PURPOSE: Emergency department (ED) patients receive medications that place them at risk for adverse events, including drug-induced prolongation of the QT interval, which can lead to Torsade de Pointes and sudden cardiac death. We report the frequency of prescription and co-prescription of QT-prolonging medications in US EDs and factors associated with high-risk prescribing practices. METHODS: We analyzed the ED component of the National Hospital Ambulatory Medical Care Survey for 1995 through 2009. Yearly rates of visits involving the prescription of QT-prolonging medications were determined. Multivariate regression analyses identified factors associated with the prescription of two or more QT-prolonging medications. RESULTS: Approximately 16.5 million visits annually (15.0%) involved prescription of a QT-prolonging drug, with 1.7 million (1.6%) involving multiple prescriptions. Visits associated with QT-prolonging drugs more than doubled over the study period (10.4% to 22.2%). Diphenhydramine, azithromycin, and ondansetron were most frequently implicated (46.1% of cases). The most commonly prescribed combination was diphenhydramine and famotidine, both QT-prolonging medications available over-the-counter. Female gender and older age were associated with co-prescription of QT-prolonging medications. The rate of EKG screening among visits associated with QT-prolonging drug combinations was low (20.9%), but more common than among visits without a QT-prolonging drug (OR 1.3; 95% CI 1.2-1.5). CONCLUSION: Use of QT-prolonging medications is increasing in EDs nationally. A small number of agents account for a large proportion of these visits and may represent an area for targeted screening or monitoring interventions in the ED.

BACKGROUND: Medical devices can be useful in a variety of diseases, but few devices have been specifically approved for use in children. The 2007 Pediatric Medical Device Safety and Improvement Act was passed to stimulate pediatric device development. The current state of trial evidence underpinning the approval of pediatric devices remains poorly described. METHODS: We identified all high-risk (ie, class III) devices approved through the premarket approval or humanitarian device exemption pathways for therapeutic use in children between 2008 and 2011. We collected key information on clinical trial design (randomization, blinding, controls, and types of end points) as well as age distribution of trial participants. We also identified US Food and Drug Administration (FDA)-mandated postmarketing trials. RESULTS: Twenty-two devices were approved for use in children via the premarket approval pathway and 3 via the humanitarian device exemption pathway. Twenty-two (88%) qualified as pediatric despite minimum approval ages of >/=18 years (the FDA Center for Devices and Radiologic Health considers patients 18-21 years old as pediatric). Most devices were approved on the basis of nonrandomized (59%), open-label (68%) studies with surrogate effectiveness end points (86%). Overall, 21 (84%) devices were not studied in any patients <18 years of age. Postmarketing studies were mandated by the FDA for 19 (76%) devices, although only 3 (18%) required enrollment of pediatric patients. CONCLUSIONS: Most high-risk pediatric devices are approved on the basis of trials in patients >/=18 years old, with few pediatric patients exposed to the devices before market availability. Few postmarketing studies require additional study in pediatric patients.

BACKGROUND: Industry funding and financial conflicts of interest may contribute to bias in the synthesis and interpretation of scientific evidence. OBJECTIVE: To examine the association between financial conflicts of interest and characteristics of systematic reviews of neuraminidase inhibitors. DESIGN: Retrospective analysis. SETTING: Reviews that examined the use of neuraminidase inhibitors in the prophylaxis or treatment of influenza, were published between January 2005 and May 2014, and used a systematic search protocol. MEASUREMENTS: Two investigators blinded to all information regarding the review authors independently assessed the presentation of evidence on the use of neuraminidase inhibitors as favorable or not favorable. Financial conflicts of interest were identified using the index reviews, other publications, and Web-based searches. Associations between financial conflicts of interest, favorability assessments, and presence of critical appraisals of evidence quality were analyzed. RESULTS: Twenty-six systematic reviews were identified, of which 13 examined prophylaxis and 24 examined treatment, accounting for 37 distinct assessments. Among assessments associated with a financial conflict of interest, 7 of 8 (88%) were classified as favorable, compared with 5 of 29 (17%) among those without a financial conflict of interest. Reviewers without financial conflicts of interest were more likely to include statements about the quality of the primary studies than those with financial conflicts of interest. LIMITATIONS: The heterogeneity in populations and outcomes examined in the reviews precluded analysis of the contribution of selective inclusion of evidence on the discordance of the assessments made in the reviews. Many of the systematic reviews had overlapping authorship. CONCLUSION: Reviewers with financial conflicts of interest may be more likely to present evidence about neuraminidase inhibitors in a favorable manner and recommend the use of these drugs than reviewers without financial conflicts of interest. PRIMARY FUNDING SOURCE: Australian National Health and Medical Research Council.

