12:00 AM
Aug 05, 2013
 |  BioCentury  |  Regulation

Rushing to abandon tQT

FDA aiming to replace clinical QT studies with suite of preclinical assays

FDA's Norman Stockbridge wants to abandon thorough QT studies by 2015, replacing them with a preclinical assay suite better able to detect proarrhythmia side effects than existing assays. However, it remains unclear whether two years is sufficient time to develop and validate the assays to a level that convinces stakeholders the QT trials are no longer necessary.

According to Stockbridge, director of CDER's Division of Cardiovascular and Renal Products, the new approach is needed because the focus on QT prolongation under the agency's current guidance has likely hindered drug development, potentially killing compounds that do not in fact cause fatal arrhythmia.

Pharma companies, life science investors, clinicians and academics who attended a workshop sponsored by FDA, the International Life Sciences Institute's Health and Environmental Sciences Institute (HESI) and the Cardiac Safety Research Consortium (CSRC) agreed.

The new assay suite would be designed to directly measure the proarrhythmia potential of compounds and thus be better suited for culling unsafe compounds than thorough QT trials (tQT) and existing preclinical assays, because neither is highly predictive of Torsades de Pointes (TdP), a rare but potentially fatal cardiac arrhythmia.

Most of the potential components of the new assay suite already are being used by companies and academics. Those include stem cell-derived cardiomyocytes, in vitro cardiac ion current measurements and computational models of cardiac cell electrical activity.

One challenge will be arriving at a consensus on what specific elements to include in the final assay suite.

A second challenge will be generating enough data to validate the new suite and support its use in place of tQT trials.

"We need to show that the new assay paradigm will do as well as current methods at detecting surprises while still not overstating [proarrhythmia] dangers," said Robert Temple, CDER's deputy director for clinical science.

FDA will work with drug developers to define the specific components of the suite and validate and standardize it across companies and CROs. HESI, a not-for-profit research and training institute that has experience validating biomarkers and platforms across organizations, will play a central role in that process.

"It's my hope the stakeholders treat July 2015 as a deadline we must work together to meet in order to get a working preclinical assay in place," Stockbridge told BioCentury after the meeting. "If we hit that deadline, I believe we can then withdraw the current guidance recommending a tQT study."

Long time coming

Much of the meeting was spent discussing the problems of using QT prolongation as a surrogate for risk of TdP.

Drug developers and regulators have long known that QT prolongation is far from an ideal predictor of TdP risk. That is because QT prolongation is necessary but not sufficient to cause TdP and therefore by itself has a low specificity for the condition. A QT prolongation signal may thus overstate a drug's TdP risk (see BioCentury, June 2, 2003).

Unfortunately, direct assessment of TdP risk during standard clinical trials has never been an option. Trials generally enroll far...

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