Successful Comparison of US Food and Drug Administration Sentinel Analysis Tools to Traditional Approaches in Quantifying a Known Drug-Adverse Event Association.

The US Food and Drug Administration's Sentinel system has developed the capability to conduct active safety surveillance of marketed medical products in a large network of electronic healthcare databases. We assessed the extent to which the newly developed, semiautomated Sentinel Propensity Score Matching (PSM) tool could produce the same results as a customized protocol-driven assessment, which found an adjusted hazard ratio (HR) of 3.04 (95% confidence interval [CI], 2.81-3.27) comparing angioedema in patients initiating angiotensin-converting enzyme (ACE) inhibitors vs. beta-blockers. Using data from 13 Data Partners between 1 January 2008, and 30 September 2013, the PSM tool identified 2,211,215 eligible ACE inhibitor and 1,673,682 eligible beta-blocker initiators. The tool produced an HR of 3.14 (95% CI, 2.86-3.44). This comparison provides initial evidence that Sentinel analytic tools can produce findings similar to those produced by a highly customized protocol-driven assessment.

Increased risk of extrapyramidal side-effect treatment associated with atypical antipsychotic polytherapy.

OBJECTIVE: To determine whether atypical antipsychotic polytherapy is a risk factor for drug treatment for extrapyramidal side-effects (anti-EPS drugs) and whether the risk is attributable to antipsychotic dose. METHOD: We studied Iowa Medicaid beneficiaries aged 18-64 years with an active atypical and no conventional antipsychotic on January 1, 2001. The association of atypical antipsychotic polytherapy with anti-EPS drug treatment was determined. Multiple logistic regression was utilized to adjust for covariates in two models, the first adjusting for age, sex and the specific antipsychotic(s) prescribed, and the second also adjusting for doses. RESULTS: Among 4400 patients, the unadjusted odds of anti-EPS treatment were increased two-fold with polytherapy. Polytherapy remained a risk factor in the first model (OR 1.5, 95% CI 1.1-2.0), but not after adjusting for doses (OR 1.0, 95% CI 0.7-1.4). CONCLUSION: Atypical antipsychotic polytherapy is a risk factor for anti-EPS drug treatment, apparently because of higher cumulative doses.

The effect of alendronate on fracture-related healthcare utilization and costs: the fracture intervention trial.

The Vertebral Fracture Arm (VFA) of the Fracture Intervention Trial (FIT) study demonstrated that alendronate reduced the incidence of spine, forearm and hip fractures in women with low bone mass and existing vertebral fractures by about 50%. The objective of the present study was to determine the effects of alendronate therapy versus placebo on fracture-related healthcare utilization and costs. Participants were randomly assigned to double-masked treatment with alendronate (5 mg/day for 2 years and then 10 mg/day for 1 year) or placebo for 3 years. For each patient experiencing a clinical fracture, we determined whether treatment in an emergency room, hospital, nursing home and/or rehabilitation hospital was a consequence of the fracture. The VFA of the FIT Study enrolled 2027 women aged 55-81 years with low bone mass and pre-existing vertebral fractures from population-based listings in 11 metropolitan areas of the United States. We measured (1) the proportion of patients who had any fracture-related healthcare event and (2) the estimated cost of fracture-related healthcare services. Alendronate significantly reduced the proportion of patients utilizing fracture-related healthcare (emergency room, hospital, rehabilitation hospital or nursing home) by 25% (p = 0.038). Alendronate significantly reduced the costs associated with hip-fracture-related care by 58%, or $181 per patient randomized (p = 0.036). The reduction in fracture-related total costs was 35% ($190 per patient randomized) in the alendronate group relative to the placebo group (p = 0.114). Alendronate thus not only reduces the incidence of clinical fractures and associated morbidity, but reduces the proportion of patients utilizing the associated healthcare resources.

Economic and health-related quality of life considerations of new therapies in Parkinson's disease.

