April 2008, Vol 1, No 3 by Dalia Buffery

THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN ™ APRIL 2008

VOLUME 1, NUMBER 3

EDITORIAL

The Great P Value: We the People Robert Emmett Henry

Health Reform in America Uwe Reinhardt, PhD REGULATORY

Medicare Coverage Policies for Biologics: The Broad Gray Line ™

Part 2 of an Interview with Joseph Antos, PhD BUSINESS

Benchmarking New Frontiers in Managed Care Pharmacy Cynthia Pigg, BSPharm, MHA; Joan Cihak, MSS, MHA

Not Waiting for Godot: The Evolution of Health Promotion at PPG Industries Alberto M. Colombi, MD, MPH; Janice L. Pringle, PhD; George T. Welsh, BS, MBA CLINICAL

Meta-Analysis 101: What You Want to Know in the Era of Comparative Effectiveness J.B. Jones, MBA; Saul Blecker, MD; Nirav R. Shah, MD, MPH

Depression Overview Thomas McCarter, MD, FACP DEPARTMENTS

Generic Drug Trends FDA Watch

Help patients in your plan benefit from always-there patient care Indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes.

Important Safety Information Boxed Warning: Congestive Heart Failure • Thiazolidinediones (TZDs), including ACTOS, cause or exacerbate congestive heart failure (CHF) in some patients. After initiation of ACTOS and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered.1 • ACTOS is not recommended in patients with symptomatic heart failure. Initiation of ACTOS in patients with established NYHA Class III or IV heart failure is contraindicated.1 Cardiac considerations: Like other TZDs, ACTOS can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate CHF. ACTOS should be used with caution in patients at risk for heart failure. Patients should be monitored for symptoms of heart failure or other adverse events related to fluid retention. In clinical trials, a small number of patients with a history of previously existing cardiac disease were reported to develop CHF when treated with ACTOS in combination with insulin. Reports of CHF have been received in postmarketing experience in patients with and without previously known heart disease.1 Hepatic safety: Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal (ULN) have been received in postmarketing experience with pioglitazone. Very rarely, these reports have involved hepatic failure with or without fatal outcome, although causality has not been established. Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with ACTOS, and periodically thereafter per the clinical judgment of the healthcare professional. If ALT >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with ACTOS.1 Other considerations: ACTOS may also be associated with hypoglycemia, edema, anemia, weight gain, and/or ovulation in premenopausal, anovulatory women. Adequate contraception should be recommended for premenopausal women. Macular edema has been reported in some diabetic patients receiving TZD therapy, although a causal relationship is unknown. Persons with diabetes should have routine eye exams and be instructed to immediately report any visual changes to their healthcare provider. An increased incidence of bone fracture was noted in female patients taking ACTOS. The risk of fracture should be considered in the care of patients treated with ACTOS, particularly females, and attention should be given to assessing and maintaining bone health according to current standards of care.1 Well-tolerated therapy: In US placebo-controlled ACTOS monotherapy clinical trials, the most common adverse events (e5%) were upper respiratory tract infection, headache, sinusitis, myalgia, tooth disorder, aggravated diabetes mellitus, and pharyngitis.1 Indications and usage: ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes. ACTOS is approved for use as monotherapy and in combination with sulfonylureas, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control.1 • ACTOS should not be used in patients with type 1 diabetes. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.1 • The major metabolic defects in type 2 diabetes are peripheral insulin resistance in muscle and fat, decreased pancreatic insulin secretion, and increased hepatic glucose output.2 Dyslipidemia in insulin resistance is represented by hypertriglyceridemia, decreased HDL levels, and increased small dense LDL particles.3 Renal and gastrointestinal function are also clinical considerations when prescribing an oral agent for type 2 diabetes.4 Please see Brief Summary of Prescribing Information on adjacent page. References: 1. ACTOS package insert, Takeda Pharmaceuticals America, Inc. 2. Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med. 2005;22:674-682. 3. American Diabetes Association. Dyslipidemia management in adults with diabetes. Diabetes Care. 2004;27(suppl 1):S68-S71. 4. American Diabetes Association. Standards of medical care in diabetes–2007. Diabetes Care. 2007;30(suppl 1):S4-S41.

ACTOS® (pioglitazone hydrochloride) Tablets Brief Summary of Prescribing Information. Please see package insert for Complete Prescribing Information. WARNING: CONGESTIVE HEART FAILURE • Thiazolidinediones, including ACTOS, cause or exacerbate congestive heart failure in some patients (see WARNINGS). After initiation of ACTOS, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to the current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered. • ACTOS is not recommended in patients with symptomatic heart failure. Initiation of ACTOS in patients with established NYHA Class III or IV heart failure is contraindicated (see CONTRAINDICATIONS and WARNINGS). INDICATIONS AND USAGE ACTOS is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes (non-insulin-dependent diabetes mellitus, NIDDM). ACTOS is indicated for monotherapy. ACTOS is also indicated for use in combination with a sulfonylurea, metformin, or insulin when diet and exercise plus the single agent do not result in adequate glycemic control. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise. These efforts are important not only in the primary treatment of type 2 diabetes, but also to maintain the efficacy of drug therapy. CONTRAINDICATIONS Initiation of ACTOS in patients with established New York Heart Association (NYHA) Class III or IV heart failure is contraindicated (see BOXED WARNING). ACTOS is contraindicated in patients with known hypersensitivity to this product or any of its components. WARNINGS Cardiac Failure and Other Cardiac Effects ACTOS, like other thiazolidinediones, can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate heart failure. Patients should be observed for signs and symptoms of heart failure. If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of ACTOS must be considered (see BOXED WARNING). Patients with NYHA Class III and IV cardiac status were not studied during pre-approval clinical trials and ACTOS is not recommended in these patients (see BOXED WARNING and CONTRAINDICATIONS). In one 16-week, U.S. double-blind, placebo-controlled clinical trial involving 566 patients with type 2 diabetes, ACTOS at doses of 15 mg and 30 mg in combination with insulin was compared to insulin therapy alone. This trial included patients with long-standing diabetes and a high prevalence of pre-existing medical conditions as follows: arterial hypertension (57.2%), peripheral neuropathy (22.6%), coronary heart disease (19.6%), retinopathy (13.1%), myocardial infarction (8.8%), vascular disease (6.4%), angina pectoris (4.4%), stroke and/or transient ischemic attack (4.1%), and congestive heart failure (2.3%). In this study, two of the 191 patients receiving 15 mg ACTOS plus insulin (1.1%) and two of the 188 patients receiving 30 mg ACTOS plus insulin (1.1%) developed congestive heart failure compared with none of the 187 patients on insulin therapy alone. All four of these patients had previous histories of cardiovascular conditions including coronary artery disease, previous CABG procedures, and myocardial infarction. In a 24-week, dose-controlled study in which ACTOS was coadministered with insulin, 0.3% of patients (1/345) on 30 mg and 0.9% (3/345) of patients on 45 mg reported CHF as a serious adverse event. Analysis of data from these studies did not identify specific factors that predict increased risk of congestive heart failure on combination therapy with insulin. In type 2 diabetes and congestive heart failure (systolic dysfunction) A 24-week post-marketing safety study was performed to compare ACTOS (n=262) to glyburide (n=256) in uncontrolled diabetic patients (mean HbA1c 8.8% at baseline) with NYHA Class II and III heart failure and ejection fraction less than 40% (mean EF 30% at baseline). Over the course of the study, overnight hospitalization for congestive heart failure was reported in 9.9% of patients on ACTOS compared to 4.7% of patients on glyburide with a treatment difference observed from 6 weeks. This adverse event associated with ACTOS was more marked in patients using insulin at baseline and in patients over 64 years of age. No difference in cardiovascular mortality between the treatment groups was observed. ACTOS should be initiated at the lowest approved dose if it is prescribed for patients with type 2 diabetes and systolic heart failure (NYHA Class II). If subsequent dose escalation is necessary, the dose should be increased gradually only after several months of treatment with careful monitoring for weight gain, edema, or signs and symptoms of CHF exacerbation. Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive) In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg once daily, or placebo (n=2633) (see ADVERSE REACTIONS). The percentage of patients who had an event of serious heart failure was higher for patients treated with ACTOS (5.7%, n=149) than for patients treated with placebo (4.1%, n=108). The incidence of death subsequent to a report of serious heart failure was 1.5% (n=40) in patients treated with ACTOS and 1.4% (n=37) in placebotreated patients. In patients treated with an insulin-containing regimen at baseline, the incidence of serious heart failure was 6.3% (n=54/864) with ACTOS and 5.2% (n=47/896) with placebo. For those patients treated with a sulfonylurea-containing regimen at baseline, the incidence of serious heart failure was 5.8% (n=94/1624) with ACTOS and 4.4% (n=71/1626) with placebo. PRECAUTIONS General ACTOS exerts its antihyperglycemic effect only in the presence of insulin. Therefore, ACTOS should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycemia: Patients receiving ACTOS in combination with insulin or oral hypoglycemic agents may be at risk for hypoglycemia, and a reduction in the dose of the concomitant agent may be necessary. Cardiovascular: In U.S. placebo-controlled clinical trials that excluded patients with New York Heart Association (NYHA) Class III and IV cardiac status, the incidence of serious cardiac adverse events related to volume expansion was not increased in patients treated with ACTOS as monotherapy or in combination with sulfonylureas or metformin vs. placebo-treated patients. In insulin combination studies, a small number of patients with a history of previously existing cardiac disease developed congestive heart failure when treated with ACTOS in combination with insulin (see WARNINGS). Patients with NYHA Class III and IV cardiac status were not studied in these ACTOS clinical trials. ACTOS is not indicated in patients with NYHA Class III or IV cardiac status. In postmarketing experience with ACTOS, cases of congestive heart failure have been reported in patients both with and without previously known heart disease. Edema: ACTOS should be used with caution in patients with edema. In all U.S. clinical trials, edema was reported more frequently in patients treated with ACTOS than in placebo-treated patients and appears to be dose related (see ADVERSE REACTIONS). In postmarketing experience, reports of initiation or worsening of edema have been received. Since thiazolidinediones, including ACTOS, can cause fluid retention, which can exacerbate or lead to congestive heart failure, ACTOS should be used with caution in patients at risk for heart failure. Patients should be monitored for signs and symptoms of heart failure (see BOXED WARNING, WARNINGS, and PRECAUTIONS, Information for Patients). Weight Gain: Dose related weight gain was seen with ACTOS alone and in combination with other hypoglycemic agents (Table 1). The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Table 1 Weight Changes (kg) from Baseline during Double-Blind Clinical Trials with ACTOS

Control Group (Placebo)

ACTOS 15 mg

ACTOS 30 mg

ACTOS 45 mg

Median (25th/75th percentile)

-1.4 (-2.7/0.0) n=256

0.9 (-0.5/3.4) n=79

1.0 (-0.9/3.4) n=188

2.6 (0.2/5.4) n=79

-0.5 (-1.8/0.7) n=187

2.0 (0.2/3.2) n=183

3.1 (1.1/5.4) n=528

4.1 (1.8/7.3) n=333

Metformin

-1.4 (-3.2/0.3) n=160

N/A

0.9 (-0.3/3.2) n=567

1.8 (-0.9/5.0) n=407

Insulin

0.2 (-1.4/1.4) n=182

2.3 (0.5/4.3) n=190

3.3 (0.9/6.3) n=522

4.1 (1.4/6.8) n=338

Monotherapy Sulfonylurea Combination Therapy

Note: Trial durations of 16 to 26 weeks Ovulation: Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus, adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes primarily occurred within the first 4 to 12 weeks of therapy and remained relatively constant thereafter. These changes may be related to increased plasma volume and have rarely been associated with any significant hematologic clinical effects (see ADVERSE REACTIONS, Laboratory Abnormalities). Hepatic Effects: In pre-approval clinical studies worldwide, over 4500 subjects were treated with ACTOS. In U.S. clinical studies, over 4700 patients with type 2 diabetes received ACTOS. There was no evidence of drug-induced hepatotoxicity or elevation of ALT levels in the clinical studies. During pre-approval placebo-controlled clinical trials in the U.S., a total of 4 of 1526 (0.26%) patients treated with ACTOS and 2 of 793 (0.25%) placebo-treated patients had ALT values e 3 times the upper limit of normal. The ALT elevations in patients treated with ACTOS were reversible and were not clearly related to therapy with ACTOS. In postmarketing experience with ACTOS, reports of hepatitis and of hepatic enzyme elevations to 3 or more times the upper limit of normal have been received. Very rarely, these reports have involved hepatic failure with and without fatal outcome, although causality has not been established. Pending the availability of the results of additional large, long-term controlled clinical trials and additional postmarketing safety data, it is recommended that patients treated with ACTOS undergo periodic monitoring of liver enzymes. Serum ALT (alanine aminotransferase) levels should be evaluated prior to the initiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional. Liver function tests should also be obtained for patients if symptoms suggestive of hepatic dysfunction occur, e.g., nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. The decision whether to continue the patient on therapy with ACTOS should be guided by clinical judgment pending laboratory evaluations. If jaundice is observed, drug therapy should be discontinued. Therapy with ACTOS should not be initiated if the patient exhibits clinical evidence of active liver disease or the ALT levels exceed 2.5 times the upper limit of normal. Patients with mildly elevated liver enzymes (ALT levels at 1 to 2.5 times the upper limit of normal) at baseline or any time during therapy with ACTOS should be evaluated to determine the cause of the liver enzyme elevation. Initiation or continuation of therapy with ACTOS in patients with mildly elevated liver enzymes should proceed with caution and include appropriate clinical follow-up which may include more frequent liver enzyme monitoring. If serum transaminase levels are increased (ALT > 2.5 times the upper limit of normal), liver function tests should be evaluated more frequently until the levels return to normal or pretreatment values. If ALT levels exceed 3 times the upper limit of normal, the test should be repeated as soon as possible. If ALT levels remain > 3 times the upper limit of normal or if the patient is jaundiced, ACTOS therapy should be discontinued. Macular Edema: Macular edema has been reported in post-marketing experience in diabetic patients who were taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, but some patients appear to have been diagnosed on routine ophthalmologic examination. Some patients had peripheral edema at the time macular edema was diagnosed. Some patients had improvement in their macular edema after discontinuation of their thiazolidinedione. It is unknown whether or not there is a causal relationship between pioglitazone and macular edema. Patients with diabetes should have regular eye examinations by an ophthalmologist, per the Standards of Care of the American Diabetes Association. Additionally, any diabetic who reports any kind of visual symptom should be promptly referred to an ophthalmologist, regardless of the patient's underlying medications or other physical findings (see ADVERSE REACTIONS). Fractures: In a randomized trial (PROactive) in patients with type 2 diabetes (mean duration of diabetes 9.5 years), an increased incidence of bone fracture was noted in female patients taking pioglitazone. During a mean follow-up of 34.5 months, the incidence of bone fracture in females was 5.1% (44/870) for pioglitazone versus 2.5% (23/905) for placebo. This difference was noted after the first year of treatment and remained during the course of the study. The majority of fractures observed in female patients were nonvertebral fractures including lower limb and distal upper limb. No increase in fracture rates was observed in men treated with pioglitazone 1.7% (30/1735) versus placebo 2.1% (37/1728). The risk of fracture should be considered in the care of patients, especially female patients, treated with pioglitazone and attention should be given to assessing and maintaining bone health according to current standards of care. Laboratory Tests FPG and HbA1c measurements should be performed periodically to monitor glycemic control and the therapeutic response to ACTOS. Liver enzyme monitoring is recommended prior to initiation of therapy with ACTOS in all patients and periodically thereafter per the clinical judgment of the health care professional (see PRECAUTIONS, General, Hepatic Effects and ADVERSE REACTIONS, Serum Transaminase Levels). Information for Patients It is important to instruct patients to adhere to dietary instructions and to have blood glucose and glycosylated hemoglobin tested regularly. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be reminded to seek medical advice promptly. Patients who experience an unusually rapid increase in weight or edema or who develop shortness of breath or other symptoms of heart failure while on ACTOS should immediately report these symptoms to their physician. Patients should be told that blood tests for liver function will be performed prior to the start of therapy and periodically thereafter per the clinical judgment of the health care professional. Patients should be told to seek immediate medical advice for unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or dark urine. Patients should be told to take ACTOS once daily. ACTOS can be taken with or without meals. If a dose is missed on one day, the dose should not be doubled the following day. When using combination therapy with insulin or oral hypoglycemic agents, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and their family members. Therapy with ACTOS, like other thiazolidinediones, may result in ovulation in some premenopausal anovulatory women. As a result, these patients may be at an increased risk for pregnancy while taking ACTOS. Thus,

adequate contraception in premenopausal women should be recommended. This possible effect has not been investigated in clinical studies so the frequency of this occurrence is not known. Drug Interactions In vivo drug-drug interaction studies have suggested that pioglitazone may be a weak inducer of CYP 450 isoform 3A4 substrate. An enzyme inhibitor of CYP2C8 (such as gemfibrozil) may significantly increase the AUC of pioglitazone and an enzyme inducer of CYP2C8 (such as rifampin) may significantly decrease the AUC of pioglitazone. Therefore, if an inhibitor or inducer of CYP2C8 is started or stopped during treatment with pioglitazone, changes in diabetes treatment may be needed based on clinical response. Carcinogenesis, Mutagenesis, Impairment of Fertility A two-year carcinogenicity study was conducted in male and female rats at oral doses up to 63 mg/kg (approximately 14 times the maximum recommended human oral dose of 45 mg based on mg/m2). Drug-induced tumors were not observed in any organ except for the urinary bladder. Benign and/or malignant transitional cell neoplasms were observed in male rats at 4 mg/kg/day and above (approximately equal to the maximum recommended human oral dose based on mg/m2). A two-year carcinogenicity study was conducted in male and female mice at oral doses up to 100 mg/kg/day (approximately 11 times the maximum recommended human oral dose based on mg/m2). No drug-induced tumors were observed in any organ. During prospective evaluation of urinary cytology involving more than 1800 patients receiving ACTOS in clinical trials up to one year in duration, no new cases of bladder tumors were identified. In two 3-year studies in which pioglitazone was compared to placebo or glyburide, there were 16/3656 (0.44%) reports of bladder cancer in patients taking pioglitazone compared to 5/3679 (0.14%) in patients not taking pioglitazone. After excluding patients in whom exposure to study drug was less than one year at the time of diagnosis of bladder cancer, there were six (0.16%) cases on pioglitazone and two (0.05%) on placebo. Pioglitazone HCl was not mutagenic in a battery of genetic toxicology studies, including the Ames bacterial assay, a mammalian cell forward gene mutation assay (CHO/HPRT and AS52/XPRT), an in vitro cytogenetics assay using CHL cells, an unscheduled DNA synthesis assay, and an in vivo micronucleus assay. No adverse effects upon fertility were observed in male and female rats at oral doses up to 40 mg/kg pioglitazone HCl daily prior to and throughout mating and gestation (approximately 9 times the maximum recommended human oral dose based on mg/m2). Animal Toxicology Heart enlargement has been observed in mice (100 mg/kg), rats (4 mg/kg and above) and dogs (3 mg/kg) treated orally with pioglitazone HCl (approximately 11, 1, and 2 times the maximum recommended human oral dose for mice, rats, and dogs, respectively, based on mg/m2). In a one-year rat study, drug-related early death due to apparent heart dysfunction occurred at an oral dose of 160 mg/kg/day (approximately 35 times the maximum recommended human oral dose based on mg/m2). Heart enlargement was seen in a 13-week study in monkeys at oral doses of 8.9 mg/kg and above (approximately 4 times the maximum recommended human oral dose based on mg/m2), but not in a 52-week study at oral doses up to 32 mg/kg (approximately 13 times the maximum recommended human oral dose based on mg/m2). Pregnancy Pregnancy Category C. Pioglitazone was not teratogenic in rats at oral doses up to 80 mg/kg or in rabbits given up to 160 mg/kg during organogenesis (approximately 17 and 40 times the maximum recommended human oral dose based on mg/m2, respectively). Delayed parturition and embryotoxicity (as evidenced by increased postimplantation losses, delayed development and reduced fetal weights) were observed in rats at oral doses of 40 mg/kg/day and above (approximately 10 times the maximum recommended human oral dose based on mg/m2). No functional or behavioral toxicity was observed in offspring of rats. In rabbits, embryotoxicity was observed at an oral dose of 160 mg/kg (approximately 40 times the maximum recommended human oral dose based on mg/m2). Delayed postnatal development, attributed to decreased body weight, was observed in offspring of rats at oral doses of 10 mg/kg and above during late gestation and lactation periods (approximately 2 times the maximum recommended human oral dose based on mg/m2). There are no adequate and well-controlled studies in pregnant women. ACTOS should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Because current information strongly suggests that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital anomalies, as well as increased neonatal morbidity and mortality, most experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible. Nursing Mothers Pioglitazone is secreted in the milk of lactating rats. It is not known whether ACTOS is secreted in human milk. Because many drugs are excreted in human milk, ACTOS should not be administered to a breastfeeding woman. Pediatric Use Safety and effectiveness of ACTOS in pediatric patients have not been established. Elderly Use Approximately 500 patients in placebo-controlled clinical trials of ACTOS were 65 and over. No significant differences in effectiveness and safety were observed between these patients and younger patients. ADVERSE REACTIONS Over 8500 patients with type 2 diabetes have been treated with ACTOS in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with ACTOS from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received ACTOS for at least 2 years. The overall incidence and types of adverse events reported in placebo-controlled clinical trials of ACTOS monotherapy at doses of 7.5 mg, 15 mg, 30 mg, or 45 mg once daily are shown in Table 2. Table 2

Placebo-Controlled Clinical Studies of ACTOS Monotherapy: Adverse Events Reported at a Frequency e 5% of Patients Treated with ACTOS (% of Patients) Placebo ACTOS N=259 N=606 Upper Respiratory Tract Infection 8.5 13.2 Headache 6.9 9.1 Sinusitis 4.6 6.3 Myalgia 2.7 5.4 Tooth Disorder 2.3 5.3 Diabetes Mellitus Aggravated 8.1 5.1 Pharyngitis 0.8 5.1

For most clinical adverse events the incidence was similar for groups treated with ACTOS monotherapy and those treated in combination with sulfonylureas, metformin, and insulin. There was an increase in the occurrence of edema in the patients treated with ACTOS and insulin compared to insulin alone. In a 16-week, placebo-controlled ACTOS plus insulin trial (n=379), 10 patients treated with ACTOS plus insulin developed dyspnea and also, at some point during their therapy, developed either weight change or edema. Seven of these 10 patients received diuretics to treat these symptoms. This was not reported in the insulin plus placebo group. The incidence of withdrawals from placebo-controlled clinical trials due to an adverse event other than hyperglycemia was similar for patients treated with placebo (2.8%) or ACTOS (3.3%). In controlled combination therapy studies with either a sulfonylurea or insulin, mild to moderate hypoglycemia, which appears to be dose related, was reported (see PRECAUTIONS, General, Hypoglycemia). In U.S. double-blind studies, anemia was reported in 2% of patients treated with ACTOS plus sulfonylurea, metformin or insulin (see PRECAUTIONS, General, Hematologic). In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with ACTOS versus 1.2% of placebo-treated patients. In combination therapy studies, edema was reported for ©1999, 2008 Takeda Pharmaceuticals North America, Inc.

PIO-00538

7.2% of patients treated with ACTOS and sulfonylureas compared to 2.1% of patients on sulfonylureas alone. In combination therapy studies with metformin, edema was reported in 6.0% of patients on combination therapy compared to 2.5% of patients on metformin alone. In combination therapy studies with insulin, edema was reported in 15.3% of patients on combination therapy compared to 7.0% of patients on insulin alone. Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General, Edema). In one 16-week clinical trial of insulin plus ACTOS combination therapy, more patients developed congestive heart failure on combination therapy (1.1%) compared to none on insulin alone (see WARNINGS, Cardiac Failure and Other Cardiac Effects).

Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive) In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg daily or placebo (n=2633) in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean HbA1c 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in the cardiovascular composite endpoint (see Table 3 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS. Table 3 Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint Placebo N=2633 First Events Total Events (N) (N) 572 900 122 186 157 118 119 96 78 63 240 101 28 15 92 57

Cardiovascular Events Any event All-cause mortality Non-fatal MI Stroke ACS Cardiac intervention Major leg amputation Leg revascularization

ACTOS N=2605 First Events Total Events (N) (N) 514 803 110 177 105 131 76 92 42 65 101 195 9 28 71 115

Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, General, Macular Edema). Laboratory Abnormalities Hematologic: ACTOS may cause decreases in hemoglobin and hematocrit. The fall in hemoglobin and hematocrit with ACTOS appears to be dose related. Across all clinical studies, mean hemoglobin values declined by 2% to 4% in patients treated with ACTOS. These changes generally occurred within the first 4 to 12 weeks of therapy and remained relatively stable thereafter. These changes may be related to increased plasma volume associated with ACTOS therapy and have rarely been associated with any significant hematologic clinical effects. Serum Transaminase Levels: During all clinical studies in the U.S., 14 of 4780 (0.30%) patients treated with ACTOS had ALT values e 3 times the upper limit of normal during treatment. All patients with follow-up values had reversible elevations in ALT. In the population of patients treated with ACTOS, mean values for bilirubin, AST, ALT, alkaline phosphatase, and GGT were decreased at the final visit compared with baseline. Fewer than 0.9% of patients treated with ACTOS were withdrawn from clinical trials in the U.S. due to abnormal liver function tests. In pre-approval clinical trials, there were no cases of idiosyncratic drug reactions leading to hepatic failure (see PRECAUTIONS, General, Hepatic Effects). CPK Levels: During required laboratory testing in clinical trials, sporadic, transient elevations in creatine phosphokinase levels (CPK) were observed. An isolated elevation to greater than 10 times the upper limit of normal was noted in 9 patients (values of 2150 to 11400 IU/L). Six of these patients continued to receive ACTOS, two patients had completed receiving study medication at the time of the elevated value and one patient discontinued study medication due to the elevation. These elevations resolved without any apparent clinical sequelae. The relationship of these events to ACTOS therapy is unknown. OVERDOSAGE During controlled clinical trials, one case of overdose with ACTOS was reported. A male patient took 120 mg per day for four days, then 180 mg per day for seven days. The patient denied any clinical symptoms during this period. In the event of overdosage, appropriate supportive treatment should be initiated according to patient’s clinical signs and symptoms. Rx only Manufactured by: Takeda Pharmaceutical Company Limited Osaka, Japan Marketed by: Takeda Pharmaceuticals America, Inc. One Takeda Parkway Deerfield, IL 60015 ACTOS® is a registered trademark of Takeda Pharmaceutical Company Limited and used under license by Takeda Pharmaceuticals America, Inc. © 1999, 2007 Takeda Pharmaceuticals America, Inc. 05-1141

September 2007

L-PIO-0907-4

1/08

Printed in U.S.A.

