Care. Reaching For the Stars

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1 A N A G E D JUNE 2014 m at.co er st um gi or re rsf nd to t a ec si ir Vi ald ic ed M MANAGED CARE Care M Reaching For the Stars VOLUME 23, NUMBER 6 Medical Directors Strive for Top Medicare Advantage Ratings PAGE 15 Q&A: Mary D. Naylor, PhD, On Discharge and Follow-Up Health Information Exchanges Promise Much, Deliver What? JUNE 2014 When to Screen For Cognitive Decline MC_1406_Cover_v10_widespine.indd 1 6/5/14 9:48 AM

2 NEW NEW TARGET. NEW POTENTIAL. The first and only non-competitive AMPA receptor antagonist 1-3 Adjunctive therapy for patients ages 12 and up with partial-onset seizures 2 To find out more information about FYCOMPA, speak to your account manager or go to FYCOMPA.com References: 1. Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 2011;11: Fycompa Prescribing Information. Woodcliff Lake, NJ: Eisai Inc.; October Hanada T, Hashizume Y, Tokuhara N, et al. Fycompa: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia. 2011;52:

3 Indication FYCOMPA (perampanel) is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older. Important Safety Information WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA Closely monitor patients particularly during the titration period and at higher doses FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening Serious Psychiatric and Behavioral Reactions Hostility- and aggressionrelated adverse reactions occurred in 12% and 20% of clinical trial patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 6% of patients in the placebo group. These effects were doserelated and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. These effects in FYCOMPA-treated patients led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Patients taking FYCOMPA should avoid the use of alcohol. Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients. Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, their caregivers, and families should be informed of the risk and advised to monitor and immediately report the emergence or worsening of depression, suicidal thoughts or behavior, thoughts about self-harm, and/or any unusual changes in mood or behavior. Should suicidal thoughts or behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Dizziness and Gait Disturbance FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination. Dizziness and vertigo were reported in 35% and 47% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 10% of placebotreated patients. Gait disturbance related events were reported in 12% and 16% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 2% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase. Somnolence and Fatigue FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events. Somnolence was reported in 16% and 18% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 7% of placebo-treated patients. Fatigue-related events were reported in 12% and 15% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 5% of placebo-treated patients. In the controlled Phase 3 epilepsy clinical trials, these adverse reactions occurred mostly during the titration phase. Patients should be advised against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known. Falls Falls were reported in 5% and 10% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 3% of placebo-treated patients. Withdrawal of AEDs A gradual withdrawal is generally recommended with antiepileptic drugs to minimize the potential of increased seizure frequency. Most Common Adverse Reactions In clinical trials, the most frequently reported dose-related adverse reactions in patients receiving FYCOMPA 8 mg or 12 mg vs placebo ( 4% and at least 1% higher than the placebo group) included dizziness (36% vs 9%), somnolence (16% vs 7%), fatigue (10% vs 5%), irritability (9% vs 3%), falls (7% vs 3%), nausea (7% vs 5%), ataxia (5% vs 0%), balance disorder (4% vs 1%), gait disturbance (4% vs 1%), vertigo (4% vs 1%), and weight gain (4% vs 1%). Drug Interactions FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel. Plasma levels of FYCOMPA were decreased when administered with carbamazepine, phenytoin and oxcarbazepine. Concomitant use with strong CYP3A inducers such as St. John s wort and rifampin should be avoided. Multiple dosing of FYCOMPA 12 mg/day enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with other CNS depressants. Pregnancy Category C and Lactation FYCOMPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Physicians are advised to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Caution should be exercised when FYCOMPA is administered to a nursing woman. Hepatic and Renal Impairment Use in patients with severe hepatic or severe renal impairment is not recommended. Dosage adjustments are recommended in patients with mild or moderate hepatic impairment. Use with caution in patients with moderate renal impairment. Drug Abuse and Dependence FYCOMPA is a Schedule III controlled drug substance and has the potential to be abused or lead to drug dependence. Please see Brief Summary of full Prescribing Information for Boxed WARNING and additional Important Safety Information on the next page. FYCOMPA is a trademark of Eisai R&D Management Co., Ltd., licensed to Eisai Inc. Manufactured and marketed by Eisai Inc., Woodcliff Lake, NJ Eisai Inc. All rights reserved. FYCO0486 April 2014

4 FYCOMPA (perampanel) tablets, for oral use, CIII Initial U.S. Approval: 2012 BRIEF SUMMARY-see package insert for full Prescribing Information WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA (5.1) These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression (5.1) Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA (5.1) Closely monitor patients particularly during the titration period and at higher doses (5.1) FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening (5.1) INDICATIONS AND USAGE FYCOMPA (perampanel) is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older. DOSAGE AND ADMINISTRATION Dosing Information In the Absence of Enzyme-Inducing AEDs The recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by 2 mg per day increments no more frequently than every week to a dose of 4 mg to 8 mg once daily taken at bedtime. In elderly patients, dosage increases during titration are recommended no more frequently than every two weeks. The recommended dose range is 8 mg to 12 mg once daily. A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. Individual dosing should be adjusted based on clinical response and tolerability [see Clinical Studies (14)]. In the Presence of Enzyme-Inducing AEDs The recommended starting dosage of FYCOMPA in the presence of enzyme-inducing AEDs, including phenytoin, carbamazepine, and oxcarbazepine, is 4 mg and patients should be monitored closely for response. Clinical trials revealed a substantially reduced effect on seizure rates in these patients. The reduction in seizure frequency was somewhat greater at 12 mg than at 8 mg [see Clinical Studies (14)]. When these enzyme-inducing AEDs are introduced or withdrawn from a patient s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary. Dosage Adjustments in Patients with Hepatic Impairment Based on higher exposure and the longer half-life of perampanel in patients with mild and moderate hepatic impairment, dosage adjustment is recommended. Starting dose should be 2 mg per day with weekly increments of 2 mg per day every two weeks until target dose is achieved. The maximum recommended daily dose is 6 mg for patients with mild hepatic impairment and 4 mg for patients with moderate hepatic impairment. Dose increases in patients with mild and moderate hepatic impairment, as with all patients, should be based on clinical response and tolerability. Use in patients with severe hepatic impairment is not recommended [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Patients with Renal Impairment FYCOMPA can be used in patients with moderate renal impairment with close monitoring. A slower titration may be considered based on clinical response and tolerability. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Serious Psychiatric and Behavioral Reactions In the controlled Phase 3 epilepsy clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. FYCOMPA-treated patients experienced more hostility- and aggressionrelated adverse reactions that were serious, severe, and led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. In general, in placebo-controlled Phase 3 epilepsy trials, neuropsychiatric events were reported more frequently in patients being treated with FYCOMPA than in patients taking placebo. These events included irritability, aggression, anger, and anxiety which occurred in 2% or greater of perampanel treated patients and twice as frequently as in placebo-treated patients. Other symptoms that were observed with perampanel treatment and more commonly than with placebo, included belligerence, affect lability, agitation, and physical assault. Some of these events were reported as serious and life-threatening. Homicidal ideation and/or threat were exhibited in 0.1% of 4,368 perampanel treated patients in controlled and open label studies, including non-epilepsy studies. In the Phase 3 epilepsy trials these events occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression. Some patients experienced worsening of their pre-existing psychiatric conditions. Patients with active psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The combination of alcohol and perampanel significantly worsened mood and increased anger [see Drug Interactions (7.3)]. Patients taking FYCOMPA should avoid the use of alcohol. In healthy volunteers taking FYCOMPA, observed psychiatric events included paranoia, euphoric mood, agitation, anger, mental status changes, and disorientation/confusional state. In the non-epilepsy trials, psychiatric events that occurred in perampanel-treated subjects more often than placebo-treated subjects included disorientation, delusion, and paranoia. Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Dose of FYCOMPA should be reduced if these symptoms occur. Permanently discontinue FYCOMPA for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebotreated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs. Table 1. Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/ Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy Psychiatric Other Total The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Neurologic Effects Dizziness and Gait Disturbance FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination [see Adverse Reactions (6.1)]. In the controlled Phase 3 epilepsy clinical trials, dizziness and vertigo were reported in 35% and 47% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 10% of placebo-treated patients. The gait disturbance related events (including ataxia, gait disturbance, balance disorder, and coordination abnormal) were reported in 12% and 16% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 2% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3% of perampanel-treated subjects compared to 1% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents. Somnolence and Fatigue FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy). In the controlled Phase 3 epilepsy clinical trials, 16% and 18% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported somnolence compared to 7% of placebo patients. In the controlled Phase 3 epilepsy clinical trials, 12% and 15% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported fatigue-related events compared to 5% of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2% of perampanel-treated patients and 0.5% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents. Risk Amelioration Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known. In the controlled Phase 3 epilepsy clinical trials these adverse reactions occurred mostly during the titration phase. Falls An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with FYCOMPA (with and without concurrent seizures). In the controlled Phase 3 epilepsy clinical trials, falls were reported in 5% and 10% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 3% of placebo-treated patients. Falls were reported as serious and led to discontinuation more frequently in FYCOMPA-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and adolescents. Withdrawal of Antiepileptic Drugs There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. FYCOMPA has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In antiepileptic clinical trials FYCOMPA was withdrawn without down-titration. Although a small number of patients exhibited seizures following discontinuation, the data were not sufficient to allow any recommendations regarding appropriate withdrawal regimens. A gradual withdrawal is generally recommended with antiepileptic drugs, but if withdrawal is a response to adverse events, prompt withdrawal can be considered. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the prescribing information: Serious Psychiatric and Behavioral Reactions [see Warnings and Precautions (5.1)] Suicidal Behavior and Ideation [see Warnings and Precautions (5.2)] Dizziness and Gait Disturbance [see Warnings and Precautions (5.3)] Somnolence and Fatigue [see Warnings and Precautions (5.3)] Falls [see Warnings and Precautions (5.4)] Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 1,038 patients on perampanel (2, 4, 8, or 12 mg once daily) constituted the safety population in the pooled analysis of Phase 3 placebo controlled studies (Studies 1, 2, and 3) in patients with partial onset seizures. Approximately 51% of patients were female and the mean age was 35 years. Adverse Reactions Leading to Discontinuation In controlled Phase 3 clinical trials (Studies 1, 2, and 3), the rate of discontinuation as a result of an adverse reaction was 3%, 8% and 19% in patients randomized to receive FYCOMPA at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 5% in patients randomized to receive placebo [see Clinical Studies (14)]. The adverse events most commonly leading to discontinuation ( 1% in the 8 mg or 12 mg FYCOMPA group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria [see Warnings and Precautions (5.1 and 5.3)]. Most Common Adverse Reactions Table 2 gives the incidence in the Phase 3 controlled trials (Studies 1, 2, and 3) of the adverse reactions that occurred in 2% of patients with partial-onset seizures in any FYCOMPA dose group. Overall, the most frequently reported dose-related adverse reactions in patients receiving FYCOMPA at doses of 8 mg or 12 mg ( 4% and occurring at least 1% higher than the placebo group) included dizziness (36%), somnolence (16%), fatigue (10%), irritability (9%), falls (7%), nausea (7%), ataxia (5%), balance disorder (4%), gait disturbance (4%), vertigo (4%), and weight gain (4%). For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation. Table 2. Adverse Reactions in Pooled Double-blind Trials in Patients with Partial-Onset Seizures (Reactions 2% of Patients in Highest FYCOMPA Dose (12 mg) Group and More Frequent than Placebo) Placebo n=442 % 4 mg n=172 % FYCOMPA 8 mg n=431 % 12 mg n=255 % Ear and Labyrinth Disorders Vertigo Eye Disorders Diplopia Blurred vision Gastrointestinal Disorders Constipation Nausea Vomiting Infections and Infestations Upper respiratory tract infection Injury, Poisoning and Procedural Complications

5 Table 2. Adverse Reactions in Pooled Double-blind Trials in Patients with Partial-Onset Seizures (Reactions 2% of Patients in Highest FYCOMPA Dose (12 mg) Group and More Frequent than Placebo) (cont.) Contusion Falls Head injury Limb injury < Skin laceration Investigations Weight gain Metabolism & Nutrition disorders Hyponatremia < Musculoskeletal and Connective Tissue disorders Arthralgia Back pain Musculoskeletal pain Myalgia Pain in extremity Peripheral edema Nervous system disorders Asthenia Ataxia Balance disorder Coordination abnormal 0 1 <1 2 Dizziness Dysarthria Fatigue Gait disturbance Headache Hypersomnia Hypoaesthesia Memory impairment Paraesthesia Somnolence Psychiatric disorders Aggression Anger < Anxiety Confusional state < Euphoric mood 0 0 <1 2 Irritability Mood altered <1 1 <1 2 Respiratory, Thoracic and Mediastinal Disorders Cough Oropharyngeal pain Weight gain Weight gain has been observed with FYCOMPA use in adults. In the controlled Phase 3 epilepsy clinical trials, FYCOMPA-treated adults gained an average of 1.1 kg (2.5 lbs) compared to an average of 0.3 kg (0.7 lbs) in placebo-treated adults with a median exposure of 19 weeks. The percentages of adults who gained at least 7% and 15% of their baseline body weight in FYCOMPA-treated patients were 9.1% and 0.9%, respectively, as compared to 4.5% and 0.2% of placebo-treated patients, respectively. Clinical monitoring of weight is recommended. Comparison of Sex and Race No significant sex differences were noted in the incidence of adverse reactions. Although there were few non-caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed. DRUG INTERACTIONS Contraceptives With concomitant use, FYCOMPA at a dose of 12 mg/day reduced levonorgestrel exposure by approximately 40% [see Clinical Pharmacology (12.3)]. Use of FYCOMPA with oral or implant contraceptives containing levonorgestrel may render them less effective. Additional non-hormonal forms of contraception are recommended. Cytochrome P450 (CYP) Inducers The concomitant use of known CYP enzyme inducers including carbamazepine, phenytoin, or oxcarbazepine with FYCOMPA decreased the plasma levels of perampanel by approximately 50~67% [see Clinical Pharmacology (12.3)]. The starting doses for FYCOMPA should be increased in the presence of enzymeinducing AEDs [see Dosage and Administration (2.1)]. When these enzyme-inducing AEDs are introduced or withdrawn from a patient s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary. As noted, however, the decrease in the therapeutic effect seen in patients on concomitant treatment, was not affected by use of higher doses (8 mg to 12 mg) [see Dosage and Administration (2.1)]. Concomitant use of FYCOMPA with other strong CYP3A inducers (e.g., rifampin, St. John s wort) should be avoided. Alcohol and Other CNS Depressants The concomitant use of FYCOMPA and CNS depressants including alcohol may increase CNS depression. A pharmacodynamic interaction study in healthy subjects found that the effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol [see Clinical Pharmacology (12.3)]. Multiple dosing of FYCOMPA 12 mg/day also enhanced the effects of alcohol to interfere with vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with other CNS depressants. Care should be taken when administering FYCOMPA with these agents. Patients should limit activity until they have experience with concomitant use of CNS depressants (e.g. benzodiazepines, narcotics, barbiturates, sedating antihistamines). Advise patients not to drive or operate machinery until they have gained sufficient experience on FYCOMPA to gauge whether it adversely affects these activities. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In animal studies, perampanel induced developmental toxicity in pregnant rat and rabbit at clinically relevant doses. FYCOMPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rats throughout organogenesis resulted in an increase in visceral abnormalities (diverticulum of the intestine) at all doses tested. In a dose-ranging study at higher oral doses (10, 30, or 60 mg/kg/day), embryo lethality and reduced fetal body weight were observed at the mid and high doses tested. The lowest dose tested (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m 2 ). Upon oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rabbits throughout organogenesis, embryo lethality was observed at the mid and high doses tested; the no effect dose for embryo-fetal developmental toxicity in rabbit (1 mg/kg/day) is approximately 2 times a human dose of 8 mg/day based on body surface area (mg/m 2 ). Oral administration of perampanel (1, 3, or 10 mg/kg/day) to rats throughout gestation and lactation resulted in fetal and pup deaths at the mid and high doses and delayed sexual maturation in males and females at the highest dose tested. No effects were observed on measures of neurobehavioral or reproductive function in the offspring. The no-effect dose for pre- and postnatal developmental toxicity in rat (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m 2 ). Pregnancy Registry To provide information regarding the effects of in utero exposure to FYCOMPA, physicians are advised to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number , and must be done by patients themselves. Information on the registry can also be found at the website: Nursing Mothers Perampanel and/or its metabolites are excreted in rat milk, and are detected at concentrations higher than that in maternal plasma. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FYCOMPA is administered to a nursing woman. Pediatric Use The safety and efficacy of FYCOMPA for the adjunctive therapy of partial-onset seizures was established by three randomized double blind, placebo-controlled, multicenter studies which included 72 pediatric patients between 12 and 16 years old exposed to perampanel [see Clinical Studies (14.1), Clinical Pharmacology (12.3)]. The safety and effectiveness of FYCOMPA in pediatric patients <12 years old have not been established. Juvenile Animal Data Oral administration of perampanel (1, 3, 3/10/30 mg/kg/day; high dose increased on postnatal days [PND] 28 and 56) to young rats for 12 weeks starting on PND 7 resulted in reduced body weight, reduced growth, neurobehavioral impairment (water maze performance and auditory startle habituation) at the mid and high doses, and delayed sexual maturation at the high doses. CNS signs (reduced activity, incoordination, excessive grooming/scratching), pup death, decreased hindlimb splay, and decreased hindlimb grip strength were observed at all doses. Effects on pup body weight, pup growth, hindlimb splay, impairment in the water maze performance and auditory startle persisted after dosing was stopped. A no-effect dose for postnatal developmental toxicity was not identified in this study. Oral administration of perampanel (1, 5, 5/10 mg/kg/day; high dose increased on PND 56) to juvenile dogs for 33 weeks, starting on PND 42, resulted in CNS signs (incoordination, excessive grooming/licking/scratching, spatial disorientation, and/or ataxic gait) at all doses tested. Geriatric Use Clinical studies of FYCOMPA did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of FYCOMPA in the elderly population. Because of increased likelihood for adverse reactions in the elderly dosing titration should proceed slowly in patients aged 65 years and older [see Dosage and Administration (2.1)]. Patients with Hepatic Impairment Use of FYCOMPA in patients with severe hepatic impairment is not recommended and dosage adjustments are recommended in patients with mild or moderate hepatic impairment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Patients with Renal Impairment Dose adjustment is not required in patients with mild renal impairment. FYCOMPA should be used with caution in patients with moderate renal impairment and slower titration may be considered. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)]. DRUG ABUSE AND DEPENDENCE Controlled Substance FYCOMPA contains perampanel and is listed as a Schedule III controlled substance. Abuse Prescription drug abuse is the intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Drug addiction, which develops after repeated drug abuse, is characterized by a strong desire to take a drug despite harmful consequences, difficulty in controlling its use, giving a higher priority to drug use than to obligations, increased tolerance, and sometimes physical withdrawal. Drug abuse and drug addiction are separate and distinct from physical dependence (for example, abuse may not be accompanied by physical dependence) [see Drug Abuse and Dependence (9.3)]. Studies of human abuse potential were performed to evaluate the abuse potential of FYCOMPA (8 mg, 24 mg, and 36 mg) as compared to alprazolam C-IV (1.5 mg and 3 mg), and oral ketamine C-III (100 mg) in recreational polydrug users. Supra-therapeutic doses of FYCOMPA 24 and 36 mg produced responses for Euphoria that were similar to ketamine 100 mg and alprazolam 3 mg. For High, FYCOMPA 24 mg and 36 mg produced responses comparable to ketamine 100 mg and significantly higher than both doses of alprazolam on a visual analog scale (VAS). Drug Liking, Overall Drug Liking, and Take Drug Again for FYCOMPA were each statistically lower than ketamine 100 mg. In addition, for Bad Drug Effects, FYCOMPA 24 mg and 36 mg produced responses significantly higher than ketamine 100 mg. For Sedation, FYCOMPA 24 and 36 mg produced responses similar to alprazolam 3 mg and higher than ketamine 100 mg. Additionally, on VAS measures related to dissociative phenomena such as Floating, Spaced Out and Detached, FYCOMPA at supra-therapeutic doses produced responses similar to ketamine 100 mg and greater than both doses of alprazolam tested. Of note, due to somnolence a number of subjects had missing data around Tmax of FYCOMPA. The above described data might represent an underestimate of FYCOMPA s effects. The duration of effects of higher doses of FYCOMPA on the majority of measures was much greater than alprazolam 3 mg and ketamine 100 mg. In this study, the incidence of euphoria following FYCOMPA administration 8 mg, 24 mg and 36 mg was 37%, 46%, 46%, respectively, which was higher than alprazolam 3 mg (13%) but lower than ketamine 100 mg (89%). Dependence Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The potential for FYCOMPA to produce withdrawal symptoms has not been adequately evaluated. OVERDOSAGE Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans There is limited clinical experience with FYCOMPA overdose. The highest reported overdose (approximately 264 mg) was intentional. This patient experienced serious adverse reactions of altered mental status, agitation, and aggressive behavior and recovered without sequelae. In general, the adverse reactions associated with overdoses were similar to the reactions at therapeutic doses with dizziness reported most frequently. There were no reported sequelae. Treatment or Management of Overdose There is no available specific antidote to the overdose reactions of FYCOMPA. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with FYCOMPA. Due to its long half-life, the reactions caused by FYCOMPA could be prolonged. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking FYCOMPA. Instruct patients to take FYCOMPA only as prescribed. Serious Psychiatric and Behavioral Reactions Counsel patients, families and caregivers of patients of the need to monitor for the emergence of anger, aggression, hostility, unusual changes in mood, personality, or behavior, and other behavioral symptoms. Advise them to report any such symptoms immediately to their health care providers. Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including FYCOMPA, may increase the risk of suicidal thinking and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers and families to report behaviors of concern immediately to healthcare providers. Neurologic Effects: Dizziness, Gait Disturbance, Somnolence, and Fatigue Counsel patients that FYCOMPA may cause dizziness, gait disturbance, somnolence, and fatigue. Advise patients taking FYCOMPA not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with FYCOMPA. Falls Counsel patients that FYCOMPA may cause falls and injuries. Withdrawal of Antiepileptic Drugs Counsel patients that abrupt discontinuation of FYCOMPA may increase seizure frequency. Contraceptives Counsel patients that FYCOMPA may decrease efficacy of contraceptives containing levonorgestrel. Alcohol and Other CNS Depressants Counsel patients that FYCOMPA may enhance the impairment effects of alcohol. These effects may also be seen if FYCOMPA is taken with other CNS depressants. Missed Doses Counsel patients that if they miss a dose, they should resume dosing the following day at their prescribed daily dose. Instruct patients to contact their physician if more than one day of dosing is missed. Controlled Substance Counsel patients that FYCOMPA is a controlled substance that can be misused and abused. Pregnancy Registry To provide information regarding the effects of in utero exposure to FYCOMPA, recommend pregnant patients treated with FYCOMPA to enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number , and must be done by patients themselves. Information on the registry can also be found at the website FYCOMPA is a trademark owned by Eisai R&D Management Co., Ltd. Manufactured and Marketed by Eisai Inc., Woodcliff Lake, NJ Eisai Inc. FYCO0327

