Contamination: How much can an individually randomized trial tolerate?

Abstract

Cluster randomization results in an increase in sample size compared to individual randomization, referred to as an efficiency loss. This efficiency loss is typically presented under an assumption of no contamination in the individually randomized trial. An alternative comparator is the sample size needed under individual randomization to detect the attenuated treatment effect due to contamination. A general framework is provided for determining the extent of contamination that can be tolerated in an individually randomized trial before a cluster randomized design yields a larger sample size. Results are presented for a variety of cluster trial designs including parallel arm, stepped‐wedge and cluster crossover trials. Results reinforce what is expected: individually randomized trials can tolerate a surprisingly large amount of contamination before they become less efficient than cluster designs. We determine the point at which the contamination means an individual randomized design to detect an attenuated effect requires a larger sample size than cluster randomization under a nonattenuated effect. This critical rate is a simple function of the design effect for clustering and the design effect for multiple periods as well as design effects for stratification or repeated measures under individual randomization. These findings are important for pragmatic comparisons between a novel treatment and usual care as any bias due to contamination will only attenuate the true treatment effect. This is a bias that operates in a predictable direction. Yet, cluster randomized designs with post‐randomization recruitment without blinding, are at high risk of bias due to the differential recruitment across treatment arms. This sort of bias operates in an unpredictable direction. Thus, with knowledge that cluster randomized trials are generally at a greater risk of biases that can operate in a nonpredictable direction, results presented here suggest that even in situations where there is a risk of contamination, individual randomization might still be the design of choice.