QT Prolongation Draft Guidance Urges Single Clinical Trial For Evaluation
This article was originally published in The Pink Sheet Daily
Executive Summary
The ECG trial should be early in clinical development (but not the first study) should be carried out in healthy volunteers and include a positive control group, FDA’s draft guidance says.
|
FDA's 1 draft guidance on clinical evaluation of QT prolongation calls for drugs to receive electrocardiogram evaluation in a single trial early in development. "In general, drugs should receive an electrocardiographic evaluation, beginning early in clinical development, typically including a single trial dedicated to evaluating their effect on cardiac repolarization," the draft guidance states. The draft guidance, prepared under the auspices of the International Conference on Harmonization, states that the trial "would usually not be the first study, as it is important to have basic clinical data for its design and conduct, including tolerability and pharmacokinetics." The study would "typically be carried out in healthy volunteers" unless the product's tolerability indicates such testing would not be suitable. The draft guidance provides recommendations to sponsors concerning clinical studies to assess the potential of a new drug to cause cardiac arrhythmias, focusing on the assessment of changes to the QT/QTc interval in the ECG as a predictor of risk. The study should use a positive control group, the draft states. "The confidence in the ability of the study to detect QT/QTc prolongation can be greatly enhanced by the use of a concurrent positive control group to establish assay sensitivity," the document states. "The positive control (whether pharmacological or non-pharmacological) should be well-characterized and consistently produce an effect corresponding to the largest change in the QT/QTc interval that is currently viewed as clinically not important to detect (a mean change of around 5 ms or less." "An adequate drug development program should ensure that the dose-response and generally the concentration-response relationship for QT/QTc prolongation have been characterized, including exploration of concentrations that are higher than those achieved following the anticipated therapeutic doses," the draft states. The document states that even if the clinical trial does not show an effect, "if other evidence of an effect in a patient population from subsequent studies were to emerge, then additional investigation would be needed." ICH also released draft guidance for the preclinical evaluation of the potential for QT prolongation (see 2 (Also see "Pre-Clinical QT Prolongation Guidance Urges In Vitro, In Vivo Studies" - Pink Sheet, 10 Sep, 2004.) ). - Andrew Shelton |