LETTER FROM THE EDITOR

The Great P Value: We the People

ew clinical, business, and regulatory healthcare systems are offering unprecedented opportunities for providing quality and value. At the heart of the healthcare debate lay evidence, balance, and competing incentives in search of a point of consensus. Data are poorly understood and do not speak for themselves. Cooperation between stakeholder groups is still elusive, with stakeholder polarization strong, despite the urge to unite forces. The healthcare system is circling around looking for an organizing principle. A recent patient advocacy conference showed promise for breaking the deadlock, suggesting that, as our governmental premise states, people are the proper source of consensus and power. For more about this radical-populist notion, read on. On March 6-7, 2008, the National Working Group on Evidence-Based Health Care convened in Washington, DC, to discuss the most important of all “p values”—the patient. This patient advocacy summit, titled “Advancing the Evidence of Experience: Practical Issues for Patient/Consumer Inclusion,” brought to light the possibilities for involving patients in the determination of quality and value in healthcare delivery. Driving the conference was the search for evidence and a balanced, humane, and effective use of resources, and the right of people—the patients—to know and drive their own medical care. We will cover this event and the topics it explored in future issues, as these suggest a worthy guiding force for the healthcare debate. The theme of the conference happens to align with topics discussed in this issue of American Health & Drug Benefits. For healthcare innovation is meaningless unless it is accurate, relevant, and practicable. Accuracy entails validating the evidence concerning disease states and the measures invoked to treat them. Relevance requires serving the people’s priorities and interests at every step of the healthcare process. Practicability means bringing these interventions into mainstream patient use, which is the process of health and drug benefits. We cover each area of inquiry across several articles. Dr Nirav Shah looks into an accuracy tool of great interest—meta-analysis—in the first of a series of articles on the evidence pyramid that has been undergoing some radical reconstruction lately. Dr Joseph Antos presents his insights on Medicare policy in regard to

biologic products. Dr Alberto Colombi reports on his model for benefit designs at PPG Industries, an innovative approach to healthcare intervention that marries patient wellness with employer productivity. Dr Thomas McCarter’s overview of depression provides an action document that summarizes the clinical reality of this disease, the clinical burden, and the tactical steps for its treatment, including a drug utilization chart. Cynthia Pigg explains the defining resource allocation measures that managed care pharmacy experts are using. Dr Gary Owens analyzes generic drugs in terms of evidentiary accuracy, relevance, and practicality. Mark Senak captures the confrontational atmosphere in Washington, DC, as Congress pushes to change the US Food and Drug Administration’s policy from pro-efficacy to pro-safety, a dynamic that is of vital interest to all stakeholders, given its impact on patient outcomes. The net effect of this editorial lineup is, we hope, a practical guide to evidence as felt by not only the providers, payors, purchasers, and policymakers, but the people as well. The same search for evidence seen in the patient advocacy summit is also evident in the tag line of this journal—The Peer-Reviewed Forum for Evidence in Benefit Design. Open dialogue and discussion must drive the research that addresses patients’ priorities. In this spirit of inclusiveness, we invite you, our readers, to join our editorial process, by joining our reading group or editorial review team, by bringing us your ideas and articles, always keeping in mind the ultimate beneficiary: “we the people.” If we grant that the pursuit of happiness involves good health, then the people are as much the basis for all scientific discovery as they are the foundation of all political activity. A free people will not only have access to good evidence, it will be part of the process of defining its intended applications.

Robert Emmett Henry Editor-in-Chief For editorial queries and submissions, please contact rhenry@AHDBonline.com.

www.AHDBonline.com

APRIL 2008

VOLUME 1, NUMBER 3

™

EDITORIAL

The Great P Value: We the People

Publisher Nicholas Englezos nick@engagehc.com

Robert Emmett Henry

Associate Publisher Maurice Nogueira maurice@engagehc.com

Health Reform in America Uwe Reinhardt, PhD

Editorial Director Dalia Buffery dalia@AHDBonline.com

REGULATORY

Contributing Editor Sandy Paton

Medicare Coverage Policies for Biologics: The Broad Gray Line An Interview with Joseph Antos, PhD

Senior Production Manager Alaina Pede Director of Human Resources Blanche Marchitto

BUSINESS

President Brian F. Tyburski brian@engagehc.com

Benchmarking New Frontiers in Managed Care Pharmacy Cynthia Pigg, BSPharm, MHA; Joan Cihak, MSS, MHA

Not Waiting for Godot: The Evolution of Health Promotion at PPG Industries Alberto M. Colombi, MD, MPH; Janice L. Pringle, PhD; George T. Welsh, BS, MBA

Editor-in-Chief Robert Emmett Henry rhenry@AHDBonline.com

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

CLINICAL

Meta-Analysis 101: What You Want to Know in the Era of Comparative Effectiveness J.B. Jones, MBA; Saul Blecker, MD; Nirav R. Shah, MD, MPH

Depression Overview Thomas McCarter, MD, FACP

This publication will provide drug benefit decision makers the integrated industry information they require to devise formularies and drug benefit designs that stand up to today’s special healthcare delivery and business needs. Contact Information: For reprints and subscription information and editorial queries, please contact: editorial@AHDBonline.com

Continued on page 6

AMERICAN HEALTH & DRUG BENEFITS

April 2008

www.AHDBonline.com

Now Available

Please visit www.simcortablets.com

ÂŠ2008 Abbott Laboratories Abbott Park, IL 60064 306-78502 March 2008 Printed in U.S.A.

APRIL 2008

VOLUME 1, NUMBER 3

™

DEPARTMENTS

Clinical Editor

Gary M. Owens, MD

Thomas McCarter, MD, FACP Chief Clinical Officer Executive Health Resources tmccarter@AHDBonline.com

FDA Watch

Business/Government Editor

Mark Senak, JD

Generic Drug Trends

Call for Papers

Kip Piper, MA, CHE President Health Results Group kpiper@AHDBonline.com

Information for Authors

Editorial Board

Pharmacy Reimbursement Policy Michael R. Schaffer, PharmD, MBA

Executive Summaries

Employers F. Randy Vogenberg, RPh, PhD Alberto M. Colombi, MD, MPH Specialty Pharmacy Rebecca M. Shanahan, Esq.

UNMANAGED MOMENTS

Managed Care Pharmacy Policy Cynthia J. Pigg, BSPharm, MHA Managed Markets Marketing Jeffrey A. Bourret, RPh, MS, FASHP Charles E. Collins, Jr, MS, MBA

Clinical Research: Hypertension and Preventive Cardiology Michael A. Weber, MD

Managed Care & Government Affairs Sharad Mansukani, MD Research & Development Michael F. Murphy, MD, PhD Wayne A. Rosenkrans, Jr, PhD

Visit us at www.AHDBonline.com

Healthcare Outcomes Gary M. Owens, MD Outcomes Research Gordon M. Cummins, MS Timothy S. Regan, BPharm, RPh

Editorial correspondence should be addressed to Editor-in-Chief, American Health & Drug Benefits, PO Box 432, Long Valley, NJ 07853. E-mail: editorial@AHDBonline.com. POSTMASTER: CORRESPONDENCE REGARDING SUBSCRIPTIONS OR CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, American Health & Drug Benefits, PO Box 432, Long Valley, NJ 07853. Fax: 732-656-7938. YEARLY SUBSCRIPTION RATES: One year: $99.00 USD; Two years: $149.00 USD; Three years: $199.00 USD. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Engage Healthcare Communications LLC, PO Box 432, Long Valley, NJ 07853. The ideas and opinions expressed in American Health & Drug Benefits do not necessarily reflect those of the Editorial Board, the Editor-in-Chief, or the Publisher. Publication of an advertisement or other product mentioned in American Health & Drug Benefits should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. Please convey any errors to the Editor-in-Chief. ISSN# applied for January 2008. American Health & Drug Benefits is published 9 times a year by Engage Healthcare Communications, LLC, PO Box 432, Long Valley, NJ 07853. Telephone: 732-656-7935. Fax: 732-656-7938. Copyright © 2008 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

AMERICAN HEALTH & DRUG BENEFITS

April 2008

Pharmacy & Specialty Products James T. Kenney, RPh, MBA Pharmacy Benefit Design Rusty Hailey, PharmD, DPh, MBA Scott R. Taylor, RPh, MBA Pharmacoeconomics Jeff Jianfei Guo, BPharm, MS, PhD Policy & Public Health Alex Hathaway, MD, MPH, FACPM Actuary David Williams Medical Research Nirav R. Shah, MD, MPH

www.AHDBonline.com

The only complete line of strengths for dosing flexibility NDC 58177-625-04 5 mg 100’s NDC 58177-625-11 5 mg 10x10 UD NDC 58177-461-04 10 mg 100’s NDC 58177-445-04 15 mg 100’s NDC 58177-462-04 20 mg 100’s NDC 58177-446-04 30 mg 100’s

Stock OXYCODONE HCI from Ethex today and be ready for prescription requests! • Generically priced • Supported by an awareness campaign to prescribers • Patient Sample Vouchers, redeemable at the pharmacy, offer a free trial of 10 mg or 20 mg tablets (with a valid prescription, void where prohibited by law) For more information log on to www.ethex.com or call 1-888-567-9176.

GUEST EDITORIAL

Health Reform in America By Uwe Reinhardt, PhD

s more and more American families find their budgets pinched by the ever-rising cost of healthcare and a growing volume of scholarly research convinces health policy experts that the quality of American health too often falls short of what it should be—given that Americans spend about twice as much per capita (in purchasing power parity dollars) on healthcare than its neighboring Canada—it is inevitable that the topic of health reform will have a prominent place in the forthcoming presidential elections. Although the details of any such reform will be mind-numbing, its overarching goals are 2-fold: (1) enhancing the “cost-effectiveness” of American healthcare, and (2) better protection for American families against the financial burden of ill health.

Enhancing Cost-Effectiveness Among health policy experts, the term “cost-effectiveness” means costs per unit of clinical outcome, or its inverse, outcome per dollar of cost—“bang for the buck,” in the vernacular. Clinical outcome can be variously defined here, from the very narrow “reduction in measured blood pressure” to a very broadly defined metric, such as quality-adjusted life-years, widely known by the acronym QALYs. The latter converts life-years in a specified, less-than-perfect health status into fewer life-years in perfect health, with the conversion ratio being based on the responses to surveys of citizens asked to evaluate different health outcomes. Embedded in the overarching goal of cost-effectiveness, of course, are 2 subgoals that must be reached— (1) enhancing the quality of healthcare in the United States, and (2) controlling spending on treatments for given illnesses. Attainment of one or the other subgoals, or both, automatically will enhance the costeffectiveness of healthcare. It may be thought that everyone should applaud the enhancement of cost-effectiveness of American healthcare. In fact, all 3 current presidential candidates— Dr Reinhardt is James Madison Professor of Political Economy and Professor of Economics and Public Affairs at Princeton University, Princeton, NJ.

Senators Clinton, McCain, and Obama— share pretty much the same view on the imperative of moving toward that goal. But the pursuit of that goal faces more obstacles than may be surmised, which is why its attainment has eluded policymakers for so many decades. First, correctly viewed, there is a large and powerful constituency for inefficiency in healthcare. It is so because, in healthcare as elsewhere, one person’s cost usually is another person’s income. To the loser, “cost-effectiveness” therefore implies reducing healthcare income. Those whose income is reduced by enhanced cost-effectiveness can be counted on to throw any barrier they can think of onto the path of greater cost-effectiveness. So far, their barriers have been largely impenetrable to employers, private insurers, and government. Second, the steps required to enhance the appropriateness and quality of healthcare and to control spending thereon are not costless. There is a wide consensus among the experts that this step requires vast upfront investments in information technology on the part of the private and public sectors. Governments in other nations—notably the United Kingdom—have stepped up to the cashier’s window to make that investment. Antigovernment ideology and tight public budgets remain major obstacles to a significant government role in constructing the required 21st-century information infrastructure for the US healthcare. The private sector has so far not seen the business case for the huge private sector outlays needed to construct a truly 21stcentury health information platform, nor will it see it as long as the public and private payors remain as willing as they have always been to adequately compensate the providers of healthcare, even for low-quality, costineffective healthcare. Financing an information infrastructure aside, there is no reason to assume that the providers of healthcare—be they physicians, hospitals, or the suppliers of medical devices and pharmaceutical products—would welcome the greater transparency on their prices and the quality of their services or products that any move toward greater cost-effectiveness would entail. Both the medical-device and pharmaceutical industries, for Continued on page 10

AMERICAN HEALTH & DRUG BENEFITS

April 2008

301

100

thousand patients helped through Lilly patient assistance programs

customer service agents to answer patient and managed care partner questions

amore patient in charge of her family’s health

Healthcare may be a numbers game, but we’re only interested in one number. At Lilly, helping you manage your patients requires a shared commitment to delivering initiatives, ideas, and positive outcomes. So we keep our focus on those who count on our medicines. From diabetes and mental health education, to patient adherence efforts, to simply offering the best answers we can,

Lilly is working towards one focus... one patient at a time.

GUEST EDITORIAL

example, have lobbied for years against the establishment of cost-effectiveness research institutes, such as those now operating in Europe, Canada, Australia, and in some parts of Asia. The raw competition likely to be unleashed by such transparency, and consumer awareness of the relative cost-effectiveness of alternative therapies, inevitably would put financial and professional pressure on the providers of healthcare—pressure they have so far had the luxury to elude.

How much public spending would it take to protect every American family from the financial inroads of ill health?

Finally, the benefits that would be yielded by the large upfront investments required for more cost-effective US healthcare would not necessarily accrue to those who make that investment. Such misalignment between investment and return, too, will remain an obstacle to the attainment of this overarching goal.

Attaining Universal Coverage If attaining the goal of cost-effectiveness is difficult, it is even more challenging to attain the second overarching goal of health reform—better protection for American families against the financial burdens triggered by ill health. This is not so much a problem of economics but rather of social ethics, that is, the hitherto open question: To what extent should Americans in the upper third or so of the nation’s distribution of family income help subsidize the healthcare received by families in the bottom third or so of that distribution? It is a problem in the political economy of sharing. The nation has long been divided into 2 camps on that issue—those who believe that healthcare is basically a private consumer good whose financing should be the responsibility of its recipients, and that rationing healthcare by income class is alright, and those who believe that healthcare is basically a social good that should be available on roughly equal terms to all who need it and financed by all members of society on the basis of their ability to pay for healthcare, so that if rationing healthcare becomes necessary, all members of society should be exposed to it with equal risk. Unfortunately, any open debate on these delicate ethical dimensions of health reform can

easily overstep the bounds of political correctness in a nation whose media (certainly the television media) convey political debates on public policy in terms of sound bites. How much public spending would it take to protect every American family from the financial inroads of ill health? How might one go about moving toward that goal, and how would we know whether we have reached the goal? Starting with the last question, the most practical approach to defining “universal coverage” would be to specify the percentage of household income that Americans believe individual families should be asked to devote out-of-pocket to the purchase of health insurance and healthcare. An honest public debate on the social ethics of healthcare may start at that point. Quite possibly, Americans may decide that that percentage should increase progressively with family income, although one cannot be sure of it. Currently in the United States, that percentage tends to decrease with family income, except for the very poor who are on Medicaid, who enjoy a truly comprehensive, firstdollar coverage. It is clear that the additional federal outlays required to reach universal coverage would rise inversely with the percentage of family income Americans would be asked to pay out-of-pocket. The lower the percentage, the higher are the required federal outlays. For example, Senator Clinton has recently proposed that this percentage should be between 5% and 10%, which is why she would ask Congress for as much as $110 billion a year to subsidize lower-income families. As to the administrative mechanism of reaching universal coverage, a myriad of alternative proposals have been developed over the past several decades, ranging all the way from a single-payor system (eg, Medicare for all) to merely plugging the gaps existing in the current health insurance system. Policy analysts differ on how best to plug such gaps, by publicly subsidizing the purchase of private health insurance or by simply expanding the existing public insurance programs—Medicare, Medicaid, and SCHIP. These differences of opinion are rarely driven by empirical research; for the most part they reflect the analyst’s personal ideology.

Health Reform in the Presidential Campaign With this general backdrop on health reform, we can look briefly at the health reform proposals put forth by the 3 current candidates for the presidency. The major design parameters one should focus on are: Continued on page 12

AMERICAN HEALTH & DRUG BENEFITS

April 2008

We focus on the human in human health care

At Eisai (a•zi), caring for people is our work Satisfying unmet medical needs and increasing benefits to patients, their families, and caregivers is Eisai’s human health care (hhc) mission. This includes the development of innovative medicines– notably the discovery of the world’s most widely used treatment for Alzheimer’s disease.

Eisai is recognized for our business and patient advocacy partnerships, as well as our commitment to working with healthcare professionals to achieve improved patient care worldwide. That is our quest. That is our promise. That is what makes us Eisai.

Ingenuity that Drives Innovation in Neurology, GI Disorders, and Oncology/Critical Care

Visit us at www.eisai.com, or 1-888-274-2378

GUEST EDITORIAL

Although Senators Clinton and Obama would use existing public programs . . . Senator McCain would not expand public programs.

1. What total added, annual federal budget is the candidate prepared to ask Congress to devote to the reform? 2. How would the extra spending proposed (whatever that is) be financed? 3. Is insurance coverage to be mandated on the individual, or will it remain a voluntary consumer choice? 4. Is extended coverage to be achieved by subsidizing private insurance coverage or by extending existing public programs? 5. What provisions are made to reorganize the market for health insurance purchased by individuals? Would there be new risk-pooling mechanisms for the individual insurance market? Or would premiums charged to the individual in that market continue to be based on that individual’s health status? 6. What would happen to employment-based health insurance? Would the tax preference now enjoyed by that arrangement be perpetuated? Would small employers be subsidized to provide insurance to their employees? 7. What cost-control mechanisms do the candidates propose? On the first design parameter, the total new federal spending for health reform, Senator Clinton has suggested $110 billion in new funding in the initial year, which would, of course, have to increase year by year in step with overall increases in health spending per capita. Senator Obama estimates the cost of his health plan at between $50 billion and $65 billion in the initial year. Senator McCain has not offered a specific budget figure. Only Senator Clinton would mandate the individual to have health insurance. She does so to prohibit adverse-risk selection (freeloading) by individuals, which occurs when insurers are required to offer anyone health insurance at “community-rated” premiums unrelated to the individual’s health status, a requirement Senator Clinton would impose on insurers. Neither Senator McCain nor Senator Obama would require individuals to be insured. Senator Obama’s opposition is based on his surmise that too many fami-

AMERICAN HEALTH & DRUG BENEFITS

April 2008

lies simply could not afford the mandated insurance, a phenomenon now manifest in Massachusetts, whose then-governor Mitt Romney did impose such a mandate on state residents. Senator McCain probably opposes such a mandate on ideological grounds alone. Finally, although Senators Clinton and Obama would use existing public programs (and new ones yet to be created) as well as private insurers to expand coverage, Senator McCain would not expand public programs and, indeed, would allow veterans to opt out of the VA system for private healthcare delivery. Space does not permit a detailed analysis of Senators Clinton’s, McCain’s, and Obama’s health reform plans on all their design parameters. A superb side-by-side summary of these can be found at http://www. health08.org/sidebyside.cfm. In reacting to these proposals, it must be kept in mind that they are merely that—proposals. It will be Congress who writes any specific health reform legislation, and the bureaucracy that “legislates” further, so to speak, through its detailed regulations. It is a lesson Senator Clinton certainly will not have forgotten.

Unmanaged Moment

“How much medical skill are you willing to pay for?”

REGULATORY

Medicare Coverage Policies for Biologics: The Broad Gray Line Part 2 of an Interview with Joseph Antos, PhD

In October 2007, American Health & Drug Benefits asked Dr Joseph Antos to discuss the forces that have shaped Medicare’s policies and their impact on the various stakeholders in US healthcare. The first part of the interview appeared in AHDB in February 2008. This second part focuses on the impact of the Centers for Medicare & Medicaid Services drug coverage on the future of biologic products. This discussion does not reflect any new developments occurring after October, such as the recent recommendation of the US Food and Drug Administration advisory committee to narrow the indication for erythropoiesis-stimulating agents to patients with cancer.

obert Henry: How are decisions being made for conventional pharmaceutical products on the one hand and biologic products on the other? Biologics have a comparative carte blanche—for now. Attempts at cost-containment in biologic treatment have been shown to be counterproductive, punitive, and not cost-effective. How adept are payors in utilizing conventional pharmaceutical products compared with the biotech products? Joseph Antos: Clearly, proliferation of unique products that promise benefits not available from conventional pharmaceuticals, and for which there are no substitutes, will be a challenge for insurers, including Medicare. Although some biologics—such as insulin, human growth factor, erythropoiesis-stimulating agents (ESAs)—have been around for a long time, we are already seeing exotic new molecules coming on the market to help narrowly defined patient populations with specific cancers and other serious diseases. These are not the mass-market blockbusters of old; these are

Dr Antos is the Wilson H. Taylor Scholar in Health Care and Retirement Policy at American Enterprise Institute for Public Policy Research. He is also a member of the Panel of Health Advisors to the Congressional Budget Office, a Commissioner of the Maryland Health Services Cost Review Commission, and Adjunct Professor at the School of Public Health of the University of North Carolina at Chapel Hill.

products that will hit the market with laserlike precision. Past experience will provide little guidance to insurers facing a more fragmented, but more intense, market demand from highly motivated groups of patients and their physicians. Virtually every decision an insurer makes will be more complex. Coverage, which was never an easy decision, will be complicated by the need to also pay for specialized patient testing to determine suitability and dosage strength. Will insurers be willing to pay for expensive tests for all patients presenting with a specific disease, possibly spending substantial sums to screen out patients who would not benefit from the drug? Patient management will take on a new look if there are no close substitutes for an expensive biologic. Moreover, patient monitoring will become even more important for tracking effectiveness of the treatment and possible side effects—both issues of interest to the payor as well as to the patient and the doctor. Price negotiations will also be perplexing. How does the insurer gauge value and potential demand from its customers, and what is the basis for price negotiations with the manufacturer? Where is the balance between cost and patient value? Insurers are not alone in this complicated new world. The innovator drug companies themselves must consider the same issues. The ultimate question they must answer at a very early stage of drug development

www.AHDBonline.com

REGULATORY

is: What is the market potential for a product that has great scientific potential but that is not fully proved, a product that will require the investment of time and a very large amount of money before it gets to market?

The search for breakthrough conventional pharmaceuticals has become increasingly difficult. Clearly, the big companies recognize that the next frontier is the biologics area.

Henry: It is a problem of alignment of stakeholders, and I am sure it fascinates the formulary and drug benefit design decision makers. Antos: “Fascinates” is probably too benign a term. “Terrifies” may be closer to the truth. There is big money at stake, and greater uncertainties than in the conventional pharmaceutical market concerning the drug efficacy, the size of the market, willingness to pay, and possible adverse consequences that can only be detected once a drug has gone into general use for the relevant group of patients. The drug may be very effective for most patients with a particular disease, or it may be valuable only to a small subset of patients. There may be hidden factors that cannot be determined through relatively small clinical trials that would dictate which subset of patients should receive the drug. Genetic or other types of patient testing could clarify this issue, but such tests may be difficult to develop and could be expensive. Henry: Can we conclude that the conventional pharmaceutical products have been overregulated with benefit design hurdles? Might this tend to induce pharmaceutical companies to abandon research and development of conventional products and focus on the higher payback areas in biotech? Antos: One could argue that there has been overregulation of conventional pharmaceuticals, but I don’t think that’s the main problem. The US Food and Drug Administration (FDA) vacillates between protecting patients from possible health problems that result from approving a drug too quickly and protecting patients from the potential loss of therapeutic value by not approving a drug quickly enough. The pendulum seems

AMERICAN HEALTH & DRUG BENEFITS

April 2008

to be swinging toward greater caution in drug approvals. However, I think the real problem is scientific; the search for breakthrough conventional pharmaceuticals has become increasingly difficult. Consequently, we see mainline pharmaceutical companies spending large sums on mergers and acquisitions of other drug companies— in many cases, to acquire the intellectual property of the smaller company. Clearly, the big companies recognize that the next frontier is the biologics area. Furthermore, while small innovator companies may have an edge on the science, they have a real disadvantage coping with the regulatory process and marketing. Big pharma has the size and experience to overcome those hurdles to market success. I think we will continue to see a strong synergy between the biologics innovators and big pharma. Henry: The utilization of drugs, biotech or otherwise, is supposed to be following evidence-based guidelines. However, recent events show that that evidence-based medicine is a thin veneer easily peeled off in the face of agenda-driven initiatives. When the robust biotech pipeline floods the market with costly drugs, we better have a grasp on evaluating their value. A riveting example of the problem was the events that followed the publication of the rosiglitazone meta-analysis, conducted by Dr Steve Nissen, in the New England Journal of Medicine last year. The publication of the study hot-wired into the professional, public, and government mainframe. Whatever you think of the study itself, it seems hard to justify the degree to which one questionably done meta-analysis affected the entire healthcare landscape. The question is, was the study critical of rosiglitazone in general or only on the branded-name product known as Avandia? For if it was the latter—I think Dr Nissen said something to the effect that he isn’t afraid to take on any of the big pharma companies—then we have some hard reckoning to do here. Antos: In politics and in healthcare, the boldly stated accusation trumps careful analysis every time. People remember the simple negatives, and hold on to them even when the more complicated truth finally comes out. That’s human nature, but it is no way to run the health system. As you indicated, the Avandia meta-analysis was done in by partial analysis. Dr Nissen had access to the preliminary results of several clinical trials and used those results to rush to judgment about the increased risk of heart attacks to patients. His conclusions were dramatic—the odds of having a heart attack increase by 43% for patients who take Avandia compared with those who take other drugs, or a placebo. No need to

REGULATORY

ask whether the FDA confirmed the clinical significance of these preliminary findings. The FDA had not made that determination in May 2007, when Dr Nissen’s story hit the media, and the FDA maintains that the studies remain inconclusive. No need to ask what may be the absolute risk of adverse consequences for patients taking the drug. Typically in drug studies, a large-percentage increase in the risk of serious side effects is based on a very small absolute risk of incurring the negative health outcome. Certainly, the industry could have been more forthcoming about potential problems with the drug. And one can legitimately criticize the regulatory process for lapses that could harm some patients. But there has to be a balance. I do not think the industry can get ahead of the Steve Nissens of the world, because there will always be a critic who can claim the company did not reveal information quickly enough or completely enough. There will always be a lawyer ready to take a product-liability case to court, and ultimately money changes hands and scalps are taken. That is part of life today for pharmaceutical companies. As a society, we should focus on the net impact of this on patients. Once a drug gets a bad reputation (regardless of its usefulness in treating disease), doctors won’t prescribe it, and patients won’t take it. Vioxx is the best-known example. This drug was vastly superior to other painkillers for patients with severe arthritis who also suffered abdominal pain and complications from other treatments. This drug obviously had risks, like all pharmaceuticals, and it was overprescribed to patients who could safely use less-powerful drugs, but it was clearly the painkiller of choice for some patients. A good outcome would have been to tighten the prescribing standards, limiting the drug to the appropriate class of patients. Nonetheless, the drug was withdrawn from the market under a barrage of negative publicity. As I said, there has to be a balance, and public scrutiny of the actions of the FDA and the pharmaceutical industry is certainly in order. There is always the need for countervailing pressure to ensure that those who stand to make money from the sale of health services and products do not overstep science or their responsibilities to patients and the broader society. Independent researchers should be able to analyze the data and draw their own conclusions about the safety and efficacy of a treatment. That is positive. The question is, do we have reasonable research standards? Are the data up to speed? Do we have a sensible process of getting that information into the system in a way that doesn’t cause panic and precipitous action that does more harm than good? We don’t now.

