QT Prolongation Risk Assessment in Oncology: Lessons Learned From Small-Molecule New Drug Applications Approved...

Area of Science:

• Pharmacology and Toxicology
• Cardiovascular Safety Assessment
• Oncology Drug Development

Background:

• The International Conference on Harmonisation (ICH) E14 guidance outlines QT prolongation assessment strategies for new drugs.
• Updated ICH E14 guidelines (last revised 2015) address situations where conventional thorough QT (TQT) studies are not feasible.
• Oncology drug development presents unique challenges for cardiac safety evaluations.

Purpose of the Study:

• To analyze QT prolongation evaluations for small-molecule new drug applications (NDAs) approved in oncology from 2011-2019.
• To extract learning experiences regarding QT assessment methods, data collection, labeling, and postmarketing requirements.
• To provide a structured understanding of FDA QT evaluation criteria in oncology settings.

Main Methods:

• Comprehensive analysis of oncology NDAs approved between 2011 and 2019.
• Evaluation of QT prolongation assessment methods, including concentration-QTc modeling, TQT studies, and dedicated QT studies.
• Review of electrocardiogram data collection, QT-related labeling, and postmarketing requirements.

Main Results:

• All analyzed NDAs included a QT assessment.
• Concentration-QTc modeling was the most common approach (59%), followed by TQT (20%) and dedicated QT studies (21%).
• QT assessment quality and quantity varied, indicating flexibility in characterizing QT liability; labeling reflected results and limitations.

Conclusions:

• Drug approval was not delayed by less robust QT studies when the benefit-to-risk ratio was acceptable and reflected in the drug label.
• The study offers insights into FDA's QT evaluation criteria for oncology drugs.
• Findings can aid in planning QT prolongation assessments for future oncology drug development.