It has been one year since the International Conference on Harmonisation (ICH) updated its 2005 cardiac safety guidelines. The 2015 update allows for specific QT interval analysis based upon concentration effect modeling up to supratherapeutic during Phase I as a reasonable substitute for a Thorough-QT (TQT) dedicated trial. These Phase I data along with preclinical results are submitted to the FDA prior to Phase III as a waiver request from a separate TQT study. This is good news! A dedicated TQT study involving time-wise comparisons of baseline corrected data is an expensive and lengthy endeavor. It typically takes place after proof of concept but before Phase III. Collection of QT information during an existing Phase I study costs substantially less and can provide go/no-go decisions much earlier.
The purpose of gathering QT interval information has not changed. It is a regulatory requirement to evaluate the proarrhythmic potential of all small molecule noncardiac drugs that have systemic bioavailability. A prolonged QT is the accepted regulatory biomarker for drug-related torsades de pointes - a fatal ventricular arrhythmia. Currently, more than 90 drugs on the market are known to cause QT prolongation and have received appropriated labeling. Conversely, cardiotoxicity has been one of the main reasons for both non-approvals and market withdrawals in the last two decades.
Many drugs will benefit from QT evaluation during Phase I. However, certain drugs may not be good candidates for a TQT waiver strategy. These include drugs that: 1) have a positive hERG in preclinical development, 2) increase heart rate or have other autonomic effects, 3) require lengthy up-titration to achieve therapeutic levels, 3) have a delayed effect, or 4) are an extended release formulation. Additionally, the Phase I ECG data that are collected and analyzed must be similar to that of a dedicated TQT with interval analysis that uses a proven methodology. The model must also be predefined and include adequate data collected over a wide range of plasma concentrations from subtherapeutic to at least three to five times higher than exposures required to achieve efficacy. If these criteria cannot be met, a standard TQT study might be necessary.
|► Does the preclinical data support following a TQT waiver approach?
► Will incorporating a QT waiver into our FIH study result in a major study design modifications?
► We do not know our asset's clinical PK data yet. How do we include Exposure Response Modeling to capture QT data?
► Is a QT Waiver the best strategy to mitigate regulatory risk?
► Does collection of QT data during Phase I ensure my asset will qualify for a Waiver?
► When is the best time to collect QT Waiver data and how many subjects are required?
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