Trials In Emergency Medicine Research Articles

Sex and gender reporting in UK emergency medicine trials from 2010 to 2023: a systematic review

BackgroundFemale participants are underrepresented in randomised control trials conducted in urgent care settings. Although sex and gender are frequently reported within demographic data, it is less common for primary outcomes...

Quality and Publication of Emergency Medicine Trials Registered in ClinicalTrials.gov

IntroductionPromoting emergency medicine (EM) clinical trials research remains a priority. To characterize the status of clinical EM research, this study assessed trial quality, funding source, and publication of EM clinical trials and compared EM and non-EM trials on these key metrics. We also examined the volume of EM trials and their subspecialty areas.MethodsWe abstracted data from ClinicalTrials.gov (February 2000 – September 2013) and used individual study National Clinical Trial numbers to identify published trials (January 2007 – September 2016). We used descriptive statistics and chi-square tests to examine study characteristics by EM and non-EM status, and Kaplan-Meier curves and log-rank tests to compare time to publication of completed EM and non-EM studies.ResultsWe found 638 interventional EM trials and 59,512 non-EM interventional trials conducted in the United States between February 2000 and September 2013, registered on ClinicalTrials.gov. EM studies were significantly less likely than non-EM studies to be National Institutes of Health-funded or to evaluate a drug or biologic. However, EM studies had significantly larger sample sizes, and were significantly more likely to use randomization and blinding. Overall, 34.3% of EM and 26.0% of non-EM studies were published in peer-reviewed journals. By subspecialty, more EM trials concerned medical/surgical and psychiatric/neurological conditions than trauma.ConclusionAlthough EM studies were less likely to have received federal or industry funding, and the EM portfolio consisted of only 638 trials over the 14-year study period, the quality of EM trials surpassed that of non-EM trials, based on indices such as randomization and blinding. This novel finding bodes well for the future of clinical EM research, as does the higher proportion of published EM than non-EM trials. Our study also revealed that trauma studies were under-represented among EM studies. Periodic assessment of EM trials with the metrics used here could provide an informative and valuable longitudinal view of progress in clinical EM research.

Bayesian group sequential designs for phase III emergency medicine trials: a case study using the PARAMEDIC2 trial

BackgroundPhase III trials often require large sample sizes, leading to high costs and delays in clinical decision-making. Group sequential designs can improve trial efficiency by allowing for early stopping for efficacy and/or futility and thus may decrease the sample size, trial duration and associated costs. Bayesian approaches may offer additional benefits by incorporating previous information into the analyses and using decision criteria that are more practically relevant than those used in frequentist approaches. Frequentist group sequential designs have often been used for phase III studies, but the use of Bayesian group sequential designs is less common. The aim of this work was to explore how Bayesian group sequential designs could be constructed for phase III trials conducted in emergency medicine.MethodsThe PARAMEDIC2 trial was a phase III randomised controlled trial that compared the use of adrenaline to placebo in out-of-hospital cardiac arrest patients on 30-day survival rates. It used a frequentist group sequential design to allow early stopping for efficacy or harm. We constructed several alternative Bayesian group sequential designs and studied their operating characteristics via simulation. We then virtually re-executed the trial by applying the Bayesian designs to the PARAMEDIC2 data to demonstrate what might have happened if these designs had been used in practice.ResultsWe produced three alternative Bayesian group sequential designs, each of which had greater than 90% power to detect the target treatment effect. A Bayesian design which performed interim analyses every 500 patients recruited produced the lowest average sample size. Using the alternative designs, the PARAMEDIC2 trial could have declared adrenaline superior for 30-day survival with approximately 1500 fewer patients.ConclusionsUsing the PARAMEDIC2 trial as a case study, we demonstrated how Bayesian group sequential designs can be constructed for phase III emergency medicine trials. The Bayesian framework enabled us to obtain efficient designs using decision criteria based on the probability of benefit or harm. It also enabled us to incorporate information from previous studies on the treatment effect via the prior distributions. We recommend the wider use of Bayesian approaches in phase III clinical trials.Trial registrationPARAMEDIC2 Trial registration ISRCTN, ISRCTN73485024. Registered 13 March 2014, http://www.isrctn.com/ISRCTN73485024

