Effect sizes in ongoing randomized controlled critical care trials

We conducted a systematic review of databases of registered clinical trials, followed by a clinician survey.

The EudraCT, ClinicalTrials.gov, and ANZCTR clinical trial registries were searched in September 2015 for critical care medicine trials in which landmark mortality was the primary outcome. Studies were excluded if they were not two-sided superiority trials, cluster, or cluster crossover trials; if they were focused on a pediatric population; if they were not related to critical care medicine; or if they were purely investigations of surgical techniques. Trials that had completed recruitment were also excluded. Trials registered on more than one database were included only once. Trial investigators were emailed to request data used to inform their sample size calculations. Any trials found to meet exclusion criteria as a result of the reply from their investigators (e.g., trials no longer recruiting) were excluded.

We recorded the following trial characteristics from online registries: sample size, eligibility criteria for trial participants, intervention details, comparison group details (e.g., placebo or usual-care strategy), trial origin country, and landmark for mortality outcome measurement (e.g., 28 days). We recorded the following from investigator replies: power used in sample size calculations, expected baseline mortality, and expected effect size (absolute mortality difference between control and intervention groups).

Each trial identified in our systematic review was presented according to the participants, intervention, comparison, outcome standard, and clinicians were asked two questions per trial. First, they were asked to estimate the percentage chance that the actual effect of the treatment being investigated in a particular trial would equal or exceed the effect postulated by investigators. Second, they were asked to specify the largest absolute mortality reduction that they considered to be plausibly attributable to each treatment being investigated. For example, for the ADjunctive coRticosteroid trEatment iN criticAlly ilL Patients with Septic Shock trial [8], which is a 3800-participant trial in which researchers are investigating the effect of a continuous 7-day intravenous infusion of 200 mg/day hydrocortisone on day 90 mortality among adults who are ventilated with septic shock and have received vasopressors/inotropes for at least 4 h, clinicians were asked the following questions:

Demographic data collected from survey respondents were region of residence (Australia and New Zealand [ANZ], United Kingdom [UK], Europe [outside UK], United States [USA], Canada, Central or South America, Asia, Africa) and training background (intensive care specialist, other specialist, training to be a specialist in intensive care medicine, training in an area of medicine other than intensive care). Intensive care specialists were asked how long they had been working as an intensive care specialist (<5 years, 5–10 years, >10 years).

The survey was piloted by 20 clinicians from ANZ, USA, Europe, and the UK who provided feedback on ease of use, interface, and the survey’s duration. The length of the survey was reduced following the pilot phase because feedback indicated that the original version was too long. Additional file 1 shows the final version of the survey, which was distributed with the weekly Critical Care Reviews newsletter over 4 consecutive weeks [9]. The newsletter had 6243 subscribers at the end of this 4-week period. No demographic data are collected from list subscribers; however, the list is free to subscribe to from anywhere in the world, and no restrictions are placed on registration. The email containing the survey was opened by between 2788 and 2889 people per week in each of the 4 weeks in which the survey was running. We chose to “crowd-source” responses from clinicians with an interest in critical care to provide us with “real-world” opinions.

The primary outcome was the clinicians’ perceptions of prior probability for each trial, which was defined as the percentage chance that each trial would demonstrate a mortality effect equal to or greater than that used in the sample size calculation for that trial.

The following were secondary outcomes:

Continuous variables are reported as median and IQR or mean ± SD, and categorical variables are reported as counts and percents. Clinician-perceived prior probability for each trial was used to derive an estimate that a statistically significant result at the P = 0.05 level would represent a true-positive using the method described in Fig. 1. Specifically, as outlined in Additional file 2, the chance of a true-positive was calculated as follows [10]:

The sample size that each trial would require to detect the median largest effect size considered plausible by clinicians was calculated using standard methods for trials designed to compare two binomial proportions. We used the same β for these calculations as investigators had used in their initial sample size calculations and assumed an α of 0.05. Analysis of variance was used to analyze differences in survey results by location and specialty. A Mann-Whitney U test was used to compare clinicians’ estimates of effect size, with treatment effect sizes used to inform sample size calculations. A P value of <0.05 was considered to indicate statistical significance. Statistical analysis was performed using Real Statistics Resource Pack release 3.8 software (London, UK).

Trial registry searches returned 656 results, and 71 trials met our criteria for the request of further information from investigators. Twenty-eight responses were received, yielding a further eight exclusions and a final set of twenty trials for analysis. All 20 eligible trials were included in the pilot survey, but feedback indicated that the survey was too long; hence, we decided to include only the 10 trials [8, 11‐19] with the smallest postulated effect sizes in the final survey (Fig. 2).

Trials included in the clinician survey had a median sample size of 3575 participants (IQR 725–7000), a median baseline mortality rate used in their sample size calculations of 26.5% (IQR 25–33%), and a median postulated treatment effect size of 5% absolute mortality reduction (IQR 3.6–10%) (Table 1).