6 MANAGI NG E D ITOR S MEMO Medical Directors Fate Rests in the MA Stars By Frank Diamond Editor John Marcille Managing Editor Frank Diamond Senior Contributing Editors MargaretAnn Cross Michael D. Dalzell Timothy Kelley Contributing Editors Joseph Burns John Carroll Thomas Reinke Design Director Philip Denlinger President Emeritus Timothy J. Stezzi President Timothy P. Search, RPh VP, Group Publisher Maureen Dwyer Liberti Director of Production Services Mary Ellen Curry Circulation Manager Jacquelyn Ott Spoiler alert, but only blue (guarded) because the movie Captain Phillips is based on something that really happened. One of the more affecting scenes comes at the end when a Navy medic examines the hero. The director uses a real medic, and Corpsman Danielle Albert plays herself beautifully. She examines the traumatized hero while asking questions in a manner that mixes clinical detachment with just the slightest pinch of empathy. She s doing her job. They told her to treat the scene as a drill and anyone familiar with life on a Navy destroyer knows that drills take up a good part of each day. You don t have to be in the Navy to identify with that character. Medical directors keep their cool as well. They are trained to do so in medical school and it carries over when they become businesspeople. Well, the pressure s on. Our cover story on page 15 examines the challenges and the stakes presented by the Five Star Quality Rating System for Medicare Advantage Plans. One star can add up to millions of dollars in bonuses. Not only that, but high-achieving plans can enroll beneficiaries all year round. It all comes down to quality. The Centers for Medicare & Medicaid Services notes, Outcome and intermediate outcome measures continue to be weighted three times as much as process measures, and patient experience and access measures are weighted 1.5 times as much as process measures. Executives in MA plans are scrambling, but medical directors who specialize in quality assurance will be particularly challenged, notes Jaan Sidorov, MD, a member of Managed Care s Editorial Advisory Board. It s hard to overestimate the luster of the money from increased payments and the threat of being put on the MA naughty list, let alone having your competition outpace you. Good luck. Managed Care is indexed in PubMed and in Scopus. The full contents of each issue are available free at Major articles are reviewed by appropriate members of the editorial advisory board and/ or other qualified experts. Opinions are those of the authors and not necessarily those of the institutions that employ the authors, nor of the publisher, editor, or editorial advisory board of Managed Care. CONTACT ADDRESSES: Editors: Editors@ManagedCareMag.com Circulation: Managedcare@icnfull.com Advertising: Advertising@ManagedCareMag.com Reprints: Reprints@ManagedCareMag.com Clinical judgment must guide each clinician in weighing the benefits of treatment against the risk of toxicity. Dosages, indications, and methods of use for products referred to in this publication may reflect the professional literature or other clinical sources, or may reflect the clinical experience of the authors, and might not be the same as what is on the approved package insert. Please consult the complete prescribing information for any products mentioned in this publication. MediMedia USA Inc. assumes no liability for the information published herein. Managed Care (ISSN ) is published monthly by MediMedia USA Inc. at 780 Township Line Road, Yardley, PA This is Volume 23, Issue 6. Phone: (267) ; fax (267) Send letters to the editor to Frank Diamond, Managed Care, 780 Township Line Road, Yardley, PA Letters may be edited for length and clarity. Copyright 2014 by MediMedia USA Inc. All rights reserved under the United States, International, and Pan-American copyright conventions. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, photocopying, electronic, or otherwise, without the prior written permission of MediMedia USA Inc. The copyright law of the United States governs the making of photocopies or other reproductions of copyrighted material. Subscriptions for individuals or institutions in the U.S.A. are $100 per year, $10 per single copy; elsewhere, $120 per year, $22 per single copy. Inquiries about paid subscriptions: Mary Ellen Curry, telephone (267) ; mecurry@medimedia.com. Postmaster: Send address changes to Managed Care, PO Box 2019, Morrisville, PA Periodicals postage paid at Morrisville, PA, and at additional mailing offices. 4 MANAGED CARE / JUNE 2014

7 15 Cynthia R. Griffin, PharmD Vol. 23, No. 6 June Mary D. Naylor, PhD, RN Joseph Schneider, MD 31 C O V E R ST O R Y Get the Star Treatment 15 The difference one star can make in the Medicare Advantage rating system can add up to millions of dollars in bonus money and a robust presence in the market place. Q&A With Mary D. Naylor, PhD, RN 27 The main proponent of the Transitional Care Model uses evidence to make her approach work. Accountable care organizations and commercial health plans are among the groups that are interested. Health Information Exchanges Not Quite Ready 31 HIEs trumpeted as a boon to insurers, physicians, hospitals, and PBMs are only just starting to roll. How they will affect insurers in the long run is still not clear, but some say they are already reducing costs. Cognitive Decline: Should Some Be Screened? 38 Many take issue with the U.S. Preventive Services Task Force s ruling that routine screening for older people is not necessary. They argue that more needs to be done about a disease whose cost to the nation is rising. 38 Albert Siu, MD Search for Managed Care Electronic Edition nxtbook Web FOCUS ON BIOLOGICS Put Genetic Tests to the Test 43 Clinical utility depends on the quality of interpretation. Is Research to Blame for the Cost of Cancer Drugs? 46 Governments around the world are not buying this argument. DEPARTMENTS Editor s Memo...4 Competition based on quality. Viewpoint...6 Some costly drugs poorly managed. Medication Management...9 Oncology medical homes studied. News & Commentary Gaps in care prove costly. Snapshot ,000 deaths a year called preventable. Formulary Files Three new allergy drugs. Tomorrow s Medicine Help for leptin deficiency. Outlook Specialty drug costs to soar. COVER: TETRA IMAGES/CORBIS JUNE 2014 / MANAGED CARE 5

8 VIEWPOINT Advancing Drug Trend Management In the Medical Benefit By Mary Dorholt, PharmD An effective medical benefit management program manages drug utilization, site of care, and payments, says Mary Dorholt, PharmD, who is in charge of Express Scripts specialty clinical strategy and protocol development. Plan sponsors are wasting $4.9 billion annually as a result of inadequate management of specialty medications in the medical benefit, according to our estimates using MarketScan data. Most of these costs could be avoided by applying the utilizationand trend-management programs that are traditionally found in the pharmacy benefit to the medical benefit, according to the data analysis by Express Scripts. The Express Scripts analysis was based on 2011 MarketScan data of specialty medication utilization across the United States. Assuming a specialty drug trend in the medical benefit that is similar to what we have seen in the pharmacy benefit, this waste is projected to grow to $9 billion next year. Our experience shows that most payers do not have adequate management tools in place to control specialty spending in the medical benefit. Often, they also lack the infrastructure to support such programs. Care Continuum, an Express Scripts subsidiary, has been able to leverage decades of drug management experience to build clinical utilization and claim management practices applicable to the medical benefit. Our data also show that plans that implement medical benefit management services have, on average, saved 10% to 15% on their specialty spending. The issue Nearly half of all specialty medications are currently billed through the medical benefit. The complexity of specialty medications, billing system limitations, and provider management make trend management in the medical benefit challenging. We have also seen that plan sponsors have basic system infrastructure gaps in their claim payment systems for drug and unit management. A comprehensive medical benefit management program can help to connect various health plan departments and serve as a single accountable party. Such a program covers different areas in a health plan, including the medical utilization management department, the medical claims department, the informatics/ data management group, the provider relations group, and network contracting. Not implementing medical benefit management programs today can limit payers ability to capitalize on future savings from other market factors, including: Expanded medical drug pipeline Increased opportunities for step therapy and medical preferences Expanded rebate opportunity Biosimilar opportunity Key components An effective medical benefit management program offers services across disease states and sites of care, consisting of three key components: 1. Utilization management. Specialty drugs billed in the medical benefit lack clinical policies applied to drugs dispensed through the pharmacy benefit. Approximately 15% 20% of drug requests billed through the medical benefit may not be medically necessary. Closing this gap can help to save $1.3 billion annually, according to our analysis. It can also improve patient care by ensuring the safe and appropriate use of specialty drugs billed through the medical benefit. Patients could also see lower costs through reduced out-of-pocket copayments or coinsurance. 2. Site-of-care management. Costs for specialty medications billed under the medical benefit vary by site of care for instance, drugs administered in a hospital outpatient setting are often significantly more expensive. Often, this is because the drugs are contracted at disadvantageous rates and most commonly billed as a percent of billed charges. Recontracting is an ef- 6 MANAGED CARE / JUNE 2014

9 VIEWPOINT Value of medical benefit management Health plan Patient Provider Guaranteed savings Safer, more effective treatment Consistent management across benefits Improved rebate opportunities from claims priced at NDC level Comprehensive reporting Optimized patient benefit Improved care and health outcomes Fewer health and safety problems Lower cost Retained buy-and-bill option (i.e., physicians may still stock medications and bill when used) Reduced administrative burden through online prior authorization Improved clinical information fective but difficult-to-achieve solution. Site-of-care programs redirect patients and medications to the most clinically appropriate and lowest-cost channel. Research by Milliman states that implementing siteof-care management can save between 12% and 34% up to $1.7 billion nationally per year, by our analysis. This includes three approaches: Redirecting specialty medication and administration from an outpatient setting to a doctor s office, ambulatory clinic, or the patient s home where clinically appropriate. Recontracting with the outpatient network to establish drug-pricing benchmarks. Moving specialty medications from the medical benefit to the pharmacy benefit when clinically appropriate. 3. Payment management. Having robust payment management ensures that claims are paid accurately and at the contracted rate and improves rebate opportunities. In the medical benefit, specialty drugs are dispensed in multiple forms of units including Healthcare Common Procedure Coding System units, National Drug Code (NDC) units, milligrams/kilogram, vials, etc. In the pharmacy benefit, specialty drug pricing is done uniformly and benchmarked using the NDC information, thus simplifying management. In addition, for drugs in the medical benefit that do not require prior authorization, applying claim edits commonly used in the pharmacy benefit can help to minimize waste. These claim-management tools could save payers $1.9 billion annually, based on our analysis. These programs can also greatly improve the data available for analysis by the health plan. Some payers may think they already have these tools in place and do not need a medical benefit management program. However, even aggressively managed plans can derive benefit from a comprehensive program. Lightly managed plans: These payers probably do not have effective systems in place and can derive all, or a vast part, of the projected savings. Moderately managed plans: Plans that have some utilization management tools, siteof-care redirection, and claim edits in place could still save significantly more. Aggressively managed plans: Payers that aggressively manage utilization and claims within the medical benefit still lack strong site-of-care redirection. We project these plans could save considerable sums. Other benefits Implementing a strong medical benefit management program can help plans to save money. It also has benefits for patients and providers, as shown in the table at the top of this page. About the author Mary Dorholt, PharmD, is a vice president in charge of Express Scripts specialty clinical strategy and protocol development. She and her team of clinical experts develop clinical guidelines for patient care and physician interaction with respect to specialty drugs. She is also responsible for organizational research strategy related to specialty medications. Earlier, she was responsible for provision of specialty strategic guidance to employer, government, and labor organizations. She was responsible for marketplace oversight and internal and external communications related to specialty drug management programs. JUNE 2014 / MANAGED CARE 7

10 Helping you win in regulated markets is our healthy obsession Attract and retain lives with expertise from the pharmacy benefits leader. With the complexities of the ACA, growing your business takes more than ordinary support. It demands a deep commitment to compliance, care and cost-control that only Express Scripts can provide. We ve been serving millions of Medicare and Medicaid members for years, and are partnering with health plans in states representing more than 90% of expected public exchange lives. Take a few minutes to see what our experts can do for you at Express-Scripts.com/GovernmentSolutions 2014 Express Scripts Holding Company. All Rights Reserved. 13-EME20243 MCM

11 MEDICATIO N MANAGEMENT Oncology Medical Home Study Examines Physician Payment Models Is it a simple matter of pay for volume vs. pay for value, or is the situation far more complicated? By Thomas Reinke The oncology medical home is an effort to engage physicians in new ways, says Daniel Winn, MD, medical director at CareFirst. CareFirst, the Maryland Washington Blue Cross Blue Shield plan, has transformed its first-generation oncology pathway program into a second-generation program that incorporates medical home principles. The change reflects CareFirst s continuing effort to encourage oncologists to improve care on a broader scale than chemotherapy regimens. Cost and complexity The most important part of this whole program is engaging oncologists to think differently, says Daniel Winn, MD, VP, and senior medical director at CareFirst. It s a unique specialty because of the difficulties physicians face every day. Complex treatment decisions are coupled with a constant focus on the cost of care driven by high-cost medications. If we can mitigate the cost and economic issues, then physicians can focus on providing high-quality care. CareFirst s oncology medical home has two major components. The first is a physician payment model that provides incentives to focus on cognitive services and patient management (evaluation and management services) rather than the margin from drugs that underlies buy and bill, the common payment arrangement in oncology. CareFirst sought to maintain adequate levels of practice revenue by increasing payment for cognitive services by 300%. The second element is expanding the care model to move beyond medication therapy and focus on the continuum of care. A recent study of the effect of the new physician payment model showed that it did not substantially alter physician behavior in comparison to the buy-and-bill model. In turn, that has raised questions about whether physician payment arrangements receive too much attention as a determinant of physician behavior and the high cost of cancer care. The study compared performance in eight medical home practices to a matched set of seven practices continuing under the first-generation buy-and-bill payment model. One year after conversion to the new model, the average number of established office visits per patient remained stable in oncology medical home practices 3.7 visits before conversion vs. 3.8 afterward. The percentage of chemotherapy administrations per patient remained steady in both groups, with approximately eight administrations per patient in each group for the pre- and post years. Likewise, the percentage of patients who received chemotherapy remained stable in the pre- and post years for both the medical home group and first-generation practices, at approximately 15%. The percentage of patients who received all-generic chemotherapy regimens was a key endpoint. There was no difference. However, use of generics increased by more than 40% for both the medical home providers and the control group. The dramatic increase was related to patent losses for gemcitabine, docetaxel, irinotecan, and oxaliplatin. Study limitations The study has many limitations. Most notably, there may be selection bias because physicians could choose whether to participate in the medical home model. Also, the behavior of the physicians may have been influenced by their previous three years of practicing under pathways. The study also did not report on the full range of prescribing behaviors or the extent to which medical home and control group physicians adhered to pathway therapy regimens. Despite limitations, Bruce Feinberg, DO, CMO for oncology at Cardinal Health Specialty Solutions Services and the study s primary JUNE 2014 / MANAGED CARE 9

12 MEDICATION MANAGEMENT The drivers of volume are not solely economic incentives, says Bruce Feinberg, DO, who is the CMO for oncology at Cardinal Health Specialty Solutions Services. author, concludes, For physicians who have been in mature pathway programs, removing all profit margins from drugs did not further alter their prescribing behavior. Broader issue That conclusion serves as a springboard to a broader issue in cancer care. Is resolving the pay-for-value versus the pay-for-volume debate one of the critical solutions for improving care and controlling costs, and what is the driver of the utilization of therapies? Is it reimbursement or is it more complicated? asks Feinberg. My concern is that the driver of the volume is more complicated than economic incentives. Our medical culture values new treatments over old, more over less, and now versus later. That philosophy characterizes patient perspectives and physician perspectives in the way we manage elevated PSA, abnormal mammograms, and cardiovascular risks. He adds, If we don t address the cultural factors in our delivery system, then I am concerned that we may go down the wrong road for improving care because we are not addressing the drivers. Feinberg says that the study s real significance is that it points out misdirected criticisms and oversimplification of the challenges in improving cancer care. The New York Times editorial offering a plan to fix cancer care and the Institute of Medicine report on the crisis in cancer care blame volume-based payment for high costs, but physician behavior is extremely complex. If we try to reform health care based on notions that are oversimplified, then we are going to miss opportunities for real improvements. Offering an alternative Feinberg has an alternative to blaming payment models for the high cost of cancer care. The way you modify physicians behavior to focus on value and quality is through active physician engagement. We need to make them aware of situations and aid them in decision support. He provides an example. The National Comprehensive Cancer Network guideline for breast cancer says there is no benefit in combination therapy for the vast majority of patients with metastatic breast cancer and that sequential monotherapy is the way to go. When we looked at claims in one program, we found that in the first three lines of treatment, two thirds of patients were getting combination therapy. When this type of information is presented to doctors in a pathway program, the heightened awareness of actual performance coming from their peers is able to drive changes in behavior. CareFirst s Winn says, The oncology medical home is an effort to engage physicians in new ways on comprehensive cancer care. We ve added chemotherapy in the last weeks of life, palliative care, and hospice as performance targets. We created a sophisticated palliative care and hospice network as a resource to physicians and we ve built palliative care and hospice algorithms into the pathway software to make it easier for doctors to make decisions about the appropriate time for referrals. Cost of care CareFirst is also working to connect its case managers more closely to physician practices. It also has maintained its focus on the cost of care, and now it has added total care costs to its physician scorecards. The oncology medical home reflects a trend in cancer care for payers and oncology practices to explore new cost-control and quality-improvement models that extend beyond chemotherapy. Those models include oncology ACOs, bundled payment arrangements, and episode-of-care models. CALL FOR PAPERS MANAGED CARE is seeking article submissions. We welcome a wide variety of manuscripts, including drug class reviews, disease state management reviews, pharmacoeconomic analyses, strategies for coping with medication errors, outcomes research evaluations, DUEs, commentaries, book reviews, and letters to the editor. Please see our author guidelines at managedcaremag.com. Interested? Write to our managing editor, Frank Diamond, at fdiamond@medimedia.com. 10 MANAGED CARE / JUNE 2014

13 At Amgen, biologic medicines are rooted in quality and nurtured by reliability. Robust quality control and a reliable supply are every bit as important as scientific innovation. For more than 30 years, Amgen has poured commitment, passion, and a drive for perfection into every medicine we make. So you can turn to Amgen for the biologic medicines that matter so much to your patients treatment for generations to come. To learn more about Amgen s commitment to consistent quality and reliable supply, visit biotechnologybyamgen.com 2013 Amgen Inc. All rights reserved R1-V1

14 NEWS & COMMENTARY 12 Million Misdiagnoses a Year Due to Gaps in Outpatient Care Nearly 12 million patients a year are misdiagnosed, and half of those cases could lead to serious health problems, according to a meta-analysis in the journal BMJ Quality & Safety. Researchers looked at three studies: one of misdiagnosis in primary care settings, and one each for colorectal cancer and for lung cancer that examine screenings and subsequent diagnosis. The meta-analysis estimates the frequency of diagnostic error to be at least 5% in U.S. outpatient adults, a number that entails a substantial patient safety risk. This populationbased estimate should provide a foundation for policymakers, health care organizations, and researchers to strengthen efforts to measure and reduce diagnostic errors. The triggers in the primary care study were unplanned hospitalizations or unscheduled return visits within 14 days of the original visit. Although we presumed that the types of errors detected in the primary care study were likely to account for the majority of outpatient diagnostic errors, we also aimed to estimate the rate of errors related to initial diagnosis of less common but serious chronic conditions, the study states. Hence, the review of colorectal and lung cancer misdiagnosis. Unlike misdiagnosis of acute conditions, these errors may not become apparent for weeks or months. Red flags were missed. For colorectal cancer this meant a lack of followup 60 days after documentation of hematochezia (bright red blood per rectum), positive fecal occult blood test, and iron deficiency anemia. For lung cancer, we defined lack of follow-up as failure to initiate further investigation or an appropriate action within seven days of a documented red flag, such as an abnormal chest X-ray. The contribution of the two cancers to the overall estimation of missed diagnoses was small, but we believe it was important to include them to show their relative contribution. This is because delayed cancer diagnosis is believed to be one of the most harmful and costly types of diagnostic error in the outpatient setting and its significance had become apparent not only in malpractice claims but also in retrospective studies of consecutive cancer cases, surveys, and studies of failures to follow-up abnormal test results. What can insurers do? Hardeep Singh, MD, MPH, the study s corresponding author, says health plans could work with researchers to identify care patterns in electronic data that suggest diagnostic errors. Singh, a researcher at the Michael E. DeBakey VA Medical Center and Baylor College of Medicine in Hous ton, says that more evaluation must be done to bring these triggers to real-world practice, but this is a start. In the future, such measurement techniques could help identify outliers in diagnostic performance. Rapid Response Teams Make No Difference Rapid response teams at hospitals shorten stays somewhat, but do not reduce mortality or transfers to intensive care units, according to a study in the Journal of Hospital Medicine. The study was conducted at eight units at Barnes-Jewish Hospital in St. Louis between January and May Patients were selected when they triggered an alert on the early warning system, which measures changes in vital signs. Such changes may precede clinical deterioration by hours, providing a chance to intervene if detected early enough, says the report, A Randomized Trial of Real-Time Automated Clinical Deterioration Alerts Sent to a Rapid Response Team. The study and control groups consisted of 257 patients each. The RRT team was a registered nurse, a secondor third-year internal medicine resident, and a respiratory therapist. Patients in the intervention group were significantly more likely to have their primary care team physician notified by an RRT nurse regarding medical condition issues and to have oximetry and telemetry started, whereas control patients were significantly more likely to have new antibiotic orders written within 24 hours of an alert, the study states. The transfer rates to the ICU (17.8% and 18.2% respectively) was not statistically significant. Neither was the need for subsequent long-term care (26.9% for the RRT intervention group and 26.3% for the control group). Length of stay for the intervention group was 8.4 days; for the control group, 9.4 days. The alert system needs to be improved, the authors state: As a result of mandates from quality improvement organizations, most U.S. hospitals currently employ RRTs for emergent mobilization of resources when a clinically deteriorating patient is identified on a hospital ward. Linking RRT actions with a validated real-time alert may represent a way of improving the overall effectiveness of such teams for monitoring general hospital units, short of having all hospitalized patients in units staffed and monitored to provide higher levels 12 MANAGED CARE / JUNE 2014

15 NEWS & COMMENTARY of supervision (e.g., ICSs, step-down units). 1 in 3 Adults Mixes Supplements, Drugs Harmful drug interaction isn t a problem confined solely to prescription medications. It also involves the mixing of dietary supplements (DSs) and prescription medications (PMs), according to a study in the Journal of the Academy of Nutrition and Dietetics. About 1 in 3 adults mixes dietary supplements and prescription medications, says the study Concomitant Dietary Supplement and Prescription Medication Use Is Prevalent Among U.S. Adults With Doctor-Informed Medical Conditions, which looks at data from about 5,000 men and 5,000 women. Diabetes soars, but complications dive From 1990 to 2010, the number of adults in the United States with diabetes tripled, from 6.5 million to 20.7 million, according to a study in the New England Journal of Medicine. That s bad. What s good is the steep drop in complications over the same period. Researchers credit preventive care for a 68% decrease in deaths from heart attack and a 64% drop in deaths from high blood sugar. Data were collected from various sources, including the National Health Interview Survey and the National Hospital Discharge Survey. Outcomes were reviewed for lower-extremity amputation, acute myocardial infarction, stroke, end-stage renal disease, and death from hyperglycemic crisis. These findings probably reflect a combination of advances in acute clinical care, improvements in the performance of the health care system, and health promotion efforts directed at patients with diabetes, the study states. It adds, The greatest declines in diabetes-related complications, in both absolute and relative terms, were observed among persons 75 years of age or older, except in the case of end-stage renal disease. Trends in age-standardized rates of diabetes-related complications among U.S. adults with diagnosed diabetes, Events per 10,000 adult population with diagnosed diabetes Acute myocardial infarction Stroke Amputation ESRD Death from hyperglycemic crisis Source: Changes in Diabetes-Related Complications in the United States, , New England Journal of Medicine, April 17, 2014 Despite popularity of DS, concerns persist regarding purity, toxicity, and mislabeling because regulation of DS under the 1994 Dietary Supplement Health and Education Act is limited relative to that of PM, says this largest population-based study to date on this subject. More than 60% of patients do not disclose their use of DS and PM providers. Thus, the risk for potential interactions between DS and PM to go undetected remains substantial. In addition, some dietary supplements have changed in nature. The study documents for the first time that multivitamins containing other or botanical ingredients were more commonly consumed with a PM than standard multivitamins containing only vitamin or mineral ingredients. The conditions and diseases more likely to encourage patients to mix the two are heart conditions, arthritis, diabetes, cancer, osteoporosis, and problems with the respiratory system, thyroid, liver, and kidney. Cardiovascular agents, including antihypertensive and antiarrhythmic agents, appear to be among the most common drug classes to have suspected interactions with DS in clinical trials and case reports, the study says. This is likely due to the high prevalence of heart and vascular conditions in the U.S. population. The study also shows that men are less likely than women to mix DSs and PMs. In addition, people with less than a college degree and those who make less than $75,000 a year are significantly less likely to mix DSs and PMs. The increasing complexity of combinations of ingredients contained in DS may also require explicit evaluation by health care and dietetics practitioners, the study states. Inquiries about patient DS use in an attempt to screen for potential DS and PM interactions may benefit from identifying ingredient information directly from labels. Multivitamin DS, in particular, may need more scrupulous evaluation and should not be assumed to contain only safe ingredients. Frank Diamond JUNE 2014 / MANAGED CARE 13

