Critical care trial design and interpretation: a primer

Abstract

Objective: Better understanding of the pathophysiology of critical illness has led to an increase in clinical trials designed to improve the clinical care and outcomes of patients with life-threatening illness. Knowledge of basic principles of clinical trial design and interpretation will assist the clinician in better applying the results of these studies into clinical practice.

Data sources: We review selected clinical trials to highlight important design features that will improve understanding of the results of critical care clinical trials designed to improve clinical care of the critically ill.

Results: Trial design features such as patient selection, bias, sample size calculation, selection of subjects and controls, and primary outcome measure may influence the results of a critical care clinical trial designed to test a therapy targeting improved clinical care. In conjunction with trial design knowledge, understanding the size of the anticipated treatment effect, the importance of any clinical end point achieved, and whether patients in the trial are representative of typical patients with the illness will assist the reader in determining whether the results should be applied to specific patients or usual clinical practice.

Conclusions: Better understanding of important aspects of trial design and interpretation, such as whether patients enrolled in both intervention arms were comparable and whether the primary outcome of the trial is clinically important, will assist the bedside clinician in determining whether to apply the findings from the clinical study into clinical practice.

Figure 1

Illustration of a case-control study. At the time of starting the study (depicted as “the present”) the investigator selects a sample of cases from subjects with the outcome of interest and selects a sample of controls from those without the outcome of interest. Exposures potentially associated with the outcome of interest (shaded areas) are then assessed retrospectively, in the past, as denoted by the dark reverse arrows.

Figure 2

Figures 2a and 2b. Illustration of a prospective and retrospective cohort study. In a prospective cohort study (2a), at the outset of the study the investigator selects a sample from the population and measures the exposures of interest (shaded areas) before following the patient over time to determine the occurrence of relevant outcomes and their association with the exposures (following the dark forward arrow). In a retrospective cohort study (2b), at the outset of the study the investigator identifies a cohort of subjects that existed in the past and assesses exposure retrospectively from that group (shaded areas), and then assesses the relevant outcomes in the present (dark forward arrow).

Figure 2

Figures 2a and 2b. Illustration of a prospective and retrospective cohort study. In a prospective cohort study (2a), at the outset of the study the investigator selects a sample from the population and measures the exposures of interest (shaded areas) before following the patient over time to determine the occurrence of relevant outcomes and their association with the exposures (following the dark forward arrow). In a retrospective cohort study (2b), at the outset of the study the investigator identifies a cohort of subjects that existed in the past and assesses exposure retrospectively from that group (shaded areas), and then assesses the relevant outcomes in the present (dark forward arrow).

Figure 3

Illustration of a randomized, controlled trial. In a randomized, controlled clinical trial, the investigator identifies a group of eligible subjects (dotted circle) from an appropriate patient population (hashed circle), and then applies the defined inclusion and exclusion criteria to enroll subjects. At the start of the study the investigator measures baseline variables and randomly allocates subjects to intervention groups (“treatment” in gray, or “control”). Outcomes are measured prospectively during the follow-up period. Ideally, allocation, intervention and outcome assessment should be blinded.