AHDB January/February 2014 Vol 7, No 1

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ January/February 2014

Volume 7, Number 1

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

“I Have a Hunch” David B. Nash, MD, MBD BUSINESS

Resource Utilization and Cost in a Commercially Insured Population with Schizophrenia Kathryn Fitch, RN, MEd; Kosuke Iwasaki, MAAA, MBA; Kathleen F. Villa, MS ™

Stakeholder Perspective: Schizophrenia: “The Forgotten Illness”?

By Atheer A. Kaddis, PharmD clinical

Fixed-Dose Combination Gel of Adapalene and Benzoyl Peroxide plus Doxycycline 100 mg versus Oral Isotretinoin for the Treatment of Severe Acne: Efficacy and Cost Analysis Pete Penna, PharmD; Matthew H. Meckfessel, PhD; Norman Preston, PhD Stakeholder Perspective: Evaluating Treatments for Acne: It’s Time to “Sweat” the Smaller Things

By Gary M. Owens, MD

Outcomes Associated with 5-HT3-RA Therapy Selection in Patients with Chemotherapy-Induced Nausea and Vomiting: A Retrospective Claims Analysis Claudio Faria, PharmD, MPH; Xuan Li, MS; Norman Nagl, PhD; Ali McBride, PharmD, MS Stakeholder Perspective: Value of Selecting the Best Antiemetic Prophylactic Agent for Patients Using Chemotherapy

By Curtis Wander, PharmD, BCPS

Y

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For your members with COPD (chronic obstructive pulmonary disease)

The only once-daily ICS/LABA (inhaled corticosteroid/long-acting beta2-agonist) for the maintenance treatment of COPD. Contact your GlaxoSmithKline Account Manager to schedule a presentation.

Indications • BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2 -adrenergic agonist (ICS/LABA) indicated for the longterm, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

• BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

Important Safety Information for BREO ELLIPTA WARNING: ASTHMA-RELATED DEATH • Long-acting beta2-adrenergic agonists (LABAs), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including vilanterol.

• The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

CONTRAINDICATIONS • BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS • BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. • BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2 -agonist.

• BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

• Oropharyngeal candidiasis has occurred in patients treated with BREO ELLIPTA. Advise patients to rinse the mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

• An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal.

– In replicate 12-month studies of 3255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving BREO ELLIPTA 100/25 mcg (6% [51 of 806 subjects]), fluticasone furoate (FF)/vilanterol (VI) 50/25 mcg (6% [48 of 820 subjects]), and FF/VI 200/25 mcg (7% [55 of 811 subjects]) than in subjects receiving VI 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving VI or FF/VI 50/25 mcg.

There was fatal pneumonia in 1 subject receiving BREO ELLIPTA at the approved strength (100/25 mcg) and in 7 subjects receiving FF/VI 200/25 mcg (<1% for each treatment group).

• Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

• Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

• Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage of inhaled corticosteroids in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly.

Important Safety Information for BREO ELLIPTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur.

• If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy.

• Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. BREO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

• Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter.

• Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

• Be alert to hypokalemia and hyperglycemia.

ADVERSE REACTIONS • The most common adverse reactions (≥3% and more common than placebo) reported in two 6-month clinical trials with BREO ELLIPTA (and placebo) were nasopharyngitis, 9% (8%); upper respiratory tract infection, 7% (3%); headache, 7% (5%); and oral candidiasis, 5% (2%).

• In addition to the events reported in the 6-month studies, adverse reactions occurring in ≥3% of the subjects treated with BREO ELLIPTA in two 1-year studies included COPD, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia.

DRUG INTERACTIONS • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur.

• BREO ELLIPTA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists, such as vilanterol, on the cardiovascular system may be potentiated by these agents.

• Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with reversible obstructive airways disease.

• Use with caution in patients taking non–potassium-sparing diuretics, as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists.

USE IN SPECIFIC POPULATIONS • Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Fluticasone furoate exposure may increase in these patients. Monitor for systemic corticosteroid effects.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for BREO ELLIPTA on the following pages.

BREO ELLIPTA was developed in collaboration with

BRIEF SUMMARY BREOTM ELLIPTATM (fluticasone furoate and vilanterol inhalation powder) FOR ORAL INHALATION USE The following is a brief summary only; see full prescribing information for complete product information WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including vilanterol, an active ingredient in BREO ELLIPTA [see Warnings and Precautions (5.1)].

The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

1 INDICATIONS AND USAGE BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

Important Limitations of Use: BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

4 CONTRAINDICATIONS The use of BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions (5.11), Description (11) of full prescribing information].

5 WARNINGS AND PRECAUTIONS 5.1 Asthma-Related Death Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death.

Data are not available to determine whether the rate of death in patients with COPD is increased by LABA. A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthmarelated death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No study adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. BREO ELLIPTA has not been studied in patients with acutely deteriorating COPD. The initiation of BREO ELLIPTA in this setting is not appropriate.

BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.

Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA no longer controls symptoms of bronchoconstriction; the patientâ&#x20AC;&#x2122;s inhaled, shortacting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of BREO ELLIPTA beyond the recommended dose is not appropriate in this situation.

5.3 Excessive Use of BREO ELLIPTA and Use With Other Long-Acting Beta2Agonists BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving the fluticasone furoate/vilanterol combination, including BREO ELLIPTA 100 mcg/25 mcg, in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences

these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 6% [48 of 820 subjects]; 100 mcg/25 mcg: 6% [51 of 806 subjects]; or 200 mcg/25 mcg: 7% [55 of 811 subjects]) than in subjects receiving vilanterol 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving fluticasone furoate/vilanterol 100 mcg/25 mcg and in 7 subjects receiving fluticasone furoate/vilanterol 200 mcg/25 mcg (less than 1% for each treatment group).

5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.7 Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD symptoms during these episodes, in recommended doses it supplies less than normal physiological amount of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (mean forced expiratory volume in 1 second [FEV1]), beta-agonist use, and COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression) despite maintenance or even improvement of respiratory function.

5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic dose of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)]. Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD symptoms should be considered.

5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3) of full prescribing information].

5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA

can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

5.11 Hypersensitivity Reactions Hypersensitivity reactions may occur after administration of BREO ELLIPTA. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not take BREO ELLIPTA [see Contraindications (4)].

5.12 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12-fold higher systemic exposure than seen in patients with COPD) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered. In replicate 12-month trials in 3,255 subjects with COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 2% [14 of 820 subjects]; 100 mcg/25 mcg: 2% [19 of 806 subjects]; or 200 mcg/25 mcg: 2% [14 of 811 subjects]) than in subjects receiving vilanterol 25 mcg alone (less than 1% [8 of 818 subjects]).

5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. In replicate 12-month trials in 3,255 subjects with COPD, similar incidences of ocular effects (including glaucoma and cataracts) were reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: less than 1% [7 of 820 subjects]; 100 mcg/25 mcg: 1% [12 of 806 subjects]; 200 mcg/25 mcg: less than 1% [7 of 811 subjects]) as those receiving vilanterol 25 mcg alone (1% [9 of 818 subjects]).

5.15 Coexisting Conditions BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 6- and 12-month duration evaluating BREO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

6 ADVERSE REACTIONS LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. BREO ELLIPTA is not indicated for the treatment of asthma. [See Boxed Warnings and Warnings and Precautions (5.1).] Systemic and local corticosteroid use may result in the following: Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)]; Increased risk for decrease in bone mineral density [see Warnings and Precautions (5.13)].

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects have received at least 1 dose of BREO ELLIPTA 100 mcg/25 mcg, and 1,087 subjects have received higher doses of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6-month and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.

6-Month Trials: The incidence of adverse reactions associated with BREO ELLIPTA in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were Caucasian. They had a mean age of 62 years and an average smoking

history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/ vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.

Table 1. Adverse Reactions With ≥3% Incidence and More Common Than Placebo With BREO ELLIPTA in Subjects With Chronic Obstructive Pulmonary Disease

Adverse Event

a

BREO ELLIPTA 100 mcg/25 mcg (n = 410) %

Vilanterol 25 mcg (n = 408) %

Fluticasone Furoate 100 mcg (n = 410) %

Placebo (n = 412) %

9

10

8

8

Infections and infestations Nasopharyngitis Upper respiratory tract infection Oropharyngeal candidiasisa

7

5

4

3

5

2

3

2

Nervous system disorders Headache

7

9

7

5

Includes terms oral candidiasis, oropharyngeal candidiasis, candidiasis, and oropharyngitis fungal.

12-Month Trials: Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg. In addition to the events shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA (N = 806) for 12 months included COPD, back pain, pneumonia [see Warnings and Precautions (5.5)], bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia.

7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol, the individual components of BREO ELLIPTA, are both substrates of CYP3A4.

Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of BREO ELLIPTA with longterm ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) of full prescribing information].

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Vilanterol, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.3 Beta Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, a component of BREO ELLIPTA, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/ or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by betaagonists, especially when the recommended dose of the beta-agonist is exceeded.

Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with BREO ELLIPTA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women should be advised to contact their physicians if they become pregnant while

taking BREO ELLIPTA. Fluticasone Furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 9 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone furoate and vilanterol, alone or in combination, up to approximately 95 mcg/kg/day). Fluticasone Furoate: There were no teratogenic effects in rats and rabbits at approximately 9 and 2 times, respectively, the MRHDID in adults (on a mcg/ m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and postnatal development in rats at approximately 3 times the MRHDID in adults (on a mcg/m2 basis at maternal doses up to 27 mcg/kg/day). Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/ day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. There were no effects on perinatal and postnatal development in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

8.2 Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of BREO ELLIPTA during labor and delivery. Because beta-agonists may potentially interfere with uterine contractility, BREO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk.

8.3 Nursing Mothers It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk. However, other corticosteroids and beta2-agonists have been detected in human milk. Since there are no data from controlled trials on the use of BREO ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman.

8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of BREO ELLIPTA for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3) of full prescribing information].

8.7 Renal Impairment There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3) of full prescribing information].

10 OVERDOSAGE No human overdosage data has been reported for BREO ELLIPTA. BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA. 10.1 Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions (5.8)]. Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days.

10.2 Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/ min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.

Treatment of overdosage consists of discontinuation of BREO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below.

Fluticasone Furoate: Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (approximately equal to the MRHDID in adults on a mcg/m2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed

in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/ day, respectively (approximately 3 and 9 times, respectively, the MRHDID in adults on a mcg/m2 basis).

Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/ day (approximately 530 times the MRHDID in adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,000 times, respectively, the MRHDID in adults on a mcg/m2 basis).

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for Use) 17.1 Asthma-Related Death Patients should be informed that LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthmarelated death. BREO ELLIPTA is not indicated for the treatment of asthma.

17.2 Not for Acute Symptoms BREO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with a rescue inhaler such as albuterol. The physician should provide the patient with such medicine and instruct the patient in how it should be used. Patients should be instructed to notify their physicians immediately if they experience any of the following: Symptoms get worse; Need for more inhalations than usual of their rescue inhaler; Significant decrease in lung function as outlined by the physician. Patients should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.

17.3 Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed BREO ELLIPTA, other medicines containing a LABA should not be used.

17.4 Risks Associated With Corticosteroid Therapy Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with BREO ELLIPTA, but at times therapy with BREO ELLIPTA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth without swallowing after inhalation is advised to help reduce the risk of thrush.

Pneumonia: Patients with COPD who have received BREO ELLIPTA have a higher risk of pneumonia and should be instructed to contact their healthcare providers if they develop symptoms of pneumonia (e.g., fever, chills, change in sputum color, increase in breathing problems).

Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

Hypercorticism and Adrenal Suppression: Patients should be advised that BREO ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk.

Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered.

17.5 Risks Associated With Beta-Agonist Therapy Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

BREO and ELLIPTA are trademarks of GlaxoSmithKline.

BREO ELLIPTA was developed in collaboration with

Š2013, GlaxoSmithKline. All rights reserved.

Revised 05/2013 Š2013 GlaxoSmithKline group of companies.

All rights reserved. Printed in USA. MH3770R0 October 2013

BRE:1BRS

january/february 2014

Volume 7, number 1

The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

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Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Founding Editor-in-Chief Robert E. Henry

Table of Contents EDITORIAL

11

“I Have a Hunch” David B. Nash, MD, MBD

BUSINESS

18 Resource Utilization and Cost in a Commercially Insured Population with Schizophrenia

Kathryn Fitch, RN, MEd; Kosuke Iwasaki, MAAA, MBA; Kathleen F. Villa, MS 25

Stakeholder Perspective: Schizophrenia: “The Forgotten Illness”?

By Atheer A. Kaddis, PharmD

CLINICAL

37 Fixed-Dose Combination Gel of Adapalene and Benzoyl Peroxide plus Doxycycline 100 mg versus Oral Isotretinoin for the Treatment of Severe Acne: Efficacy and Cost Analysis

Pete Penna, PharmD; Matthew H. Meckfessel, PhD; Norman Preston, PhD 44 Stakeholder Perspective: Evaluating Treatments for Acne: It’s Time to “Sweat” the Smaller Things

By Gary M. Owens, MD

Continued on page 9

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

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

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The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonato Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications

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Vol 7, No 1

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For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

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editorial board Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia Aging and Wellness

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

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

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

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

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

Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy, University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD health & value promotion

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

GOVERNMENT

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

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

HEALTH INFORMATION TECHNOLOGY

PATIENT ADVOCACY

Kelly Huang, PhD President, HealthTronics, Inc. Austin, TX Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

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

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

Grant D. Lawless, RPh, MD, FACP Assoc. Prof. and Director, Healthcare Decision Analysis, Dept. of Clinical Pharmacy Univ. of Southern California, Los Angeles PHARMACY BENEFIT DESIGN

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

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

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

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

PHARMACOECONOMICs

SPECIALTY PHARMACY

Personalized medicine

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, Univ. of Cincinnati Medical Center, OH

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

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Volume 7, number 1

The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

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™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Table of Contents

(Continued)

CLINICAL

50 Outcomes Associated with 5-HT3-RA Therapy Selection in Patients with Chemotherapy-Induced Nausea and Vomiting: A Retrospective Claims Analysis

Claudio Faria, PharmD, MPH; Xuan Li, MS; Norman Nagl, PhD; Ali McBride, PharmD, MS 58 Stakeholder Perspective: Value of Selecting the Best Antiemetic Prophylactic Agent for Patients Using Chemotherapy

By Curtis Wander, PharmD, BCPS

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512.

Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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NEW FOR 2014

Principles in Value and Market Access

An educational session for product managers, reimbursement specialists, account managers, and marketers focusing on access, reimbursement, proving product value, and international markets.

CO-CHAIRS

MAY 6, 2014 Loews Hollywood Hotel Los Angeles, CA

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Gary M. Owens, MD

President Gary Owens Associates

AGENDA 10:45am – 11:00am

Introductions and Opening Remarks Grant Lawless, RPh, MD, FACP; Gary M. Owens, MD

11:00am – 11:40am

Changing Access and Payer Challenges in Oncology - Medicare and Commercial Speaker TBD

11:40am – 12:20pm

Proving the Value for Oncology Therapy Using Comparative Effectiveness Research Dan Malone, PhD, Professor, University of Arizona College of Pharmacy

12:20pm – 1:30pm

Lunch

1:30pm – 2:10pm

Methods and Tools for Optimal Reimbursement Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead

2:10pm – 2:50pm

Impact of Healthcare Reform, Affordable Care Act, and Accountable Care Organizations on the Coverage of Cancer Treatments Speaker TBD

2:50pm – 3:30pm

Impact of New Risk Models on Traditional Pharmaceutical Relationships Ken Schaecher, MD, FACP, CPC, Medical Director, SelectHealth

3:30pm – 4:00pm

Break

4:00pm – 4:40pm

Using Competitive Intelligence to Maintain Coverage and Access Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting

4:40pm – 5:20pm

Panel Discussion - Will improvements in clinical outcomes and efficacy come from new products or a more thoughtful use of existing products using new adaptations?

Cyrus Arman, MS, PhD, Principal & Head of West Coast Operations, Deallus Consulting Sasha Richardson, BSC, PT, MBA, Vice President, GfK Bridgehead Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE) AVBCC2014May6agenda Asize_20714

REGISTER TODAY! www.regonline.com/avbcc2014

Editorial

“I Have a Hunch” David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits Jefferson School of Population Health, Philadelphia, PA

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ike many persons who are concerned about the future of our healthcare delivery system, I have been carefully following the evolving literature and evidence on the patient-centered medical home (PCMH). I would therefore like to share with you a “hunch” I have about the future of PCMHs, with a special emphasis on an assessment of the current evidence about their effectiveness and long-term implications.

Alexander and colleagues assessed the policy context of PCMHs from the perspective of primary care providers.1 Let us begin by defining our terms. The PCMH is described by joint principles agreed upon by several professional societies. In essence, these include (1) a personal physician, (2) a physician-directed medical practice, (3) whole person orientation, (4) coordinated care, (5) an emphasis on quality and safety, (6) improved access, and (7) some changes in the payment system.

It is true, say Alexander and colleagues, that medical home models vary greatly in their practice and structure, “but their success is assumed to rest fundamentally on the ability to focus the work of a defined team on the needs of a patient or family, recruiting social services, specialty medical services, and patient capabilities to solve problems and coordinate care.”1 Through qualitative, semistructured, in-person interviews with key representatives of physician organizations and multiple primary care practices that were pursuing the creation of a PCMH, Alexander and his colleagues come to a sobering conclusion.

In essence, they found that “providers’ motivation to embrace the PCMH and their level of confidence regarding the results of such change are greatly influenced by their perception of the external environment and the control they believe they have over this environment.”1 More simply, Alexander and colleagues found that to turn a typical small primary care practice into a PCMH-designated center requires truly transformational change and a considerable amount of costly resources and organizational support that are not currently readily available.1 What I took away from the analysis by Alexander and colleagues is that it may be impossible to help providers recognize that unnecessary testing is a cost burden to the healthcare system rather than an income stream, without some kind of intervention from a large organization, such as a hospital-based

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integrated delivery system, managed care plan, or similar entities.

A later study by Fifield and colleagues added to my hunch that this transformation will not be easily or readily achievable.2 In their randomized controlled trial, Fifield and her team found that, regardless of size, “practices can make rapid and sustained transition to a PCMH when provided external supports, including practice redesign, care management and payment reform. Without such supports, change is slow and limited in scope.”2 In my assessment, given the current environment, we could rationally expect that such change would come quite slowly to the average primary care practice. Fifield and her colleagues had embedded personnel at the practice sites they studied for months, to facilitate the transition to a PCMH,2 knowing that physicians have little direct experience in instituting patient self-management programs and performance reporting and improvement scorecards on their own.