The progressive disability of Parkinson's disease results in substantial burdens for patients, their families and society in terms of increased health resource use, poorer quality of life, caregiver burden, disrupted family relationships, decreases in social and leisure activities, deteriorating emotional well-being, and direct and indirect costs of illness. Health-related quality of life (HR-QOL) measures have been used successfully in cross-sectional studies to identify and characterise these burdens; however, there is not yet substantial evidence that these instruments will be responsive to changes in patients over time and that the results will provide patients and health professionals with clinically meaningful information useful in making decisions about treatment strategies. The few studies documenting direct and indirect costs indicate increased use of ancillary health and community services, significant adaptations in home and transportation, increased use of mobility and self-care aids, and lack of access to appropriate healthcare providers. Patients with Parkinson's disease incur higher hospital expenses, have increased number of prescriptions, and experience earnings loss; the latter also applies to family caregivers. The choice, intensity and timing of therapy are determined by a variety of factors: presenting symptoms, age, employment status, comorbidity, cognitive impairment and level of functional impairment. Choices must be individually tailored to a patient's physical and personal needs. To be useful for patients with Parkinson's disease in clinical practice, clinicians should be able to use HR-QOL measures to identify appropriate medical interventions or socio-behavioural modifications to modify the HR-QOL deficits. However, while the interplay of interventions and clinical outcomes are often well understood, the effects of interventions on HR-QOL outcomes have not been studied extensively. Little research has been done that explicitly links the signs and symptoms of Parkinson's disease to the HR-QOL outcomes. The only Parkinson's disease cost-effectiveness study as yet performed indicated higher costs for patients receiving pramipexole than for those not taking the drug, but additional quality life-years were gained. Longer term effectiveness of many treatment strategies, and the usefulness of HR-QOL instruments to assess these treatments for individual patients over time, are critical areas for future research.

Dollars and sense: a practical guide to cost analysis for hospital epidemiology and infection control.

This paper explains practical approaches for collecting inpatient cost data for cost-of-illness and cost-effectiveness analyses. The economic definition of cost of an item is the value of the resources that are consumed in its production. Cost analysis should collect the resources hypothesized to be affected by the illness or intervention. The dollar value of these resources can also be estimated. Diagnosis-related group (DRG) reimbursements are not helpful when all study patients have the same DRG or when no DRG exists (e.g., nosocomial infection). Hospital charges are not a good surrogate for costs. Hence, data needed include resources used, charges, and cost-to-charge ratios, so that cost can be estimated. Resources used can be obtained from hospital information systems. For some resource use (e.g., physician services, pharmacy, and intravenous fluids), charges or cost-to-charge ratios may not be available, and an external standard may be needed to estimate the dollar value. For many types of resources, hospital financial systems provide both charges and cost-to-charge ratios. This yields an estimate of average cost (total cost divided by patient days) when marginal cost (change in variable cost per day of patient stay) is a better estimate of the value of the resources consumed. However, cost-to-charge ratios remain the only practical way of estimating cost in many circumstances and are commonly used in economic studies. Cost-of-illness estimates vary among the various nonrandomized study designs used. "Real-world" randomized trials are potentially useful to obtain advantages of randomization but avoid the protocol-induced biases of traditional double-blind controlled trials.

System for exchanging information among pharmacists in different practice environments.

OBJECTIVES: A system for exchanging patient information among hospital, long-term-care (LTC), and ambulatory care pharmacies is described, and the influence of that system on pharmacist interventions is reported. METHODS: Study sites consisted of three ambulatory care pharmacies, one LTC pharmacy, and one hospital in a small Midwestern city. Meetings were held by clinicians, the investigators, and hospital administrators to plan the information-exchange system. From January through June 1996, patients admitted to the hospital were checked to see if they came from a participating (source) pharmacy; if so, they were randomly assigned to experimental and control groups. The hospital requested preadmission information from the source pharmacy for experimental group patients and did not do so for control patients. After the information arrived, the hospital pharmacists could use it to identify and document drug therapy problems. When an experimental group patient was discharged, the hospital sent information to the appropriate source pharmacy. A total of 156 patients were enrolled in the study. RESULTS: Complete information transfer occurred for 75% of experimental group patients. Significantly more experimental group patients than control patients had at least one in-hospital pharmacist intervention recorded. Similarly, in the ambulatory care pharmacies (but not the LTC pharmacy) significantly more interventions per patient were documented for the experimental group. CONCLUSION: Hospital and ambulatory care pharmacists documented more interventions for patients about whom information had been supplied than for patients for whom that information had not been supplied. No difference in intervention rates was observed for LTC pharmacists, who were already being supplied information by the LTC facilities about patients discharged from the hospital.

System for exchanging information among pharmacists in different practice environments.