16 SNAPSHOT 260,000 deaths a year from 5 causes called preventable The five leading causes of death are heart disease, cancer, chronic lower respiratory diseases, stroke, and unintentional injuries, according to the Centers for Disease Control and Prevention. A study in the CDC s publication Morbidity and Mortality Weekly Report ( tinyurl.com/deaths-preventable) says that these five causes were responsible for 63% of deaths in 2010 and that the next five were responsible for about 12%. Many of the deaths from the five leading causes are preventable. If all states achieved the lowest observed mortality levels for the five leading causes, when considered separately, as many as 91,757 premature heart disease deaths, 84,443 cancer deaths, 28,831 chronic lower respiratory disease deaths, 16,973 stroke deaths, and 36,836 unintentional injury deaths might be prevented each year, the study states. These calculations translate to approximately 1 in 3 premature heart disease deaths, 1 in 5 premature cancer deaths, 2 out of 5 chronic lower respiratory deaths, 1 out of every 3 stroke deaths, and 2 out of every 5 unintentional injury deaths that could be prevented. But just how to do this? The study recommends screening, early intervention, successful treatment, and reducing risk factors. Risk factors for heart disease are, for instance, smoking, high blood pressure, high cholesterol, type 2 diabetes, poor diet, being overweight, and lack of physical activity. The mortality data are from the National Vital Statistics System for The calculations are for U.S. residents up to age 80. Annual number of deaths observed and potentially preventable* for the 5 leading causes of death for persons up to age 80 in the United States, Diseases of the heart Cancer Chronic lower respiratory diseases Cerebrovascular diseases Potentially preventable Deaths observed Unintentional injuries 0 50, , , , , , , , ,000 Number of deaths *Expected deaths are the lowest three-state average, age-specific death rate, multiplied by the age-specific state population rounded to the nearest whole number. Potentially preventable deaths are observed deaths minus expected deaths rounded to the nearest whole number. Source: Potentially Preventable Deaths from the Five Leading Causes of Death United States, , Morbidity and Mortality Weekly Report, May 2, MANAGED CARE / JUNE 2014

17 Reaching for the Stars Medical Directors Feel Pressure To Score Medicare Advantage Points This key clinician executive has a lot of responsibility as CMS gets set to distribute 2015 s bonus payments By Nan Myers The difference one star can make in the Five Star Quality Rating System for Medicare Advantage Plans could come to millions of dollars in bonuses for a health plan and assure a robust presence in the market. Quality matters more than ever, and that means clinician executives at health plans will really feel the pressure to hit benchmarks. Today a medical director at a Medicare Advantage (MA) plan must wear many hats and serve many masters. Compared with even 10 years ago, he or she has a greater external focus and a widely expanded range of responsibilities. These include involvement with such strategic issues as organizational planning and developing and maintaining working relationships with the corporation s top management, the Centers for Medicare & Medicaid Services (CMS), the clinical staffs, and members. An effective medical director will be a leader with the skills to influence others to abide by the rules and yet achieve success. The program has five broad categories outcomes, intermediate outcomes, patient experience, access, and process. Says CMS: For 2014, outcome and intermediate outcome measures continue to be weighted three times as much as process measures, and patient experiences and access measures are weighted 1.5 times as much as process measures. That shapes the medical director s current efforts regarding star quality ratings improvement. Money matters, as anyone knows who s been watching how hospital readmission rates have gone down since CMS began imposing penalties last year. The star system for MA plans is the same idea, It takes a lot to move the needle, says Jill Sumfest, MD, market vice president and medical director at Humana South Florida Senior Products. And it takes not being satisfied with the status quo... We work with our physicians to close gaps in care. says Paul Cotton, director of federal affairs at the National Committee for Quality Assurance. You want to be paying for performance and good outcomes, like making sure that people don t go back into the hospital, says Cotton. We call it the value agenda. CMS uses a complicated formula to dole out bonus payments to Medicare Advantage plans. For instance, of the $1.3 billion the agency allotted in 2012, UnitedHealthcare got $547 million, and Kaiser Permanente received $380 million. They were both five-star plans that year, so why the $167 million difference? Because many factors some of which can keep accountants awake at night go into the bonus payments other than the number of stars a plan receives. For example, the number of enrollees will influence bonus payments. The ACA requires that quality bonus payments be calculated as a share of the MA benchmarks the maximum amount Medicare will pay the plans to provide Part A and B benefits in the county which vary by county, according to CMS. So the size of the bonuses will vary by county. (To find out more about how bonuses are calculated, go to CMS-bonus-info. The relevant section is on pages 9 14.) High stakes A draft of a not-yet-published study that Cotton cowrote points out that the stakes are high for all MA plans: Medicare is flagging poor performing plans that have less than three stars on the Medicare.gov plan finder [and] advising beneficiaries not to enroll and requiring those who wish to enroll to contact the plans directly. Medicare has used demonstration authority to provide smaller JUNE 2014 / MANAGED CARE 15

18 bonuses to star plans (which have the most MA beneficiaries) through Medicare officials said they did this to test whether providing scaled bonuses will lead to more rapid and larger year-to-year quality improvements in Medicare Advantage program quality scores. Medical directors overseeing quality assurance will be most involved, says Jaan Sidorov, MD, a consultant and former medical director who is a member of Managed Care s Editorial Advisory Board. My advice to non-qa expert medical directors is to stay out of the way, says Sidorov, whose specialty when he was a medical director was care management. We all share basic skills, but QA is one of those career focus trajectories that not all participate in. It s hard to overestimate the luster of the money from increased payments and the threat of being put on the MA naughty list, let alone having your competition outpace you. While meeting this broad range of standards and criteria is not easy, most agree that the star ratings are a good thing. CMS reports that MA quality continues to improve, and more than one third of MA contracts will receive four or more stars, an increase from 28% in The star measures have made the Medicare Advantage program stronger, says Peggy Haines, RN, vice president for quality management at Health Net. The company already had a quality improvement program, which included a process for appeals and grievances, in place before there were stars. Now, though, in addition to diabetes, congestive heart failure, chronic obstructive pulmonary disease, and asthma for some members, we focus on all of the majors required by Medicare. The stars program is further evi- Overall rating distribution for MA-PD contracts, About 38% of Medicare Advantage plans that include prescription drug coverage earned four stars or higher for this year s rating, according to the Centers for Medicare & Medicaid Services. Weighted by enrollment, these contracts (an insurer can have more than one MA contract) serve about 52% of MA enrollees. This is a nearly 14 percentage-point increase from 38% of enrollees in contracts with four or more stars last year, CMS says in a fact sheet. Information on the stars program can be found at Rating distribution, weighted by enrollment, Percent of enrollees Percent of enrollees Percent of enrollees stars stars stars 2.5 stars 2.5 stars 2.5 stars 3 stars 3 stars 3 stars Source: Centers for Medicare & Medicaid Services 3.5 stars 3.5 stars 3.5 stars 4 stars 4 stars 4 stars 4.5 stars 4.5 stars 4.5 stars 5 stars 5 stars 5 stars 16 MANAGED CARE / JUNE 2014

19 dence (if any were needed) that insurers need to think about their customers customers patients. A white paper by the law firm Peppers & Rogers says, An overall rating is the sum of many factors, largely driven by that member s experience with the health plan across multiple interventions. Raises all boats Sidorov agrees, but he s not sure how many health insurers do. A medical director like me in the care and case management space believes that taking good care of patients raises all boats, including stars. That s not the short-term perspective of many health plans, however, who are coming at this with a far more targeted quality assurance approach. Cotton s study states, Anecdotally, we are seeing that several plans that before paid minimal attention to their five-star scores are now aggressively working to improve. There has been great interest in several conferences and presentations on how to improve MA star ratings. Also, adding stick to carrot, Medicare is actively discouraging enrollment in poor-performing plans and authorized to exclude them from the program. Plan medical directors are key stakeholders in the quality improvement process. They participate in teams made up of representatives of clinical, business, customer service, and other staff members to impact and measure results, explains Jill Sumfest, MD, market vice president and medical director at Humana South Florida Senior Products. Each star has many components and the weighting means that not every star measurement requires the same amount of intensity, says Joseph V. Agostini, MD, chief medical officer for provider collaboration and large groups at Aetna Medicare. For example, ordering a screening test is a onetime event. The patient makes an appointment and gets it done. By contrast, ensuring that a patient takes medication every day requires a much different effort. To deal with these challenges, he adds, we work with the provider and can offer the services of our multidisciplinary outreach teams. For the prescription issues, clinicians on the teams contact Things that help a plan perform well include a tight plan model with employed physicians and all of the services the patient needs in a convenient location, says Cynthia R. Griffin, PharmD, a manager at Florida Blue. and work with the member to promote ongoing medication adherence. Sumfest says that It takes a lot to move the needle. And it takes not being satisfied with the status quo. All of the plans work with physicians to teach them to look at their patients prescriptions. Take the prescribing of high-risk medications, which is specifically a stars measure. The rating system doesn t take into consideration the fact that a frail 80-yearold reacts differently from a relatively healthy 60-year-old, says Cynthia R. Griffin, PharmD, senior director for pharmacy government programs and Medicare stars at Florida Blue. He or she may have started taking a highrisk medication when they were much younger and may have been taking it many years with no adverse effects. As a result, they are often resistant to change. It is contingent upon the provider to help the patient understand the need to change and prescribe a safer alternative. Or, to take another stars measure, if a patient with osteoporosis has a fracture and is prescribed a drug with numerous side effects, the patient may stop taking it because he or she can t tolerate it, says Griffin. The stars measure counts the number of people with an osteoporosis fracture who are prescribed the drug but doesn t take into account that it may be causing problems for the patient. We must continue to work with the provider and the patient to find another drug one he or she will tolerate and help to promote adherence and lead to an improved outcome. Agostini says that Another challenge is to get doctors to prescribe fewer higher-risk drugs. For example, amitriptyline is sometimes overprescribed to older adults. If a physician is overprescribing, it becomes a prescription-quality issue. We work with the physician to identify solutions, such as to suggest that an alert about the drug be placed in his or her electronic medical system. Beyond core measures The stars system enables Medicare Advantage plans to institute other quality initiatives by reaching beyond the rating system s core measures to embrace innovation. The star ratings recognize JUNE 2014 / MANAGED CARE 17

20 and can provide incentives to innovation by using optional measures that award extra credit to the innovators. The medical director often works directly with physicians and physician groups to ensure that they follow the rules. Representatives of the health plan can call a patient and send letters, but if the doctor or the doctor s office contacts the patient, there is more likelihood that the request will be honored because it is the doctor with whom the patient has a relationship. Things that help a plan perform well include having a tightly integrated model with employed or highly engaged physicians and all of the services the patient needs in a convenient centralized location, says Griffin, at Florida Blue. When the patient visits a provider and finds he or she must go to several different places for tests and screenings, this decreases the likelihood of completion particularly when there are transportation challenges. Repeated outreach and attempts to get them to close a care gap could lead to an unhappy patient. The overall experience is reflected in the member satisfaction survey. A relentless focus We work with physician practice groups, says Agostini, from Aetna. It may be in person, by phone, or by webinar. We meet with the larger groups regularly, usually quarterly, to share data and to discuss problems. The educational component is a key factor in my role as medical director, he continues. Some groups may not be very familiar with the star ratings. We have a relentless focus on improving our core clinical and quality programs. Sidorov adds, Health plans correctly surmise that they need to bring their docs on board to help with stars. One approach is pay for performance. Health Net has assigned a medical officer to its two contracted Medicare groups. That physician meets with each group regularly, up to four times a year. We provide reports that show gaps in patient records and have clinical gap warnings on electronic medical records that the physicians get, says Haines, VP for quality management. This Working with physicians In 2010, a Humana Medicare Advantage HMO contract that included Florida, Mississippi, Oregon, and North Carolina got only 3.5 stars. The company had work to do. We realized we had to get the physicians on board, says Jill Sumfest, MD, market vice president and medical director for Humana South Florida Senior Products. Humana began to provide monthly reports for patients who had gaps in care for example, for those who were missing tests. We continued this effort to help the physician s office and it worked. Two years later, the plan was at 4.5 stars. The plan did this by focusing on achieving one of Humana s highest performance scores in HEDIS, improving patient safety measures such as medication adherence. It is truly a partnership, says Sumfest. We work with the provider and can offer the services of our multidisciplinary outreach teams, says Joseph V. Agostini, MD, chief medical officer for product collaboration and large groups at Aetna Medicare. This, for instance, can promote medication adherence. way we can show a doctor that he or she has a patient who hasn t gotten a mammogram in the specified time. In addition to reaching out to providers and patients, we concentrate on improving our data capture, Haines adds. Sumfest says, To improve member satisfaction responses on CAHPS [Consumer Assessment of Healthcare Providers and Systems] surveys, we started a campaign with voice-activated telephone calls. Patients can respond to prompts, which enable us to work with them further. Once a patient agrees to speak with us and we learn of his or her experience at a physician s office, we share the member comments in aggregate with the physician. Medicare is the starting point, Agostini notes. Aetna also reaches out to non-medicare patients with educational messages and materials to alert them to opportunities to improve their health or to get screenings. Those with the most stars do best. As the clock winds down and CMS announces the bonus payments in 2015 for Medicare Advantage plans that achieve at least four stars the role of the medical director as chief cheerleader and motivator will continue to evolve. Nan Myers writes frequently about health care. 18 MANAGED CARE / JUNE 2014

21 Covered for more than 80% of commercially insured patients without prior authorization 1 EXPERIENCE THE DIFFERENCE The recommended starting dose of INVOKANA (canagliflozin) is 100 mg once daily. 2 INVOKANA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. INVOKANA is not recommended in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS >> History of a serious hypersensitivity reaction to INVOKANA. >> Severe renal impairment (egfr <30 ml/min/1.73 m 2 ), end stage renal disease, or patients on dialysis. WARNINGS and PRECAUTIONS >> Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA, particularly in patients with impaired renal function (egfr <60 ml/min/1.73 m 2 ), elderly patients, and patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (eg, angiotensin-convertingenzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

22 EXPERIENCE THE DIFFERENCE INVOKANA 300 mg vs Januvia 100 mg at 52 weeks, each in combination with metformin + a sulfonylurea (SU) 2 Greater reductions in A1C 2 Mean baseline: Adjusted Mean Change in A1C From Baseline (%) 8.13% 8.12% Januvia 100 mg + metformin and an SU (n=378) INVOKANA 300 mg + metformin and an SU (n=377) < Difference from Januvia (sitagliptin): 0.37% (95% CI: 0.50, 0.25); P<0.05 INVOKANA (canagliflozin) starting dose: 100 mg once daily. In patients tolerating the starting dose who have an egfr 60 ml/min/1.73 m 2 and require additional glycemic control, the dose can be increased to 300 mg once daily. 2 Indicated trademarks are registered trademarks of their respective owners. IMPORTANT SAFETY INFORMATION (cont d) >> Impairment in Renal Function: INVOKANA increases serum creatinine and decreases egfr. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA. More frequent renal function monitoring is recommended in patients with an egfr below 60 ml/min/1.73 m 2. >> Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the reninangiotensin-aldosterone system are more likely to develop hyperkalemia. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions.

23 INVOKANA 300 mg demonstrated greater reductions in A1C vs Januvia 100 mg......as well as greater reductions in body weight and systolic blood pressure 2 Greater reductions in body weight 2 * Difference from Januvia 100 mg: 2.8%; P<0.001 Greater reductions in systolic blood pressure 3 * Difference from Januvia 100 mg: 5.9 mm Hg; P<0.001 INVOKANA is not indicated for weight loss or as antihypertensive treatment. *Adjusted mean. Prespecified secondary endpoint. Incidence of hypoglycemia 2 INVOKANA 300 mg: 43.2%; Januvia 100 mg: 40.7% The incidence of hypoglycemia increases when used in combination with insulin or an insulin secretagogue. Adverse reactions (ARs) 3 Incidences of ARs were similar between groups except for: Male/female genital mycotic infection, INVOKANA 300 mg: 9.2%/15.3%; Januvia 100 mg: 0.5%/4.3% Increased urine frequency/volume, INVOKANA 300 mg: 1.6%/0.8%; Januvia 100 mg: 1.3%/0% Learn more and register for updates at INVOKANAhcp.com A randomized, double-blind, active-controlled, 52-week study of patients with type 2 diabetes inadequately controlled on maximum doses of metformin ( 2000 mg/day, or 1500 mg/day if higher dose not tolerated) and near-maximally or maximally effective doses of an SU. 2 >> Hypoglycemia With Concomitant Use With Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. >> Genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections. Monitor and treat appropriately. >> Hypersensitivity Reactions: Hypersensitivity reactions (eg, generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA ; treat per standard of care and monitor until signs and symptoms resolve. Please see additional Important Safety Information and brief summary of full Prescribing Information on the following pages.

24 IMPORTANT SAFETY INFORMATION (cont d) >> Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C occur with INVOKANA (canagliflozin). Monitor LDL-C and treat per standard of care after initiating INVOKANA. >> Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug. DRUG INTERACTIONS >> UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (eg, rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an egfr greater than 60 ml/min/1.73 m 2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an egfr of 45 to less than 60 ml/min/1.73 m 2 receiving concurrent therapy with a UGT inducer and requiring additional glycemic control. >> Digoxin: There was an increase in the area AUC and mean peak drug concentration (C max ) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately. USE IN SPECIFIC POPULATIONS >> Pregnancy Category C: There are no adequate and wellcontrolled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at 0.5 times clinical exposure from a 300-mg dose. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. >> Nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats, reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother. >> Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. >> Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration), particularly with the 300-mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years of age. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). >> Renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (egfr 30 to <50 ml/min/ 1.73 m 2 ). These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in egfr compared to patients with mild renal impairment or normal renal function (egfr 60 ml/min/1.73 m 2 ); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium. The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (egfr <30 ml/min/1.73 m 2 ), with end-stage renal disease (ESRD), or receiving dialysis. INVOKANA is not expected to be effective in these patient populations. Janssen Pharmaceuticals, Inc. Canagliflozin is licensed from Mitsubishi Tanabe Pharma Corporation. Janssen Pharmaceuticals, Inc June

25 >> Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and it is therefore not recommended. OVERDOSAGE >> There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, eg, remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. ADVERSE REACTIONS >> The most common ( 5%) adverse reactions were female genital mycotic infections, urinary tract infections, and increased urination. Adverse reactions in 2% of patients were male genital mycotic infections, vulvovaginal pruritus, thirst, nausea, and constipation. Please see brief summary of full Prescribing Information on the following pages. References: 1. Data on file. Janssen Pharmaceuticals, Inc., Titusville, NJ. 2. INVOKANA [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; Schernthaner G, Gross JL, Rosenstock J, et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial [published correction appears in Diabetes Care. 2013;36(12):4172]. Diabetes Care. 2013;36(9): INVOKANA (canagliflozin) tablets, for oral use Brief Summary of Prescribing Information. INDICATIONS AND USAGE INVOKANA (canagliflozin) is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies (14) in full Prescribing Information]. Limitation of Use: INVOKANA is not recommended in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis. CONTRAINDICATIONS History of a serious hypersensitivity reaction to INVOKANA [see Warnings and Precautions]. Severe renal impairment (egfr less than 30 ml/min/1.73 m 2 ), end stage renal disease or patients on dialysis [see Warnings and Precautions and Use in Specific Populations]. WARNINGS AND PRECAUTIONS Hypotension: INVOKANA causes intravascular volume contraction. Symptomatic hypotension can occur after initiating INVOKANA [see Adverse Reactions] particularly in patients with impaired renal function (egfr less than 60 ml/min/1.73 m 2 ), elderly patients, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs]), or patients with low systolic blood pressure. Before initiating INVOKANA in patients with one or more of these characteristics, volume status should be assessed and corrected. Monitor for signs and symptoms after initiating therapy. Impairment in Renal Function: INVOKANA increases serum creatinine and decreases egfr. Patients with hypovolemia may be more susceptible to these changes. Renal function abnormalities can occur after initiating INVOKANA [see Adverse Reactions]. More frequent renal function monitoring is recommended in patients with an egfr below 60 ml/min/1.73 m 2. Hyperkalemia: INVOKANA can lead to hyperkalemia. Patients with moderate renal impairment who are taking medications that interfere with potassium excretion, such as potassium-sparing diuretics, or medications that interfere with the renin-angiotensin-aldosterone system are more likely to develop hyperkalemia [see Adverse Reactions]. Monitor serum potassium levels periodically after initiating INVOKANA in patients with impaired renal function and in patients predisposed to hyperkalemia due to medications or other medical conditions. Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues: Insulin and insulin secretagogues are known to cause hypoglycemia. INVOKANA can increase the risk of hypoglycemia when combined with insulin or an insulin secretagogue [see Adverse Reactions]. Therefore, a lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with INVOKANA. Genital Mycotic Infections: INVOKANA increases the risk of genital mycotic infections. Patients with a history of genital mycotic infections and uncircumcised males were more likely to develop genital mycotic infections [see Adverse Reactions]. Monitor and treat appropriately. Hypersensitivity Reactions: Hypersensitivity reactions (e.g., generalized urticaria), some serious, were reported with INVOKANA treatment; these reactions generally occurred within hours to days after initiating INVOKANA. If hypersensitivity reactions occur, discontinue use of INVOKANA; treat per standard of care and monitor until signs and symptoms resolve [see Contraindications and Adverse Reactions]. Increases in Low-Density Lipoprotein (LDL-C): Dose-related increases in LDL-C occur with INVOKANA [see Adverse Reactions]. Monitor LDL-C and treat per standard of care after initiating INVOKANA. Macrovascular Outcomes: There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with INVOKANA or any other antidiabetic drug. ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Hypotension [see Warnings and Precautions] Impairment in Renal Function [see Warnings and Precautions] Hyperkalemia [see Warnings and Precautions] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions] Genital Mycotic Infections [see Warnings and Precautions] Hypersensitivity Reactions [see Warnings and Precautions] Increases in Low-Density Lipoprotein (LDL-C) [see Warnings and Precautions] Clinical Studies Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pool of Placebo-Controlled Trials: The data in Table 1 is derived from four 26-week placebo-controlled trials. In one trial INVOKANA was used as monotherapy and in three trials INVOKANA was used as add-on therapy [see Clinical Studies (14) in full Prescribing Information]. These data reflect exposure of 1667 patients to INVOKANA and a mean duration of exposure to