Finally, in a systemic review of the PCMH, Jackson and his colleagues concluded that “the PCMH holds promise for improving the experiences of patients and staff and potentially for improving care processes, but current evidence is insufficient to determine effects on clinical and most economic outcomes.”3 So there you have it. The way I see it, and based on my review of the evidence, there is much more to this PCMH transformation than the average practice could essentially handle on its own at this time.

From a broader policy perspective, this means that integrated delivery systems, seeking to pivot from filling beds to caring for populations, are going to be woefully unprepared for this transition if they rely too heavily on a strategy of building National Committee for Quality Assurance (NCQA)-certified PCMH structures.

Another hunch I have is that most well-trained, well-meaning, hardworking primary care physicians have no “on the ground” sense of what many of the healthcare reform–associated changes will truly mean. Jackson and his team concluded their review by noting that although “implementing the PCMH principles is something to be considered by organizations seeking to enhance patient experience and quality of care, no menu is yet available for specific actions that are most likely to enhance benefits to patients, staff, and organizations.”3 Continued

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Editorial

Well, I do have another hunch: if no “menu” is yet available, how can we choose a particular meal? If randomized controlled trials on PCMH implementation do not specifically identify the components of this much-­ needed menu, what are practices supposed to do?

The drive to create accountable care organizations has obscured our vision at the ground level. It is my hunch that the PCMH, as the building block of an accountable system, is truly where the core challenge lies.

We have not seen the end, or maybe even the beginning, of the PCMH movement. We have missed the central tenet—without physician leadership and physician commitment to organizational change (2 arenas where most clinicians have little formal training), PCMHs are bound to fail. And this, of course, calls into

question the greater strategy of accountability and population-based medicine.

The drive to create accountable care organizations has obscured our vision at the ground level. It is my hunch that the PCMH, as the building block of an accountable system, is truly where the core challenge lies.

Even as multiple specialty societies embrace the PCMH nomenclature, and as NCQA provides us with a greater number of operational measures, we are a long way from having the leadership skills and organizational understanding that clinicians will need to effectively implement this core strategy for reform. n

References

1. Alexander JA, Cohen GR, Wise CG, Green LA. The policy context of patient-centered medical homes: perspectives of primary care providers. J Gen Intern Med. 2013;28:147-153.

2. Fifield J, Forrest DD, Martin-Peele M, et al. A randomized, controlled trial of implementing the patient-centered medical home model in solo and small practices.

J Gen Intern Med. 2013;28:770-777.

3. Jackson GL, Powers BJ, Chatterjee R, et al. The patient-centered medical home: a systematic review. Ann Intern Med. 2013;158:169-178.

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Resource Utilization and Cost in a Commercially Insured Population with Schizophrenia Kathryn Fitch, RN, MEd; Kosuke Iwasaki, MAAA, MBA; Kathleen F. Villa, MS

Kathryn Fitch

Stakeholder Perspective, page 25 Am Health Drug Benefits.

2014;7(1):18-26 www.AHDBonline.com Disclosures are at end of text

Background: Schizophrenia is a serious public health concern and a leading cause of disability. Previous studies have shown this disease is associated with an economic burden of more than $60 billion annually in direct and indirect costs in the United States.

Objective: To analyze the annual and longitudinal costs associated with the treatment of patients with schizophrenia from a payer perspective.

Methods: Two claim-based analyses were conducted using data from the Truven Health MarketScan database of a commercially insured population: (1) an annual snapshot of patients with newly diagnosed and chronic schizophrenia, and (2) a 24-month longitudinal analysis of patients with newly diagnosed schizophrenia. The snapshot analysis included individuals who had â&#x2030;Ľ2 claims with a diagnosis code for schizophrenia on separate dates during 2011 (with the date of the first claim designated as the index date), and who were enrolled for 12 months before the index date. For the longitudinal analysis, patients were included if they were continuously enrolled for 24 months after the date of schizophrenia diagnosis, which was designated as the index date. The claims were grouped by inpatient, outpatient, professional, and prescription drug categories, and were further segmented by claims for schizophrenia, other psychiatric, and nonschizophrenia/nonpsychiatric conditions.

Results: A total of 8985 patients with schizophrenia met the inclusion criteria for the snapshot analysis.

The mean cost per patient per month (PPPM) for a patient with schizophrenia was $1806 versus $419 per member per month for the demographically adjusted nonschizophrenic (ie, matched for age and sex) population. The PPPM cost of $1806 for patients with schizophrenia was 42% for inpatient expenditures, 33% for outpatient, and 25% for prescription drug costs. The annual inpatient admission rates were 636 per 1000 patients with schizophrenia and 48 per 1000 persons for the demographically adjusted population without schizophrenia. The annual emergency department visits for patients with schizophrenia were 2270 per 1000 patients and 158 per 1000 persons without schizophrenia for the demographically adjusted population. For the longitudinal analysis, 1902 patients with newly diagnosed schizophrenia were identified. The total claim costs for patients increased from $800 monthly in the 12 months before the index date to approximately $2000 in the month before the index date. The highest costs occurred in the month of diagnosis (designated as the index month; mean cost, $6601). The total all-cause claim cost after the index date decreased to $1635 monthly for months 2 to 6, $1456 monthly for months 7 to 12, $1324 monthly for months 13 to 18, and $1218 monthly for months 19 to 24.

Conclusion: Although the prevalence of schizophrenia is low in a commercially insured US population, this analysis shows that the average total claim cost per patient with schizophrenia is more than 4 times the average total claim cost for a demographically adjusted population without schizophrenia. Furthermore, for newly diagnosed patients with schizophrenia, the cost, which is largely driven by inpatient charges, is highest in the month of diagnosis.

S

chizophrenia is a serious public health problem that affects approximately 1% of the US population.1 Schizophrenia is a leading cause of disability, and is associated with an economic burden of more than $60

Ms Fitch is Principal and Healthcare Consultant, Milliman, Inc, New York, NY; Mr Iwasaki is Director, Japan Healthcare Practice and Data Analytics, Milliman, Inc, New York, NY; Ms Villa was Senior Health Economist, Genentech, Inc, South San Francisco, CA, at the time of writing.

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billion annually in direct and indirect costs in the United States.2 Schizophrenia is a severe form of mental illness broadly characterized by 3 domains of psychopathology, including negative symptoms (ie, social withdrawal, lack of motivation, and lack of emotional reactivity), positive symptoms (ie, hallucinations and delusions), and cognitive deficits (ie, working memory, attention, and executive function).3-6 In addition, serious medical conditions, such as type 2 diabetes, obesity, hypertension, and dyslipidemia, are more common in patients with

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schizophrenia than in the general population; in turn, these conditions may increase the risk for cardiovascular disease and lead to increased morbidity and mortality.7 Notably, the estimated prevalence of diabetes in patients with schizophrenia is 13% to 15%; dyslipidemia, 25%; obesity, 42%; and hypertension, 19% to 58%.8 Numerous studies have investigated the cost and resource utilization associated with schizophrenia in commercially insured, self-insured, Medicare, Medicaid, and Veterans Administration populations.2,9-14 Data have consistently shown that schizophrenia represents a substantial economic burden for patients and their families, healthcare providers, and for society in terms of costs associated with the healthcare, social, and justice systems; informal caregivers; and productivity loss as a result of unemployment or premature death.15 Schizophrenia is one of the most expensive disorders in adults,12,16 accounting for an estimated 2.5% of the total healthcare expenditures in the United States.17,18 Although schizophrenia is costly and difficult to treat, it has not received the level of attention from commercial payers that many other chronic diseases (eg, diabetes, asthma, and hypertension) receive. The 2013 addition of several schizophrenia Healthcare Effectiveness Data and Information Set (HEDIS) criteria will bring increased attention to the population of patients with schizophrenia by insurers and represents an opportunity for treatment improvement.19 In particular, the HEDIS criteria include adherence to antipsychotic medications for patients with schizophrenia, diabetes screening for patients with schizophrenia or bipolar disorder who are using antipsychotics, cardiovascular monitoring for patients with cardiovascular disease and schizophrenia, and diabetes monitoring for patients with diabetes and schizophrenia.19 In addition, the Affordable Care Act (ACA) will affect insurance coverage for the uninsured population of patients with schizophrenia in 2014, with Medicaid expansion and insurance subsidies available for qualified individuals purchasing insurance on state exchanges. The 2011 federally mandated extension of commercial coverage to adult children until age 26 years has increased the prevalence of patients with schizophrenia in commercially insured populations, because most patients with schizophrenia are diagnosed in their early 20s.4,20 A recent study estimated that there would be an increase of approximately 2.3 million new users of mental health services in Medicaid and approximately 2 million covered by commercial insurance by the time healthcare reform according to the ACA is fully implemented in 2019.20 With the expected rise in the number of insured patients with schizophrenia and an increased focus on the management of schizophrenia as a result of the new

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Key Points Schizophrenia is a serious medical condition and a leading cause of disability. ➤ Although the prevalence of schizophrenia is low in commercially insured populations, the total annual cost burden of the disease is more than $60 billion in the United States. ➤ This new study involved 2 claims-based analyses of the annual and longitudinal costs associated with the treatment of schizophrenia in a commercially insured population. ➤ Among patients with newly diagnosed schizophrenia, the cost was highest (mean cost, $6601) in the month of diagnosis, and was largely driven by inpatient charges. ➤ The annual inpatient admission rate was 636 per 1000 patients with schizophrenia versus 48 per 1000 persons in a demographically adjusted population without schizophrenia, a 13-fold difference. ➤ The mean monthly cost for a patient with schizophrenia was $1806, which is more than 4 times the mean monthly cost of $419 for a demographically matched member without schizophrenia. ➤ As this analysis shows, the cost of treating schizophrenia is substantial, yet this chronic disease does not receive the same level of payer attention afforded to other chronic diseases. ➤ The 2013 addition of HEDIS criteria for schizophrenia will likely draw more attention from insurers to this patient population and represents an opportunity for treatment improvement. ➤

HEDIS criteria, the intent of the current study was to provide an up-to-date descriptive analysis of the schizophrenia population from the payer perspective, including (1) relevant demographic characteristics, (2) a snapshot analysis of resource utilization and healthcare costs, and (3) a longitudinal analysis of resource utilization and healthcare costs over a period of 24 months by patients with newly diagnosed schizophrenia.

Methods Data Source The study population was selected from the Truven Health MarketScan commercial claim data files between 2007 and 2011. These files contain all paid claims generated by more than 40 million commercially insured individuals annually, as well as member identification codes that allow members to be followed longitudinally over

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Figure 1 Prevalence Rate of Patients with Schizophrenia, 2011 0.16 Male Female

Prevalence of schizophrenia, %

0.14 0.12 0.10 0.08 0.06 0.04 0.02 0.00

13-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64

Patients’ age range, yrs

Source: Truven Health MarketScan database; 2011.

time. This administrative claim data set contains standard codes for diagnosis, procedure, diagnosis-related group (DRG), and National Drug Code (NDC); site of service information and amounts paid by commercial insurers; and cost-sharing by members. We performed 2 analyses: (1) an annual snapshot analysis of patients with newly diagnosed and chronic schizophrenia, using 2011 as the index year, and (2) a longitudinal analysis of patients with newly diagnosed schizophrenia using 2008 and 2009 as index years, and 2008 to 2011 for the 24month postdiagnosis period.

Study Population The study population for each analysis consisted of individuals aged 13 to 64 years who met the HEDIS claimsbased identification criteria of 2 or more inpatient or outpatient claims with International Classification of Diseases, Ninth Revision (ICD-9) code 295.xx for schizophrenia on separate dates during the index year. Patients were included in the study if they had a newly diagnosed schizophrenia and had no claim coded with schizophrenia in the 12 months before the index date (“newly diagnosed” was defined as having no claim with an ICD-9 diagnosis code of schizophrenia in any position in the 12 months before the index date). In both analyses, all patients were required to be continuously enrolled for the 12-month look-back period. For the snapshot analysis, patients were not required to be enrolled continuously during the entire 2011 index year, and each patient’s cost contribution was weighted by

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member months of enrollment during 2011. For the longitudinal analysis, the patients were required to be continuously enrolled for 24 months after the index date (ie, date of schizophrenia diagnosis).

Methodology All claims for patients meeting the schizophrenia identification and eligibility criteria were grouped into major utilization categories (eg, inpatient or outpatient) using a combination of revenue codes, Healthcare Common Procedure Coding System (HCPCS) codes, DRGs, Current Procedural Terminology (CPT)-4 codes, ICD-9 procedure codes, and NDC codes that included inpatient, outpatient, professional, and prescription drug.

The claims were further segmented by claims for schizophrenia and other psychiatric and nonschizophrenia/ nonpsychiatric conditions.

Schizophrenia-related inpatient claims were identified via a psychiatric DRG (880-887), as well as an ICD-9 295.xx diagnosis code in any position of the in­ patient claim. Schizophrenia-related emergency department visits and professional fee claims were identified if an ICD-9 diagnosis code in the 295.xx range was coded in any position of the claim. Psychiatric inpatient claims were coded with a psychiatric DRG (880-887) and were not coded with ICD-9 295.xx code in any position of the inpatient claim. Psychiatric-related emergency department and professional claims were coded with an ICD-9 code of 291 to 319.xx (excluding 295.xx) in any position of the claim.

All other claims were considered to be related to nonschizophrenia/nonpsychiatric conditions. Outpatient facility claims other than emergency department were not designated as schizophrenia or other psychiatric. The use of electroconvulsive therapy was identified by claims coded with ICD-9 procedure codes 94.23, 94.24, 94.26, or 94.27, or with the CPT-4 code 90870. Drug use by class—including antipsychotics, antidepressants, anticonvulsants, or antianxiety—was identified using NDC code lists from the Medi-Span 2013 drug data.

To compare the costs and medical utilization of the population of patients with schizophrenia and the population of individuals without schizophrenia in the Truven Health MarketScan claims data, we demographically adjusted the nonschizophrenic population to contribute the same weighting by 5-year age and sex bands.

Results Snapshot Analysis Prevalence/incidence. A total of 8985 patients in the 2011 MarketScan database met the criteria for schizophrenia (newly diagnosed, N = 2827; chronic, N = 6158), and the average member enrollment in a plan was 11.5

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Figure 2 Incidence Rates of Patients with Schizophrenia, 2011 0.07 Male Female

0.06

Incidence of schizophrenia, %

months. Of the 8985 patients with schizophrenia, 3550 (39.5%) were employees, 2599 (28.9%) were spouses, and 2836 (31.6%) were categorized as children/other.

The prevalence of schizophrenia was 0.54 per 1000 persons in the 13- to 64-year-old age range, with the highest prevalence observed in men in the 20- to 24-year-old age cohort (1.45 per 1000 persons) and the prevalence in women ranging from 0.32 per 1000 persons to 0.69 per 1000 persons for the 30- to 34-year-old and 55- to 59-year-old age cohorts, respectively. The incidence of patients with schizophrenia (and with no schizophrenia claims in the 12 months before the index date) was 0.17 per 1000 persons among the 13- to 64-year-old cohort, with the highest incidence in men (0.65 per 1000 persons) and women (0.27 per 1000 persons) in the 20- to 24-year-old age cohorts. Figure 1 and Figure 2 outline the prevalence and incidence of schizophrenia, by age and by sex.

Costs. For the patients with schizophrenia, the mean cost per patient per month (PPPM), including paid amount by the insurer and patient cost-sharing, was $1806, more than 4 times higher than that of $419 for the population without schizophrenia in the MarketScan database with the same demographic (ie, age and sex) weighting (Table).

The cost for patients with schizophrenia included $762 (42%) PPPM for inpatient costs (facility and professional), $592 (33%) PPPM for outpatient costs (facility and professional), and $452 (25%) PPPM for prescription drug costs. The most common prescription drug

0.05 0.04 0.03 0.02 0.01 0.00

13-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64

Patients’ age range, yrs

Source: Truven Health MarketScan database; 2011.

claims for patients with schizophrenia were antipsychotics (84% of patients with schizophrenia), followed by antidepressants (56% of patients with schizophrenia), anticonvulsants (43% of patients with schizophrenia), and antianxiety drugs (32% of patients with schizophrenia), with allowed PPPM costs of $302.20, $24.32, $16.65, and $2.60, respectively.

Hospitalization. The annual inpatient admission rate

napshot Analysis: Mean PPPM and PMPM Costs and Resource Utilization for Patients with Schizophrenia Table S Compared with Demographically Adjusted Total Commercially Insured Population Patients with schizophrenia

Matched population with similar demographics, without schizophrenia

Total PPPM/PMPM cost, $

1806

419

Inpatient PPPM/PMPM cost, $

762

97

Outpatient PPPM/PMPM cost, $

592

239

Prescription drug PPPM/PMPM cost, $

452

83

Annual inpatient admissions per 1000 patients, N

636

48

Schizophrenia-related inpatient cases, N

322

—

Psychiatric/nonschizophrenia-related inpatient cases, N

155

—

Nonschizophrenia/nonpsychiatric-related inpatient cases, N

158

—

Annual emergency department visits per 1000 patients, N

2270

158

Schizophrenia-related emergency department visits, N

242

—

Psychiatric/nonschizophrenia-related emergency department visits, N

513

—

Nonschizophrenia/nonpsychiatric-related emergency department visits, N

1516

—

Variable

PMPM indicates per member per month; PPPM, per patient per month.

Source: Truven Health MarketScan database; 2011.

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L ongitudinal Analysis: Mean PPPM Monthly Cost Figure 3 Allowed after Index Date for Patients with Newly Diagnosed Schizophrenia Claims category Inpatient schizophrenia Inpatient psychiatric Inpatient nonpsychiatric, nonschizophrenia Emergency department schizophrenia Emergency department psychiatric Emergency department nonpsychiatric, nonschizophrenia Professional schizophrenia Professional psychiatric Professional nonpsychiatric, nonschizophrenia Facility

Allowed cost PPPM, $ US

4000 3000 800 700 600 500 400 300 200 100 0

Month 1

Months 2-6

Months 7-12 Months 13-18 Months 19-24

PPPM indicates per patient per month.

Source: Truven Health MarketScan database; 2011.

during the study period was 13 times higher in the population with schizophrenia than in the general population, with an annual rate of 636 admissions per 1000 patients with schizophrenia compared with an annual rate of 48 admissions per 1000 persons in the general demographically adjusted commercial population (Table).

