Boyang Bian

A Review of Quantitative Risk–Benefit Methodologies for Assessing Drug Safety and Efficacy—Report of the ISPOR Risk–Benefit Management Working Group

OBJECTIVE Although regulatory authorities evaluate the risks and benefits of any new drug therapy during the new drug-approval process, quantitative risk-benefit assessment (RBA) is not typically performed, nor is it presented in a consistent and integrated framework when it is used. Our purpose is to identify and describe published quantitative RBA methods for pharmaceuticals. METHODS Using MEDLINE and other Internet-based search engines, a systematic literature review was performed to identify quantitative methodologies for RBA. These distinct RBA approaches were summarized to highlight the implications of their differences for the pharmaceutical industry and regulatory agencies. RESULTS Theoretical models, parameters, and key features were reviewed and compared for the 12 quantitative RBA methods identified in the literature, including the Quantitative Framework for Risk and Benefit Assessment, benefit-less-risk analysis, the quality-adjusted time without symptoms and toxicity, number needed to treat (NNT), and number needed to harm and their relative-value-adjusted versions, minimum clinical efficacy, incremental net health benefit, the risk-benefit plane (RBP), the probabilistic simulation method, multicriteria decision analysis (MCDA), the risk-benefit contour (RBC), and the stated preference method (SPM). Whereas some approaches (e.g., NNT) rely on subjective weighting schemes or nonstatistical assessments, other methods (e.g., RBP, MCDA, RBC, and SPM) assess joint distributions of benefit and risk. CONCLUSIONS Several quantitative RBA methods are available that could be used to help lessen concern over subjective drug assessments and to help guide authorities toward more objective and transparent decision-making. When evaluating a new drug therapy, we recommend the use of multiple RBA approaches across different therapeutic indications and treatment populations in order to bound the risk-benefit profile.

Utilization, Spending, and Price Trends for Benzodiazepines in the US Medicaid Program: 1991-2009

Background: Although it is well-known that drug costs in the US have risen precipitously over the last 25 years, what is much less appreciated is how this rise in cost has occurred across so many seemingly distinct drug markets. Objective: To describe trends in the utilization, spending, and average per-prescription cost of benzodiazepines individually, in subgroups, and overall, in the Medicaid program. Medicaid has been the primary public payer for benzodiazepines over the past 2 decades. Methods: A retrospective, descriptive analysis was performed for the years 1991-2009 using the publicly available national Summary Files from the Medicaid State Drug Utilization Data maintained by the Centers for Medicare & Medicaid Services. Quarterly prescription counts and reimbursement amounts were calculated for all benzodiazepines reimbursed by Medicaid. Average per-prescription spending as a proxy for drug price was found by dividing reimbursement by the number of prescriptions. Results: Prescriptions for benzodiazepines among Medicaid beneficiaries increased from 8.0 million in 1991 to 17.1 million in 2009. Expenditures rose from

Treatment of obesity: Pharmacotherapy trends in the United States from 1999 to 2010

131.6 million to

Evaluating Safety of Long-Acting Beta Agonists (LABAs) in Patients with Asthma

171.1 million over the same time period. The average per-prescription price was a little over

Safety of long-acting beta agonists and inhaled corticosteroids in children and adolescents with asthma

10 in 2009. Whereas utilization of intermediate- and long-acting agents increased over time, prescriptions for short-acting drugs fell from 1.1 million to 0.3 million (1991-2009). The percentage rise in Medicaid spending on benzodiazepines since 1991 (30.0%) was less than the general rate of inflation (57.5%), as measured by the percentage change in the consumer price index over the same time period. Conclusions: Relative to the rise in the number of Medicaid beneficiaries (more than doubled over the study period), there is no evidence of an extraordinary rise in the utilization of benzodiazepines. Moreover, both nominal and real average prices of benzodiazepines have fallen, primarily because of generic entry over the last 2 decades.

Evidence-Based Prediction of Statin Use with Lipid-Panel Data from the National Health and Nutrition Examination Survey

To describe the antiobesity drug‐prescribing patterns of US physicians over the past decade.

