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European Pharmaceutical Contractor
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| Benoit Tyl, Bill Wheeler and Joy Olbertz at MDS Pharma Services examine practical considerations in the execution of a thorough QT/QTc study and emphasise the importance of decreasing variability
Several non-cardiovascular drugs were withdrawn from the market during the late 1980s and early 1990s due to an increased risk of sudden death related to the cardiac arrhythmia known as torsades de pointes (TdP). TdP is associated with prolongation of the QT interval on the surface electrocardiogram (ECG). Because the typical registration dossier was inadequate for detecting this risk, regulators around the world attempted to develop a strategy that would provide an indication of the risk of TdP during development rather than after extensive patient exposure to a potentially lethal drug in post-marketing surveillance. This effort culminated in ICH E14, which was adopted in Europe and in the US in 2005. ICH E14 advocates a dedicated study – ‘thorough QT/QTc’ study (TQTS) – to assess this risk. The assumption inherent in the requirement for a TQTS is that, if a drug induces a certain level of QT prolongation in this study, it might cause further QT prolongation in patients and present increased risk of TdP.
The results of this study are critical to drug development programmes. If there is no evidence of QT prolongation beyond the level of ‘regulatory concern,’ the later-stage development of the compound can proceed as usual for that type of compound or indication. If, however, the TQTS is ‘positive,’ the drug developer must carefully evaluate future development costs and potential patient benefit. A positive result will require extensive ECG evaluation in later stages of development, thus increasing development cost and trial complexity. The difference between a positive and negative TQTS is relatively small, especially considering the inherent variability of the QT measurement. |
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Benoît Tyl MD has worked as a Senior Cardiologist and European Medical Director for MDS Pharma
Services Central Lab, SA, since 2006, focusing on study design, protocol and clinical report writing,
and is also a member of their advisory board. Prior to this, Benoît has held a variety of cardiological
positions within MDS, examining the development of user interfaces dedicated to ECG/Holter
interpretation, and the validation of ECG results for clinical trial studies. Benoît earned a Master’s
in Pharmacology from the University of Paris VII & X, France.
William S Wheeler MD, a board-certified cardiologist with over 30 years’ experience, is the leader
of cardiac monitoring and safety services for the centralised cardiac division of MDS Pharma Services
in North America. William is responsible for advising clients on study protocol design, as well
as cardiac monitoring and safety, and related regulatory issues. He also leads the MDS Cardiac
Advisory Board where he focuses on quality control programme reviews, best practices for cardiac
interpretations and the future development of relevant technology. He earned his medical degree
from the University of California in Los Angeles.
Joy Olbertz PhD is the QTc Project Coordinator at MDS Pharma Services and has had a major role in
developing the Cardiac Safety Center of Excellence and in the evolution of thorough QT trial protocols
and procedures. Before taking on her current role, Joy was a Clinical Research Pharmacist at MDS
Pharma Services. Prior to joining MDS, she was a staff pharmacist at the Portneuf Medical Center
in Pocatello, Idaho, and a research assistant at Idaho State University. She was also an instructor
at the University in their Pharmacy and Nursing departments. |
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