A prolonged QTc has been defined as > 450 ms in males and > 470 ms in females. A QTc increase to > 500 ms during therapy should
arouse concern among investigators. According to the International Conference on Harmonization (ICH) and concept papers, a
change from baseline QTc greater than 30 ms must be addressed in the categorical analysis.
Which QT correction formula gives the best data?
Because the QT interval changes with heart rate, correction formulae (traditionally, those applied by Fridericia (QTcF) or
Bazett (QTcB)) are used to "correct" QT levels to represent a standardized heart rate of 60 beats per minute. Scientific literature
suggests that these formulae show QT variations at different heart rates. Bazett's method, in particular, overcorrects at
elevated heart rates and undercorrects at low heart rates. Linear-regression techniques and correction formulae derived from
subject data have been suggested by the concept papers for QT correction. Regulatory authorities also propose these data to
be submitted in addition to QTcB and QTcF data.
Why is a prolonged QT interval dangerous?
A prolonged QT interval creates an electrophysiological environment that is favorable for the development of cardiac arrhythmias,
especially the polymorphic ventricular tachyarrhythmia known as TdP. When a drug—especially a drug that is not designed for
heart ailments—prolongs the QT interval, prolongation acts as a surrogate marker for the proarrhythmic potential of the drug.
The concern is that some drugs that prolong the QT interval could cause life-threatening arrhythmias.
What We Don't Know Yet
How much QT prolongation are regulators likely to allow?
The FDA concept paper issued in 2002 says drugs that prolong the mean QT/QTc by 5 to 10 ms have not been associated with proarrhythmic
risks. However, drugs causing a mean increase of 10 to 20 ms are of concern, and those correlating with increases beyond 20
ms have an increased likelihood of being proarrhythmic. Both the concept papers and the E14 document have invited the scientific
community for comments on the choice of 5 ms as the threshold value for safety concerns. (See "What We Don't Yet Know.")
How early in the R&D process can a QT/QTc study be carried out?
To maximize return on investment, QT-interval studies should be moved up as early in the development process as possible.
A 2003 paper in Toxicologic Pathology suggests the use of beagle dogs as the most reliable model for preclinical assessment of the QT interval. This will streamline
the early drug-development process and enable sponsors to eliminate some drugs before they reach the costly clinical stages.
This data also can reduce the need for intensive ECG evaluation in Phase II/III for other compounds. Both of these outcomes
will result in substantial cost savings in the later stages of development. Preclinical QT/QTc studies indicating prolongation
call for an expanded ECG evaluation in later stages of development. This helps sponsors decide early on whether to continue
investment in the molecule. (See "The Integrated Cardiac Safety Solution".)
Beginning cardiac safety studies as early as the preclinical phase enables clinical research teams to make go/no-go decisions
earlier in the process and maximize their return on investment.
How reliable is ECG data collection across a group of patients?
The data are reliable as long as collection methods are consistent. Study sponsors must use a small group of readers to evaluate
and interpret the ECGs. All the readings should be done under a set of consistent standard operating procedures defined prior
to study start.