BACKGROUND: Few medicines have been approved for children, leading to rates of off-label prescribing reported to be as high as 90%. In 2007, the European Union adopted the Paediatric Regulation, which mandates that pharmaceutical companies conduct paediatric studies for all new medicines, unless granted a waiver. We aimed to evaluate the availability of paediatric trial results from studies required under the Paediatric Regulation for new medicines authorised in the EU. METHODS AND FINDINGS: The European Medicines Agency (EMA) public database of paediatric investigation plans was searched for new medicines centrally authorised in the EU between 1 January 2010 and 31 December 2014 with at least 1 required paediatric study. For our study cohort of paediatric clinical trials required for these medicines, we used internal EMA databases and publicly available trial registries to determine changes to the planned completion date or study design, rates of trial completion, time to trial completion, and results reporting (peer-reviewed publication or posting on trial registry). Cox proportional hazards regression models were constructed to examine factors associated with study completion. A total of 326 paediatric clinical trials were required for 122 novel medicines authorised by the EMA between 2010 and 2014. In all, 76% (247/326) of paediatric studies were not planned to be completed until after the initial marketing authorisation. The planned completion dates for 50% (162/326) were further postponed by a median of 2.2 years. Overall, 38% (124/326) of paediatric studies were completed as of 30 November 2017. The rate of trial completion for paediatric studies planned to be completed after initial marketing authorisation was 23% (56/247), versus 86% (68/79) for trials planned to be completed before authorisation (adjusted hazard ratio 0.11; 95% CI 0.06-0.19). Among completed studies, the results were reported in a public registry or in the peer-reviewed literature for 85% (105/124) at a median of 1.1 years after study completion, and 60% (74/124) were published in a peer-reviewed journal. Limitations of this study include the potential lack of generalisability to medicines not authorised by the EMA and the possibility for more of these trials to be completed or published in the future. CONCLUSIONS: The completion of many paediatric studies required under the Paediatric Regulation has been delayed. Paediatric studies planned to be completed after marketing authorisation were associated with a lower likelihood of eventual completion, highlighting the need to examine the implementation of current policies in ensuring timely availability of important paediatric information.
PURPOSE: Greater than 50% of drugs lack pediatric labeling information, resulting in widespread "off-label" use in children. To increase pediatric prescribing information, the Pediatric Research Equity Act (PREA) was passed in 2003, requiring new drug applications to include pediatric assessments. We evaluated the study of new drugs in children since PREA was implemented. METHODS: We performed a cross-sectional analysis of new drug applications submitted to the FDA from December 2003 to July 2012, using publicly available documents at Drugs@FDA. We calculated the proportion of new drugs that included a pediatric assessment at the time of approval and at a final review performed in July 2016. RESULTS: We identified 92 new drugs requiring pediatric assessments. Only 20 (21.7%) had been fully studied in children at the time of approval, while 9 (9.8%) had been partially assessed, and 63 (68.5%) did not have pediatric data. Among drugs approved without pediatric assessments, 4.2% met FDA deferral deadlines and 34.9% eventually submitted pediatric data. At the time of our final review, allowing for a mean of 8.6 years since drug approval, 57.6% of new drugs had not been fully assessed in children. The mean time between approval in adults and availability of pediatric data for drugs approved without pediatric assessments was 6.5 years. CONCLUSIONS: These results represent a comprehensive evaluation of the study of new drugs in children and demonstrate that many drugs continue to be approved without pediatric data. Our findings serve to inform approaches to strengthen adherence to PREA requirements.
