Experience in QT evaluation of oncology drug products since ICH E14 guidance
Q. Liu, Rajanikanth Madabushi, Christine E. Garnett, B Booth · Journal of Clinical Oncology · 2008
2554 Background: The objective of a ‘thorough QT (TQT) study’ is to determine whether a drug at supratherapeutic concentrations has a pharmacological effect on cardiac repolarization as detected by QT/QTc prolongation. The design is a randomized, (preferably) double-blinded, placebo- and positive-controlled study typically conducted in healthy male and female volunteers. There are several challenges with implementing a TQT study for oncology drug products: toxicities preclude administering the drug at supratherapeutic concentrations to cancer patients or to healthy volunteers and it is not feasible to administer the positive control to cancer patients. Methods: NDAs submitted during 2006–2007 were reviewed for QT evaluation. The study design, analysis methods and labeling implications were compared across submissions. Lapatinib submission was used as a case study. Results: Nine original NDAs were submitted of which five have been approved, three are under-review and one was withdrawn. Seven (78%) of the submissions contained QT evaluation from phase 1/2 studies. Of the submissions with QT data, two submissions contained a dedicated QT study but these studies did not meet the criteria of a TQT study defined by ICH E14. Time-matched concentrations and ECGs were available in six (85%) of the seven submissions. Concentration-QT analysis was performed in all six submissions by FDA reviewers. Of the five approved submissions, four were found to prolong the QT interval and labeled accordingly. The lapatinib case study underlines the need for collecting useful and interpretable data when using alternative designs. Conclusions: It is important to assess QT prolongation of oncology drug products. A TQT should be conducted if the drug can be administered to healthy subjects or placebo controls can be used in patients. Alternative designs can be used to evaluate QT when TQT study cannot be conducted. However, strategic planning of the alternate designs early in development will aid in collecting useful, interpretable data. Studies employing time-matched baseline ECGs and time-matched concentrations are essential for assessing drug effects on QT interval when employing alternate designs. No significant financial relationships to disclose.