 Developing a core outcome set for clinical trials involves selecting appropriate outcomes that are relevant and important to key stakeholders, including patients and healthcare professionals, in order to compare the effects of different interventions directly. This process should be guided by a four-step approach, as recommended by the Comet Initiative, with the aim of updating the handbook as further research is identified. This article was authored by Paula R. Williamson, Douglas G. Altman, Heather Bagley, and others.