Do health care institutions value research? A mixed methods study of barriers and facilitators to methodological rigor in pediatric randomized trials

BACKGROUND: Pediatric randomized controlled trials (RCTs) are susceptible to a high risk of bias. We examined the barriers and facilitators that pediatric trialists face in the design and conduct of unbiased trials. METHODS: We used a mixed methods design, with semi-structured interviews building upon the results of a quantitative survey. We surveyed Canadian (n=253) and international (n=600) pediatric trialists regarding their knowledge and awareness of bias and their perceived barriers and facilitators in conducting clinical trials. We then interviewed 13 participants from different subspecialties and geographic locations to gain a more detailed description of how their experiences and attitudes towards research interacted with trial design and conduct. RESULTS: The survey response rate was 23.0% (186/807). 68.1% of respondents agreed that bias is a problem in pediatric RCTs and 72.0% felt that there is sufficient evidence to support changing some aspects of how trials are conducted. Knowledge related to bias was variable, with inconsistent awareness of study design features that may introduce bias into a study. Interview participants highlighted a lack of formal training in research methods, a negative research culture, and the pragmatics of trial conduct as barriers. Facilitators included contact with knowledgeable and supportive colleagues and infrastructure for research. CONCLUSIONS: A lack of awareness of bias and negative attitudes towards research present significant barriers in terms of conducting methodologically rigorous pediatric RCTs. Knowledge translation efforts must focus on these issues to ensure the relevance and validity of trial results

Treatment in the pediatric emergency department is evidence based: a retrospective analysis

BACKGROUND: Our goal was to quantify the evidence that is available to the physicians of a pediatric emergency department (PED) in making treatment decisions. Further, we wished to ascertain what percentage of evidence for treatment provided in the PED comes from pediatric studies. METHODS: We conducted a retrospective chart review of randomly selected patients seen in the PED between January 1 and December 31, 2002. The principal investigator identified a primary diagnosis and primary intervention for each chart. A thorough literature search was then undertaken with respect to the primary intervention. If a randomized control trial (RCT) or a systematic review was found, the intervention was classified as level I evidence. If no RCT was found, the intervention was assessed by an expert committee who determined its appropriateness based on face validity (RCTs were unanimously judged to be both unnecessary and, if a placebo would have been involved, unethical). These interventions were classified as level II evidence. Interventions that did not fall into either above category were classified as level III evidence. RESULTS: Two hundred and sixty-two patient charts were reviewed. Of these, 35.9% did not receive a primary intervention. Of the 168 interventions assessed, 80.4% were evidence-based (level I), 7.1% had face validity (level II) and 12.5% had no supporting evidence (level III). Of the evidence-based interventions, 83.7% were supported by studies with mostly pediatric patients. CONCLUSION: Our study demonstrates that a substantial proportion of PED treatment decisions are evidence-based, with most based on studies in pediatric patients. Also, a large number of patients seen in the PED receive no intervention

Controlled Trials in Children: Quantity, Methodological Quality and Descriptive Characteristics of Pediatric Controlled Trials Published 1948-2006

BACKGROUND: The objective of this study was to describe randomized controlled trials (RCTs) and controlled clinical trials (CCTs) in child health published between 1948 and 2006, in terms of quantity, methodological quality, and publication and trial characteristics. We used the Trials Register of the Cochrane Child Health Field for overall trends and a sample from this to explore trial characteristics in more detail. METHODOLOGY/PRINCIPAL FINDINGS: We extracted descriptive data on a random sample of 578 trials. Ninety-six percent of the trials were published in English; the percentage of child-only trials was 90.5%. The most frequent diagnostic categories were infectious diseases (13.2%), behavioural and psychiatric disorders (11.6%), neonatal critical care (11.4%), respiratory disorders (8.9%), non-critical neonatology (7.9%), and anaesthesia (6.5%). There were significantly fewer child-only studies (i.e., more mixed child and adult studies) over time (P = 0.0460). The proportion of RCTs to CCTs increased significantly over time (P<0.0001), as did the proportion of multicentre trials (P = 0.002). Significant increases over time were found in methodological quality (Jadad score) (P<0.0001), the proportion of double-blind studies (P<0.0001), and studies with adequate allocation concealment (P<0.0001). Additionally, we found an improvement in reporting over time: adequate description of withdrawals and losses to follow-up (P<0.0001), sample size calculations (P<0.0001), and intention-to-treat analysis (P<0.0001). However, many trials still do not describe their level of blinding, and allocation concealment was inadequately reported in the majority of studies across the entire time period. The proportion of studies with industry funding decreased slightly over time (P = 0.003), and these studies were more likely to report positive conclusions (P = 0.028). CONCLUSIONS/SIGNIFICANCE: The quantity and quality of pediatric controlled trials has increased over time; however, much work remains to be done, particularly in improving methodological issues around conduct and reporting of trials