26 INVOKANA (canagliflozin) tablets INVOKANA of 24 weeks. Patients received INVOKANA 100 mg (N=833), INVOKANA 300 mg (N=834) or placebo (N=646) once daily. The mean age of the population was 56 years and 2% were older than 75 years of age. Fifty percent (50%) of the population was male and 72% were Caucasian, 12% were Asian, and 5% were Black or African American. At baseline the population had diabetes for an average of 7.3 years, had a mean HbA1C of 8.0% and 20% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean egfr 88 ml/min/1.73 m 2 ). Table 1 shows common adverse reactions associated with the use of INVOKANA. These adverse reactions were not present at baseline, occurred more commonly on INVOKANA than on placebo, and occurred in at least 2% of patients treated with either INVOKANA 100 mg or INVOKANA 300 mg. Table 1: Adverse Reactions From Pool of Four 26 Week Placebo-Controlled Studies Reported in 2% of INVOKANA-Treated Patients* Placebo N=646 INVOKANA 100 mg N=833 INVOKANA 300 mg N=834 Adverse Reaction Female genital mycotic 3.2% 10.4% 11.4% infections Urinary tract infections 4.0% 5.9% 4.3% Increased urination 0.8% 5.3% 4.6% Male genital mycotic 0.6% 4.2% 3.7% infections Vulvovaginal pruritus 0.0% 1.6% 3.0% Thirst # 0.2% 2.8% 2.3% Constipation 0.9% 1.8% 2.3% Nausea 1.5% 2.2% 2.3% * The four placebo-controlled trials included one monotherapy trial and three add-on combination trials with metformin, metformin and sulfonylurea, or metformin and pioglitazone. Female genital mycotic infections include the following adverse reactions: Vulvovaginal candidiasis, Vulvovaginal mycotic infection, Vulvovaginitis, Vaginal infection, Vulvitis, and Genital infection fungal. Percentages calculated with the number of female subjects in each group as denominator: placebo (N=312), INVOKANA 100 mg (N=425), and INVOKANA 300 mg (N=430). Urinary tract infections include the following adverse reactions: Urinary tract infection, Cystitis, Kidney infection, and Urosepsis. Increased urination includes the following adverse reactions: Polyuria, Pollakiuria, Urine output increased, Micturition urgency, and Nocturia. Male genital mycotic infections include the following adverse reactions: Balanitis or Balanoposthitis, Balanitis candida, and Genital infection fungal. Percentages calculated with the number of male subjects in each group as denominator: placebo (N=334), INVOKANA 100 mg (N=408), and INVOKANA 300 mg (N=404). # Thirst includes the following adverse reactions: Thirst, Dry mouth, and Polydipsia. Abdominal pain was also more commonly reported in patients taking INVOKANA 100 mg (1.8%), 300 mg (1.7%) than in patients taking placebo (0.8%). Pool of Placebo- and Active-Controlled Trials: The occurrence of adverse reactions was also evaluated in a larger pool of patients participating in placebo- and active-controlled trials. The data combined eight clinical trials [see Clinical Studies (14) in full Prescribing Information] and reflect exposure of 6177 patients to INVOKANA. The mean duration of exposure to INVOKANA was 38 weeks with 1832 individuals exposed to INVOKANA for greater than 50 weeks. Patients received INVOKANA 100 mg (N=3092), INVOKANA 300 mg (N=3085) or comparator (N=3262) once daily. The mean age of the population was 60 years and 5% were older than 75 years of age. Fifty-eight percent (58%) of the population was male and 73% were Caucasian, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 11 years, had a mean HbA1C of 8.0% and 33% had established microvascular complications of diabetes. Baseline renal function was normal or mildly impaired (mean egfr 81 ml/min/1.73 m 2 ). The types and frequency of common adverse reactions observed in the pool of eight clinical trials were consistent with those listed in Table 1. In this pool, INVOKANA was also associated with the adverse reactions of fatigue (1.7% with comparator, 2.2% with INVOKANA 100 mg, and 2.0% with INVOKANA 300 mg) and loss of strength or energy (i.e., asthenia) (0.6% with comparator, 0.7% with INVOKANA 100 mg, and 1.1% with INVOKANA 300 mg). In the pool of eight clinical trials, the incidence rate of pancreatitis (acute or chronic) was 0.9, 2.7, and 0.9 per 1000 patient-years of exposure to comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In the pool of eight clinical trials with a longer mean duration of exposure to INVOKANA (68 weeks), the incidence rate of bone fracture was 14.2, 18.7, and 17.6 per 1000 patient years of exposure to comparator, INVOKANA INVOKANA (canagliflozin) tablets 100 mg, and INVOKANA 300 mg, respectively. Upper extremity fractures occurred more commonly on INVOKANA than comparator. In the pool of eight clinical trials, hypersensitivity-related adverse reactions (including erythema, rash, pruritus, urticaria, and angioedema) occurred in 3.0%, 3.8%, and 4.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Five patients experienced serious adverse reactions of hypersensitivity with INVOKANA, which included 4 patients with urticaria and 1 patient with a diffuse rash and urticaria occurring within hours of exposure to INVOKANA. Among these patients, 2 patients discontinued INVOKANA. One patient with urticaria had recurrence when INVOKANA was re-initiated. Photosensitivity-related adverse reactions (including photosensitivity reaction, polymorphic light eruption, and sunburn) occurred in 0.1%, 0.2%, and 0.2% of patients receiving comparator, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Other adverse reactions occurring more frequently on INVOKANA than on comparator were: Volume Depletion-Related Adverse Reactions: INVOKANA results in an osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with INVOKANA was associated with a dosedependent increase in the incidence of volume depletion-related adverse reactions (e.g., hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300 mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (egfr 30 to less than 60 ml/min/1.73 m 2 ), and age 75 years and older (Table 2) [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Use in Specific Populations]. Table 2: Proportion of Patients With at Least One Volume Depletion-Related Adverse Reaction (Pooled Results from 8 Clinical Trials) Comparator Group* % INVOKANA 100 mg % INVOKANA 300 mg % Baseline Characteristic Overall population 1.5% 2.3% 3.4% 75 years of age and older 2.6% 4.9% 8.7% egfr less than 60 ml/min/1.73 m 2 2.5% 4.7% 8.1% Use of loop diuretic 4.7% 3.2% 8.8% * Includes placebo and active-comparator groups Patients could have more than 1 of the listed risk factors Impairment in Renal Function: INVOKANA is associated with a dosedependent increase in serum creatinine and a concomitant fall in estimated GFR (Table 3). Patients with moderate renal impairment at baseline had larger mean changes. Table 3: Changes in Serum Creatinine and egfr Associated with INVOKANA in the Pool of Four Placebo-Controlled Trials and Moderate Renal Impairment Trial Pool of Four Placebo- Controlled Trials Moderate Renal Impairment Trial Baseline Week 6 Change End of Treatment Change* Baseline Week 3 Change End of Treatment Change* Placebo N=646 INVOKANA 100 mg N=833 INVOKANA 300 mg N=834 Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Placebo N=90 INVOKANA 100 mg N=90 INVOKANA 300 mg N=89 Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) Creatinine (mg/dl) egfr (ml/min/1.73 m 2 ) * Week 26 in mitt LOCF population In the pool of four placebo-controlled trials where patients had normal or mildly impaired baseline renal function, the proportion of patients who experienced at least one event of significant renal function decline, defined as an egfr below 80 ml/min/1.73 m 2 and 30% lower than baseline, was 2.1% with placebo, 2.0% with INVOKANA 100 mg, and 4.1% with INVOKANA 300 mg. At the end of treatment, 0.5% with placebo, 0.7% with INVOKANA 100 mg, and 1.4% with INVOKANA 300 mg had a significant renal function decline.

27 INVOKANA (canagliflozin) tablets In a trial carried out in patients with moderate renal impairment with a baseline egfr of 30 to less than 50 ml/min/1.73 m 2 (mean baseline egfr 39 ml/min/1.73 m 2 ) [see Clinical Studies (14.3) in full Prescribing Information], the proportion of patients who experienced at least one event of significant renal function decline, defined as an egfr 30% lower than baseline, was 6.9% with placebo, 18% with INVOKANA 100 mg, and 22.5% with INVOKANA 300 mg. At the end of treatment, 4.6% with placebo, 3.4% with INVOKANA 100 mg, and 3.4% with INVOKANA 300 mg had a significant renal function decline. In a pooled population of patients with moderate renal impairment (N=1085) with baseline egfr of 30 to less than 60 ml/min/1.73 m 2 (mean baseline egfr 48 ml/min/1.73 m 2 ), the overall incidence of these events was lower than in the dedicated trial but a dose-dependent increase in incident episodes of significant renal function decline compared to placebo was still observed. Use of INVOKANA was associated with an increased incidence of renalrelated adverse reactions (e.g., increased blood creatinine, decreased glomerular filtration rate, renal impairment, and acute renal failure), particularly in patients with moderate renal impairment. In the pooled analysis of patients with moderate renal impairment, the incidence of renal-related adverse reactions was 3.7% with placebo, 8.9% with INVOKANA 100 mg, and 9.3% with INVOKANA 300 mg. Discontinuations due to renal-related adverse events occurred in 1.0% with placebo, 1.2% with INVOKANA 100 mg, and 1.6% with INVOKANA 300 mg [see Warnings and Precautions]. Genital Mycotic Infections: In the pool of four placebo-controlled clinical trials, female genital mycotic infections (e.g., vulvovaginal mycotic infection, vulvovaginal candidiasis, and vulvovaginitis) occurred in 3.2%, 10.4%, and 11.4% of females treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Patients with a history of genital mycotic infections were more likely to develop genital mycotic infections on INVOKANA. Female patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrence and require treatment with oral or topical antifungal agents and anti-microbial agents [see Warnings and Precautions]. In the pool of four placebo-controlled clinical trials, male genital mycotic infections (e.g., candidal balanitis, balanoposthitis) occurred in 0.6%, 4.2%, and 3.7% of males treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Male genital mycotic infections occurred more commonly in uncircumcised males and in males with a prior history of balanitis or balanoposthitis. Male patients who developed genital mycotic infections on INVOKANA were more likely to experience recurrent infections (22% on INVOKANA versus none on placebo), and require treatment with oral or topical antifungal agents and anti-microbial agents than patients on comparators. In the pooled analysis of 8 controlled trials, phimosis was reported in 0.3% of uncircumcised male patients treated with INVOKANA and 0.2% required circumcision to treat the phimosis [see Warnings and Precautions]. Hypoglycemia: In all clinical trials, hypoglycemia was defined as any event regardless of symptoms, where biochemical hypoglycemia was documented (any glucose value below or equal to 70 mg/dl). Severe hypoglycemia was defined as an event consistent with hypoglycemia where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained). In individual clinical trials [see Clinical Studies (14) in full Prescribing Information], episodes of hypoglycemia occurred at a higher rate when INVOKANA was co-administered with insulin or sulfonylureas (Table 4) [see Warnings and Precautions]. Table 4: Incidence of Hypoglycemia* in Controlled Clinical Studies Monotherapy Placebo INVOKANA 100 mg INVOKANA 300 mg (26 weeks) (N=192) (N=195) (N=197) Overall [N (%)] 5 (2.6) 7 (3.6) 6 (3.0) In Combination with Metformin (26 weeks) Placebo + Metformin (N=183) INVOKANA 100 mg + Metformin (N=368) INVOKANA 300 mg + Metformin (N=367) Overall [N (%)] 3 (1.6) 16 (4.3) 17 (4.6) Severe [N (%)] 0 (0) 1 (0.3) 1 (0.3) In Combination with Metformin (52 weeks) Glimepiride + Metformin (N=482) INVOKANA 100 mg + Metformin (N=483) INVOKANA 300 mg + Metformin (N=485) Overall [N (%)] 165 (34.2) 27 (5.6) 24 (4.9) Severe [N (%)] 15 (3.1) 2 (0.4) 3 (0.6) In Combination with Sulfonylurea (18 weeks) Placebo + Sulfonylurea (N=69) INVOKANA 100 mg + Sulfonylurea (N=74) INVOKANA 300 mg + Sulfonylurea (N=72) Overall [N (%)] 4 (5.8) 3 (4.1) 9 (12.5) In Combination with Metformin + Sulfonylurea (26 weeks) Placebo + Metformin + Sulfonylurea (N=156) INVOKANA 100 mg + Metformin + Sulfonylurea (N=157) INVOKANA 300 mg + Metformin + Sulfonylurea (N=156) Overall [N (%)] 24 (15.4) 43 (27.4) 47 (30.1) Severe [N (%)] 1 (0.6) 1 (0.6) 0 INVOKANA (canagliflozin) tablets Table 4: Incidence of Hypoglycemia* in Controlled Clinical Studies (continued) In Combination with Metformin + Sulfonylurea (52 weeks) Sitagliptin + Metformin + Sulfonylurea (N=378) INVOKANA 300 mg + Metformin + Sulfonylurea (N=377) Overall [N (%)] 154 (40.7) 163 (43.2) Severe [N (%)] 13 (3.4) 15 (4.0) In Combination with Metformin + Pioglitazone (26 weeks) Placebo + Metformin + Pioglitazone (N=115) INVOKANA 100 mg + Metformin + Pioglitazone (N=113) INVOKANA 300 mg + Metformin + Pioglitazone (N=114) Overall [N (%)] 3 (2.6) 3 (2.7) 6 (5.3) In Combination with Insulin Placebo INVOKANA 100 mg INVOKANA 300 mg (18 weeks) (N=565) (N=566) (N=587) Overall [N (%)] 208 (36.8) 279 (49.3) 285 (48.6) Severe [N (%)] 14 (2.5) 10 (1.8) 16 (2.7) * Number of patients experiencing at least one event of hypoglycemia based on either biochemically documented episodes or severe hypoglycemic events in the intent-to-treat population Severe episodes of hypoglycemia were defined as those where the patient required the assistance of another person to recover, lost consciousness, or experienced a seizure (regardless of whether biochemical documentation of a low glucose value was obtained) Laboratory Tests: Increases in Serum Potassium: Dose-related, transient mean increases in serum potassium were observed early after initiation of INVOKANA (i.e., within 3 weeks) in a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information]. In this trial, increases in serum potassium of greater than 5.4 meq/l and 15% above baseline occurred in 16.1%, 12.4%, and 27.0% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. More severe elevations (i.e., equal or greater than 6.5 meq/l) occurred in 1.1%, 2.2%, and 2.2% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. In patients with moderate renal impairment, increases in potassium were more commonly seen in those with elevated potassium at baseline and in those using medications that reduce potassium excretion, such as potassium-sparing diuretics, angiotensinconverting-enzyme inhibitors, and angiotensin-receptor blockers [see Warnings and Precautions]. Increases in Serum Magnesium: Dose-related increases in serum magnesium were observed early after initiation of INVOKANA (within 6 weeks) and remained elevated throughout treatment. In the pool of four placebo-controlled trials, the mean change in serum magnesium levels was 8.1% and 9.3% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to -0.6% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], serum magnesium levels increased by 0.2%, 9.2%, and 14.8% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Serum Phosphate: Dose-related increases in serum phosphate levels were observed with INVOKANA. In the pool of four placebo controlled trials, the mean change in serum phosphate levels were 3.6% and 5.1% with INVOKANA 100 mg and INVOKANA 300 mg, respectively, compared to 1.5% with placebo. In a trial of patients with moderate renal impairment [see Clinical Studies (14.3) in full Prescribing Information], the mean serum phosphate levels increased by 1.2%, 5.0%, and 9.3% with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively. Increases in Low-Density Lipoprotein Cholesterol (LDL-C) and non-high- Density Lipoprotein Cholesterol (non-hdl-c): In the pool of four placebocontrolled trials, dose-related increases in LDL-C with INVOKANA were observed. Mean changes (percent changes) from baseline in LDL-C relative to placebo were 4.4 mg/dl (4.5%) and 8.2 mg/dl (8.0%) with INVOKANA 100 mg and INVOKANA 300 mg, respectively. The mean baseline LDL-C levels were 104 to 110 mg/dl across treatment groups [see Warnings and Precautions]. Dose-related increases in non-hdl-c with INVOKANA were observed. Mean changes (percent changes) from baseline in non-hdl-c relative to placebo were 2.1 mg/dl (1.5%) and 5.1 mg/dl (3.6%) with INVOKANA 100 mg and 300 mg, respectively. The mean baseline non-hdl-c levels were 140 to 147 mg/dl across treatment groups. Increases in Hemoglobin: In the pool of four placebo-controlled trials, mean changes (percent changes) from baseline in hemoglobin were g/dl (-1.1%) with placebo, 0.47 g/dl (3.5%) with INVOKANA 100 mg, and 0.51 g/dl (3.8%) with INVOKANA 300 mg. The mean baseline hemoglobin value was approximately 14.1 g/dl across treatment groups. At the end of treatment, 0.8%, 4.0%, and 2.7% of patients treated with placebo, INVOKANA 100 mg, and INVOKANA 300 mg, respectively, had hemoglobin above the upper limit of normal. DRUG INTERACTIONS UGT Enzyme Inducers: Rifampin: Co-administration of canagliflozin with rifampin, a nonselective inducer of several UGT enzymes, including

28 INVOKANA (canagliflozin) tablets UGT1A9, UGT2B4, decreased canagliflozin area under the curve (AUC) by 51%. This decrease in exposure to canagliflozin may decrease efficacy. If an inducer of these UGTs (e.g., rifampin, phenytoin, phenobarbital, ritonavir) must be co-administered with INVOKANA (canagliflozin), consider increasing the dose to 300 mg once daily if patients are currently tolerating INVOKANA 100 mg once daily, have an egfr greater than 60 ml/min/1.73 m 2, and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an egfr of 45 to less than 60 ml/min/1.73 m 2 receiving concurrent therapy with a UGT inducer and require additional glycemic control [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) in full Prescribing Information]. Digoxin: There was an increase in the AUC and mean peak drug concentration (C max ) of digoxin (20% and 36%, respectively) when co-administered with INVOKANA 300 mg [see Clinical Pharmacology (12.3) in full Prescribing Information]. Patients taking INVOKANA with concomitant digoxin should be monitored appropriately. USE IN SPECIFIC POPULATIONS Pregnancy: Teratogenic Effects: Pregnancy Category C: There are no adequate and well-controlled studies of INVOKANA in pregnant women. Based on results from rat studies, canagliflozin may affect renal development and maturation. In a juvenile rat study, increased kidney weights and renal pelvic and tubular dilatation were evident at greater than or equal to 0.5 times clinical exposure from a 300 mg dose [see Nonclinical Toxicology (13.2) in full Prescribing Information]. These outcomes occurred with drug exposure during periods of animal development that correspond to the late second and third trimester of human development. During pregnancy, consider appropriate alternative therapies, especially during the second and third trimesters. INVOKANA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known if INVOKANA is excreted in human milk. INVOKANA is secreted in the milk of lactating rats reaching levels 1.4 times higher than that in maternal plasma. Data in juvenile rats directly exposed to INVOKANA showed risk to the developing kidney (renal pelvic and tubular dilatations) during maturation. Since human kidney maturation occurs in utero and during the first 2 years of life when lactational exposure may occur, there may be risk to the developing human kidney. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from INVOKANA, a decision should be made whether to discontinue nursing or to discontinue INVOKANA, taking into account the importance of the drug to the mother [see Nonclinical Toxicology (13.2) in full Prescribing Information]. Pediatric Use: Safety and effectiveness of INVOKANA in pediatric patients under 18 years of age have not been established. Geriatric Use: Two thousand thirty-four (2034) patients 65 years and older, and 345 patients 75 years and older were exposed to INVOKANA in nine clinical studies of INVOKANA [see Clinical Studies (14.3) in full Prescribing Information]. Patients 65 years and older had a higher incidence of adverse reactions related to reduced intravascular volume with INVOKANA (such as hypotension, postural dizziness, ortho static hypotension, syncope, and dehydration), particularly with the 300 mg daily dose, compared to younger patients; more prominent increase in the incidence was seen in patients who were 75 years and older [see Dosage and Administration (2.1) in full Prescribing Information and Adverse Reactions]. Smaller reductions in HbA1C with INVOKANA relative to placebo were seen in older (65 years and older; -0.61% with INVOKANA 100 mg and -0.74% with INVOKANA 300 mg relative to placebo) compared to younger patients (-0.72% with INVOKANA 100 mg and -0.87% with INVOKANA 300 mg relative to placebo). Renal Impairment: The efficacy and safety of INVOKANA were evaluated in a study that included patients with moderate renal impairment (egfr 30 to less than 50 ml/min/1.73 m 2 ) [see Clinical Studies (14.3) in full Prescribing Information]. These patients had less overall glycemic efficacy and had a higher occurrence of adverse reactions related to reduced intravascular volume, renal-related adverse reactions, and decreases in egfr compared to patients with mild renal impairment or normal renal function (egfr greater than or equal to 60 ml/min/1.73 m 2 ); patients treated with INVOKANA 300 mg were more likely to experience increases in potassium [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Adverse Reactions]. The efficacy and safety of INVOKANA have not been established in patients with severe renal impairment (egfr less than 30 ml/min/1.73 m 2 ), with ESRD, or receiving dialysis. INVOKANA is not expected to be effective in these patient populations [see Contraindications and Clinical Pharmacology (12.3) in full Prescribing Information]. Hepatic Impairment: No dosage adjustment is necessary in patients with mild or moderate hepatic impairment. The use of INVOKANA has not been studied in patients with severe hepatic impairment and is therefore not recommended [see Clinical Pharmacology (12.3) in full Prescribing Information]. INVOKANA (canagliflozin) tablets OVERDOSAGE There were no reports of overdose during the clinical development program of INVOKANA (canagliflozin). In the event of an overdose, contact the Poison Control Center. It is also reasonable to employ the usual supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring, and institute supportive treatment as dictated by the patient s clinical status. Canagliflozin was negligibly removed during a 4-hour hemodialysis session. Canagliflozin is not expected to be dialyzable by peritoneal dialysis. PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Instructions: Instruct patients to read the Medication Guide before starting INVOKANA (canagliflozin) therapy and to reread it each time the prescription is renewed. Inform patients of the potential risks and benefits of INVOKANA and of alternative modes of therapy. Also inform patients about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and HbA1C testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. Advise patients to seek medical advice promptly during periods of stress such as fever, trauma, infection, or surgery, as medication requirements may change. Instruct patients to take INVOKANA only as prescribed. If a dose is missed, advise patients to take it as soon as it is remembered unless it is almost time for the next dose, in which case patients should skip the missed dose and take the medicine at the next regularly scheduled time. Advise patients not to take two doses of INVOKANA at the same time. Inform patients that the most common adverse reactions associated with INVOKANA are genital mycotic infection, urinary tract infection, and increased urination. Inform female patients of child bearing age that the use of INVOKANA during pregnancy has not been studied in humans, and that INVOKANA should only be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Instruct patients to report pregnancies to their physicians as soon as possible. Inform nursing mothers to discontinue INVOKANA or nursing, taking into account the importance of drug to the mother. Laboratory Tests: Due to its mechanism of action, patients taking INVOKANA will test positive for glucose in their urine. Hypotension: Inform patients that symptomatic hypotension may occur with INVOKANA and advise them to contact their doctor if they experience such symptoms [see Warnings and Precautions]. Inform patients that dehydration may increase the risk for hypotension, and to have adequate fluid intake. Genital Mycotic Infections in Females (e.g., Vulvovaginitis): Inform female patients that vaginal yeast infection may occur and provide them with information on the signs and symptoms of vaginal yeast infection. Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Genital Mycotic Infections in Males (e.g., Balanitis or Balanoposthitis): Inform male patients that yeast infection of penis (e.g., balanitis or balanoposthitis) may occur, especially in uncircumcised males and patients with prior history. Provide them with information on the signs and symptoms of balanitis and balanoposthitis (rash or redness of the glans or foreskin of the penis). Advise them of treatment options and when to seek medical advice [see Warnings and Precautions]. Hypersensitivity Reactions: Inform patients that serious hypersensitivity reactions such as urticaria and rash have been reported with INVOKANA. Advise patients to report immediately any signs or symptoms suggesting allergic reaction or angioedema, and to take no more drug until they have consulted prescribing physicians. Urinary Tract Infections: Inform patients of the potential for urinary tract infections. Provide them with information on the symptoms of urinary tract infections. Advise them to seek medical advice if such symptoms occur. Active ingredient made in Belgium Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ Finished product manufactured by: Janssen Ortho, LLC Gurabo, PR Licensed from Mitsubishi Tanabe Pharma Corporation 2013 Janssen Pharmaceuticals, Inc

