Table 1.

Summary of trial designs

Trial design type	Purpose	Limitations	Comments, recommendations
Randomized controlled trial	To determine proof of causality	Heterogeneous patient populations reduce ability of the trial to ascertain differences in treatment effect. Logistic burden and cost	Participating centers should have a phase-in period that allows demonstration of the capacity of the center to perform the study safely and effectively. Use of a smaller, well-defined, and homogeneous population may increase the probability of determining a true treatment effect
Observational study	Hypothesis generation	Do not provide proof of causality	Collaborations among centers with large databases. Standardization of reporting metrics
Individual patient meta-analysis	To avoid the limitations and complications inherent in comparing disparate studies. Allows interpretation of patient-specific events that would not normally be identified in aggregate trial data	Hugely time and resource intensive	The analysis will be confounded by the same limitations as present in the original trials
Cluster randomization	To reduce variations in process of care for complex interventions as a confounding factor in randomized controlled trials	Requires more complex statistical methodology to account for the effects of clustering	May be particularly suitable for complex interventions, such as glucose control in the critically ill