Florence T. Bourgeois

Outcome Reporting Among Drug Trials Registered in ClinicalTrials.gov

BACKGROUND Clinical trial registries are in widespread use to promote transparency around trials and their results. OBJECTIVE To describe characteristics of drug trials listed in ClinicalTrials.gov and examine whether the funding source of these trials is associated with favorable published outcomes. DESIGN An observational study of safety and efficacy trials for anticholesteremics, antidepressants, antipsychotics, proton-pump inhibitors, and vasodilators conducted between 2000 and 2006. SETTING ClinicalTrials.gov, a Web-based registry of clinical trials launched in 1999. MEASUREMENTS Publications resulting from the trials for the 5 drug categories of interest were identified, and data were abstracted on the trial record and publication, including timing of registration, elements of the study design, funding source, publication date, and study outcomes. Assessments were based on the primary funding categories of industry, government agencies, and nonprofit or nonfederal organizations. RESULTS Among 546 drug trials, 346 (63%) were primarily funded by industry, 74 (14%) by government sources, and 126 (23%) by nonprofit or nonfederal organizations. Trials funded by industry were more likely to be phase 3 or 4 trials (88.7%; P < 0.001 across groups), to use an active comparator in controlled trials (36.8%; P = 0.010 across groups), to be multicenter (89.0%; P < 0.001 across groups), and to enroll more participants (median sample size, 306 participants; P < 0.001 across groups). Overall, 362 (66.3%) trials had published results. Industry-funded trials reported positive outcomes in 85.4% of publications, compared with 50.0% for government-funded trials and 71.9% for nonprofit or nonfederal organization-funded trials (P < 0.001). Trials funded by nonprofit or nonfederal sources with industry contributions were also more likely to report positive outcomes than those without industry funding (85.0% vs. 61.2%; P = 0.013). Rates of trial publication within 24 months of study completion ranged from 32.4% among industry-funded trials to 56.2% among nonprofit or nonfederal organization-funded trials without industry contributions (P = 0.005 across groups). LIMITATIONS The publication status of a trial could not always be confirmed, which could result in misclassification. Additional information on study protocols and comprehensive trial results were not available to further explore underlying factors for the association between funding source and outcome reporting. CONCLUSION In this sample of registered drug trials, those funded by industry were less likely to be published within 2 years of study completion and were more likely to report positive outcomes than were trials funded by other sources. PRIMARY FUNDING SOURCE National Library of Medicine and National Institute of Child Health and Human Development, National Institutes of Health.

Adverse Drug Events in the Outpatient Setting: An 11-Year National Analysis

Adverse drug events (ADEs) are a common complication of medical care resulting in high morbidity and medical expenditure. Population level estimates of outpatient ADEs are limited. Our objective was to provide national estimates and characterizations of outpatient ADEs and determine risk factors associated with these events.

Association of Race/Ethnicity with Emergency Department Wait Times

Objective. To determine whether wait times for children treated in emergency departments (EDs) nationally are associated with patient race/ethnicity. Methods. Data were obtained from the National Hospital Ambulatory Medical Care Survey, which collects information on patient visits to EDs throughout the United States. We examined data for patients ≤15 years of age who presented to EDs during the 4-year period of 1997–2000. Sample weights were applied to the identified patient records to yield national estimates. For the purposes of this study, race/ethnicity was analyzed for 3 major groups, ie, non-Hispanic white (NHW), non-Hispanic black (NHB), and Hispanic white (HW). Results. During the 4-year study period, 20633 patient visits were surveyed, representing a national sample of 92.9 million children ≤15 years of age. The race/ethnicity distribution included 9019 NHW children (59.5%), 3910 NHB children (23.9%), and 2991 HW children (16.6%). The wait time for all groups was 43.6 ± 1.7 minutes (mean ± SEM). There were significant unadjusted intergroup differences in wait times (38.5 ± 1.6 minutes, 48.7 ± 0.5 minutes, and 54.5 ± 0.1 minutes for NHW, NHB, and HW children, respectively). Visit immediacy (triage status), when reported, was categorized as <15 minutes for 2203 children (17.1%), 15 to 60 minutes for 5324 (41.4%), 1 to 2 hours for 3010 (25.1%), and >2 to 24 hours for 1910 (16.4%). There were significant unadjusted differences in triage status according to race, with 14.6% of NHW patients being placed in the >2-hour immediacy range, compared with 18.8% of NHB patients and 20.0% of HW patients. In a linear regression analysis with logarithmically transformed wait time as a dependent variable and with adjustment for potential confounders, including hospital location, geographic region, and payer status, both NHB and HW patients waited longer than NHW patients, although the results were statistically significant only for HW patients. Conclusions. These nationally representative data suggest that children who come to EDs have wait times that vary according to race/ethnicity. There are several potential explanations for this observation, including discrimination, cultural incompetence, language barriers, and other social factors. These data and similar data from the National Hospital Ambulatory Medical Care Survey are useful in identifying nonclinical influences on the delivery of pediatric emergency care.