A system for exchanging patient information among hospital, long-term-care (LTC), and ambulatory care pharmacies is described, and the influence of that system on pharmacist interventions is reported. Study sites consisted of three ambulatory care pharmacies, one LTC pharmacy, and one hospital in a small Midwestern city. Meetings were held by clinicians, the investigators, and hospital administrators to plan the information-exchange system. From January through June 1996, patients admitted to the hospital were checked to see if they came from a participating (source) pharmacy; if so, they were randomly assigned to experimental and control groups. The hospital requested preadmission information from the source pharmacy for experimental group patients and did not do so for control patients. After the information arrived, the hospital pharmacists could use it to identify and document drug therapy problems. When an experimental group patient was discharged, the hospital sent information to the appropriate source pharmacy. A total of 156 patients were enrolled in the study. Complete information transfer occurred for 75% of experimental group patients. Significantly more experimental group patients than control patients had at least one in-hospital pharmacist intervention recorded. Similarly, in the ambulatory care pharmacies (but not the LTC pharmacy) significantly more interventions per patient were documented for the experimental group. Hospital and ambulatory care pharmacists documented more interventions for patients about whom information had been supplied than for patients for whom that information had not been supplied. No difference in intervention rates was observed for LTC pharmacists, who were already being supplied information by the LTC facilities about patients discharged from the hospital.

The usefulness of the Functional Status Questionnaire and Medical Outcomes Study Short Form in Parkinson's disease research.

Parkinson's disease (PD) has no cure and is a progressive neurological disorder with treatment aimed at the maintenance of function and limitation of the symptoms. No extensive studies of the disease's impact on health-related quality of life (HRQoL) have been conducted. The purpose of this study was to assess the potential usefulness of the Medical Outcomes Study Short Form (SF-36) and the Functional Status Questionnaire (FSQ) in Parkinson's disease research. This cross-sectional study of 193 PD patients who visited two hospital-based neurology clinics used self-administered in-clinic and take-home questionnaires to ascertain the demographic and environmental characteristics of the subjects and to gain health profile measures from the SF-36 and the FSQ. The two health profiles provide important HRQoL information supplementary to the traditional signs and symptoms evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS). Many of the HRQoL measures discriminate progressive stages of disease in this study group and distinguish those with complications of therapy from subjects without complications.

The health burdens of Parkinson's disease.

Parkinson's disease (PD) is likely to have a substantial impact on an individual's health-related quality of life (HRQL), health-related resource use, and productivity. Data about the health burdens of PD by disease stage are fundamental to understanding the effectiveness of care, both from a clinical and a fiscal point of view. This study's goal was to describe the associations of patient-reported HRQL and economic characteristics with PD stage. We hypothesized that later stages of PD would be associated with poorer HRQL, greater health-related resource use, and lower work productivity than early stages of PD. We used a cross-sectional analysis to study 193 PD patients attending two hospital-based neurology clinics. Self-administered questionnaires and in-person interviews measured clinical features, functional status, general health perceptions, well-being, overall HRQL, work productivity, and health-related resource use. Consistent, strong associations were found between stage and functional status, general health perceptions, well-being, and overall HRQL even after controlling for age, gender, and comorbid conditions. Most resource use and work productivity measures were also associated with disease stage. However, physician services use was not. This study confirms that the burdens of illness are progressively higher for PD patients with early, moderate, and advanced illness. The results suggest that such important facets of the health burden as HRQL and health-related resource use may be seriously misjudged if not carefully measured but inferred from clinical observations alone.

Cost effectiveness of pramipexole in Parkinson's disease in the US.