Henry: The interesting takeaway of the rosiglitazone study is the gaping system-flaw it reveals. Antos: And nobody seems to be working on it, either. Clearly, individuals have the right to analyze evidence, draw conclusions, and publicize them. What we cannot seem to find is the line between providing information and hollering “fire!” in the theater. In the case of pharmaceuticals, I think that line is very broad and very gray. Different individuals and organizations will have differing views about when a result is solid enough to call for action on the part of the FDA or the manufacturers. Good judgment is hard to come by, and there will be disagreements about what constitutes good scientific evidence.

Patients rarely have only one medical condition, and the physician must weigh the likely efficacy of alternative treatments for a patient who often differs greatly from the subjects in a clinical trial.

This raises the issue of comparative effectiveness analysis—the latest “silver bullet” that promises to simultaneously improve the quality of care and reduce unnecessary health spending. An oversimplified, but increasingly popular view, is that better data collection on treatments and outcomes can lead to unbiased analysis that produces clear conclusions about the best way to treat diseases. Unfortunately, determining the best course of treatment for actual patients is not that straightforward. The fundamental problem is that healthcare decisions are not simple yes or no questions. Patients rarely have only one medical condition, and the physician must weigh the likely efficacy of alternative treatments for a patient who often differs greatly from the subjects in a clinical trial or an observational study. Moreover, we are severely limited in our ability to collect adequate data, and methodological challenges in the use of such data abound. Electronic medical records can help here, but we have been talking about health information technology (IT) for several decades and have yet to have a functioning health IT system. Controlled clinical trials are a kind of gold standard for assessing treatment efficacy, but comparative studies would

www.AHDBonline.com

REGULATORY

require much larger, more time-consuming, and more expensive trials than would be practical to implement. Observational data may provide an alternative basis for analysis, but such data also have limitations. Many politicians are drawn to comparative effectiveness analysis, hoping that evidence-based medicine will allow painless spending cuts in government health programs. If we eliminated coverage for a treatment that does not work, the savings could not be viewed as a sacrifice by patients or a reduction in benefits (although healthcare providers may not take the same benign view of such a policy). In other words, difficult political judgments would become technical decisions, absolving policymakers from having to make hard decisions. However, someone—the physician—will have to make those hard decisions for patients with multiple conditions and other complications who fall outside the limits of even the most thorough comparative effectiveness study. Insurers and government will have to build in flexibility in their coverage and payment policies to account for patients with exceptional and justifiable needs. Such policies will have to balance the needs of patients, the incentives for innovation, and the cost of healthcare. That’s a tall order.

Perhaps the most powerful motivator for constructive change is payment. Financial incentives drive the system, and changing those incentives will change the system.

Over time, we will improve our ability to collect and analyze patient data, and increasingly financial and treatment decisions will be driven by a growing body of hard evidence on efficacy. The alternative is what we have now—a system of coverage and treatment decisions that is only partly informed by what we could, in concept, already know about what works for whom in healthcare. And where there is no systematic application of scientific knowledge that we could already use, even with the inadequacies of our current system. Insurers continue to make coverage decisions by asking a committee of physicians to examine research studies with inherent limitations, applying their judgment and experience in a consensus process. Although such committees typically include well-trained and thoughtful experts, they can only know the slice of the world they

AMERICAN HEALTH & DRUG BENEFITS

April 2008

are familiar with. Often, the coverage policy does not reflect the inherent uncertainties of this deliberation. Henry: Would you say that right now we are at a shrill level, where the healthcare debate is waged in very adversarial terms? Antos: Adversarial, and likely to get worse, given the rising political tensions over healthcare as demonstrated in the presidential campaign. The shrillness may soon be at a frequency that only dogs can hear, but it will still be painful for patients, physicians, insurers, and suppliers. We must quit looking for scapegoats, because all of us have some responsibility for unnecessary spending and poor decisions. We need to begin to collect the information that already exists on treatments, outcomes, and cost so that we can understand the pattern of our decision-making at all levels. The scientific facts only take you a part of the way to a sensible health system. We must also look at the financial incentives and other factors that drive decisionmaking. What motivates physicians? Partly a sense of professionalism, partly medical school training that the doctor may have received 15 or 20 years ago, and partly new information the doctor could be getting through electronic means that may prompt a better treatment decision. Technology can help. For example, electronic prescribing systems can be designed to give the physician important clinical information as well as identify what the drug will cost the patient, and whether there are possible substitutes. This may lower cost for the patient and may also prompt busy physicians to look more closely at the patient’s condition, and whether they are prescribing the best course of treatment. Perhaps the most powerful motivator for constructive change is payment. Financial incentives drive the system, and changing those incentives will change the system. We saw this in the mid-1980s, when Medicare shifted from cost reimbursement to prospective payment for hospitals. Private insurers quickly followed suit. The result was a substantial increase in efficiency and an improvement in the delivery of inpatient care. We went almost overnight from long hospital stays that kept beds filled and money flowing under cost reimbursement to shorter stays and a shift to preadmission testing on an outpatient basis. The orientation of hospitals went from holding on to patients to treating them expeditiously and discharging them as soon as possible, since under prospective payment a hospital no longer received additional payment for another day’s stay. Smart payment systems breed smart healthcare

REGULATORY

delivery, but it can be difficult to devise payment systems that work well. Payment also drives medical innovation, including the development of new pharmaceuticals, an area that has proved challenging for Medicare. The patent system grants a period of marketing exclusivity—in other words, a monopoly—to successful drug innovators. That gives the innovator an opportunity to recoup the typically large costs of bringing a new drug to market, particularly if the drug is the first in its class and faces little or no competition. Medicare has long covered physician-administered drugs through its Part B plan, substantially overpaying physicians for those products based on a formula. Recent changes in the formula have brought the extent of overpayment down, but the new formula also has flaws. With that background, the recent controversy over ESAs begins to make sense. ESAs represent the largest single-drug spending category for Medicare Part B. ESAs improve the ability of very sick patients to function normally, relieving them of the chronic fatigue brought on by a low red blood cell count. If ESAs were not available, the only alternative would be blood transfusions for many of these patients. There are concerns about the potential for overdosing, and there is scientific debate over which patients, with which conditions, would benefit from treatment with ESAs. There are also concerns that financial considerations may have prompted overuse and inappropriate use of this drug class. In my view, the line between the FDA and the Centers for Medicare & Medicaid Services (CMS) in their respective responsibilities to regulate the pharmaceutical market blurred in the recent ruling affecting the use of ESAs. The FDA is responsible for ensuring the safety and efficacy of pharmaceuticals; CMS, through Medicare, is responsible for ensuring that appropriate payment is made for appropriate medical treatment. However, payment drives medical practice. Medicare’s recent coverage decision effectively dictates the clinical circumstances under which ESAs will be used for Medicare patients, and private insurers were quick to adapt similar policies. The chronology of events is interesting. Faced with new preliminary findings suggesting that dosing standards should be lowered, the FDA convened an advisory panel that met in March 2007 but failed to draw clear conclusions about the appropriate dosage. Subsequently, warning language that had been on the label was elevated to a “black box” status, without strengthening the language. Within 2 months of that meeting, CMS issued a

proposed national coverage decision affecting cancer patients whose physicians prescribed ESAs. It offered a detailed explanation for limiting ESA dosing regimens and the range of conditions Medicare would cover. The proposed decision eliminated payment for ESAs for a variety of cancers and cancer-related conditions, and it effectively prescribed the course of treatment for patients who were covered, by requiring that hemoglobin levels be maintained within tight boundaries. This ran counter to long-established (20 years) successful medical practice with ESAs. Oncologists rose up in a fury over this; patients protested; but the final coverage decision was made only slightly more flexible.

With that background, the recent controversy over ESAs begins to make sense. ESAs represent the largest single-drug spending category for Medicare Part B. ESAs improve the ability of very sick patients to function normally.

Henry: The American Society of Hematology (ASH) issued a formal declaration opposing this. They had been consulted before the decision was made and were aghast that their official guidelines were roundly ignored. So here we have this intersection of the FDA, CMS, and ASH. Antos: Yes, and each of those entities has a potential conflict of interest. ASH advocates for patients, but its members also gain financially by a favorable Medicare coverage decision. CMS is charged with paying for appropriate care, but they also worry about the bottom line. The FDA regulates the introduction of new drugs to ensure safety and efficacy, and it has been under increasing political pressure that has pushed toward the safety side of the equation. When he was FDA commissioner, Dr Mark McClellan emphasized the parallel risks that the FDA must balance: the risk of harming patients from approving a new drug, and the risk of harming patients from withholding approval of a drug that offers therapeutic benefits. So, there is a balancing of risks in the FDA’s approval process. Henry: The eternal yin and yang. The FDA is going to emphasize that drugs are safe or effective, but it cannot guarantee that drugs will be perfectly safe and perfectly efficacious.

www.AHDBonline.com

REGULATORY

Antos: Exactly. The regulatory pendulum swings between the goals of safety and efficacy, but lately it seems to be moving more toward safety. CMS has its own yin and yang challenge. By law, Medicare cannot dictate the practice of medicine, but dictating the payment for medicine does dictate the practice of medicine to a large extent. Obviously, CMS would like to avoid causing their patients great difficulties. They do not want to have to answer to Congress because a politically sensitive group of patients is not getting access to necessary treatment. But CMS is also under pressure from Congress about cost. Healthcare providers have the same problem. They want to do what they think is right for their patients, but they also profit from the services they deliver.

The regulatory pendulum swings between the goals of safety and efficacy, but lately it seems to be moving more toward safety. CMS has its own yin and yang challenge.

And patients in the Internet era are much more informed than they have been, but most patients are not in a good position to make clinical judgments. With certain diseases, the patient will know immediately if something has gone wrong. For example, a patient being given an ESA will know when his energy level has dropped, an indication that he might need an increased or an additional dose. But a patient’s impression may be misleading, and there are many factors that determine how a patient reacts to a drug. Moreover, patients generally cannot know whether a treatment is putting them at increased risk for serious complications. That is a judgment call based on the clinical evidence but tempered by the unknowns posed by the specific patient who may be far from average in the way his body reacts to the therapy. What is the right course of treatment for me, not for some statistical average, is the important question, which is often difficult to answer with any certainty. Henry: It is that gray line again, especially as ESAs do not increase longevity but rather quality of life. Antos: What has been proved is that ESAs do what they are supposed to do. They enable the patient to make it through the day. And patients with more energy are more likely to adhere to their treatment regimen,

AMERICAN HEALTH & DRUG BENEFITS

April 2008

more likely to do what is necessary to stay alive. Medicare pays for many treatments that do not extend life but improve quality of life. Another aspect of this controversy is how good were the studies used as evidence? And how reliable was CMS’s interpretation of those studies? Again, it goes back to this gray area of healthcare. It is unlikely that a single study or group of studies could give us clear evidence of how a treatment should be used without any uncertainty, or without the need to make exceptions based on the specific patient. I find it particularly concerning that CMS’s decision is different from the FDA’s label. The label states clearly that dosing should seek to maintain a patient’s hemoglobin level between 10 and 12 g/dL, yet the CMS coverage decision permits payment when the level is below 10 g/dL. Despite official denials, this looks like a disagreement between the 2 agencies on the science, and it raises questions about their respective roles. To what extent should the latest scientific judgments drive Medicare coverage policy, and vice versa? Is CMS operating on the medical science or on cost-containment grounds here? This is likely to be a continuing controversy, given the inherent scientific uncertainties associated with any medical treatment. Henry: And meanwhile patients are in limbo? Antos: They are not in limbo, since the coverage decision is binding. Given the cost of the drug and the difficulty of challenging such decisions for a single patient, the vast majority of physicians will conform their treatment protocols to fit the CMS ruling. That means patients will be taken off ESAs once their hemoglobin level exceeds 10 g/dL. Some patients will be put on a biological rollercoaster, going on and off the treatment as their blood levels change. Obviously, hemoglobin levels fluctuate, but the payment standard is perfectly rigid. Some patients who previously would have had continuous treatment with ESAs will now be required to go on and off, with the inevitable consequence of periods of extreme fatigue. That won’t be good for their quality of life, and it may have an impact on their overall health status. Henry: While the private insurers and employers may have differing views on where to set coverage, with Aetna deciding that 10 g/dL is appropriate but SIGNA deciding on a different level, CMS is a monolithic purchaser of healthcare. This could be loosely called the “California effect,” where the

REGULATORY

trends all start in California and drift East, and the trends that started with CMS drift over to the private industry. Antos: Yes, but it is more powerful than that. Medicare is probably the dominant payor for this class of patients, thus Medicare policy will be even more important for cancer patients than for the average person. And what Medicare decides to do will greatly influence what Aetna, Humana, Prudential, and other insurers decide to do. One can expect private insurers to line up behind the Medicare coverage decision, since that decision may seem more conservative medically, and tighter coverage limits can save money. And let’s not forget that the new coverage decision could open up a basis for malpractice liability. One could imagine litigation over a patient suffering adverse consequences, where the first piece of evidence in the case is the fact that the insurer covered ESA treatment for patients with hemoglobin levels above 10 g/dL. Henry: The litigation threat is one of the other drivers of utilization. Antos: Yes, and in this case, less utilization. Henry: So less utilization is legally, not necessarily medically, safer? Antos: I’m not a physician, but that appears to be the case. The implication is that Medicare coverage and payment policy will have a very powerful impact on the pharmaceutical industry, more so than we have seen in the past. Henry: In the biologics area? Antos: Yes, although Medicare will probably move carefully here because of the newness of such products and the targeting of small patient populations. That may mean that Medicare will take a wait-and-see attitude. The traditional approach to coverage is wait to see whether a new, expensive biotech drug becomes an essential part of the community’s standard of practice. Medicare may use the Coverage with Evidence Development (CED) process for these drugs. There will be political, as well as clinical, reasons to do that. But whereas CED is a way CMS has adopted to allow limited coverage for expensive treatments, it is unclear that coverage could be withdrawn if the drug proves to be only modestly efficacious; that remains to be seen. Given the high financial and political stakes, Medicare

will be loath to rush into anything and will want the private insurers and the medical community at the local level to lead the way. The new biotech drugs will pose a harder problem for CMS. Medicare will exert more pressure on manufacturers for supporting evidence, genetic testing or protein markers, or other ways of identifying the patient population who would most benefit from an expensive new biotech drug.

The implication is that Medicare coverage and payment policy will have a very powerful impact on the pharmaceutical industry, more so than we have seen in the past.

Henry: So that is the only true cost-containment tool that has any practical utility for biologics. Antos: If there are reliable ways of distinguishing among patients. I suspect that we have a long way to go before tools such as genomic testing are widely available, and even longer before they are used routinely as part of Medicare or a private insurer’s decision about payment. How do we square the circle between rising healthcare costs and scientific uncertainties? We must recognize that resources are finite, and eventually we will have to make hard decisions about how we want to divide those finite resources between healthcare and other forms of consumption. That will require a change in the unrealistic but common view that health insurance should pay for every medical intervention that might confer some benefit on the patient. This problem cannot be solved solely by technical judgments about the comparative effectiveness of alternative treatments, since the resource constraint is an absolute limit on consumption. Consequently, we must discard the hope that science will solve the health financing crisis in a way that is totally painless, with unnecessary treatments eliminated and everyone getting all the care that could provide some benefit, regardless of cost. Even with good information on the efficacy of alternative treatment, we will not be able to avoid the value judgments that will be forced on us by resource limitations. Henry: You said that the FDA has safety advocates and efficacy advocates. Is there a similar division within CMS: cost-containment versus quality advocates?

www.AHDBonline.com

REGULATORY

Antos: Yes, but I would characterize the safety/ efficacy debate as one that is weighed by decision makers in both agencies rather than between advocates. Of course, experts can disagree about the relative importance of safety and efficacy in considering a specific case, but both issues are considered. There has been a rising consciousness in CMS about the importance of quality and access to treatment as well as cost. A similar evolu-

AHDB Stakeholder Perspective CMS Coverage Policies for Biologics: Defining a Lagrangian Point for Cost, Quality, and Access Biopharmaceuticals—including such diverse entities as antibodies, recombinant proteins, and vaccines —provide a convergence point for the interests of all stakeholders in healthcare delivery. These agents are characterized by remarkably diverse and innovative mechanisms of action that create a compelling rationale for therapeutic use in life-threatening or chronic, debilitating disorders, while simultaneously challenging all traditional management mechanisms about cost and access, such as tier placement, patient copays, and prior authorization. Because the molecular basis for activity can preclude application across all patients with a given clinical phenotype, prudent use may require evaluation of genetic and phenotypic hallmarks to identify patients with optimal prospects for response; that is, fractionating a hitherto-homogeneous medical condition into multiple “orphan” indications, by restricting the therapeutic target and creating a portfolio of recommendations where therapeutic substitutions are neither possible nor appropriate. Similarly, the molecular basis of activity of many biopharmaceuticals invites (mandates) exploratory evaluations of efficacy and safety in other therapeu-

tion in thinking has occurred among private insurers. Responsible CMS officials worry about the balance between cost and efficacy in every decision they make. And reasonable people can disagree about how well they maintain that balance in Medicare policy. For inquiries or comments, please contact editorial@AHDBonline.com.

tic areas, where pathophysiologic mechanisms share common features (tumor necrosis factor inhibitors in rheumatoid arthritis vs ulcerative colitis). Structuring evaluations to maximize the value of repetitive “N of 1” experiments in which every physician– patient transaction seemingly becomes an opportunity for research is a burgeoning area of interest, where all stakeholders can contribute. Because therapeutic value is weighted differently by different stakeholders, development programs also must incorporate measures that resonate with multiple audiences as a condition of commercialization. Expressed methodologically, this imperative results in prospective evaluation of subgroups, accelerates the use of patient preference and quality-of-life assessments, and extends the length of formal observation before and beyond the time of registration, to assess long-term safety and inform adjustments in dose or regimen due to concomitant medication or illnesses (“researchers worship at the mean, clinicians use the standard deviation”). Biotechnology products have biological properties, routes of administration, and therapeutic targets that challenge conventional research, regulatory, and commercialization processes. Defining a Lagrangian point that balances cost, quality, and access provides a template for pharmaceutical product development in the 21st century. Michael F. Murphy, MD, PhD Chief Medical Scientific Officer Worldwide Clinical Trials

SUBSCRIBE TO AMERICAN HEALTH & DRUG BENEFITS™ at www.AHDBonline.com Engage Healthcare Communications, LLC • PO Box 423 • Long Valley, New Jersey 07853

AMERICAN HEALTH & DRUG BENEFITS

April 2008

Global Resources. Uncompromising Standards.

Over the past year, Mylan has blossomed into one of the largest generic companies in the world— with operations in more than 90 countries. By acquiring the Generics Business of Merck KGaA, we have dramatically diversified our product portfolio into new therapeutic areas, dosage forms and delivery systems. As we expand beyond our shores, we take with us knowledge and expertise gained for more than 45 years. We recognize the trust that pharmacists place in Mylan Products, that’s why we will continue to do what we do best . . . make proven medicine more affordable for the patients who need them. 800-RX-MYLAN www.mylan.com ©2008 Mylan Inc.

MYNMKT202

BUSINESS

Benchmarking New Frontiers in Managed Care Pharmacy Cynthia Pigg, BSPharm, MHA Joan Cihak, MSS, MHA

In 2006, the Foundation for Managed Care Pharmacy—a nonprofit charitable trust affiliated with the Academy of Managed Care Pharmacy—sponsored a survey that was conducted by The HSM Group, a national healthcare market research and consulting firm, and supported by an unrestricted grant from Merck & Co. The survey was repeated in 2007 and was designed to track the evolution of new healthcare trends, gauge the role of managed care pharmacy experts in these trends and the initiatives evolving from them, and disseminate that information to the various stakeholders of the industry. The authors examine the responses of 186 respondents from 71 national health plans, 54 pharmacy Cynthia Pigg, benefit management companies, as well as several hospitals, health systems, physician BSPharm, MHA groups, or pharmacies. Survey findings highlight emerging trends in healthcare today and provide insight into the role of managed care pharmacy experts in today’s healthcare environment, as well as other variables that may affect the future of the US healthcare delivery system.

n 2006 and 2007, the Foundation of Managed Care Pharmacy (FMCP) sponsored a survey of pharmacy, clinical, and business managed care leaders that was supported by an unrestricted grant from Merck & Co and was conducted by The HSM Group, a national healthcare market research and consulting firm. The goal of the survey was to obtain insights from managed care pharmacy leaders in decision-making roles or those who had informed opinions related to managed care activities about their use of health information technology (e-HIT and e-prescribing), consumer-driven healthcare (CDH) programs, a variety of pay-for-performance (P4P) initiatives, and disease management efforts. Trends hitting leaders’ radar screens were also queried. Some 2448 managed care pharmacy experts were invited to complete an Internet survey, which was fielded over 6 weeks, ending in mid-September 2007. A total of 186 respondents completed the survey (Table). In addition to tracking the evolution of health trends, the survey was aimed at identifying emerging

Ms Pigg is Executive Director and Chief Executive Officer of the Foundation for Managed Care Pharmacy; Ms Cihak is Executive Vice President of The HSM Group.

AMERICAN HEALTH & DRUG BENEFITS

April 2008

trends and examining the pharmacy experts’ roles in these evolving initiatives, while also providing them with useful educational tools. In the second year of the survey, trends clearly began to emerge as respondents reported greater concern for value through increased collaboration, a greater focus on improved patient outcomes, and a continuation of the emphasis on cost.

Shift from Cost to Quality and Cost In the first year of the survey, the issue identified as of greatest concern was cost reduction. The most prominent theme to emerge in the second year of the survey was value—that is, concerns about costs and efforts aimed at reducing costs revolved around maintaining and improving quality of care. Cost and quality were combined, especially with regard to disease management and in the use of generic drugs; the use of generic drugs was no longer viewed mainly from the perspective of cost but also from a quality-of-care objective. The most critical themes to emerge in 2007 were: • Disease management initiatives • Medicare medication therapy management • Electronic (e-) prescribing. Many organizations are concentrating on improved

BUSINESS

point-of-care information and efficiency in their e-HIT initiatives. Whereas in 2006 organizations measured the success of their e-HIT programs in a process-oriented manner, in 2007 they began concentrating more on outcomes. The increase in generic utilization and the importance of compliance with their formularies altered the way they interpreted the success of e-HIT programs. As many as 3 times more disease/utilization management programs were anticipated in 2007 compared with 2006. Nearly 60% of respondents have now established electronic billing. Provider electronic payment almost doubled in 2007, despite inherent difficulties with the system.

Collaboration Another important emerging theme involves expanding collaboration among healthcare professionals and employers in healthcare decision-making. Collaboration in 2006 was mainly done with hospitals and physician groups. In 2007, increased collaboration was evident among associations, business coalitions, and pharmacy benefit management (PBM) groups (Figure 1). Approximately 50% of the organizations are now collaborating on disease management and e-prescribing, representing a continued broadening of collaborative efforts since 2006. e-Prescribing In 2007, twice as many organizations had plans in place for e-prescribing compared with 2006. In addition, in 2007 almost 40% of health organizations were actively involved in instituting e-prescribing programs, or were in the process of investing in technology to support e-prescribing, compared with about 30% in 2006. Nearly 60% of respondents expect their e-prescribing programs to be in place by the end of 2008. The primary objectives for e-prescribing in 2007 remained similar to those identified in 2006. These include: • Reducing dispensing and prescribing errors • Improving formulary compliance by plan physicians and prescribers • Improving doctor–patient interactions through point-of-care information • Improving patient care • Providing quality initiatives (eg, adherence management). Lowering costs, which was noted as an important consideration in 2006 by 54% respondents, fell by 11% in 2007, and less attention was given to the increased

KEY POINTS Survey responses of managed care pharmacy stakeholders during 2006 and 2007 show that their focus has shifted from cost to cost plus quality of care. Consumer-driven healthcare has emerged as a major driver of value, and pharmacy has a key role to play in that. Employers are the main stakeholders driving this trend. E-prescribing is also seen as a value trend: reducing prescribing errors and enhancing patient care are main objectives. The emphasis on collaboration in disease management reflects the growing role of quality of care in benefit design.

Table Survey Respondent Demographics Type of respondent

Total, N

Pharmacy leaders Clinical leaders: physicians, pharmacists Business leaders: contracting, marketing consultants

66 62 58

Organizations Health plans Pharmacy benefit management Hospitals, health systems, physician groups, pharmacies

71 54 42

Covered lives for each organization >10 million 1 million-10 million <1 million

36 35 65

use of generics in 2007 compared with 2006 (30% vs 40%, respectively). Consistent with the shift in focus from cost of care to quality and cost of care, improving quality of patient care and reducing errors were considered critical e-prescribing outcomes by 80% of 2007 respondents. Fewer respondents in 2007 (37%) who had a Medicare line of business were uncertain that eprescribing would be implemented compared with 50% of 2006 respondents. The focus in e-prescribing is clearly on reducing medication errors and improving quality of care, namely, ensuring that the right person gets the right medication.

www.AHDBonline.com

BUSINESS

Figure 1 Collaborative Efforts of Health Organizations: 2006 versus 2007

PBM indicates pharmacy benefit management.

Figure 2 CDH Products Seen by Respondents as Percentage of Business by 2010

CDH indicates consumer-driven healthcare.