29 Q&A A Conversation With Mary D. Naylor, PhD, RN Managing the Transition From the Hospital A pioneering advocate for transitional care for older adults and their caregivers sees growing interest in her evidence-based approach Even though Mary Naylor, PhD, RN, and her team could prove that their approach to caring for elderly patients as they made the transition from hospital to home could improve outcomes and reduce costs, that didn t mean that the model would be adopted, at least not overnight. The success was years in the making and their Transitional Care Model is still far from ubiquitous. But today s environment of change and the advent of accountable care organizations means that the odds are better than ever that more patients will have access to advanced practice nurses who provide continuity of care and coordination of health and social services, says Naylor, the Marian S. Ware Professor in Gerontology and director of the NewCourtland Center for Transitions and Health at the University of Pennsylvania School of Nursing. I am glad we hung in there. We are seeing the care delivery systems align better with people s needs. Managed health care is creating the conditions and the incentives both quality and financial for this kind of approach to care to scale more quickly than it has. Her team s patience and meticulous attention to collecting data on effectiveness can also be an example for other proposed innovations in the health care system, she says. Naylor, a fellow of the American Academy of Nursing, is a member of the Medicare Payment Advisory Commission MedPAC. She is the national program director for the Robert Wood Johnson Foundation s Interdisciplinary Nursing Quality Research Initiative, a member of the Rand Health advisory board and of the National Quality Forum board of directors, and the founding chairwoman of the Long Term Quality Alliance. She also serves on the Institute of Medicine s health care services board. She spoke recently with Managed Care Editor John Marcille. Managed Care: How did the Transitional Care Model come about? Mary D. Naylor, PhD, RN: When I came to the University of Pennsylvania School of Nursing, I had just completed a W. K. Kellogg leadership fellowship with the Senate Committee on Aging. When I arrived at Penn, I connected with Dorothy Brooten, the Transitional Care Model s (TCMs) original architect. Her team had tested this care delivery innovation with very-low-birth-weight infants. Study results demonstrated the capacity of the TCM to reduce length of stay and costs, if an infant s care was coordinated by advanced practice nurses who were working collaboratively with the family, physicians, and other health care team members. Our team recognized a common vulnerability with older adults: It s not just progression of health problems that contributes to poor outcomes; it is often social issues. It might be economic issues, such as inability to pay the copays for medications or challenges with health literacy. A new mutidisciplinary team agreed that these common-ground issues were sufficient to apply the model to older adults. MC: You spent years proving that your version of the TCM could work. Naylor: Many National Institutes of Health multisite randomized clinical trials showed that we can get to better patient outcomes, better experiences with care, and reduced costs with this model. We had papers published in top-tiered journals, with substantial publicity, as each trial was reported. But JUNE 2014 / MANAGED CARE 27

30 then we realized that nobody was applying what we had uncovered. Over time, we realized there was little alignment of this model with quality and payment incentives. Hospital staff were not conditioned to speak as they are now with home care and skilled-nursing staff or family caregivers. Ultimately, we realized we didn t have a care culture focused on older adults and their complex needs. MC: Things are different today? Naylor: There are many promising signs. There s no question that the importance of transitional care is now understood. CMS recently introduced transitional care payment codes. This small advance does not support the TCM, but is evidence of the need for follow-up care of hospitalized Medicare beneficiaries. CMS is testing many transitional care delivery and payment approaches that, if proven successful, can be quickly scaled. Leaders of evolving accountable care organizations understand that they have to optimize care that clearly aligns with the needs of people, in order to get these results. They are very interested in the TCM. MC: What was the key in moving the Transitional Care Model from clinical trials to practice? Naylor: We partnered with Aetna to determine whether we could replicate what we learned in clinical trials in the real world. We were able to demonstrate improvements in all assessed patient outcomes as well as in the physicians experience in managing high-risk, chronically ill older adults,reductions in rehospitalizations and costs. The University of Pennsylvania Health System (UPHS) and many others have adopted or adapted the model. Independence Blue Cross and Aetna are reimbursing the UPHS to deliver this evidence-based approach to care for their members. Managed care leaders understand the capacity of this care approach to improve population health and achieve longer term value MC: What product are you selling? Naylor: The product depends on the site. Our team initially focused on the movement of older adults from hospitals to home. We have extended our efforts to include transitions through skillednursing facilities to home. We have tested the model in patient-centered medical homes, integrating the model to focus on high-risk, chronically ill older adults and prevent initial hospitalizations. MC: How does the model work? Naylor: We use evidence-based criteria to identify who will benefit from transitional care. So if Mr. Smith is screened as at-risk for poor outcomes and agrees to the service, a master s-prepared advanced practice nurse, who has achieved certain competencies related to transitional care, is deployed. The transitional nurse works with staff to promote positive hospital outcomes and prevent common problems such as functional decline, falls, and infection. That same nurse visits Mr. Smith in his home within 24 hours and accompanies him to the first follow-up visit with his community-based provider to make sure there s optimal communication between the hospital and the community-based clinician. If, during a home visit, for example, the nurse notices that Mr. Smith is declining, the nurse and physician can collaborate to avoid preventable emergency department visits or hospitalizations. Older adults really value care continuity. The same nurse is involved in the entire episode of care, from the initial hospital admission through an average of two months post transition. MC: The advanced practice nurse is providing the home care? Naylor: The program substitutes for traditional home care by nurses. Older adults really value care continuity. The same nurse is involved in the entire episode of care, from the initial hospital admission through an average of two months post transition. Throughout this period, the nurse is helping Mr. Smith figure out how to manage or prevent all of the challenges that resulted in multiple emergency room visits or hospitalizations in the past. The care plan is driven by Mr. Smith his goals, preferences, and needs. MC: Everything depends on the nurses? Naylor: It depends on the nurses capacity to engage Mr. Smith, his family caregivers, physicians and other health team members. Mr. Smith is not someone who s hospitalized for a minor health problem for the first time. He is typically coping with multiple chronic illnesses or a serious, advanced illness. The transitional care nurses are very sophisticated in their ability to assess the priority problems that, if unaddressed, will probably result in poor outcomes for Mr. Smith, and they are very system-savvy. They work to assure all members of 28 MANAGED CARE / JUNE 2014

31 the health team agree on a plan of care that is aligned with Mr. Smith s goals and preferences and needs. That means that they have a capacity to communicate and collaborate and advocate on behalf of Mr. Smith. The nurses emphasizes palliative care and, when appropriate and consistent with Mr. Smith s goals, help in the transition to hospice. MC: This all seems desirable from several points of view. Naylor: We have been at this for many years, and some days, we wonder why the move to this approach is so challenging, especially since our team seeks this approach for our loved ones and ourselves. We are using multiple strategies to scale the TCM, including a commercial venture through Penn s technology transfer department. MC: Can your business case inspire insurers to get on board? Naylor: The business case is exceedingly important. From the outset, we have examined the TCM from the perspectives of both benefits and costs. Are people able to manage their symptoms better? Do they feel that someone has been in charge of their care? Do they have a sense that their quality of life is better? These are things that matter to people. We also looked at what it costs in our system to achieve these benefits; what is the long-term impact? One clinical trial demonstrated significant reductions in rehospitalizations among heart failure patients through one year following enrollment. We also have compared the effectiveness of the TCM to other evidence-based approaches. Not surprisingly, the cost findings have received the most attention. We view 30-day rehospitalization rates as a marker but certainly not the end point. The real definition of success is interrupting the progression of chronic illnesses and helping people receive the services that matter to them. That is, our efforts emphasize long-term value. MC: Are certain organizations more interested in that than others? Naylor: Accountable care organizations are certainly interested in making the TCM a part of their care system. We are also working with patientcentered medical homes. These community-based practices place a premium on care coordination, but often they don t have the capacity to do the things that we can do in partnership with them. So advanced practice nurses can target the high-risk patients, go into the home, and follow up on the priority issues. They do this in strong collaboration with the primary care physicians. MC: How widespread is the use of the TCM? Naylor: The Robert Wood Johnson Foundation is funding a national study that will help us to know how sites have adopted or adapted the TCM. We certainly know about some health systems and communities, because we are working with them. But we also know that the provisions in the Affordable Care Act regarding community-based care transition programs, hospital readmission reduction programs, and shared savings programs, all highlight the importance of evidence-based transitional care not necessarily our approach, but evidence-based transitional care models. We have developed a training program for nurses and other health care team members across the country to help them get oriented to the TCM. We provide consultation services. For example, we worked with Baylor Health Care System at its very early stages, and I understand that multiple hospitals within this system are now implementing the model. We are working on a project at Cedars-Sinai Medical Center in Los Angeles, where they are attempting to connect the great work that they have been doing with frail elders with better follow-up care in the community. A community in northern New Jersey is implementing the Transitional Care Model to target a growing population of older adults living in rural communities to enable them to stay in their homes. Roles, at least for some clinicians, cannot be bounded by hospital doors. They need to extend across settings and teams. MC: Are you also studying how insurers are paying for this kind of care? Naylor: As noted earlier, the UPHS the has established the TCM as a service line within its home care and hospice division and local insurers are reimbursing for this service. We are examining the effects of innovative payment methods such as case rates and risk bearing contracts in partnership with these insurers. MC: Would a large organization bring that inhouse? Naylor: This is care delivery, and so it s a partnership between the managed care organization and the care deliverers. Most insurers rely on case JUNE 2014 / MANAGED CARE 29

32 management, typically deployed through telephonic services. Our efforts are to partner with insurers, to extend care to those who require more than telephonic support. MC: What would be the typical caseload for a nurse in this role? Naylor: Reported studies suggest that one nurse can care for 20 high risk patients, assuming responsibility for daily hospital visits, building the transitional care plan, delivering and implementing that plan in the patient s home, and delivering and coordinating care for an average of two months following a hospital discharge. MC: It sounds like a lot of work. Naylor: In health care, we have often positioned people to work well in one setting, such as in an emergency department or intensive care unit. But in our model we have nurses working with all team members that are involved in Mr. Smith s care while hospitalized. These nurses are responsible for the delivery of care in post-acute care facilities and the patient s home following transition from the hospital. Care in the home often requires a very different skill set, where nurses are figuring out how to help Mr. Smith access community services such as Meals on Wheels and transportation, to make sure that Mr. Smith is not going back to the emergency room because he is not well nourished or doesn t have transportation to follow-up visits. We have also been trying to figure out how to prepare the existing work force to focus much more on chronic illness and population health vitally important issues for accountable systems. That means that roles, at least for some clinicians cannot be bounded by hospital doors. MC: What are some of the things that make your nurses more flexible? Naylor: These nurses are credentialed in primary care practices and in hospitals, in the sites that match Mr. Smith s experience over an episode of care. The nurses possess competencies that enable them to address acute and post-acute needs. MC: You are optimistic? Naylor: Our conversations about the importance of patient engagement nationally, and the conversations about payment for care coordination broadly, are all signs of movement from a fee-for-service system to a payment model that aligns much better with this approach to care. Consumers who have lived with the experience or witnessed what has happened to relatives and friends are beginning to become a strong voice for change. They expect and deserve better alignment with their care needs better care coordination. We are not going to turn the current payment system upside down tomorrow, but incrementally can change the system to support evidence-based services such as the TCM, then we will be on the path to better health outcomes for the growing population of chronically and seriously ill people and much wiser use of our finite resources. MC: You have given policymakers a lot of evidence to get behind this model. That s not always the case when legislators consider innovations. Naylor: The TCM has been recognized by the Coalition for Evidence-Based Policy as a top-tier evidence-based approach that if scaled could result in major savings and do something very good for the care of people. From the outset, Mark V. Pauly, PhD, has been the lead health care economist on our team. We have always looked at this as trying to figure out how evidence creates a foundation for change. It is in the best interest of our society to mount change based on what we know works and doesn t work. Decisions based on how we are going to change care design should be grounded in what we know works for whom, for how long, and at what cost. MC: What are you doing to promote evidencebased change broadly? Naylor: In addition to my role on a number of key policy-making groups, Mark and I head a program for the Robert Wood Johnson Foundation that is designed to try to show health system leaders and policymakers, through rigorous evidence, how nurses contribute to health care value. MC: You are preparing a road map for others who want to bring empirically tested research into their organizations. Is that related? Naylor: When multiple clinical trials demonstrated little impact on practice, our team decided it was up to us to move evidence into real-world systems. We built high risk screening tools. We created a Web-based system to prepare nurses and other team members to implement the TCM. We built and tested performance improvement programs. While we always have had benchmarks to measure progression, these have become more sophisticated over time. Every time we work with a system, we assess facilitators and barriers to change and, as a result, we anticipate challenges and get better. MC: Thank you. 30 MANAGED CARE / JUNE 2014

33 Health Information Exchanges Not Ready for Prime Time Touted as a cost-saving and quality improvement tool, HIEs public and private are just beginning to show what they can do By Michael Levin-Epstein HIEs have been MIA, at least up until now. Health information exchanges trumpeted as a boon to payers, providers, hospitals, and pharmacy benefit managers (PBMs) in the effort to improve care, reduce costs, and comply with federal mandates are still a work in progress. While experts continue to tout the benefits of both public- and private-sector HIEs, their effect on health plans is unclear, as stakeholders explore options and alternative models for sharing vital diagnosis and treatment information. Those models vary among both public and private HIE network members, depending on their needs. As far as public HIEs are concerned, the federal program began with much promise and fanfare. In March 2010, the Department of Health and Human Services made a huge splash when it unveiled State Health Information Exchange Cooperative Agreement Program awardees. Fifty-six states, territories, and qualified state-designated entities (SDEs) received awards totaling almost $550 million. In January 2011, an additional $16 million was made available to states through HHS s Office of the National Coordinator for Health Information Technology. The federal program funded states rapid efforts to build capacity for exchanging health information within and between states. Awardees were responsible for increasing connectivity and enabling patient-centric information flow to improve the quality and efficiency of care. The national co-ordinator identified several key issues for optimal exchange of health information in the areas of governance, policies, technical services, business operations, and financing mechanisms for HIE over the four-year performance period. Its Insurers have significant concerns about the uncertainty of national standards of interoperability when it comes to using health information exchanges, says David Gonzales, CEO of the Texas Association of Health Plans. hope: Health care providers and payers would see both short-term and long-term benefits. Not-so-little black book But four years later, the outlook, at least for public HIEs, doesn t look quite so rosy at least according to one major study. Earlier this year, Black Book Market Research, in its annual satisfaction survey of HIE users, found that large numbers of payers are investing in private HIEs because public ones are too bureaucratic, expensive, and complex. Many of the current public HIEs were funded by the Health Information Technology for Economic and Clinical Health Act (HITECH), but the federal money has begun to dry up. That means public HIEs face the prospect of needing to increase fees or develop alternative revenue sources, experts say. And according to Black Book, payers appear skeptical of the ability of the public exchanges to do that, as well as their ability to improve the delivery of health care services over time. Specifically, Black Book researchers found that 94% of payers don t see HIEs being worth the cost and effort, and 97% of insurers claimed that public HIEs are struggling to exchange trusted patient data sets between payers and providers. As a result, some public HIEs have been shutting down as federal funding has diminished, while others are undertaking changes to allow people to continue to use the system. Kaiser out front in Colorado But health plans are far from abandoning public HIEs. In February, Kaiser Permanente Colorado agreed to join the Colorado Regional Health Information Organization (CORHIO), the statedesignated HIE network. Participation provides Kaiser Permanente s physicians and other clinical JUNE 2014 / MANAGED CARE 31

34 Colorado s experience with HIEs and ACOs Christine Baker, spokeswoman for the Colorado Regional Health Information Organization, says that the exchange is working with Colorado Access, which is developing an accountable care organization for Medicare patients. Denver-based Colorado Access is a not-for-profit health plan established in 1994 to provide access to behavioral and physical health services for Coloradans. The company is sponsored by Children s Hospital Colorado, Colorado Community Managed Care Network and the University of Colorado Hospital/University Physicians. The company wants to obtain additional data, which may help in providing better patient care and in reducing costs, Baker says. For example, she says, analysis of additional information could allow identification of high-use individuals who might benefit from having a case manager appointed to monitor and assist them. Exchange users are in the process of determining ways to use the large volume of information that is available, and different users have somewhat different goals, Baker noted. And it appears that health plans will be making use of both public and private HIEs to meet those goals. caregivers with information on their members when care is provided outside of the health plan s centralized network. Kaiser Permanente plans to use the HIE information initially for members in southern Colorado and later to expand to other parts of the state. Kaiser organizations also are involved with the Maryland state exchange and a regional public exchange in San Diego. Fluid situation In Florida, says Heidi Fox, administrator of that state s Office of Health Information Exchange, the situation for HIEs is fluid and likely to remain so for much of the year: It s all unfolding pretty quickly. The market is still shaking out. We ll need to look at the end of the year. That means after the Centers for Medicare & Medicaid Services (CMS) Stage 2 meaningful use requirements kick in. Stage 2 has taken effect in federal fiscal year 2014 (ending September 30) for eligible hospitals and critical access hospitals, and in calendar year 2014 for eligible professionals. Stage 2 focuses on advanced clinical procedures, including: Measures focused on more rigorous health information exchange Additional requirements for electronic prescribing and incorporating lab results Electronic transmission of patient care summaries across multiple settings Data inconsistencies can show up when an HIE is in use, says Joseph Schneider, MD, chief medical information officer at Baylor Scott & White Health System in Dalllas. That s good, because it means that errors are being discovered and corrected. The public HIE exchange was launched by Florida s Agency for Health Care Administration (AHCA). The AHCA awarded a company called Harris a four-year, $19 million contract for the statewide HIE. The exchange s 22 initial participants have access to technical assistance from Harris. After July 2014, organizations can continue to join the exchange, but technical assistance won t be available through the state contract. Subscribers are charged a fee for the HIE s service, a fee implemented to replace federal funding. Health plans currently are participating in the HIE s event information feature, which provides information on when a patient has an encounter with a hospital, such as admission, treatment, or discharge, according to Fox. Texas experience Meanwhile, in Texas, with its large population and extensive and varied geography, multiple public and private HIEs are at work. The Lone Star State used $28.8 million from the American Recovery and Reinvestment Act of 2009 to support statewide HIEs, with $18.8 million of that amount used to support the initial planning, development, and operation of 16 local, community-based HIE networks. Ten of those are currently operating. Joseph Schneider, MD, chief medical information officer and medical director of clinical information 32 MANAGED CARE / JUNE 2014

35 for the Dallas-based Baylor Scott & White Health System, says its HIE developed out of the need for the Baylor Health Care system to share information among many EMRs even before Baylor merged with Scott & White. The initial effort was to determine ways to move information among physician offices and hospitals, and Schneider says that effort has been successful, adding that it has always been in Baylor s plans to connect eventually with state and national HIEs as they become available. As they develop over time, we will be looking at joining, Schneider says. The Texas Health Services Authority functions as a hub for the state s local HIEs, he says. But Schneider cautions that there are various concerns to be worked out for public and private HIEs before it becomes possible to move health care information smoothly among exchange members. Among those concerns are costs, resources, system compatibility, and finding the right way to protect privacy and to resolve data inconsistencies. A Texas HIE will bring together records for about 2 million people, says Gijs Van Oort, who heads that organization, Healthcare Access San Antonio. Of course, he notes, providers have to provide the information. HIV status One example of a privacy issue faced by Baylor has been the reporting of a patient s HIV status. Some HIE systems report a patient s positive HIV status while others do not, making it difficult for physicians to discover the truth in a dependable way about a patient. Data inconsistencies can include differences in reports by two doctors one records that a patient is allergic to a particular medication, while another says the patient is not allergic. Schneider expects those issues to be worked out, partly by getting patients more involved in their personal health records. Meanwhile, he says, the development of HIEs will continue to be driven by government pressure to promote interoperability as part of cost-saving measures, and that s a good thing. Eliminating unnecessary duplication of tests, such as MRIs and CT scans, and ensuring that the correct tests are being performed can reduce costs. HIEs can unquestionably help achieve those types of savings, says Schneider. He also says managed care administrators probably can help by financially supporting HIEs, by advocating increased patient involvement through portable personal medical health records, and by coordinating efforts to boost quality and report measurable outcomes. Effective, secure So, what s been the managed care industry s reaction to efforts such as those of Baylor to utilize public HIEs, especially on the question of costs? David Gonzales, CEO of the Texas Association of Health Plans (TAHP), says that insurers encourage the use of the most effective and secure means of exchanging health information. Each health plan is in a different stage of development of HIE efforts, he says. However, a significant concern exists with the uncertainty of national standards of interoperability and the interests of providers and consumers in the marketplace. Gijs Van Oort, executive director of Healthcare Access San Antonio (HASA), a public HIE covering the city and surrounding areas, has seen the Black Book report but doesn t believe it indicates that all public exchanges are doomed. On March 12, HASA selected Mana Health s Patient Gateway as its patient portal system. The system expected to be launched by July 1 will be the first of its kind in Texas to give patients an aggregated medical record across multiple organizations from a single community portal, Van Oort says. The portal will aggregate all of a patient s health records into one easily accessible and navigable site, and it will be available to the 2 million residents in HASA s 22- county service area to facilitate access to, and use of, their personal health care data. Of course, one condition is that the patient s physician provides the information to HASA. Selling point Van Oort expects that capability will be a selling point for providers and hospitals. Another selling point is that HASA is a neutral organization for receiving and relaying information, and it provides a level playing field for users, he says, noting that HIE usage is very new still in Texas, but is maturing. JUNE 2014 / MANAGED CARE 33

36 HASA currently is providing services to Community First Health Services, San Antonio, which offers Medicaid HMO, CHIP, and commercial health benefit plans. The HIE is able to provide information quickly on patients who have been to emergency rooms or have been hospitalized to assist in deciding whether to assign a case manager, Van Oort reports. So, will Texas MCOs have a clearcut choice when it comes to public- vs. private-sector HIEs? Joe Lastinger, CEO of Dallas-based North Texas Accountable Healthcare Partnership (NTAHP), says he doesn t see the use of public or private HIEs as an either/or proposition but as part of the response to the need by health care providers to run their businesses in an increasingly complex environment. HIEs in various forms are the tip of the spear in moving key information among facilities providers, Lastinger says, but he argues that there isn t one blueprint for how to accomplish that goal or for how HIEs should be structured. No two HIEs are exactly the same, he says, and health care markets are different as well. Another consideration Lastinger believes that health care systems choose public or private exchanges by deciding what best fits their needs. Some of those systems are large and complex, including joint ventures that may comprise hospitals, clinics, physicians, and various vendors, Lastinger says. The fact that hospitals are quickly purchasing physician practices adds another consideration for HIE needs. Private HIEs are growing because health care systems are developing more of the technology needed to stay in business, but that doesn t mean they re not connecting with us, Lastinger says, citing North Texas as an area where systems are operating an increasingly complicated business in complicated geography. He compares the development of HIEs in the densely populated area to the development of physical infrastructure and fiscal policies. There are some 50 cities, with 50 mayors and town councils with some cities in multiple counties and highways connecting them, Lastinger says. Use of HIEs is one way providers are responding to the need to run their businesses in an increasingly complex environment, says Joe Lastinger, CEO of the North Texas Accountable Healthcare Partnership. Over the years, those municipalities have developed protocols and policies for financing, providing, maintaining, and sharing that infrastructure. He cites an example: If you re taking someone in an ambulance, you don t have to stop and move the person to another ambulance when you get to a different town. Lastinger says four payers (Blue Cross Blue Shield of Texas, UnitedHealthcare, Aetna and Cigna) are part of NTAHP s board of directors and help set policy for NTAHP and the NTAHP HIE. All four provide financial support to NTAHP and the exchange. NTAHP HIE has not yet created a policy framework to support payer connectivity, but all four plans have indicated interest in connecting to the HIE as part of their efforts to reduce gaps in care of their members when the policy framework and desired functionality are in place, Lastinger says. The Texas Health Services Authority (THSA) reports that through the first calendar quarter of 2013, the state ranked second in the number of enabled HIE users, with 26,268 clinical and administrative staff enabled for query-based exchange. Providers can query a network to find clinical data produced by other providers, enabling HIE use in cases such as checking for the presence of lab results before performing lab tests or querying for medical history for patients arriving in the emergency department. With 581 organizations enabled for query-based exchanges, Texas ranks third among the states; it has 357 ambulatory entities and 56 acute care hospitals actively participating in query-based exchanges. Level of engagement varies Tony Gilman, THSA s CEO, reports that the 10 publicly funded HIEs in Texas have been signing up MCOs, particularly in the Dallas, Houston, and San Antonio areas. Managed care organizations are engaging with our local HIEs, but the level of engagement varies from participation on a governing board to contributing financially to receiving data from the HIE to a mix of each of those, Gilman says. Health plans working with public HIEs in Texas include Community Health Choice and Texas Children s Health Plan, both of which are working 34 MANAGED CARE / JUNE 2014