The Results of Randomized Controlled Trials in Emergency Medicine Are Frequently Fragile

Randomized controlled trials govern evidence-based clinical practice, and it is therefore critical that their results be robust. We aim to investigate the fragility of randomized controlled trials in emergency medicine by determining how often significance would be nullified with small changes in outcomes using the fragility index. We conducted a methodological systematic review of randomized controlled trials in emergency medicine published in the top10 general medicine journals and the top 10 emergency medicine journals. Inclusion criteria required that trials be emergency medicine studies structured with a 2-arm or 2-by-2 factorial design and report at least 1 statistically significant dichotomous outcome. A total of 180 trials met inclusion criteria. The median fragility index across all trials in emergency medicine was 4 (interquartile range [IQR] 2 to 10) and the median sample size was 140 (IQR 69.5 to 286). For trials from general medicine journals (n=32), the median fragility index was 9 (IQR 4 to 16.5) and the median sample size was 415.5 (IQR 219.5 to 901); for trials from emergency medicine journals (n=148), the median fragility index was 4 (IQR 1 to 9) and the median sample size was 119 (IQR 60 to 227.25). One third of all trials (62/180) had a loss to follow-up that was greater than or equal to the fragility index. There was a modest correlation between fragility index and total number of events (r=0.36; 95% confidence interval [CI] 0.23 to 0.48) and a weak correlation between fragility index and total sample size (r=0.26; 95% CI 0.12 to 0.39). There was no correlation between fragility index and either P value (r=-0.14; 95% CI -0.28 to -0.006) or Science Citation Index (r=0.07; 95% CI -0.08 to 0.22). The statistical significance of the results of randomized controlled trials in emergency medicine was often contingent on a small number of events. Until frequentist interpretation of clinical trials is replaced with Bayesian analysis, the fragility index may have utility as a tool to aid clinicians in assessing the robustness of randomized controlled trials in emergency medicine when considered in conjunction with the fragility quotient and other reported metrics.

Regulations and ethics surrounding cluster randomized controlled trials and other clinical trials in emergency medicine

Introduction: A cluster randomized controlled trial is performed as an intervention in a group of subjects (collectively labeled as a “cluster”), rather than for an individual. Despite practical challenges and ethical issues inherent in obtaining informed consent for patient participation in cluster randomized controlled trials, many countries and regions have aggressively pursued these trials to increase the quality of medical evidence. However, Japan has yet to create an established protocol for obtaining informed consent for clinical trials in emergency medicine, including resuscitation science, and cluster randomized controlled trials. The aim of this study was to develop a method for obtaining informed consent in cluster randomized controlled trials of resuscitation science in Japan and other regions.

Can emergency medicine research benefit from adaptive design clinical trials?

BackgroundAdaptive design clinical trials use preplanned interim analyses to determine whether studies should be stopped or modified before recruitment is complete. Emergency medicine trials are well suited to these designs...

Clinical trials in emergency medicine: Comparison among European countries, United States and Japan

Clinical trials in emergency medicine: Comparison among European countries, United States and Japan

The Protocol Acuity Scoring Tool for Prediction of Emergency Medicine Research Study Workload

