I n the past few decades, multicenter trials have replaced single-center studies as the norm, mainly due to the scientific rigor and external validity required to support widespread changes in clinical practice. 1 Improving clinical trial efficiency has been a common goal among research organizations, and much attention has been specifically focused on multicenter clinical trial start-up periods.The use of a single or central institutional review board (IRB) has been posited as one method for increasing multicenter trial efficiency during the start-up phase. According to the Office of Scientific Policy at the National Institutes of Health (NIH), a single IRB is the reviewing IRB for a given study, whereas a central IRB (CIRB) is the reviewing IRB designated as the reviewing IRB for a group of studies (e.g., for a research network). 2 For the purposes of this article, CIRB review of "multicenter" research refers to CIRB review of all studies that would be implemented across a network of many sites, as opposed to a single study carried out at more than one site. On June 21, 2016, the NIH released what is, at the time of this writing, their most recent policy on the use of a single IRB for multicenter research. 3 Newly funded investigators of multicenter studies are now expected to rely on a single IRB or CIRB to carry out the functions of IRB review of human subjects research as required by the Common Rule. 4 However, little guidance is available in the peer-reviewed literature on use of CIRBs for multicenter trials. 5 Centralization of the IRB process requires resources for managing submission to the CIRB while also meeting the remaining human research protection program (HRPP) review requirements at each participating site. This may be achieved through a central administrative group or data coordinating center that acts as a liaison between the CIRB and the participating sites. This article will describe the issues and challenges of creating and implementing a CIRB model for a federally funded ABSTRACT Implementing the National Institutes of Health's (NIH's) new single institutional review board (IRB) policy has caused a paradigm shift in IRB review across the country. IRBs and human research protection programs are looking more closely at their processes for ceding review and developing procedures to handle local review when relying on a single IRB. This article describes an NIH-funded network that proactively instituted a central IRB (CIRB) in 2012, anticipating the NIH future mandate. Lessons learned are described. There was a steep learning curve for IRBs and participating sites. IRB submission workload burden shifted from study teams to the data coordinating center, which created new workflow challenges, especially preparing hundreds of consent documents centrally. Despite difficulties encountered with CIRB review, this network is now fully functioning under a CIRB model. Further review and experience are needed to determine whether this shift in IRB review has eliminated duplicative review or regulatory bur...