BACKGROUND: Clinical trial registries can be used to monitor the production of trial evidence and signal when systematic reviews become out of date. However, this use has been limited to date due to the extensive manual review required to search for and screen relevant trial registrations. Our aim was to evaluate a new method that could partially automate the identification of trial registrations that may be relevant for systematic review updates. MATERIALS AND METHODS: We identified 179 systematic reviews of drug interventions for type 2 diabetes, which included 537 clinical trials that had registrations in ClinicalTrials.gov. Text from the trial registrations were used as features directly, or transformed using Latent Dirichlet Allocation (LDA) or Principal Component Analysis (PCA). We tested a novel matrix factorisation approach that uses a shared latent space to learn how to rank relevant trial registrations for each systematic review, comparing the performance to document similarity to rank relevant trial registrations. The two approaches were tested on a holdout set of the newest trials from the set of type 2 diabetes systematic reviews and an unseen set of 141 clinical trial registrations from 17 updated systematic reviews published in the Cochrane Database of Systematic Reviews. The performance was measured by the number of relevant registrations found after examining 100 candidates (recall@100) and the median rank of relevant registrations in the ranked candidate lists. RESULTS: The matrix factorisation approach outperformed the document similarity approach with a median rank of 59 (of 128,392 candidate registrations in ClinicalTrials.gov) and recall@100 of 60.9% using LDA feature representation, compared to a median rank of 138 and recall@100 of 42.8% in the document similarity baseline. In the second set of systematic reviews and their updates, the highest performing approach used document similarity and gave a median rank of 67 (recall@100 of 62.9%). CONCLUSIONS: A shared latent space matrix factorisation method was useful for ranking trial registrations to reduce the manual workload associated with finding relevant trials for systematic review updates. The results suggest that the approach could be used as part of a semi-automated pipeline for monitoring potentially new evidence for inclusion in a review update.
OBJECTIVES: Trial registries can be used to measure reporting biases and support systematic reviews, but 45% of registrations do not provide a link to the article reporting on the trial. We evaluated the use of document similarity methods to identify unreported links between ClinicalTrials.gov and PubMed. STUDY DESIGN AND SETTING: We extracted terms and concepts from a data set of 72,469 ClinicalTrials.gov registrations and 276,307 PubMed articles and tested methods for ranking articles across 16,005 reported links and 90 manually identified unreported links. Performance was measured by the median rank of matching articles and the proportion of unreported links that could be found by screening ranked candidate articles in order. RESULTS: The best-performing concept-based representation produced a median rank of 3 (interquartile range [IQR] 1-21) for reported links and 3 (IQR 1-19) for the manually identified unreported links, and term-based representations produced a median rank of 2 (1-20) for reported links and 2 (IQR 1-12) in unreported links. The matching article was ranked first for 40% of registrations, and screening 50 candidate articles per registration identified 86% of the unreported links. CONCLUSION: Leveraging the growth in the corpus of reported links between ClinicalTrials.gov and PubMed, we found that document similarity methods can assist in the identification of unreported links between trial registrations and corresponding articles.
OBJECTIVES: Describe the trends in pediatric sedation use over time and determine variation in use of procedural sedation across children's hospital emergency departments (EDs). METHODS: We analyzed ED data from 35 hospitals within the Pediatric Health Information System for patients <19 years old who received sedation medications and were discharged from 2009 to 2014. Patients with chronic comorbidities or undergoing intubation were excluded. We determined frequency and trends in use of sedation and compared these between EDs. Descriptive statistics with appropriate weighting were used. RESULTS: Of the 1 448 011 patients potentially requiring sedation who presented to the ED, 99 951 (7.9%) underwent procedural sedation. Medication usage in 2014 included ketamine (73.7%), fentanyl and midazolam (15.9%), ketofol (7.3%), and propofol (2.7%). Use of fentanyl and midazolam increased, whereas use of ketamine, pentobarbital, etomidate, chloral hydrate, and methohexital decreased over time. Significant variation exists in the use of sedation across hospitals; in 2014, the sedation rate ranged 0.2% to 32.0%, with a median of 8.0%. The diagnosis with the largest variation in procedural sedation use was dislocation, with sedation rates ranging from 2% to 35%. CONCLUSIONS: There is significant variability across pediatric EDs in the use of procedural sedation, suggesting sedations may be performed too often or too little in some hospitals.