Value: Key to Patient Care in 2007 In healthcare technology, the emphasis was clearly placed on quality and cost, with ever-increasing efforts at collaboration—all of which translates into value. More attention was paid to reducing prescribing errors and improved outcomes. The bigger picture, however, is one of total patient care. The individual silos of pharmacy, medical, and disease management are becoming increasingly less isolated, with all silos looking beyond

AMERICAN HEALTH & DRUG BENEFITS

April 2008

their own silo to make formulary and benefit design decisions. Moreover, all silos are looking beyond their area with regard to the continuity of patient care from hospital to home, rehabilitation, or nursing care.

Consumer-Driven Healthcare Respondents in 2007 expected their CDH products to represent a larger percentage of their business within the next few years; CDH products currently represent less than 10% of their business but respondents expect growth to more than 20% of the total products by 2010 (Figure 2). The stakeholders driving CDH are the purchasers of healthcare—the employers. Most respondents sought to reduce costs and to shift the accountability to the beneficiary (Figure 3). Doing so is thought to shift the responsibility of healthcare directly to the beneficiaries and encourage continued collaboration in the process. In 2007, the increased use of generics was more likely to be seen as an objective of CDH. Most organizations are still using a tiered copay structure to manage their pharmacy benefits, most frequently waiting until after the deductible is met before initiating use of a tiered formulary benefit. In selected classes, pharmacy expenditures are covered without consideration of the deductible. Cost and Quality Considerations of CDH Some uncertainly remains about the impact of CDH, although about 50% of respondents expect that it would lower pharmacy expenses. However, more than 10% of respondents think CDH may increase pharmacy expenses rather than lowering them in the short- and long-term. When asked about the potential impact of CDH on plan medical expenses, respondents predicted that expenses would decrease in both the short- and the long-term. Overall, CDH is seen as an opportunity for greater savings, especially with the use of generic drugs. Fewer respondents in 2007 compared with 2006 are looking to add benefit choices for healthcare from a menu-driven account as an important CDH offering. In 2006, respondents felt that health savings accounts with high deductibles were more likely to be important CDH offerings over the next 2 to 3 years, but this is not as important in 2007. “Improving the quality of patient care” ranked higher in 2007 (22% vs 15% in 2006) when managed care pharmacy experts were asked to identify the 3 primary objectives for offering a CDH plan, although this option was one of the least selected options for both years. Reports regarding the impact of CDH on the quality of care are emerging.

BUSINESS

In October 2007, CIGNA HealthCare released the findings of a 2-year study of the healthcare claims experience of more than 430,000 CIGNA CDH plans and traditional HMO and PPO members. Results of their study showed the following findings related to pharmacy1: • Medication compliance improved, while costs decreased • Use of maintenance medications that support chronic conditions increased, while costs decreased.

Barriers to P4P Implementation The percentage of networks that offered P4P incentives was consistent in 2007 and 2006 with regard to network physician services (32% vs 31%, respectively). Organizations offering network pharmacies P4P rewards stayed fairly constant (11% in 2006 vs 13% in 2007). Anticipated gains from P4P remained similar for both years as well—the use of generics, formulary products compliance, and the provision of preventive screenings. The perception of barriers to the implementation of P4P incentives is increasing, the survey findings suggest. The greatest barriers are no surprise—a lack of performance standards, inability to track providers systematically, and not knowing how to gain provider buy-in (Figure 4). The concern has centered on a lack of appropriate criteria for measuring performance. Pharmacy Is Changing Although barriers facing pharmacy P4P appear formidable, there is activity in the area of pharmacy standards and measurement, and progress has been made. The Utilization Review Accreditation Commission released their standards for PBM in October 20072; the mission of a Pharmacy Quality Alliance is to improve healthcare quality and patient safety through a collaborative process, in which key stakeholders agree on a strategy for measuring performance at the pharmacy and pharmacist levels; collecting data in the least burdensome way; and reporting meaningful information to consumers, pharmacists, employers, health insurance plans, and other healthcare decision makers to help make informed choices, improve outcomes, and stimulate the development of new payment models; and a Pharmacy Quality Alliance is working to fulfill their mission.3 In addition, the National Quality Forum is working on the National Voluntary Consensus Standards for the Reporting of Therapeutic Drug Management Quality.4 Disease Management Programs Resources allocated for disease management and member education increased by a similar percentage of

Figure 3 Respondents’ Perception of Goals of CDH

CDH indicates consumer-driven healthcare.

Figure 4 Perceived Barriers to Implementing P4P

P4P indicates pay-for-performance.

organizations in 2006 and 2007 (55% and 56%, respectively). Disease management was considered extremely or very important by 80% of respondents. The continued importance of disease management has been attributed to a desire for greater patient compliance, an attempt to meet employer expectations, and to rise above cost pressures. Employer expectations and cost pressures are very tightly related, because the cost pressures often define employers’ demands. The majority of organizations administer their disease management programs internally, although the trend toward outsourcing is increasing, the survey find-

www.AHDBonline.com

BUSINESS

Figure 5 Respondents’ Views of Specialty Pharmacy and Healthcare Reform: Emerging Trends

ings show. Few organizations outsource all their disease management programs; rather, they tend to use a variety of methods for additional access and have added the Internet (47%), interactive voice recognition (29%), and text messaging (9%) in addition to phone and mail methods. The most frequently offered disease management programs in 2007 have focused on: • Diabetes (80%) • Asthma (69%) • Heart failure (56%) • Depression (33%). A similar emphasis was found in Medicare plans and in medication therapy management programs. The driving factors behind disease management were quality and cost as a unit. It was once thought that increasing compliance would increase pharmacy costs, but pharmacy stakeholders are increasingly viewing the total medical cost of an illness, not just one aspect of it.

Wellness Programs A new question was added in the 2007 survey to determine which wellness programs were being offered. Smoking-cessation (49%) and weight-management (46%) programs were the top 2 wellness programs, followed by fitness (38%). Emerging Trends in the Marketplace The 2007 results about reference-based pricing were consistent with 2006 findings. One third of organizations were very likely, likely, or somewhat likely to use refer-

AMERICAN HEALTH & DRUG BENEFITS

April 2008

ence-based pricing. Efforts to track improvement in formulary compliance were also consistent with the previous year. This was motivated by the organizations’ measure of success in utilizing formulary products by therapeutic class, which consequently reduced total pharmacy spending. The utilization of formulary products by therapeutic class remained the top metric for tracking improvements in formulary compliance in 2007. For formulary management, financial incentives have increased, shifting away from out-of-pocket moves. More incentives to patients are being offered, such as the addition of zero copay for generics, to encourage patients to select generic products. A few organizations are now also offering zero copay for branded products for select disease states, such as diabetes or heart disease. Most respondents did not see changes occurring about loosening formulary management. Others found ways to lower some of the patients’ out-of-pocket costs. In short, the emphasis in 2007 remained on quality and cost. The entry of blockbuster generics was predicted to change the picture on generics. It was further thought possible that value-based benefits could become an important issue, but few respondents have them in place or under development. The overall goal of this practice is to ultimately improve the overall quality of care by encouraging the use of the right drug or treatment at the right time for each patient. The attention to lowering costs has not been lost, but the focus on quality has increased.

Healthcare Reform Other emerging trends anticipated to have a significant impact on the future of managed care pharmacy include specialty pharmacy and healthcare reform (Figure 5). There was considerably less concern in 2007 compared with 2006 on Medicare Part D impact or changes. The current Medicare emphasis remains on medication therapy management programs. Conclusions The growing emphasis on value, combined with cost, quality, and the increased involvement of the pharmacist in healthcare is very encouraging. The discussion in many of these trends is still focused on cost, but a focus on combining cost and quality is emerging. These findings are a hopeful testament to the value of making decisions based on the evidence. The goal of these surveys was to provide useful information for managed care pharmacists and other interested parties, as well as encourage increased managed care pharmacy

BUSINESS

expert involvement in a broader healthcare role. Managed care pharmacy experts possess specialized knowledge related to one of the most utilized components of healthcare benefits—the pharmacy benefit— and their expertise serves to help people optimize their medication therapy.

Disclosure Statement Ms Pigg is on the Advisory Board of Lilly, Centocor, and Daiichi-Sankyo. Ms Cihak is a contractor with Merck & Co.

AHDB Stakeholder Perspective Emerging Trends in Managed Care Pharmacy: Familiar Gaps but Great Potentials PATIENTS & EMPLOYERS: Thinking about the “new frontiers” outlined in this research from an outsider’s viewpoint, it looks much the same landscape as before. Granted, progress has been made, but significant gaps remain in the performance of the healthcare delivery system, along with managed care pharmacy. For example, only one third of stakeholders have integrated communication; consumer-driven healthcare pharmacy remains a cost-shifting vehicle, without major improvements in empowering patients as decision makers; and cost-management issues remain prime, without addressing the root value basis across silos that are all paid for by employers or by government programs. PHARMACY LEADERS: As a benchmark for the future of managed care pharmacy, this paper can

References 1. CIGNA HealthCare. CIGNA Choice Fund Experience Study. October 2007. http://cigna.tekgroup.com/images/56/CIGNA_ CDHP_Study.pdf. 2. Utilization Review Accreditation Commission. Pharmacy Benefit Management Accreditation—Do you measure up? http://www. pbm.urac.org/pbm.asp. http://www.pbm.urac.org/files/URAC-PBMBrochure.pdf. 3. For more information on the PQA missions and current efforts, see http://www.pqaalliance.org. 4. For more information on the National Quality Forum’s work on consensus standards, see http://www.qualityforum.org.

For inquiries or comments, please contact editorial@AHDBonline.com.

be most useful and empowering to leaders of this sector, even more so perhaps than imagined. There is a real opportunity here to drive new thinking and improvements in the delivery of value-based healthcare services that can deliver improved, cost-effective outcomes. As an example, the promise of e-prescribing includes a collaborative effort among various provider and administrative stakeholders to drive improvements in the quality of care. Furthermore, consumerdriven solutions and benefit designs will continue to emerge as well as offer more sophisticated value-driven options that can reach the promise envisioned when consumer-driven healthcare pharmacy entered the healthcare landscape about 10 years ago. Along with great promise, there remain many opportunities in managed care pharmacy to fulfill its evolving role in the US healthcare frontier. F. Randy Vogenberg, RPh, PhD Chief Strategic Officer Employer-based Pharmaceutical Strategies, LLC

SUBSCRIBE TO

at www.AHDBonline.com Engage Healthcare Communications, LLC • PO Box 423 • Long Valley, New Jersey 07853

www.AHDBonline.com

BUSINESS

Not Waiting for Godot: The Evolution of Health Promotion at PPG Industries Alberto M. Colombi, MD, MPH Janice L. Pringle, PhD George T. Welsh, BS, MBA

PPG Industries is a manufacturer of coatings, chemicals, optical products, specialty materials, glass, and fiberglass. The company’s approach to healthcare combines perhaps 2 disparate concepts. The first is that employee health and behavior change relies to a large degree on employee awareness and ownership of their own health and second that “what gets measured gets done.” It is widely acknowledged that one of the best tools for employee awareness is the health risk appraisal tool. Additional components of employee awareness include knowing key individual health metrics and effectively engaging with healthcare providers. As a leading global manufacturer, PPG well understands the Alberto M. Colombi, critical importance of cost accounting and financial metrics to drive business decisions. MD, MPH PPG’s perhaps unique approach comes from the strong marriage of individual health/ wellness promotion and frequent, timely, and informative financial metrics on health and the cost of care. Combining capacity building through the mobilization of volunteer wellness teams with expert interventions and financial discipline is a feature of the experience here described. This approach has resulted in both management and employee engagement in the issue and has allowed PPG to bend the curve of ever-increasing healthcare costs and achieve cost increases per employee at one half the reported national average for companies of comparable size. Because this journal is dedicated to health and drug benefits, we gathered an appropriately representative team composed of a physician, an epidemiologist who resides in a pharmacy school, and a benefits manager. The team evolved from a common vision to identify ways of improving employee health and well-being. The team presented both as keynote speakers and as contributors to a breakout session at the National Symposium on Work-Life organized in 2007 by the National Institute for Occupational Safety and Health, a federal agency of the Centers for Disease Control and Prevention in the Department of Health and Human Services. This article is an account of why and how such a unique team was formed.

PG Industries, headquartered in Pittsburgh, Pennsylvania, is a manufacturer of coatings, chemicals, optical products, specialty materials, glass, and fiberglass. PPG operates more than 125 man-

Dr Colombi is Corporate Medical Director, PPG Industries, Pittsburgh, PA; Dr Pringle is Research Assistant Professor, University of Pittsburgh School of Pharmacy, Pittsburgh, PA; Mr Welsh is Director, Benefits and Human Resources Services, PPG Industries, Pittsburgh, PA.

AMERICAN HEALTH & DRUG BENEFITS

April 2008

ufacturing facilities in 23 countries, and has 32,200 employees globally, 20,000 of which are in the United States. From occupational health, PPG has been evolving toward comprehensive employee health. The PPG Industries experience is not about being perfect, but about what is possible. Thus, we present an objectively measured experience of what an employer can envision, attempt, and accomplish to promote employee physical and mental health; how it reduces the burden of disease on health and productivity; and

BUSINESS

how it has mitigated rising medical care inflation. Thus, we offer ourselves as an example of learning how leaders from different worlds (medical, financial, and scientific program evaluation) can work together to make a difference. The breadth of PPG’s locations and manufacturing specialties implies profound differences in business plans, site size, resources, environmental contexts, cultures, languages, management, and labor philosophies and expectations. This workplace diversity requires the implementation of health protection and promotional programs that exercise a degree of flexibility, while still maintaining relevant consistency. We do know that work may affect health. What is not readily acknowledged, is that health may also affect work.1 Even if health may be categorized as occupational or personal, and along administrative or regulatory lines, health is at the center of a two-way system. In our work, we envision health as a whole and a key attribute of human capital that should be preserved, increased, and invested in. In optimizing this human capital, we also need to acknowledge the individual and population dimensions of health. Efforts designed to preserve and improve health must consider how health is affected from the perspective of the individual, the population health management, and the environment in which individuals and populations exist. In PPG’s experience, health promotion has been built on a strong foundation based on health protection, safety, and quality. Wellness does not exist in isolation but as the result of innovative applications derived from decades of health protection, safety, industrial hygiene, and ergonomic improvement programs. For instance, when prompted by the question, “Who is responsible for health?” we naturally point to the principle that all employees are responsible, similarly that safety is a line responsibility, not just the responsibility of the safety manager. When challenged by implementing a knowyour-numbers campaign, most understood that this was meant to contribute to risk quantification in a way not dissimilar from industrial hygiene measurements. Finally, having had about 2 decades of experience in training and supporting ergonomics improvement teams, based on volunteer employees’ participation, no one seems to be scandalized by the idea of establishing, training, and supporting volunteer wellness teams. As a global manufacturer, PPG has also built a strong foundation in cost accounting and financial reporting metrics. Perhaps the uniqueness of the experience here reported comes in the marriage of health promotion and

financial metrics to attract management and employee attention, ultimately resulting in healthier behaviors, prevention, and care cost containment. Yet, our numbers show us that if we compare the money spent for workers’ compensation—the correlate of occupational injury and illnesses—with the money spent for personal or nonoccupational healthcare, personal or nonoccupational healthcare costs are at least one order of magnitude higher than occupational costs.2

Wellness does not exist in isolation but as the result of innovative applications derived from decades of health protection, safety, industrial hygiene, and ergonomic improvement programs.

The impact of these workplace health and safety protection programs is one reason why the occupationally associated costs are relatively lower than the personal healthcare costs; however, we cannot lower our guard in implementing these workplace programs. If we did, injuries, work-related illnesses, suffering, and cost would rise again. Moreover, whereas decades of efforts in the occupational side of healthcare costs have resulted in a measurable effect, not much attention has been paid to the “nonoccupational” side of the equation. Even today most of the price of conformance is spent on the occupational side, with few resources being allocated to promoting employee health on the assumption that it is not the employer’s business. Actually, everincreasing healthcare costs are becoming, worldwide, everybody’s business, and for the self-insured employer, healthcare costs directly affect the bottom line. During the past 2 decades, personal healthcare costs have increased precipitously. Although the inflation rate for healthcare costs at the beginning of this decade was double (12%) of what was currently projected (6%), healthcare costs are still increasing year after year in excess of salary increases (typically an average of 2%-3%).3 This dramatic (and largely unabated) rise in healthcare costs has resulted in millions within the United States, where approximately 35% of the population remains uninsured or underinsured.4 The combined effect of these uninsured or underinsured individuals is to further elevate healthcare costs for employers who seek to

www.AHDBonline.com

BUSINESS

In an employer/employee self-efficacy strategy, the idea is not to develop health promotion strategies that make you a poster child for some brilliant but esoteric theory, but rather to work in a participatory manner with employees to accomplish what you can with what you have from the vantage point of where you are. Clarifying the association between prevention and cost avoidance and the burden of disease on health and productivity is essential.

Figure 1 Overall Burden on Health and Productivity

Burden on Health & Productivity Y=f(22 X) Current Measure Occupational X

Additional Measure

Non-Occupational 10X

Direct Costs

Indirect Costs 11X

Workers’ Comp

Lost time

Direct Costs A&S

H. Care

LTD

Benefit Design

PPG I&I Productivity

Disease Management

All Injuries

Care variance

Impaired Non-ergo Injuries

Ergo Injuries

Screening

Fatigue

Job Content

ADI

Non-ADI Impairment

Risk reduction score

Exposure

Force

Repetition

Posture

Hours of work

H. Care Risk/Utilization

HRA participation

Reprinted with permission of The Institute for Health and Productivity Management. Health & Productivity Management Magazine. 2006;5(1).

provide access to effective healthcare services.5 Personal health costs not only comprise direct costs associated with medical, surgical, rehabilitative, and pharmaceutical care, but also indirect costs. Although these indirect costs do not appear in any financial book, they are not any less real, and include costs associated with absenteeism, presenteeism, productivity loss, and all the ancillary costs owing to replacement, retraining, and litigation. The disease burden on health and productivity is therefore of interest even where the direct healthcare costs are paid through taxes rather than through employer-based benefit systems. The prophetic words of Dr Gro Harlem Brundtland, former director of the World Health Organization, come to mind: “Improving health will generate vastly greater profits to society than playing the stock market or downsizing the microchip.”6

How Will Progress Be Made? We believe that both social and market forces should play a role. National and regional business alliances can offer an effective strategy that will prod policymakers to support the development of affordable, accessible, and effective healthcare; however, the realization of this goal is still a distance away. Therefore, we need to emphasize the role of self-efficacy. An alliance between the employer and employee toward this end is objectively possible. At PPG, we call this a win-win approach, a “life partnership.”

AMERICAN HEALTH & DRUG BENEFITS

April 2008

Known Facts About Health and Cost First, we know that costs increase as disease evolves downstream along a continuum from health to disability and finally death.7 Second, we know that reducing morbidity costs as high upstream as possible in the disease progression is associated with a more disabilityfree quality of life that has productivity implications.8 Third, we know that certain at-risk behaviors will drive healthcare costs up, and the more concomitant the risk behaviors, the greater the cost.9 In a seminal study by the University of Michigan demonstrated in 2000, it was concluded that the concomitant presence of 7 or more at-risk behaviors would quadruple the average healthcare costs.10 Fourth, we know all health costs— occupational and nonoccupational, direct and indirect—must be accounted for to fully understand the impact of health on our workplace and our employees. Fifth, we know that the best investment in time and energy is not so much focusing on the “tail of the distribution” (ie, those already in extreme trouble), but rather in shifting the entire distribution toward a healthier zone by keeping the healthy people healthy.11 Sixth, we have learned that to reduce healthcare costs, we should not simply manage costs, but influence its drivers by managing health. If we were to put all these concepts in one picture, this could be summarized in a relatively unattractive but comprehensive model defining the total burden of disease on health and productivity (Figure 1). This model takes into consideration occupational direct costs, nonoccupational direct costs, and the indirect costs for both. The model expands our understanding of a final health outcome by exposing its components and some of its measurable and presumably modifiable influencers invoking the quality concept of Y = f(x). Let us take, for instance, the nonoccupational side of the model. Nonoccupational costs comprise healthcare costs, costs related to short-term and long-term disability, accident and illness, and salary replacement. The measurable health influencers include benefit

BUSINESS

design, disease management strategies, and care variance. The platform from which these influencers can be identified is the employee/population health risk profile, obtained through the results of employee screenings and health risk appraisals (HRAs). The 5 areas of healthcare cost reduction are shown in Figure 2, which conveys the idea that simultaneous, rather than mutually exclusive, interventions in all 5 areas may put PPG in a better position to promote health and mitigate care costs. At the center of our road map is the need for some degree of cost sharing of the disease burden. This is the typical domain of benefit design. But a particularly apt benefit design would not merely shift costs, but also facilitate the adoption of certain purchasing strategies that could foster preventive care versus catastrophic care and individual proactive responsibility for health maintenance versus reactive, passive sick care system responses. At the left in Figure 2, we question the size of the burden. Rather than simply cutting the pie without thought to its size, we suggest that at-risk behavior modification may significantly contribute to shrinking

the burden to be shared by the 2 partners, namely, the employer and employee. Adjacent to that we added an area dealing with early diagnosis, recognizing that upstream management of early intervention can reduce the downstream size of suffering and costs. On the right side of Figure 2, we included an area that recognizes the economic opportunity derived from eliminating waste from the healthcare delivery system, whether from overuse, underuse, or misuse of certain procedures. Although not an easy thing to practice and far from being mature, the healthcare quality movement with its market effects, policy-making, and patient implications is being recognized as a critical feature in the improvement of healthcare quality and access.12 There is no market without choice, and there is no choice without information. Market forces, policy-making, and consumers cannot be indifferent toward good and bad quality of care. Although employers may object that this is beyond their purview, we may insist that at least purchasing specifications could be introduced to purchase value, and that educating our employees in quality-of-care recognition, to the extent possible, may help qualify demand.

Figure 2 Five Areas for Healthcare Cost Reduction 1. BEHAVIORS

2. PREVENTION

3. PLAN DESIGN

4. CARE EFFICIENCY

5. WORK PERFORMANCE

Content

•Participation •Incentives •Motivation •Skills •HRA expand

Best in class •Promotion •Protection •Screenings •Case mgmt

Consumer-driven core competenies •Accountable •Transparent •Coordinated •Pay for value

Challenge waste •Misuse •Overuse •Underuse Up-coding Late care Business alliances

Total burden on health and productivity •Lost days •Absenteeism •Presenteeism

Measure

HRA participation rate, risk reduction

Preventive screening rates, avoidable admissions

Disease management healthcare cost and utilization (PMPM)

Quality indicators Avoidable “rework”

Avoidable STD Lost work days, presenteeism

Aim

Shift upstream Shrink Prevent

Clear waste The Other face of the moon

PMPM indicates per member, per month; STD, sexually transmitted disease.

www.AHDBonline.com

BUSINESS

Figure 3 High-Impact Conditions

+ Musculoskeletal

Prevalence

Flu Cardiovascular Allergies

Diabetes Depression

Migraine

Low-birth-weight baby Transplant Cancer

Cost Reprinted with permission of The Institute for Health and Productivity Management. Health & Productivity Management Magazine. 2006;5(1).

Finally, the last area in the model has to do with work performance and productivity. Not only the canonic return-to-work and disability management programs find their place here, but also the entire concept of total productivity loss, namely, absenteeism and presenteeism (being at work but at subpar potential). A third, minor but useful, model (Figure 3) is one that considers both cost and prevalence. This frame can be filled with population-based data that take into account the actual past claim experience both in terms of unit cost and prevalence of the condition. If we take the example of influenza, the unit cost of treating each individual case of flu is very modest, but the high seasonal prevalence of the condition makes it economically viable to offer a flu vaccination program. At the other extreme, there are conditions that happen rarely but are nonetheless very costly (eg, having a very low-birth-weight baby or a liver transplant procedure). Not all such events are preventable; however, even if prenatal care, hepatitis B vaccination, and problem-drinking prevention pre-

AMERICAN HEALTH & DRUG BENEFITS

April 2008

vent only a part of these corresponding problems, these efforts are worth pursuing. Costly and prevalent conditions include cardiovascular events, musculoskeletal disorders, and chronic conditions such as diabetes. Mental illness, which often co-occurs with many other chronic diseases, is associated with an assortment of indirect costs.13 In addition, the relative ranking changes when indirect costs are factored in. In the case of depression, for example, indirect costs related to productivity loss far exceed the costs of treatment. It is estimated that the total per capita costs (including direct and indirect costs) associated with depression in the workplace is $5415 per year.14 The stigma associated with mental illness and a typically fragmented healthcare system has served to hide the importance of addressing mental health by employers.15

Capacity Building Although having some models and road maps may give a sense of direction and priority, it is only half of

BUSINESS

the story. The other half lies in making things happen, which, to a certain degree, involves building the necessary capacity and leadership. In phase 1 of our strategy (2000-2004), we focused on creating management awareness and obtaining commitment for funding to launch the “Lifestyle Partnership” initiative. The Lifestyle Partnership established a health information management system comprising claims data and a self-reported online HRA in 8 languages prominently embedded in a Web-based wellness resource center; disease-specific health promotion priorities (eg, cardiovascular disease, musculoskeletal diseases, depression, diabetes, and women’s health issues); and facility-based wellness teams comprising groups of employee volunteers as an adjunct to the limited occupational health nursing staff. At the end of 2004, we counted 71 wellness teams in more than two thirds of the major manufacturing facilities, involving 28 nurses and 448 wellness volunteers. In phase 2 of our strategy (2004-2007), we focused on developing the conceptual model—establishing metrics, targets, and reports; developing leadership and management engagement through health summits; conducting annual wellness conferences; developing an occupational nurse career ladder; and extending the HRA to family and retirees. The most prominent feature of this phase was the development of an intervention process for plants with the highest healthcare costs through a series of “health summits.” A typical “summit” would entail (1) involving plant leadership, the wellness team, and other employee health stakeholders in a participatory review of the facility HRA and claims data to develop a strategy for addressing the problems revealed by this review; (2) examining existing plant health promotion initiatives and providing input into how these can be enhanced to meet employee health risk needs; and (3) defining, empowering, and supporting the role of the local leadership team, and refocusing wellness teams to provide appropriate direction, tools, and support.