37 with Greater Houston Healthconnect. Meanwhile, in El Paso, El Paso First Health Plans participates on the Paso del Norte HIE governing board and supports the HIE financially, although at this time no data are being shared, Gilman says. Cautiously optimistic So, what s been the reaction from health insurers to what s happening in Texas and other states, in terms of HIEs in general and in the public- versus private-sector HIE debate? AHP CEO Gonzales asserts that, overall, health plans are encouraged but cautiously optimistic about processes that will empower consumers and clinicians to make better health care decisions and also help improve health care quality, value, and efficiency through better care coordination, the prevention of medical errors, and a reduction in inappropriate care. The bottom line, according to experts contacted for this story: Despite the Black Book study, health plans are still attracted to public HIEs because those exchanges have a greater ability to capture and provide access to public health data. Matt Conens, spokesman for the California Department of Public Health (CDPH), says that in the six months since CDPH launched the Health Information Exchange Gateway, 2,623 public health submitters (including HIEs with providers, hospitals, health information organizations, and laboratories) have registered or enrolled in at least one CDPH program via the HIE Gateway with the intent of sending data to CDPH. The HIE Gateway has expanded to public health programs such as the California Cancer Registry, and soon the CDPH Childhood Lead Poisoning Prevention Program and the CDPH Genetic Disease Screening Program will be added, Conens reports. Insurer involvement has included Kaiser Permanente, Sutter Health, and Molina Healthcare. There is increasing evidence that HIEs do, in fact, reduce costs. Last fall, researchers at the Medical University of South Carolina found that having access to data from an exchange improved the quality of emergency care and saved more than $1 million in patient charges, or nearly $2,000 per patient. The 12-month study involved 325,740 patient encounters and 7,525 log-ons to the HIE by 231 eligible clinicians at 11 emergency departments in South Carolina. The researchers based their conclusions on a sample of 532 patients who had information available in the HIE and for whom the clinicians caring for the patients completed a survey. Within the sample, researchers found that having access to an HIE for emergency patients resulted in savings from avoiding several types of services: Laboratory/microbiology: 187 patients, $2,073 Radiology: 298 patients, $476,840 Consultations: 61 patients, $6,461 Hospital admissions: 56 patients, $551,282 Total savings for patients in the sample was $1,035,654, based on Medicare-allowable charges, or $1,947 per patient. In addition, in a study on the connection between HIE participation and imaging in hospital emergency departments, researchers at Mathematica Policy Research and the University of Michigan found that redundant CT scans, X-rays, and ultrasounds decreased significantly with HIE use. Reduced imaging Researchers compared the rates of repeat CT scans, chest X-rays, and ultrasounds at 37 emergency departments connected to an HIE to the rates at 410 emergency departments not connected to an HIE in California and Florida between 2007 and The study found that hospital emergency departments participating in an HIE had reduced imaging in all of the modalities, compared with those without an HIE link. Departments using an HIE were 8.7% less likely to repeat CT scans, 9% less likely to repeat ultrasounds, and 13% less likely to repeat X-rays. The researchers concluded that if all of the hospital emergency departments in California and Florida participated in HIEs, the two states could save approximately $3 million annually by avoiding repeats of the three imaging modalities. As with almost everything, experts say, in the development of health information exchanges, follow the money. Michael Levin-Epstein is a free lance health care writer specializing in federal legislative and administrative issues. JUNE 2014 / MANAGED CARE 35

38 In Active, Mild to Moderate Ulcerative Colitis (UC) POWER YOUR PATIENTS CAN HANDLE MMX technology is designed to target delivery of budesonide throughout the full length of the colon 1,2 3 times more patients taking UCERIS achieved combined clinical and endoscopic remission compared with placebo 3 * The rates of overall glucocorticoid-related side effects were similar for UCERIS and placebo at 8 weeks 10.2% vs 10.5%, respectively 1 * Through the UCERIS savings program, 90% of eligible patients with commercial insurance will pay only $25 3 INDICATION: UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. IMPORTANT SAFETY INFORMATION: UCERIS (budesonide) extended release tablets are contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Since UCERIS extended release tablets are a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS extended release tablets, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Taper patients slowly from systemic corticosteroids if transferring to UCERIS extended release tablets. Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections, or ocular herpes simplex. More serious or even fatal course of chickenpox or measles can occur in susceptible patients. Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. Concomitant use of inhibitors of Cytochrome P450 3A4 (for example ketoconazole and erythromycin) should be avoided and patients should be closely monitored for increased signs and/or symptoms of hypercorticism. Avoid grapefruit juice, which is known to inhibit CYP3A4, when taking UCERIS. In clinical studies, the most common adverse reactions (incidence 2%) were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. Please see Brief Summary for UCERIS extended release tablets on adjacent page and complete Prescribing Information at CORE STUDY DESIGNS: Two randomized, double-blind, placebo-controlled studies were conducted in a total of 899 adult patients with active, mild to moderate UC (Ulcerative Colitis Disease Activity Index [UCDAI]: 4 and 10 at entry). The primary endpoint was induction of combined clinical and endoscopic remission (defined as a UCDAI score of 1, with scores of 0 for both rectal bleeding and stool frequency, normal mucosa with no friability on endoscopy, and a 1-point reduction in the Endoscopic Index [EI] score) after 8 weeks of treatment. 1,4,5 *In a pooled analysis of 2 Phase III clinical trials. Some restrictions apply. Please see the evoucherrx and Instant Savings Card Program brochure for Terms and Conditions. Santarus, Inc. reserves the right to modify or cancel these offerings at any time. Source: RelayHealth, June References: 1. UCERIS Prescribing Information. Salix Pharmaceuticals, Inc. January Brunner M, Ziegler S, Di Stefano AF, et al. Gastrointestinal transit, release and plasma pharmacokinetics of a new oral budesonide formulation. Br J Clin Pharmacol. 2005;61: Data on file. Salix Pharmaceuticals, Inc. 4. Sandborn WJ, Travis S, Moro L, et al. Once-daily budesonide MMX extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study. Gastroenterology. 2012;143: Travis SPL, Danese S, Kupcinskas L, et al. Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study. Gut. 2014;63: UCERIS is a registered trademark of Santarus, Inc., a wholly owned subsidiary of Salix Pharmaceuticals, Inc. MMX is a registered trademark of Cosmo Technologies, Ltd. evoucherrx is a trademark of RelayHealth Salix Pharmaceuticals, Inc. / Santarus, Inc. UCE April 2014 Printed in the USA.

39 BRIEF SUMMARY UCERIS (budesonide) extended release tablets, for oral use Rx Only The following is a brief summary only. See complete Prescribing Information on or request complete Prescribing Information by calling INDICATIONS AND USAGE UCERIS (budesonide) extended release tablets are indicated for the induction of remission in patients with active, mild to moderate ulcerative colitis. CONTRAINDICATIONS UCERIS is contraindicated in patients with hypersensitivity to budesonide or any of the ingredients of UCERIS. Anaphylactic reactions have occurred with other budesonide formulations. WARNINGS AND PRECAUTIONS Hypercorticism and Adrenal Axis Suppression When glucocorticosteroids are used chronically, systemic effects such as hypercorticism and adrenal suppression may occur. Glucocorticosteroids can reduce the response of the hypothalamuspituitary-adrenal (HPA) axis to stress. In situations where patients are subject to surgery or other stress situations, supplementation with a systemic glucocorticosteroid is recommended. Since UCERIS is a glucocorticosteroid, general warnings concerning glucocorticoids should be followed. Transferring Patients from Systemic Glucocorticosteroid Therapy Care is needed in patients who are transferred from glucocorticosteroid treatment with higher systemic effects to glucocorticosteroids with lower systemic effects, such as UCERIS, since symptoms attributed to withdrawal of steroid therapy, including those of acute adrenal suppression or benign intracranial hypertension, may develop. Adrenocortical function monitoring may be required in these patients and the dose of glucocorticosteroid treatment with high systemic effects should be reduced cautiously. Immunosuppression Patients who are on drugs that suppress the immune system are more susceptible to infection than healthy individuals. Chicken pox and measles, for example, can have a more serious or even fatal course in susceptible patients or patients on immunosuppressant doses of glucocorticosteroids. In patients who have not had these diseases, particular care should be taken to avoid exposure. How the dose, route and duration of glucocorticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior glucocorticosteroid treatment to the risk is also not known. If exposed, therapy with varicella zoster immune globulin (VZIG) or pooled intravenous immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See prescribing information for VZIG and IG.) If chicken pox develops, treatment with antiviral agents may be considered. Glucocorticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic infections. Replacement of systemic glucocorticosteroids with UCERIS tablets may unmask allergies (e.g., rhinitis and eczema), which were previously controlled by the systemic drug. Increased Systemic Glucocorticoid Susceptibility Reduced liver function affects the elimination of glucocorticosteroids, and increased systemic availability of oral budesonide has been demonstrated in patients with liver cirrhosis. Other Glucocorticosteroid Effects Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or with any other condition where glucocorticosteroids may have unwanted effects. ADVERSE REACTIONS Systemic glucocorticosteroid use may result in the following: Hypercorticism and Adrenal Suppression Symptoms of steroid withdrawal in those patients transferring from Systemic Glucocorticosteroid Therapy Immunosuppression Increased Systemic Glucocorticosteroid Susceptibility Other Glucocorticosteroid Effects Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of UCERIS has been evaluated in controlled and open-label clinical trials which enrolled a combined total of 1105 patients with ulcerative colitis. In two 8-week, placebo-controlled studies in patients with active disease (Study 1 and Study 2), a total of 255 patients received UCERIS 9 mg, 254 patients received UCERIS 6 mg, and 258 patients received placebo. They ranged in age from years (mean 43), 56% were male, and 75% were Caucasian. The most common adverse reactions were headache, nausea, decreased blood cortisol, upper abdominal pain, fatigue, flatulence, abdominal distension, acne, urinary tract infection, arthralgia, and constipation. The adverse reactions occurring in 2% or more of patients on therapy with UCERIS 9 mg are summarized in Table 1. Table 1. Summary of Adverse Reactions in Two Placebo Controlled Trials Experienced by at Least 2% of the UCERIS 9 mg Group (Studies 1 and 2) UCERIS 9 mg (N = 255) n (%) UCERIS 6 mg (N = 254) n (%) Placebo (N = 258) n (%) Headache 29 (11.4) 37 (14.6) 27 (10.5) Nausea 13 (5.1) 12 (4.7) 11 (4.3) Decreased Blood Cortisol 11 (4.3) 6 (2.4) 1 (0.4) Upper Abdominal Pain 10 (3.9) 8 (3.1) 5 (1.9) Fatigue 8 (3.1) 5 (2.0) 5 (1.9) Flatulence 6 (2.4) 8 (3.1) 5 (1.9) Abdominal Distension 6 (2.4) 4 (1.6) 2 (0.8) Acne 6 (2.4) 2 (0.8) 5 (1.9) Urinary Tract Infection 5 (2.0) 1 (0.4) 1 (0.4) Arthralgia 5 (2.0) 5 (2.0) 4 (1.6) Constipation 5 (2.0) 1 (0.4) 2 (0.8) Of UCERIS 9 mg patients, a total of 15% discontinued treatment due to any adverse event (including adverse reactions) compared with 17% in the placebo group. Table 2 summarizes the percentages of patients reporting glucocorticoid related effects in the 2 placebocontrolled studies. Table 2. Summary of Glucocorticoid Related Effects in Two Placebo-Controlled Trials (Studies 1 and 2) UCERIS 9 mg (N = 255) n (%) UCERIS 6 mg (N = 254) n (%) Placebo (N = 258) n (%) Overall 26 (10.2) 19 (7.5) 27 (10.5) Mood changes 9 (3.5) 10 (3.9) 11 (4.3) Sleep changes 7 (2.7) 10 (3.9) 12 (4.7) Insomnia 6 (2.4) 6 (2.4) 8 (3.1) Acne 6 (2.4) 2 (0.8) 5 (1.9) Moon face 3 (1.2) 3 (1.2) 4 (1.6) Fluid retention 2 (0.8) 3 (1.2) 3 (1.2) Hirsutism 1 (0.4) 0 0 Striae rubrae (0.8) Flushing 0 1 (0.4) 3 (1.2) No clinically significant differences were observed with respect to the overall percentages of patients with any glucocorticoid related effects between UCERIS and placebo after 8 weeks of induction therapy. Study 3 was an open-label study evaluating UCERIS 9 mg once daily for 8 weeks in 60 patients who had previously completed an 8-week induction study (Study 1), but had not achieved remission. Among patients who took UCERIS 9 mg up to 16 weeks cumulatively across Study 1 and Study 3 combined, similar rates of adverse reactions and glucocorticoid-related effects were seen compared to those who took UCERIS 9 mg for 8 weeks in Study 1. In Study 4, the safety of long-term treatment with UCERIS 6 mg was evaluated in a placebo-controlled 12-month maintenance study of 123 patients. Patients who had previously completed 8 weeks of therapy in any induction study (Study 1, 2, or 3) and were in remission were randomized to UCERIS 6 mg or placebo once daily for 12 months. In patients who took UCERIS 6 mg for up to 12 months, similar rates of adverse reactions were seen between placebo and UCERIS 6 mg. After up to 12 months of study treatment, 77% (27/35) of the patients in the UCERIS 6 mg and 74% (29/39) of the patients in the placebo treatment groups had normal bone density scans. In Study 4, the glucocorticoid related effects were similar in patients with up to 12 months of therapy with UCERIS 6 mg and placebo. (Table 3) Table 3. Summary of Glucocorticoid Related Effects Over 12-month Treatment (Study 4) UCERIS 6 mg (N = 62) n (%) Placebo (N = 61) n (%) Overall 9 (14.5) 7 (11.5) Insomnia 4 (6.5) 4 (6.6) Mood changes 4 (6.5) 2 (3.3) Moon face 3 (4.8) 3 (4.9) Sleep changes 3 (4.8) 3 (4.9) Acne 3 (4.8) 0 Hirsutism 3 (4.8) 0 Flushing 1 (1.6) 1 (1.6) Fluid retention 1 (1.6) 1 (1.6) Postmarketing Experience The following adverse reactions have been identified during postapproval use of oral budesonide. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: anaphylactic reactions Nervous System Disorders: benign intracranial hypertension Psychiatric Disorders: mood swings DRUG INTERACTIONS Interaction with CYP3A4 inhibitors Concomitant oral administration of ketoconazole (a known inhibitor of CYP3A4 activity in the liver and in the intestinal mucosa) caused an eightfold increase of the systemic exposure to oral budesonide. If treatment with inhibitors of CYP3A4 activity (such as ketoconazole, itraconazole, ritonavir, indinavir, saquinavir, erythromycin) is indicated, discontinuation of UCERIS should be considered. After extensive intake of grapefruit juice (which inhibits CYP3A4 activity predominantly in the intestinal mucosa), the systemic exposure for oral budesonide increased about two times. Ingestion of grapefruit or grapefruit juice should be avoided in connection with UCERIS administration. Inhibitors of Gastric Acid Secretion Since the dissolution of the coating of UCERIS is ph dependent, the release properties and uptake of the compound may be altered when UCERIS is used after treatment with gastric acid reducing agents (e.g., PPIs, H2 blockers and antacids). USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Budesonide was teratogenic and embryocidal in rabbits and rats. Budesonide produced fetal loss, decreased pup weights, and skeletal abnormalities at subcutaneous doses of 25 mcg/kg in rabbits (approximately 0.05 times the maximum recommended human dose on a body surface area basis) and 500 mcg/kg in rats (approximately 0.5 times the maximum recommended human dose on a body surface area basis). There are no adequate and wellcontrolled studies in pregnant women. Budesonide should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving glucocorticosteroids during pregnancy. Such infants should be carefully observed. Nursing Mothers The disposition of budesonide when delivered by inhalation from a dry powder inhaler at doses of 200 or 400 mcg twice daily for at least 3 months was studied in eight lactating women with asthma from 1 to 6 months postpartum. Systemic exposure to budesonide in these women appears to be comparable to that in non-lactating women with asthma from other studies. Breast milk obtained over eight hours post-dose revealed that the maximum budesonide concentration for the 400 and 800 mcg total daily doses was 0.39 and 0.78 nmol/l, respectively, and occurred within 45 minutes after inhalation. The estimated oral daily dose of budesonide from breast milk to the infant is approximately and mcg/kg/day for the two dose regimens used in this study, which represents approximately 0.3% to 1% of the dose inhaled by the mother. Budesonide plasma concentrations obtained from five infants at about 90 minutes after breast feeding (and about 140 minutes after drug administration to the mother) were below quantifiable levels (<0.02 nmol/l in four infants and <0.04 nmol/l in one infant). The recommended daily dose of UCERIS extended release tablets is higher (9 mg daily) compared with inhaled budesonide (up to 800 μg daily) given to mothers in the above study. The maximum budesonide plasma concentration following a 9 mg daily dose (in both single- and repeated-dose pharmacokinetic studies) of oral budesonide is approximately 5-10 nmol/l which is up to 10 times higher than the 1-2 nmol/l for an 800 mcg daily dose of inhaled budesonide at steady state in the above inhalation study. Since there are no data from controlled trials on the use of UCERIS by nursing mothers or their infants, and because of the potential for serious adverse reactions in nursing infants from UCERIS, a decision should be made whether to discontinue nursing or to discontinue UCERIS, taking into account the clinical importance of UCERIS to the mother. Budesonide, is secreted in human milk. Data from budesonide delivered via dry powder inhaler indicates that the total daily oral dose of budesonide available in breast milk to the infant is approximately 0.3% to 1% of the dose inhaled by the mother. Assuming the coefficient of extrapolation between the inhaled and oral doses is constant across all dose levels, at therapeutic doses of UCERIS, budesonide exposure to the nursing child may be up to 10 times higher than that by budesonide inhalation. Pediatric Use Safety and effectiveness of UCERIS in pediatric patients have not been established. Glucocorticosteroids, such as UCERIS may cause a reduction of growth velocity in pediatric patients. Geriatric Use Clinical studies of UCERIS did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, UCERIS should be used cautiously in elderly patients due to the potential for decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Hepatic Impairment Patients with moderate to severe liver disease should be monitored for increased signs and/or symptoms of hypercorticism. Discontinuing the use of UCERIS tablets should be considered in these patients. OVERDOSAGE Reports of acute toxicity and/or death following overdosage of glucocorticosteroids are rare. Treatment consists of immediate gastric lavage or emesis followed by supportive and symptomatic therapy. PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information). Patients being treated with UCERIS extended release tablets should receive the following information and instructions. This information is intended to aid the patient in the safe and effective use of UCERIS. Hypercorticism and Adrenal Suppression Patients should be advised that UCERIS extended release tablets may cause systemic glucocorticosteroid effects of hypercorticism and adrenal suppression. Patients should taper slowly from systemic corticosteroids if transferring to UCERIS extended release tablets. Immunosuppression Patients who are on immunosuppressant doses of glucocorticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physician immediately. If exposure to such a person occurs, and the patient has not had chicken pox or been properly vaccinated, a physician should be consulted immediately. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex. How to Take UCERIS extended release tablets UCERIS extended release tablets should be swallowed whole with water and NOT CHEWED, CRUSHED, OR BROKEN. Patients should be advised to avoid the consumption of grapefruit juice for the duration of their UCERIS therapy. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch or call FDA To report adverse events, a product complaint, or for additional information, call: Manufactured for: Salix Pharmaceuticals, Inc Colonnade Center Drive, Raleigh, NC UCERIS is a registered trademark of Santarus, Inc., a wholly owned subsidiary of Salix Pharmaceuticals, Inc. U.S. Patent Nos: 7,410,651; 7,431,943; RE43799; 8,293, Salix Pharmaceuticals, Inc. / Santarus, Inc. UCE-RALAB

40 Is the USPSTF Right About Early Screening For Cognitive Impairment? Alzheimer s and other dementias pose an enormous economic threat, but for now, the task force says, routine screening is unwarranted By Susan Worley In November 2013, shortly after the U.S. Preventive Services Task Force (USPSTF) released its draft recommendation on screening for cognitive impairment in adults age 65 and older, it began to hear from prominent academic and clinical researchers and institutions, who urged the task force to assign a grade A or B, which would signify full endorsement. Some argued that by failing to support early cognitive screening, the task force was reinforcing a discredited notion that physicians ought to diagnose only conditions for which they We found insufficient evidence to recommend routine screening of asymptomatic individuals, but if a patient complains of memory loss, then test, says Albert Siu, MD, co-vice chairman of the USPSTF. have a cure. Others were concerned about impeding efforts to grasp the full scope of the public health care burden of dementia, and about undermining efforts to recruit participants in clinical trials that might eventually lead to a treatment. Perhaps most important, critics listed the many ways in which early identification of cognitive impairment might benefit both the impaired and society. Many noted, for example, that early recognition of dementia could significantly reduce health care costs by preventing avoidable complications related to delirium, ranging from the mishandling of multiple medications to unnecessary hospitalizations. Then in March, the task force, which does not factor health care costs into its decisions, issued its final recommendation, declaring that there is currently insufficient evidence to recommend early cognitive screening. Unlike controversial USPSTF decisions regarding screening for prostate cancer and breast cancer, which inspired passionate opposition, this decision has been met with some confusion. Considered logical by some experts, the decision is regarded by many others as oddly out of tune with current events. Recent efforts to increase awareness that Alzheimer s disease may begin decades before symptoms emerge, a new era of prevention trials in the realm of clinical research and Medicare s decision to include the detection of cognitive impairment as part of its annual wellness visit suggest a collective interest in addressing dementia at the earliest possible stage. All experts agree on an urgent need for more research, but as critical research resumes, it may be necessary to identify practices that, at least on a general population level, offer greater health care gains and cost savings than screening of asymptomatic individuals. Highlights of the decision Our recent recommendations really pertain to the individual age 65 or older who visits his or her health care provider without expressing any concerns or complaints about memory or cognition whatsoever, says Albert Siu, MD, co-vice chairman of the USPSTF. We set out to determine whether health care providers should be routinely screening such individuals. It s important to note that our I grade [not enough evidence] does not recommend against screening; rather we have determined that the decision about whether to screen must be left to the judgment of the clinician. We found insufficient evidence to recommend routine screening of asymptomatic individuals, but clearly, if a patient complains of memory impairment, or if a family member comes 38 MANAGED CARE / JUNE 2014