OBJECTIVE: Pramipexole was recently approved in the US for treatment of the symptoms of idiopathic Parkinson's disease (PD). Although pramipexole has been found to be safe and efficacious when compared with placebo, little data are yet available on its cost effectiveness when compared with baseline treatment. The aim of this study was to estimate the costs and cost effectiveness (cost utility) of pramipexole compared with baseline treatment in patients with early and advanced PD. DESIGN AND SETTING: We developed a cost-effectiveness (CE) model in the US setting that linked Unified Parkinson's Disease Rating Scale (UPDRS) Part II (activities of daily life) and III (motor) scores to disease progression, costs and patient utility. Data for the model were obtained from clinical trials, a literature review and a survey of 193 patients' health resource use and utility. We used cost and quality-adjusted life-year (QALY) estimates from the model to estimate the incremental cost effectiveness of pramipexole relative to baseline treatment patterns. We performed separate analyses for patients with early and advanced PD. We also performed extensive sensitivity analyses by adding other dopamine agonists to the no-pramipexole treatment regimen and varying disease progression parameters. The study was conducted from the societal perspective, although data presentation allows interpretation of cost effectiveness from either the societal or payer perspective. MAIN OUTCOME MEASURES AND RESULTS: For patients with both early and advanced PD, treatment with pramipexole had higher costs but was more effective than baseline treatment. For patients with early onset of PD, the incremental total CE ratio for pramipexole was $US8837/QALY. For patients with advanced PD, the incremental CE ratio was $US12 294/QALY (1997 costs). These ratios were lower than the CE ratios of many widely used medical treatments. CONCLUSIONS: Subject to the inherent limitations of modelling chronic disease progression and subsequent healthcare costs and patient utility, the results suggested that pramipexole was a cost effective treatment for patients with early and advanced PD in the US.

Do practice guidelines augment drug utilisation review?

Drug utilisation review (DUR) or drug use evaluation (DUE) studies or programmes are intended to detect and/or correct inappropriate drug use. Appropriateness can be assessed at 3 levels: (i) whether any medication is warranted, or whether either no therapy or nondrug therapy is preferred (level 1); (ii) assuming drug therapy is indicated, which of several alternative drugs is the preferred choice? (level 2); and (iii) appropriateness of the drug regimen, including dosage, duration, type and frequency of monitoring, and drug interactions (level 3). The traditional approach to DUR/DUE has been to begin the appropriateness evaluation after a drug is prescribed. However, changes in healthcare organisation provide the basis for a disease-management or health-maintenance approach to DUR/DUE, and practice guidelines afford a possible source for guiding such studies. We hypothesised that the latter approach to DUR/DUE would be more likely to result in evaluation of level 1 drug-therapy issues than the traditional DUR/DUE approach. We tested this hypothesis by reviewing 56 practice guidelines involving drug therapy and also reviewed research studies published from 1992 to 1996. We found that studies that used the traditional DUR/DUE approach were most likely to examine level 3 drug-therapy issues, never addressed level 1 issues, and typically evaluated adherence to provider- or study team-developed guidelines rather than published guidelines. In contrast, the disease- or health-management approach nearly always examined level 1 issues, seldom addressed level 3 issues, and almost always evaluated adherence to a published practice guideline. Regardless of the DUR/DUE approach, about 40% of studies evaluated level 2 issues. The guidelines themselves were much more likely to include recommendations about level 1 and level 2 issues than about level 3 issues; however, even when a guideline included level 2 or level 3 issues, studies of adherence to the guideline rarely assessed anything beyond level 1 issues. This suggests that guideline recommendations about level 2 and level 3 issues may be too imprecise for use in evaluative studies. The drug-information compendia, on the other hand, provide detailed recommendations about level 3 issues. Revision of drug compendia may be warranted to include recommendations about all levels of drug-therapy issues. The results of intervention studies to improve drug-therapy compliance with guidelines suggest that information provided at the time of prescribing, information presented by local health professionals and information provided with a large amount of provider contact may be more likely to demonstrate significant improvements in drug therapy. We conclude that practice guidelines are a useful resource for augmenting DUR/DUE but that challenges to optimising their use include whether they can be kept current, acceptable and accessible to providers.

The impact of Parkinson's disease on health status, health expenditures, and productivity. Estimates from the National Medical Expenditure Survey.

Parkinson's disease (PD) is a common disorder that leads to severe disability, despite pharmacological and surgical interventions. As PD progresses, patients and their families experience substantial health and economic burdens. Little research has been conducted into the economic consequences of PD or the impairment of health dimensions, such as social function and mental health, that may accompany the deterioration in economic resources and physical function. In the current study, the US National Medical Expenditure Survey (NMES) was examined as a source of population-based information about health-resource use, medical expenditures and health status. 43 patients with PD were identified, and each was matched with 3 individuals without PD to estimate the costs attributable to PD. Data from the NMES demonstrate the serious health and economic burdens of PD. The patients with PD were clearly shown to have decreased health status, increased health expenditures and lost productivity relative to controls. However, these estimates of the magnitude of disease burden must be used with caution. The small sample size appears to have inadequately represented patients in the earliest and the most advanced stages of PD. There was also considerable variability in case-control groups, resulting in wide confidence intervals for the estimates.