OBJECTIVES: To explore the variation in diagnostic testing and management for males diagnosed with three testicular conditions (testicular torsion, appendix testis torsion, epididymitis/orchitis) using a large pediatric health care database. Diagnostic testing is frequently used in evaluation of the acute scrotum; however, there is likely variability in the use of these tests in the emergency department setting. METHODS: We conducted a cross-sectional study of males with the diagnoses of testicular torsion, appendix testis torsion, and epididymitis/orchitis. We identified emergency department patients in the Pediatric Health Information Systems (PHIS) database from 2010 to 2015 using diagnostic and procedure codes from the International Classification of Diseases Codes 9 and 10. Frequencies of diagnoses by demographic characteristics and of procedures and diagnostic testing (ultrasound, urinalysis, urine culture and sexually transmitted infection testing) by age group were calculated. We analyzed testing trends over time. RESULTS: We identified 17,000 males with the diagnoses of testicular torsion (21.7%), appendix testis torsion (17.9%), and epididymitis/orchitis (60.3%) from 2010 to 2015. There was substantial variation among hospitals in all categories of testing for each of the diagnoses. Overall, ultrasound utilization ranged from 33.1-100% and urinalysis testing ranged from 17.0-84.9% for all conditions. Only urine culture testing decreased over time for all three diagnoses (40.6% in 2010 to 31.5 in 2015). CONCLUSIONS: There was wide variation in the use of diagnostic testing across pediatric hospitals for males with common testicular conditions. Development of evaluation guidelines for the acute scrotum could decrease variation in testing.
OBJECTIVE: To compare the complexity and severity of presentation of children in general vs pediatric emergency departments (EDs). STUDY DESIGN: We performed a cross-sectional study of pediatric ED visits using the National Emergency Department Sample from 2008 to 2012. We classified EDs as "pediatric" if >75% of patients were <18 years old; all other EDs were classified as "general." The presence of an International Classification of Diseases, Ninth Revision code for a complex chronic condition was used as an indicator of patient complexity. Patient severity was evaluated with the severity classification system. In addition, rates of critical procedures and hospitalization were assessed. RESULTS: We identified 9.6 million encounters to pediatric EDs and 169 million to general EDs. Younger children account for a greater proportion of visits at pediatric EDs than general EDs; children <1 year of age account for 18% of visits to a pediatric ED compared with 9% of visits to a general ED (P < .01). Encounters at pediatric EDs had greater complexity (5% vs 2%; P < .01). Although severity classification system scores did not significantly differ by ED type, pediatric EDs had greater rates of hospitalization (10% vs 4%). CONCLUSIONS: Pediatric EDs provided care to a greater proportion of medically complex children than general EDs and had greater rates of hospitalization. This information may inform educational efforts in residency or postgraduate training to ensure high-quality care for children with complex health care needs.
BACKGROUND: Debates about the benefits and harms of mammography continue despite the accumulation of evidence. We sought to quantify the disagreement across systematic reviews of mammography and determine whether author or design characteristics were associated with conclusions that were favourable to the use of mammography for routine breast cancer screening. METHODS: We identified systematic reviews of mammography published between January 2000 and November 2015, and extracted information about the selection of evidence, age groups, the use of meta-analysis, and authors' professions and financial competing interest disclosures. Conclusions about specific age groups were graded as favourable if they stated that there were meaningful benefits, that benefits of mammography outweighed harms, or that harms were inconsequential. The main outcome measures were the proportions of favourable conclusions relative to review design and author characteristics. RESULTS: From 59 conclusions identified in 50 reviews, 42% (25/59) were graded as favourable by two investigators. Among the conclusions produced by clinicians, 63% (12/19) were graded as favourable compared to 32% (13/40) from other authors. In the 50-69 age group where the largest proportion of systematic reviews were focused, conclusions drawn by authors without financial competing interests (odds ratio 0.06; 95% CI 0.07-0.56) and non-clinicians (odds ratio 0.11; 95% CI 0.01-0.84) were less likely to be graded as favourable. There was no trend in the proportion of favourable conclusions over the period, and we found no significant association between review design characteristics and favourable conclusions. CONCLUSIONS: Differences in the conclusions of systematic reviews of the evidence for mammography have persisted for 15 years. We found no strong evidence that design characteristics were associated with greater support for the benefits of mammography in routine breast cancer screening. Instead, the results suggested that the specific expertise and competing interests of the authors influenced the conclusions of systematic reviews.