Of the inpatient admissions (N = 636) in patients with schizophrenia, 51% (N = 322) were schizophrenia-related, 24% (N = 155) were psychiatric-related (nonschizophrenia), and 25% (N = 158) were neither schizophrenia-related nor psychiatric-related.

Similarly, the annual emergency department utilization rate for patients with schizophrenia was 14 times higher than in the general populationâ&#x20AC;&#x201D;2270 visits per 1000 patients with schizophrenia compared with 158 visits per 1000 persons in the demographically adjusted commercial population (Table). Of the emergency department visits (N = 2270) by patients with schizophrenia, 11% (N = 242) were schizophrenia-related, 23% (N = 513) were psychiatric-related, and 67% (N = 1516) were neither schizophrenia-related nor psychiatric-related.

Longitudinal Analysis The longitudinal analysis required patients with schizophrenia to be continuously enrolled for 3 years, which allowed for a 12-month look back from the index

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date and a 24-month follow-up from the index date. Two index years were used to increase the sample size: index year 2008 required eligibility in 2007 to 2010 and index year 2009 required eligibility in 2008 to 2011. A total of 1902 patients were identified with newly diagnosed schizophrenia.

The cost for patients with schizophrenia gradually increased from approximately $800 in the 12 months before the index date to approximately $2000 in the month before the index date. The highest costs were incurred in the index month (ie, month of diagnosis), with an average cost of $6601 for the index month. Inpatient costs accounted for $4597 (70%) of the costs in the index month; 413 (22%) of the patients with schizophrenia were admitted to the hospital at some point during the index month. In addition to the patients who were admitted to the hospital in the index month, 307 (16%) patients had visited the emergency department at some point during the index month.

The cost in the months after the index date decreased to an average of $1635 monthly for months 2 to 6, $1456 monthly for months 7 to 12, $1324 monthly for months 13 to 18, and $1218 monthly for months 19 to 24. The percentage of patients with schizophrenia who had an antipsychotic claim was 58% in the index month, 71% during months 2 to 6, 66% during months 7 to 12, 63% during months 13 to 18, and 61% during months 19 to 24. The use of antidepressants and anticonvulsants were also high: 34% and 27% of patients with schizophrenia, respectively, had a prescription claim in the index month; 49% and 39% during months 2 to 6 after the index month; 48% and 37% during months 7 to 12; 47% and 36% during months 13 to 18; and 44% and 36% during months 19 to 24. Figure 3, Figure 4, and Figure 5 provide details of the cost and the use of key services in the months after the index date.

Discussion Our findings corroborate the findings of previous studies in terms of schizophrenia cost and resource utilization for a commercially insured population. Data regarding the prevalence of schizophrenia in commercially insured populations are limited. One study based on 1999 to 2002 claims data from 17 self-insured US employers representing 3 million commercially insured individuals aged <65 years reported a prevalence rate of 1.3 per 1000 persons, but it used criteria that only required 1 claim with a schizophrenia code during a 3-year period.10 Our analysis identified a lower prevalence rate of 0.54 per 1000 persons, which would be expected, because our criteria required 2 or more claims with a schizophrenia code in a 12-month period. The prevalence of schizophrenia in Medicaid populations has been more fre-

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Monthly utilization per 1000 patients with schizophrenia, N

Longitudinal Analysis: Monthly Inpatient Admissions Figure 4 and Emergency Department Visits after Index Date for Patients with Newly Diagnosed Schizophrenia 450 400 350 300 250 200 150 100 50 0

Claims category Schizophrenia Psychiatric Nonpsychiatric, nonschizophrenia

Inpatient Emergency Inpatient Emergency Inpatient Emergency Inpatient Emergency Inpatient Emergency department department department department department

Months 2-6

Month 1

Months 7-12 Months 13-18 Months 19-24

Monthly inpatient admissions and emergency department visits after index date

Source: Truven Health MarketScan database; 2011.

Longitudinal Analysis of Patients with Newly Figure 5 Diagnosed Schizophrenia and â&#x2030;Ľ1 Claim for Antipsychotics during Months after Index Date

Patients with â&#x2030;Ľ1 antipsychotic prescription, %

quently reported, with the rate of 17 per 1000 persons in the Medicaid population aged <65 years.10 Nicholl and colleagues used medical and pharmacy claims data from the PharMetrics Integrated Database (1998-2007) to explore the effect of duration of illness on the cost of inpatient care and the overall economic burden of treatment in patients with recently diagnosed (N = 970) and with chronic (N = 2996) schizophrenia.9 A greater proportion of patients with recently diagnosed schizophrenia compared with patients with chronic schizophrenia were hospitalized (22.3% vs 12.4%, respectively; P <.001), and the former group spent a greater number of days in the hospital than the latter group (mean, 5.1 vs 3 days, respectively; P = .065). The average annual healthcare costs in recently diagnosed patients and in patients with chronic disease were $20,654 and $15,489, respectively, and inpatient costs constituted a higher proportion of total costs in the former group than in the latter group (62.9% vs 38.5%, respectively),9 which was similar to our findings.

Wilson and colleagues conducted a retrospective claims analysis using a large, privately insured claimsbased database in California to determine the direct costs of treating schizophrenia in a privately insured setting (June 2001-May 2004) and compared the costs in newly diagnosed patients versus the costs of previously diagnosed patients.11 The overall direct annual treatment costs and schizophrenia-specific costs were $12,885 and $6220, respectively; inpatient services and medications comprised most of the schizophrenia-specific costs ($2762 and $2479, respectively). Patients with newly diagnosed schizophrenia had significantly higher inpatient costs than previously diagnosed patients ($4222 vs $2240, respectively; P <.05), and had significantly lower schizophrenia-specific medication costs ($1593 vs $2438, respectively; P <.05).11 Crown and colleagues used the MarketScan (now Truven Health) database, the same database that was used in our study, but with older data (1991-1993) to compare the expenditures of privately insured patients with schizophrenia who were hospitalized (N = 185) with data for patients who were not hospitalized (N = 480) in the 1-year period after the initial diagnosis.21 The unadjusted mean total healthcare costs were $20,161 in the hospitalized patients and $2966 in the nonhospitalized group; after adjusting for differences in the characteristics of the 2 groups, the incremental cost of hospitalization was $15,805.21 Our study shows that the reduction in costs after the index date is largely driven by a reduction in hospitalization and emergency department admission in subsequent months. This is expected, because the diagnosis itself can be triggered by a psychotic episode, resulting in an inpa-

Medication claims Antidepressants Antianxiety drugs Hypnotic drugs Anti-ADHD Anticonvulsants Antipsychotics Antimanic drugs

80 60

40 20

0

Month 1

Months 2-6

Months 7-12 Months 13-18 Months 19-24

Period after index date

ADHD indicates attention-deficit/hyperactivity disorder.

Source: Truven Health MarketScan database; 2011.

tient stay. In the months after the index date, patients may receive various interventions, including medications, psychosocial therapy, family therapy, and support groups, which may contribute to the stabilization of their disease.

As a result of the very high costs associated with inpatient services, the interventions that are most effective at

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lowering the probability of hospital admission or readmission for patients with schizophrenia have the potential to realize the greatest cost-savings. For example, a consistent cost driver for patients with schizophrenia is suboptimal adherence to antipsychotic therapy through its association with an increased risk for relapse and rehospitalization, as well as increased hospitalization costs.14,16,22 Sun and colleagues used data from 7 published articles on the economic impact of antipsychotic nonadherence among Medicaid patients with schizophrenia to estimate the costs of rehospitalization.16 The estimated total national rehospitalization cost associated with antipsychotic nonadherence in patients with schizophrenia in 2005 was $1.479 billion.16

The present study highlights the high cost of schizophrenia to commercial payers, with a total cost PPPM that is more than 4 times higher than for an average commercially insured person with similar demographics but without schizophrenia. dosReis and colleagues used retrospective Maryland Medicaid administrative data of 1727 patients with schizophrenia to study the relationship between antipsychotic treatment patterns and acute hospitalizations.14 The average duration of antipsychotic use was 6 months in any 1-year period and 4.5 years across the 7-year study period. The likelihood of hospitalization in patients with moderate adherence (50%-75% of eligible days) and light adherence (<50% of eligible days) to antipsychotic medication was 52% and 72% greater, respectively, than in patients with greater adherence (75%-100% of eligible days) to antipsychotic medication; furthermore, the average length of hospital stay was approximately 20% longer in light than in continuous users of antipsychotic medications.14 Marcus and Olfson analyzed the correlation between gaps in antipsychotic medication and hospital admission in patients with schizophrenia based on Medicaid data (2001-2003).22 The total number of annual acute care inpatient admissions of Medicaid patients with schizophrenia was approximately 87,000 (approximately 930,000 hospital days), at a total annual cost of $806 million. The investigators determined that improving adherence to antipsychotic medication could reduce the number of acute care admissions by approximately 12.3%, and the number of inpatient treatment days by approximately 13.1%, thereby saving an estimated $106 million in inpatient costs.22 Our analysis provides data regarding the prevalence of

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schizophrenia in a commercially insured population using recent data, as well as new HEDIS claims-based identification criteria, which has not been presented previously. In addition, more recent estimates of annual costs incurred by commercial payers across the populations of patients with newly diagnosed and chronic schizophrenia are provided, as well as a longitudinal view of resource utilization and costs during the first 2 years after diagnosis, showing that patients with schizophrenia represent a high-cost population for commercial payers.

Limitations Our analysis was based on Truven Health MarketScan data, which we are unable to audit; however, we assumed that the data were accurate and comprehensive. Claims data limitations include the potential for provider coding inaccuracies, as well as the inability to identify clinical or psychosocial factors that may impact the mix of individual patient severity levels. We recognize that individuals conducting a similar analysis using other data sets or alternative coding logic would potentially produce results that are different from ours.

Our definition of â&#x20AC;&#x153;newly diagnosedâ&#x20AC;? (ie, no claim with an ICD-9 diagnosis code of schizophrenia in any position in the 12 months before the index date) could have included some patients with schizophrenia who had infrequent contact with a healthcare provider in the 12 months before our assigned index date, although we expect that this would be a small portion of the population with schizophrenia.

Because we limited the longitudinal analysis to patients with 3 years of continuous eligibility and enrollment, we excluded individuals for whom the primary insurer changes insurers (MarketScan has consistent member identification numbers for individuals enrolled in the same plan annually), and we excluded patients with schizophrenia who lost insurance, such as those who were covered by their parents and reached the age of 26 years. These patients might have purchased a separate insurance policy or might have qualified for Medicaid, which we could not distinguish and, as such, the resource utilization patterns and costs for these patients are not reflected in this study.

Conclusions Schizophrenia is a debilitating disease associated with substantial medical, social, and economic burdens. The 2013 addition of several schizophrenia HEDIS criteria will most likely bring increased attention from insurers to the population of patients with schizophrenia.19 The present study highlights the high cost of schizophrenia to commercial payers, with a total cost PPPM that is more than 4 times higher than for an average commercially insured person with similar demographics but without schizophre-

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nia. Although the costs peak in the month of diagnosis, the average monthly costs remain disproportionately high throughout the 24-month follow-up period. Further claims data analyses that investigate patterns of care, drug therapy adherence patterns, and barriers to medication adherence among patients with schizophrenia are necessary to improve the quality of care for patients with schizophrenia and to more efficiently manage the cost of the care. n Source of Funding This research was funded by Genentech, Inc. Author Disclosure Statement Ms Fitch provides consulting services to Genentech; Mr Iwasaki is an employee of Milliman, which provides consulting services to Genentech; and Ms Villa was an employee of and had stocks in Genentech at the time of writing.

References

1. Regier DA, Narrow WE, Rae DS, et al. The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services. Arch Gen Psychiatry. 1993;50:85-94.

2. Wu EQ, Birnbaum HG, Shi L, et al. The economic burden of schizophrenia in the United States in 2002. J Clin Psychiatry. 2005;66:1122-1129.

3. Chumakov I, Blumenfeld M, Guerassimenko O, et al. Genetic and physiological data implicating the new human gene G72 and the gene for D-amino acid oxidase in schizophrenia. Proc Natl Acad Sci U S A. 2002;99:13675-13680. Erratum in: Proc Natl Acad Sci U S A. 2002;99:17221.

4. World Health Organization. Schizophrenia. www.who.int/mental_health/manage ment/schizophrenia/en/. Accessed September 26, 2013.

5. Switaj P, Anczewska M, Chrostek A, et al. Disability and schizophrenia: a systematic review of experienced psychosocial difficulties. BMC Psychiatry. 2012;12:193.

6. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 4. Clinical features and conceptualization. Schizophr Res. 2009;110:1-23.

7. Jacob R, Chowdhury AN. Metabolic comorbidity in schizophrenia. Indian J Med Sci. 2008;62:23-31.

8. Newcomer JW. Medical risk in patients with bipolar disorder and schizophrenia.

J Clin Psychiatry. 2006;67(suppl 9):25-30.

9. Nicholl D, Akhras KS, Diels J, Schadrack J. Burden of schizophrenia in recently diagnosed patients: healthcare utilisation and cost perspective. Curr Med Res Opin.

2010;26:943-955.

10. Wu EQ, Shi L, Birnbaum H, et al. Annual prevalence of diagnosed schizophrenia in the USA: a claims data analysis approach. Psychol Med. 2006;36:1535-1540.

11. Wilson LS, Gitlin M, Lightwood J. Schizophrenia costs for newly diagnosed versus previously diagnosed patients. Am J Pharm Benefits. 2011;3:107-115.

12. Bartels SJ, Clark RE, Peacock WJ, et al. Medicare and Medicaid costs for schizophrenia patients by age cohort compared with costs for depression, dementia, and medically ill patients. Am J Geriatr Psychiatry. 2003;11:648-657.

13. McDonald M, Hertz RP, Lustik MB, Unger AN. Healthcare spending among community-dwelling adults with schizophrenia. Am J Manag Care. 2005;11(8 suppl): S242-S247.

14. dosReis S, Johnson E, Steinwachs D, et al. Antipsychotic treatment patterns and hospitalizations among adults with schizophrenia. Schizophr Res. 2008;101:304-311.

15. Charrier N, Chevreul K, Durand-Zaleski I. The cost of schizophrenia: a literature review. Encephale. 2013;39(suppl 1):S49-S56.

16. Sun SX, Liu GG, Christensen DB, Fu AZ. Review and analysis of hospitalization costs associated with antipsychotic nonadherence in the treatment of schizophrenia in the United States. Curr Med Res Opin. 2007;23:2305-2312.

17. Albers LJ, Musenga A, Raggi MA. Iloperidone: a new benzisoxazole atypical antipsychotic drug. Is it novel enough to impact the crowded atypical antipsychotic market? Expert Opin Investig Drugs. 2008;17:61-75.

18. Bernardo M, Ramón Azanza J, Rubio-Terrés C, Rejas J. Cost-effectiveness analysis of schizophrenia relapse prevention: an economic evaluation of the ZEUS (Ziprasidone-Extended-Use-In-Schizophrenia) study in Spain. Clin Drug Investig. 2006; 26:447-457.

19. National Committee for Quality Assurance. HEDIS 2013. www.ncqa.org/Portals/ 0/HEDISQM/HEDIS2013/List_of_HEDIS_2013_Measures_7.2.12.pdf. Accessed Sep­ tember 26, 2013.

20. Garfield RL, Zuvekas SH, Lave JR, Donohue JM. The impact of national health care reform on adults with severe mental disorders. Am J Psychiatry. 2011;168:486-494.

21. Crown WH, Neslusan C, Russo PA, et al. Hospitalization and total medical costs for privately insured persons with schizophrenia. Adm Policy Ment Health. 2001;28:335-351.

22. Marcus SC, Olfson M. Outpatient antipsychotic treatment and inpatient costs of schizophrenia. Schizophr Bull. 2008;34:173-180.

Stakeholder Perspective

Schizophrenia: “The Forgotten Illness”?

By Atheer A. Kaddis, PharmD Senior Vice President, Sales and Business Development, Diplomat Specialty Pharmacy, Flint, MI

PAYERS: Schizophrenia, the forgotten illness? That may be too dramatic a description of the disease, but it nevertheless brings to light the lack of focus on schizophrenia as a disease that is rapidly growing in treatment costs, and the impact that it will have on commercial payers in the United States over the next decade.

Schizophrenia is an important disease state that will become even more important to commercial insurers as a result of the healthcare coverage expansion beginning in 2014. The cost burden of the disease state is underesti-

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mated: more attention should be focused on this disease, and how to cost-effectively manage it in the future.

The article by Fitch and colleagues provides an excellent overview of the costs resulting from a diagnosis of schizophrenia, and it details how costs change over time after the index diagnosis. Of particular interest is that the mean per-patient per-month (PPPM) cost for a patient with schizophrenia was more than 4 times greater than the PPPM cost for a demographically adjusted population without schizophrenia. In addition, Continued

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Stakeholder Perspective Continued the highest cost was associated with the month of diagnosis (designated as the index month), which was a mean cost of $6601.

PROVIDERS/PATIENTS: What can we do about the costs of treating patients with schizophrenia? We do not have to look far to find meaningful ways to address schizophrenia costs, while also improving patient care.

The answer can be found with appropriate medication therapy, focusing on medications with improved effectiveness and a lower incidence of side effects, and on improving medication adherence. In the current analysis, medications accounted for 25% of the overall costs of managing patients with schizophrenia compared with 42% for inpatient expenditures, and 33% for outpatient expenditures, respectively. Although medication costs would increase by choosing newer therapies and improving adherence, studies have shown that improving medication adherence can result in lower medical expenditures overall.1,2 The latest therapies to be approved for use in the United States include oral medications with significantly less impact on exacerbating negative symptoms (eg, social withdrawal, lack of motivation, etc). Newer therapies have also been introduced in depot formulations, which provide longer periods of controlling schizophrenia with only once-monthly dosing.3 Overall, this can result in improved medication adherence, which should

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reduce emergency department visits and hospitalizations resulting from symptoms of the disease.

PHARMACISTS: Although the newer medications are more expensive overall for payers, the impact on medical expenditure reductions should not be overlooked. Pharmacists can play a significant role in improving medication adherence, and this has been proven within the specialty pharmacy industry where medication possession ratios regularly exceed 80% as a result of adherence calls, compliance packaging, financial assistance, side-effect management, etc.4 POLICYMAKERS: If you believe that schizophrenia is the forgotten illness, you need not wait any longer, because the changes occurring in healthcare today, as they relate to schizophrenia, will bring this illness to the forefront for all payers. Understanding the costs and utilization associated with schizophrenia is the first step, but we need to focus next on providing cost-effective care for patients in need. n 1. dosReis S, Johnson E, Steinwachs D, et al. Antipsychotic treatment patterns and hospitalizations among adults with schizophrenia. Schizophr Res. 2008;101:304-311.