Emergency care for children in pediatric and general emergency departments.

Objective: We examine the pediatric emergency department (ED) population and their clinical course in pediatric versus general EDs and identify potential factors contributing to differences in performance metrics between the 2 ED settings. Methods: This was a retrospective analysis of pediatric visits to nationally representative EDs participating in the National Hospital Ambulatory Medical Care Survey from 1995 to 2002. Differences between pediatric and general EDs were examined in terms of patient characteristics and clinical course. Results: Pediatric EDs treated more children with medical problems than general EDs, which treated more children with injuries. Visits by children to pediatric EDs were associated with longer wait times to see a physician (median, 40 vs. 25 minutes; P < 0.001) and longer stays in the ED (median, 130 vs. 98 minutes; P = 0.006). In multivariate analysis, the type of ED treating a pediatric patient was a significant determinant of wait time (percent change for pediatric EDs, 23.1; 95% confidence interval [CI], 3.4-46.6), length of stay (percent change for pediatric EDs, 23.0; 95% CI, 5.1-43.9), and rate of discharge (odds ratio for pediatric EDs, 0.75; 95% CI 0.61-0.92). Children in pediatric EDs seemed to be sicker than those in general EDs. Conclusions: These data provide the first glimpse of health care delivery to children seen in EDs nationally. Our findings indicate that significant differences exist between pediatric visits to pediatric and general EDs. These findings may be useful in establishing performance metrics for the care of ill and injured children in both pediatric and general EDs.

Influenza and Other Respiratory Virus–Related Emergency Department Visits Among Young Children

BACKGROUND. Influenza and other winter respiratory viruses cause substantial morbidity among children. Previous estimates of the burden of illness of these viruses have neglected to include the emergency department, where a large number of patients seek acute care for respiratory illnesses. This study provides city- and statewide population estimates of the burden of illness attributable to respiratory viruses for children receiving emergency department–based care for respiratory infections during the winter months. METHODS. The number of patients ≤7 years of age presenting to the emergency department of an urban tertiary care pediatric hospital with acute respiratory infections was estimated by using a classifier based on presenting complaints. The rates of specific viral infections in this population were estimated by using the rates of positivity for respiratory syncytial virus, influenza virus, parainfluenza virus, adenovirus, and enterovirus. Local emergency department market share and US Census data enabled determination of the rates of emergency department visits in the Boston, Massachusetts, area and in Massachusetts. RESULTS. During the 11-year study period, the mean yearly number of patients ≤7 years of age presenting to the study emergency department during the winter season was 17397. On the basis of the respiratory classifier, the mean number of patients with an acute respiratory infection was 6923, or 398 per 1000 emergency department visits. In the city population, the mean number of emergency department visits for acute respiratory infections was 17906, which is equivalent to 113.9 per 1000 children residing in the city, and in the state population the mean number was 61529, or 94.5 per 1000 children residing in the state. At the state level, 23114 of the visits were for respiratory syncytial virus, 5650 for influenza, 1751 for parainfluenza virus, 2848 for adenovirus, and 798 for enterovirus. For patients 6 to 23 months of age in the state population, there were 19860 emergency department visits for acute respiratory infections, or 168 per 1000 children in this age group, with 6235 visits resulting from respiratory syncytial virus and 2112 resulting from influenza. CONCLUSION. There is a high incidence of emergency department visits for infectious respiratory illnesses among children. This important component of health care use should be included in estimates of the burden of illness attributable to influenza and other winter respiratory viruses.

