ABSTRACT
This chapter defines the key terms—biomarker, surrogate endpoint, validation, and qualification to clarify the various meanings with which these terms are often used. It provides a conceptual framework for the development and utilization of biomarkers in drug development and in clinical practice. The chapter reviews a number of experimental paradigms, clinical and nonclinical, that have been utilized to evaluate the propensity of a drug to prolong the QTc interval. It discusses the regulatory implications of the use of QTc as a biomarker including the efforts by International Conference on Harmonization to achieve consensus in generating guidelines for the evaluation and use of drugs associated with prolongation of the QTc interval. Validation and qualification are other key terms used for discussion of biomarkers. The chapter explores in greater depth issues surrounding the use of the electrocardiographic QT interval as an emerging biomarker predicting risk for cardiac arrhythmias including torsade de pointes.