It is difficult to predict a priori how much work will be required for a proposed emergency medicine research study. This complicates resource allocation and feasibility assessment. The Protocol Acuity Scoring Tool (PAST) is a 32-item tool that assesses six major areas of conducting a clinical trial from startup to follow-up each on a scale from 1 to 3. It has been proposed as an instrument to predict the workload required for a proposed trial. We sought to determine the inter-rater reliability of the PAST score among multiple members of a research team and compare PAST scores to gestalt estimates of trial workload. Design: Prospective inter-rater reliability study. Raters: Four members of our clinical trials team each rated 5 different study protocols first by gestalt (using a range of 32-96) and then using the PAST score. The raters have a range of clinical trial experience (2 to 15 years) and training backgrounds (Clinical Research Coordinator, Registered Nurse, Medical Doctorate). The protocols included 3 randomized controlled treatment trials and 2 diagnostic blood marker studies that were familiar to the study team. Each protocol was independently scored by each rater using the PAST. Analysis: Free-marginal multirater kappa was calculated for inter-rater agreement for each PAST item. Gestalt estimates of protocol workload (mean, range and 95% confidence intervals) were compared to PAST scores. The range and median kappa for each major area are shown in Table 1. In general, the PAST score items showed poor inter-rater agreement with the exception of four items with a kappa >0.70: estimated enrollment, study arms, recruitment feasibility, and randomization. Six other items showed fair inter-rater agreement with a kappa >0.40. PAST scores tended to be lower and in a more narrow range than gestalt scores but were not significantly different. The PAST showed poor inter-rater agreement and did not provide different information from gestalt ratings. Future work should seek to tailor it to emergency medicine trials and create more reproducible items.Table 1Kappa ValuesNumber of ItemsMinimumMaximumMedianFeasibility10-0.050.750.23Pre-Start-up50.000.350.05Recruitment20.450.700.58Start-up40.250.700.45Study Process70.000.450.20Follow-up40.100.500.28 Open table in a new tab Table 2Gestalt and PAST Scores for each ProtocolStudies12345GestaltMean81.353.368.375.348.5Range73-8543-7058-8066-8540-6495% CI72.2 to 90.333.6 to 72.950.9 to 85.661.3 to 89.230.4 to 66.6PAST ScoresMean69.547.862.571.547.0Range55-8142-5160-6668-7646-4895% CI51.9 to 87.141.5 to 54.057.7 to 67.365.6 to 77.445.7 to 48.395% CI= 95% Confidence Intervals Open table in a new tab

Influence of Adaptive Analysis on Unnecessary Patient Recruitment: Reanalysis of the RATPAC Trial

Recruitment to clinical trials is a challenging but essential activity in emergency medicine. Conventional fixed-sample trials may continue to recruit patients after efficacy has been demonstrated or when further recruitment is futile. Adaptive trials make use of emerging information to modify aspects of a trial or terminate it prematurely, potentially resulting in savings in terms of sample size, time, and cost. We aim to use sequential testing procedures to reanalyze data from a fixed-sample trial, the Randomised Assessment of Treatment Using Panel Assay of Cardiac Markers (RATPAC) trial, and investigate the potential for adaptive designs to reduce unnecessary recruitment. The trial was reanalyzed with a triangular group sequential design, with interim analyses planned every 3 months. Patients were analyzed in the order in which they entered the original trial. We found that the RATPAC trial could potentially have stopped 1 year earlier, with 722 patients enrolled compared with 2,243 patients in the original trial, making a potential saving of approximately $390,000. Estimates of effect were similar, and the qualitative conclusions of the original and group sequential RATPAC trials were in agreement. However, the group sequential approach is not without limitations and would have resulted in less precise estimates of effect and less information available for the subsequent evaluation of secondary endpoints. Sequential designs are well suited in emergency medicine because of the rapidly obtained outcomes and the need to avoid unnecessary recruitment. We recommend that group sequential designs be considered for clinical trials in emergency medicine.

Informed consent for clinical trials in acute coronary syndromes and stroke following the European Clinical Trials Directive: investigators' experiences and attitudes.