We conducted a systematic review of trial registries to identify ongoing trials in the field of critical care medicine in which researchers are reporting landmark mortality as the primary outcome. We then conducted a clinician survey to establish views about the prior probability that the interventions in ten of these trials would reduce mortality by at least as much as postulated by investigators. Moreover, we also sought to establish clinicians’ estimates of the largest plausible mortality reduction that might be attributable to each study intervention. We found that, in aggregate, respondents’ estimates of prior probability were low, but we also found that individual estimates varied widely, from 0% to 100%, for most trials. We also found that the median largest absolute reduction in mortality considered plausible was ≤5% for all study interventions. Although some trials were powered to detect such effect sizes, many were underpowered to detect effects of this magnitude by more than 2000 participants.

This study represents the first attempt to provide quantitative estimates of clinicians’ perceptions about prior probability and plausible effect sizes for ongoing trials in the field of critical care medicine. Researchers in a number of previous studies have systematically evaluated rates of reported positive results in trials of critically ill patients with mortality endpoints. In one study, researchers reported positive results in 10 (14%) of 72 multicenter RCTs with mortality as the primary endpoint published before August 2006 [20]; in a second, investigators reported that 7 (18%) of 38 trials published in 5 major medical journals between 1999 and 2009 showed positive results [5]; and in a third study, in evaluating ICU-based trials published between January 2007 and May 2013 in 16 high-impact general or critical care journals, researchers identified that 3 (9%) of 34 were positive [21]. Authors of a more recent systematic review identified that 44 (5%) of 862 multicenter critical care medicine trials reported significant differences in mortality [22]. These data confirm that ICU-based trials with mortality endpoints are frequently negative and indicate that the median predictions of prior probability offered by survey respondents in our study are broadly congruent with the observed frequency of positive trials in the critical care medicine literature. However, they do not necessarily support the accuracy of the estimates of low prior probability provided for the ten large trials included in our survey. Logically, the accuracy of such estimates can only be determined prospectively by comparing prior probabilities and actual trial results for a large number of trials over time.

Our method of eliciting priors through clinician survey is importantly different from other ways of eliciting priors in that it is a pragmatic, “real-world” method employing actual end-users of the trials to be assessed, whose beliefs ultimately will decide the impact of the trials on their practice. Previous work has used abstract modeling or “experts” (i.e., generators of research rather than end-users) [23, 24].

The extreme variability of the estimates, coupled with some manifestly implausible responses (e.g., suggestions that particular treatments might reduce mortality by 100%), could be interpreted as an indication that our estimates lack validity. However, outlier responses have a limited effect on estimates based on medians, and the clinical equipoise required for the initiation of a trial [25] might reasonably be expected to result in a range of estimates from the members of clinical community. That said, our finding that effect sizes postulated by investigators often appear to be larger than the median effect sizes considered plausible by clinicians is consistent with previous literature suggesting that effect sizes used to inform sample size calculations are often inflated [5, 21]. For the range of interventions being tested in the studies in our survey, the largest treatment-associated mortality differences considered plausible would not be excluded by the 95% CIs in the vast majority of the 40 trials with a primary endpoint of mortality identified in a recent systematic review of high-impact critical care-based trials [21]. Only six superiority trials identified in this systematic review had ≥80% power to detect a treatment-associated mortality reduction of ≤5% [21].

Although our survey response rate was low (2.7%), a sufficient number of responses was achieved to provide broad geographical representation among respondents. In the descriptions of trials used in our survey, we asked respondents to assume that estimates of control arm mortality used by investigators were accurate. However, it appears that control arm mortality rates are often overestimated in critical care medicine trials [21]. We chose not to alter control arm mortality rates in our survey, because doing so would have added substantial complexity to the scenarios being considered. On the one hand, as the control arm mortality rate falls, the proportion of potentially salvageable patients would be expected to fall, making the same absolute mortality reductions less likely. However, on the other hand, as the control arm mortality rate moves away from 50%, the power to detect given absolute differences increases.

Our approach to determining the chances of a true-positive for each trial provides only a point estimate and does not account for the true distribution of probability estimates [26]. For our calculations, we assumed a P value of 0.05. If lower P values were observed, this would lead to correspondingly higher probabilities of a true-positive result. Our approach was chosen because it provides estimates that are likely to be readily understood by clinicians. The probability of a true-positive result for a given trial that should be accepted or rejected is not established, but logically this should depend on the particular treatment being considered. For comparisons between standard treatments with similar known risk profiles and similar costs, the threshold value for practice change should probably be lower than for expensive new treatments, where risk profiles are less certain.

The low perceived prior probabilities and exaggerated effect sizes suggested by our results are potentially of concern to clinicians who will need to interpret the results of these trials when they are completed. Rejecting the null hypothesis in favor of the experimental hypothesis on the basis of a P value threshold of 0.05 in the setting of low prior probability will potentially result in clinicians and investigators drawing erroneous conclusions [26, 27]. If clinicians’ perceptions of low prior probabilities are correct, then the predominance of low prior probability in hypotheses being evaluated may explain the frequent failure to replicate positive results in critical care medicine trials [28] and in trials in other disciplines [29]. However, as we have highlighted, the accuracy of the estimates of prior probability and effect size provided by our survey respondents is unknown. Nevertheless, our study is an important first step toward developing more robust assessments of prior probability in the future.