QT Myopia and Cardiac Safety: Expanding the Aperture of Arrhythmia Assessment in Early Phase Drug Development.

Regulatory agencies such as the Food and Drug Administration (FDA), European Medicines Agency (EMA), Health Canada, and the Japanese Pharmaceutical and Medical Device Agency (PMDA) provide scientific and public health guidance with cardiac safety being paramount in drug development of new investigational products (IP). Cardiac safety is not a singular undertaking but rather encompasses many elements to be considered beyond measurement of the QT interval before a candidate drug receives regulatory approval. These safety assessments may include evaluation of additional targeted and non-targeted cardiovascular effects such as whether the IP mediates cardiac or pericardial inflammation or affects blood pressure, the coronary or systemic vasculature, heart valves, or cardiac muscle. Historically, the primary cardiac safety concern of regulators was the proarrhythmic risk of new chemical entities and has been centered on the QT interval as a marker of a drug's ability to delay ventricular repolarization and its potential to precipitate lethal ventricular rhythms. Beyond this biomarker, there has only been tangential focus on the PR and QRS intervals, conduction disturbances and supraventricular arrhythmias, and formal regulatory guidance pertaining to these findings has not been published. Hence, this review is designed to expand the myopic view of cardiac safety beyond the QT interval and highlight the importance of clinical nonlethal arrhythmias and conduction abnormalities involving novel non-antiarrhythmic small molecules for which more robust monitoring and surveillance should be contemplated.