QTc: FDA proposes labeling for heart drugs with heart rhythm risk

The US Food and Drug Administration (FDA) on Monday issued draft guidance offering recommendations for sponsors to include labeling information on QTc interval prolongation for certain heart drugs, which can increase the risk for torsade de pointes (TdP) and eventually lead to potentially fatal complications, such as ventricular fibrillation.

Patients who are prescribed non-antiarrhythmic drugs, such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and corticosteroids to prevent atrial fibrillation (AF) may experience delayed cardiac repolarization.

“An undesirable property of some non-antiarrhythmic drugs is their ability to delay cardiac repolarization, an effect that can be measured as prolongation of the QT interval on the surface electrocardiogram (ECG),” said FDA. “A delay in cardiac repolarization creates an electrophysiological environment that favors the development of torsade de pointes (TdP), which can degenerate into ventricular fibrillation, leading to sudden death.”

FDA’s newly issued draft guidance provides sponsors of such drugs with labeling recommendations for corrected QT (QTc) interval prolongation-related information.

“While the degree of QT prolongation is recognized as an imperfect biomarker for proarrhythmic risk, in general, there is a qualitative relationship between QT prolongation and the risk of TdP, especially for drugs that cause prolongation of the QT interval due to inhibition of the delayed rectifier potassium channel,” said the agency.

FDA’s guidance is in line with recommendations shared by the International Council for Harmonization (ICH), which asks sponsors of antiarrhythmic drugs to evaluate their product for cardiac repolarization early in their drug development. The agency said that figuring out the QTc effect earlier in the drug’s development may help determine how to continue looking for the effect in ECG data later in clinical trials.

“FDA/ICH recommend that sponsors conduct a single clinical trial, named the ‘thorough QT/QTc study’ (TQT study), to assess the effect of a drug on the QTc interval; this trial is typically conducted in healthy subjects who may receive a placebo, a positive control, and therapeutic dose(s) and/or doses above the maximum usual or recommended dose of the drug,” the guidance stated. “In some cases, early clinical trials (e.g., first-in-human studies, multiple-ascending dose studies) that include robust, high-quality ECGs and evaluate the QTc interval response at a sufficient multiple (commonly 2 times) of the high clinical exposure can be used as a substitute for a TQT study.”

The guidance explicitly recommends that sponsors include clinically relevant information on QTc interval data in the labeling so patients know what risks to consider. It lists examples sponsors can emulate to describe their drug’s effect on QTc interval.

FDA notes that failure to detect TdP episodes during drug development is not an adequate justification to dismiss the possibility of arrhythmogenic risks. The agency acknowledges that this risk is not always described in clinical databases, even for drugs that are known to be associated with the side effect.

Sometimes sponsors may also be unable to conduct a conventional TQT study to get the QTc interval data. In such situations, FDA said there may be alternative strategies to assess the drug's effect, and sponsors should discuss the issue with the agency before submitting their marketing application.

Stakeholders can comment on the guidance on www.regulation.gov under docket no. FDA-2023-D-2439 until 7 October.

FDA draft guidance

QTc: FDA proposes labeling for heart drugs with heart rhythm risk

Related topics

Recommended content

Welcome to the new RAPS Digital Experience