Engl J Med. 1996;334:34-41. 3. Schizophrenia facts and statistics. Schizophrenia.com Web site. http://schizo phrenia.com/szfacts.htm#. Accessed November 7, 2014. 4. Buchanan RW, Kreyenbuhl J, Kelly DL, et al. The 2009 Schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36:71-93. 5. Gentile S. Adverse effects associated with second-generation antipsychotic long-acting injection treatment: a comprehensive systematic review. Pharmacotherapy. 2013;33:1087-1106. 6. Miyamoto S, Duncan GE, Marx CE, et al. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry. 2005;10:79-104. 7. Lieberman JA, Stroup TS, McEvoy JP, et al; for the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005; 353:1209-1223. 8. Kishimoto T, Agarwal V, Kishi T, et al. Relapse prevention in schizophrenia: a systematic review and meta-analysis of second-generation antipsychotics versus first-generation antipsychotics. Mol Psychiatry. 2013;18:53-66. 9. de Sena EP, Santos-Jesus R, Miranda-Scippa A, et al. Relapse in patients with schizophrenia: a comparison between risperidone and haloperidol. Rev Bras Psiquiatr. 2003;25:220-223. 10. Robinson D, Woerner MG, Alvir JM, et al. Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry. 1999;56:241-247. 11. Emsley R, Nuamah I, Hough D, et al. Treatment response after relapse in a placebo-controlled maintenance trial in schizophrenia. Schizophr Res. 2012;138: 29-34. 12. Wyatt RJ. Neuroleptics and the natural course of schizophrenia. Schizophr Bull. 1991;17:325-351. 13. Hall MJ, DeFrances CJ, Williams SN, et al. National Hospital Discharge Survey: 2007 summary. Natl Health Stat Report. 2010;1-20, 24. 14. Kreyenbuhl J, Buchanan RW, Dickerson FB, et al. The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull. 2010;36:94-103. 15. Ascher-Svanum H, Zhu B, Faries DE, et al. Medication adherence levels and differential use of mental-health services in the treatment of schizophrenia. BMC Res Notes. 2009;2:6. 16. Weiden PJ, Kozma C, Grogg A, et al. Partial compliance and risk of rehospitalization among California Medicaid patients with schizophrenia. Psychiatr Serv. 2004;55:886-891.

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17. Velligan DI, Weiden PJ, Sajatovic M, et al; Expert Consensus Panel on Adherence Problems in Serious and Persistent Mental Illness. The expert consensus guideline series: adherence problems in patients with serious and persistent mental illness. J Clin Psychiatry. 2009;70(suppl 4):1-46. 18. Lacro JP, Dunn LB, Dolder CR, et al. Prevalence of and risk factors for medication nonadherence in patients with schizophrenia: a comprehensive review of recent literature. J Clin Psychiatry. 2002;63:892-909. 19. Weiden PJ, Schooler NR, Weedon JC, et al. Maintenance treatment with long-acting injectable risperidone in first-episode schizophrenia: a randomized effectiveness study. J Clin Psychiatry. 2012;73:1224-1233. 20. Patel MX, Taylor M, David AS. Antipsychotic long-acting injections: mind the gap. Br J Psychiatry Suppl. 2009;52:S1-S4. 21. Gopalakrishna G, Aggarwal A, Lauriello J. Long-acting injectable aripiprazole: how might it fit in our tool box? Clin Schizophr Relat Psychoses. 2013;7: 87-92. 22. McEvoy JP. Risks versus benefits of different types of long-acting injectable antipsychotics. J Clin Psychiatry. 2006;67(suppl 5):15-18. 23. De Berardis D, Marini S, Carano A, et al. Efficacy and safety of long acting injectable atypical antipsychotics: a review. Curr Clin Pharmacol. 2013;8: 256-264. 24. Jaeger M, Rossler W. Attitudes towards long-acting depot antipsychotics: a survey of patients, relatives and psychiatrists. Psychiatry Res. 2010;175:58-62. 25. Heres S, Schmitz FS, Leucht S, et al. The attitude of patients towards antipsychotic depot treatment. Int Clin Psychopharmacol. 2007;22:275-282. 26. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73: 617-624. 27. Detke HC, Weiden PJ, Llorca PM, et al. Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia. J Clin Psychopharmacol. 2014;34: 426-434. 28. Pandina GJ, Lindenmayer J-P, Lull J, et al. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol. 2010;30:235-244. 29. Buckley PF, Schooler NR, Goff DC, et al. Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study [published online ahead of print May 27, 2014]. Schizophr Bull. doi:10.1093/schbul/sbu067. 30. Starr HL, et al. Paliperidone research in demonstrating effectiveness (PRIDE): managing schizophrenia patients with a history of incarceration and substance use. Presented at: American Psychiatric Association 167th Annual Meeting; May 3-7, 2014; New York, NY. Abstract NR8-150. 31. Hudson TJ, Owen RR, Thrush CR, et al. A pilot study of barriers to medication adherence in schizophrenia. J Clin Psychiatry. 2004;65:211-216. 32. Zygmunt A, Olfson M, Boyer CA, et al. Interventions to improve medication adherence in schizophrenia. Am J Psychiatry. 2002;159:1653-1664. 33. McDonald HP, Garg AX, Haynes RB. Interventions to enhance patient adherence to medication prescriptions: scientific review. JAMA. 2002;288: 2868-2879. 34. Valenstein M, Kavanagh J, Lee T, et al. Using a pharmacy-based intervention to improve antipsychotic adherence among patients with serious mental illness. Schizophr Bull. 2011;37:727-736. 35. Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry. 2005;66:1122-1129. 36. Sun SX, Liu GG, Christensen DB, et al. Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. Curr Med Res Opin. 2007;23:2305-2312. 37. Almond S, Knapp M, Francois C, et al. Relapse in schizophrenia: costs, clinical outcomes and quality of life. Br J Psychiatry. 2004;184:346-351. 38. Harrington C, Gregorian R, Gemmen E, et al. Access and utilization of new antidepressant and antipsychotic medications. Falls Church, Va.: Lewin Group, 2000. http://aspe.hhs.gov/health/reports/Psychmedaccess/index.htm. Accessed November 8, 2014. 39. Furiak NM, Ascher-Svanum H, Klein RW, et al. Cost-effectiveness of olanzapine long-acting injection in the treatment of patients with schizophrenia in the United States: a micro-simulation economic decision model. Curr Med Res Opin. 2011;27:713-730. 40. Lafeuille M-H, LalibertĂŠ-Auger F, Lefebvre P, et al. Impact of atypical long-acting injectable versus oral antipsychotics on rehospitalization rates and emergency room visits among relapsed schizophrenia patients: a retrospective database analysis. BMC Psychiatry. 2013;13:221.