Pediatric Adverse Drug Events in the Outpatient Setting: An 11-Year National Analysis

OBJECTIVE: Adverse drug events (ADEs) are a common complication of medical care, but few pediatric data are available describing the frequency or epidemiology of these events. We estimated the national incidence of pediatric ADEs requiring medical treatment, described the pediatric population seeking care for ADEs, and characterized the events in terms of patient symptoms and medications implicated. METHODS: Data were obtained from the National Center for Health Statistics, which collects information on patient visits to outpatient clinics and emergency departments throughout the United States. We analyzed data for children 0 to 18 years of age seeking medical treatment for an ADE between 1995 and 2005. RESULTS: The mean annual number of ADE-related visits was 585922 (95% confidence interval [CI]: 503687–668156) of which 78% occurred in outpatient clinics and 12% occurred in emergency departments. Children 0 to 4 years of age had the highest incidence of ADE-related visits, accounting for 43.2% (95% CI: 35.6%–51.2%) of visits. The most common symptom manifestations were dermatologic conditions (45.4% [95% CI: 36.9%–54.1%]) and gastrointestinal symptoms (16.5% [95% CI: 11.1%–23.8%]). The medication classes most frequently implicated in an ADE were antimicrobial agents (27.5% [95% CI: 21.5%–34.5%]), central nervous system agents (6.5% [95% CI: 4.0%–10.5%]), and hormones (6.1% [95% CI: 3.1%–11.6%]). While ADEs related to antimicrobial agents were most common among children 0 to 4 years old and decreased in frequency among older children, ADEs resulting from central nervous system agents and hormones increased in frequency among children 5 to 11 and 12 to 18 years old. CONCLUSIONS: ADEs result in a substantial number of health care visits, particularly in outpatient clinics. The incidence of ADEs and medications implicated vary by age, indicating that age-specific approaches for monitoring and preventing ADEs may be most effective.

Pediatric Versus Adult Drug Trials for Conditions With High Pediatric Disease Burden

BACKGROUND AND OBJECTIVE: Optimal treatment decisions in children require sufficient evidence on the safety and efficacy of pharmaceuticals in pediatric patients. However, there is concern that not enough trials are conducted in children and that pediatric trials differ from those performed in adults. Our objective was to measure the prevalence of pediatric studies among clinical drug trials and compare trial characteristics and quality indicators between pediatric and adult drug trials. METHODS: For conditions representing a high burden of pediatric disease, we identified all drug trials registered in ClinicalTrials.gov with start dates between 2006 and 2011 and tracked the resulting publications. We measured the proportion of pediatric trials and subjects for each condition and compared pediatric and adult trial characteristics and quality indicators. RESULTS: For the conditions selected, 59.9% of the disease burden was attributable to children, but only 12.0% (292/2440) of trials were pediatric (P < .001). Among pediatric trials, 58.6% were conducted without industry funding compared with 35.0% of adult trials (P < .001). Fewer pediatric compared with adult randomized trials examined safety outcomes (10.1% vs 16.9%, P = .008). Pediatric randomized trials were slightly more likely to be appropriately registered before study start (46.9% vs 39.3%, P = .04) and had a modestly higher probability of publication in the examined time frame (32.8% vs 23.2%, P = .04). CONCLUSIONS: There is substantial discrepancy between pediatric burden of disease and the amount of clinical trial research devoted to pediatric populations. This may be related in part to trial funding, with pediatric trials relying primarily on government and nonprofit organizations.

