 The Trial Innovation Network has developed an infrastructure for single institutional review board, IRB, review in order to comply with federal regulations. Through this network, over 70 multi-site studies have been conducted using over 800 reliance agreements. Lessons learned from these experiences include differentiating the role of the single IRB from the institution's Human Research Protection Program, developing a consistent single IRB review model, standardizing the collection of local context and supplementary study-specific data, and training and empowering lead study teams to support their sites. This article was offered by N. R. Johnson, Megan Kasamati Singleton, Julie Ozier, and others.