Effect of a training program on community pharmacists' detection of and intervention in drug-related problems.

OBJECTIVE: To develop and present a pharmaceutical care training program for pharmacists, and to examine the ability of these pharmacists to provide pharmaceutical care in a community pharmacy setting. DESIGN: Prospective, randomized study. INTERVENTION: A 40-hour pharmaceutical care training program was developed and presented to pharmacists, and 1,078 patients were randomly assigned to receive either (1) traditional pharmacy services or (2) pharmaceutical care, consisting of initial patient work-up and follow-up with documentation in a patient record. MEASUREMENTS: The study period was six months. Pharmacists documented problems identified, actions taken, and time required for all patients. RESULTS: Pharmacists consistently identified and intervened to address problems in both study groups. Patients receiving pharmaceutical care were more than seven times as likely to have any problems identified (odds ratio [OR] 7.5; confidence interval [CI] 4.2-13.1), more than eight times as likely to have an intervention performed (OR, 8.1; CI 4.7-14.2), and more than eight times as likely to have a drug-related problem identified (OR 8.6; CI 4.8-15.5) than were patients receiving traditional pharmacy services only. Time spent counseling patients was similar for the two groups. CONCLUSIONS: The training program proved to be an effective way to increase the number of problems identified and addressed by pharmacists.

Economic evaluation of interventions in endocrinology.

This article provides a review of methods for conducting cost-effectiveness, cost-utility, and cost-benefit studies. Economic evaluations of interventions designed to improve outcomes of patients with diabetes and osteoporosis are reviewed, and key issues for future research are discussed. The role of cost-effectiveness analysis in reimbursement decision making at the public and private levels is explored.

A cost minimization approach to the diagnosis of skeletal neoplasms.

OBJECTIVE: Percutaneous needle aspiration (PNA) has been widely used to diagnose bone malignancies. Successful aspirates hinge on the ability of the operator to obtain an adequate or diagnostic sample, and a skilled cytologist to make a diagnosis on needle aspirates. False-negative aspirates could pose a serious problem. This study is designed to evaluate the cost-effectiveness of PNA in the diagnosis of skeletal neoplasms using a cost minimization approach. DESIGN: All PNA performed over a 44-month period were reviewed retrospectively. Ninety-four skeletal biopsies were performed to diagnose a clinically or roentgenographically suspicious lesion: 69 for a suspected metastatic malignancy, and 25 for a suspected primary malignancy. The PNA results were collected and reviewed, sensitivities and specificities were determined (compared with open biopsy results or clinical follow-up as the gold standards), and the probabilities were applied to a decision tree. Charges were obtained from the patient's billing and converted into costs by a cost-charge ratio. Sensitivity analysis was performed to determine the costs of each branch of the decision tree, and ultimately the final cost of the two strategies: (1) PNA for all suspected neoplasms followed by open biopsy for negative and non-diagnostic PNA results, or (2) open biopsy for all suspected neoplasms. RESULTS: In diagnosing a suspected metastatic skeletal neoplasm, PNA had a sensitivity of 88%, a specificity of 100%, and a non-diagnostic result in 3% of cases. Cost analysis determined a savings of $ US 2486 per patient when "PNA strategy" was used instead of "open biopsy strategy". In diagnosing a suspected primary neoplasm, PNA hat a sensitivity 75%, a specificity of 100%, and a non-diagnostic result in 16% of cases. Cost analysis determined a savings of $ US 954 per patient when "PNA strategy" was used instead of "open biopsy strategy". By using "PNA strategy" instead of "open biopsy strategy" at this institution we would have saved $ US 195384 over the 44-month period. CONCLUSIONS: Metastatic skeletal neoplasms could be reliably diagnosed by PNA, and followed by open biopsy if the PNA result is negative or non-diagnostic, at a significant cost saving over open biopsy. Diagnosing primary skeletal neoplasms using "PNA strategy" offers a slight cost saving compared with "open biopsy strategy", but too few primary skeletal neoplasms were evaluated to recommend the best diagnostic approach.

Nonsteroidal antiinflammatory drugs and cognitive decline in the elderly.