41 in expressing concerns about memory, our recommendations don t apply. If a patient is complaining about an issue, then, of course, testing might well be appropriate. Was cognitive impairment defined? Some experts found that the current USPSTF recommendation lacks a clear definition of cognitive impairment. Of particular concern is the fact that the terms cognitive impairment and dementia are used interchangeably in some parts of the USPSTF statement. Howard Fillit, MD, executive director and chief science officer of the Alzheimer s Drug Discovery Foundation, shares this concern with some other experts: When a clinician uses screening tests such as the MMSE [Mini-Mental State Examination], it is really to evaluate cognitive function across multiple domains. It would be a misnomer to talk about screening for dementia. The diagnosis of dementia is, of course, made not from screening tests but by a clinician, usually according to DSM IV criteria. The clinician determines whether the patient has cognitive impairment in more than one domain, whether it has been progressing, and whether the impairment is severe enough to lead to loss of functioning in the patient s daily life. The clinician must ensure that the impairment is not caused by something potentially reversible, such as depression or the side effects of medications. So the clinician must evaluate not just cognitive functioning but the patient s overall status, in proper context. The tests mentioned in the statement are used to screen for cognitive impairment, and if impairment is detected, the appropriate steps must be taken to diagnose dementia. Screening the wrong population? Many experts agree that general screening of asymptomatic people beginning at age 65 is unwarranted, and for many this seems to raise the question of whether the task force examined the right population. The current recommendation results in a lack of guidance, and indirectly, in a lack of payment for screening elderly people who have a much greater likelihood of being impaired than do younger people. Cognitive screening in a general population is obviously wrong, says Jason Karlawish, MD, professor of medicine, medical ethics, and health IBC has no specific coverage for routine screening Don Liss, MD, senior medical director of clinical programs and policy at Independence Blue Cross, which covers approximately 3 million lives in greater Philadelphia and New Jersey, talks about the United States Preventive Services Task Force Guidelines on cognitive screening. The USPSTF is one of the most respected bodies in the field of prevention. They apply a very elegant and careful process to the analysis of very complicated issues. In this case they found that while currently available cognitive tests, such as the MMSE [Mini-Mental State Examination], perform pretty well, the results of such tests make relatively little difference in outcomes for patients. The drug therapies that are available to slow cognitive decline are not very effective. We certainly hope that better treatments will be developed, and if that happens, cognitive screening may be appropriate. It s important to note that the current recommendation should not discourage a clinician from performing an analysis if the clinician believes there is a reason to do so if, for example, the patient s family is concerned. If a change in behavior or personality suggests cognitive decline, then it s very appropriate to engage in testing. Currently we do not categorize cognitive screening as a separately compensable service. The tests that the task force examined were largely tests that can be given in 10 minutes or less, and such tests can be performed as part of a routine office visit. If this testing is performed as part of an annual preventive or wellness visit, there is no separate claim, or CPT code for the service, and no separate payment is made. If, in the future, cognitive testing is given a grade of A or B [testing is recommended], we will need to consider whether such testing should be included as a part of a wellness visit just as the task force recommends that blood pressure should be checked, and we consider that part of the visit or whether it should be a separately compensable service. Insurers faced a similar issue when the task force recommended screening for domestic violence as a woman s preventive service. Questions such as Have you been threatened or subjected to violence? are part of a typical office visit, with no separate payment provided for this screening. JUNE 2014 / MANAGED CARE 39

42 policy at the University of Pennsylvania. Screening really must be focused on an older population. The lower we set the age, the more we increase the chance of false positive detection. I m in favor of screening when the probability that you are going to pick up cognitive impairment is reasonably high, and that is in the setting of practices that care for older adults. Among geriatricians, I would say, it is a fairly standard practice to assess your patients cognition. Jason Brandt, PhD, professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, concurs. There are many good cognitive screening tests that hover at about 90% sensitivity and about 90% specificity, but to get the best value from these tests, it s important to administer them to the right population. If you administer a particular cognitive test to all patients over 65 at a general practitioner s office, you will have many more false positives than true positives, while if you test a geriatric population, you will have many more true positives. The prevalence of a condition in the population you are testing makes a huge difference. Letting clinicians decide Most experts agree with the task force that decisions regarding the screening of some, but not all, people age 65 and older should be left to the judgment of each clinician. Currently, testing is covered by private insurers and Medicare only when patients have received a diagnosis based on signs and symptoms. To say that we will only do testing in patients who have signs or symptoms of cognitive impairment is highly problematic in my opinion, says Pierre Tariot, MD, a geriatric psychiatrist and director of the Banner Alzheimer s Institute, and it raises this question: How do you know whether patients have signs or symptoms unless you look? You are left with a tautological absurdity. I m embedded in a large health care system that is attempting to grapple with this very problem. Baseline testing on everybody is not practical, but we are designing a pathway for people for who have a reasonably high risk of having dementia. These patients will be evaluated in a primary care setting, and the results of that evaluation will trigger a care path for clinicians to follow. Reid Blackwelder, MD, president of the American Academy of Family Physicians offers his perspective. Approximately 25% of our patient base is made up of individuals age 65 or older, so family If we could delay onset by five years, we would be able to reduce cases by approximately 50%, says Howard Fillit, MD, head of the Alzheimer s Drug Discovery Foundation. The benefits of dementia treatment may include improvements in mood or cognition, but they are not easy to measure, says Jason Karlawish, MD, a medical ethicist. physicians play a significant role in caring for an aging population. We encourage our members to regard USPSTF recommendations as important guidelines for practice, and we agree that routine screening of asymptomatic individuals over the age of 65 is not warranted. However, we also recognize that the I recommendation by the task force is not a recommendation against screening. Guidelines are for general populations, and clinicians don t treat general populations, they treat individuals. Depending on each patient s unique circumstances, we outline current evidence regarding any preventive test and what the benefits would be for a particular patient, and then allow that patient to decide. Value of early detection In assessing the value of early detection, the task force focused largely on the limited effectiveness and adverse events associated with current medical interventions, as well as the limited evidence supporting harms or benefits of current non-pharmacologic interventions. Difficulties associated with measuring the benefits of diagnosing and treating dementia have haunted the field of Alzheimer s disease for a long time, says Karlawish. The benefits of treating dementia are not easily measured, compared with the benefits of treating, for example, heart disease, which has easy-to-measure events such as death, stroke, or blood lipid levels. The benefits of dementia treatment may include improvements in functioning, mood, behavior, or cognition. These are not so easy to measure and in clinical 40 MANAGED CARE / JUNE 2014

43 Should we all know our cognitive status? Some experts anticipate the availability of a simple predictive test for Alzheimer s disease (AD) sometime this decade. But if such a test should become available before the discovery of a diseasemodifying treatment, who exactly should be screened? Most people at risk for Alzheimer s disease don t want to know, says Jason Brandt, PhD, professor of psychiatry at Johns Hopkins School of Medicine. Screening refers to an attempt to detect, among the populace, disorders or risk factors of which people are unaware, says Jason Brandt, PhD, professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine. Based on that definition, it certainly would be problematic for any organization to mandate screening, particularly for a disease for which there is no cure or highly effective treatment, and to which a lot of stigma may be attached. However, it is reasonable to make available, to those people who want it, information about their risk of getting AD or a related dementia information that is individually tailored and helpful, and which may help an individual better plan for the future. Brandt draws on his experience conducting pre-symptomatic testing for Huntington s disease (HD) at Johns Hopkins in one of the first programs in the country to offer such testing. He draws parallels between the two types of testing, while pointing out obvious differences. The people who were tested for HD in our program were at 50% risk before testing, Brandt says, because HD is caused by a single dominant gene and each person had a parent with the neurological disorder. Our program was one of the first to discover the consequences of informing people that they will develop a devastating disease. We learned a great deal about how people handle that news, and about whether most people really want to know their future risk in the first place. We learned how to provide predictive testing, only to those who really wanted to know, in a way that maximizes usefulness and minimizes psychiatric or social morbidity. We ended up testing many fewer people than we thought we would, because it turned out that most people who were at risk for HD didn t want to know. However, for those who did want to know, having the knowledge was very beneficial. The at-risk people we tested all said that they would take the test again, even those who received bad news. We did not see significant psychological fallout among those who tested positive for the HD gene mutation. Brandt points out that testing for Alzheimer s disease is more complicated. In HD, we have a single-gene test with essentially 100% accuracy, and we don t have anything nearly that predictive for AD yet. It s unlikely that we will have a test for AD that has high predictive validity any time soon. But even if we did, how many people would want a test for such a late-life disorder? In HD, onset occurs around age 40; knowing your gene status can affect how you lead your life, including decisions regarding having children or career options. I suppose you might do things differently if you knew early in life that you were sure to get AD around age 75. You might not wait until retirement to take that roundthe-world trip, or make different financial decisions, or plan for eventual nursing home care. But the implications for one s life would clearly be different. practice clinicians don t routinely use these scales. Instead, a family may tell you that a patient is less agitated, that the patient feels better, and also that the family feels better since they aren t spending so much time and money traveling to and from the ER, and so forth. You can measure some of these things, but it s difficult to do so, and therefore it s difficult to prove that there is a benefit to screening or that a treatment is cost-effective. The task force has acknowledged that we have good instruments to detect cognitive impairment, but our inability to measure the benefits of identifying and addressing impairment is still a source of frustration. It s estimated, says Tariot, that more than half of all patients with dementia never receive a diagnosis, and patients with dementia consume approximately 300% more health care dollars per year than patients without dementia who are otherwise clinically identical. They cost more because they develop delirium and behavioral problems, the mismanagement of their other medical conditions is common, and they have inappropriate hospitalizations and emergency room visits and JUNE 2014 / MANAGED CARE 41

44 prolonged hospitalizations. Patients with dementia and their families have very unsatisfactory interactions with the health care system, and providers also may have unsatisfactory interactions because they aren t sure what to do. We have to fix this, and ignoring this problem is not going to make it go away. Are interventions available? At an early stage of Alzheimer s disease or a related dementia, says Jeffrey Cummings, MD, ScD, of the Lou Ruvo Center for Brain Health at the Cleveland Clinic, the patient embarks on a journey in which he or she must learn to cope with the disease. It seems to be the opinion of the task force that because there is no disease-modifying treatment, and because symptomatic treatments have limited effectiveness, it is therefore best for a patient not to know that he or she is on a journey. It s as if they are saying, You ve left shore, but we don t think it s important for you to know that you ve left shore. At the Cleveland Clinic, we have a different perspective. We say, You ve left shore, you re on a new journey, you need guidance, and we want to help guide you. Expressing the sentiments of most experts interviewed for this article, Cummings adds, There are many types of intervention currently available. It s important to educate the family, to help them understand that although the patient has a disorder that interferes with memory, the patient may retain some skills, and adjustments may be made to compensate for others. There are safety issues that should be guarded against. Patients may consider clinical trials. And early recognition may enable families to defer nursing home placement, one of the most costly aspects of health care, avoid emergency room visits, and better manage co-morbidities and medications related to them. Value of delaying dementia Until a disease-modifying treatment is available, the greatest impact on health care outcomes and costs may lie in a focus on the modifiable risk factors associated with dementia. Indeed, this is one point on which task force members, researchers and clinicians, and insurers seem to agree. Evidence suggests that the incidence of dementia is greater It s as if they are saying, You ve left shore, but we don t think it s important for you to know that you ve left shore, says Jeffrey Cummings, MD, ScD. among individuals with diseases that damage the heart or blood vessels, and it is estimated that up to 50% of all cases of Alzheimer s disease may be related to modifiable risk factors associated with chronic conditions such as diabetes, hypertension, and obesity. In the past, says Fillit, AD was regarded solely as a neurodegenerative illness of the brain, but now epidemiological and other data are clearly indicating that systemic diseases such as diabetes, hypertension, and obesity are risk factors for AD, and by managing these illnesses we can at least delay the onset of AD. If we could delay onset by five years, we would be able to reduce cases by approximately 50%. While research investigating the value of early screening for cognitive impairment continues, it may be a source of consolation for patients and clinicians that many screening tests for modifiable risks factors associated with dementia are covered by major insurers. Aetna supports the current position of the USPTF and does not cover screening for cognitive impairment, says James Cross, MD, vice president and head of Aetna s national medical policy and operations. However, Aetna does support and provide coverage for the USPSTF recommendations that are related to several of the risk factors for cognitive impairment, including counseling on tobacco cessation, alcohol use, a healthful diet, and physical activity. We also cover screening for high cholesterol, hypertension, and depression. For further reading Moyer VA. Screening for cognitive impairment in older adults: U.S. Preventive Services Task Force Recommendation Statement. 2104; Ann intern Med Lin P-J, Fillit HM, Cohen JT, Neumann PJ. Unintended benefits: The potential impact of addressing risk factors to prevent Alzheimer s disease. Health Affairs. 2014; 33: Karlawish, J. How are we going to live with Alzheimer s disease? Health Affairs. 2014; 33: Cordell CB, Boorson S, Boustani M, et al. Alzheimer s Association s recommendations for operationalizing the detection of cognitive impairment during the Medicare Annual Wellness Visit in a primary care setting. Alzheimer s and Dementia 2013; 9: Aretouli E, Konstantino KT, Brandt J. 4 year outcome of mild cognitive impairment the contributions of executive dysfunction. Neuropsychology 2103; 27: MANAGED CARE / JUNE 2014

45 FOCUS ON BIOLOGICS Utility of Genetic Testing Linked to Clinical Interpretation Health care systems join NIH in studying significance of mutations By Thomas Reinke Contributing Editor Health plans face a daunting task in keeping up with the increased demand for genetic testing. The National Institutes for Health (NIH) says that 16,000 tests for 4,200 medical conditions and 2,800 genes are in its Gene Test Registry. Genetic testing is expanding quickly, driven by the availability of tests, guideline recommendations for genetic testing, sensationalistic marketing of tests that identify scary heritable diseases, and incredibly powerful assay technologies that have reduced costs considerably. We have increased the number of policies relating to genetic testing to close to 100 policies, says Stanley Harris, MD, medical director of Horizon Blue Cross Blue Shield of New Jersey. The fact that we have so many policies related to genetic testing reflects our attempt to provide guidance on the medical management of these tests based on evidence published in the peer-reviewed literature. One underlying reason for the increased number of policies is that Many tests do not have evidence that supports a positive coverage decision because clinical utility how the test will improve the management of the patient or improve the patient s health outcome has not been adequately demonstrated, says Harris. In May, Horizon implemented a new medical policy for panel testing of cancers that provides insight regarding the requirements for coverage analytic validity, clinical validity, and clinical utility of genetic tests. Horizon determined that panel testing is still investigational because these tests do not demonstrate validity and utility. One laboratory reported that it was to able save $76,000 in a single month by reviewing orders for genetic tests and correcting orders for the wrong or unnecessary tests, according to Michael Watson, PhD, of the American College of Medical Genetics and Genomics. Regarding clinical validity, Horizon s policies noted there were no published studies of the analytic validity of panel tests. To demonstrate validity, a panel test would have to show, consistently and reproducibly, sensitivity in detecting variants in the genes it targets. But it can be hard to show that samples used in a study are highly likely to include all of the variants frequently enough that the test s ability to detect them can be assessed. Horizon says the clinical validity of the panels as a whole cannot be determined because of the many different mutations in the large number of potential cancers that [they] can be used for. Clinical validity would need to be reported for each specific mutation for a particular type of cancer. To determine clinical utility, Horizon says, Controlled trials are required in which a strategy of cancer mutation testing followed by targeted treatment based on mutation analysis is compared to standard treatment without mutation testing. In genetics, clinical utility depends on the quality of the clinical interpretation. The cost of machine-based sequencing of an entire genome is moving toward the magic $1,000 mark, but experts jest that the power of the technologies to detect an increasing number of variants is leading to the $1 million interpretation. The NIH recognizes this problem and is funding work to improve the clinical interpretation of genetic tests. The standards used to evaluate panel tests apply equally to tests of single genes, and very few genetic tests have passed muster. The NIH has gone one step further to express concern about other limitations of genetic testing. It says systematic and comprehensive profiling of genetic variations is severely underdeveloped in many patient-oriented research or clinical settings. JUNE 2014 / MANAGED CARE 43

46 As a result, information on few genomic variants is used in clinical practice. Genetic testing routinely identifies novel variants with unknown significance as well as a large number of insignificant variations. Thus, curation the process of determining a variant s pathogenicity and looking in genetic databases to see the extent to which those variations have been found previously is a necessity, requiring a database with a large number of confirming cases and very detailed information about the characteristics of each case. ClinVar and ClinGen The NIH has initiated two projects, ClinVar and ClinGen, that may improve the reporting of test results and help to demonstrate the clinical utility of genetic testing. The NIH says there are about 2,000 separate databases on specific genes and diseases, and many labs have their own protocols for assessing whether the genomic variants they have identified are clinically relevant. It describes a need to agree on the evidence required to decide whether the effects of a variant are medically relevant and to make that evidence available to the public as well as the research and clinical communities. ClinVar is a project to establish an authoritative reference database with standardized information on genetic variations and also to standardize reporting on genetic variations. It is a public and freely accessible database of genotype (specific genetic alterations), phenotype (observable physical or biochemical traits), clinical interpretation, and supporting evidence. A major goal is to enable the ongoing evolution and development of knowledge regarding variations and associated phenotypes. ClinVar accepts reports from research and clinical labs and it aggregates information to transparently reflect both consensus and conflicting assertions of clinical significance. The ClinGen project complements the ClinVar database project. It includes researchers at the Geisinger Health System and Boston s Partners Healthcare, who will design and implement a framework for evaluating which variants play a role in disease and are relevant to patient care. The investigators will develop and curate authoritative information on what is expected to be millions of genomic variants relevant to human disease and the thousands that are useful for clinical practice. ClinGen will help to give guidance on how to take the vast amount of data being gathered and put it to effective use in clinical practice, says Michael Watson, PhD, executive director of the American College of Medical Genetics and Genomics (ACMG), a ClinGen grantee. The starting point is to create clinical domain work groups in cancer, cardiovascular disease, and metabolic disorders, and the focus is on evaluating variants for their clinical relevance, says Watson. Christa Martin, PhD, is a ClinGen investigator who is also director of the autism and developmental medicine institute at Geisinger. The specialized work groups have been brought together for one purpose: to improve clinical interpretation and bring genomics into everyday medicine, she says. The work groups will also set standards for curation and study ways to get this information into electronic health records. ClinGen is seen as a tool that will help professional organizations develop clinical practice guidelines. Separately, ACMG is working to improve the quality of genetic testing by focusing on standards for reporting sequence variations. We are coming to the end of a public process to develop a practice guideline for interpreting sequence variation, not at a gene level but at a genome sequencing level where many issues come into play, says Watson. The new guideline deals with the data elements, procedures, and standards for reporting the significance of sequencing variations. The guideline identifies variant characteristics that are strong indicators of pathogenicity, Watson says. For example, when a variant is de novo in a family, it is highly likely that it is pathogenic, particularly if it is in a gene that is associated with a particular disease. There are many types of variant data, and each data element differs in terms of strength of indicators of pathogenicity. The guideline sets data standards for test reports and for conclusions, saying a variant is pathogenic, probably pathogenic, a variant of unknown significance, probably benign, or benign. Physicians lack expertise ClinVar and ACMG practice guidelines deal with the quality of test results, but that is only part of the picture. Experts point out that health plans need to pay attention to the full range of genetic testing activities, including support for clinicians in ordering tests, understanding test results, and 44 MANAGED CARE / JUNE 2014

47 Partners, Geisinger build strong genetic testing programs While health plans work to effectively manage genetic testing, and while the National Institutes of Health works to improve the quality of genetic testing, two of the nation s leading health systems have taken concrete steps to put genetic testing at the core of their clinical research and patient care activities. The Geisinger Health System and Partners Healthcare, two leaders of ClinGen, are committed to performing large-scale gene sequencing on scores of thousands of patients, then use that information in every aspect of their clinical research and patient care activities. In addition, Geisinger plans to feed important genetic information to patients. Geisinger s goal is to profile 100,000 patients. Partners is shooting for 75,000. Geisinger has already obtained samples from 45,000 patients, and Partners is at 12,000. One way that we are going to improve patient care is through linking clinical research with genomics one of the most important areas for clinical research, says Christa Martin, PhD, director of Geisinger s autism and developmental medicine institute and a principal investigator on the ClinGen grant. Geisinger s senior executives have made a commitment to function as a learning health care system, and MyCode is a systemwide program for collecting biospecimens, sequencing the specimens, and using the clinically actionable results in daily patient care. Geisinger is collaborating with New York-based Regeneron Pharmaceuticals which will sequence DNA samples to study the relationship between genes and specific diseases. The sequencing results will be linked to the health system s EHR to access important patient, treatment, and diagnostic data. We have a stable population within the Geisinger catchment area where patients can be tracked over a long period. The combination of genetic data and longitudinal medical information has incredible value for clinical research, says Martin. The goal is to improve care and accelerate the discovery of innovative treatments and new medications. We believe that over time this collaboration will yield significant breakthroughs that will benefit patients not only at Geisinger, but around the world, notes Glenn D. Steele, Jr., MD, PhD, Geisinger president and CEO. Genetic information is already routinely used in many of Geisinger s programs, and steps are being taken to build an infrastructure to educate physicians and other clinicians on incorporating genetic information into their activities, says Martin. For example, Geisinger s autism and developmental medicine institute performs chromosomal microarray analysis which is capable of detecting genetic intellectual and physical abnormalities. It is pretty much standard of practice to do chromosomal microarray testing to identify causative deletion or duplication errors, and we are finding they can occur in about 25% of patients, says Martin. The MyCode project is setting up a process to feed significant genetic information to patients. Any clinically relevant or incidental findings will be confirmed in a clinical lab and returned to the patient, says Martin. This is an important undertaking with potential complex issues because that feedback may include findings for heritable conditions or variations whose significance is simply unknown now. The Partners Healthcare Biobank at Massachusetts General Hospital and Brigham & Women s Hospital is similar to Geisinger s program, aimed at accelerating medical research and cutting costs in the Partners system. The bank stores blood samples from patients for sequencing and linking to clinical data in the system s electronic medical record. One example is a study of the genetic profiles of pediatric asthma. There are several types of asthma, such as virus-induced asthma or obesity-related asthma. There is little information that correlates with the different types of asthma, and tracking patients long term and analyzing genetic and patient care data will allow researchers to more accurately diagnose and treat these patients. subsequent patient management decisions. One laboratory reported that it was able to save $76,000 in a single month by reviewing orders for genetic tests and correcting orders for the wrong or unnecessary tests, says Watson. Doctors have ordered the RET gene test, thinking it is for Rett syndrome, but they are entirely different. Amber Trivedi, the senior vice president of InformedDNA, a genetic counseling company, says, There is a real need for support of clinicians who do not specialize in genetics. Even with simple tests, we see a lot of difficulty with understanding the meaning of test reports. Even for tests that are very well known and have excellent reports, we see providers and patients who do not necessarily know what the results mean and whether or not they should act on it. A BRCA test patient may be told, You re negative, you re good, but based on family history alone, the patient may meet American Cancer Society guidelines for receiving annual breast MRI. JUNE 2014 / MANAGED CARE 45

