Abstract
Power considerations for trials evaluating vaccines against infectious diseases are complicated by indirect protective effects of vaccination. While cluster-randomized trials (cRCTs) are less statistically efficient than individually randomized trials (iRCT), 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 three determinants of power: the effect size being measured, disease incidence, and intra-cluster correlation. We simulate trials conducted in a collection of small communities to assess how indirect protection and clustering affect the power of cRCTs and iRCTs during an emerging epidemic. Across diverse parameters, we find that within the same trial population, cRCTs are never more powerful than iRCTs, although the difference can be small. We also identify two effects that attenuate the loss of cRCT power traditionally associated with increased cluster size. First, if enrollment of fewer, larger clusters is performed to achieve higher vaccine coverage within vaccinated communities, this increases 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.
Footnotes
Financial support: This work was supported by Award Number U54GM088558 from the National Institute Of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of General Medical Sciences or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. S.E.B. was supported by a National Institute of Allergy and Infectious Diseases K01 award (K01AI125830). R.W. was supported by a National Institute of Allergy and Infectious Diseases R37 award (R37 AI051164).
Conflicts of interest: ML declares research support through his institution from Pfizer and PATH Vaccine Solutions, consulting income (donated in full to charity) from Affinivax, Pfizer and Merck, and consulting income from Antigen Discovery, Inc. The other authors declare that no competing interests exist.
Data availability: Code that can be used to generate data presented in this study is available on Github at https://github.com/mhitchings/Code.