2. Marcus SC, Olfson M. Outpatient antipsychotic treatment and inpatient costs of schizophrenia. Schizophr Bull. 2008;34:173-180.

3. Abilify Maintena (aripiprazole) extended-release injectable suspension, for intramuscular use [prescribing information]. Tokyo, Japan: Otsuka America Pharmaceutical, Inc; February 2013.

4. Tschida S, Aslam S, Khan TT. Managing specialty medication services through a specialty pharmacy program: the case of oral renal transplant immunosuppressant medications. J Manag Care Pharm. 2013;19:26-41.

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JOIN AHDBâ&#x20AC;&#x2C6;Peer Review American Health & Drug Benefits (AHDB) is looking for medical and pharmacy directors, P & T Committee members, and other healthcare experts who are interested in joining our peer reviewers and assist in maintaining the high quality of articles published in the journal.

You will be asked to review at least 1 or 2 articles per year in your area of expertise. Reviewersâ&#x20AC;&#x2122; names will be published online at the end of the year.

Please indicate at least 1 area of expertise in a health-related field for which they feel qualified to assess the content and quality of manuscripts submitted to AHDB.

Articles fall into 3 main areas related to healthcare: Regulatory, Business, and Clinical. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to) those listed below.

Please mark the categories that apply to your expertise: Administration/management Benefit design Disease management/state (eg, asthma, diabetes, heart disease, infectious diseases, pain management, etc) Drug therapy (including biologics, generics) Drug utilization Employers/health plans Finance/health economics Health information technology Health policy/reform Patient education/initiatives/quality-of-life issues Payer perspectives Pharmacoeconomics analyses Pharmacy management: pharmacology, specialty pharmacy, pharmacy benefits Reimbursement: Medicare/Medicaid, health insurance, prior authorization Research: methods, study design, data collection/analysis

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

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage A t 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1568 per 3.5-mg vial as of January 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVErsE rEACtIons Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

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

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group.

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively.

The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

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

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

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

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

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

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

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

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

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

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

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-12-0306a

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The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Call for Papers Hematology/Oncology Theme Issue American Health & Drug Benefits is publishing a Hematology/Oncology Theme Issue in May. Readers are invited to submit manuscripts for this issue, including original research, cost analyses, evidence-based comprehensive reviews, case studies, and industry surveys/trends.

All articles will undergo the journal’s rigorous peer-review process.

ORIGINAL RESEARCH

REVIEW ARTICLES

• Clinical research

• Benefit design in hematology/oncology

• Best practices in oncology

• Disease state overview

• Case reports/case series

• Drug therapy/new drug classes

• Claims-based analyses

• End-of-life issues

• Cost-effectiveness analyses/efficacy

• Evidence-based comprehensive reviews

comparisons

• Data-driven innovation in oncology • Drug therapy • Health economics research outcomes • Pathways outcomes • Pharmacoeconomics • Survey analyses

• Innovation in practice management • Managing toxicities • Molecular diagnostics • Pathways-based patient care/guidelines • Quality-of-life issues • Survivorship programs • Targeted therapies • Value-based patient care

Submission Deadline: March 17, 2014 Follow the Information for Authors at www.AHDBonline.com.

Submit articles to editorial@engagehc.com or online at www.AHDBonline.com.

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CLINICAL

Fixed-Dose Combination Gel of Adapalene and Benzoyl Peroxide plus Doxycycline 100 mg versus Oral Isotretinoin for the Treatment of Severe Acne: Efficacy and Cost Analysis Pete Penna, PharmD; Matthew H. Meckfessel, PhD; Norman Preston, PhD Background: Acne vulgaris is a chronic skin disease with a high prevalence. Left untreated or inadequately treated, acne vulgaris can lead to psychological and physical scarring, as well as to unnecessary medical expenses. Oral isotretinoin is an effective treatment for severe resistant nodular and conglobate acne vulgaris.

A regimen consisting of a fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (ABPO) with oral doxycycline 100 mg (A-BPO/D) has been demonstrated to be efficacious and well tolerated in patients with severe acne and may be an alternative to oral isotretinoin for some patients with severe acne.

Objective: The objective of this analysis was to compare the relative efficacy and associated costs of A-BPO/D versus oral isotretinoin.

Methods: In this analysis, comparisons of relative efficacy were made using previously published studies involving similar patient populations with severe acne that warrant the use of oral isotretinoin. The pricing for oral doxycycline and oral isotretinoin was estimated based on the maximum allowable cost from 9 states, and the pricing for A-BPO was calculated as the range between the average wholesale price and the wholesale acquisition cost. For this analysis, 2 treatment models were generated to compare costs: (1) a basic treatment model that examined the costs of an initial regimen of either A-BPO/D or oral isotretinoin without considering probable outcomes, and (2) a long-term model that factored in likely treatment outcomes and subsequent treatments into associated costs. The basic treatment model assumed that patients would be prescribed a single regimen of A-BPO/D for 12 weeks or oral isotretinoin for 20 weeks.

The long-term model considered the probability of each treatment successfully managing patientsâ&#x20AC;&#x2122; acne, as well as likely additional regimens of A-BPO monotherapy or an additional regimen of oral isotretinoin.

As a result of different treatment durations, the costs for each treatment were normalized to weekly cost of treatment.

Results: Based on evidence from the published literature, patients treated with A-BPO/D would be expected to have an initial 72% reduction in inflammatory lesions, and patients treated with oral isotretinoin would have an 80% to 90% reduction of these lesions. The median weekly cost for the basic treatment model was $44 for A-BPO/D and $62 for oral isotretinoin. The weekly median costs for the long-term model were $44 for patients initially receiving a regimen of A-BPO/D followed by a maintenance regimen of A-BPO monotherapy and $50 for patients receiving an initial regimen of A-BPO/D who required a subsequent regimen of oral isotretinoin. The weekly cost for oral isotretinoin in the long-term model was $62.

Conclusions: The comparison of these 2 treatments demonstrated that they are both effective in treating severe acne, and that A-BPO/D was less expensive weekly than oral isotretinoin. These models show that A-BPO/D is safer than and is a more cost-effective alternative to oral isotretinoin for treating patients with severe acne vulgaris.

A

cne vulgaris is a chronic skin disease predominantly affecting the face, trunk, and back.1 The prevalence of acne vulgaris is high in many

Dr Penna is Principal and Cofounder, Formulary Resources, LLC, Mercer Island, WA; Dr Meckfessel is a Medical Writer, Galderma Laboratories, LP, Fort Worth, TX; Dr Preston was Manager of Biostatistics and Data Management, Galderma Laboratories, LP, at the time of the manuscript preparation.

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2014;7(1):37-45 www.AHDBonline.com Disclosures are at end of text

countries: acne afflicts up to 87% of adolescents and up to 54% of adults.2,3 Skin diseases, including acne, are often dismissed as being trivial or not as important as diseases of other organ systems.4 However, acne can negatively affect the patientâ&#x20AC;&#x2122;s quality of life (QOL).4 Responses to the 36-Item Short Form Survey, a generic QOL questionnaire, demonstrate that patients with acne report social, psychological, and emotional problems at levels as great as patients with epilepsy, diabetes, back

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Key Points Acne vulgaris is a chronic, prevalent skin disease that can affect a patient’s quality of life and lead to unnecessary medical expenses. ➤ Oral isotretinoin is indicated for the treatment of severe resistant nodular and conglobate acne vulgaris and is the only therapy that targets all 4 causitive factors. ➤ However, oral isotretinoin is a teratogenic drug that is associated with significant side effects and carries a REMS program; and although it is indicated for severe recalcitrant acne, it is often prescribed for mild or moderate acne. ➤ A fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (A-BPO) is efficacious and well tolerated in patients with severe acne. ➤ This new analysis of previously published data shows that although oral isotretinoin and A-BPO plus oral doxycycline 100 mg (A-BPO/D) are both effective for treating severe acne, A-BPO/D is less expensive per patient per week. ➤ Because the 2 treatment regimens are different in nature, a weekly cost analysis was used for comparison, showing that the median weekly cost for A-BPO/D is $44 compared with $62 for oral isotretinoin. ➤ In addition to being safer than oral isotretinoin for the management of patients with severe acne vulgaris, A-BPO/D is a cost-effective alternative to oral isotretinoin, which is associated with potential serious side effects that may further increase the indirect costs of treatment. ➤

pain, disabling asthma, or arthritis.4 Patients with acne also have fewer feelings of pride, lower self-esteem, lower body image satisfaction, more depressive symptoms, and more feelings of uselessness than people without acne.5 Adolescents with severe acne have suicidal thoughts more frequently than those with less severe acne.6 If left untreated, acne can result in significant psychosocial morbidity.7 Treatment improves the QOL of patients with acne and can prevent scarring.8-10 The pathophysiology of acne is multifactorial, involving 4 causative factors, including inflammation, hyperkeratinization, Propionibacterium acnes proliferation, and excess sebum production.11 Several topical and oral treatment options target the various causative mechanisms. The Global Alliance to Improve Outcomes in Acne has published recommended guidelines for the treatment of acne.12 Topical treatment is recommended for milder forms of acne. Oral isotretinoin is indicated for the most

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severe forms of nodular and conglobate acne and is the only available therapy that targets all 4 causative factors.

Although indicated for severe recalcitrant acne, oral isotretinoin is frequently prescribed for the treatment of mild or moderate acne.13 However, oral isotretinoin is a pregnancy category X teratogen and is associated with significant side effects.14 The reported side effects associated with the use of oral isotretinoin include depression, attempted suicide, cheilitis, dermatitis, myalgia, dry eyes, nonspecific gastrointestinal symptoms, and arthralgia, among others.14 Patients who are prescribed oral isotretinoin must enroll in the Risk Evaluation and Mitigation Strategy (REMS) program iPLEDGE.15 Patients also require laboratory tests to monitor liver function and serum lipid levels.14 For patients with severe acne with less nodular involvement, an oral antibiotic with a topical retinoid and benzoyl peroxide is recommended.12 Doxycycline 100 mg once daily is efficacious against acne and is relatively well tolerated.16 Adapalene, a third-generation retinoid with an established safety profile, has anticomedogenic and anti-inflammatory properties that are effective against acne.17-21 Benzoyl peroxide is an antimicrobial agent with demonstrated efficacy in treating acne.22 Benzoyl peroxide is more advantageous than other topical antibiotics, because it does not induce bacterial resistance and because it is effective against resistant P acnes strains.23 A fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (A-BPO; Epiduo Gel) was approved by the US Food and Drug Administration in 2008. This is the only fixed-dose drug combination that is formulated with a topical retinoid and benzoyl peroxide. The safety and efficacy of A-BPO for the treatment of acne have been established in clinical trials.24,25 Two related clinical trials investigated the use of A-BPO with oral doxycycline 100 mg once daily (A-BPO/D) for 12 weeks,26 followed by a maintenance therapy of A-BPO in patients with severe acne for an additional 24 weeks.27 Severe acne vulgaris in these studies was defined as up to 3 nodules or cysts, 30 to 120 noninflammatory lesions, and at least 20 inflammatory lesions.26,27 In the study by Gold and colleagues, patients who were treated with A-BPO/D had significantly better improvement in acne symptoms and in the acne symptom portion of the Acne-QOL questionnaire than patients given vehicle gel and doxycycline 100 mg.9,26 Patients with at least a “good” improvement in the first study, whether they were in the A-BPO/D group or in the vehicle gel plus doxycycline group, were eligible for the second study and were randomized to a maintenance regimen of A-BPO or to vehicle gel. Symptoms of acne and the QOL of patients using A-BPO continued to improve, whereas in patients using vehicle gel, QOL and

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acne symptoms worsened during the 24-week period.9,27 The majority of adverse events were mild and included erythema, scaling, dryness, and stinging and burning.26,27 In addition to treating severe acne, A-BPO is also recommended for the treatment of mild and moderate acne, making it a versatile topical medication that can treat a spectrum of disease severity.12 A model was developed to compare the efficacy and related costs of A-BPO/D versus oral isotretinoin in treating severe acne vulgaris.

Methods Efficacy Efficacy estimates used for the present comparison were based on the percent in reduction of inflammatory lesions from previously reported data.26-30 These data were pulled from independent studies with different study populations. However, all patients in these studies had severe acne, for which a specialist would likely prescribe oral isotretinoin.

Efficacy data for oral isotretinoin were pulled from 3 clinical studies using different doses28-30 so that an accurate range of the drug’s efficacy could be calculated and used for this analysis rather than selecting an individual study for our comparison.

The treatment period for A-BPO/D is 12 weeks and for oral isotretinoin it is 20 weeks. Therefore, comparisons of efficacy were made between A-BPO/D and oral isotretinoin after 12 weeks and 20 weeks of treatment, respectively. However, because the treatment regimens are different, the percent reduction in lesions was also determined after 20 weeks for A-BPO/D by combining the 12 weeks of A-BPO/D treatment with the 8 subsequent weeks of A-BPO maintenance therapy. This additional efficacy measurement was determined to facilitate a relative comparison between A-BPO/D and oral isotretinoin after 20 weeks of treatment.

Pricing Pricing for oral doxycycline and oral isotretinoin was estimated from the maximum allowable cost from 9 states, including Texas, Illinois, New York, Pennsyl­ vania, New Jersey, Michigan, Georgia, Iowa, and Wyoming. The maximum allowable cost pricing data were downloaded from these states’ respective Medicaid agencies on June 7, 2012, and May 15, 2012, for oral doxy­ cycline (100 mg) and for oral isotretinoin (10-40 mg), respectively. Currently only generic forms of oral isotretinoin are available in the United States. Maximum allowable cost pricing was unavailable for A-BPO. Pricing was set to be the range between the average wholesale price (AWP) and the wholesale acquisition cost (WAC). Because the duration of treatment differs

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between the 2 regimens, pricing was calculated as cost per week of treatment.

Treatment Models Two treatment models were generated. The basic treatment model examined the cost of drugs in the treatment regimen of A-BPO/D or of oral isotretinoin and did not take into account the likely outcomes or costs of the follow-up treatments. A long-term model was developed that factored in likely treatment outcomes and subsequent treatments. This model also considered in the cost of drugs the probability that a certain treatment would be required.

Basic treatment model. A basic decision tree was constructed in which patients could only receive either a regimen of A-BPO/D for 12 weeks or a regimen of oral isotretinoin for 20 weeks. Two tubes of A-BPO were distributed to patients during the 12-week regimen; the second tube was given between weeks 8 and 12 to ensure that patients had sufficient study drug to complete the 12-week regimen (unpublished data). Therefore, it was assumed that 2 tubes of A-BPO would be distributed in a 12-week period. It was also assumed that 1 dose of doxy­ cycline or of oral isotretinoin would be used daily during the treatment period. The weekly cost of treatment for both regimens was then calculated and compared, using the pricing details previously described.

Long-term treatment model. This latter decision tree begins with an initial 12-week treatment with A-BPO/D or a 20-week treatment with oral isotretinoin. The longterm treatment model considered the probability of each treatment being successful in managing acne. This model did not assess likely reductions in acne lesions.

The percentages of patients with symptoms under control or those with relapsed disease were obtained from previously published data.26,27,31 The long-term treatment model assumed that patients whose symptoms were not controlled or whose disease relapsed, regardless of the initial treatment regimen, would receive a 20-week regimen of oral isotretinoin.

All patients who were enrolled in the clinical study that investigated A-BPO/D had an investigator’s global assessment (IGA) score of 4 (severe) on a 6-point scale from 0 (clear) to 5 (very severe).26 Patients were considered to have their symptoms controlled if they improved at least 1 score on the IGA at the end of the 12-week regimen, which indicated that the patient no longer had severe acne.

Patients who had a 1-score improvement after the 12-week regimen of A-BPO/D would be eligible for a follow-up regimen of 24 weeks of A-BPO maintenance monotherapy.

Patients whose symptoms regressed to an IGA score of 4 at the end of the maintenance regimen would have re-

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Table 1 E xpected Reduction in Inflammatory Lesions after Treatment with A-BPO/D or Oral Isotretinoin Treatment Reduction in Treatment period, wks inflammatory lesions, %a A-BPO/D

12 20b

72 81b

Oral isotretinoin

20

80-90

References 26-30.

A-BPO/D for 12 weeks followed by 8 weeks of A-BPO maintenance therapy.

A-BPO indicates adapalene and benzoyl peroxide gel, 0.1%/2.5%; A-BPO/D, adapalene and benzoyl peroxide gel, 0.1%/2.5% with oral doxycycline 100 mg.

a

b

Table 2 Pricing for Each Unit of Drug Mean cost, $ (SD)

Median cost, $

Cost range, $ (min-max)

A-BPO (45-g tube)

259.43 (40.76)

259.43

230.60-288.25

Oral doxycycline 100 mg (tablet or capsule)

0.66 (0.92)

0.11

0.05-3.17

Oral isotretinoin 10-40 mg (tablet or capsule)

10.30 (3.94)

8.84

6.22-24.04

Drug

A-BPO indicates adapalene and benzoyl peroxide gel, 0.1%/2.5%; SD, standard deviation.

asic Treatment Model with Probable Outcomes Figure 1 B and Costs for A-BPO/D and Oral Isotretinoin

Begin with patients with severe acne vulgaris

Patients with severe acne

Treatment options

A-BPO/D for 12 weeks

Oral isotretinoin (10-40 mg) for 20 weeks

Probable outcomes

72% reduction in inflammatory lesions

80%-90% reduction in inflammatory lesions

$47.86 ($3.57) $44.01

$72.10 ($10.42) $61.88

Weekly cost per patient Average (SD) Median

A-BPO/D indicates adapalene and benzoyl peroxide gel, 0.1%/2.5% with oral doxycycline 100 mg; SD, standard deviation.

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gressed back to having severe acne and would have been considered to have relapsed disease. These patients would be eligible for a 20-week regimen of oral isotretinoin.

For patients who were initially treated with oral isotretinoin and did not respond to treatment, it was assumed that they would use an additional regimen of oral isotretinoin.

Additional treatment was not considered for patients whose disease responded to oral isotretinoin at any point.

To calculate costs, it was assumed that 2 tubes of A-BPO would be required for the initial 12-week regimen and 4 tubes would be required for the 24-week follow-up regimen, and patients would take 1 dose of doxycycline or oral isotretinoin daily. Costs that did not account for the probability of treatment outcomes were calculated and compared using pricing described above.