BACKGROUND: The allocation of research resources should favor conditions responsible for the greatest disease burden. This is particularly important in pediatric populations, which have been underrepresented in clinical research. Our aim was to measure the association between the focus of pediatric clinical trials and burden of disease and to identify neglected clinical domains. METHODS: We performed a cross-sectional study of clinical trials by using trial records in ClinicalTrials.gov. All trials started in 2006 or after and studying patient-level interventions in pediatric populations were included. Age-specific measures of disease burden were obtained for 21 separate conditions for high-, middle-, and low-income countries. We measured the correlation between number of pediatric clinical trials and disease burden for each condition. RESULTS: Neuropsychiatric conditions and infectious diseases were the most studied conditions globally in terms of number of trials (874 and 847 trials, respectively), while intentional injuries (5 trials) and maternal conditions (4 trials) were the least studied. Clinical trials were only moderately correlated with global disease burden (r = 0.58, P = .006). Correlations were also moderate within each of the country income levels, but lowest in low-income countries (r = .47, P = .03). Globally, the conditions most understudied relative to disease burden were injuries (-260 trials for unintentional injuries and -160 trials for intentional injuries), nutritional deficiencies (-175 trials), and respiratory infections (-171 trials). CONCLUSIONS: Pediatric clinical trial activity is only moderately associated with pediatric burden of disease, and least associated in low-income countries. The mismatch between clinical trials and disease burden identifies key clinical areas for focus and investment.

OBJECTIVE: To measure the hospital-level variation in admission rates for children receiving treatment of common pediatric illnesses across emergency departments (EDs) in US children's hospitals. METHODS: We performed a multi-center cross sectional study of children presenting to the EDs of 35 pediatric tertiary-care hospitals participating in the Pediatric Health Information System (PHIS). Admission rates were calculated for visits occurring between January 1, 2009, and December 31, 2012, associated with 1 of 7 common conditions, and corrected to adjust for hospital-level severity of illness. Conditions were selected systematically based on frequency of visits and admission rates. RESULTS: A total of 1288706 ED encounters (13.8% of all encounters) were associated with 1 of the 7 conditions of interest. After adjusting for hospital-level severity, the greatest variation in admission rates was observed for concussion (range 5%-72%), followed by pneumonia (19%-69%), and bronchiolitis (19%-65%). The least variation was found among patients presenting with seizures (7%-37%) and kidney and urinary tract infections (6%-37%). Although variability existed in disease-specific admission rates, certain hospitals had consistently higher, and others consistently lower, admission rates. CONCLUSIONS: We observed greater than threefold variation in severity-adjusted admission rates for common pediatric conditions across US children's hospitals. Although local practices and hospital-level factors may partly explain this variation, our findings highlight the need for greater focus on the standardization of decisions regarding admission.