Measuring Progress To establish baselines and measure progress, we gave ourselves the capacity of reporting both healthcare costs and health/risk assessment through a worksite–specific Healthcare Initiative Scorecard based on the following 5 measures reported quarterly: • Gross per employee healthcare costs • Net per employee healthcare costs (after cost sharing) • Percent of employees who have taken the HRA at least once in the past 3-year period • Percent of HRA takers who are at low or no risk

• Percent of HRA takers who have participated in a screening activity (“Know Your Numbers”) and at least remember and engage to the point of entering their cholesterol and blood pressure readings In this dynamic process, our understanding about our employees’ health risks as well as the HRA process increased. For example, our analyses reinforced the importance of the Prochaska model16 based on both risk prevalence and on readiness to change for a given atrisk behavior. We learned, for example, that stress risk is self-reported by about 60% of participants, but readiness to change in this area is less than 10%. In contrast, although self-reported weight risk is more than 50%,

Our analyses reinforced the importance of the Prochaska model based on both risk prevalence and on readiness to change for a given at-risk behavior.

only 30% of respondents are willing to take action in this area. This comparison permits an understanding of which risk-specific health promotion programs are mature for action and which may require the application of initiatives to increase employee awareness and knowledge and ultimately change attitudes. We also learned that HRA’s change over time can be multidirectional and dynamic and static.17 Following health promotion advice in the course of time, some individuals may take action for better, some may worsen because of at-risk behaviors, and some may simply increase their risk through aging. Doing nothing to address employee health at a minimum will carry the burden of aging and increase the underlying risk burden that comes with it. If upon comparing health risk (and outcomes) at Time1 and Time2, the number of individuals who improved is not substantially higher than the number of those who worsened, our attempts at health promotion will have accomplished little.

SMART Goals We have also learned the importance of establishing “SMART” health promotion goals (Specific, Measurable, Agreed, Reasonable, and Time-bound). Our overarching goal has been to reduce the burden of disease on health and productivity to half of the prevailing national average change over 5 years, compared

www.AHDBonline.com

BUSINESS

with companies of like size. Other goals have included realizing an HRA participation rate of 80% of the employee population on a 3-year rolling period, maintaining the employee population at low or no risk at 70%, and having at least 80% of the employee population know their key health metrics (ie, body mass index, cholesterol level, blood pressure).

Lifestyle behavior modification may be a key component of the strategy to improve the future health of our associates and to avoid suffering and economic loss.

Although we succeeded from 2002 to 2006 in achieving our overarching goal, and although we are still less than the national average with respect to healthcare costs, our costs are bouncing back. The favorable economics we realized during this 5-year period were mainly influenced by benefit design, employee attrition, and health promotion effects that, at least in part, offset the inevitable aging effect. We realize that much remains to be done to improve the health of our employees who are several years older than the average age of employees in similar industries. We do have reason to be encouraged: As the HRA participation rate has increased from 20% to 71%, the proportion of employees at low or no risk has increased from 29% to 35%, and the employees “who know their numbers” have increased from 38% to 51%. We believe that, although benefit design may have a faster impact, it has also consumed most of its available options. Whereas health promotion has a slower rate of impact, lifestyle behavior modification may actually be a key component of the strategy to improve the future health of our associates and to avoid suffering and economic loss; however, given health promotions’ lag time, the time for employers to use this strategy to affect workers’ health is now. Through this process, we have also learned to appreciate the differences and complementary nature of “data.” HRA data provide the opportunity to project our employees’ health currently and in the future, even in the absence of claims data. HRA data are immediately available and permit both individual and population-based risk management “before the fact.” On the other hand, claims data afford a look backwards, after

AMERICAN HEALTH & DRUG BENEFITS

April 2008

healthcare has been provided. Even though PPG has access to 100% of the financial side of its self-insured claims data, and 80% of de-identified clinical information thereof, these data tell little about employees who do not have claims. Moreover, healthcare claims data take months to collect, clean, and verify before they can be used to analyze utilization, cost, and disease management priorities. Thus, by definition, this is “after the fact” information. In the process of organizing system changes and health promotion interventions, we focus on several priorities for which we call on both wellness teams’ mobilization and expert intervention, which we do not have time here to describe (nutrition, exercise, obesity, modifiable cardiovascular risk factors, etc). Rather than describing the obvious, we want here to attract the attention to the fact that one major lesson that we learned is that an important focus of our health promotion activities is missing—mental health. This is even more relevant when considering not just the direct healthcare costs, but also the more relevant impact on loss of function and its productivity correlate. As mentioned above, stress is the most frequently reported health complaint by our employees. As part of our HRA experience, we offer, on a voluntary basis, a validated depression screening tool, Patient Health Questionnaire-9 (PHQ-9),18 and a self-reported evaluation of absenteeism and presenteeism, the Work Limitation Questionnaire (WLQ).19,20 The addition of these 2 instruments to our HRA helped us to further evaluate the attendant risk factors and work consequences associated with reported “stress.” Provokingly, HRA, PHQ-9, and WLQ have brought to light areas we expected to be unprepared for, but in such a compelling way that they are impossible to ignore. Although we still do not quite understand the meaning of the findings, we see the relevance of stress, depression, and even moderate alcohol use* as an association that is impossible to ignore. The results of our preliminary analyses indicate that employees who reported higher stress were more likely to report a higher alcohol risk. Moreover, female employees who reported moderate to high alcohol use also were more likely to report greater weight/obesity, increased blood pressure and cholesterol, increased number of health risks overall, and increased number of chronic conditions. As indicated in Table 1, when the results of the *According to the National Institute on Alcohol Abuse and Alcoholism, moderate drinking is no more than 1 drink per day for most women and no more than 2 drinks per day for most men. http://www.niaa.nih.gov/FAQs/General-English/.

BUSINESS

Table 1 Self-Reported Productivity Loss (Absenteeism + Presenteeism) by Job Tasks

No at-risk or chronic conditions Known heart disease Moderate to high alcohol risk Moderate to high stress risk

Mental interpersonal (%)

Time management (%)

Output demands (%)

Physical demands (%)

1.8 13.5 15.9 13.2

3.4 15.4 18.9 13.8

2.2 12.9 11.6 11.4

3.8 21.4 18.2 18.1

Table 2 Self-Reported Productivity Loss: Financial Impact, Based on Average Salary

No at-risk or chronic conditions Known heart disease Moderate to high alcohol risk Moderate to high stress risk

Per employee ($)

Per 1000 employees ($)

683 7055 6244 4550

24,194 236,323 598,264 2,770,042

WLQ were applied to HRA data, we imputed that employees who reported moderate to high alcohol use also reported greater productivity losses than workers who reported moderate to high stress. In addition, employees who reported moderate to high alcohol use also had a higher imputed financial impact per employee ($6244) owing to self-reported productivity loss (absenteeism + presenteeism) than workers who reported moderate to high stress ($4550), and a higher productivity loss per 1000 employees ($598,264) than those with known heart disease ($236,323) (Table 2). The results of these analyses suggest that addressing employee stress should also involve addressing employee alcohol use, as the association between stress and alcohol use may be bidirectional. People may drink to relieve stress, but drinking may generate stress. Regardless of whether employee stress is experienced at home and/or at work, stress provides a frame of reference that should include a focus on work-life balance and “organizational ergonomics.” Although the selfreported absenteeism and presenteeism cost of heart disease is higher than the corresponding indirect cost for high stress on an individual employee basis, the much higher prevalence of reported stress makes the associated indirect costs ($2,770,042) 10 times higher than those associated with heart disease ($236,323).

Where to Go From Here? We need to work rapidly and simultaneously in several directions. First, we need to further analyze HRA data to ascertain specific risk areas to target via health

promotions that will produce the best outcomes. Second, we need to make better use of HRA data. We would like to make the HRA easier to access and improve employee response rates, so that employees will take the HRA multiple times and thus compare their results over time. We would like to expand the use of HRA to spouses and retirees, and we need a strong continued protected health information focus to avoid jeopardizing the trust upon which the integrity of self-reported data are founded. We would like to allow individuals to opt to link their HRA data to manage their own benefits, including the possibility of receiving individually-tailored preventive prompts, beforethe-fact risk coaching, and after-the-fact disease management, as indicated. Third, we need to expand collection and include disability and absence metrics for active employees in our measuring system. Most important of all—and most difficult—will be to give equal status to mental wellness as it is given to physical well-being. This would require further destigmatizing mental health, increasing familiarity with screening devices for depression, alcohol problems (as people are now familiar with cholesterol and blood pressure and glucose screenings), facilitation of access to care and employee assistance programs, and overcoming the fragmentation of mental healthcare.

References 1. Davis K, Collins SR, Doty MM, et al. Health and productivity among U.S. workers. Commonw Fund. 2005 Aug;(856):1-10. 2. Goetzel RZ, Guindon AM, Turshen JI, et al. Health and productiv-

www.AHDBonline.com

BUSINESS

ity management: establishing key performance measures, benchmarks, and best practices. J Occup Environ Med. 2001;43(1):10-17. 3. Schoen C, Guterman S, Shih A, et al. Bending the curve: options for achieving savings and improving value in U.S. health spending. Commonw Fund. December 2007. 4. Schoen C, Doty MM, Collins SR, et al. Insured but not protected: how many adults are underinsured? Health Aff. 2005 Jan-Jun;(suppl Web Exclusives):W5-289-W5-302. 5. Stoll K. Paying a premium: the added cost of care for the uninsured. A Families USA Publication #05-101. Washington, DC; June 2005. 6. Altman LK. The doctor’s world; next W.H.O. chief will brave politics in name of science. New York Times. February 3, 1998. 7. Dzau VJ, Antman EM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes. Circulation. 2006;114(25):2871-2891. 8. Hubert HB, Bloch DA, Oehlert JW, Fries JF. Lifestyle habits and compression of morbidity. J Gerontol. A Biol Sci Med Sci. 2002; 57(6):M347-M351. 9. Edington DW. Emerging research: a view from one research center. Am J Health Promotion. 2001;15(5):341-349. 10. Musich S, Schultz AB, Burton WN, et al. Overview of disease management approaches: implications for corporate-sponsored programs. Dis Manage Health Outcomes. 2004;12(5):299-326. 11. Musich S, Lu C, McDonald T, et al. Association of additional health risks on medical changes and prevalence of diabetes within body mass categories. Am J Health Promotion. 2004;18(3):264-268.

AHDB Stakeholder Perspective The Evolution of Health Promotion by Employers Many initiatives and changes we are seeing in the commercial healthcare delivery or payment system have their roots in the employer segment. As illustrated in the article by Colombi and colleagues, employers have implemented various initiatives to change how healthcare benefits are developed, offered, and evaluated in the context of corporate goals related to health. The market has seen differing, successful health benefit innovations through Pitney Bowes, Dow Chemical, Marriott, City of Asheville, SCANA, University of Michigan, and now PPG Industries.

12. Kizer KW. Establishing health care performance standards in an era of consumerism. JAMA. 2001;286(10):1213-1217. 13. Knapp M. Hidden costs of mental illness. Br J Psychiatry. 2003; 183:477-478. 14. Sipkoff M. Depression is prevalent and pernicious, costing employers billions each year. Depression in the workplace. Manage Care Mag. 2006;1:4-8. 15. Stuart H. Mental illness and employment discrimination. Curr Opin Psychiatry. 2006;19(5):522-526. 16. Evers KE, Prochaska JO, Johnson JL, et al. A randomized clinical trial of population and transtheoretical model-based stress management intervention. Health Psychol. 2006;25(4):521-529. 17. Musich S, McDonald T, Hirschland D, et al. Examination of risk status transitions among active employees in a comprehensive worksite health promotion program. J Occup Environ Med. 2003; 45(4):393-399. 18. Cannon DS, Tiffany ST, Coon H, et al. The PHQ-9 as a brief assessment of lifetime major depression. Psychol Assess. 2007;19:247-251. 19. Lerner D, Amick BC, Rogers WH, et al. The Work Limitation Questionnaire. Med Care. 2001;39(1):72-85. 20. Lerner D, Adler DA, Chang H, et al. The clinical and occupational correlates of work productivity loss among employed patients with depression. J Occup Environ Med. 2004;46(6 suppl):S46-S55.

For inquiries or comments, please contact editorial@AHDBonline.com.

Each has been innovated in response to the individual organization’s needs and priorities for employee health status, along with employee performance and return on investment for the organization. This illustrates the difficulty in replicating a single success combined with the recognition that each organization does differ from one another and responds to financial constraints individually or at most by industry sector. In the approach to wellness at PPG, the authors have clearly established a how-to tactic from which most organizations can begin to implement improvement in team strategies that will diminish the disease burden on employer health and productivity. F. Randy Vogenberg, RPh, PhD Chief Strategic Officer Employer-based Pharmaceutical Strategies, LLC

SUBSCRIBE TO AMERICAN HEALTH & DRUG BENEFITS™ at www.AHDBonline.com Engage Healthcare Communications, LLC • PO Box 423 • Long Valley, New Jersey 07853

AMERICAN HEALTH & DRUG BENEFITS

April 2008

Keeping it fresh. 650 generics to market. 350 more under development. One of the industryâ&#x20AC;&#x2122;s strongest generic pipelines. To learn more, call Actavis customer service at 800.432.8534 or visit us at www.actavis.us

CLINICAL

Meta-Analysis 101: What You Want to Know in the Era of Comparative Effectiveness J.B. Jones, MBA Saul Blecker, MD Nirav R. Shah, MD, MPH

In the era of “comparative effectiveness” research, each of the major stakeholders in healthcare—payors, patients, providers, and government—face a similar challenge. When making a decision about whether a new device, drug, or a diagnostic modality should be considered for use or coverage, what choices are best supported by the evidence? Medical evidence is defined by randomized controlled trials and by observational studies that vary greatly in their design, the accuracy of their analyses, and the relevance of their conclusions and recommendations. Hence, key decision makers increasingly rely on systematic reviews and meta-analyses to facilitate the interpretation and application of research eviNirav R. Shah, MD, MPH dence. Knowing how to evaluate meta-analyses and understanding the potential pitfalls of the method are crucial for those involved in designing drug benefits. The authors highlight the process, strengths, and weaknesses of meta-analysis and explain how to judge the value of the results.

“C

omparative effectiveness” research is the best tool available today for making decisions about which new medication, medical device, or diagnostic test is most supported by the evidence.1 The purpose of a systematic review is to synthesize the results of multiple primary studies using explicit and reproducible methods.2,3 Meta-analysis is a form of systematic review that goes one step further. Rather than qualitatively synthesizing the results of multiple studies, the purpose of a meta-analysis is to develop a quantitative summary of the evidence with the help of special statistical techniques. Whereas a systematic review may conclude that a certain drug is

effective in preventing a morbid event, a meta-analysis will tell us that the drug is, say, 3.7 times more effective than a placebo in preventing that morbid outcome. Conceptually, the distinction between the 2 types of reviews is straightforward. Despite the appeal inherent in developing a quantitative synthesis, the decision to conduct, or to make decisions based on, a meta-analysis must be made carefully, with an understanding of the benefits and limitations of the method. This paper provides an overview of the meta-analysis process, highlights the strengths and weaknesses of the method, and offers guidance on how to interpret and judge the value of meta-analytic results.

Mr Jones is with the Center for Health Research, Geisinger Health System, Danville, PA; Dr Blecker is with the Division of General Internal Medicine, NYU School of Medicine, New York, NY; Dr Shah is Assistant Professor of Medicine, NYU School of Medicine, Associate Investigator at the Geisinger Center for Health Research, and Principal of MetaResearch, LLC.

Key Elements of Meta-Analysis Meta-analysis is a method used to critically evaluate evidence in an attempt to develop a single synthesis of the results and, where appropriate, to use statistical methods to combine findings from different studies into a single “pooled estimate.” The pooled estimate is also called the “overall treatment effect,” even when

AMERICAN HEALTH & DRUG BENEFITS

April 2008

CLINICAL

referring to pooling of diagnostic tests, screening studies, or other areas that are not treatments per se. The reasons to perform a meta-analysis are to: • Increase statistical power (relative to individual studies) and determine if a treatment effect exists by combining multiple trials • Improve the precision of the measurement of a treatment effect • Combine data from conflicting studies and determine if a treatment effect exists • Explore the impact on the treatment effects associated with differences in the design, conduct, analysis, and results of individual studies. A meta-analysis begins with a systematic review of the literature, followed by a statistical analysis. Generally, it proceeds according to these steps: 1. Formulation of a study question 2. Setting inclusion and exclusion criteria for studies to be reviewed 3. Searching the literature 4. Triaging articles 5. Retrieving data from the selected studies 6. Pooling the data by applying specific statistical techniques 7. Investigating sources of differences between studies 8. Summarizing and presenting results.

Selecting the Data To conduct a meta-analysis, one must begin by formulating the study question. A well-focused study question has 4 components that are referred to as PICO: Population—a description of the patient population to be addressed Intervention—a detailed description of the intervention or exposure to be investigated Comparison—a well-defined comparison group Outcome—a specific outcome. For example, the following research question includes all 4 PICO elements. In adult patients with type 2 diabetes, does monotherapy with rosiglitazone improve A1c levels compared with metformin at 6 months? To minimize bias, inclusion and exclusion criteria should be identified before performing the literature search. Many of the inclusion criteria are determined as a direct result of the research question (eg, definition of the patient population or the outcome to be studied); other criteria (eg, study design) are determined by the research team. Ideally, meta-analyses are limited to one type of study design. Significant problems are associated with metaanalyses that combine results across different study

KEY POINTS Meta-analyses and systematic reviews are important tools for use by healthcare decision makers when deciding which medication, medical device, or test to include in their benefit design programs. A good meta-analysis study question has 4 components, denoted by the acronym PICO—population, intervention, comparison, and a specific outcome. The majority of meta-analyses now report results by random effects, and those that report results only by fixed effects should be viewed with skepticism. Not all meta-analyses are of equal quality. Determine if a technique such as meta-regression was used to assess heterogeneity. Look for publication bias—the exclusion of negative studies that might have influenced the conclusions.

designs (eg, randomized controlled trials and case-control studies). Other inclusion and exclusion criteria may include years of publication, language of publication, and minimum study size. Because the quality of a metaanalysis is very dependent on the studies that comprise it, well-thought-out inclusion and exclusion criteria are necessary to ensure the validity of the conclusions. Once selection criteria are established, an extensive literature search should be performed. A literature review typically begins with a systematic, well-documented, and repeatable search of electronic databases, such as PubMed, Embase, and/or the Cochrane Database of Systematic Reviews. The search should also include a “hand-search” of the reference lists of individual studies included in the meta-analysis. A well-designed search strategy will also utilize other sources, for example, “grey” literature (ie, not published in a peer-reviewed journal but in the form of reports, unpublished theses, books, and so on).4 A reliable literature search must be exhaustive and should be reproducible, with specific search terms reported in the methods section.5 The literature search will produce an extensive list of potentially relevant citations. Articles must then be triaged for possible inclusion. The Quality of Reporting of Meta-Analyses (QUOROM) committee has created a flowchart that outlines a recommended format for presenting the “flow” of included and excluded studies. This chart clearly shows how the investigators move from the entire pool of articles identified to the final set of articles included in the pooled analysis.6 This allows readers to evaluate the number of and the rationale for all exclusions. Each study included in the meta-analy-

www.AHDBonline.com

CLINICAL

Figure 1 Meta-Analysis Forest Plot: Description and Sample

sis should be evaluated for quality. Ideally, this assessment should follow a generally accepted scale or checklist, such as the Jadad Score for randomized trials7 or STROBE (Strengthening the Reporting of Observational Studies in Epidemiology).8 Data such as measures of treatment effects, confidence intervals, study characteristics, and other variables hypothesized to affect the study results are then abstracted from the chosen studies, using a standardized form. The identification of studies and the data abstraction process should be carried out independently by at least 2 researchers (who resolve disagreements by consensus) to minimize bias in article selection and reduce errors in data collection.

Statistical Analysis The next step is to decide whether statistical pooling is justified. Although the goal is to obtain meaningful results from previous studies, there is also a possibility of reaching erroneous conclusions, especially if data are pooled from studies that are too diverse. If the differences between studies are significant—different patient populations or different comparison groups— combining results may not make clinical sense. In such cases, results should not be pooled but rather be presented in a systematic review. The extent of variability between studies is subjective, and meta-analyses are often criticized for inappropriately combining heterogeneous data (see below).9 The results of a meta-analysis are graphically expressed in a type of graph called a “forest plot” (Figure 1), which displays the independent results of each study and the overall pooled result on the same plot. This allows the reader to quickly visualize the treatment effect in individual studies relative to the combined treatment effect across all studies. The results of each study are represented by squares that vary in size according to the relative size of the study (ie, larger squares denote larger studies). Each square is bisected by a horizontal line, the length of which spans the 95% confidence interval for the treatment effect reported in that study. The overall pooled estimate is shown at the bottom of the figure, represented by a diamond, whose center and edges correspond to the mean overall result and confidence interval, respectively.10

B ES indicates effect size; CI, confidence interval. Sources: Adapted from (A) Moja L, Moschetti I, Liberati A, et al. Understanding systematic reviews: the meta-analysis graph (also called ‘forest plot’). Intern Emerg Med. 2007 Jun;2(2):140-142. (B) Shah NR, Jones JB, Aperi J, et al. Selective serotonin reuptake inhibitors for premenstrual syndrome and premenstrual dysphoric disorder: a systematic review and meta-analysis. Obstetr Gynecol. 2008 [in press].

AMERICAN HEALTH & DRUG BENEFITS

April 2008

How to Identify Potential Problems Once the studies to be included in the pooled analysis have been identified, some differences will still be evident between studies. The nature and magnitude of these differences play a critical role in determining the

CLINICAL

Figure 2 Heterogeneity, with Inclusion of the Million Women Study

WA BCDDP 3 State WHS CARES Million WS

Combined 0.5

1.0

2.0 Odds Ratio

WA indicates Washington State; BCDDP, Breast Cancer Detection Demonstration Project; WHS, Women’s Health Study; CARES, Contraceptive And Reproductive Experiences Study; WS, Women Study.

Figure 3 Publication Bias Funnel Plot published unpublished

Study size

methods to be used in the statistical analysis. Researchers have developed summary measures that quantify the degree of interstudy “heterogeneity.” Cochran’s Q (based on the chi-square) test is the most common test for heterogeneity. If “significant” heterogeneity is identified (ie, P <.20 is a typical cut-off in meta-analysis), it is important to determine whether it is valid to combine heterogeneous studies into a single pooled measure of treatment effect. For example, in a meta-analysis of hormone replacement therapy (HRT) and breast cancer, the Q test identified heterogeneity (Figure 2). One study clearly stood out—the Million Women Study, not only because it was the largest and only study conducted in Europe but also because of other important underlying clinical differences. When this study was excluded, the Q test was no longer significant, and the point estimate better reflected the pooling of similar studies.11 The I2 statistic (also referred to as “inconsistency”) is an updated version of the Q test. This updated measure is designed to allow comparison of heterogeneity between meta-analyses with different numbers of pooled studies, which cannot be done with the Q test alone.12 An I2 value of less than 25% is considered good, 25% to 50% is acceptable, and more than 50% is unacceptable. When heterogeneity is identified by the Q test or by I2, several approaches can be considered to address the differences. The first approach is to simply ignore the interstudy differences. Some investigators have argued that “one true effect” must underlie all studies on a given topic, and results should be pooled by use of a “fixed effects” model. A second method is to use a “random effects” model, which statistically accounts for heterogeneity and considers several “true effects.” (The difference between fixed and random effects models13 is beyond the scope of this review.) In general, a random effects model results in the same pooled treatment estimate but with a wider confidence interval than the fixed effects model. The majority of meta-analyses now report random effects results, and those that report only fixed effects results should be viewed with skepticism, especially those that report pooled treatment effects with marginal statistical significance.13 Another common approach to addressing heterogeneity is using meta-regression, which involves applying traditional regression techniques—and their inherent explanatory power—to meta-analysis. In meta-regression, the dependent variable is the outcome (eg, the odds ratio or the relative risk), and the independent variables are study factors, such as publication year, country, study

Treatment Effect (eg, odds ratio)

size, or type of drug, that may reasonably be expected to contribute to interstudy differences. Stratifying and conducting subgroup meta-analyses based on these factors may help identify important sources of heterogeneity (eg, the HRT example). Although meta-regression is useful to assess heterogeneity, the results should be considered “hypothesis generating.” The final step in meta-analysis is to look for evidence of publication bias—the exclusion of negative studies that might have influenced the conclusions. Studies published in peer-reviewed journals tend to report positive results more than negative results. In practice, researchers who find negative results often do

www.AHDBonline.com

CLINICAL

not believe them, and editors may not as readily accept negative studies.14 Publication bias is typically evaluated by using a funnel plot. A funnel plot is a type of scatter plot in which each study’s treatment effect is plotted on the x-axis, and a measure of study size is plotted on the y-axis (Figure 3). Small studies are more likely to have less precise effect estimates than large studies and are therefore more likely to be scattered along the bottom of the plot.15 In the absence of publication bias, the resulting plot should resemble an upside-down funnel, as seen in Figure 3. If publication bias is present, smaller studies that fail to show a significant effect will likely be missing, and the funnel plot will appear asymmetric (ie, the open circles in Figure 3 would be absent).15 Techniques for assessing publication bias continue to be refined,16 thus it’s best to confirm that publication bias assessment was conducted in the meta-analysis rather than to assess the specific techniques used.17

The Limits of Meta-Analysis Meta-analysis can be a powerful technique for summarizing evidence. Each meta-analysis is, in and of itself, a scientific investigation, and its quality is dependent on the methods used in carrying out the “experiment.”2 Different researchers may use different techniques, include different studies, and draw different conclusions. Like any experiment, meta-analyses are subject to bias and error, both of which may affect the validity of the conclusions and their utility for decision makers. As a result, not all meta-analyses are of equal quality. Thus “consumers” of meta-analyses— especially decision makers—must carefully assess the quality of each meta-analysis by considering the research questions asked, the methods used, the analysis and interpretation of the data, the investigation of heterogeneity, and the conclusions drawn. Evaluating Quality Several instruments for assessing the quality of a systematic review have been developed.15 It is important to differentiate between the quality of the reporting of a meta-analysis and the quality of the meta-analysis itself. The report may, for a number of reasons (eg, space limits, author preferences), omit important information. The QUOROM statement offers a checklist of evidence-based standards for reporting the results of meta-analyses of randomized trials.6 The QUOROM checklist—which identifies 18 key items to be included in a report and explains how to describe them—is widely used in the reporting and the evaluation of

AMERICAN HEALTH & DRUG BENEFITS

April 2008

published meta-analyses. The Meta-analyses of Observational Studies in Epidemiology (MOOSE) is a similar checklist that is used to guide the reporting of meta-analyses of observational studies.18 Over the past 20 years there has been tremendous growth in the number of systematic reviews and metaanalyses. A recent study investigated the average length of time until a published systematic review requires updating.19 The authors searched the relevant literature to determine whether new evidence had been published that would either invalidate the results of a previous systematic review or would affect clinical decision-making in an important way. In almost 60% of the systematic reviews, the evidence showed that the previously published review required updating. The average length of time from publication to the emergence of new evidence was about 5.5 years, with 25% of studies becoming outdated by 2 years. This suggests that meta-analyses may have a relatively short “shelf-life,”20 and that the longer it has been since publication, the more important it is to assess whether new evidence has emerged that may change that study’s conclusions.