The expected cost of each treatment, factoring in the probability of success of each treatment, was calculated based on the following formula: (Probability of success Ă&#x2014; cost of success) + (probability of failure Ă&#x2014; cost of failure) Ancillary costs for office visits, laboratory tests, and the iPLEDGE program were not considered.

Results Efficacy Based on the study by Gold and colleagues, patients using A-BPO/D would be expected to have an initial 72% reduction in inflammatory lesions after 12 weeks of treatment (Table 1).26 If those patients were using maintenance therapy of A-BPO, an additional 9% reduction would be expected, for an 81% reduction over 20 weeks (based on unpublished data). Data from clinical studies suggest that patients receiving oral isotretinoin would be expected to have an 80% to 90% reduction in inflammatory lesions after 20 weeks.26-30 It should be noted that the A-BPO/D study design did not include nodules or cysts in the reduction of inflammatory lesions, whereas reductions in nodules or cysts were included for oral isotretinoin.28-30 No head-to-head studies have been conducted comparing A-BPO/D with oral isotretinoin that would allow direct comparisons to be made between the 2 treatments.

Therefore, the comparison of efficacy in the current analysis was for descriptive purposes, because the data were not directly comparable.

Treatment Models Basic treatment model. Table 2 shows the pricing used for the 2 models. The goal of the basic treatment model was to assess the potential savings associated with using A-BPO/D instead of oral isotretinoin for patients with severe acne vulgaris (Figure 1). The cost of the 2 drugs favors A-BPO/D over oral isotretinoin.

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The cost of treatment of a 12-week regimen of A-BPO/D is between $465 and $842 per patient, with an average weekly cost of $47.86 (Table 3). The cost of a 20-week regimen of oral isotretinoin ranges from $868 to $3365.60 per patient, with an average weekly cost of $72.10. Although oral isotretinoin is more efficacious overall, A-BPO/D is less expensive in absolute drug cost and in weekly drug cost, while still effectively treating severe acne vulgaris (Figure 2).

Long-term treatment model. The basic treatment model only considered initial treatments and the expected efficacy associated with those treatments; however, most patients with severe acne vulgaris will require additional treatments.32 For the current analysis, the treatment response rates and relapse rates were compared for each regimen.

The estimated treatment response rates and relapse rates are shown in Table 4. At the end of the A-BPO/D regimen, 97% of patients would have improved at least 1 grade and would no longer have acne that is considered to be severe.26 Their symptoms would be considered under control, and they would be eligible for a 24-week regimen of A-BPO maintenance monotherapy. The disease of the other 3% of patients would not have improved or would have worsened and the patients would be considered to be eligible for oral isotretinoin therapy by many dermatologists.

Of the 97% of patients who received A-BPO as a maintenance therapy, 78% would be expected to continue to not have severe acne and would therefore not be eligible for oral isotretinoin. These patientsâ&#x20AC;&#x2122; acne would have improved or not worsened, and they would have continued to have their acne under control. In the other 22% of patients, acne would have likely worsened after a 24-week maintenance regimen of A-BPO. These patientsâ&#x20AC;&#x2122; acne would be considered severe, making them eligible for oral isotretinoin.27 The definitions of improvement in trials with oral isotretinoin may have been different from those used for A-BPO/D. To account for the differences, it was assumed that patients who received a regimen of oral isotretinoin who would need an additional regimen would be considered to not have their acne under control for the purposes of the long-term model. For patients who were initially treated with oral isotretinoin, 22% to 39% will likely need an additional 20-week regimen of oral isotretinoin.31 These patients would be eligible for an additional regimen of oral isotretinoin.

A decision tree was modeled with an initial treatment option of A-BPO/D or oral isotretinoin with probable treatment outcomes and additional therapies (Figure 3).

For all possible treatment outcomes, an initial regimen of A-BPO/D costs less weekly than an initial regimen of

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eekly Comparative Costs per Patient for the Basic Table 3 W Treatment Model: A-BPO/D vs Oral Isotretinoin Absolute drug Average Median costs for treatment weekly cost weekly cost Treatment regimen,a $ per patient, $ per patient, $ A-BPO/D

465-842

47.86

44.01

868-3365

72.10

61.88

Not applicable

24.24 (51%)

17.87 (41%)

Oral isotretinoin Difference

b

Treatment duration of 12 weeks for A-BPO/D and 20 weeks for oral isotretinoin. b Difference in costs equal oral isotretinoin minus A-BPO/D; percent difference relative to cost of A-BPO/D. A-BPO/D indicates adapalene and benzoyl peroxide gel, 0.1%/2.5% with oral doxycycline 100 mg. a

Figure 2 Comparative Efficacy and Drug Costs for Each Initial Treatment Regimen: A-BPO/D vs Oral Isotretinoin

100

Reduction in inflammatory lesions, %

80

Average weekly cost per patient, $

70

80

60 50

60

40 40

30 20

20 0

10 A-BPO/D

Oral isotretinoin

0

A-BPO/D

Oral isotretinoin

A-BPO/D indicates adapalene and benzoyl peroxide gel, 0.1%/2.5% with oral doxycycline 100 mg.

Table 4 Response and Relapse Rates for Each Regimen Patients with acne Patients with symptoms under control, % relapse, %

Treatment A-BPO/D for 12 weeks

97

3

A-BPO maintenance therapy for 24 weeks

78

22

61-78

22-39

Oral isotretinoin

A-BPO indicates adapalene and benzoyl peroxide gel, 0.1%/2.5%; A-BPO/D, adapalene and benzoyl peroxide gel, 0.1%/2.5% with oral doxycycline 100 mg.

Sources: References 26-30.

oral isotretinoin; however, these calculations did not consider the probability that a patient would receive a particular regimen. When the probability of each possible treatment outcome is factored in, the cost of treat-

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Figure 3 L ong-Term (up to 36 Weeks) Decision Tree with Probable Outcomes and Costs for A-BPO/D and Oral Isotretinoin

Begin with patients with severe acne vulgaris

Likely outcomes

Weekly cost per patienta Average (SD) Median

Oral isotretinoin for 20 weeks

A-BPO for 12 weeks

Initial treatment

Follow-up treatment

Patients with severe acne

A-BPO/D for 24 weeks

Oral isotretinoin for 20 weeks

None

Oral isotretinoin for 20 weeks

97% of patients

3% of patients

61%-78% of patients

22%-39% of patients

Acne under control

Oral isotretinoin for 20 weeks

Acne under control

Acne under control

78% of patients

22% of patients

$45 ($17) $44

$55 ($15) $50

$72 ($10) $62

$72 ($10) $62

Costs are rounded to the nearest dollar and are not adjusted for likelihood of treatment outcomes.

A-BPO indicates adapalene and benzoyl peroxide gel, 0.1%/2.5%; A-BPO/D, adapalene and benzoyl peroxide gel, 0.1%/2.5% with oral doxycycline 100 mg; SD, standard deviation.

a

Table 5 E xpected Weekly Costs per Patient for the Long-Term Model Average weekly Median weekly Treatment cost per patient, $ cost per patient, $ A-BPO/D with A-BPO maintenance therapy

47.41

45.25

Oral isotretinoin

72.10

61.88

24.69 (52%)

16.63 (37%)

Difference

a

Difference in costs equal oral isotretinoin minus A-BPO/D; percent difference relative to cost of A-BPO/D. A-BPO indicates adapalene and benzoyl peroxide gel, 0.1%/2.5%; A-BPO/D, adapalene and benzoyl peroxide gel, 0.1%/2.5% with oral doxycycline 100 mg.

a

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ment still favors an initial treatment with A-BPO/D over oral isotretinoin (Table 5).

To achieve the goal of getting a patientâ&#x20AC;&#x2122;s acne under control would cost an average of $24.69 more weekly if that patient initially received oral isotretinoin.

Discussion The current cost analysis shows that an initial regimen of A-BPO/D is less expensive per patient per week than an initial regimen of oral isotretinoin in treating severe acne vulgaris. Both regimens have been shown to be effective in improving severe acne.26-30 The basic treatment model compared the efficacy and costs of a single regimen of either treatment. Although no head-to-head data exist comparing the 2 treatments, patients using oral isotretinoin could expect to have the number of inflammatory lesions reduced by an additional 8% to 18% over the A-BPO/D regimen. However, such a reduction would require an additional 8 weeks of treatment and would cost an additional $24.24 per patient weekly, on average, during 12 weeks of treatment with A-BPO/D. Patients with severe acne vulgaris frequently require additional therapy, depending on the initial treatment outcomes. A second model was developed that incorporated the probability of possible treatment outcomes on either regimen. That model assumed that patients who failed treatment with the initial A-BPO/D regimen or the A-BPO maintenance therapy would receive a 20week regimen of oral isotretinoin. Even when the probability of receiving oral isotretinoin at some point after the initial A-BPO/D therapy was factored into the treatment costs, an initial regimen of A-BPO/D was still less expensive per patient weekly than an initial regimen of oral isotretinoin. The goal of the A-BPO/D regimen is to get acne under control so that topical medications may be used to avoid the side effects of additional oral anti­ biotics or oral isotretinoin.

Oral isotretinoin is recommended only for severe forms of resistant nodular/conglobate acne vulgaris.12 For less severe forms of severe acne, an oral antibiotic with a topical retinoid and a benzoyl peroxide regimen are recommended. However, oral isotretinoin is frequently prescribed for less severe acne than is indicated, in patients in whom A-BPO/D would be a more appropriate initial therapy.13 Oral isotretinoin is also associated with several severe side effects.14 It has a pregnancy category X label, indicating that it is a teratogenic drug that can cause severe birth defects. The use of oral isotretinoin also requires enrollment in the iPLEDGE program and healthcare provider visits and laboratory tests for liver function and lipid testing.33 A-BPO/D is efficacious in improving severe acne vul-

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garis.26,27 This regimen is well tolerated, with side effects that were comparable with vehicle gel plus doxycycline 100 mg, and it does not require enrollment in a REMS program. A-BPO is currently the only available fixeddose combination topical therapy formulated with a retinoid and benzoyl peroxide.

Other available fixed-dose combination therapies combine retinoids with antibiotics, such as clindamycin.34 However, the antibiotic resistance of patients with P acnes to clindamycin and other antibiotics has been reported,23,35 whereas resistance to benzoyl peroxide has not. In addition, A-BPO is suitable and is recommended for mildto-severe acne, demonstrating its versatility in treating the disease.12 Therefore, A-BPO is a logical choice for a topical fixed-dose combination therapy, thanks to its efficacy, tolerability, and lack of antibiotic resistance.

Because of its efficacy and safety in treating severe acne, a regimen of A-BPO/D provides an alternative to oral iso­ tretinoin, especially in patients with medical histories or conditions for which oral isotretinoin is contraindicated.

Although patients receiving oral isotretinoin may see better reductions in inflammatory lesions, that improvement comes at a higher cost, requires longer initial treatment duration, and is associated with more side effects than A-BPO/D. Oral isotretinoin should only be used in severe cases of nodular acne vulgaris, as is recommended by the Global Alliance to Improve Outcomes in Acne.12 An initial regimen of A-BPO/D is a more suitable choice for severe cases of acne vulgaris that do not warrant treatment with oral isotretinoin.

Limitations This analysis has several limitations. The efficacy data were extracted from independent studies with various study populations. Although comparisons in efficacy were made for descriptive purposes, they may not be relevant, because patients using oral isotretinoin may have more severe acne than patients in the A-BPO/D study group.

A controlled study that investigated oral isotretinoin and A-BPO/D in similar populations would allow a valid comparison of efficacy. It would also allow costs to be modeled according to the degree of symptomatic improvement rather than by week. However, although the patient populations were different and were not directly comparable, patients in the A-BPO/D studies had severe acne, for which a specialist would likely prescribe oral isotretinoin for treatment. Therefore, although the groups are not identical, they are comparable, because the patientsâ&#x20AC;&#x2122; acne in both groups is severe enough to warrant consideration for treatment with oral isotretinoin.

Another limitation is that maximum allowable cost pricing was used for doxycycline 100 mg and for oral isotretinoin, whereas the average of AWP and WAC

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pricing was used for A-BPO. No maximum allowable cost pricing is available for A-BPO, because it is unavailable as a generic, so the average of AWP and WAC is a realistic price. An average of the AWP and WAC pricing could have been used for doxycycline 100 mg and for oral isotretinoin; however, it is unlikely that this pricing is what would be used in a real-world situation. Because doxycycline 100 mg and oral isotretinoin are available as generics, the maximum allowable cost pricing would be used to determine the costs of these 2 drugs in a managed care setting.

Furthermore, the true costs of oral isotretinoin may have been underestimated in this analysis, because this analysis only considered drug costs, and not ancillary costs.

Oral isotretinoin requires enrollment in the iPLEDGE program. No REMS program is required for A-BPO/D therapy. Oral isotretinoin also requires healthcare provider visits to monitor liver function and serum lipids, and women of child-bearing potential must use 2 forms of contraception. These additional costs are not accrued for A-BPO/D.

Conclusions Severe acne is a serious skin disease that affects the QOL in affected individuals. A regimen of A-BPO/D is suitable for most cases of severe acne vulgaris and may be considered for use as a first-line therapy. Oral isotretinoin should only be used in severe recalcitrant cases of nodular acne, because it is associated with severe side effects; however, it is frequently prescribed for less severe and even moderate cases of acne. A comparison of these 2 treatments using previously published data to evaluate efficacy and costs, modeled on a recent clinical study, demonstrates that both treatments are effective in managing severe acne and that a weekly treatment with A-BPO/D is less expensive than a weekly treatment of oral isotretinoin. Even when probable rates of success are considered, A-BPO/D is still less expensive per week than oral isotretinoin.

Furthermore, ancillary medical costs, such as required laboratory tests, birth control, and the iPLEDGE program, were not considered in this analysis; those additional costs are only associated with oral isotretinoin.

Therefore, the total costs of A-BPO/D are even likely less expensive than what is presented here. As is shown in the current analysis, A-BPO/D is well tolerated, efficacious, and less expensive than oral isotretinoin; for these reasons it may be considered for first-line use for severe acne with up to 3 nodules or cysts.

Funding Source This analysis was funded by Galderma Laboratories, LP, Fort Worth, TX. Continued

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Author Disclosure Statement Dr Penna is a partner of Formulary Resources and a con­ sultant to Galderma Laboratories; Dr Meckfessel is an em­ ployee of Galderma Laboratories; and Dr Preston was an employee of Galderma Laboratories at the time of the manu­ script preparation.

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2. Dreno B, Poli F. Epidemiology of acne. Dermatology. 2003;206:7-10.

3. Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol. 1999;41:577-580.

4. Mallon E, Newton JN, Klassen A, et al. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol. 1999; 140:672-676.

5. Dalgard F, Gieler U, Holm JØ, et al. Self-esteem and body satisfaction among late adolescents with acne: results from a population survey. J Am Acad Dermatol. 2008; 59:746-751.

6. Halvorsen JA, Stern RS, Dalgard F, et al. Suicidal ideation, mental health problems, and social impairment are increased in adolescents with acne: a population-based study. J Invest Dermatol. 2011;131:363-370.

7. Layton AM. Acne scarring: reviewing the need for early treatment of acne. J Der­ matolog Treat. 2000;11:3-6.

8. Fried R, Nighland M. Acne quality of life and patient satisfaction following treatment with tretinoin pump. J Drugs Dermatol. 2009;8:1080-1085.

9. Brodell RT, Schlosser BJ, Rafal E, et al. A fixed-dose combination of adapalene 0.1%-BPO 2.5% allows an early and sustained improvement in quality of life and patient treatment satisfaction in severe acne. J Dermatolog Treat. 2012;23:26-34.

10. Fried RG, Webster GF, Eichenfield LF, et al. Medical and psychosocial impact of acne. Semin Cutan Med Surg. 2010;29(2 suppl 1):9-12.

11. Zaidi Z. Acne vulgaris—an update on pathophysiology and treatment. J Pak Med Assoc. 2009;59:635-637.

12. Thiboutot D, Gollnick H, Bettoli V, et al; for the Global Alliance to Improve Outcomes in Acne. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol. 2009; 60(5 suppl):S1-S50.

13. Chen K, White TJ, Juzba M, Chang E. Oral isotretinoin: an analysis of its utilization in a managed care organization. J Manag Care Pharm. 2002;8:272-277.

14. Charakida A, Mouser PE, Chu AC. Safety and side effects of the acne drug, oral isotretinoin. Expert Opin Drug Saf. 2004;3:119-129.

15. US Food and Drug Administration. Isotretinoin (marketed as Accutane) capsule information. Updated October 22, 2010. www.fda.gov/Drugs/DrugSafety/Postmarket DrugSafetyInformationforPatientsandProviders/ucm094305.htm. Accessed January 2, 2014.

16. Kircik LH. Doxycycline and minocycline for the management of acne: a review of efficacy and safety with emphasis on clinical implications. J Drugs Dermatol. 2010; 9:1407-1411.

17. Brogden RN, Goa KE. Adapalene. A review of its pharmacological properties and clinical potential in the management of mild to moderate acne. Drugs. 1997;53:511-519.

18. Shroot B, Michel S. Pharmacology and chemistry of adapalene. J Am Acad Dermatol. 1997;36(6 pt 2):S96-S103.

19. Michel S, Jomard A, Démarchez M. Pharmacology of adapalene. Br J Dermatol.

1998;139(suppl 52):3-7.

20. Cunliffe WJ, Poncet M, Loesche C, Verschoore M. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol. 1998;139(suppl 52):48-56.

21. Waugh J, Noble S, Scott LJ. Adapalene: a review of its use in the treatment of acne vulgaris. Drugs. 2004;64:1465-1478.

22. Leyden JJ. Current issues in antimicrobial therapy for the treatment of acne. J Eur Acad Dermatol Venereol. 2001;15(suppl 3):51-55.

23. Sagransky M, Yentzer BA, Feldman SR. Benzoyl peroxide: a review of its current use in the treatment of acne vulgaris. Expert Opin Pharmacother. 2009;10:2555-2562.

24. Thiboutot DM, Weiss J, Bucko A, et al; for the Adapalene-BPO Study Group.

Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol. 2007;57:791-799.

25. Pariser DM, Westmoreland P, Morris A, et al. Long-term safety and efficacy of a unique fixed-dose combination gel of adapalene 0.1% and benzoyl peroxide 2.5% for the treatment of acne vulgaris. J Drugs Dermatol. 2007;6:899-905.

26. Gold LS, Cruz A, Eichenfield L, et al. Effective and safe combination therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg. Cutis. 2010;85:94-104.

