Design and Analysis of Thorough QT Studies

by Alex Dmitrienko, PhD, Charles Beasley, MD, Malcolm Mitchell, MD

This is a comprehensive and well thought out summary of design and 
analysis issues in QTc trials.
 
QTc is an imperfect biomarker for cardiovascular outcome.  It is used 
as a surrogate in ICH E14 guidance with good reason.  Regulators and 
patients obviously wish to avoid a repeat of the terfenadine experience.  
QTc prolongation is a necessary but not sufficient condition for the 
subsequent or coincident occurrence of torsades de pointes.
 
As digital ECG data acquisition becomes a reality, it is to be expected
that more accurate and precise surrogate measures of CV outcome will be 
defined and used for the purpose of patient and population safety.  
These technical advances of the near future targeting the ECG should 
obviate the need for measurement of QTc and would be expected to lead 
to smaller, more expert studies for the assessment of cardiovascular risk. 
 
In brief, I advise folks not to get too used to QTc and thorough QTc 
trials.  Things are expected to  change.  If someone looks back in 2108 
at advances in science and medicine in the area of study of cardiovascular 
risk, it is to be expected that what we do now will appear as antiquated 
(though groundbreaking) as the research of Bazett and Fridericia does 
to us now.  In the meantime, we should do our best with the measures and 
studies we can conduct. 
 
Scott Patterson, PhD
Senior Director of Statistical Science,
Vaccines and Infectious Disease
Wyeth Research and Development