Conclusions Meta-analysis is a sophisticated tool for decision makers. As with all medical evidence, however, systematic reviews and meta-analyses should be regarded with due skepticism and be read critically, focusing on the elements discussed here. As meta-analyses begin to address the development of pooled estimates of cost, adverse effects, and comparative effectiveness (in addition to efficacy and effectiveness), their relevance to our understanding of how to define and measure value in healthcare will continue to grow. Disclosure Statement Dr Shah has received unrestricted research grants from GlaxoSmithKline, Novartis, AstraZeneca, Roche, Berlex, and Pfizer. Mr Jones and Dr Blecker have nothing to disclose.

References 1. Shah NR. What is the best evidence for making clinical decisions? JAMA. 2000 Dec 27; 284(24):3127-3128. 2. Cook DJ, Mulrow CD, Haynes RB. Systematic reviews: synthesis of best evidence for clinical decisions. Ann Intern Med. 1997 March 1;126(5):376-380. 3. Greenhalgh T. Papers that summarise other papers (systematic reviews and meta-analyses). BMJ. 1997 Sep 13;315(7109):672-675. 4. Hopewell S, McDonald S, Clarke M, Egger M. Grey literature in meta-analyses of randomized trials of health care interventions.

CLINICAL

Cochrane Database of Systematic Reviews 2003, Issue 4. Art No: MR000010. DOI: 10.1002/14651858.MR000010.pub3. 5. Egger M, Smith GD, Phillips AN. Meta-analysis: principles and procedures. BMJ. 1997 Dec 6; 315(7121):1533-1537. 6. Moher D, Cook DJ, Eastwood S, et al. Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet. 1999 Nov 27; 354(9193):1896-1900. 7. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996 Feb; 17(1):1-12. 8. von Elm E, Altman DG, Egger M, et al, for the STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008 Apr;61(4):344-349. 9. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6. [Updated September 2006]. In: The Cochrane Library, Issue 4, 2006. Chichester, UK: John Wiley & Sons, Ltd. http://www.cochrane.org/resources/handbook/Handbook4.2.6 Sep2006.pdf. 10. Lewis S, Clarke M. Forest plots: trying to see the wood and the trees. BMJ. 2001 Jun 16; 322(7300):1479-1480. 11. Shah NR, Borenstein J, Dubois RW. Postmenopausal hormone therapy and breast cancer: a systematic review and meta-analysis. Menopause. 2005;12(6):668-678.

AHDB Stakeholder Perspective Meta-Analyses and Patient Care With the proliferation of medical research studies over the past few decades, healthcare providers needed evidence synthesis more sophisticated than the traditional narrative review. Systematic reviews and meta-analyses have filled that void and are now routinely used by those on the front lines of patient care. PAYORS: Payors have been slower to adopt these techniques, but have now been embracing them more fully. The broad and rigorous overview of a topic provided by such a synthesis, when conducted by independent and transparent entities, makes available the data they have long needed, but to which they have not had access. At the same time, payors remain cautious that these evidence summaries may include populations different from those in their managed population. MANUFACTURERS: Manufacturers have been among the most refined in their use of meta-analyses, using them not only to get early signals of effectiveness but also to explore new possibilities in the lifecycle of drugs and devices through meta-regression and other advanced techniques. Although certainly considered an opportunity, meta-analysis also presents risk. For example, the Avandia meta-analysis led to

12. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003 Sep 6;327(7414):557-560. 13. Shuster JJ, Jones LS, Salmon DA. Fixed vs random effects meta-analysis in rare event studies: the rosiglitazone link with myocardial infarction and cardiac death. Stat Med. 2007 Oct 30;26(24):4375-4385. 14. CMAJ Editorial. The “file drawer” phenomenon: suppressing clinical evidence. CMAJ. 2004 Feb 17;170(4):437 [editorial]. 15. Egger M, Smith GD, Altman DG, eds. Systematic Reviews in Health Care: Meta-Analysis in Context. 2nd ed. London, UK: BMJ Books; 2001. 16. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006 Feb 8;295(6):676-680. 17. Ioannidis JP, Trikalinos TA. The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ. 2007 Apr 10; 176 (8):1091-1096. 18. Stroup DF, Berlin JA, Morton SC, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000 Apr 19;283(15):2008-2012. 19. Shojania KG, Sampson M, Ansari MT, et al. How quickly do systematic reviews go out of date? A survival analysis. Ann Intern Med. 2007 Aug 21;147(4):224-233. 20. Jones JB, Shah NR. Meta-analyses: caveat lector. J Clin Outcomes Manag. 2008 Feb;15(2):61-62.

the convening of an FDA Task Force to more closely review all data available on thiazolidinediones, which changed the labeling on this medication. GOVERNMENT: The National Institutes of Health (NIH) and the Centers for Medicare & Medicaid Services (CMS) have only recently considered systematic reviews and meta-analyses as credible sources of evidence. Through funding “evidencebased practice centers” and comparative effectiveness reviews, the NIH and CMS have quickly become major sponsors of high-quality systematic reviews. In addition, the FDA is looking for new data sources and tools to efficiently monitor treatment effectiveness and safety, and meta-analyses provide a valuable source of fresh information after medications have been commercially available. PATIENTS: With the increasing prevalence of so-called consumer-driven healthcare, consumers play an important role in assessing the quality and cost-benefit of various treatment options. Metaanalyses and systematic reviews can be an effective tool for consumers, but it is important to educate consumers about the strengths and limitations of the technique, and the applicability of the results to their specific decision or concern. Scott R. Taylor, RPh, MBA Associate Director, Industry Relations Geisinger Health System

www.AHDBonline.com

CLINICAL

Depression Overview Thomas McCarter, MD, FACP

Depression is a common condition that often remains undiagnosed and untreated; however, symptoms are more likely to be recognized today than in past decades. Survey data suggest that female, nonwhite patients are more likely to report depressive symptoms, especially those who are less educated, poor, and covered by Medicaid. Depression may be a finding suggestive of dysthymic disorder, minor or major depressive disorder, seasonal affective disorder, episodic depression, or a sign of an associated mood disorder, such as bipolar disorder. Many effective treatments are available that are well tolerated. This article outlines the diagnostic approach used in primary care, as well as the different treatment options available for this condition. Depression can have serious consequences and must be treated appropriately.

mong adults responding to the 2006 National Health Interview Survey, 11% reported having feelings of sadness during all, most, or some of the time in the 30 days before the interview; 6% reported feeling hopeless; 5% felt worthless; and 14% felt that everything was an effort.1 Women were more likely to report such symptoms than men (13% vs 9%, respectively). Non-Hispanic black adults and Hispanic adults were more likely to report feelings of sadness or hopelessness than non-Hispanic white adults. Level of education was inversely associated with feelings of sadness, hopelessness, worthlessness, or with the feeling that everything was an effort. Adults with less than a high school diploma reported the highest levels of such feelings, and those classified as poor were twice as likely to report these feelings as those not classified as poor. Persons under age 65 who were covered by Medicaid were more likely (27%) to report depressive symptoms than those who were uninsured (14%) or those with private health insurance (7%). Among those aged 65 and older, Medicare and Medicaid “dual-eligible” patients were more likely to report feelings of sadness (28%) than those covered by Medicare alone (13%) or those with private health insurance (11%).1 Depression is a common condition that frequently remains undiagnosed and untreated. Nevertheless, depression is more likely to be diagnosed today than in past decades, because the social stigma associated with this condition has lessened; available treatments are

Dr McCarter is Chief Clinical Officer, Executive Health Resources in Newtown Square, PA.

AMERICAN HEALTH & DRUG BENEFITS

April 2008

effective and well tolerated; and primary care physicians, to whom most patients initially present and from whom most patients receive initial therapy, have become more willing to diagnose and treat this condition. Depression may be suggestive of dysthymic disorder, major depressive disorder (MDD), seasonal affective disorder, episodic depression, or a sign of an associated mood, bipolar, or psychotic disorder. Depression may also be episodic, in response to bereavement or a major life change. In addition, it may play a significant role in specific clinical settings, such as during pregnancy or the postpartum period,2 adolescence, or at the end of life.3 This type of depression is beyond the scope of this discussion.

Diagnosis Risk Factors Risk factors that predispose patients to depression include: • Female gender • History of anxiety • History of eating disorders • First-degree relative with a history of depression • History of or current drug or alcohol abuse • History of or current sexual abuse or domestic violence. In addition, patients with major medical conditions or with chronic medical conditions are at a greater risk of experiencing depressive symptoms. These conditions may include cardiac illnesses (ie, myocardial infarction, coronary artery atherosclerotic disease, and arrhythmias), cerebrovascular disease (after a stroke or a transient ischemic attack), diabetes, chronic lung or renal disease, cancer, and chronic pain disorders.4

CLINICAL

Table 1 DSM-IV Criteria for Major Depression A. Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure Note: Do not include symptoms that are clearly due to a general medical condition, or mood-incongruent delusions or hallucinations 1. Depressed mood most of the day, nearly every day, as indicated by either subjective report (eg, feels sad or empty) or observation made by others (eg, appears tearful) Note: In children and adolescents, can be irritable mood 2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation made by others) 3. Significant weight loss when not dieting or weight gain (eg, a change of more than 5% of body weight in a month) or decrease or increase in appetite nearly every day Note: In children, consider failure to make expected weight gains 4. Insomnia or hypersomnia nearly every day 5. Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down) 6. Fatigue or loss of energy nearly every day 7. Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely selfreproach or guilt about being sick) 8. Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others) 9. Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide B. The symptoms do not meet the criteria for a mixed episode (ie, no symptoms or signs of manic episode) C. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning D. The symptoms are not due to the direct physiological effects of a substance (eg, a drug of abuse, a medication) or a general medical condition (eg, hypothyroidism) E. The symptoms are not better accounted for by bereavement, that is, after the loss of a loved one, the symptoms persist for longer than 2 months or are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation Adapted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (Copyright 2000). American Psychiatric Association.

Although the rates of major depression are highest among the 25- to 44-year-old age-groups, patients in older age-groups may be at increased risk, because of the loss of or separation from a spouse or peers, cognitive or physical impairments, and a higher prevalence of chronic diseases.5 This population may present specific challenges regarding the diagnosis and treatment because of a high prevalence of comorbid conditions and a higher utilization of other medications.6

Symptoms The characteristic symptoms of depression include loss of interest in activities that have historically proved to be pleasurable, sadness, irritability, feelings of worthlessness, hopelessness, guilt or anxiety, concerns over death, or suicidal ideation. Associated symptoms may include changes in appetite, weight loss or weight gain, sleep disturbances,

psychomotor activity, decreased energy, indecisiveness, or distracted attention. Patients with depression may also present with somatic complaints and may be frequent users of primary care, urgent care, and emergency or inpatient services. Patients with depression may also be those whom clinical staff identifies as “difficult” to treat. The American Psychiatric Association’s (APA) criteria for a major depression episode are listed in Table 1. Patients who are experiencing psychosocial stressors and who do not meet the criteria of major depression episode may be suffering from an adjustment disorder, or posttraumatic stress disorder. Recurrent episodes of major depression are called major depressive disorder, a condition associated with a high mortality. Patients with severe MDD have a high rate of suicide, and epidemiologic studies indicate that patients with MDD who are older than age 55 have a 4-fold increase in

www.AHDBonline.com

CLINICAL

Figure Assessing Depression with the PHQ-9 PATIENT HEALTH QUESTIONNAIRE (PHQ-9)

FOR DOCTOR OR HEALTHCARE PROFESSIONAL USE ONLY

English This questionnaire is an important part of providing you with the best health care possible. Your answers will help in understanding problems that you may have. Please answer every question to the best of your ability unless you are requested to skip a question. Name:________________________________________Age:________________________________________ Sex:

Female

Today’s Date:___________________________________________________

Male

Several days

More than half the days 2

Nearly every day 3

#ONSIDER -AJOR $EPRESSIVE $ISORDER

#ONSIDER /THER $EPRESSIVE $ISORDER

Over the last 2 weeks, how often have you been bothered by any of the following problems? Not at all

1. Little interest or pleasure in doing things 2. Feeling down, depressed, or hopeless

3. Trouble falling or staying asleep, or sleeping too much

4. Feeling tired or having little energy

7. Trouble concentrating on things, such as reading the newspaper or watching television

8. Moving or speaking so slowly that other people could have noticed. Or the opposite—being so fidgety or restless that you have been moving around a lot more than usual

FOR HEALTHCARE PROFESSIONAL USE ONLY

9. Thoughts that you would be better off dead, or of hurting yourself in some way

If you checked “several days” or higher for some of the questions above, discuss your answers with a doctor. Only a doctor can make a diagnosis of depression. Also talk to your doctor if you checked “several days” or higher for (9), thinking that you would be better off dead or wanting to hurt yourself. Having repeated thoughts of death or suicide is the most serious symptom of depression. If you are thinking of harming yourself, get help immediately; make your feelings known to someone who can help you—your doctor, family members, friends. Your doctor is an excellent person to tell. KEY (for physician’s use): MDD if answer to # 1 or 2 and 5 or more of # 1-9 are at least “More than half the days” (count # 9 if present at all). All rights reserved.

6. Feeling bad about yourself, or that you are a failure, or have let yourself or your family down

5. Poor appetite or overeating

ZT254386G

Printed in USA/September 2005

rates of death.7 Depressive episodes associated with manic episodes are classified as bipolar disorder.

History and Physical Examination When taking the medical history, it is important to identify the severity and duration of the symptoms and any previous episodes, because depression tends to be recurrent. One should determine whether there is a family history of depression or other psychiatric illness— both major depression and bipolar disorder are heritable conditions. Recognition of manic or psychotic symptoms may identify patients who may require earlier referral to a psychiatrist. A history of suicidal thoughts, plans, or actions must be ascertained and again may identify patients who need more urgent referral. Although the physical examination is fairly insensitive for identifying depression, a thorough physical examination is important to identify contributing or causal ill-

AMERICAN HEALTH & DRUG BENEFITS

April 2008

nesses, such as chronic liver or renal disease, endocrine disease (hypothyroidism or adrenal insufficiency), congestive heart failure, dementia, or other conditions. In primary care settings, the point prevalence of major depression ranges from 5% to 9% among adults, and up to 50% of depressed patients are not recognized.8 The related conditions of dysthymia (a chronic low-grade depression) and minor depression are as common as major depression in primary care settings. Depressive disorders are estimated to affect from 0.8% to 2.0% of children and 4.5% of adolescents.9 Some of the barriers that may contribute to these percentages include: • Inadequate knowledge of diagnostic criteria • Competing priorities and comorbid conditions • Time limitations • Stigma associated with “labeling” a patient as depressed • Poor reimbursement mechanisms.

CLINICAL

Because of these barriers, a number of case-finding instruments have been developed and validated, including the Beck Depression Inventory, the Center for Epidemiological Studies-Depression Scale, the Zung Self-Assessment Depression Scale, the General Health Questionnaire, and the Hopkins Symptom Checklist, among others.9 Recently, 2 related tools are increasingly being used to screen and diagnose depression. The Patient Health Questionnaire (PHQ)-2 is an abbreviated version, consisting of the anhedonia and mood items of the PHQ-9. The PHQ2 can be used as a very brief and quick depression-screening tool in primary care. In primary care patients, a PHQ2 score of 3 or more has 83% sensitivity and 92% specificity for identifying patients with major depression.10 If the PHQ-2 is positive, screening may be confirmed by completing all the questions on the PHQ-9 (Figure). The PHQ-9 can be used as a screening tool, with summed score ranging from 0 (no depressive symptoms) to 27 (all symptoms occurring daily). A PHQ-9 score of 10 or more has been found to have 88% sensitivity and 88% specificity for a diagnosis of major depression.10 The PHQ-9 can also be used as a diagnostic assessment; with major depression diagnosed if 5 or more of the 9 symptoms have been present at least more than half the days of the past 2 weeks and 1 of these symptoms is either depressed mood or anhedonia.

Drug Therapy Untreated depression is associated with increased deaths, adverse outcomes, deficits in function, increased use of health services, poor on-the-job performance, and increased absenteeism. Treatments most frequently used by primary care physicians are (1) medications and (2) psychotherapy in cooperation with a psychologist, psychiatrist, or therapist. More than half of depressed patients respond to initial treatment with medications. Medication options are numerous (Table 2), and treatment recommendations should be tailored to the individual patient on the basis of the symptom profile, side effects of the drugs, comorbid conditions, and previous responses to treatment if available. Most drugs focus on serotonin and norepinephrine levels in the brain, supported by the major theory of depression known as the monoamine-deficiency hypothesis. The biochemical basis for this hypothesis and numerous other theories have been recently reviewed elsewhere.11 Several classes of drugs have been found effective in treating depression, through increasing the concentrations of the neurotransmitters serotonin and norepinephrine in the postsynaptic cleft of neurons in the cen-

tral nervous system. These agents include selective serotonin reuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors (NRIs), and dual-action agents that inhibit the reuptake of serotonin and norepinephrine. Monoamine oxidase inhibitors (MAOIs) increase concentrations of neurotransmitters by inhibiting their degradation. Other agents increase the availability of neurotransmitters by blocking alpha-adrenergic autoreceptors, as well as serotonin (5-HT)2a reuptake and 5HT3 receptors, and histamine H1 receptors. Mood stabilizers, such as lithium, and anticonvulsants, such as lamotrigine, valproic acid, divalproex, or carbamazepine, may play an adjunctive role to antidepressants in the treatment of bipolar disorder. Antipsychotics and atypical antipsychotics may play a role in treating depression with psychotic features, as well as resistant major depression and bipolar depression.12 However, patients with these conditions may be more appropriately managed in conjunction with a psychiatrist. There are 3 phases in the treatment of depression— the acute phase, the continuation phase, and the maintenance phase. During the acute phase, treatment should be initiated and follow-up scheduled at 1- to 2week intervals to ensure a response. If a certain medication has worked previously for a patient or a family member, this may be an appropriate first choice. Antidepressants are started at low doses and titrated upward at appropriate time intervals based on response and side effects. If a patient’s response to a drug is inadequate at appropriate treatment doses, a change to a medication in the same or another class may be appropriate (patients who do not respond to one SSRI may respond to another agent within the class). Once an adequate response has been achieved in the acute phase, the continuation phase begins and can last as long as 9 months from remission. During this phase, treatment goals are to eliminate residual symptoms, to restore previous level of functioning, and to prevent recurrence or relapse. If there is no recurrence of symptoms during the first 6 months of treatment, a consideration to wean the medication and assess for the possibility of “early discontinuation” may be reasonable. If symptoms return, the medication should be re-titrated upwards to an effective dose and maintained for an additional 3 to 6 months. Early discontinuation does have a higher rate of relapse.12 Discontinuation in itself may produce symptoms (“discontinuation syndrome”), including balance problems, gastrointestinal upset, myalgias, weakness, sensory and sleep disturbances, anxiety, agitation, and emotional volatility. A maintenance phase treatment for 12 to 36 months may be indicated for patients with recurrent episodes of

www.AHDBonline.com

CLINICAL

Table 2 Antidepressants: Dosing, Indications, and Off-Label Use Maintenance dosage

Indications

Off-label use

Side effects (>10%)

Contraindications

40 mg/d

MDD

Somnolence, insomnia, nausea, xerostomia, diaphoresis

Lexapro (escitalopram) Luvox (fluvoxamine) Luvox CR

10 mg/d

MDD, GAD

100 mg bid

OCD

Alcoholism, coronary arteriosclerotic depression, OCD, panic disorder, PMDD, tension-type headache Mixed anxiety and depressive disorder, panic disorder Autism, depression, eating disorder, panic disorder

100 mg/d

Paxil (paroxetine)

20 mg/d

Paxil CR

25 mg/d

Pexeva (paroxetine) Prozac (fluoxetine)

30 mg/d

20 mg/d

Prozac Weekly

90 mg/wk

OCD, Social anxiety disorder GAD, MDD, OCD, panic disorder, PTSD, social anxiety disorder MDD, panic disorder, PMDD, social anxiety disorder MDD, OCD, panic disorder, GAD Bulimia nervosa, MDD, OCD, panic disorder MDD

Headache, somnolence, insomnia, nausea, ejaculation disorder Headache, somnolence, insomnia, nausea, nervousness, dizziness, diarrhea, xerostomia, weakness

Sarafem (fluoxetine) Zoloft (sertraline)

20 mg/d

PMDD

50 mg/d

MDD, OCD, panic disorder, PTSD, PMDD, social phobia

Alzheimer's depression, post-MI depression, dysthymia, night-eating syndrome

Dizziness, fatigue, headache, insomnia, somnolence, decreased libido, anorexia, diarrhea, nausea, xerostomia, ejaculatory disturbances, tremors, diaphoresis

60 mg/d

Diabetic neuropathy, GAD, MDD

Fibromyalgia, urinary incontinence

37.5 mg bid

MDD

Hot sweats, OCD, PMDD

75 mg/d

50 mg/d

MDD, GAD, social anxiety disorder, panic disorder MDD

100 mg 3 times daily 150 mg bid 300 mg/d

MDD

25 mg 3 times daily

OCD

Asendin (amoxapine)

150 mg/d

Elavil (amitriptyline)

50 mg/d

MDD, endogenous depression, severe major depression with psychosis MDD

Norpramin (desipramine)

100 mg/d

MDD

Pamelor (nortriptyline)

25 mg 3 times daily

MDD

Class/Drug brand name (nonproprietary name) Selective Serotonin Reuptake Inhibitors Celexa (citalopram)

Mixed/Dual Cymbalta (duloxetine) Effexor (venlafaxine) Effexor XR

Pristiq (desvenlafaxine) Wellbutrin (bupropion) Wellbutrin SR Wellbutrin XL Tricyclics Anafranil (clomipramine)

Generic available?

Y Y*

Compulsive gambling, drug-induced depression, hot sweats, premature ejaculation

Body dysmorphic disorder, cancerdepression, DM-depression, dysthymia, fibromyalgia, hot sweats, PTSD, Raynaud's

Chronic pain, delusional disorder, MDD, ejaculatory disorder, panic disorder, pervasive development disorder

Headache (treatment/prophylaxis), pain, polyneuropathy, postherpetic neuralgia ADHD, diabetic neuropathy

ADHD, neurogenic bladder, nicotine dependence, nocturnal enuresis, postherpetic neuralgia

AMERICAN HEALTH & DRUG BENEFITS

April 2008

Somnolence, insomnia, headache, dizziness, decreased libido, nausea, xerostomia, constipation, diarrhea, weakness, ejaculatory disturbances, diaphoresis

Insomnia, headache, anxiety, nervousness, somnolence, decreased libido, nausea, diarrhea, anorexia, xerostomia, weakness, tremor, pharyngitis, yawning

Market share, %

Cost of 30-day supply

Concomitant use of MAOI + pimozide

8.29

Concomitant use of MAOI + pimozide Concomitant use w/ alosetron, pimozide, thioridazine, tizanidine, MAOI Concomitant use of linezolid, MAOI, pimozide, thioridazine

13.78

($$$) $$$$

$$$

7.98

1.27

($$$)

Concomitant use of MAOIs, pimozide, thioridazine

$ ($$$$)

11.36

($$$$)

Concomitant use of disulfiram, MAOIs, pimozide

15.12

Somnolence, dizziness, headache, insomnia, nausea, xerostomia, diarrhea, constipation Headache, insomnia, somnolence, nervousness, dizziness, nausea, xerostomia, anorexia, constipation, sexual dysfunction, weakness, diaphoresis

Concomitant use of MAOI, uncontrolled narrow-angle glaucoma Concomitant use of MAOIs

6.4

($$$$)

Nausea, dry mouth, diarrhea, dizziness, headache, hyperhidrosis Tachycardia, headache, insomnia, dizziness, xerostomia, weight loss, nausea, pharyngitis

Concomitant use of MAOIs Contraindicated in bulimia or anorexia, MAOI, seizure disorders, abrupt discontinuation of alcohol or sedative

$$$$ 8.77

($$$)

NA $$$

5.26

$$$ $$$$

Dizziness, somnolence, libido changes, xerostomia, constipation, nausea, dyspepsia, weight gain, anorexia, abdominal pain, drowsiness, fatigue Drowsiness, xerostomia, constipation

Coadministration with MAOI, contraindication in acute recovery period of MI

$$$

Coadministration w/ MAOI, contraindication in acute recovery period of MI

$$$

Weight gain, bloating symptom, constipation, xerostomia, asthenia, dizziness, headache, somnolence, blurred vision, fatigue Weight gain/loss, bloating symptom, constipation, loss of appetite, nausea, xerostomia, asthenia, dizziness, headache, somnolence, blurred vision, fatigue Weight gain, bloating symptom, constipation, xerostomia, asthenia, dizziness, headache, somnolence, blurred vision, fatigue, loss of appetite

Coadministration w/ cisapride, MAOI during acute recovery period of MI

6.86

Coadministration w/ MAOI or during acute recovery period of MI hypersensitivity to dibenzazepines

Coadministration with MAOI, contraindication in acute recovery period of MI; hypersensitivity to dibenzazepines

1.59

CLINICAL

Table 2 Antidepressants: Dosing, Indications, and Off-Label Use (continued) Generic available?