Relative Impact of Influenza and Respiratory Syncytial Virus in Young Children

OBJECTIVE: We measured the relative impact of influenza and respiratory syncytial virus (RSV) infections in young children in terms of emergency department (ED) visits, clinical care requirements, and overall resource use. METHODS: Patients who were aged ≤7 years and treated in the ED of a tertiary care pediatric hospital for an acute respiratory infection were enrolled during 2 winter seasons between 2003 and 2005. We quantified health care resource use for children with influenza or RSV infections, and extrapolated results to estimate the national resource use associated with influenza and RSV infections. RESULTS: Nationally, an estimated 10.2 ED visits per 1000 children were attributable to influenza and 21.5 visits per 1000 to RSV. Children who were aged 0 to 23 months and infected with RSV had the highest rate of ED visits with 64.4 visits per 1000 children. Significantly more children required hospitalization as a result of an RSV infection compared with influenza, with national hospitalization rates of 8.5 and 1.4 per 1000 children, respectively. The total number of workdays missed yearly by caregivers of children who required ED care was 246965 days for influenza infections and 716404 days for RSV infections. CONCLUSION: For young children, RSV is associated with higher rates of ED visits, hospitalization, and caregiver resource use than is influenza. Our results provide data on the large number of children who receive outpatient care for influenza and RSV illnesses and serve to inform analyses of prevention programs and treatments for both influenza and RSV disease.

Validation of Syndromic Surveillance for Respiratory Infections

Study objective A key public health question is whether syndromic surveillance data provide early warning of infectious outbreaks. One cause for skepticism is that biological correlates of the administrative and clinical data used in these systems have not been rigorously assessed. This study measures the value of respiratory data currently used in syndromic surveillance systems to detect respiratory infections by comparing it against criterion standard viral testing within a pediatric population. Methods We conducted a longitudinal study with prospective validation in the emergency department (ED) of a tertiary care children’s hospital. Children aged 7 years or younger who presented with a respiratory syndrome or who were tested for respiratory syncytial virus (RSV), influenza virus, parainfluenza virus, adenovirus, or enterovirus between January 1993 and June 2004 were included. We assessed the predictive ability of the viral tests by fitting generalized linear models to respiratory syndrome counts. Results Of 582,635 patient visits, 89,432 (15.4%) were for respiratory syndromes, and of these, 7,206 (8.1%) patients were tested for the viruses of interest. RSV was significantly related to respiratory syndrome counts (adjusted rate ratio [RR] 1.33; 95% confidence interval [CI] 1.04 to 1.71). In multivariate models including all viruses tested, influenza virus was also a significant predictor of respiratory syndrome counts (RR 1.47; 95% CI 1.03 to 2.10). This model accounted for 81.6% of the observed variability in respiratory syndrome counts. Conclusion Respiratory syndromic surveillance data strongly correlate with virologic test results in a pediatric population, providing evidence of the biologic validity of such surveillance systems. Real-time outbreak detection systems relying on syndromic data may be an important adjunct to the current set of public health systems for the detection and surveillance of respiratory infections.

Adult Prescription Drug Use and Pediatric Medication Exposures and Poisonings

BACKGROUND AND OBJECTIVES: Nontherapeutic medication ingestions continue to be a major pediatric health problem, with recent increases in ingestions despite a number of public health interventions. It is unknown how changes in adult prescription drug use relate to pediatric medication poisonings. The objective of the study was to measure the association between changing adult prescription drug patterns and pediatric medication exposures and poisonings and identify high-risk classes of medications and pediatric age groups. METHODS: We measured monthly pediatric exposures and poisonings using the National Poison Data System and prescriptions written for adults using the National Ambulatory Medical Care Surveys for 2000 through 2009. Associations between adult prescriptions for oral hypoglycemics, antihyperlipidemics, β-blockers, and opioids and exposures and poisonings among children 0 to 5, 6 to 12, and 13 to 19 years were analyzed by using multiple time-series analysis. Emergency department visits, serious injuries, and hospitalizations stemming from these associations were described. RESULTS: Adult medication prescriptions were statistically significantly associated with exposures and poisonings in children of all ages, with the strongest association observed for opioids. Across medications, the greatest risk was among children 0 to 5 years old, followed by 13- to 19-year-olds. Rates of emergency department visits were highest for events related to hypoglycemics (60.1%) and β-blockers (59.7%), whereas serious injuries and hospitalizations occurred most frequently with opioids (26.8% and 35.2%, respectively) and hypoglycemics (19.5% and 49.4%, respectively). CONCLUSIONS: Increasing adult drug prescriptions are strongly associated with rising pediatric exposures and poisonings, particularly for opioids and among children 0 to 5 years old. These associations have sizable impacts, including high rates of serious injury and health care use.