BACKGROUND: Attention-deficit hyperactivity disorder (ADHD) is a chronic condition and pharmacotherapy is the mainstay of treatment, with a variety of ADHD medications available to patients. However, it is unclear to what extent the long-term safety and efficacy of ADHD drugs have been evaluated prior to their market authorization. We aimed to quantify the number of participants studied and their length of exposure in ADHD drug trials prior to marketing. METHODS: We identified all ADHD medications approved by the Food and Drug Administration (FDA) and extracted data on clinical trials performed by the sponsor and used by the FDA to evaluate the drug's clinical efficacy and safety. For each ADHD medication, we measured the total number of participants studied and the length of participant exposure and identified any FDA requests for post-marketing trials. RESULTS: A total of 32 clinical trials were conducted for the approval of 20 ADHD drugs. The median number of participants studied per drug was 75 (IQR 0, 419). Eleven drugs (55%) were approved after 100 participants were studied and 14 (70%) after 300 participants. The median trial length prior to approval was 4 weeks (IQR 2, 9), with 5 (38%) drugs approved after participants were studied 4 weeks and 10 (77%) after 6 months. Six drugs were approved with requests for specific additional post-marketing trials, of which 2 were performed. CONCLUSIONS: Clinical trials conducted for the approval of many ADHD drugs have not been designed to assess rare adverse events or long-term safety and efficacy. While post-marketing studies can fill in some of the gaps, better assurance is needed that the proper trials are conducted either before or after a new medication is approved.

Pediatric populations continue to be understudied in clinical drug trials despite the increasing use of pharmacotherapy in children, particularly with psychotropic drugs. Most pertinent to the clinical selection of drug interventions are trials directly comparing drugs against other drugs. The aim was to measure the prevalence of active drug comparators in neuropsychiatric drug trials in children and identify the effects of funding source on comparator selection. We analyzed the selection of drugs and drug comparisons in clinical trials registered between January 2006 and May 2012. Completed and ongoing interventional trials examining treatments for six neuropsychiatric conditions in children were included. Networks of drug comparisons for each condition were constructed using information about the trial study arms. Of 421 eligible trial registrations, 228 (63,699 participants) were drug trials addressing ADHD (106 trials), autism spectrum disorders (47), unipolar depression (16), seizure disorders (38), migraines and other headaches (15), or schizophrenia (11). Active drug comparators were used in only 11.0% of drug trials while 44.7% used a placebo control and 44.3% no drug or placebo comparator. Even among conditions with well-established pharmacotherapeutic options, almost all drug interventions were compared to a placebo. Active comparisons were more common among trials without industry funding (17% vs. 8%, p=0.04). Trials with industry funding differed from non-industry trials in terms of the drugs studied and the comparators selected. For 73% (61/84) of drugs and 90% (19/21) of unique comparisons, trials were funded exclusively by either industry or non-industry. We found that industry and non-industry differed when choosing comparators and active drug comparators were rare for both groups. This gap in pediatric research activity limits the evidence available to clinicians treating children and suggests a need to reassess the design and funding of pediatric trials in order to optimize the information derived from pediatric participation in clinical trials.

BACKGROUND AND OBJECTIVE: Neuropsychiatric conditions represent a large and increasing disease burden in children. A number of drugs are available for the treatment of these conditions, but most drugs have not been adequately tested in children, and off-label drug use remains widespread. We sought to define and quantify recent and ongoing clinical research on the use of neuropsychiatric drugs in children. METHODS: Drug trials registered in ClinicalTrials.gov between 2006 and 2011 and studying neuropsychiatric conditions were selected and classified based on the drug's Food and Drug Administration (FDA) approval status in children. We measured the proportion of trials seeking to expand the use of a drug to pediatric patients and the proportion of available drugs studied in children. RESULTS: Only 10% of neuropsychiatric trials focused on children. Of 303 drugs studied in both pediatric and adult populations, 90% lacked FDA approval in children and 97% were not approved in children for the indication studied. However, only 19% of all neuropsychiatric drugs were under study in pediatric populations, with as few as 8% of either antidepressant or antipsychotic drugs. Overall, 76% of pediatric drug trials examined a drug previously unapproved in children and 26% explored the use of a drug for a new indication. CONCLUSIONS: Despite the rising prevalence of neuropsychiatric disease and the paucity of FDA-approved pediatric drugs, only a small proportion of trials focus on pediatric populations and these trials cover only a fraction of available drugs. This deficiency is most pronounced for depression and schizophrenia.