48 BIOLOGICS IN DEVELOPMENT Is Research to Blame for High Cost of Cancer Drugs? When it was attempting to take over AstraZeneca, Pfizer cited that company s research and development capacity and its pipeline of new cancer drugs as primary reasons. Pfizer CEO Ian Read claims that governments around the world are pressuring drugmakers to produce products of higher value and lower cost. The easy integration of the two companies, Read says, would be a win-win for society and for shareholders. Pressure is building to lower cancer drug prices. A recent study by IMS Institute for Healthcare Informatics says that global oncology spending hit $91 billion in 2013 and is growing by 5% annually. But insurers in the United Kingdom, Europe, and the United States say that trend can t be sustained. Targeted therapies, such as Pfizer s crizotinib (Xalkori) for lung cancer and Roche s vemurafenib (Zelboraf) for melanoma, now make up 46% of cancer sales, according to IMS. In an article published in the May AARP Bulletin, Donald W. Light, PhD, professor of comparative health care at Rowan University School of Osteopathic Medicine, and Hagop Kantarjian, MD, at the University of Texas MD Anderson Cancer Center, state that of the 12 new cancer drugs approved in 2012, 11 were priced above $100,000 annually and a 20% 30% copayment would make them unaffordable even for well-insured patients. Cancer research costs are comparatively low, Light and Kantarjian say, and pharmaceutical companies are simply price-gouging. Bloomberg reports that since 2007, the cost of brand-name medications has surged one diabetes drug quadrupled in price and another rose by 160%. And 15 cancer drugs introduced in the last five years cost more than $10,000 a month, according to Memorial Sloan-Kettering Cancer Center data. But Eric Althoff, a spokesman for Novartis, maintains that imatinib mesylate (Gleevec), for treating leukemia, remains the most competitively priced drug in its class. And PhRMA contends that drug spending growth is in line with other medical spending. The American Society of Clinical Oncology (ASCO) also raises cost concerns in its just-published The State of Cancer Care in America 2014, stating that financial pressures and instability are a major threat to practices and that the quality of care throughout the United States is inconsistent. Ann Steagall, director of clinical policy at Biologics Inc., says the rising costs of cancer care are unsustainable for every stakeholder. But ASCO remains shy about holding drugmakers responsible for the high cost of cancer care. Diabetes drug gains in trials Peglispro (Lilly Diabetes), a oncedaily treatment for type 2 diabetes, showed a statistically superior reduction in HbA1c compared with insulin glargine in three completed phase 3 clinical trials. The trials evaluated three specific patient populations with type 2 diabetes: those who were not taking insulin (IMAGINE 2); those taking basal insulin with mealtime insulin (IMAGINE 4), and those currently taking a basal insulin (IMAGINE 5). Secondary endpoints of nocturnal hypoglycemia rates and changes in weight were also evaluated. In all three trials, patients experienced statistically significant lower rates of nocturnal hypoglycemia and had comparable to statistically significantly less weight gain. IMAGINE 2 is a randomized 51-week double blind study of BIL (n+1,002) compared with insulin glargine (n+535) in insulin-naïve patients. A subset of patients is continuing until 78 weeks of treatment. IMAGINE-4 is a 26-week randomized double-blind study comparing BIL (n=691) with insulin glargine (n=678) in combination with mealtime insulin. IMAGINE 5 is a 52-week open-label study evaluating BIL (n=307) compared with insulin glargine (n=159). Lilly expects U. S. and European regulatory submissions by the end of first quarter Protein restoration promising In a phase 3 study of patients with nonsense mutation cystic fibrosis (nmcf), PTC Therapeutics Ataluren demonstrated positive trends in both the primary endpoint, lung function as measured by relative change in % predicted FEV1 (forced expiratory volume in one second), and the secondary outcome measure, rate of pulmonary exacerbations. Results were published in Lancet Respiratory Medicine. Ataluren is a protein restoration therapy designed to enable the formation of a functioning protein in patients with genetic disorders caused by a nonsense mutation, an alteration in the genetic code that prematurely halts the synthesis of an essential protein. Boehringer Ingelheim announced new overall survival data from two phase 3 trials, LUX-Lung 3 and LUX-Lung 6 for afatinib (Gilotrif) in patients with advanced non smallcell lung cancer whose tumors have the most common epidermal growth factor receptor (EGFR) mutation, exon 19 deletion. Afatinib is an oral, oncedaily kinase inhibitor that is designed to irreversibly bind and inhibit the EGFR (ErbB1), HER2 (ErbB2) and ErbB4 receptors. The company said it would 46 MANAGED CARE / JUNE 2014

49 BIOLOGICS IN DEVELOPMENT announce additional safety and efficacy results at the ASCO meeting in Chicago. 2 heart drugs in trouble Novartis biologics license application for RLX030 (serelaxin) for treatment of acute heart failure was rejected by the FDA, which stated that further evidence on efficacy would be required for a U.S. license to be granted. The RLX030 submission to the FDA included phase 2 and 3 efficacy and safety data from the clinical development program, including the pivotal phase 3 RELAX-AHF study. Novartis plans to expand the data with an extensive global clinical program, including the RELAX-AHF-2 trial, which will enroll more than 6,300 patients. Much to GlaxoSmithKline s dismay, darapladib failed to reduce heart attacks or other major events in patients with acute coronary syndrome. The second phase 3 study did not support a regulatory submission, the company said. The drug had already failed in a late-stage trial for patients with well-treated heart disease. Phase 2 studies look OK Medimmune s mavrilimumab and sifalimumab met their primary endpoints in respective phase 2b studies. Mavrilimumab, an investigational monoclonal antibody, inhibits a key pathway in the development of rheumatoid arthritis. Sifalimumab is an investigational human monoclonal antibody to treat lupus. AstraZeneca expects to present additional study results for both molecules at a medical conference later this year. Belgium-based Galapagos and partner GlaxoSmithKline s anti-inflammation treatment GSK met its primary endpoint of improving psoriasis severity at 12 weeks in a 66-patient study with no reported serious adverse events. JAK was a phase 2a placebo-controlled, dose-ranging study that evaluated the safety and efficacy of GSK compared with placebo in 66 patients with chronic plaque psoriasis. GSK said that it would review all data before moving on to phase 3. Myriad Genetics has started the FDA s premarket approval review process for its breast cancer gene test BRAS Analysis as a companion diagnostic to AstraZeneca s olaparib. Myriad announced that results from 11 clinical studies with its molecular diagnostic tests would be featured at the ASCO meeting. Biosimilars around the world Smarting from lessons learned in the large-molecule drug world, Merck KGaA recently announced that it will invest about $138 million in biosimilars. Teva also plans to become a major player in the biosimilars race by courting Cipla, in Mumbai, India, although Cipla has denied such a bid. Cipla recently developed a copy of Amgen s etanercept (Enbrel) for rheumatoid arthritis and announced that it plans to invest $1.5 million to acquire a 14.6% stake in U.S.-based Chase Pharmaceuticals. Chase focuses on developing novel approaches to treat Alzheimer s disease. Celltrion, based in South Korea and partnering with Hospira, anticipates receiving FDA approval in early 2015 for its biosimilar Remsima, a TNF-α antagonist for treating rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, and adult Crohn s disease, but in the meantime it has filed a lawsuit against Janssen in Massachusetts, which it says is attempting to extend its monopoly after its initial patents expired for infliximab (Remicade). Celltrion is also starting a phase 3 clinical trial for its trastuzumab biosimilar CT-P6 candidate for patients with early breast cancer, which is expected to last three years and will include 25 countries worldwide. Sales of Roche s trastuzumab worldwide were $6.8 billion in A ruling handed down by the High Court in London on Thursday determined that both the 115 and 455 patents on the drug, which relate to dosage and composition, were invalid, paving the way for a biosimilar. Trastuzumab biosimilars have been approved in India. Japan s Pharmaceuticals and Medical Devices Agency has approved a biosimilar for Sandoz s filgrastim BS for treating cancer. To date, Japan has approved five biosimilars in the product classes of human growth hormone and granulocyte colony-stimulating factor. Amgen recently called on pharmaceutical firms to educate doctors on biosimilars. At the DIA Euromeeting in Vienna in April, Virginia Acha, director of regulatory affairs at Amgen UK, said that some doctors are unaware of the difference between biosimilars and smallmolecule generics and that other stakeholders are also trailing behind in their knowledge of biosimilars. And in the United States, Indiana Governor Mike Pence has signed Senate Bill 262, bipartisan legislation passed 87 5 that enables a retail pharmacy to substitute a biosimilar for the original biologic it is replacing. The intent, legislators said, is to ensure transparent communication within a patient s health care team. The bill aligns with the Biotechnology Industry Organization principles on biologic substitution. Indiana is the fifth state to enact such legislation although the FDA has yet to approve a biosimilar. Still, there s hope the FDA has JUNE 2014 / MANAGED CARE 47

50 BIOLOGICS IN DEVELOPMENT Selected FDA approvals of biologic and specialty drugs, March 15 May 14, 2014 Date (type) Manufacturer Drug/trade name; administration Indication Notes April 15, 2014 GSK Albiglutide/Tanzeum Glycemic control in type 2 diabetes April 21, 2014 Lilly Ramucirumab/Cyramza For patients with advanced stomach cancer or gastroesophageal junction (GEJ) adenocarcinoma. April 29, 2014 Novartis Ceritinib/Zykadia For patients with metastatic ALK-positive NSCLC previously treated with crizotinib. April 23, 2014 Sylvant/ Janssen Biotech Approval includes Boxed Warning: Cannot be used in patients with personal/family history of medullary thyroid carcinoma (MTC) Wiltuximab Multicentric Castleman s Disease For patients HIV-negative and HHV-8 negative. April 24, 2014 Roche Cobas HPV test Cervical cancer screening First human HPV test for primary cancer screening. Can identify P=HPV DNA from 14 high-risk genital HPV types. Selected FDA-related activities, March 15 May 14, 2014 Manufacturer Drug (trade name) Type of drug Proposed use Notes Merck MK3475 Anti-PD-1 immunotherapy Advanced melanoma, Non-small cell lung cancer. Head and neck cancer. Granted FDA priority review. New data to be presented at 2014 ASCO Meeting. GSK=GlaxoSmithKline HIV=human immunodeficiency virus; HH-8=human herpes virus HPV=human papillomavirus Sources: American Society of Clinical Oncology, FDA, FierceBiotech, New York Times, Thompson Reuters, and manufacturers news releases and product labeling just issued draft guidance, Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product, in which four tiers of possible similarity are proposed. Drug developers have until August 12 to provide feedback. Here come the devices With Apple signaling interest in biosensor devices and Google not far behind the medical device field seems poised for a rebirth. Apple has announced that it plans to exploit this field, which CEO Tim Cook says is primed to explode. The company has registered its biometric iwatch in Japan and in February filed a patent for a smart earbud device that can track steps and detect gestures. Other devices may track heart rate and body temperature and monitor blood pressure. Apple is also exploring medical devices and sensors that can help predict heart attacks by studying the sound blood makes at it flows through arteries. Earlier this year, Apple s senior vice president for operations, Jeff Williams, met with FDA chief Margaret Hamburg and Jeffrey Shuren, MD, JD, who oversees the agency s approval for medical devices, to discuss mobile medical applications. In March, Google unveiled Android Wear, and it s exploring contact lenses that can monitor glucose levels in tears. Google also recently bought thermostat maker Nest Labs for $3.2 billion, robot maker Boston Dynamics, and artificial intelligence startup DeepMind Technologies Ltd. The picture all this conjures up, though people wearing devices that keep all their vitals constantly monitored, not to mention medication and doctor appointment schedules and medical instructions gives pause: What kind of humans will we be in 50 years? Katherine T. Adams 48 MANAGED CARE / JUNE 2014

51 THE FORMULARY FILES Three allergy medications approved in one month The FDA s approval of three sublingual immunotherapy tablets marks the entrance of orals into the allergen immunotherapy market that is dominated by allergen extracts administered subcutaneously. Oralair and Grastek are both approved for treatment of moderate to severe allergy to grass pollen, whereas Ragwitek is approved for allergy to ragweed pollen. Patients who do not respond adequately to symptomatic treatments now have a more convenient and viable option. Despite these drugs convenient dosing, formulary decision makers must consider the threat to adherence that these drugs pose, as patients can now take their allergy treatment at home rather than having to visit physicians offices, where adherence is assured. With Oralair and Grastek having similarities in indication and in efficacy, it is important to pinpoint minute differences. Below we have a bird s-eye view of the three allergy medications, which were approved in April. Krishna Rutvij Patel, PharmD Oralair (approved April 1) Grastek (approved April 14) Sources: Prescribing information documents for Grastek and Ragwitek; news release regarding Oralair approval Ragwitek (approved April 17) Sublingual tablet Dosing frequency Once daily Once daily Once daily Indicated for allergy to grass pollen Indicated for allergy to ragweed pollen Number of pollen extracts within tablet Approved age group 10 years 5 years 18 years Months prior to pollen season when therapy should be initiated Beyond continuing education, you need to demonstrate your command of the critical skills needed to excel in an ever-changing environment. HCQM Certification is a definitive benchmark of achievement that lets everyone know you operate at a higher level of proficiency. Validate your expertise with a certification that demonstrates deep commitment to patient safety, health care quality, and effective care; while addressing the need for effectiveness, efficiency, utilization review, safety, and timeliness. Bring your dedication into laser-sharp focus with additional sub-specialty certifications in the following categories: Transitions of Care Managed Care Patient Safety / Risk Management Case Management Workers Compensation ADMC0314 JUNE 2014 / MANAGED CARE 49

52 TOM O RROW S MEDI C I NE Myalept Approved for Treatment Of Disorders Marked by Loss of Body Fat Medication is aimed at leptin deficiency, but clinical trials may be hard for managed care plans to evaluate properly Thomas Morrow, MD Thomas Morrow, MD, is the immediate past president of the National Association of Managed Care Physicians. He has 24 years of managed care experience at the payer or health plan level. Contact him at TMorrow@ManagedCareMag.com. Given the current state of obesity in the United States and the explosion of associated diabetes and metabolic syndrome, some people may assume that fat is an enemy of good health. But fat actually is a metabolically active human tissue and its absence can lead to severe disease. Lipodystrophy comprises a group of rare disorders characterized by extensive to nearcomplete loss of body fat. Such dramatic loss of fat in turn causes the loss of a critical hormone derived from fat tissue: leptin. In normal circumstances, leptin plays a significant role in energy homeostasis, lipid levels, and insulin resistance. The loss of leptin can result in severe metabolic abnormalities with hypertriglyceridemia, insulin resistance, hyperglycemia, and type 2 diabetes. Circulating levels of leptin closely correlate with the amount of adipose tissue present. These disorders can also result in the deposition of triglyceride material in organs, the most common being muscle and liver. When the deposition occurs in the liver, it can lead to steatohepatitis, cellular injury, inflammation, and cirrhosis. Additional complications are the result of the metabolic as well as the infiltrative effects of this disorder, and can include pancreatitis and accelerated cardiovascular disease. Of note, the loss of leptin, which communicates to the central nervous system the status of energy stores within the body, results in excess caloric intake, which exacerbates the metabolic abnormalities. Clinicians have classified lipodystrophy based on etiology (genetic or acquired) and the extent of adipose loss (generalized or partial). The genetic diseases are Berardinelli-Seip syndrome (also called congenital generalized lipodystrophy) and familial partial lipodystrophy. Berardinelli-Seip syndrome is the worst form of lipodystrophy. It occurs in about 1 in 10 million births, is characterized by a nearly complete absence of adipose tissue, and can be recognized at birth. It is associated with the most severe levels of hyperinsulinemia and hypertriglyceridemia, and results in recurrent acute pancreatitis and a voracious appetite in early childhood. Liver failure is common. Several distinct genetic subtypes of this syndrome are described in the literature. Autosomal dominant disorders There are several forms of familial partial lipodystrophy; all are autosomal dominant disorders. The most prevalent is the Dunnigan variety, which is associated with mutations of the LMNA gene. These infants are born with normal fat distribution, but during puberty the subcutaneous fat gradually disappears from arms and legs giving the appearance of a muscular build. Later fat loss occurs from the anterior abdomen and chest. Interestingly, many patients, women in particular, gain fat in the face and neck and intra-abdominal region resulting in a Cushingoid appearance. This disorder is difficult to diagnose, particularly in males, as the muscular appearance is not as distinctive as it is in women. These patients develop diabetes, hypertriglyceridemia, atherosclerotic vascular disease, and low levels of HDL. The acquired form of lipodystrophy, also called Barraquer-Simons syndrome, typically follows autoimmune disease, particularly systemic lupus erythematosus and dermatomyositis. Barraquer-Simons syndrome primarily causes loss of fat in the face, neck, arms, thorax, and upper abdomen. Prevalence of this group of diseases is difficult to determine, but about 1,350 cases are known 50 MANAGED CARE / JUNE 2014

53 Tomorrow s Medicine to exist in the world, with approximately 1,000 patients with the inherited form and 350 with the acquired forms. Treatments have historically been supportive and have been aimed at the metabolic derangements of elevated triglycerides and blood glucose. Recently, the FDA approved a new drug, Myalept, that gets closer to the heart of the matter. Myalept, an analog of leptin, is a 147 amino aid recombinant polypeptide produced in E. coli that differs from leptin by one added amino acid on its terminal end. The FDA approved Myalept as an adjunct to diet as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy. HIV can also cause lipodystrophy, but this drug was not studied in HIV patients and thus is not approved in that setting. The development of Myalept came directly from the knowledge that the loss of fat can lead to a deficiency of leptin. Hence, treatment with leptin or its analog was thought to be of benefit to those with a leptin deficiency. Soon after the discovery of leptin in 1996, an analog (metreleptin) was developed and empirically tried in a small group of patients with lipodystrophy. The findings were so compelling that it was thought to be unethical to use a placebo in future studies. But because of the absence of the placebo control arm, results of clinical trials will be difficult for managed care plans to interpret. Approval of Myalept The clinical trial leading to the approval of Myalept consisted of a 48-patient, open-label, single-arm study comprising patients with congenital generalized lipodystrophy (32 subjects) and acquired lipodystrophy (16 subjects) with a median age of 15 years. The median duration of treatment was 2.7 years. Although studied in either once- or twice-daily dosing, the final recommended subcutaneous injection dosage is weight-based and contains a dose escalation The author is the chief medical officer of Next IT. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow s Medicine are the author s alone. schedule to a maximum dose of 10 mg per day. The FDA label cautions that possible large reductions of insulin and other antidiabetes drugs may be necessary to prevent hypo glycemia. The subjects had a mean drop in HbA1c of 2 percentage points, a drop in fasting glucose of 49 g/dl, and a drop in fasting triglycerides of 184 mg/dl. From the discovery of leptin to the characterization of its effect to its replication through recombinant technology to clinical trial to approval, the process took about 18 years. Myalept contains a black box warning concerning the risk of antimetreleptin antibodies with neutralizing activity and risk of lymphoma. During early development with normal subjects, neutralizing antibodies developed, resulting in metabolic derangements that were due to loss of endogenous leptin activity. Lymphoma has been reported in patients with acquired generalized lipodystrophy, both treated and untreated. Therefore, Myalept is available only through a risk evaluation and mitigation strategy program. The development and approval of Myalept have followed a course similar to other drug approvals. From the discovery of leptin to the characterization of its effect to its replication through recombinant technology to clinical trial to approval, the process took about 18 years. Given the pace of scientific discovery, evidenced by nearly hourly news reports, we can only imagine what Tomorrow s Medicine holds for mankind. ADVERTISING INDEX American Board of Quality Assurance and Utilization Review Physicians Health Care Quality and Management Certification Amgen Corporate Communications...11 Eisai Fycompa... C2 3 Express Scripts Corporate...8 Janssen Invokana Salix Uceris... 36,37 JUNE 2014 / MANAGED CARE 51

54 MANAGED CARE OUTLOOK Specialty, traditional drug cost divide to widen Insurers can expect spending on traditional medications to remain relatively flat over the next few years, but watch out for specialty drugs because that s where costs will soar, according to the 2013 Drug Trend Report by Express Scripts, released in April. Spending on traditional drugs will climb about 2% annually until 2016, while spending on specialty drugs is expected to jump 16% during the same period. (The specialty drug estimate is very conservative; about half of specialty medication costs are billed through Traditional drugs: Spending on diabetes drugs to increase most Annual growth 15% the medical benefit and therefore not included in the Express Scripts calculations.) Utilization of specialty drugs will be driven in part by development of targeted therapies. Immunotherapies are also highly anticipated, and probably will be billed as a medical benefit. As for traditional medications, Express Scripts says the largest increases this year are expected for diabetes medications, which it says continue to see brand drug innovation, and for drugs to treat attention disorders. 10% 5% 0% 5% Diabetes High blood cholesterol High blood pressure/ heart disease Ulcer disease Asthma Attention disorders Depression Mental/ neurological disorders Pain Infections Contraceptives Seizures Total 10% 15% % 25% Expenditure for specialty drugs to increase dramatically Annual growth 250% 200% % 100% 50% 0% 50% Inflammatory conditions Multiple sclerosis Cancer HIV Growth deficiency Central nervous system conditions Respiratory disorders Transplant Pulmonary hyper tension Hepatitis C Total Source: 2013 Drug Trend Report, Express Scripts, Maryland Heights, Mo., MANAGED CARE / JUNE 2014

55 SAVE $300 OFF YOUR REGISTRATION FEE WHEN YOU MENTION PROMO CODE MCARE MHEALTH + TELEHEALTH WORLD 2014 Increase Efficiency, Encourage Engagement, and Ensure Sustainability of Connected Health Programs J U L Y , H Y A T T R E G E N C Y B O S T O N, M A ELITE SUMMIT FACULTY INCLUDES: Jeffrey L. Brown Chief Information Officer LAWRENCE GENERAL HOSPITAL David Chou Chief Information Officer UNIVERSITY OF MISSISSIPPI MEDICAL CENTER Edward Marx Chief Information Officer, Senior Vice President TEXAS HEALTH RESOURCES John Mattison, MD Chief Medical Information Officer, Assistant Medical Director KAISER PERMANENTE SOUTHERN CALIFORNIA Khalid Moidu Chief Information Officer, Chief Medical Information Officer FAMILY PHYSICIANS GROUP S. Luke Webster, MD Vice President, Chief Medical Information Officer CHRISTUS HEALTH NEW FOR THE 2014 PROGRAM: Combined programming for mhealth and Telehealth brings together experts from both areas to discuss how these tools and practices can be used together to transform health care delivery A focus on new technologies and the future of mhealth and Telehealth provides insight on where the industry is headed and how organizations can prepare for the expansion of connected health to meet consumer demand Real-life successes and failures of digital health programs provide tools and strategies to overcome challenges, promote hospital and provider buy-in, and prove the ROI of utilizing mhealth and Telehealth as part of normal delivery of care A jam packed agenda, including 3 days of content and networking, offers ample opportunities to connect with industry experts and time to focus on numerous areas of mhealth and Telehealth OVER 40 SPEAKERS FROM HEALTH CARE ORGANIZATIONS INCLUDING: CATHOLIC HEALTH INITIATIVES CHRISTUS HEALTH CLEVELAND CLINIC CTEL HEALTHAGEN, AN AETNA COMPANY HUMANA KAISER PERMENENTE SOUTHERN CALIFORNIA MASSACHUSETTS GENERAL HOSPITAL PARTNERS CENTER FOR CONNECTED HEALTH TEXAS HEALTH RESOURCES UCLA HEALTH SYSTEM OPTUM, A UNITEDHEALTH GROUP COMPANY UNIVERSITY OF MISSISSIPPI MEDICAL CENTER UPMC UC DAVIS Educational Underwriters Supporting Partners Official Mobile App Sponsor Organized by HEALTH PLAN MARKET TRENDS #mhealth14 TO REGISTER, please visit Phone: Fax: wcreg@worldcongress.com