The use of therapeutic drugs is associated with potential risks; therefore, public health surveillance systems have been developed to monitor the safety of medicines through a process of signal detection and assessment. Prescription-event monitoring (PEM) is one such active system, based on the study of cohorts of patients exposed to a recently licensed drug. As signal detection (SD) is a fundamental part of postmarketing surveillance, an understanding of factors influencing the performance of SD is paramount to plan and operate effective surveillance. This study aims to: characterize and evaluate the determinants that affect SD; design and pilot a systematic process, including SD methods and a work flow for planning and operating SD in PEM.