Payer costs for inpatient treatment of pathologic fracture, surgery to bone, and spinal cord compression among patients with multiple myeloma or bone metastasis secondary to prostate or breast cancer.

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy with evidence that their use led to improved lung function and quality of life. However, the use of LABAs has raised safety concerns, such as their potential to provoke severe asthma exacerbations (SAEs) and death. This systematic review of major findings discusses the safety controversy surrounding LABA therapy and provides background for the U.S. Food and Drug Administrations warnings concerning LABA use. Findings from large clinical trials and several meta-analyses are described and compared in terms of their implications for the safety of LABAs. Monotherapy LABA therapy in the treatment of asthma remains controversial and is not recommended by the most recent asthma management guidelines. Despite the existence of numerous published studies, we conclude that more well-designed research on this topic --- to determine whether LABAs are associated with SAEs, such as asthma-related hospitalizations, intubations, and emergency room visits, or death --- is required. Particularly needed is research that makes use of large, secondary longitudinal databases.

Risk of serious asthma exacerbations associated with long-acting beta agonists among patients with asthma: A retrospective cohort study

The introduction of long-acting beta agonists (LABAs) was considered a major advance in bronchodilator therapy for adult, as well as pediatric, patients with asthma. However, the use of LABAs has raised safety concerns, especially the potential for severe asthma exacerbations (SAEs) resulting in hospitalizations or even death. Meanwhile, the use of inhaled corticosteroids (ICSs), a cornerstone in the treatment of mild-to-severe persistent asthma, has been associated with growth suppression in children. The purpose of this review was to identify and discuss the major published safety studies surrounding LABA, ICS, and combined LABA/ICS usage in children. By way of a critical search for influential published clinical trials, meta-analyses, and observational studies, six studies relevant to the safety of LABA monotherapy, seven studies relevant to ICS monotherapy, and four studies on the subject of LABA/ICS combination usage were identified and reviewed. Based on the reviewed literature, the controversy surrounding these anti-asthma medications was clearly exposed. On the one hand, there is some evidence that LABA monotherapy may be associated with SAEs and asthma-related death, while ICS monotherapy may be associated with a higher risk of growth suppression. On the other hand, the concurrent use of a LABA with an ICS has been associated with positive outcomes including symptom reduction and reduced rate and severity of exacerbations. Further clinical research is warranted and has been called for by the US Food and Drug Administration.

ACE Inhibitor and ARB Utilization and Expenditures in the Medicaid Fee-For-Service Program from 1991 to 2008

OBJECTIVES This study compared actual use of individual statin drugs to expected use based on their efficacy and safety profiles. METHODS Five panels covering the years 1999 to 2008 from the National Health and Nutrition Examination Survey provided interview, demographic, and laboratory data for 8769 (365,503,838 weighted) people aged 20 years or older who were not taking a statin medication. An individuals risk for coronary heart disease and low-density lipoprotein (LDL) cholesterol goal were determined, following the Adult Treatment Panel III Cholesterol Guidelines. The percentage LDL cholesterol lowering required to reach his/her LDL cholesterol level goal was calculated. Depending on the amount of LDL cholesterol lowering needed and on if the individual had a liver condition (i.e., enhanced risk of rhabdomyolysis) statins were hypothetically prescribed. Predicted use was compared to actual use by U.S. Medicaid beneficiaries in the third quarter of 2009, obtained from the Medicaid State Drug Utilization Data maintained by the Centers for Medicare and Medicaid Services. RESULTS Results showed that 72.34% of the population was in the lowest coronary heart disease risk group and that 86.30% required no statin therapy. Among the people who did require LDL cholesterol lowering, a significant majority (37.3 million or 10.22% of the population) needed 30% lowering or less. Only 314,784 (0.09%) required LDL cholesterol lowering of greater than 60%. Utilization shares based on safety and efficacy were estimated at 19.26% (rosuvastatin), 18.67% (atorvastatin), 16.48% (simvastatin), 16.30% (lovastatin), 14.93% (pravastatin), and 14.36% (fluvastatin). CONCLUSIONS Actual statin use differed substantially from predicted use. It may be appropriate to develop and maintain policies that encourage use of less costly products that have essentially equivalent safety profiles and efficacy.