Determining a Bayesian predictive power stopping rule for futility in a non-inferiority trial with binary outcomes.

Background/Aims: Non-inferiority trials investigate whether a novel intervention, which typically has other benefits (i.e., cheaper or safer), has similar clinical effectiveness to currently available treatments. In situations where interim evidence in a non-inferiority trial suggests that the novel treatment is truly inferior, ethical concerns with continuing randomisation to the inferior intervention are raised. Thus, if interim data indicate that concluding non-inferiority at the end of the trial is unlikely, stopping for futility should be considered. To date, limited examples are available to guide the development of stopping rules for non-inferiority trials. Methods: We used a Bayesian predictive power approach to develop a stopping rule for futility for a trial collecting binary outcomes. We evaluated the frequentist operating characteristics of the stopping rule to ensure control of the Type I and Type II error. Our case study is the Intranasal Ketamine for Procedural Sedation trial (INK trial), a non-inferiority trial designed to assess the sedative properties of ketamine administered using two alternative routes. Results: We considered implementing our stopping rule after the INK trial enrols 140 patients out of 560. The trial would be stopped if 12 more patients experience a failure on the novel treatment compared to standard care. This trial has a type I error rate of 2.2% and a power of 80%. Conclusions: Stopping for futility in non-inferiority trials reduces exposure to ineffective treatments and preserves resources for alternative research questions. Futility stopping rules based on Bayesian predictive power are easy to implement and align with trial aims. Trial registration: ClinicalTrials.gov NCT02828566 July 11, 2016

A descriptive analysis of child-relevant systematic reviews in the Cochrane Database of Systematic Reviews

<p>Abstract</p> <p>Background</p> <p>Systematic reviews (SRs) are considered an important tool for decision-making. There has been no recent comprehensive identification or description of child-relevant SRs. A description of existing child-relevant SRs would help to identify the extent of available child-relevant evidence available in SRs and gaps in the evidence base where SRs are required. The objective of this study was to describe child-relevant SRs from the Cochrane Database of Systematic Reviews (CDSR, Issue 2, 2009).</p> <p>Methods</p> <p>SRs were assessed for relevance using pre-defined criteria. Data were extracted and entered into an electronic form. Univariate analyses were performed to describe the SRs overall and by topic area.</p> <p>Results</p> <p>The search yielded 1666 SRs; 793 met the inclusion criteria. 38% of SRs were last assessed as up-to-date prior to 2007. Corresponding authors were most often from the UK (41%). Most SRs (59%) examined pharmacological interventions. 53% had at least one external source of funding. SRs included a median of 7 studies (IQR 3, 15) and 679 participants (IQR 179, 2833). Of all studies, 48% included only children, and 27% only adults. 94% of studies were published in peer-reviewed journals. Primary outcomes were specified in 72% of SRs. Allocation concealment and the Jadad scale were used in 97% and 25% of SRs, respectively. Adults and children were analyzed separately in 12% of SRs and as a subgroup analysis in 14%. Publication bias was assessed in only 14% of SRs. A meta-analysis was conducted in 68% of SRs with a median of 5 trials (IQR 3, 9) each. Variations in these characteristics were observed across topic areas.</p> <p>Conclusions</p> <p>We described the methodological characteristics and rigour of child-relevant reviews in the CDSR. Many SRs are not up-to-date according to Cochrane criteria. Our study describes variation in conduct and reporting across SRs and reveals clinicians' ability to access child-specific data.</p