OBJECTIVE: To better define the role of nonsteroidal antiinflammatory drugs (NSAID) in cognitive decline of the elderly. METHODS: Population based inception cohort of the rural elderly. NSAID user status was characterized as high dose, low/medium dose, or nonuser at 2 successive in-person interviews 3 years apart (F3 and F6). Respondents were from the Iowa 65+ Rural Health Study, one of the 4 cohorts of the National Institute on Aging's Established Populations for Epidemiologic Studies of the Elderly. Memory decline was assessed by a change in immediate word recall between F3 and F6. Multivariable logistic regression models were created to determine important predictors of the F3 to F6 recall memory decline in groups with poor, average, and good word recall at the F3 interview. Specific NSAID were compared to assess which drugs, if any, were associated with memory decline. RESULTS: The 2 factors most strongly associated with a significant immediate word recall decline between F3 and F6 among individuals in the average F3 word recall group were limitation in functional status [odds ratio (OR) = 2.31, 95% Confidence Interval (CI) (1.51, 3.52)] and high dose NSAID use [OR = 2.04, 95% CI (1.07, 3.89)]. No single NSAID agent was significantly more strongly associated with word recall decline than the others. However, in exploratory analyses use of high dose NSAID of the proprionic acid family neared significance for recall decline [OR = 3.17, 95% CI (0.92, 10.9). CONCLUSION: In elderly respondents with average baseline recall memory, high dose NSAID were a significant risk factor for longitudinal memory decline in this community based cohort. Although a large scale clinical trial is needed to definitely address this issue, we provide further evidence that NSAID play a role in cognitive dysfunction in the elderly.

Use of antihypertensive drugs and trends in blood pressure in the elderly.

BACKGROUND: During the 1980s data became available from randomized trials concerning the clear benefits of treating hypertension in the elderly. In three large communities, we examined the impact of these findings on rates of treatment, use of specific antihypertensive drugs, and rates of elevated blood pressure as well as distributions of levels. METHODS: In 1981 the National Institute on Aging initiated population-based cohort studies in the residents of three communities who were 65 years and older. East Boston, Mass; Washington and Iowa counties, Iowa; and New Haven, Conn. Participation rates ranged from 80% to 85% across sites with 10,294 community-dwelling participants in the combined cohorts. Baseline evaluation included inhome blood pressure assessment and medication inventory. Repeated in-home evaluations occurred 3 and 6 years after baseline and follow-up rates ranged from 71% to 88%. RESULTS: Use of antihypertensive drugs increased over time in all three communities: the age- and sex-adjusted rates of use were between 14% and 32% higher in 1988 and 1989 relative to 1982 and 1983. Parallel declines in the use of thiazide diuretics occurred in all three populations along with large increases in the use of angiotensin-converting enzyme inhibitors and calcium channel blockers. In East Boston and New Haven mean systolic blood pressure decreased substantially over time and the prevalence of elevated systolic pressure (> or = 160 mmHg) decreased overall as well as by age and sex. In Iowa the mean levels of systolic blood pressure were lowest at baseline and increased slightly. CONCLUSIONS: The reported evidence about the benefits of treatment for hypertension in the elderly was followed by substantial increases in treatment rates. The use of drugs with proven efficacy declined while the use of newer agents with theoretical advantages, not yet tested in clinical trials of mortality, increased. In the United States, the ongoing therapeutic efforts to lower elevated blood pressure in elderly populations may be contributing to the continuing decline in cardiovascular and stroke mortality.

Pharmacists as agents of change for rational drug therapy.

We analyze what is known and unknown about the contribution of the pharmacist as patient educator, physician consultant, and agent to affect patient outcomes in ambulatory settings. The need for pharmacist services is discussed, as are the theoretical underpinnings and quality of the scientific evidence to support their efficacy. The analysis is conducted in the context of a shift in pharmacists' roles from product to patient orientation as well as recent U.S. legislation mandating enhanced pharmacists' roles via drug utilization review for all Medicaid patients. We conclude with a research and action agenda, calling for stronger research designs in evaluating pharmacists' interventions. The shifting paradigm in the pharmacy profession, coupled with the implementation of the Omnibus Budget Reconciliation Act of 1990, provide unique opportunities for rigorous evaluations of pharmacists as agents of change for rational drug therapy.