ICH E14/S7B Q&As adopted in 2022 allow for an integrated risk assessment using nonclinical in vitro and in vivo data, together with results from early clinical trials, to inform the design of clinical investigations and interpretation of QTc-related findings. Specifically, adequate and satisfactory nonclinical data may qualify as a “double-negative” and be used with supporting clinical results to potentially avoid the need for a dedicated clinical thorough QT study with a positive control drug. This presentation will highlight features of the Q&As, including best practices for nonclinical studies, and summarize case examples where this approach has been implemented within our organization. Overarching themes and learnings will also be reviewed.