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Brief Summary

VELC3X0043_A_Velcade_BS_7x10_r3.indd 1

Embryo-fetal: Pregnancy Category D. Women of reproductive 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 administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) 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 (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each). In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%). In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group. 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. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, 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, VELCADE 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 bortezomib 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 VELCADEHCP.com.

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 © 2013, Millennium Pharmaceuticals, Inc. V-12-0306a All rights reserved. Printed in USA V-14-0258

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INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE 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 (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: 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. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group. Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy. Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. 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 8%. 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 Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, 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 of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively. The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred 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, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted. Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES 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 PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known. Gastrointestinal Toxicity: 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. Interrupt VELCADE for severe symptoms. 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 of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered. Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. Monitor patients closely and take appropriate precautions. Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

What is the value of one year on velCaDe (bortezomib)? ®

for patients with previously untreated multiple myeloma, 1 year of treatment with velCaDe in combination with MP* delivered a >1-year sustained median overall survival (os) advantage.1† At 60.1-month median follow-up: VELCADE (bortezomib)+MP provided a median OS of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05) At 3-year median follow-up: VELCADE+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 Results were achieved using VELCADE twice weekly followed by a weekly dosing for a median of 50 weeks (54 weeks planned)1

the additional value of choice of administration. Subcutaneous VELCADE demonstrated efficacy consistent with IV for the primary endpoints2‡: At 12 weeks, subcutaneous VELCADE: 43% achieved overall response rate (ORR) and 7% complete response (CR) vs IV: 42% ORR and 8% CR §II

The median age of patients in the VISTA† trial was 71 years (range: 48-91).

At 24 weeks, subcutaneous VELCADE ± dexamethasone: 53% achieved ORR and 11% CR vs IV: 51% ORR and 12% CR§II More than 80% of previously untreated patients starting on VELCADE receive subcutaneous administration 3¶

Indication and Important Safety Information for VELCADE® (bortezomib) INDICATION VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma. CONTRAINDICATIONS VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS, PRECAUTIONS, AND DRUG INTERACTIONS ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration. ▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms.

▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ thrombocytopenia or neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ hepatic toxicity: Monitor hepatic enzymes during treatment. ▼ embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CyP3a4 inhibitors. Avoid concomitant use of strong CyP3a4 inducers. ADVERSE REACTIONS Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia. Please see Brief Summary for VELCADE adjacent to this advertisement. For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADE-HCP.com.

*Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed. ‡ SuBCuTAnEouS VS IV was a randomized (2:1), open-label, non-inferiority phase 3 trial (N=222) in patients with relapsed multiple myeloma designed to establish whether subcutaneous VELCADE (bortezomib) was non-inferior to intravenous administration.2 Non-inferiority was defined as retaining 60% of the intravenous treatment effect, measured by ORR, at the end of 4 cycles.2 The primary endpoint was ORR at 4 cycles. The secondary endpoints were response rate at 8 cycles, median TTP and PFS (months), 1-year OS, and safety. § Responses were based on criteria established by the European Group for Blood and Marrow Transplantation.2 II 82 patients (55%) in the subcutaneous VELCADE group and 39 patients (53%) in the IV group received dexamethasone. ¶ Out of 275 estimated unique patients receiving VELCADE as of May 2013.3 References: 1. Mateos MV, 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. 2. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 2011;12(5):431-440. 3. Data on file 59, Millennium Pharmaceuticals, Inc.