Abstract
BackgroundEnrollment problems are common among randomized controlled trials conducted in the ICU. However, little is known about actual trial enrollment rates and influential factors. We set out to determine the overall enrollment rate in recent randomized controlled trials (RCTs) of patients with acute respiratory distress syndrome (ARDS), acute lung injury (ALI), or sepsis, and which factors influenced enrollment rate.MethodsWe conducted a systematic review by searching Pubmed using predefined terms for ARDS/ALI and sepsis to identify individually RCTs published among the seven highest impact general medicine and seven highest impact critical care journals between 2009 and 2019. Cluster randomized trials were excluded. Data were extracted by two independent reviewers using an electronic database management system. We conducted a random-effects meta-analysis of the eligible trials for the primary outcome of enrollment rate by time and site.ResultsOut of 457 articles identified, 94 trials met inclusion criteria. Trials most commonly evaluated pharmaceutical interventions (53%), were non-industry funded (78%), and required prospective informed consent (81%). The overall mean enrollment rate was 0.83 (95% confidence interval: 0.57–1.21) participants per month per site. Enrollment in ARDS/ALI and sepsis trials were 0.48 (95% CI 0.32–0.70) and 0.98 (95% CI 0.62–1.56) respectively. The enrollment rate was significantly higher for single-center trials (4.86; 95% CI 2.49–9.51) than multicenter trials (0.52; 95% CI 0.41–0.66). Of the 36 trials that enrolled < 95% of the target sample size, 8 (22%) reported slow enrollment as the reason.ConclusionsIn this systematic review and meta-analysis, recent ARDS/ALI and sepsis clinical trials had an overall enrollment rate of less than 1 participant per site per month. Novel approaches to improve critical care trial enrollment efficiency are needed to facilitate the translation of best evidence into practice.
Highlights
Enrollment problems are common among randomized controlled trials conducted in the ICU
Data sources We searched PubMed to identify all acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) and sepsis randomized controlled trials (RCTs) published from 2009 to 2019 in the seven highest-impact critical care and seven highest impact general medicine journals according to InCites Journal Citation Reports [15]
Consistent with prior systematic reviews that limited the literature search to high-impact journals when asking questions related to trial design and metrics [6, 16], we restricted our search to high-impact journals in order to increase the likelihood of capturing the highest quality trials and are most likely to reflect the “best-case scenario” of enrollment rate
Summary
Enrollment problems are common among randomized controlled trials conducted in the ICU. Critical care trials are often underpowered to detect a clinically meaningful difference in mortality due to, at least in part, enrollment difficulties [6] several recently published high profile critical care trials were terminated early due to difficulties with enrollment [7,8,9]. Underpowered trials, and those terminated strictly due to feasibility issues, raise ethical concerns as they expose participants to any risks involved in participation with a reduced likelihood of social benefit [10]. Reporting of trial recruitment and enrollment metrics varies, and little is known about trial factors that influence the enrollment rate
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