BackgroundDuring clinical trials in emergency medicine, providing appropriate oral and written information to a patient is usually a challenge. There is little published information regarding patients' opinions and competence to provide informed consent, nor on physicians' attitudes towards the process. We have investigated the problem of obtaining consent from patients in emergency-setting clinical trials (such as acute coronary syndromes (ACS) and stroke) from a physicians' perspective.MethodsA standardised anonymous 14-item questionnaire was distributed to Polish cardiac and stroke centres.ResultsTwo hundred and fourteen informative investigator responses were received. Of these investigators, 73.8% had experience with ACS and 25.2% had experience with acute stroke trials (and 1% with both fields). The complete model of informed consent (embracing all aspects required by Good Clinical Practice (GCP) and law) was used in 53.3% of cases in emergency settings, whereas the legal option of proxy consent was not used at all. While less than 15% of respondents considered written information to have been fully read by patients, 80.4% thought that the amount of information being given to emergency patients is too lengthy. Although there is no legal obligation, more than half of the investigators sought parallel consent (assent) from patients' relatives. Most investigators confirmed that they would adopt the model proposed by the GCP guidelines: abbreviated verbal and written consent in emergency conditions with obligatory "all-embracing" deferred consent to continue the trial once the patient is able to provide it. However, this model would not follow current Polish and European legislation.ConclusionAn update of national and European regulations is required to enable implementation of the emergency trial consent model referred to in GCP guidelines.

Inappropriate Claims of Equivalence/Non-Inferiority in Failed Randomized Trials in Emergency Medicine

Inappropriate Claims of Equivalence/Non-Inferiority in Failed Randomized Trials in Emergency Medicine

The birth of the NETT: NIH-funded network will launch emergency neurological trials

The birth of the NETT: NIH-funded network will launch emergency neurological trials

Publication Bias of Randomized Controlled Trials in Emergency Medicine

Publication Bias of Randomized Controlled Trials in Emergency Medicine

Publication Bias of Randomized Controlled Trials in Emergency Medicine

To determine the publication status and time to publication of randomized controlled trials (RCTs) that were presented at the Society for Academic Emergency Medicine (SAEM) meetings from 1995 to 2003. The impact of positive-outcome bias, time-lag bias, and gray literature bias also was assessed. Retrospective cohort study of RCT abstracts presented at nine SAEM scientific meetings. Electronic searches identified publications from the abstracts. Of 4,399 abstracts, 383 (8.7%; 95% confidence interval [CI] = 7.8% to 9.5%) were identified as RCTs. One hundred ninety-four (50.7%; 95% CI = 45.7% to 55.7%) were subsequently published up to May 2004. The median time to publication was 32 months (95% CI = 23 to 41), with 59% of RCT abstracts published within five years of presentation. No evidence of positive-outcome bias or time-lag bias was identified; however, changes from abstract to manuscript were found. Manuscripts were less likely to endorse the experimental intervention than were abstracts (OR, 0.2; 95% CI = 0.0 to 0.6). The proportion of emergency medicine RCT abstracts published is slightly lower than that for other biomedical specialties; however, biases reported by investigators in other biomedical areas do not appear to be as problematic in emergency medicine research. Differences between conclusions from abstracts and manuscripts must be considered when employing meeting abstracts as a source of evidence for future research or for systematic reviews in emergency medicine.

Analysis of two-treatment, two-period crossover trials in emergency medicine

In an AB/BA crossover trial, patients are randomly assigned to receive either treastment A in the first period followed by treatment B in the second period or treatment B in the first period followed by treatment A in the second period. The crossover trial allows for a within-patient comparison between treatments because each patient serves as his or her own control subject, removes the interpatient variability from the comparison between treatments, and can provide unbiased estimates for the differences between treatments. When applied inappropriately, crossover designs have serious problems that might adversely influence and invalidate their results. The primary concern is the residual carryover effect of a treatment in subsequent treatment periods. Rather than depending on a statistical procedure to eliminate the possibility of the presence of carryover effects, it is more important that the crossover design be used only in those situations in which the likelihood of a carryover effect is exceptionally small. Even though the AB/BA crossover trial appeals to the physician researcher, it is surprisingly difficult to take advantage of this design. The primary objective of this article is to introduce readers and trialists to some of the issues surrounding crossover trials. Researchers who use this design should explicitly examine the assumptions about crossover effects and the adequacy of the lead-in washout period and the between-period washout period and clearly indicate that the results of the study are conditional on the acceptance of those conditions.