27. Poulin Y, Sanchez NP, Bucko A, et al. A 6-month maintenance therapy with adapalene-benzoyl peroxide gel prevents relapse and continuously improves efficacy among patients with severe acne vulgaris: results of a randomized controlled trial. Br J Dermatol. 2011;164:1376-1382.

28. Jones DH, King K, Miller AJ, Cunliffe WJ. A dose-response study of I3-cis-retinoic acid in acne vulgaris. Br J Dermatol. 1983;108:333-343.

29. Strauss JS, Rapini RP, Shalita AR, et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol. 1984;10:490-496.

30. Strauss JS, Leyden JJ, Lucky AW, et al. A randomized trial of the efficacy of a new micronized formulation versus a standard formulation of isotretinoin in patients with severe recalcitrant nodular acne. J Am Acad Dermatol. 2001;45:187-195.

31. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotretinoin for acne vulgaris—10 years later: a safe and successful treatment. Br J Dermatol. 1993;129:292-296.

32. Strauss JS, Krowchuk DP, Leyden JJ, et al; for the American Academy of Dermatology/American Academy of Dermatology Association. Guidelines of care for acne vulgaris management. J Am Acad Dermatol. 2007;56:651-663.

33. The iPLEDGE Program Pharmacist Guide for Isotretinoin. http://health.cat/ref/ pdf.php?search=The+iPLEDGE+Program+Pharmacist+%3Cstrong%3EGuide%3C/ strong%3E+For+Isotretinoin. Accessed January 17, 2014.

34. Schlessinger J, Menter A, Gold M, et al; for the ZIANA Study Group. Clinical safety and efficacy studies of a novel formulation combining 1.2% clindamycin phosphate and 0.025% tretinoin for the treatment of acne vulgaris. J Drugs Dermatol.

2007;6:607-615.

35. Leyden JJ. Antibiotic resistance in the topical treatment of acne vulgaris. Cutis.

2004;73(6 suppl):6-10.

Stakeholder Perspective Evaluating Treatments for Acne: It’s Time to “Sweat” the Smaller Things

By Gary M. Owens, MD President, Gary Owens Associates, Ocean View, DE

PHARMACY/MEDICAL DIRECTORS: Pharmacy management is changing. Our previous focus on large populations and on the small-molecule “blockbuster” drugs that are used to treat them is being de­ emphasized and replaced with the world of specialty pharmaceuticals that are typically used to treat small patient populations. Although specialty drugs will be

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the major drivers of pharmacy cost increases in 2014 and beyond, they still account for less than 25% of most pharmacy budgets.1 The majority of pharmacy cost is associated with small-molecule drugs. In 2012, the generic prescribing rate was 84% and is currently helping to hold the cost of small-molecule drugs relatively flat, but there is still a need to actively manage the cost of

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A-BPO/D versus Oral Isotretinoin: Efficacy and Cost

Stakeholder Perspective Continued small-molecule drugs.2 However, it is sometimes easy to overlook savings opportunities for less-costly disease categories—“the small things.”

Dermatologic conditions account for 12.4% of all diseases that are treated by family physicians.3 This high prevalence is largely driven by a relatively small number of common dermatologic conditions. Acne is the most common skin disorder in the United States, affecting 40 million to 50 million Americans, with nearly 85% of all people having acne at some point in their lives.4 The cost of treating acne in 2004, which is the most recent year with available data, exceeded $2.2 billion, including substantial costs for prescription and over-the-counter treatments.4 In their article in this issue, Penna and colleagues use existing data sources to compare the outcomes for 2 different treatment regimens for severe acne. A regimen consisting of a fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% combined with oral doxycycline 100 mg (ABPO/D) was compared with a regimen containing isotretinoin. The clinical outcomes for these 2 regimens were similar, with some enhanced clinical benefit from isotretinoin. However, when the costs of the 2 regimens were compared, the ABPO/D treatment was substantially less expensive on a weekly basis than the isotretinoin regimen. In addition, fewer safety and monitoring issues were associated with the ABPO/D regimen compared with isotretinoin. Ultimately, the authors conclude that the ABPO/D regimen is “suitable for most cases of severe acne vulgaris and may be considered for use as a first-line therapy.”

PHARMACY & THERAPEUTICS COMMITTEES: To make informed formulary management decisions, Pharmacy & Therapeutics (P&T) committees need access to good comparative data. Although head-

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to-head studies that directly compare both clinical and economic outcomes are most desirable, they are generally not available for most formulary management decisions. Penna and colleagues provide the type of analysis that is becoming increasingly necessary to effectively manage clinical outcomes and cost. Although the majority of dermatologic treatments are not among the leading drivers of pharmacy cost, it is still important to find the best balance of clinical outcome and cost for the majority of patients.

Based on this study, a P&T committee can potentially develop a preferred treatment pathway that is adequate for most cases of severe acne, resulting in a win-win scenario of lower cost and a safer treatment regimen for the majority of patients. The cost-savings to a plan resulting from this pathway may not be large in absolute terms, but it is an example of cost-effective drug therapy management. Ultimately, the cumulative savings from relatively small cost categories of the pharmacy budget are essential contributors to the continued affordability of the benefit.

Prudent management of the pharmacy benefit requires attention to such detail in all disease areas.

Penna and colleagues have provided us with a good example of how to manage one of those small things on the pharmacy budget with good clinical outcomes at a reasonable cost. n 1. Express Scripts. Drug Trend Report. Updated October 2013. www.drugtrendreport. com/docs/DTR_FULLPDF-1029.pdf. Accessed February 10, 2014.

2. IMS Institute for Healthcare Informatics. Declining medicine use and costs: for better or worse? A review of the use of medicines in the United States in 2012. May 2013. www.imshealth.com/deployedfiles/ims/Global/Content/Insights/IMS%20Institute %20for%20Healthcare%20Informatics/2012%20U.S.%20Medicines%20Report/ 2012_U.S.Medicines_Report.pdf. Accessed February 10, 2014.

3. Verhoeven EW, Kraaimaat FW, van Weel C, et al. Skin diseases in family medicine: prevalence and health care use. Ann Fam Med. 2008;6:349-354.

4. American Academy of Dermatology. Acne. www.aad.org/media-resources/stats-andfacts/conditions/acne. Accessed February 2, 2014.

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The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Call for Papers Neurology Theme Issue American Health & Drug Benefits is publishing a theme issue on neurology in September.

Take part in the important conversation regarding the aging of the population and the growing clinical and economic burdens associated with neurologic disorders.

Readers are invited to submit original research and systematic reviews or case reports on the increasing understanding of the biology of the brain and neurologic conditions, and their role in the overall well-being of the American population.

All articles will undergo the journal’s rigorous peer-review process.

ORIGINAL RESEARCH

REVIEW ARTICLES

• Clinical research

• Alzheimer’s disease: diagnosis, treatment

• Case studies/case series

• Benefit design for multiple sclerosis

• Comparative effectiveness analyses

• Best practices in neurology

• Cost-effective analyses

• Cost considerations in multiple sclerosis

• Data-driven innovation in neurology

• Dementia

• Health economics research outcomes

• Emerging therapies for neurologic disorders

• Drug therapy

• Headache management

• Patient-reported outcomes

• Pain medicine

• Pharmacoeconomics

• Parkinson’s disease

• Quality-of-life issues

• Sleep disorders

• Survey analyses

• Stroke management/cerebrovascular disease • Value-based issues in neurology

Submission Deadline: July 1, 2014 Follow the Information for Authors at www.AHDBonline.com Submit articles to editorial@engagehc.com or online at www.AHDBonline.com

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NeW foR 2014

Government and Employers An educational session for policymakers and employers focusing on healthcare reform, benefit design, insurance, and coverage trends.

Co-Chairs

May 7, 2014 Loews Hollywood Hotel Los angeles, Ca

aGEnda

Jayson Slotnik, JD, MPH

Vice President of Reimbursement Strategy & Innovation United BioSource Corporation

F. Randy Vogenberg, PhD, RPh

Principal Institute for Integrated Healthcare

8:30am – 8:40am

Introductions and Opening Remarks Jayson Slotnik, JD, MPH; F. Randy Vogenberg, PhD, RPh

8:40am – 9:25am

Session 1: Investor Community Views on Healthcare Market Winners and Losers Michael E. Meyers, MPH, Managing Director, Head of Investment Banking, T.R. Winston & Company

9:25am – 10:10am

Session 2: Insurance Innovation on Reinsurance and Benefit Design Trends Matthew Palmgren, PharmD, President, Healthcare Solutions in Int’Ovation Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC

10:10am – 10:15am

Break

10:15am – 11:00am

Session 3: Private Exchanges: Why Different from Public Exchange Trends for Oncology Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions

11:00am – 11:40am

Session 4: Diagnostics: Recent FDA and CMS Policies Impacting Access to Diagnostic and Oncology Drugs John Ridge, Senior Director, Managed Care and Reimbursement, Exact Sciences Timothy J. Thompson, Chief Executive Officer, Intervention Insights

11:40am – 12:00pm

Session 5: What’s Next with Healthcare Reform – Fixes or More Related to Oncology?

Denise Pierce, President and CEO, DK Pierce & Associates Jayson Slotnik, JD, MPH, Vice President of Reimbursement Strategy & Innovation, United BioSource Corporation F. Randy Vogenberg, PhD, RPh, Principal, Institute for Integrated Healthcare

12:00pm – 12:15pm

Break

12:15pm – 1:15pm

Lunch/Product Theater

1:15pm – 1:30pm

Break

1:30pm – 2:15pm

Session 6: Employer Onsite Clinic Trends from Wellness into Infusion and Emergent Care Larry Boress, President & CEO, Midwest Business Group on Health; Executive Director, National Association of Worksite Health Centers

2:15pm – 3:45pm

Meet the Experts Roundtables Alex Jung, Principal, Global Strategic Advisory Services, Ernst & Young LLP John Kahle, Senior Vice President, Chief Wellness Officer, Intercare Insurance Solutions Ryan Siemers, Finance & Insurance Risk Consultant, Aegis Risk, LLC Andrew Stainthorpe, Executive Director, National Institute for Health and Clinical Excellence (NICE)

3:45pm – 4:15pm

Poster Presentations

4:15pm – 5:00pm

Poster and Session Discussant

5:00pm – 7:00pm

Cocktail Reception in the Exhibit Hall

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clinical

Outcomes Associated with 5-HT3-RA Therapy Selection in Patients with ChemotherapyInduced Nausea and Vomiting: A Retrospective

Claims Analysis

Claudio Faria, PharmD, MPH; Xuan Li, MS; Norman Nagl, PhD; Ali McBride, PharmD, MS

Stakeholder Perspective, page 58 Am Health Drug Benefits.

2014;7(1):50-58 www.AHDBonline.com Disclosures are at end of text

Background: Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of chemotherapy, and may present during the administration of chemotherapy (ie, acute CINV) or within 25 to 120 hours of chemotherapy (ie, delayed CINV). Preventing CINV with the initiation of chemotherapy is impor足 tant, because the risk for CINV in future chemotherapy cycles increases if CINV occurs in the first or previous treatment cycle. Inadequately controlled CINV is associated with increased resource utilization and costs, particularly for patients receiving highly or moderately emetogenic chemotherapy.

Objective: To evaluate the clinical and economic impacts of delayed CINV events in patients who receive initial and maintenance therapy with the newer-generation 5-hydroxytryptamine3 receptor antagonist (5-HT3-RA) palonosetron compared with patients who receive initial and maintenance therapy with an older 5-HT3-RA agent.

Methods: A retrospective database analysis was conducted using the OptumInsight database covering the years 2005-2011 (96% commercially insured members, 4% Medicaid members). Patients with cancer who received initial therapy with an emetogenic single-day chemotherapy regimen and a 5-HT3-RA agent (ie, dolasetron, granisetron, ondansetron, or palonosetron) were included in the analysis. The outcomes measured included the overall rates of delayed CINV for cycles 1 to 6, by 5-HT3-RA cohort. For cycles 2 to 6, calculations were based on patients who experienced CINV in the previous cycle, maintained the same 5-HT3-RA for all cycles, and had chemotherapy with a similar level of emetic potential. The economic outcomes (ie, cost and utilization) were also collected and calculated.

Results: A total of 26,974 patients were included in the analysis. The overall rate for delayed CINV at cycle 1 was 15.6%, and the lowest rate was for palonosetron at 15%. The patients who initiated palonosetron had lower CINV rates throughout all cycles. The regression analysis compared individual agents to palonosetron and demonstrated higher odds of CINV in the second cycle for the older agents (ondansetron: odds ratio [OR], 1.41; 95% confidence interval [CI], 1.14-1.74; P <.002; granisetron: OR, 1.70; 95% CI, 1.39-2.08; P <.001; dolasetron: OR, 1.65; 95% CI, 1.27-2.15; P = .002). This trend continued through cycle 6, and not all ORs were significant. Over 6 cycles, ondansetron cost an additional $126,775 compared with palonosetron; granisetron an additional $169,838 versus palonosetron; and dolasetron an additional $148,960.

Conclusions: Current guidelines support the use of 5-HT3-RA agents for the prevention of CINV. As shown in this analysis, the selection of a specific 5-HT3-RA agent has a clinical and subsequent economic impact on patients with cancer experiencing delayed CINV. Specifically, patients receiving therapy with palonosetron had a lower incidence of delayed CINV and incurred lower overall costs.

C

hemotherapy-induced nausea and vomiting (CINV) is a common side effect of chemotherapy, and may present during or soon after (0-24 hours) chemotherapy administration (ie, acute CINV) or be-

Dr Faria is Director, Health Economics and Outcomes Research, Eisai, Inc, Woodcliff Lake, NJ; Mr Li is biostatistician, Eisai, Inc; Dr Nagl is Medical Director, Eisai, Inc; Dr McBride is Clinical Coordinator, Hematology/Oncology, University of Arizona Cancer Center, Department of Pharmacy, Tucson, AZ.

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tween 25 to 120 hours after chemotherapy administration (ie, delayed CINV).1,2 In the absence of antiemetic prophylaxis, many emetogenic agents will cause emesis in more than 90% of patients within 24 hours of the administration of chemotherapy.1-3 Preventing CINV during the initiation of chemotherapy is important, because the risk for CINV in future chemotherapy cycles increases if CINV occurs in the first or previous treatment cycle.4-8 The 5-hydroxytryptamine3 receptor antagonists (5-HT3RAs) have proved to be very effective in the prevention

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of CINV, with current guidelines supporting the use of the 5-HT3-RA agents for CINV prophylaxis.9-11 Despite the effectiveness of the 5-HT3-RAs, uncontrolled CINV still occurs in more than 25% of patients receiving chemotherapy.4 Antiemesis guidelines from the American Society of Clinical Oncology, National Comprehensive Cancer Network (NCCN), and Multinational Association of Supportive Care in Cancer/European Society for Medical Oncology (MASCC/ESMO) recommend palonosetron as a preferred treatment among the 5-HT3-RAs for CINV prophylaxis before moderately emetogenic chemotherapy (MEC).9-11 In addition, the NCCN’s antiemesis guidelines have granted palonosetron preferred status for the prevention of CINV with strongly emetogenic chemotherapy (HEC) regimens.10 The MASCC/ESMO guidelines consider palonosetron as the preferred 5-HT3-RA for anthracycline plus cyclophosphamide chemotherapy regimens when a neurokinin 1 receptor antagonist is not available.11 The effectiveness of palonosetron has also been supported by studies conducted in solid tumors, as well as in blood cancers, demonstrating that patients receiving palonosetron had significantly lower CINV event rates than patients receiving other 5-HT3-RAs, and that palonosetron can be safely and effectively administered to patients receiving chemotherapy regimens administered over multiple days per cycle.12-15 Although the effectiveness of the older 5-HT3-RA agents (ie, ondansetron, dolasetron, and granisetron) in preventing emesis in the acute phase (0-24 hours after chemotherapy administration) has been well documented, delayed CINV (2-5 days after chemotherapy adminis­ tration), particularly nausea, continues to pose clinical (ie, including negative impact on quality of life)16 and economic burdens for patients with cancer.

Uncontrolled delayed CINV has been defined as nausea and/or vomiting or a diagnosis of dehydration made during an office visit, emergency department visit, or hospitalization.4,14 The rates of uncontrolled CINV have been estimated to be as high as 28%,4 and uncontrolled CINV has been associated with 25% to 50% of patients delaying or refusing chemotherapy.17 Up to 82% of women receiving MEC or HEC can experience delayed nausea.18 Even if patients do not experience CINV in the first 24 hours of chemotherapy administration, delayed CINV affects activities of daily life in 23% of patients.18-20 Uncontrolled CINV has been shown to be associated with increased resource utilization and costs, particularly for patients receiving MEC or HEC.21,22 In a study assessing CINV costs for the first cycle of a MEC or HEC regimen, 64% of CINV-associated visits included an inpatient visit and 26% included an outpatient visit, with the mean cost of a CINV visit calculated to be $5299 (stan-

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Key Points Without antiemetic prophylaxis, emesis occurs in more than 90% of patients within 24 hours of receiving emetogenic chemotherapy. ➤ Uncontrolled CINV is associated with increased costs and resource utilization, as well as poorer quality of life. ➤ The risk for CINV in future chemotherapy cycles increases if it occurs early in the treatment cycle. ➤ Based on the current analysis, patients receiving 5-HT3-RA agents, especially palonosetron, have fewer delayed CINV events and incur lower costs than other agents. ➤ Overall, palonosetron was found to reduce all CINV events compared with the older 5-HT3-RA agents. ➤ Delayed CINV was 15% with palonosetron, followed by 16.9% with ondansetron, 17% with granisetron, and 17.3% with dolasetron. ➤ Over 6 cycles of chemotherapy, ondansetron cost an additional $126,775 compared with palonosetron, granisetron an additional $169,838, and dolasetron an additional $148,960. ➤ In addition, when CINV is not controlled early, palonosetron can still exhibit benefits in subsequent cycles compared with the older 5-HT3-RA agents. ➤ This analysis also shows that choosing the most effective 5-HT3-RA agent for the first chemotherapy cycle can help to reduce CINV rates in subsequent cycles, and therefore reduce costs. ➤ For patients receiving chemotherapy, considering the efficacy and associated costs of the 5-HT3-RA agent used for CINV prevention can improve the patient’s quality of life and reduce overall costs. ➤

dard deviation [SD], $6639).21 Another study has estimated the average daily cost of CINV to be approximately $1850.22 These costs further show the need to establish control of CINV at the first chemotherapy cycle.

