QT assessments in oncology drug development and related labels.

Abstract

e14127 Background: A thorough QT (TQT) study, designed to evaluate whether a new drug excludes a small mean increase in the QTc interval (i.e., > 10 ms) which is considered to have low proarrhythmic risk, is often not feasible for oncology drugs. Alternative designs that assess the QTc changes in cancer patients are used to exclude large mean increases (i.e., > 20 ms) for drugs where the expected benefit outweighs the small proarrhythmic risk. A retrospective analysis was conducted to evaluate QT study designs and the consistency of QT labeling for oncology drugs. Methods: This analysis included FDA approved oncology drugs with QT studies reviewed by CDER’s Interdisciplinary Review Team as of 10/01/2019. Information collected included the clinical study design (i.e., TQT, alternative designs such as a sub-study in a Phase 2/3 trial), primary analysis (i.e., central tendency or concentration-QTc [CQT] analysis), QT findings at the therapeutic dose (i.e., the mean [M] and the upper bound of 90% confidence interval [UCI] of QTc changes), supportive data (i.e., nonclinical cardiac safety data, if applicable), conclusion of the QT assessment, and labeling statements in Section 12.2 (Pharmacodynamics) and Section 5 (Warnings & Precautions) of the product labels. Baseline QTc values in these alternative studies were compared to those in TQT studies across different therapeutic areas. Results: The analysis included 72 oncology drugs. The mean baseline QTc value is 411.2 ms in male patients (n = 6951) and 394.6 ms in male healthy volunteers (n = 22288), and 414.3 ms in female patients (n = 6412) and 408.8 ms in female healthy volunteers (n = 15682). Alternative study designs were used for 63 (87.5%) drugs while TQT study was only used for 9 (12.5%) drugs. CQT was used as the primary analysis for 11 (15.3%) drugs. Among the 72 product labels, 8 labels do not have QT information in Section 12.2 and 9 labels inconsistently describe the results of an alternative study. Warnings and Precautions for QT Prolongation in Section 5 of the labels were triggered by positive signals in the QT assessment or clinical trial safety monitoring experience. Conclusions: Cancer patients had higher QTc and less sex difference at baseline than healthy volunteers. QT labeling consistency in Section 12.2 could be improved by standardizing the description of study results based on QT study designs. Disclaimer: The contents reflect the views of the authors and should not be construed to represent the FDA's views or policies.