Maintenance dosage

Indications

Off-label use

Side effects (>10%)

Contraindications

75 mg/d

Urticaria

Weight gain, bloating sympton, constipation, xerostomia, dizziness, somnolence, blurred vision, urinary retention

Glaucoma, urinary retention

1.06

Surmontil (trimipramine)

50-150 mg/d at bedtime for 3 mo

AlcoholismAnxiety/Depression, anxiety, depression, psychoneurotic personality disorderA/D, pruritus MDD

Cost of 30-day supply $

Alopecia, petechiae, photosensitivity, weight changes, dizziness, headache, blurred vision, anxiety, urinary retention, fatigue

$$$

Tofranil (imipramine)

MDD, Nocturnal enuresis

Binging, diabetic neuropathy, panic disorder, urinary incontinence

Vivactil (protriptyline)

Inpatient: 75-150 mg at bedtime Outpatient: 50-150 mg/d 15-60 mg 3-4 times daily

MDD

Orthostatic hypotension, photosensitivity, asthenia, blurred vision, agitation, nausea, loss of appetite

Coadministration with an MAOI during the acute recovery period of an MI, hypersensitivity to dibenzazepines Coadministration with an MAOI, hypersensitivity to dibenzazepines during the acute recovery period of an MI Contraindication in the acute recovery period after MI, cisapride or during or within 14 d following MAOI therapy

($$$)

9 mg patch/ 24 h

MDD

Nausea, dizziness, headache, insomnia, application site reactions

($$$$$)

Marplan (isocarboxazid)

20 mg bid

MDD

Dizziness, headache, insomnia, xerostomia

($$$)

Nardil (phenelzine)

15 mg 3 times daily

Atypical MDD (nonendogenous/ neurotic)

($$$)

Parnate (tranylcypromine)

10 mg bid

MDD (without melancholia)

Edema, orthostatic hypotension, weight gain, constipation, xerostomia, somnolence, dizziness

Coadministration with meperidine, Zelapar, or other selegiline products or meperidine within 14 d of Zelapar discontinuation Cardiovascular disorder, hypertension, or patients receiving antihypertensives, cerebrovascular disorders, concomitant use of bupropion, buspirone, dextromethorphan, cheese or foods with high concentrations of tyramine Concomitant use, or within 14 d of another MAOI, SSRI, bupropion, buspirone, CNS depressants, meperidine, guanethidine, tryptophan Excessive caffeine use, CVD, cerebrovascular defect, combination therapy w/ CNS depressant, dexfenfluramine, bupropion, buspirone, meperidine, or SSRI

($$$)

MDD

Hypersensitivities to trazodone Coadministration with an MAOI during the acute recovery period of an MI, seizure disorder

Remeron (mirtazapine)

30 mg/d

Bipolar disorder (depressed phase), MDD, dysthymia, mixed anxiety/ depressive disorder MDD

Dizziness, headache, sedation, nausea, xerostomia, blurred vision Drowsiness, xerostomia, constipation, weight gain, headache, blurred vision, agitation, fatigue

7.89

50 mg 3 times daily 50 mg bid

Hypersensitivities to mirtazapine

2.62

Serzone (nefazodone)

200 mg bid

MDD

Somnolence, increased cholesterol, xerostomia, increased appetite, constipation, weight gain Headache, drowsiness, insomnia, agitation, dizziness, xerostomia, nausea, constipation, weakness

Class/Drug brand name (nonproprietary name) Sinequan (doxepin)

Monoamine Oxidase Inhibitors Emsam (selegiline)

Miscellaneous Desyrel (trazodone) Ludiomil (maprotiline)

Agoraphobia, bulimia nervosa, panic disorder, social phobia

Pain

Anxiety, cancer symptomatology, dysthymia, OCD, panic disorder, SSRI-induced sexual dysfunction

Weight gain, bloating symptom, constipation, xerostomia, blurred vision, headache, urinary retention, fatigue

Edema, orthostatic hypotension, weight gain, constipation, xerostomia, increased liver aminotransferase levels, fatigue, dizziness

Coadministration of astemizole, carbamazepine, cisapride, pimozide, terfenadine or with full doses of triazolam

ADHD indicates attention-deficit/hyperactivity disorder; DM, diabetes mellitus; GAD, generalized anxiety disorder; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; PMDD, premenstrual dysphoric disorder; PTSD, posttraumatic stress disorder; SAD, seasonal affective disorder. Sources: (1) Clinical data compiled from Micromedex. (2) Price information from Lexi-Comp, at www.drugstore.com. (3) Market share information from â&#x20AC;&#x153;Top 200 Medications for 2007,â&#x20AC;? www.drugtopics.com.

Market share, %

Cost information $ 0-25 $$ 26-50 $$$ 51-100 $$$$ 101-200 $$$$$ >200

www.AHDBonline.com

CLINICAL

depression, residual symptoms, chronic major depression, or patients with severe episodes (ie, high risk of suicide, severe psychosis). Initial pharmacologic therapy may include SSRIs, NRIs, or mixed/dual-action medications. MAOIs should be restricted to patients who do not respond to other treatments because of potential side effects, interactions, and the need for dietary restrictions.13 Recent concerns regarding reports of life-threatening hepatic failure in patients treated with nefazodone have prompted the US Food and Drug Administration (FDA) to alter the drug’s labeling and to include a “black box” warning regarding liver failure. A combination product of the SSRI fluoxetine plus the antipsychotic olanzapine (called Symbyax) has been approved by the FDA for the treatment of bipolar depression, but it may also be effective in some patients whose major depression is complicated by psychotic features, and in treatment-resistant depression.14

Nonpharmacologic Therapies Psychotherapy Psychotherapy may be an effective treatment for depression alone, or in combination with medications for mild to moderate disease, but psychotherapy alone is not recommended for severe disease. Cognitive behavioral therapy, interpersonal therapy, marital therapy, and certain problem-solving techniques may be effective as treatment or adjuvant treatment in patients with substantial psychosocial stressors, interpersonal difficulties, or comorbid developmental or personality disorders. Electroconvulsive Therapy Electroconvulsive therapy (ECT) should be considered with appropriate expert consultation for patients with MDD who have a high degree of symptom severity and functional impairment, or for patients in whom psychotic symptoms or catatonia are present. ECT may be the treatment of choice when there is an urgent need for a response, such as in patients who are suicidal or are refusing food and nutritionally compromised.15 The maximum response to ECT is typically achieved within 3 weeks and also may be useful in patients who are medication-resistant or pregnant. Monitoring, Patient Education Posttreatment monitoring should include ongoing assessment of the risk of suicide, as well as the incidence of manic or psychotic symptoms, which may develop over the course of appropriate therapy. Monitoring should include measurement of treatment effectiveness, assessing the need to adjust doses, or identify alternative

AMERICAN HEALTH & DRUG BENEFITS

April 2008

or adjunctive therapies, and should actively assess the patient for side effects. The use of a defined tool may help patients to see a quantifiable improvement in symptoms associated with treatment, and may make patients more likely to adhere to therapeutic regimens. Patient education should include information regarding the responsiveness of symptoms to treatment, risks of treatment, issues related to suicide, and the recurrent nature of the disorder. Information regarding birth control and breast-feeding may be important for female patients of childbearing age.

Depression and Suicide Risk The worst possible outcome in a case of diagnosed or undiagnosed depression is suicide. In 2001, suicide was the 11th leading cause of death (n = 30,000; age-adjusted rate, 10.7 per 100,000 persons)16; the age-adjusted rate for the period 2002-2005 was 10.86 per 100,000.17 Although the US Preventive Services Task Force has concluded that in the general population there is insufficient evidence to recommend for or against screening for suicide risk,16,18 the task force has recognized that the strongest risk factors for attempted suicide include mood disorders or other mental disorders, comorbid substance abuse disorders, a history of deliberate self-harm, and a history of suicide attempts.18 Therefore, it is reasonable to conclude that in any patient diagnosed with depression, suicide risk screening should take place at the time of diagnosis, and at every follow-up intervention. There is little evidence to determine best practices for how this can best be achieved. Not only is there a baseline risk that patients with depression may attempt suicide, but during the course of treatment the concern is that this risk may be increased transiently. As stated in the APA’s Practice Guideline for Depression, “The risk of suicide in some patients recovering from major depressive disorder increases transiently as they develop the energy and capacity to act on self-destructive plans made earlier in the course of their illness.”15 The FDA’s review of relevant research on this topic in response to concerns about the safety of antidepressant use in children and adolescents has led to additional warnings and a “black box” warning for all antidepressant medications regarding their use in children and adolescents.19 The label change notes, “Pooled analyses of short-term (4-16 weeks) placebo-controlled trials of 9 antidepressant drugs (SSRIs and others) in children and adolescents with MDD, obsessive compulsive disorder, or other psychiatric disorders (a total of 24 trials involving over 4400 patients) have revealed a greater risk of adverse events representing suicidal thinking or behavior (suicidality)

CLINICAL

during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, twice the placebo risk of 2%. No suicides occurred in these trials.”19 It is unclear whether this risk is the same for all drugs, or whether it extends to adults to this degree. Over the long-term, treating depression is necessary to reduce risk of injury, yet in the short-term the treatment may increase the risk, meaning that caregivers must be especially vigilant. For more information on depression see: • Fochtmann LJ, Gelenberg AJ. Practice Guideline for the Treatment of Patients with Major Depressive Disorders. 2nd ed. Arlington, VA: American Psychiatric Association, 2005 [April 2000]. http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm. • “Depression is Real. So is Hope.” A program of the American Psychiatric Foundation. www.DepressionIsReal.org. • Download forms for PHQ-2 and PHQ-9 screening tools from http://www.depression-primarycare.org/clinicians/toolkits/ materials/forms/phq9/.

References 1. Pleis JR, Lethbridge-Cejku M. Summary health statistics for U.S. adults: National Health Interview Survey, 2006. Vital Health Stat, Series 10 (235);Dec 2007:7-9. 2. Miller L. Postpartum depression. JAMA. 2002 Feb 13;287(6):762-765. 3. Qaseem A, Snow V, Shekelle P, Casey DE Jr, Cross JJ Jr, Owens DK. Evidence-based intervention to improve the palliative care of pain, dyspnea, and depression at the end of life: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2008;148(2):141-146. 4. Roose SP, Glassman AH, Seidman SN. Relationship between depression and other medical illnesses. JAMA. 2001 Oct 10;286(14):1687-1690. 5. Crystal S, Sambamoorthi U, Walkup JT, Akincigil A. Diagnosis and treatment of depression in the elderly medicare population: predictors,

AHDB Stakeholder Perspective Depression is common and is associated with high costs to society. Improvements in case identification and treatment can be achieved through practice improvements and through the applications of more advanced care systems, through chronic disease state management techniques, improved patient education, telephone follow-up, and intensive case management.1 These models may be developed through employer-provider models, payor-employer models, and so on.2 Once identified, patients must have access and the ability to afford appropriate treatment modalities. There must be no barriers to treatment, appropriate modalities must be able to be initiated quickly

disparities and trends. J Am Geriatr Soc. 2003 Dec;51(12):1718-1728. 6. Unützer J. Clinical practice: late life depression. N Engl J Med. 2007 Nov 29;357(22):2269-2276. 7. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition/Text Revised. DSM-IV-TR. Washington, DC: American Psychiatric Association; 2000. 8. Mulrow CD, Williams JW, Gerety MB, et al. Case-finding instruments for depression in primary care settings. Ann Intern Med. 1995 June 15;122(12):913-921. 9. U.S. Preventive Services Task Force. Screening for depression in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136(10):760-764. 10. Kroenke K, Spitzer RL, Williams JB. The Patient Health Questionnaire-2: validity of a two-item depression screener. Med Care. 2003 Nov;41(11):1284-1292. 11. Belmaker RH, Agam G. Mechanisms of disease: major depressive disorder. N Engl J Med. 2008 Jan 3;358(1):55-68. 12. Mann JJ. The medical management of depression. N Engl J Med. 2005 Oct 27;353;17:1819-1834. 13. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. Am J Psychiatry. 2000 Apr;157(4 suppl):1-45. 14. Fochtmann LJ, Gelenberg AJ. Practice Guideline for the Treatment of Patients with Major Depressive Disorders. 2nd ed. Arlington, VA: American Psychiatric Association; 2005. http://www.psychiatry online.com/pracGuide/pracGuideHome.aspx. Accessed March 21, 2008. 15. Karasu TB, Gelenberg A, Merriam A, Wang P. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 2nd ed. April 2000. American Psychiatric Association. www.psych.org. Accessed March 21, 2008. 16. Gaynes BN, West SL, Ford CA, et al. Screening for suicide risk in adults: a summary of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2004 May 18;140(10):822-835. 17. National Center for Injury Prevention and Control. WISQARS (Webbased Injury Statistics Query and Reporting System). http://webappa. cdc.gov/sasweb/ncipc/mortrate.html. Accessed March 24, 2008. 18. U.S. Preventive Services Task Force. Screening for suicide risk: recommendation and rationale. Ann Intern Med. 2004 May 18;140(10):820-821. 19. US Food and Drug Administration. Labeling change request letter for antidepressant medications. Rockville, MD; October 28, 2004. http://www.fda.gov/cder/drug/antidepressants/SSRIlabelChange.htm. Accessed March 24, 2008.

at diagnosis, and they must be continued uninterrupted through the course of treatment. Clinical professionals with expertise in medical management and psychotherapy must be available to initiate therapy. Specialists with expertise must be made available to handle referrals for more specialized care, including those who do not respond to initial therapy, candidates for ECT, and more complex cases of depression with manic or with psychotic symptoms, or those at high risk for suicide. 1. Dobscha SK, Corson K, Hickam DH, et al. Depression decision support in primary care: a cluster randomized trial. Ann Intern Med. 2006 Oct 3;145(7):477-487. 2. Dietrich AJ, Oxman TE, Williams JW, et al. Re-engineering systems for the treatment of depression in primary care: cluster randomised controlled trial. Br Med J. 2004;329:602. doi:10. 1136/bmj.38219.481250.55.

www.AHDBonline.com

GENERIC DRUG TRENDS

Seizing the Opportunity Gary M. Owens, MD

n 2007, generic drugs accounted for an unprecedented 63% of all prescriptions dispensed in the United States.1 This level of generic prescribing is significantly changed from less than a decade ago, when the generic drugs accounted for less than 40% of all prescriptions.2 What has caused this shift in generic utilization, and what are the ongoing and future opportunities and issues of concern for the various stakeholdersâ&#x20AC;&#x201D;health plans, pharmacy benefit plan managers, pharmaceutical manufacturers, and consumers? Will consumers continue to benefit from this trend going forward? Are there unforeseen consequences of this trend, and what might some of those consequences be? These are some of the issues explored in this article. In the first part of this series, the author traces the history of generic drugs in the United States from 1984 to 2006 and outlines the causes for the dramatic increase in generic drug prescriptions in the past few years. The next articles will continue this discussion, focusing on costs and current and future trends.

The History of Generic Drugs To better understand the increase in growth spending on generic drugs, it is important to understand the history of generic drug use in the United States. In 1984, only about 18.6% of all prescriptions in the United States were filled with generic medications.1 Before 1984, generic drug makers were obligated to conduct the same safety and efficacy tests that had been required of the original manufacturer (of the brand-name drug) to receive US Food and Drug Administration (FDA)

Average relative price per dose, %

Figure 1 Generic Competition and Drug Pricing 100

94%

Average relative price (generic vs brand)

80 70 60

52%

44%

39% 33% 26%

26% 22% 20% 24% 15%

23% 21% 20%

20 10

13% 11% 9%

No. of generic manufacturers

Source: FDA analysis of retail sales data from IMS Health, MS National Sales Perspective, 1999-2004, extracted February 2005. http://www.fda.gov/cder/ogd/generic_competition.htm.

AMERICAN HEALTH & DRUG BENEFITS

April 2008

approval. This requirement created steep financial barriers to the development of generic drugs. In 1984, the Hatch-Waxman Act, also known as the Drug Price Competition and Patent Restoration Act of 1984, was enacted, which significantly changed the landscape of generic drug prescription practices. This act attempted to balance the need for the developers of generic pharmaceuticals to compete with brand-name products with the need to protect legitimate intellectual property rights. The act contained 3 features that essentially changed the competitive landscape for generic products. The act: 1. Established an abbreviated FDA approval process for generic drugs. This abbreviated process required only the need to demonstrate bioequivalence of the product and adherence to manufacturing standards to receive approval. 2. Allowed a generic manufacturer to apply for FDA approval and do their bioequivalence testing before the patent on an existing medication had expired. 3. Provided structure for patent dispute resolution. Furthermore, the act granted the first manufacturer to file for an abbreviated new drug application a period of 180 days of market exclusivity. The provisions of this act radically changed the landscape of the generic drug industry.1 Fast forward now more than 20 years, to 2006. In that year alone, pharmaceuticals that had $17 billion in sales lost patent protection, opening the way to the introduction of less expensive generic alternative medications. Specifically, in 2006 some of the drugs that lost patent protection were in major therapeutic categories. The branded drugs Flonase (fluticasone), Pravachol (pravastatin), Zocor (simvastatin), Zoloft (sertraline), ToprolXL, 25 mg (metoprolol), and Ditropan XL (oxybutinin) were among the group of products that saw the emergence of generic equivalents in 2006. Initially, because of the period of exclusivity on some of these products, the overall price did not fall rapidly but the cumulative changes of these and other first-time generic introductions had a profound impact on the market. Generics generally cost 30% to 80% less than their branded equivalents. The level of market competition is often the determinant of the cost of a generic product. According to the FDAâ&#x20AC;&#x2122;s Center for Drug Evaluation and Research, the cost of a generic drug is directly related to the number of unique generic manufacturers for the product.3 Figure 1 shows the relationship between generic drug competition and generic drug prices. The generic price per dose is expressed as a percentage of the brand drug price per dose (Y axis) and the number

GENERIC DRUG TRENDS

Rising Cost of Healthcare and of Drugs According to CMS, 2006 saw the US healthcare reach a new cost milestone of more than $2.0 trillion in direct health-related spending—virtually doubling in the past decade.4 That translates to an average spending of $7000 per person for every resident of the United States. This level of spending represents 16% of the gross domestic product, a larger portion of the economy than any other industrialized nation in the world spends on healthcare. With the launch of the prescription drug benefit in 2006, Medicare spending grew at its fastest pace since 1981. During the same period, private health insurance spending increased at its slowest rate since 1997, in part as a result of “deceleration in employer payments for private health insurance,” according to Health & Human Services economist Aaron C. Catlin.5 In 2006, retail spending on prescription drugs rose by 8.7%, to $216.7 billion, in part driven by Medicare beneficiaries filling more prescriptions under the Part D benefit.5 Other factors that drove up drug spending were (1) the expanding use of existing drugs for new indications, and (2) the relatively rapid growth of high-cost biotechnology drugs. At the same time, Medco, one of the nation’s largest pharmacy benefit management (PBM) companies, reported that the average cost of drug benefits to their clients increased by only 2.8%, continuing a pattern of moderating growth that has characterized the past few years.6 In the new decade, before 2004, double-digit rates of pharmacy inflation were present. Figure 2 shows actual cost trends for prescription drugs, physician services, and hospital care from 2000 to 2005, with CMS projections for spending from 2006 to 2012. Note that in 2000, prescription drug annual trend was nearly 16%; however, by 2005 the actual rate of growth had moderated to less than 6% annually, and although the 2006 CMS projection of a 6.5% growth rate was surpassed, the increase in prescription drug spending was below double digits. For 2007 and beyond, CMS projects drug spending trends to remain under 9%. Latest data actually show that for 2007, the prescription drug rate of spending grew only 3.8%—the slowest rate of growth since 1961—and

Figure 2 National Healthcare Cost Trends, 2000-2012 Prescription drugs

Physician & clinical services

Hospital care

16% 14%

National trends

of generic manufacturers making the product (X axis). Figure 1 demonstrates that for drugs with a single manufacturer, the relative level of savings is inconsequential, at about 6%. However, by the time the number of manufacturers for a specific drug reaches 4, the level of savings off the branded price exceeds 70%, and by the time 16 manufacturers enter the picture, the savings typically approach 90%.

12% 10% 8% 6% 4% 2000

2001

2002

2003

2004

2005

2006*

Year

2007*

2008*

2009*

2010*

2011*

2012*

*CMS projection

significantly less than the CMS projection of 7.8%.3 This change in the rate of growth of drug spending is in sharp contrast to some other trends in pharmaceuticals. According to the sanofi-aventis’ Managed Care Digest Series, the number of prescriptions dispensed per non-Medicare managed care member has increased from 7.0 prescriptions annually in 1998 to 8.8 prescriptions annually in 2005, a 25.7% increase in utilization.7 In addition, the average ingredient cost during that same period increased by almost 56% per prescription.7 A number of factors have affected this decreasing rate of growth in prescription drug spending, including increased management activities by health plans and PBMs and increased patient cost-sharing for prescriptions, but no factor has had more impact in the past 3 years than the dramatic change in the utilization of generic drugs. As noted earlier, 63% of all prescriptions filled in the United States in 2007 were for generic drugs. Between 2007 and 2010, another 110 brand-name drugs will lose patent protection, representing another $50 billion in sales.8 In 2007 alone, the antihypertensive drug Norvasc (amlodipine) saw $4.9 billion in sales eroded by the introduction of a generic. The total of $67 billion in branded-drug sales potentially converting to a generic market between 2006 and 2010 can be hailed as a health policy success for the Hatch-Waxman Act.

Unintended Consequences There may be several unintended consequences of the Hatch-Waxman legislation. First, the development of new small-molecule products appears to have dramatically slowed in recent years. In part, this may be caused by the potential of decreasing profitability of branded drugs and the erosion of the blockbuster model. According to

www.AHDBonline.com

GENERIC DRUG TRENDS

Diana Conmy, director of IMS Markets Division, “The blockbuster model is slowing.”3 In fact, in 2007 only 19 new products were approved by the FDA, the smallest number of approvals since 1983. Moreover, of drugs that have been recently approved, many are considered to be of little additional therapeutic value. According to Helene Sherman, PharmD, chief pharmacy officer at Regence, “There are fewer and fewer products adding value, and there are a number of drivers toward that.”9 Among the drivers of fewer products are such things as: • Fears that new drugs have been doing more harm than good • Lack of significant new pipeline products in the smallmolecule arena • A focus on the development of reformulations of existing products, which may be a reaction to the prospect of patent expirations. By creating different formulations of an existing product, often with a different delivery system, a longer-running patent can be created with lower developmental cost as compared with the development of a completely new molecular entity. Examples of this strategy include

long-acting reformulations of an existing drug and reformulations into nonpill forms. The strategy here is to induce some users and the doctors who prescribe their medications to switch to the version that has the longerrunning patent before the generic version of the original compound is introduced into the market. Some brand-name manufacturers have also tapped into the revenue stream by launching their own “authorized generic” version of a product at the same time the first generic version of the drug hits the market. This is often done by a contractual agreement with the generic manufacturer. The authorized generic competes with the generic drug that was approved with a period of exclusivity. This move decreases the financial benefit of the period of exclusivity for the generic manufacturer and, therefore, may ultimately discourage patent challenges by generic manufacturers. Another strategy is for the branded manufacturer to enter into a contractual arrangement with the generic manufacturer to delay the launch of the generic version. As one may expect, these contracts have been fiercely contested by managed care organizations, consumer

It’s About Being Available. 1

Ranked Number One In Building Customer Relationships.

1Based on a survey by Retail Pharmacy Management, 2006.

04334

March 2008

GENERIC DRUG TRENDS

groups, and the Federal Trade Commission as anticompetitive. However, a recent appeals court did rule that such agreements are legal, so this practice is likely to continue in the future.

Conclusion It is evident that both branded and generic manufacturers have attempted to manage the provisions of the Hatch-Waxman Act to maximize their profits under the construct of the regulations. Some of the consequences, including drug reformulations to extend patent life, authorized generics, and contractual delays of drug launches, need to be balanced with the overall societal benefit of greater availability of generic drugs now. Disclosure Statement Dr Owens is a consultant to Amgen, Genzyme, Novartis, and Wyeth and receives honorarium from Encysive. References 1. Frank RG. The ongoing regulation of generic drugs. N Engl J Med. 2007 Nov 15;357(20):1993-1996.

First In Service Because We Put Service First

2. US Food and Drug Administration Center for Drug Evaluation and Research. Generic competition and drug prices. April 4, 2006. www.fda.gov/cder/ogd/generic_competition.htm. Accessed January 21, 2008. 3. Waters R, Pettypiece S. Drug sales in the US grow at slower pace as generic use surges. Bloomberg news, March 12, 2008. http://www. bloomberg.com/apps/news?pid=newsarchive&sid=aLfUw7_sYMRY. Accessed March 13, 2008. 4. Center for Medicare and Medicaid Services. National health expenditure data: historical. 2008. http://www.cms.hhs.gov/National HealthExpendData/02_NationalHealthAccountsHistorical.asp#To pOfPage. Accessed February 26, 2008. 5. Pear R. Health care spending exceeded record $2 trillion in 2006. New York Times. January 8, 2008. http://www.nytimes.com/2008/ 01/08/us/08health.html. Accessed January 21, 2008. 6. Medco Health Solutions. 2007 Drug Trend Report. 2007, vol 9. http:// www.medco.com/art/pdf/Drug_Trend_2007.pdf. 7. sanofi-aventis U.S. LLC. Pharmacy utilization. Managed Care Digest Series. http://www.managedcaredigest.com/MainReport.aspx?rid=4808 &Digest=42&sea=1. Accessed February 3, 2008. 8. Projected brand drug patent expirations by quarter and total 2006 Rx volume. Drug Benefit News. 2007 Sept 12, p 4. 9. Carroll J. Plans look askance at me-too medications. Manag Care. 2008 Jan;17:37-38, 41-42.

Dr Owens is President, Gary Owens Associates and former chair of Pharmacy & Therapeutic Committees, Independence Blue Cross.

FDA WATCH

Regulatory Concerns Fuel Hunger in Congress for FDA Reform Mark Senak, JD

here is a hunger for reform of the US Food and Drug Administration (FDA). To a great extent, that hunger is fueled by the prevailing sentiment in today’s regulatory atmosphere—a drive to make our environment as risk free as possible when it comes to medical treatment.

The 1990s Regulatory Reform During the 1990s, when the HIV epidemic was raging out of control, and the amount of time it took to approve a new drug was a worrisome reality to the medical community fighting the epidemic, there was a tremendous public outcry for faster access to medicines. That public outcry, in turn, led to policymaker

Congressmen are asking what additional powers the FDA may need to compel companies to complete phase 4 trials.

action. The result was an FDA reform through the Prescription Drug User Fee Act and the FDA Modernization Act, which brought fast-track authorization and accelerated approval. These regulatory reforms brought new medicines faster and broadened our understanding of the use of surrogate end points. For example, anti-HIV medications had to be approved using a surrogate end point, namely, viral load in the bloodstream. The clinical benefit of lower viral load is now obvious; the drugs have saved hundreds of thousands, if not millions, of lives.