Increasingly, biobanks are being developed to support organized collections of biological specimens and associated clinical information on broadly consented, diverse patient populations. We describe the implementation of a pediatric biobank, comprised of a fully-informed patient cohort linking specimens to phenotypic data derived from electronic health records (EHR). The Biobank was launched after multiple stakeholders' input and implemented initially in a pilot phase before hospital-wide expansion in 2016. In-person informed consent is obtained from all participants enrolling in the Biobank and provides permission to: (1) access EHR data for research; (2) collect and use residual specimens produced as by-products of routine care; and (3) share de-identified data and specimens outside of the institution. Participants are recruited throughout the hospital, across diverse clinical settings. We have enrolled 4900 patients to date, and 41% of these have an associated blood sample for DNA processing. Current efforts are focused on aligning the Biobank with other ongoing research efforts at our institution and extending our electronic consenting system to support remote enrollment. A number of pediatric-specific challenges and opportunities is reviewed, including the need to re-consent patients when they reach 18 years of age, the ability to enroll family members accompanying patients and alignment with disease-specific research efforts at our institution and other pediatric centers to increase cohort sizes, particularly for rare diseases.
OBJECTIVES: To measure exclusion of elderly adults from randomized trials studying drug interventions for ischemic heart disease (IHD) and describe the characteristics of these trials. DESIGN: Cross-sectional analysis. SETTING: Interventional clinical trials studying a drug intervention for IHD that started in 2006 and after were identified in ClinicalTrials.gov. Data were extracted on study features, including age-based inclusion criteria. Data on participants and their age distribution were collected from trial publications, investigator inquiry, and result data in ClinicalTrials.gov. PARTICIPANTS: Individuals aged 65 and older. MEASUREMENTS: Proportion of trials excluding individuals based on age, mean age of trial participants, and proportion of enrolled participants aged 65 and older and 75 and older. RESULTS: Of 839 identified trials, 446 (53%) explicitly excluded elderly adults. The most-frequent upper age limits were 80 (n = 164) and 75 (n = 114), with a median upper age limit of 80 (interquartile range 75-80). Trials with upper age limit exclusions tended to be smaller (median number of participants 100 vs 201, P < .001) and were more likely to be funded primarily by nonindustry sources (78.3% vs 70.0%, P = .006). The overall mean age of trial participants was 62.7 (mean maximum age 74). The estimated proportion of participants aged 65 and older was 42.5% and the estimated proportion aged 75 and older was 12.3%. CONCLUSION: Despite the high burden of IHD in elderly adults, the majority of drug trials do not enroll participants reflective of age-related prevalence of the disease.
BACKGROUND: Studies measuring the completeness and consistency of trial registration and reporting rely on linking registries with bibliographic databases. In this systematic review, we quantified the processes used to identify these links. METHODS: PubMed and Embase databases were searched from inception to May 2016 for studies linking trial registries with bibliographic databases. The processes used to establish these links were categorised as automatic when the registration identifier was available in the bibliographic database or publication, or manual when linkage required inference or contacting of trial investigators. The number of links identified by each process was extracted where available. Linear regression was used to determine whether the proportions of links available via automatic processes had increased over time. RESULTS: In 43 studies that examined cohorts of registry entries, 24 used automatic and manual processes to find articles; 3 only automatic; and 11 only manual (5 did not specify). Twelve studies reported results for both manual and automatic processes and showed that a median of 23% (range from 13 to 42%) included automatic links to articles, while 17% (range from 5 to 42%) of registry entries required manual processes to find articles. There was no evidence that the proportion of registry entries with automatic links had increased (R (2) = 0.02, p = 0.36). In 39 studies that examined cohorts of articles, 21 used automatic and manual processes; 9 only automatic; and 2 only manual (7 did not specify). Sixteen studies reported numbers for automatic and manual processes and indicated that a median of 49% (range from 8 to 97%) of articles had automatic links to registry entries, and 10% (range from 0 to 28%) required manual processes to find registry entries. There was no evidence that the proportion of articles with automatic links to registry entries had increased (R (2) = 0.01, p = 0.73). CONCLUSIONS: The linkage of trial registries to their corresponding publications continues to require extensive manual processes. We did not find that the use of automatic linkage has increased over time. Further investigation is needed to inform approaches that will ensure publications are properly linked to trial registrations, thus enabling efficient monitoring of trial reporting.