Because CINV in the delayed phase is still a problem for patients receiving chemotherapy, the evidence for the effectiveness of palonosetron, and the increasing pressure to contain healthcare costs, we conducted this study to evaluate the clinical and economic impacts of delayed CINV in patients who initiated therapy with palonosetron and maintained therapy with palonosetron versus patients who initiated therapy with an older 5-HT3-RA and received maintenance therapy with that older agent throughout their chemotherapy cycles.

Methods A retrospective database analysis was conducted uti-

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clinical

Figure 1 Study Design Index date 6-month baseline period

6-month follow-up period

06/01/2005 12/01/2005

06/30/2011 12/31/2011

Index date period

lizing the OptumInsight database from the years 2005 through 2011. The OptumInsight database covers millions of lives, with a distribution of 96% of patients being commercially insured and 4% of patients covered by Medicaid. Pharmacy and medical claims are available from healthcare providers, facilities, and pharmacies.

Information on individual physician visits, medical procedures, hospitalizations, medications, and laboratory tests are available, with charged amounts reported for the services rendered.

Study Population Patients with cancer were initially identified based on an International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) diagnosis code for any type of cancer. Patients receiving initial MEC, HEC, low emetogenic chemotherapy, or a minimally emetogenic single-day chemotherapy regimen in conjunction with a 5-HT3-RA (ie, dolasetron, granisetron, ondansetron, or palonosetron) were subsequently eligible for study inclusion. All emetogenic levels of chemotherapy were included as part of the initial inclusion criteria to ensure that patients were chemotherapy naïve.

The index date was defined as the first date of the administration of chemotherapy and 5-HT3-RA, and patients were classified into 1 of 4 treatment cohorts based on the 5-HT3-RA prescribed on the index date.

All patients were required to have 12 months of continuous enrollment; information from the 6 months before the index date was used to capture baseline information on patients, and information from the 6 months after the index date was used to assess for CINV or CINV-related utilization and costs (Figure 1).

Patients included in the analysis were required to be chemotherapy naïve. Patients who had a claim for a previous antiemetic 5-HT3-RA or for chemotherapy during the preindex period were excluded. Patients receiving multiday chemotherapy were also excluded.

Once patients received initial chemotherapy, they were required to remain on the same level of emetogenicity (ie, MEC or HEC), as well as maintain therapy with the

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same 5-HT3-RA agent throughout the entire analysis period. Patients who switched their 5-HT3-RA agent were excluded from the study at that particular point during the observation; however, their data were accumulated and included in the final analysis.

Outcomes The clinical outcomes that were measured in the analysis included unadjusted rates of delayed CINV for cycles 1 to 6 in the overall study population and by specific 5-HT3-RA cohort. Delayed CINV was defined as a primary or secondary diagnosis of nausea, vomiting, or de­ hydration (ICD-9-CM: 787.0, 787.01, 787.02, 787.03, 276.5, 276.51, 276.52) on days 2 to 5 after chemotherapy, or by the use of rescue antiemetic therapy after the administration of chemotherapy. Rescue medications were identified by J-codes or by National Drug Codes and consisted of olanzapine, promethazine, haloperidol, prochlorperazine, lorazepam, metoclopramide, and/or intravenous antiemetic administration of dolasetron, gra­ nisetron, ondansetron, or palonosetron.10 Any administration of rescue medications, antiemetic medications, or hydration procedures on the day of chemotherapy administration was not considered to be for delayed CINV. For the purpose of calculating delayed CINV rates for chemotherapy in cycles 2 to 6, the calculations were based on patients who experienced CINV in the previous chemotherapy cycle (ie, breakthrough nausea/vomiting or treatment failure), were maintained on the same 5-HT3RA agent, and had chemotherapy with the same level of emetic potential. For example, a patient who remained in this analysis at cycle 5, experienced breakthrough CINV in cycles 1 to 4, received the same 5-HT3-RA, and had the same level of emetogenic chemotherapy (eg, HEC) in cycles 1 to 5. Patients who did not meet the criteria were dropped from the CINV rate calculation. In addition to CINV rates, the adjusted odds ratios (ORs) for CINV were also calculated for each 5-HT3-RA cohort.

The economic outcomes related to CINV were also collected and were calculated by cycle. The charges for delayed CINV were calculated as a mean for each patient, and then by aggregate for the entire population remaining in the analysis by cycle. The charges in the model included physician, outpatient facility, inpatient facility, pharmacy, and “other” medical costs. The charges were then entered into a model representing an overall random sample of 1000 patients at cycle 1. A charge per patient was calculated and was used to determine an average charge for all patients in each 5-HT3-RA cohort based on the percentage of patients in each cycle who experienced delayed CINV. As was the case for the CINV rate calculation, patients without CINV in the previous cycle, patients who

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Table 1 Patient Characteristics 5-HT3-RA agents Variable

All patients (N = 26,974)

Palonosetron (N = 18,597)

Ondansetron (N = 3170)

Granisetron (N = 3289)

Dolasetron (N = 1918)

P value

55.7 (11)

55.3 (10.8)

56.4 (11.3)

56.3 (11.2)

57.9 (11.4)

<.001

18,649 (69.1)

13,244 (71.2)

2081 (65.5)

2123 (64.6)

1201 (62.6)

<.001

4.6 (2)

4.6 (1.9)

4.8 (2)

4.8 (2)

4.9 (2)

<.001

Mean age, yrs (SD) Female, N (%) Preindex Charlson Comorbidity Index score, mean (SD)

5-HT3-RA indicates 5-hydroxytryptamine3 receptor antagonist; SD, standard deviation.

Table 2 Treatment Characteristics at Cycle 1, by 5-HT3-RA Therapy 5-HT3-RA agents All patients Palonosetron Ondansetron (N = 26,974) (N = 18,597) (N = 3170)

Variable Any use of dexamethasone at cycle 1, N (%)

Granisetron (N = 3289)

Dolasetron (N = 1918) P value

24,749 (91.8)

17,309 (93.1)

2784 (87.8)

2968 (90.2)

1688 (88)

<.001

2234 (8.3)

1996 (10.7)

115 (3.6)

75 (2.3)

48 (2.5)

<.001

11,942 (44.3) 11,202 (41.5)

7991 (43) 8568 (46.1)

1495 (47.2) 1077 (34)

1502 (45.7) 1021 (31)

954 (49.7) 536 (28)

<.001

Delayed CINV, N (%)

4124 (15.6)

2788 (15)

536 (16.9)

558 (17)

332 (17.3)

<.001

Delayed CINV by ICD-9 code, N (%)

1561 (5.8)

1087 (5.9)

177 (5.6)

174 (5.3)

123 (6.4)

NR

Delayed CINV by rescue medication, N (%)

3488 (12.9)

2237 (12)

467 (14.7)

498 (15.1)

286 (14.9)

NR

Any use of aprepitant at cycle 1, N (%) Chemotherapy type at cycle 1 MEC, N (%) HEC, N (%)

5-HT3-RA indicates 5-hydroxytryptamine3 receptor antagonist; CINV, chemotherapy-induced nausea and vomiting; HEC, highly emetogenic chemotherapy; ICD-9, International Classification of Diseases, Ninth Revision; MEC, moderately emetogenic chemotherapy; NR, not reported.

switched 5-HT3-RA therapy, and patients who changed the level of chemotherapy emetogenicity were excluded from subsequent calculations. Palonosetron was used as a baseline marker, and all patients remained in the analysis until they dropped off, based on the rates calculated from our analysis. The costs were accumulated for this population over 6 cycles.

Statistical Analysis Descriptive statistics for patient and treatment characteristics were calculated. Comparisons of baseline and treatment characteristics were conducted using t-tests, nonparametric Wilcoxon rank-sum tests, and chi-square tests. Logistic regression was utilized to calculate adjusted ORs for experiencing CINV while controlling for age, sex, Charlson Comorbidity Index (a higher score indicating higher clinical disease burden), type of chemotherapy regimen (HEC vs other regimens), additional

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antiemetic therapy (eg, with dexamethasone and aprepitant), and specific 5-HT3-RA.

Results A total of 26,974 patients met the inclusion criteria for the study. The overall average age was 55.7 years, with patients in the dolasetron cohort having the oldest average age of 57.9 years (P <.001). Patients receiving palonosetron were younger, with an average age of 55.3 years. The majority of patients across all cohorts were female, with 71% of patients who were receiving palonosetron being female. Preindex comorbidity scores were lowest in the palonosetron cohort (4.6) and highest in the dolasetron cohort (4.9; Table 1).

Most patients (72%) had a cancer diagnosis for a single site. Of these patients, 53% had a diagnosis of breast cancer, 20% had a diagnosis of lung cancer; the remainder of patients were split between ovarian, colon, and other can-

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Figure 2 Increases in Delayed CINV Rates from Cycle to Cycle 35

31.7%

30

CINV rate, %

25

21.8%

20 15

13.5%

10 5 0

Cycle 1-2

Cycle 2-3

Cycle 3-4

2.4%

3.3%

Cycle 4-5

Cycle 5-6

NOTE: The overall baseline CINV rate was 15.6%. The increase from cycle 1 to cycle 2 is based on the difference in CINV rates (37.4% for cycle 2 and 15.6% for cycle 1). Increases were calculated based on the difference in CINV rate from one cycle to the next.

The CINV rates for cycles 2 to 6 were calculated based on the number of patients in the previous cycle who received a subsequent chemotherapy cycle and were maintained on the same 5-HT3-RA. 5-HT3-RA indicates 5-hydroxytryptamine3 receptor antagonist; CINV, chemotherapy-induced nausea and vomiting.

CINV rate, %

elayed CINV Rates, per Cycle, for the Older 5-HT3-RA Figure 3 D Agents versus Palonosetron Ondansetron Granisetron Dolasetron

20 18 16 14 12

15% 13% 11% 10%

10 8 6 4 2 0

14%

13%

12%

10%

10% 8%

7%

12% 9% 9%

4%

Cycle 2

Cycle 3

Cycle 4

Cycle 5

Cycle 6

NOTE: The percentage of patients experiencing CINV for each agent was calculated using palonosetron as the baseline reference.

Palonosetron was chosen as the reference agent because it had the lowest incidence of CINV across all chemotherapy cycles.

Therefore, these percentages represent the proportion of patients with CINV above that for palonosetron for each cycle. For example, the CINV rate in cycle 2 was 34.6% for palonosetron and 41.2% for ondansetron, a difference of approximately 7%. It should be noted that CINV percentages for cycles 2 to 6 were calculated based on the number of patients in the previous cycle who had CINV and received a subsequent chemotherapy cycle and were using the same 5-HT3-RA agent for all cycles.

5-HT3-RA indicates 5-hydroxytryptamine3 receptor antagonist; CINV, chemotherapy-induced nausea and vomiting.

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cers. More patients in the palonosetron cohort received an HEC regimen than any other type of chemotherapy, which was in contrast to the other 5-HT3-RA groups, where MEC was the predominant regimen (Table 2).

Dexamethasone was consistently used in the first cycle for all treatment groups, with the palonosetron cohort having the highest (93.1%) utilization rate. In addition, aprepitant was most often used in the palonosetron cohort, with 10.7% of patients receiving aprepitant (Table 2).

As shown in Table 2, the overall rate for delayed CINV at cycle 1 was 15.6%. When stratified by 5-HT3RA cohorts, delayed CINV was lowest (15%) in the palonosetron cohort, followed by ondansetron (16.9%), granisetron (17%), and dolasetron (17.3%).

The rates of delayed CINV increased for each subsequent chemotherapy cycle when evaluating patients who experienced CINV in the previous chemotherapy cycle. The delayed CINV rates increased by 21.8% from cycle 1 to cycle 2, by 31.7% from cycle 2 to cycle 3, they began to level off by cycle 4, and then increased slightly (5.7%) by cycle 6 (Figure 2).

When evaluating delayed CINV rates by the specific 5-HT3-RA therapy, patients initiating therapy with palonosetron had lower delayed CINV rates throughout all 6 cycles of chemotherapy. These numbers are dependent on the percentage of patients experiencing CINV in the previous chemotherapy cycle. Ondansetron was the next lowest cohort, with dolasetron and granisetron demonstrating intermittent results from cycle to cycle (Figure 3). The type of chemotherapy that patients with CINV received is reported in Table 3.

A multivariate regression analysis comparing the individual 5-HT3-RA agents to palonosetron demonstrated higher odds of delayed CINV in the second cycle (ondansetron: OR, 1.41; 95% confidence interval [CI], 1.14-1.74; P <.002; granisetron: OR, 1.70; 95% CI, 1.39-2.08; P <.001; dolasetron: OR, 1.65; 95% CI, 1.272.15; P = .002). This trend continued for all agents through cycle 6; however, not all ORs were statistically significant (Table 4).

With regard to economic outcomes, physician charges constituted the largest component of overall pharmacy and medical charges. As a result, medical costs constituted the largest component of the total costs. For cycle 1, the average total cost per patient, regardless of CINV status, was $5902 (SD, $4920), including $5705 attributable to medical costs and $197 attributable to pharmacy costs. Similar trends occurred for subsequent cycles. The unadjusted mean charges are reported for all patients and for patients who did and did not experience CINV in Table 5.

As expected, patients experiencing CINV incurred higher charges. Based on our model of 1000 patients,

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Selecting 5-HT3-RA Therapy for CINV Prevention

patients receiving palonosetron had the lowest charges associated with delayed CINV over 6 cycles of chemotherapy. As shown in Figure 4, using palonosetron as a baseline measure, patients receiving granisetron incurred the highest charges over 6 cycles. Over 6 cycles, ondansetron cost an additional $126,775 compared with palonosetron; granisetron an additional $169,838 versus palonosetron; and dolasetron an additional $148,960 (Figure 4).

Table 3 T ype of Chemotherapy, by Cycle, for Patients with Delayed CINV Patients with delayed CINV, by cycle, % 5-HT3-RA agent Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5

Discussion The overall rates of delayed CINV increased in subsequent cycles of chemotherapy for patients who had experienced CINV in the previous chemotherapy cycle and remained on the same 5-HT3-RA therapy throughout the duration of the study period. Among the different 5-HT3-RA cohorts, patients receiving palonosetron had lower rates of CINV and associated charges, a trend which was consistent across all 6 cycles of chemotherapy.

These results are congruent with findings from other studies evaluating palonosetron for delayed CINV. Real-world studies have demonstrated that patients receiving palonosetron have decreased CINV event rates compared with patients receiving older 5-HT3-RAs.4,12,13 In their study, Balu and colleagues predicted an overall 13.7% decrease in CINV rates for patients treated in the clinic setting and a 12.5% decrease in CINV rates for patients in the hospital outpatient setting receiving palonosetron as prophylaxis per cycle of chemotherapy compared with patients receiving an older 5-HT3-RA.12 Patients in

Palonosetron MEC

45.5

43.6

43.6

59.9

60.7

HEC

47.2

50.1

49.9

32.4

33.1

Other

7.3

6.3

6.5

7.7

6.2

MEC

47.6

50.3

45.6

58.1

58.1

HEC

39.3

38.2

41.7

29

25.6

Other

13.1

11.5

12.7

12.9

16.3

MEC

48.4

46.1

47.9

66.1

63.6

HEC

36

41.9

44.5

23.2

27.3

Other

15.6

12

7.6

10.7

9.1

51.4

55.2

58.9

2.9

4

HEC

34

35.4

35.7

26.5

20

Other

14.6

9.4

6.4

70.6

76

Ondansetron

Granisetron

Dolasetron MEC

CINV indicates chemotherapy-induced nausea and vomiting; HEC, highly emetogenic chemotherapy; MEC, moderately emetogenic chemotherapy.

Table 4 Adjusted Odds Ratios for CINV in Chemotherapy Cycles 2 to 6 Cycle 2 Cycle 3 Cycle 4 Variable OR (95% CI) OR (95% CI) OR (95% CI)

Cycle 5 OR (95% CI)

Cycle 6 OR (95% CI)

Age

1 (0.99-1)

Sex

0.98 (0.99-1.01)

1.01 (0.99-1.03)

0.98 (0.95-1.01)

1.03 (0.99-1.07)

1.34 (1.15-1.55)

1.46 (1.1-1.93)

0.84 (0.54-1.31)

1.6 (0.84-3.05)

0.44 (0.19-1.03)

CCI

1.02 (0.99-1.06)

1 (0.93-1.06)

1.01 (0.9-1.13)

0.86 (0.73-1.01)

0.79 (0.62-0.99)a

HEC vs other regimen

1.22 (1.05-1.41)a

1.21 (0.93-1.58)

1.08 (0.70-1.68)

1.21 (0.59-2.5)

0.62 (0.24-1.59)

Received dexamethasone (yes/no)

1.01 (0.77-1.34)

0.88 (0.52-1.46)

1.08 (0.48-2.42)

0.19 (0.03-1.47)

2.58 (0.73-9.1)

1.76 (1.4-2.2)a

1.14 (0.79-1.65)

0.94 (0.53-1.65)

0.46 (0.2-1.08)

0.78 (0.25-2.41)

Ondansetron

1.41 (1.14-1.74)a

1.91 (1.27-2.88)a

3.35 (1.56-7.2)a

1.29 (0.56-2.92)

2.66 (0.71-9.98)

Granisetron

1.70 (1.39-2.08)

a

2.15 (1.47-3.15)

2.51 (1.31-0.78)

4.2 (1.2-14.46)

2.54 (0.68-9.46)

Dolasetron

1.65 (1.27-2.15)

1.59 (0.97-2.58)

1.67 (0.75-3.68)

2.37 (0.66-8.48)

4.64 (0.58-37.53)

a

Received aprepitant (yes/no)

a

5-HT3-RAb a a

a

a

P â&#x2030;¤.05.

Palonosetron is the reference group for all comparisons.

5-HT3-RA indicates 5-hydroxytryptamine3 receptor antagonist; CCI, Charlson Comorbidity Index; CI, confidence interval; CINV, chemotherapy-induced nausea and vomiting; HEC, highly emetogenic chemotherapy; OR, odds ratio. a

b

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INV and Non-CINV Average Charge, per Patient, by Table 5 C Chemotherapy Cycle Chemotherapy All charges, Non-CINV, CINV, cycle mean (SD) mean (SD) mean (SD) Cycle 1

N = 26,974 $5902 ($4920)

N = 22,760 $5765 ($4901)

N = 4214 $6645 ($4956)

Cycle 2

N = 3691 $5916 ($4264)

N = 2309 $5426 ($3924)

N = 1382 $6736 ($4665)

Cycle 3

N = 1213 $6815 ($4808)

N = 375 $6208 ($4551)

N = 838 $7087 ($4897)

Cycle 4

N = 705 $6836 ($4726)

N = 123 $5995 ($3877)

N = 582 $7013 ($4871)

Cycle 5

N = 359 $7753 ($5156)

N = 54 $6053 ($3327)

N = 305 $8054 ($5364)

Cycle 6

N = 257 $8022 ($5511)

N = 30 $7912 ($5556)

N = 227 $8036 ($5518)

CINV indicates chemotherapy-induced nausea and vomiting; SD, standard deviation.