A Bayesian response-adaptive dose-finding and comparative effectiveness trial

Background/Aims: Combinations of treatments that have already received regulatory approval can offer additional benefit over Each of the treatments individually. However, trials of these combinations are lower priority than those that develop novel therapies, which can restrict funding, timelines and patient availability. This article develops a novel trial design to facilitate the evaluation of New combination therapies. This trial design combines elements of phase II and phase III trials to reduce the burden of evaluating combination therapies, while also maintaining a feasible sample size. This design was developed for a randomised trial that compares the properties of three combination doses of ketamine and dexmedetomidine, given intranasally, to ketamine delivered intravenously for children undergoing a closed reduction for a fracture or dislocation. Methods: This trial design uses response-adaptive randomisation to evaluate different dose combinations and increase the information collected for successful novel drug combinations. The design then uses Bayesian dose-response modelling to undertake a comparative effectiveness analysis for the most successful dose combination against a relevant comparator. We used simulation methods determine the thresholds for adapting the trial and making conclusions. We also used simulations to evaluate the probability of selecting the dose combination with the highest true effectiveness the operating characteristics of the design and its Bayesian predictive power. Results: With 410 participants, five interim updates of the randomisation ratio and a probability of effectiveness of 0.93, 0.88 and 0.83 for the three dose combinations, we have an 83% chance of randomising the largest number of patients to the drug with the highest probability of effectiveness. Based on this adaptive randomisation procedure, the comparative effectiveness analysis has a type I error of less than 5% and a 93% chance of correcting concluding non-inferiority, when the probability of effectiveness for the optimal combination therapy is 0.9. In this case, the trial has a greater than 77% chance of meeting its dual aims of dose-finding and comparative effectiveness. Finally, the Bayesian predictive power of the trial is over 90%. Conclusions: By simultaneously determining the optimal dose and collecting data on the relative effectiveness of an intervention, we can minimise administrative burden and recruitment time for a trial. This will minimise the time required to get effective, safe combination therapies to patients quickly. The proposed trial has high potential to meet the dual study objectives within a feasible overall sample size

Nebulised hypertonic saline solution for acute bronchiolitis in infants (Review)

Acute viral bronchiolitis is the most common lower respiratory tract infection in infants up to two years old. Currently there is no effective treatment so standard treatment remains supportive care. Airway oedema (abnormal accumulation of fluid) and mucus plugging can cause wheezing and difficulty breathing in these patients. Nebulised hypertonic saline may be a beneficial treatment to manage acute bronchiolitis because it can improve airway hygiene. This review was conducted to assess the effects of hypertonic (≥ 3%) saline solution administered via a nebuliser in infants with acute bronchiolitis, compared with nebulised normal (0.9%) saline. The establishment of a therapeutic role for hypertonic saline solution may provide a cheap and effective therapy for these patients. We included 11 randomised trials involving 1090 infants with mild to moderate bronchiolitis. All but one of the 11 trials are considered as high-quality studies with low risk of error (i.e. bias) in their conclusions. Meta-analysis suggests that nebulised hypertonic saline could lead to a reduction of 1.2 days in the mean length of hospital stay among infants hospitalised for non-severe acute bronchiolitis and improve the clinical severity score in both outpatient and inpatient populations. No significant short-term effects (at 30 to 120 minutes) of one to three doses of nebulised hypertonic saline were observed among emergency department patients. However, more trials are needed to address this question. There were no significant adverse effects noted with the use of nebulised hypertonic saline when administered along with bronchodilators. Given the clinically relevant benefit and good safety profile, nebulised hypertonic saline used in conjunction with bronchodilators should be considered an effective and safe treatment for infants with mild to moderate acute viral bronchiolitis