Postmarketing Reform Focus in 2008 Today’s environment is much different. Since 2004, confidence in the FDA has been waning, and the gold image of the agency tarnished, as several high-profile issues washed over the agency during a time when it was mostly without steady leadership. The crisis of

AMERICAN HEALTH & DRUG BENEFITS

April 2008

confidence on the part of the public has led to an outcry for safety, and policymakers are correspondingly responding as they did in the early 1990s, yet not from the benefit end of the spectrum, as was the focus then, but rather from the safety end point. The late 2000s are a completely different environment. An indicator for the types of reforms that are going to be proposed these days are visible today in the kinds of investigations Congress is conducting into FDA practices. For example, in January 2008, Senator Sherrod Brown (D-Ohio) asked the Congressional Research Service, a research arm of the Library of Congress, to conduct an investigation of fast track at the FDA, to see whether the practice of fast track is indeed speeding up the availability of drugs. Senator Charles Grassley (R-Iowa) is known for his dramatic antic last June, when he marched from Capitol Hill to the offices of Health and Human Services to demand answers regarding the FDA’s handling of the approval of the branded antibiotic Ketek (telithromycin). In March 2008, he has moved on to more substantive means to get the information he wants, when he issued a letter asking the Government Accountability Office to investigate the FDA approval standards and postmarketing practices. Specifically, Senator Grassley has requested investigation into: • The number of drugs that were approved based on surrogate end points • The surrogate end points that the FDA uses to approve drugs • The date of approval for each of these 3 drugs— Avandia (rosiglitazone), Avastin (bevacizumab), and Vytorin (ezetimibe/simvastatin)—and whether the FDA required the relevant companies to complete phase 4 trials on these drugs • The date each of the phase 4 trials were started and completed or are expected to be completed • A description of the tools the FDA has to compel companies to complete phase 4 trials • A description of any actions the FDA has taken against companies for failing to complete phase 4 trials or failing to complete trials in a timely manner • A description of any additional powers the FDA may need to compel companies to complete phase 4 trials, in the event the tools that the FDA has presently are insufficient. Senator Grassley is asking questions to which he already knows the answers. The FDA has very limited authority when it comes to postmarketing phase 4 studies. A section on the FDA website lists postmar-

MiraLAX The ONLY PEG 3350 Available* ONLY Over-the-Counter ONLY MiraLAX® (polyethylene glycol 3350, powder for solution) offers effective constipation relief without harsh side effects.

• NO Bloating • NO Cramps • NO Gas • NO Sudden Urgency

MiraLAX, the # 1 physician recommended laxative is Only Available OTC

Now you can… Costs your patients as little as

STOP Prescribing. START Recommending.

$ 0.47 a dose†

*FDA has stated that Rx PEG 3350 may not be legally marketed and it is no longer available in many pharmacies. †Based on retail price of MiraLAX 30-dose 17.9 oz (510 g) twin pack at leading club store.

FDA WATCH

keting commitments and informs about progress, but the FDA has no ability to strictly enforce phase 4 study commitments. The investigations and research by these senators clearly point the way for future proposed reforms. These senators believe that in the interests of safety, and even of efficacy, they may have to refashion or even abolish the reforms of the 1990s that brought drugs to the market more quickly to minimize risk.

Winds of Change: FDA Surveillance These reform proposals will be cast on fertile ground. There is a sweeping decline in regard for the FDA on the part of members of Congress. In February 2008, Congresswoman Rosa DeLaurio (D-Connecticut) referred to the management of the FDA as “Keystone cops.” Also in February, Congressman Bart Stupak (DMichigan) called for the resignation of FDA Commissioner Andrew C. von Eschenbach. The House Committee on Energy and Commerce, Subcommittee on Oversight and Investigations is conducting 6 investigations of various aspects of FDA operations. In addition, each of the 3 leading candidates for president—Barack Obama, Hillary Clinton, and John

McCain—is a proponent of the importation of prescription drugs and the renegotiation of Medicare Part D to allow the federal government to have the power to negotiate prices. Both issues present the FDA with unique challenges. The winds of change blow naturally during an election cycle. But of all federal agencies, perhaps one of the most sweeping sets of reforms stand to be blueprinted by the reports that will result from the many investigations currently being conducted by Congress. Those who want to know the shape of the reforms to come need look no further. It stands to reason that at a minimum there will likely be proposals to: • Modify the use of surrogate end points in assessing drug candidates • Modify in some way fast-track authority to ensure that more rigorous standards are applied • Give postmarketing surveillance authority and teeth to the FDA.

Mr Senak is Senior Vice President at Fleishman-Hillard in Washington, DC, and author of the Eye on FDA blog, www.eyeonfda.com.

Call for Papers The editors of American Health & Drug Benefits (AHDB) are pleased to invite readers to submit articles for publication on topics examining advances in clinical, business, and regulatory developments relevant to attaining value—a balance of cost, quality, and access—in formulary and benefit design strategies. AHDB offers an open forum for all healthcare stakeholders to present their needs, initiatives, and data, with the goal of achieving patient-centered health and drug benefits that meet the needs of all stakeholders—patients, providers, payors, purchasers, distributors, regulatory, manufacturers, evaluators, and researchers. Articles should discuss key issues that can improve the quality and efficiency of our healthcare delivery system in general and of formulary and drug benefit strategies in particular. Types of articles and topics sought include: • • • • • • • •

Original research Review articles Expert opinions Diagnosis/treatment guidelines Drug updates Government reports Foundation reports Off-label use/misuse

• Clinical topics: Alzheimer’s/dementia Asthma/allergies Cholesterol management Diabetes Depression

Hypertension Infectious diseases Pain management Schizophrenia Cancer therapy

All papers will undergo a peer-review process. Please submit your manuscript electronically to editorial@AHDBonline.com, or mail to AHDB, PO Box 423, Long Valley, NJ 07853.

AMERICAN HEALTH & DRUG BENEFITS

April 2008

New Edition Now Available Award-winning Depression Benchmarks!

Gold Award

Aster Awards, May 2007

Merit Awards (2)

Healthcare Advertising Awards, April 2007

Depression Benchmarks

A comprehensive, claims-based analysis of more than 600,000 patient episodes of depression (1 episode = 1 year) highlighting direct costs and utilization of resources across 5 domains of care: Inpatient care Outpatient care Ancillary care (labs, tests, procedures) Emergency department Pharmaceuticals

Do you measure resource utilization and costs associated with depression? Managing quality and cost is the foundation of today’s managed care structure. Wyeth recognizes that balancing quality and cost is a formidable challenge for managed health care professionals. We also recognize that success, in part, hinges on tools and resources that can aid in the evaluation of care management and may lead to reinforcing solutions. As part of our continuing efforts to improve the quality of care for patients with depression, we are proud to sponsor this comprehensive claims-based review to promote ongoing clinical and financial assessments that improve care in this patient population.

To learn more about this exclusive program, please contact your Wyeth Pharmaceuticals Account Manager today! “Depression Benchmarks” and “TRU Benchmarks” are trademarks owned by Managed Care Measures, LLC. Depression Benchmarks publication cover design, photograph, and color scheme (except for Total Resource Utilization blue banner): © 2008, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101. Total Resource Utilization blue banner: © 1999-2008 Managed Care Measures, LLC. The remainder of this advertisement: © 2008, Wyeth Pharmaceuticals Inc., Philadelphia, PA 19101. 223008-01 TM

INFORMATION FOR AUTHORS

American Health & Drug Benefits THE PEER-REVIEWED FORUM FOR EVIDENCE IN BENEFIT DESIGN

Manuscripts submitted to American Health & Drug Benefits (AHDB) must be original and must not have been published previously, either in print or in electronic form. Manuscripts cannot be submitted elsewhere while under consideration by AHDB. To be considered for publication, manuscripts must adhere to the format described in this document. All manuscripts are subject to peer review, and acceptance is based on that review. If accepted, authors will be notified of any recommended revisions, and a revised manuscript should be resubmitted in its entirety, with all changes made. Routine editorial changes will be made to conform to house style, following the AMA Manual of Style, 10th ed. (New York, NY: Oxford University Press, 2007). The edited manuscript is sent to the author for a final review and approval. Time from submission to publication is generally 3 to 5 months. COPYRIGHT/DISCLOSURE Authors are required to sign a Copyright Transfer Form, assigning all copyrights to Engage Healthcare Communications, LLC, publisher of AHDB, as well as a Financial Disclosure Form. Authors are required to disclose any financial interests—direct or indirect—and any affiliations or involvement (competitive or amiable) with organizations that have a financial interest in the subject matter or materials discussed in the manuscript. FORMAT All manuscripts should be accompanied by a cover letter with the name, address, telephone numbers, fax number, and e-mail address (if available) of the corresponding author. Include a brief abstract and a proper conclusion. Double space the entire manuscript and number the pages. Cite all tables and figures in the text, but place the actual graphic elements at the end of the article, after the references. GENERAL STYLE AND FORMATTING FOR ALL COPY Please follow the American Medical Association Manual of Style, 10th ed. • Length = up to 3,500 words, including an abstract of no more than 200 words and a summary of no more than 300 words. • Use spellings as provided in Stedman’s Medical Dictionary for all medical terms. AUTHORS Provide authors’ highest academic degree and all affiliations. Provide the name, address, telephone number, e-mail, and fax of the corresponding author. REFERENCES Cite all references consecutively in the text, then list all references at the end of the article. Provide the most up-to-date, post-1990 references, using primary sources only. Try to limit the references to 30. Do not use automatic numbering or footnote/endnote features. PHOTOGRAPHS All photographs should be attached as an Adobe Photoshop file with a resolution of 300 dots per inch (dpi) or a jpeg file with the highest possible dpi.

AMERICAN HEALTH & DRUG BENEFITS

April 2008

FIGURES AND LEGENDS • Submit 1 complete set of no more than 10 figures, preferably horizontal color images. We will accept digital images only, at least 300 dots per inch (dpi), 3 inches wide, and 4 color (CMYK). • We accept 3 graphic file formats: jpg, tiff, and eps. Please include a color printout of each image. • Be sure to write your name, the figure number, and orientation indicators on the front of each printout (“front” and “top”). • Be sure to identify all slides or prints with the name of the author and a number corresponding to their appearance in the article. Please call out the figure in the text. “Figure 1 demonstrates the continually increasing costs associated with chemotherapy”; or “The costs associated with chemotherapy continue to rise (Figure 1).” • Slides or figures of patients or identifiable body parts must be accompanied by written permission from the subject. TABLES Tables should be created using the Table function in your word-processing software. Please do not use tabs to create a table. Permission to Use Tables or Figures If a table or figure is reprinted or adapted from another source, the author must secure a permission letter from the primary source. The source should be credited below the table or figure in the manuscript. CATEGORIES ACCEPTED Articles—original research, review Disease state Drug reviews Commentary Editorial Expert problem solving (offer problems or solutions to problems previously published) Profile—KOLs, innovators, agencies, other key organizations Primers—summaries of key concepts or processes, new rules, legislation Reviews—government reports, think-tank reports, industry white papers, foundation reports HOW TO SUBMIT MANUSCRIPTS The editors of AHDB prefer to receive manuscripts electronically. Save the manuscript as a Word document. Each image must be saved individually, as an image file (eg, jpeg, tiff, eps). Digital graphics must be saved at a high resolution of at least 300 dpi. Images not saved appropriately or saved within the Word document will delay the peer-review process significantly. Send your entire manuscript electronically to: editorial@AHDBonline.com. If you prefer to submit your manuscript by mail, send a disk and a hard copy of the article, typed double-spaced throughout, to: Editorial AHDB PO Box 423 Long Valley, NJ 07853 REPRINTS Reprints may be ordered at a nominal fee by contacting editorial@AHDBonline.com.

Executive Summaries CMS Coverage Policies for Biologics: The Broad Gray Line Part 2 of an interview with Joseph Antos, PhD

Dr Joseph Antos, of the American Enterprise Institute, examines how cost-containment decisions differ for biologics compared with other drugs, what drives these decisions, and how things are likely to change given the current political atmosphere. Dr Antos urges those in the industry to collect information that already exists on treatments, outcomes, and costs to determine each course of action and then to examine the impact of financial incentives and other factors that

drive decision-making. He uses the recent controversy surrounding erythropoiesis-stimulating agents (ESAs) to demonstrate how payment can drive medical practice. Through its Part B plan, Medicare had overpaid physicians based on a given formula. To curb overpayments, Medicare is now dictating clinical circumstances in which ESAs may be used for their patients, and thus seriously limiting their usage. Dr Antos explains that although Medicare cannot dictate the practice of medicine, dictating payment does dictate practice. Medicare’s decision regarding ESAs will have an impact on patients’ quality of life. Discussions will continue regarding safety and efficacy, but cost plus quality and access must remain part of the equation in all decision-making.

Unmanaged Moment

Benchmarking New Frontiers in Managed Care Pharmacy By Cynthia Pigg, BSPharm, MHA; and Joan Cihak, MSS, MHA

The HSM Group, a national healthcare market research and consulting firm, conducted surveys of medical associations, pharmaceutical companies, and medical device companies to determine the extent of managed care activities and use of health information technology. There was an apparent shifting of trends between the 2006 and the 2007 surveys. Concerns about cost in 2006 were shifting to focus more on cost plus quality, especially in disease management areas, with the emphasis on quality of care on the rise. Disease management initiatives, expanding collaboration among healthcare professionals and employers in health decision-making, Medicare medication therapy management, and the ascendance of e-prescribing were but a few of the areas of concentration in the 2007 survey. Although lowering costs remained important, it was now considered a part of a larger picture that is focused on value plus cost—providing the most for the least.

Not Waiting for Godot: The Evolution of Health Promotion at PPG Industries “It was a completely successful textbook surgery. Unfortunately, we operated on the wrong person.”

By Alberto M. Colombi, MD, MPH; Janice L. Pringle, PhD; and George T. Welsh, BS, MBA

The authors examine the unique approach taken by PPG Industries, a

www.AHDBonline.com

EXECUTIVE SUMMARIES

manufacturer of coatings, chemical, optical products, specialty materials, glass, and fiberglass, to provide healthcare for their employees. The companyâ&#x20AC;&#x2122;s efforts to promote volunteer wellness teams and encourage financial discipline of healthcare needs for management and employees have resulted in cost increases per employee at half the national average for companies of comparable size. The authors reveal 3 models detailing the total burden of disease on health and productivity, areas for cost reduction, and costly health conditions that have a high impact on construct. They admit that the models offer a road map, but that building the road that will make it work involves plant leadership, engagement in the wellness team, and direction and support for all involved stakeholders. PPG Industries aims to reduce the burden of disease on health and productivity to half of the national average in 5 years.

fits based on them. Because each meta-analysis is a unique scientific investigation, all conclusions drawn from them must be examined for quality and validity. The authors take us through the processes, strengths, and weaknesses of meta-analysis, identifying potential pitfalls as they relate to the continually evolving understanding of value in healthcare.

Depression Overview By Thomas McCarter, MD, FACP

Dr McCarter provides an overview of depression from susceptible populations to diagnosis, treatment, and monitoring. Although depression remains too often undiagnosed

and therefore untreated, it is more widely recognized today than in the past. Nonetheless, the stakes in depression continue to be high for both patient and society, and suicide is a serious and common consequence of depression. Dr McCarter provides diagnostic tools that can enhance recognition and expedite appropriate treatment. An extensive table listing common antidepressants offers a quick overview of available medications and their many indications, as well as off-label uses. The development and implementation of employer-provider models are urged to ensure timely and unimpeded access to medical care, affordability of care, and continuity of care.

Unmanaged Moment

Meta-Analysis 101: What You Want to Know in the Era of Comparative Effectiveness By J.B. Jones, MBA; Saul Blecker, MD; and Nirav R. Shah, MD, MPH

Determining what represents the best medical evidence, as defined by randomized controlled trials and by disparate observational studies, is by no means a straightforward task for payors, patients, providers, and government. Thus, decision makers must rely increasingly on systematic reviews and meta-analyses to interpret and apply evidence provided by research. Inaccurate interpretations and misunderstanding about the method can confound the process required to design drug bene-

AMERICAN HEALTH & DRUG BENEFITS

â&#x20AC;&#x153;Jerry, the Hermans take the same pharmaceuticals we do!â&#x20AC;?

April 2008

Brief Summary of Prescribing Information USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDISÂŽ tablets should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality INDICATIONS MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. CONTRAINDICATIONS MICARDIS (telmisartan) is contraindicated in patients who are hypersensitive to any component of this product. WARNINGS Fetal/Neonatal Morbidity and Mortality Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature in patients who were taking angiotensin converting enzyme inhibitors. When pregnancy is detected, MICARDIS (telmisartan) tablets should be discontinued as soon as possible. The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of MICARDIS tablets as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment. If oligohydramnios is observed, MICARDIS tablets should be discontinued unless they are considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. There is no clinical experience with the use of MICARDIS tablets in pregnant women. No teratogenic effects were observed when telmisartan was administered to pregnant rats at oral doses of up to 50 mg/kg/day and to pregnant rabbits at oral doses up to 45 mg/kg/day. In rabbits, embryolethality associated with maternal toxicity (reduced body weight gain and food consumption) was observed at 45 mg/kg/day [about 12 times the maximum recommended human dose (MRHD) of 80 mg on a mg/m2 basis]. In rats, maternally toxic (reduction in body weight gain and food consumption) telmisartan doses of 15 mg/kg/day (about 1.9 times the MRHD on a mg/m2 basis), administered during late gestation and lactation, were observed to produce adverse effects in neonates, including reduced viability, low birth weight, delayed maturation, and decreased weight gain. Telmisartan has been shown to be present in rat fetuses during late gestation and in rat milk. The no observed effect doses for developmental toxicity in rats and rabbits, 5 and 15 mg/kg/day, respectively, are about 0.64 and 3.7 times, on a mg/m2 basis, the maximum recommended human dose of telmisartan (80 mg/day). Hypotension in Volume-Depleted Patients In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of therapy with MICARDISÂŽ tablets. This condition should be corrected prior to administration of MICARDIS tablets, or treatment should start under close medical supervision with a reduced dose. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized. PRECAUTIONS General. Impaired Hepatic Function: As the majority of telmisartan is eliminated by biliary excretion, patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance. MICARDIS (telmisartan) tablets should be used with caution in these patients. Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensinaldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensinconverting enzyme inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with MICARDIS tablets. In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen were observed. There has been no long term use of MICARDIS tablets in patients with unilateral or bilateral renal artery stenosis but an effect similar to that seen with ACE inhibitors should be anticipated. Information for Patients. Pregnancy: Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to drugs that act on the renin-angiotensin system, and they should also be told that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible. Drug Interactions. Digoxin: When telmisartan was coadministered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. It is, therefore, recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing telmisartan to avoid possible overor under-digitalization. Warfarin: Telmisartan administered for 10 days slightly decreased the mean warfarin trough plasma concentration; this decrease did not result in a change in International Normalized Ratio (INR). Other Drugs: Coadministration of telmisartan did not result in a clinically significant interaction with acetaminophen, amlodipine, glibenclamide, simvastatin, hydrochlorothiazide or ibuprofen. Telmisartan is not metabolized by the cytochrome P450 system and had no effects in vitro on cytochrome P450 enzymes, except for some inhibition of CYP2C19. Telmisartan is not expected to interact with drugs that inhibit cytochrome P450 enzymes; it is also not expected to interact with drugs metabolized by cytochrome P450 enzymes, except for possible inhibition of the metabolism of drugs metabolized by CYP2C19. Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of carcinogenicity when telmisartan was administered in the diet to mice and rats for up to 2 years. The highest doses administered to mice (1000 mg/kg/day) and rats (100 mg/kg/day) are, on a mg/m2 basis, about 59 and 13 times, respectively, the maximum recommended human dose (MRHD) of telmisartan. These same doses have been shown to provide average systemic exposures to telmisartan >100 times and >25 times, respectively, the systemic exposure in humans receiving the MRHD (80 mg/day). Genotoxicity assays did not reveal any telmisartanrelated effects at either the gene or chromosome level. These assays included bacterial mutagenicity tests with Salmonella and E. coli (Ames), a gene mutation test with Chinese hamster V79 cells, a cytogenetic test with human lymphocytes, and a mouse micronucleus test. No drug-related effects on the reproductive performance of male and female rats were noted at 100 mg/kg/day (the highest dose administered), about 13 times, on a mg/m2 basis, the MRHD of telmisartan. This dose in the rat resulted in an average systemic exposure (telmisartan AUC as determined on day 6 of pregnancy) at least 50 times the average systemic exposure in humans at the MRHD (80 mg/day). Pregnancy Pregnancy Categories C (first trimester) and D (second and third trimesters). See WARNINGS, Fetal/Neonatal Morbidity and Mortality. Nursing Mothers It is not known whether telmisartan is excreted in human milk, but telmisartan was shown to be present in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Of the total number of patients receiving MICARDIS in clinical studies, 551 (18.6%) were 65 to 74 years of age and 130 (4.4%) were 75 years or older. No overall differences in effectiveness and safety were observed in these patients compared to younger patients and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. ADVERSE REACTIONS MICARDIS (telmisartan) has been evaluated for safety in more than 3700 patients, including 1900 treated for

over six months and more than 1300 for over one year. Adverse experiences have generally been mild and transient in nature and have only infrequently required discontinuation of therapy. In placebo-controlled trials involving 1041 patients treated with various doses of telmisartan (20-160mg) monotherapy for up to 12 weeks, an overall incidence of adverse events similar to that of placebo was observed. Adverse events occurring at an incidence of 1% or more in patients treated with telmisartan and at a greater rate than in patients treated with placebo, irrespective of their causal association, are presented as follows: The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of e1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). In addition to the adverse events, the following events occurred at a rate of 1% but were at least as frequent in the placebo group: influenza-like symptoms, dyspepsia, myalgia, urinary tract infection, abdominal pain, headache, dizziness, pain, fatigue, coughing, hypertension, chest pain, nausea and peripheral edema. Discontinuation of therapy due to adverse events was required in 2.8% of 1455 patients treated with MICARDIS tablets and 6.1% of 380 placebo patients in placebo-controlled clinical trials. The incidence of adverse events was not dose-related and did not correlate with gender, age, or race of patients. The incidence of cough occurring with telmisartan in six placebo-controlled trials was identical to that noted for placebo-treated patients (1.6%). In addition to those listed above, adverse events that occurred in more than 0.3% of 3500 patients treated with MICARDIS monotherapy in controlled or open trials are listed below. It cannot be determined whether these events were causally related to MICARDIS tablets: Autonomic Nervous System: impotence, increased sweating, flushing; Body as a Whole: allergy, fever, leg pain, malaise; Cardiovascular: palpitation, dependent edema, angina pectoris, tachycardia, leg edema, abnormal ECG; CNS: insomnia, somnolence, migraine, vertigo, paresthesia, involuntary muscle contractions, hypoaesthesia; Gastrointestinal: flatulence, constipation, gastritis, vomiting, dry mouth, hemorrhoids, gastroenteritis, enteritis, gastroesophageal reflux, toothache, non-specific gastrointestinal disorders; Metabolic: gout, hypercholesterolemia, diabetes mellitus; Musculoskeletal: arthritis, arthralgia, leg cramps; Psychiatric: anxiety, depression, nervousness; Resistance Mechanism: infection, fungal infection, abscess, otitis media; Respiratory: asthma, bronchitis, rhinitis, dyspnea, epistaxis; Skin: dermatitis, rash, eczema, pruritus; Urinary: micturition frequency, cystitis; Vascular: cerebrovascular disorder; and Special Senses: abnormal vision, conjunctivitis, tinnitus, earache. During initial clinical studies, a single case of angioedema was reported (among a total of 3781 patients treated with telmisartan). Clinical Laboratory Findings In placebo-controlled clinical trials, clinically relevant changes in standard laboratory test parameters were rarely associated with administration of MICARDIS tablets. Hemoglobin: A greater than 2 g/dL decrease in hemoglobin was observed in 0.8% telmisartan patients compared with 0.3% placebo patients. No patients discontinued therapy due to anemia. Creatinine: A 0.5 mg/dL rise or greater in creatinine was observed in 0.4% telmisartan patients compared with 0.3% placebo patients. One telmisartan-treated patient discontinued therapy due to increases in creatinine and blood urea nitrogen. Liver Enzymes: Occasional elevations of liver chemistries occurred in patients treated with telmisartan; all marked elevations occurred at a higher frequency with placebo. No telmisartan-treated patients discontinued therapy due to abnormal hepatic function. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of MICARDIS tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to MICARDIS tablets. The most frequently spontaneously reported events include: headache, dizziness, asthenia, coughing, nausea, fatigue, weakness, edema, face edema, lower limb edema, angioneurotic edema, urticaria, hypersensitivity, sweating increased, erythema, chest pain, atrial fibrillation, congestive heart failure, myocardial infarction, blood pressure increased, hypertension aggravated, hypotension (including postural hypotension), hyperkalemia, syncope, dyspepsia, diarrhea, pain, urinary tract infection, erectile dysfunction, back pain, abdominal pain, muscle cramps (including leg cramps), myalgia, bradycardia, eosinophilia, thrombocytopenia, uric acid increased, abnormal hepatic function/liver disorder, renal impairment including acute renal failure, anemia, and increased CPK. Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers, including MICARDIS. OVERDOSAGE Limited data are available with regard to overdosage in humans. The most likely manifestation of overdosage with MICARDIS (telmisartan) tablets would be hypotension, dizziness and tachycardia; bradycardia could occur from parasympathetic (vagal) stimulation. If symptomatic hypotension should occur, supportive treatment should be instituted. Telmisartan is not removed by hemodialysis. DOSAGE AND ADMINISTRATION Dosage must be individualized.The usual starting dose of MICARDIS (telmisartan) tablets is 40 mg once a day. Blood pressure response is dose related over the range of 20-80 mg. Special Populations: Patients with depletion of intravascular volume should have the condition corrected or MICARDIS tablets should be initiated under close medical supervision (see WARNINGS, Hypotension in Volume-Depleted Patients). Patients with biliary obstructive disorders or hepatic insufficiency should have treatment started under close medical supervision (see PRECAUTIONS, General, Impaired Hepatic Function, and Impaired Renal Function). Most of the antihypertensive effect is apparent within two weeks and maximal reduction is generally attained after four weeks. When additional blood pressure reduction beyond that achieved with 80 mg MICARDIS is required, a diuretic may be added. No initial dosing adjustment is necessary for elderly patients or patients with mild-to-moderate renal impairment, including those on hemodialysis. Patients on dialysis may develop orthostatic hypotension; their blood pressure should be closely monitored. MICARDIS tablets may be administered with other antihypertensive agents. MICARDIS tablets may be administered with or without food. Rx only MC-BS (03/07)

Printed in U.S.A.

(10/07)

MC48827

More than in the early morning2

USE IN PREGNANCY When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS Tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality). MICARDIS is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents. MICARDIS is contraindicated in patients who are hypersensitive to any component of this product. The most common adverse events occurring with MICARDIS Tablets monotherapy at a rate of e1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%). Please see Brief Summary of Product Information on adjacent page.

References: 1. Weber MA,White WB,Giles TD,et al.An effectiveness study comparing algorithm-based antihypertensive therapy with previous treatments using conventional and ambulatory blood pressure measurements. J Clin Hypertens. 2006;8:241-250. 2. White WB,Giles T,Bakris GL,et al.Measuring the efficacy of antihypertensive therapy by ambulatory blood pressure monitoring in the primary care setting. Am Heart J. 2006;151:176-184.

Printed in U.S.A.

(10/07)

MC48828