The New S7B/E14 Q&A Document Provides Additional Opportunities to Replace the Thorough QT Study.

Area of Science:

• Pharmacology
• Clinical Pharmacology
• Drug Development

Background:

• Concentration-QTc (C-QTc) analysis has replaced thorough QT (TQT) studies in many clinical pharmacology studies since 2015.
• Revisions to E14 guidelines encourage earlier QT interval evaluation in first-in-human (FIH) studies.
• Updated S7B/E14 Q&A guidance (February 2022) integrates nonclinical data into regulatory decisions.

Purpose of the Study:

• To describe the understanding required by clinicians in early development regarding hERG and in vivo studies.
• To determine if these nonclinical studies meet best practices for integrated QT/QTc risk assessment.
• To support the use of integrated clinical/nonclinical QT/QTc risk assessment in drug development.

Main Methods:

• Review of C-QTc analysis and its role in replacing TQT studies.
• Evaluation of E14 and S7B/E14 Q&A document revisions.
• Assessment of best practices for nonclinical hERG and in vivo studies.
• Description of integrated clinical/nonclinical QT/QTc risk assessment framework.

Main Results:

• C-QTc analysis enables the replacement of TQT studies with serial ECGs in FIH studies.
• Negative hERG and non-rodent in vivo studies meeting best practices can reduce required QTc assessment concentrations.
• ECG evaluation in patients at therapeutic doses, supported by negative nonclinical studies, can indicate low proarrhythmic potential.

Conclusions:

• Clinicians need to understand best practices for hERG and in vivo studies for integrated QT/QTc risk assessment.
• Successful integration of nonclinical and clinical data can streamline drug development and regulatory review.
• This approach supports informed decisions on a drug's QT/QTc liability early in development.