OBJECTIVES: Trial registries can be used to measure reporting biases and support systematic reviews but 45% of registrations do not provide a link to the article reporting on the trial. We evaluated the use of document similarity methods to identify unreported links between ClinicalTrials.gov and PubMed. STUDY DESIGN AND SETTING: We extracted terms and concepts from a dataset of 72,469 ClinicalTrials.gov registrations and 276,307 PubMed articles, and tested methods for ranking articles across 16,005 reported links and 90 manually-identified unreported links. Performance was measured by the median rank of matching articles, and the proportion of unreported links that could be found by screening ranked candidate articles in order. RESULTS: The best performing concept-based representation produced a median rank of 3 (IQR 1-21) for reported links and 3 (IQR 1-19) for the manually-identified unreported links, and term-based representations produced a median rank of 2 (1-20) for reported links and 2 (IQR 1-12) in unreported links. The matching article was ranked first for 40% of registrations, and screening 50 candidate articles per registration identified 86% of the unreported links. CONCLUSIONS: Leveraging the growth in the corpus of reported links between ClinicalTrials.gov and PubMed, we found that document similarity methods can assist in the identification of unreported links between trial registrations and corresponding articles.
Conflicts of interest held by researchers remain a focus of attention in clinical research. Biases related to these relationships have the potential to directly impact the quality of healthcare by influencing decision-making, yet conflicts of interest remain under-reported, inconsistently described, and difficult to access. Initiatives aimed at improving the disclosure of researcher conflicts of interest are still in their infancy but represent a vital reform that must be addressed before potential biases associated with conflicts of interest can be mitigated, and trust in the impartiality of clinical evidence restored. In this review, we examine the prevalence of conflicts of interest, evidence of the effects that disclosed and undisclosed conflicts of interest have had on the reporting of clinical evidence, and the emerging approaches for improving the completeness and consistency of disclosures. Through this review of emerging technologies, we recognize a growing interest in publicly-accessible registries for researcher conflicts of interest, and propose five desiderata aimed at maximizing the value of such registries: mandates for ensuring that researchers keep their records up to date; transparent records that are made available to the public; interoperability to allow researchers, bibliographic databases, and institutions to interact with the registry; a consistent taxonomy for describing different classes of conflicts of interest, and the ability to automatically generate conflicts of interest statements for use in published articles.
