Competing Effects of Indirect Protection and Clustering on the Power of Cluster-Randomized Controlled Vaccine Trials.

Power considerations for trials evaluating vaccines against infectious diseases are complicated by indirect protective effects of vaccination. While cluster-randomized controlled trials (cRCTs) are less statistically efficient than individually randomized controlled trials (iRCTs), a cRCT's ability to measure direct and indirect vaccine effects may mitigate the loss of efficiency due to clustering. Within cRCTs, the number and size of clusters affects 3 determinants of power: the effect size being measured, disease incidence, and intracluster correlation. We simulated trials conducted in a collection of small communities to assess how indirect protection and clustering affected the power of cRCTs and iRCTs during an emerging epidemic. Across diverse parameters, we found that within the same trial population, cRCTs were never more powerful than iRCTs, although the difference can be small. We also identified 2 effects that attenuated the loss of cRCT power traditionally associated with increased cluster size. First, if enrollment of fewer, larger clusters was performed to achieve higher vaccine coverage within vaccinated communities, this increased the effect to be measured and, consequently, power. Second, the greater rate of imported transmission in larger communities may increase the attack rate and similarly mitigate loss of power relative to a trial in many, smaller communities.