On August 27th, I have the honor of giving a talk at the European Society of Cardiology’s Annual Congress, in Barcelona, on Cardiac Safety in Drug Development.

The talk is based on a poster developed by a team of QuintilesIMS cardiac safety experts, on the important topic of Individual-specific corrected QT interval (QTcI) obtained from ECGs recorded at fixed timepoints versus those captured using a wider range of stable heart rates.

Rare but fatal

Cardiac safety is a critical component of contemporary new drug development. It is unfortunate that no new drug is free from the possibility of causing adverse reactions in certain individuals who are genetically and/or environmentally susceptible. This includes adverse effects on the heart’s natural electrical activity, which ensures that our hearts beat regularly and hence provide our bodies with the oxygen every cell needs to function. While serious drug-induced interruptions of this electrical activity are very rare, they can be fatal if they are not addressed by expert medical care.

Since 2005 the international regulatory landscape requires all new drugs to be tested for proarrhythmic liability in a dedicated clinical trial, called the Thorough QT/QTc (TQT) Trial.  These trials are typically conducted in clinical pharmacology units where there are cardiologists and other medical experts who can take immediate action should any participant in these trials need treatment.

The cardiovascular parameter that is assessed in TQT trials is the QT interval, which is the interval from the start of the Q wave to the end of the T wave in an electrocardiogram, and an important measure of the pattern of the heart’s electrical activity. QT interval prolongation increases the risk of the life-threatening ventricular arrhythmia known as torsades de pointes (TdP) and is considered to be an imperfect yet important biomarker for potential drug-induced proarrhythmia. 

However, assessing a drug’s potential to lead to proarrhythmia is difficult as the QT interval can be affected by concurrent heart rate even in the absence of any drug-induced influence.  Various techniques of ‘correcting’ for heart rate have therefore been developed. Such corrections are called “QTc”, with the ‘c’ standing for ‘corrected for heart rate.’ These correction factors are of particular importance when a given drug is known to have an effect on heart rate.

The poster and associated talk I’m giving at this year’s Congress provides the rationale for a new and improved methodology for correcting observed changes in the QT interval for heart rate.

QTc, ECGs, and CiPA

It is currently an exciting time to work in the field of cardiac safety.  Until recently, cardiac safety evaluations first involved research employing animal models, and then focused on the dedicated TQT trial involving human participants.  However, over the last few years, much work has been conducted internationally to propose and develop a new paradigm known as the Comprehensive in vitro Proarrhythmia Assay (CiPA).  CiPA is a novel safety screening proposal intended to replace the 2005 regulatory strategy recommended by the International Conference of Harmonisation S7B guideline, and is intended to move safety pharmacology from a predominantly traditional pharmacodynamics approach to in silico and in vitro drug toxicity assessment. CiPA includes computer-based modeling (in silico research) and in vitro data obtained from human stem cell-derived ventricular cardiomyocytes to estimate proarrhythmic risk of new drugs with improved accuracy. 

This approach is notable in that it is in keeping with a set of standards knows as the “3Rs” --- the reduction, refinement, and replacement of laboratory animal studies in drug development.  The fundamental principle here is that animals are only used when there is no alternative.  Drug development researchers have an ethical duty (and in some countries, a legal duty) to obtain and review all of the available scientific literature to determine if there is an alternative way of acquiring the information that would be gained from an animal study. 

Innovation in any field of investigation that allows drug efficacy and drug safety information to be gained from alternative research methodology not involving animals is welcomed by the pharmaceutical industry.

And, while clinical trials will still be needed to verify information gained from previous steps in the drug development, the information gained from in silico research and stem cell-derived cardiomyocytes means that humans participating in TQT studies will do so with an even greater degree of safety.

If successfully developed and accepted by regulatory agencies, the CiPA paradigm will be a considerable step forward for our industry. In the evolving field of cardiac safety, is vital that we constantly assess our methods, and seek out opportunities to improve the efficacy of our approach. CiPA is an excellent example of this evolution, and I look forward to discussing its potential benefits to patients, sponsors, and clinical research at this very important Congress.

I look forward to seeing you there.