Risk monitoring of randomized trials in emergency medicine: Experience of the Brain Resuscitation Clinical Trial II

Risk monitoring for the Brain Resuscitation Clinical Trial II, a multicenter, placebo-controlled trial to evaluate the efficacy of the calcium-entry blocker lidoflazine in the amelioration of brain damage in comatose cardiac-arrest survivors, posed unexpected challenges. Concern arose when monitoring of adverse reactions showed an excess of dangerous cardiac arrhythmlas, including rearrest, in the lidoflazine group. To ascertain the cause of this problem and determine whether it was ethical for the trial to continue, an in-depth review of data was conducted, outside experts were consulted, and additional data were collected. These efforts suggested possible causes for the problem. Existing drug administration protocols for blood pressure control were reinforced, resulting in lower subsequent arrhythmia rates. Thus, through an efficient monitoring system, an important problem was uncovered and resolved, allowing the trial to be completed without major changes.

Sequential clinical trials in emergency medicine

In a traditional clinical trial, a fixed number of patients are evaluated before the data are analyzed. This has the disadvantage that more patients may be enrolled than are necessary to achieve a statistically significant result. Sequential statistical techniques provide a method for the analysis of clinical trials so that a reliable result is obtained with a minimum number of patients. In a sequential trial, the data are analyzed after each patient's outcome is known, and the trial is halted as soon as treatment efficacy or lack thereof is demonstrated. This study was undertaken to confirm the advantages of sequential statistical techniques over conventional fixed-sample-size statistical techniques for the analysis of clinical trials. Using sequential techniques, we conducted computer simulations of two fixed-sample-size clinical studies from the literature - a trial of hepatitis B vaccine in homosexual men (N Engl J Med 1980;303:833-841) and a trial of the pneumatic antishock garment in hypotensive patients with penetrating abdominal trauma (Ann Emerg Med 1987;16:653-658). In the trial simulations, patients were randomly assigned to the control and test groups, their outcomes were determined randomly according to the frequency of outcomes observed in the actual studies, and the simulated sequential studies were continued until conclusions were reached. Thousands of possible realizations of each trial were simulated; thus, the distribution of required patient numbers was determined.(ABSTRACT TRUNCATED AT 250 WORDS)

Sequential clinical trials in emergency medicine

Sequential clinical trials in emergency medicine

The beta error and sample size determination in clinical trials in emergency medicine

In the analysis of a clinical trial an investigator may fail to discern a statistically significant difference in outcome between control and experimental groups, when in fact one exists. Failure to demonstrate such a difference when it actually exists is known as "type II" error, and its probability of occurring is termed "beta." The purpose of our study was to determine the distribution of beta errors in negative trials in the Journal of the American College of Emergency Physicians (JACEP) (1972-1979) and Annals of Emergency Medicine (1980-1984). All negative comparative clinical trials appearing in JACEP and Annals from volume 1 (1972) to volume 13 (1984) were surveyed and were eligible for inclusion in the study. A trial was defined as negative if the investigator specifically stated that there was no significant difference in outcome between the experimental and control groups. For each negative trial the following parameters were calculated: beta error, based on the sample size used and the difference determined to be important to detect clinically; sample size required to detect a clinically meaningful difference as determined by the authors of this study; and minimum true difference that had to be detected in the trial at a beta equal to 0.20, to discern a statistically significant result. For the 13 years surveyed, we found 21 endpoints in 14 negative trials that were analyzable. Only one of the trials (7.1%) addressed the issues of beta errors and sample size determination. In the remaining 13 negative trials, the calculated beta error ranged from .60 to .97. For the endpoints analyzed, a sample size of up to 450 times larger than that used would have been required to detect a clinically important difference.(ABSTRACT TRUNCATED AT 250 WORDS)

Methods of randomization in controlled clinical trials.

In this second article of a series that explores design and analysis issues in controlled clinical trials in emergency medicine, we have discussed the case for randomization, reviewed the methods involved in simple randomization, highlighted some of the practical problems involved with randomization, and presented some modified randomization schemes intended to remedy these problems.