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Keys to a Successful Thorough QT/QTc Trial
Thursday, November 15
9:00 am – 11:00 am
Roundtable
ACPE #073-999-07-550-L04
The advent of the thorough QT/QTc (TQT) trial has transformed cardiac monitoring in clinical trials. Withdrawal of several drugs in the last decade due to cardiac concerns has drawn attention to the potential of medications to induce life threatening arrhythmias. In an attempt to better characterize the cardiac safety of new compounds, a TQT trial is now required by the FDA as outlined in the ICH E14 guidance, “The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.” The final ICH E14 guidance describes basic requirements for a TQT trial, but leaves many aspects open for interpretation. For example, it is clear that four treatments are necessary; placebo, therapeutic dose, supra-therapeutic dose, and positive control. However, are four distinct treatment arms required? In addition, what qualifies as a supra-therapeutic dose? Safety concerns may prevent use of high doses for some compounds and other well tolerated compounds could be dosed at ten or even one hundred times the anticipated therapeutic dose. What criteria should be used to determine this dose? Even more fundamental is the question of how to ensure quality ECG data. What are the important variables to control, and how should those variables be controlled? If a positive result is obtained from the TQT trial, extensive QT/QTc evaluation is required during phase II/III trials to better characterize the cardiac safety of the drug. This can add significant time and cost to drug development thus it is imperative that good quality data is obtained to ensure accuracy of results. The primary factors impacting ECG data quality are the recording technique and method used for ECG acquisition. The standard 12 lead cardiograph is the most common method used to acquire ECG data. However, in TQT trials the inefficiencies of the cardiograph can make it difficult to collect the large amount of ECG data required. The ease of use makes the holter monitor better adapted for use in TQT trials and studies suggest that equal quality data can be obtained using either method. However, most holter monitors do not allow for real time visualization of the ECG tracing so data quality cannot be determined until the end of the study when it may be too late to make necessary adjustments. Because the recording technique can significantly impact the ECG data quality, an understanding of the equipment limitations is important to ensure study success. The discussion of these questions and others are necessary when designing and conducting a TQT trial. The significant impact of the TQT trial on future drug development makes these decisions critical to the success of new compounds.
Moderator
Joy L. Olbertz, Ph.D.
MDS Pharma Services
Overview of TQT Design and Analysis
Benoit Tyl, M.D.
MDS Pharma Services
Technical Factors that Affect the ECG Measurement of QT
Paul D. Kligfield, M.D.
Weill Medical College, Cornell Medical Center