PS30: Statistical Consideration of Concentration-QTc Modeling in Oncology

Since the publication of the ICH E14 Q&As (R3), concentration-QTc (C-QTc) modeling based on early Phase 1 studies has emerged as the primary analytical method for evaluating the proarrhythmic risk and delayed cardiac repolarization of new drugs. This approach offers the advantage of detecting potential QT risks earlier and at a reduced cost compared to traditional Thorough QT (TQT) studies. To aid in the implementation of C-QTc modeling in clinical drug development, a scientific white paper has been released, providing recommendations for planning and conducting definitive QTc assessments of drugs. However, it is important to note that this white paper primarily focuses on non-oncology drugs, acknowledging the complexities inherent in the design of Phase 1 oncology studies. For instance, oncology trials typically do not incorporate placebo controls, which poses challenges in estimating the QTc effect relative to other factors, such as diurnal variation. Moreover, the prevalence of combination therapies in the current oncology landscape further complicates C-QTc analyses. This session will feature esteemed representatives from academia, industry, and regulatory agencies who will discuss the design considerations and analytical methods for conducting C-QTc assessments in early Phase 1 oncology trials. The regulatory perspective will encompass various types of oncology drugs, including chemotherapy, immunotherapy, and antibody-drug conjugates (ADCs), as well as the implications of combination therapies and criteria for evaluating QT prolongation. Furthermore, the session aims to provide practical insights into enabling robust C-QTc assessments within the framework of existing Phase 1 oncology study designs, covering aspects such as sample size, QTc data collection, and C-QTc modeling approaches. Special attention will be given to the complexities in performing C-QTc assessments for combination therapies. The objective of this session is to raise awareness among drug developers regarding the significance of C-QTc assessments in oncology trials, while also exploring best practices and design recommendations to support robust C-QTc analyses in Phase 1 oncology studies.