Figure 4 CINV-Related Charges per 1000 in Each 5-HT3-RA Cohort $470,131

500,000

CINV-related charges, $

$427,068

$449,253

400,000 300,000

$300,293

200,000 100,000 0

Palonosetron

Ondansetron

Granisetron

Dolasetron

5-HT3-RA indicates 5-hydroxytryptamine3 receptor antagonist; CINV, chemotherapy-induced nausea and vomiting.

that study who received palonosetron were younger, and were more likely to be female, white, to receive an HEC regimen, and to have breast or lung cancer, many of which were similar patient demographics to the patients included in our study.12 Several of these characteristics (ie, younger age, female sex, treatment with HEC) place patients at increased risk for the development of CINV. Of note, a higher proportion of these patients who are at greater risk for the development of CINV were administered palonosetron in this claims analysis.12 In another study, Lin and colleagues evaluated patients with a diagnosis of breast or lung cancer receiving an MEC or HEC regimen who initiated therapy with

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palonosetron and maintained therapy on palonosetron versus patients who initiated therapy with an older 5-HT3-RA and later switched to palonosetron.13 Patients who received palonosetron from cycle 1 and maintained palonosetron therapy experienced a lower incidence of CINV and lower resource utilization associated with CINV than patients initiating therapy with an older 5-HT3-RA and later switching to palonosetron. Patients in the palonosetron cohort had 22% to 51% fewer 5-HT3-RA claims and fewer CINV events (3.5% vs 5.5% in the breast cancer cohort, 9.5% vs 12.8% in the lung cancer cohort receiving carboplatin, and 16.4% vs 21.7% in the lung cancer cohort receiving cisplatin). In addition, patients in the palonosetron cohort had a lower risk for CINV events (OR, 0.62 for patients with breast cancer; OR, 0.71 for patients with lung cancer).13 In our study, we took a slightly different approach than that used in the study by Lin and colleagues: patients in our study did not switch 5-HT3-RA therapy, allowing for an insight into the effects of therapy in subsequent chemotherapy cycles for patients who failed antiemetic therapy in cycle 1 and continued to experience breakthrough CINV in cycles 2 to 6 but did not switch 5-HT3-RA therapy. Evaluating the rates of CINV in this manner highlights the potential advantages of utilizing palono足 setron from the initiation of chemotherapy.

Tina Shih and colleagues evaluated working-aged patients with cancer and determined that, despite the use of 5-HT3-RAs, uncontrolled CINV is still problematic for approximately 28% of patients.4 The study demonstrated the need to control CINV from cycle 1 to curb resource utilization and the associated costs. That study included data before the advent of palonosetron and aprepitant, but the authors conducted a sensitivity analysis to determine the threshold at which the benefit of a newer antiemetic would outweigh the cost of the agent.4 Our study results support the use of newer agents (specifically palonosetron). The higher success rate in the delayed setting at cycle 1 resulted in fewer patients experiencing CINV in subsequent chemotherapy cycles.

Even the subset of patients that experienced breakthrough CINV in the previous chemotherapy cycle subsequently treated with palonosetron exhibited favorable outcomes with lower rates of CINV throughout the remainder of cycles.

The cost-effectiveness of palonosetron is shown by the economic results of our analysis. In our random sample of 1000 patients for each 5-HT3-RA cohort, patients receiving palonosetron would have incurred a lower cost of $126,000 to $170,000 in CINV-related charges compared with patients in the older 5-HT3-RA cohorts. This is an important consideration given the economic implications of uncontrolled CINV.

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Tina Shih and colleagues determined that the average monthly medical costs for patients with uncontrolled CINV were 29.79% higher than those for patients whose CINV was being controlled, even after adjusting for demographic, socioeconomic, and clinical characteristics.4 This difference translated to approximately $1280 in 2007 dollars.4 In addition, Burke and colleagues calculated the CINV-related costs for the first cycle of an MEC or an HEC regimen and found that the mean cost of a CINV-­ related visit was $5299 (SD, $6639).22 Our study further confirms the value of preventing CINV early in chemotherapy treatment, because the cohort with lower rates of CINV (in our study patients receiving palonosetron) incurred fewer charges over the 6 cycles of chemotherapy.

Limitations Several limitations associated with this analysis merit disclosure. Because this was a claims analysis, it is possible that not all cases of CINV were captured. However, severe cases of CINV were likely captured, because patients would have incurred resource utilization for treatment prompting a medical claim.

Furthermore, drug therapy was also evaluated for rescue medications utilizing ICD-9 codes and National Drug Codes, which would signal a CINV event. It should be acknowledged that patients may receive a supply of rescue medications for as-needed use at home. In these instances, delayed CINV rates may not be captured; therefore, our estimates may actually underestimate the incidence of delayed CINV. Finally, the study population consisted primarily (96%) of commercially insured patients and, therefore, may not apply in the same way to other populations; this should be considered when generalizing this information to other patient populations.

Conclusions Although all 5-HT3-RA agents are effective in preventing CINV, the evidence has shown that there are differences in efficacy, as well as cost-effectiveness, between the older agents and palonosetron, the newer 5-HT3-RA agent. Based on the current analysis, delayed CINV rates increased subsequent to the first chemotherapy cycle for patients with CINV who maintained therapy with the same 5-HT3-RA from one cycle to the next.

For patients who initiated therapy and maintained therapy with palonosetron, the incidence of delayed CINV in the first cycle and in subsequent cycles was lower than in the patients receiving one of the older 5-HT3-RA agents. Similar trends were found with regard to resource utilization and associated costs. Selecting the most appropriate 5-HT3-RA during the first cycle of chemother-

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apy is imperative, because the risk for developing CINV in subsequent chemotherapy cycles increases if CINV is not prevented at the time of chemotherapy initiation. If CINV is not controlled early, palonosetron can still exhibit benefits in subsequent cycles compared with the older 5-HT3-RAs. The information gleaned from this analysis can assist healthcare providers with treatment selection as well as guide healthcare decision makers with formulary decisions. n Acknowledgment Meg Franklin, PharmD, PhD, of Franklin Pharmaceutical Consulting, LLC, assisted with the writing and preparation of the manuscript.

Funding Source Funding for this study was provided by Eisai, Inc. Author Disclosure Statement Dr Faria is an employee of, Mr Li is a consultant to, and Dr Nagl is an employee of Eisai, Inc. Dr McBride reported no conflicts of interest.

References

1. ASHP therapeutic guidelines on the pharmacologic management of nausea and vomiting in adult and pediatric patients receiving chemotherapy or radiation therapy or undergoing surgery. Am J Health Syst Pharm. 1999;56:729-764.

2. Roila F, Hesketh PJ, Herrstedt J; for the Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer. Prevention of chemotherapyand radiotherapy-induced emesis: results of the 2004 Perugia International Antiemetic Consensus Conference. Ann Oncol. 2006;17:20-28.

3. Hesketh PJ, Kris MG, Grunberg SM, et al. Proposal for classifying the acute emetogenicity of cancer chemotherapy. J Clin Oncol. 1997;15:103-109.

4. Tina Shih YC, Xu Y, Elting LS. Costs of uncontrolled chemotherapy-induced nausea and vomiting among working-age cancer patients receiving highly or moderately emetogenic chemotherapy. Cancer. 2007;110:678-685.

5. Schnell FM. Chemotherapy-induced nausea and vomiting: the importance of acute antiemetic control. Oncologist. 2003;8:187-198.

6. Roila F, Boschetti E, Tonato M, et al. Predictive factors of delayed emesis in cisplatin-treated patients and antiemetic activity and tolerability of metoclopramide or dexamethasone. A randomized single-blind study. Am J Clin Oncol. 1991;14:238-242.

7. Roila F. Ondansetron plus dexamethasone compared to the ‘standard’ metoclo­ pramide combination. Oncology. 1993;50:163-167.

8. Italian Group for Antiemetic Research. Ondansetron + dexamethasone vs metoclopramide + dexamethasone + diphenhydramine in prevention of cisplatin-induced emesis. Lancet. 1992;340:96-99.

9. Basch E, Prestrud AA, Hesketh PJ, et al; for the American Society of Clinical Oncology. Antiemetics: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2011;29:4189-4198.

10. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): antiemesis. Version 1.2014. 2013. www.nccn.org/ professionals/physician_gls/pdf/antiemesis.pdf. Accessed January 5, 2014.

11. Roila F, Herrstedt J, Aapro M, et al; for the ESMO/MASCC Guidelines Working Group. Guideline update for MASCC and ESMO in the prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the Perugia consensus conference. Ann Oncol. 2010;21(suppl 5):v232-v243.

12. Balu S, Buchner D, Craver C, Gayle J. Palonosetron versus other 5-HT(3) receptor antagonists for prevention of chemotherapy-induced nausea and vomiting in patients with cancer on chemotherapy in a hospital outpatient setting. Clin Ther. 2011; 33:443-455.

13. Lin SJ, Hatoum HT, Buchner D, et al. Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study. BMC Health Serv Res. 2012;12:215.

14. Einhorn LH, Brames MJ, Dreicer R, et al. Palonosetron plus dexamethasone for prevention of chemotherapy-induced nausea and vomiting in patients receiving multiple-day cisplatin chemotherapy for germ cell cancer. Support Care Cancer.

2007;15:1293-1300.

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15. Giralt SA, Mangan KF, Maziarz RT, et al. Three palonosetron regimens to prevent CINV in myeloma patients receiving multiple-day high-dose melphalan and hematopoietic stem cell transplantation. Ann Oncol. 2011;22:939-946.

16. Cohen L, de Moor CA, Eisenberg P, et al. Chemotherapy-induced nausea and vomiting: incidence and impact on patient quality of life at community oncology settings. Support Care Cancer. 2007;15:497-503.

17. Ritter HL Jr, Gralla RJ, Hall SW, et al. Efficacy of intravenous granisetron to control nausea and vomiting during multiple cycles of cisplatin-based chemotherapy.

Cancer Invest. 1998;16:87-93.

18. Dibble SL, Isreal J, Nussey B, et al. Delayed chemotherapy-induced nausea in women treated for breast cancer. Oncol Nurs Forum. 2003;30:E40-E47.

19. Bloechl-Daum B, Deuson RR, Mavros P, et al. Delayed nausea and vomiting

continue to reduce patientsâ&#x20AC;&#x2122; quality of life after highly and moderately emetogenic chemotherapy despite antiemetic treatment. J Clin Oncol. 2006;24:4472-4478.

20. Hickok JT, Roscoe JA, Morrow GR, et al. 5-Hydroxytryptamine-receptor antagonists versus prochlorperazine for control of delayed nausea caused by doxorubicin: a URCC CCOP randomised controlled trial. Lancet. 2005;6:765-772.

21. Burke TA, Wisniewski T, Ernst FR. Resource utilization and costs associated with chemotherapy-induced nausea and vomiting (CINV) following highly or moderately emetogenic chemotherapy administered in the US outpatient hospital setting. Support Care Cancer. 2011;19:131-140.

22. Craver C, Gayle J, Balu S, Buchner D. Clinical and economic burden of chemotherapy-induced nausea and vomiting among patients with cancer in a hospital outpatient setting in the United States. J Med Econ. 2011;14:87-98.

Stakeholder Perspective Value of Selecting the Best Antiemetic Prophylactic Agent for Patients Using Chemotherapy

By Curtis Wander, PharmD, BCPS Clinical Pharmacy Team Lead, SelectHealth, Murray, UT

A

ntiemetic therapy is often used in patients receiving chemotherapy, because chemotherapy-induced nausea and vomiting (CINV) is common in this patient population. The various 5-hydroxytryptamine3 receptor antagonists (5-HT3-RAs) are all used for the prevention of CINV, but differences exist in terms of their efficacy and costs.

PAYERS: Appropriate antiemetic prophylaxis is a priority to payers, because highly and moderately emetogenic treatment regimens are often recommended in the treatment guidelines and algorithms for various cancers. These highly and moderately emetogenic regimens can, however, have many negative implications for payers.

Although payers may often only consider acquisition costs associated with individual 5-HT3-RA therapies, the potential cost avoidance from CINV should be considered when evaluating 5-HT3-RA therapies for formulary placement.

In their current analysis, Faria and colleagues show that in their data set palonosetron was more often used with highly emetogenic regimens compared with the other 5-HT3-RA therapies, and patients receiving palonosetron had a lower rate of delayed CINV. This, along with the delayed CINV rates that were shown to cost more when using dolasetron, granisetron, or ondansetron, than when palonosetron was administered, are of potential value to payers during medication evaluation when considering the class of medications, as well as each individual agent used.

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Side effects of highly and moderately emetogenic chemotherapies are inherent risks associated with these therapies; and as is often the case, when side effects increase, they can negatively impact patient adherence to the chemotherapy regimen. This, in turn, has the potential to increase the total costs to the payer in the management of CINV. In the event that decreased patient adherence or switching of regimens occurs, the associated costs are increasing, as a result of abandoning therapies, along with the resultant potential for poorer outcomes for the patient.

PATIENTS/PROVIDERS: The management of CINV has improved with the introduction of newer agents; however, the incidence of CINV is still of concern to patients and to providers. Patients often face the uncertainty related to the nausea associated with their chemotherapy regimen, even when appropriate prophylaxis is used. These concerns can often correlate with decreased adherence to the chemotherapy regimen or with the patientâ&#x20AC;&#x2122;s reluctance to use a moderately or highly emetogenic regimen. In turn, this may result in a providerâ&#x20AC;&#x2122;s choice of a less-than-ideal regimen for the patient in the attempt to ensure medication adherence and avoid the concerns related to nausea.

As Faria and colleagues show, palonosetron was associated with a lower overall rate of delayed CINV than the 3 comparator treatments, which may support providers in their conversations with reluctant patients when addressing concerns regarding moderately or highly emetogenic chemotherapy regimens. n

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Personalized Medicine and Payers An educational session for payers focusing on cost efficiency, value, outcomes, and impacts on treatment of personalized medicine.

Co-ChAirs

May 8, 2014 Loews Hollywood Hotel Los angeles, Ca

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10:40am – 11:20am

11:20am – 12:00pm

12:00pm – 12:15pm 12:15pm – 1:15pm 1:15pm – 2:45pm

2:45pm – 3:00pm 3:00pm – 4:00pm 4:00pm – 5:00pm 5:00pm – 7:00pm

Michael A. Kolodziej, MD National Medical Director Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP

Program Director Associate Professor University of Southern California

Special Session: Value-Based Strategies for Patients with Multiple Myeloma Supported by funding from Millennium: The Takeda Oncology Company Introductions and Opening Remarks Michael A. Kolodziej, MD; Grant Lawless, RPh, MD, FACP Session 1: Personalized Medicine and Value Peter Bach, MD, MAPP, Memorial Sloan-Kettering Cancer Center Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna Session 2: Measuring the Value of Prognostic and Predictive Outcomes Gary Palmer, MD, JD, MBA, MPH, Senior Vice President, Medical Affairs and Commercial Development, Foundation Medicine Macey Johnson, Vice President of Managed Care and Reimbursement, BioTheranostics Session 3: Utilizing Big Data to ID Phenotypes and Predictive Outcomes Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint George W. Sledge, MD, FASCO, Chief of Oncology, Stanford University Department of Medicine Session 4: Value Paradigm in Drug Development Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Kevin Knopf, MD, MPH, California Pacific Medical Center Christiane Langer, MD, Lead Medical Director for CRC, GU, and GBM, Genentech Panel Discussion - How will personalized medicine impact future treatment and use existing therapy?

Louis Jacques, MD, Director, Coverage and Analysis Group, Centers for Medicare & Medicaid Services Jennifer Malin, MD, PhD, Medical Director, Oncology, WellPoint Break Lunch/Product Theater Meet the Experts Roundtables Al Benson, MD, Professor of Medicine and Oncology, Northwestern University Medical School Mark Kris, MD, Oncologist, Memorial Sloan-Kettering Cancer Center Break Poster Presentations Poster and Session Discussant Cocktail Reception in the Exhibit Hall AVBCC2014May8agenda Asize_20714

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NEW FOR 2014

Oncology Practice Management, Advocacy, and Navigation An educational session for practice managers and other care providers focusing on cancer care and innovative delivery techniques.

CO-CHAIRS

MAY 9, 2014 Loews Hollywood Hotel Los Angeles, CA

Linda Bosserman, MD, FACP President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AGENDA 8:30am – 8:45am

Introductions and Opening Remarks Linda Bosserman, MD, FACP; Vicki Kennedy, LCSW

8:45am – 9:15am

Session 1: Cancer Care in Crisis: An Imperative for Change Douglas Blayney, MD, Ann & John Doerr Medical Director, Cancer Center, Stanford University Medical Center; Professor of Medicine, Stanford University School of Medicine

9:15am – 10:30am

Session 2: Innovation in Practice Management and Care Delivery: A Progress Report on Value-Based Innovation Linda Bosserman, MD, FACP, President, Wilshire Oncology Medical Group John Fox, MD, Associate Vice President of Medical Affairs, Priority Health John Sprandio, MD, Chief of Medical Oncology and Hematology, Oncology Management Services

10:30am – 10:45am

Break

10:45am – 11:45am

Session 3: Uniting the Patient, Provider, and Community Voice in Value-Based Cancer Care Terry Langbaum, Chief Administrative Officer, Kimmel Center, Johns Hopkins School of Medicine Lillie Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center Kim Thiboldeaux, President & CEO, Cancer Support Community

11:45am – 1:00pm

Lunch/Meet the Experts Roundtables John Fox, MD, Associate Vice President of Medical Affairs, Priority Health Lillie Shockney, RN, BS, MAS, Administrative Director, The Johns Hopkins Breast Center John Sprandio, MD, Chief of Medical Oncology and Hematology, Oncology Management Services

1:00pm – 1:45pm

Keynote Address Michael A. Kolodziej, MD, National Medical Director, Oncology Solutions, Aetna

1:45pm – 2:00pm

Closing Remarks

AVBCC2014May9agenda Asize_20714

REGISTER TODAY! www.regonline.com/avbcc2014