BACKGROUND: Trial discontinuation and nonpublication represent potential waste in research resources and lead to compromises in medical evidence. Pediatric trials may be particularly vulnerable to these outcomes given the challenges encountered in conducting trials in children. We aimed to determine the prevalence of discontinuation and nonpublication of randomized clinical trials (RCTs) conducted in pediatric populations. METHODS: Retrospective, cross-sectional study of pediatric RCTs registered in ClinicalTrials.gov from 2008 to 2010. Data were collected from the registry and associated publications identified (final search on September 1, 2015). RESULTS: Of 559 trials, 104 (19%) were discontinued early, accounting for an estimated 8369 pediatric participants. Difficulty with patient accrual (37%) was the most commonly cited reason for discontinuation. Trials were less likely to be discontinued if they were funded by industry compared with academic institutions (odds ratio [OR] 0.46, 95% confidence interval [CI] 0.27-0.77). Of the 455 completed trials, 136 (30%) were not published, representing 69 165 pediatric participants. Forty-two unpublished trials posted results on ClinicalTrials.gov. Trials funded by industry were more than twice as likely to result in nonpublication at 24 and 36 months (OR 2.21, 95% CI 1.35-3.64; OR 3.12, 95% CI 1.6-6.08, respectively) and had a longer mean time to publication compared with trials sponsored by academia (33 vs 24 months, P < .001). CONCLUSIONS: In this sample of pediatric RCTs, discontinuation and nonpublication were common, with thousands of children exposed to interventions that did not lead to informative or published findings. Trial funding source was an important determinant of these outcomes, with both academic and industry sponsors contributing to inefficiencies.
OBJECTIVES: Children treated with chronic medications are at risk of drug-drug interactions (DDIs) when hospitalized with an acute illness and prescribed new medications. We aimed to measure the prevalence of potential DDIs (pDDIs) among hospitalized children treated with antiepileptic drugs (AEDs) and to evaluate the impact of computerized physician order entry (CPOE) on pDDIs. METHODS: We analyzed a national sample of pediatric hospitalizations from 2005 to 2012 associated with administration of an AED and identified those prescribed a second medication with risk of a DDI. The prevalence of hospitalizations associated with a pDDI was calculated for each AED. We identified the drugs most commonly implicated in pDDIs and factors associated with pDDIs. Rates of pDDIs were measured in pre- and post-CPOE implementation periods. RESULTS: A pDDI was identified in 181 380 (41.7%) hospitalizations associated with the use of an AED, with 117 880 (27.1%) classified as severe pDDIs. AEDs most often implicated with a pDDI were phenobarbital, valproic acid, and phenytoin. Hospitalizations with pDDIs were associated with increased length of stay and a greater number of medications, ICU admissions, and operating room procedures. The implementation of CPOE did not result in a change in the rate of pDDIs (42.7% before versus 40.8% after; P = .48). CONCLUSIONS: Children treated with AEDs are at risk of pDDIs while hospitalized. The use of CPOE has not been associated with a significant decrease in the rate of pDDIs. Additional investigation to better define the impact of pDDIs and to advance development of clinical decision support within CPOE systems is warranted.
OBJECTIVES: Research findings are not consistently adopted in the clinical setting and there is a gap between best evidence and clinical practice across a range of conditions and settings. A number of factors may contribute to this discrepancy, including the direction of the research findings (i.e., whether positive or negative for an intervention). The objectives of this study were to measure the translation of results from randomized controlled trials (RCTs) into clinical care and to determine whether the direction of the trial findings influence the uptake of research reports into clinical practice. METHODS: This was a retrospective study of clinical care provided in emergency departments (EDs) across the United States with data collected by the National Hospital Ambulatory Medical Care Survey from 1992 to 2010. RCTs published in journals with the highest impact factors and conducted in ED settings were selected and data were extracted on the interventions under study, the patient populations examined, and the trial findings. Changes in clinical practice corresponding to the RCT results were measured by comparing the rates of treatment with the intervention during the 3-year period before and after publication of the trial. RESULTS: Twenty-one RCTs met the inclusion criteria. Ten studies reported positive interventions, of which nine (90%) were associated with an increased ED use of the intervention after trial publication. Four studies showing the lack of benefit of interventions were not used in ED practice prior to the trial and practice did not change in the postpublication period. The remaining eight trials presented negative findings or results comparing two different interventions, and of these, three (38%) were associated with small changes in the ED use of the interventions, consistent with the trial results. CONCLUSIONS: In the ED setting, results of RCTs published in high-impact journals are more likely to be translated into clinical care when they demonstrate the benefits of an intervention. Our findings indicate that direction of research evidence is an important factor when evaluating knowledge uptake into clinical practice.