New Options for TQT Waivers from First-in-Human and Oncology Phase I Studies

Life Sciences, Clinical Trials, Drug Discovery & Development, Drug Safety,
  • Thursday, March 30, 2023

Cardiac safety continues to be the #1 reason for trial failure amongst drug candidates as drug-induced QT interval prolongation can lead to sudden cardiac death. However, addressing this risk through a full Thorough QT (TQT) study in later phases is costly and leaves sponsors vulnerable to black box warnings and outright rejection in the 11th hour. Early phase QT assessment amongst healthy volunteers is available and can minimize QT risk at a fraction of the cost. However, securing TQT waivers with this approach historically required supratherapeutic doses that were sometimes not achievable due to limited tolerability.


In 2022, new revisions were made to the ICH E14 and S7B cardiac safety guidance documents, which specifically addresses the risk of QT interval prolongation amongst drugs in development. Endorsed by all regions and subsequently released for use, this guidance document includes a new, combined E14/S7B Q&A document with the goal of building an integrated risk assessment that is more reliant upon non-clinical data. The Q&A aims to improve non-clinical assay standardization so regulators can better evaluate QT risk from preclinical data and sponsors can more easily obtain TQT study waivers even in cases where supratherapeutic doses cannot be achieved. Section 5.1 of the new guidance outlines how ECG assessment in First-in-Human, Healthy Volunteer studies can be used to request TQT waivers, provided the hERG and in vivo assays are performed in a standardized way.

For the development of drugs that cannot be safely administered to healthy subjects, such as oncology drugs, or those that may be problematic at supratherapeutic doses (e.g., insulin),  traditional healthy volunteer QT assessment is often not possible. In oncology trials, ECG evaluation is typically conducted with the therapeutic dose in cancer patients only, and without placebo control. Assessing QT risk for this class of drugs in late stage can incur undue burden on patients and, conversely, assuming a QT risk can unnecessarily limit the number of patients who will be able to access the treatment in the future. Section 6.1 of the ICH E14/S7B Q&A provides guidance on leveraging non-clinical data to better assess QT risk in First-in-Human oncology studies, when PK/PD data is already available, thus minimizing patient burden and increasing the chances of demonstrating a ‘low likelihood of proarrhythmic effect’.

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In this webinar, the featured speakers will describe how the new ICH S7B/E14 revisions open up new opportunities for drug developers and discuss on-going trends in First-In-Human ECG studies. The speakers will dive into various case studies and look at the impacts of early-stage QT assessment given positive and negative results as well as the context of the drug development project. Additional consideration will be given to best practices with non-clinical hERG assays and in vivo QT studies as well as Section 6.1 of the guidance, covering drugs such as oncologics.

Join this webinar to learn about new developments that enable easier TQT waivers from early phase heathy volunteer and oncology studies. Sign up early to get your question in the queue for the experts!


Borje Darpo, MD, PhD, Chief Scientific Advisor, Cardiac Safety, Clario

Dr. Borje Darpo is the Chief Scientific Officer, Cardiac Safety at Clario, with board certifications in cardiology and internal medicine. He completed his cardiology training at Sahlgrenska University Hospital, Göteborg and was appointed Associate Professor at Karolinska Hospital, Stockholm in 2000. Borje held various positions within CROs and pharmaceutical industry covering a wide variety of therapeutic areas.

Borje represented the European pharmaceutical industry on the ICH E14 Expert- and Implementation Working group between 2000 and 2008. In collaboration with industry and the FDA, he led the IQ-CSRC study, which validated the concept of applying exposure-response analysis on data from early-stage clinical trials to replace the Thorough QT study. This contributed to the revision of the ICH E14 guideline, which since December 2015 allows this approach to replace the TQT study.

In his current role, he supports business development and provides cardiac safety consultative services advising sponsors on optimal cardiac safety strategy for their development program (e.g. clinical protocol development, expert cardiac report development and regulatory support).

Message Presenter
Robert Kleiman, Clario

Robert Kleiman, MD, Vice President, Cardiology & Chief Medical Officer, Clario

Dr. Robert Kleiman is the Chief Medical Officer at Clario, with board certifications in cardiology and cardiac electrophysiology. He has performed research in both basic cellular electrophysiology as well as clinical electrophysiology. Dr. Kleiman trained at the University of Pennsylvania and practiced clinical cardiology for 12 years before joining Clario in 2003.

In his current role, he currently oversees all of Clario’s cardiology services, supports business development and provides cardiac safety consultative services advising sponsors on optimal cardiac safety strategy for their development program (e.g. clinical protocol development, expert cardiac report development and regulatory support).

Message Presenter

Who Should Attend?

Senior Professionals from Biotech, Pharma and CROs, including:

  • Clinical Pharmacologists
  • Clinical Operations (early phase)
  • TA Experts (oncology)
  • PK Experts
  • Medical Monitors/Heads of Development for Program
  • Clinical Innovation
  • Regulatory Affairs
  • Drug Safety professionals
  • Project Management
  • Clinical Research Scientists
  • Drug/Clinical Development
  • Biostatisticians
  • Medical Directors
  • Scientific & Medical Affairs
  • Heads, VPs, Directors of Oncology, Cardiology, CNS and other Therapeutic Areas
  • Chief Scientific Officers (CSO)
  • Clinical Directors & Leads
  • Chief Medical Officers (CMO)

What You Will Learn

Attendees will:

  • Look at how the new guidance can make TQT waivers more accessible for typical drugs
  • Follow the journey of several drug candidates leveraging early phase QT assessment
  • Examine QT assessment for oncologics and the impact of the new guidance

Xtalks Partner


Clario delivers the leading endpoint technology solutions for clinical trials. Through experience gained from over 19,000 clinical trials delivered in support of 870 regulatory approvals, Clario fuses scientific expertise and global scale into the broadest endpoint technology platform to enable pharmaceutical, biotech and medical device partners to transform lives. Through Trial Anywhere™, Clario has mastered the ability to generate rich evidence across all trial models: decentralized, hybrid and site-based clinical trials. With 30 facilities in nine countries across North America, Europe and Asia Pacific, Clario’s global team of science, technology and operational experts has been delivering the richest clinical evidence for nearly 50 years.

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