An Earlier Look at QT Prolongation
September 1,2014 Lorraine Rusch

The 2005 regulatory guideline “The Clinical Evaluation of Qt/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs” created a change in methodology for evaluating the potential for a New Chemical Entity (NCE) to prolong the cardiac QT interval.

Stethoscope and EKG

Over the last decade, QTc studies have been conducted for almost all NCEs exhibiting systemic exposure. At a cost of $2 to 4 million per study, TQT represents a significant investment and development risk considering a positive finding can result in onerous late-stage or post-approval commitments for safety monitoring. It can also completely end the development of the compound.

Traditionally, a TQT study is conducted prior to, or at the latest in parallel with, Phase III. The earlier Phase I clinical studies are typically conducted to gain Proof-of-Concept and mechanism of action data, with only basic preclinical and human cardiac safety data available.

What if someone told you that there may soon be a possibility to establish human TQT safety in a phase I Single Ascending Dose (SAD) or Multiple Ascending Dose (MAD) study? Instead of waiting more than two years and making an investment of millions of dollars to run parallel IND development activities at risk (preclinical, toxicology, contract and manufacturing, regulatory, etc.) you could assess the potential for the NCE of interest to prolong the QT interval in a statistically powered study.

You could de-risk your program…increase the value of your product for potential licensing…evaluate lead candidates for further development…address potentially confounding preclinical cardiac safety data It’s a very attractive concept.

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This concept is under consideration by the Cardiac Safety Research Consortium and the FDA itself. A current clinical study designed in cooperation by both parties is in the final stages of analysis and its prospective design was published. This study postulates that the QTc effects of drugs could be detected within a traditional First-in-Human (FIH) study design utilizing a paired approach of pharmacokinetic exposure data and QTc prolongation data versus the current methodology that simply correlates time and dose to response.

Newer and more rigorous modeling techniques are being utilized to maximize the power of smaller sized studies with increased data collection and analysis. The methodology includes a significant increase in ECG data evaluation, use of improved algorithms for cardiac assessment and careful analysis of compound systemic exposure to create a powerful combination of maximal data points in a smaller clinical trial performed as part of a required FIH study.

Stethoscope Heart Shape

It is conceivable that the traditional, standalone TQT study may become less common as the gold standard but rather an exception in cases of need.

Many of these studies do not meet the objective, failing to demonstrate clear QTc potential due to operational issues at the clinical site. The expertise of the technical staff at the clinical pharmacology site often makes the difference between a successful (i.e., negative finding) study and a positive finding.

The ability to execute ECG readings that are interpretable, with all data points, and also clearly demonstrate placebo and positive control effects are crucial to fulfilling the study objectives. These studies require much orchestration, planning and an eye on safety. FIH studies have become increasingly complex with additional sampling, biomarkers, assessments and procedures. The additional parameter of cardiac monitoring requires the technical training to competently acquire clean, quality data that can then be analyzed in tandem with the pharmacokinetic exposure data.

Vince & Associates Clinical Research is well positioned to support the current and potentially shifting guidance, expected next year. The expertise of the technical staff at our state-of-the-art clinical pharmacology campus is key for the successful completion of these complex cardiac safety studies. Our unique focus on early phase clinical development means that our facility and staff are designed to conduct studies that are complex and have additional safety parameters so as to mitigate risk.

For more information please contact us or meet with us at one of our upcoming meetings.

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