The ECGs must be recorded using the standard 12-lead ECGs, read manually (hand-held calipers, on-screen digital calipers,
digitizing pads), and interpreted by cardiologists. The systems used for ECG evaluation must be calibrated, validated, and
What the Regulators Say
How do regulatory bodies want to receive the data?
The regulatory agencies are clear about the importance of complete, integrated cardiac safety data in any regulatory submission.
The sponsor must provide complete, comprehensive, and authentic data in a uniform format. The recommended formats are digital
ECG collection, and submission in XML format. This allows the regulatory authorities to view the annotations on the ECGs.
How much can an early study tell us about a drug's cardiac effects on the general population?
A thorough QT/QTc study on healthy volunteers will give researchers a fairly good idea about the cardiac repolarization effects
of a drug. More data can be gleaned from the additional ECGs during the development process. However, the most important sources
of information about QT effects remain post-marketing data and reported adverse events.
It is very important to assess the need of a thorough QT/QTc study in light of preclinical data on cardiovascular safety.
It is ideal to plan a thorough QT/QTc study early in the development phase to strengthen the case for an approval/disapproval
from regulatory bodies. It also allows for further planning of cardiac safety evaluation during the later stages of development.
A study on QT prolongation, demonstrated by nine non-cardiac drugs during in-vitro studies in dogs compared with in-vivo studies,
revealed that six of the drugs showed a positive finding with in-vitro methods and seven with in-vivo methods. Thus, a well-designed
preclinical assessment of QT interval prolongation, in accordance with ICH guidelines, will serve as a good indicator of the
need for future cardiac safety investigations.
A robust preclinical evaluation, combined with a thorough QT/QTc study, if negative, may preclude the need for intensive ECG
evaluation in Phase II/III—thus resulting in substantial cost saving in the later stages of development. A positive QT/QTc
study almost always will call for an expanded ECG evaluation in later stages of development. This also is in the best interest
of sponsors. Since they are in a position early on to decide about further investment in the molecule, having the appropriate
data may bring more efficiency to their R&D strategy.
How does the risk-benefit analysis vary from drug to drug?
While it is important to do thorough cardiac-safety profiles for all drugs, the benefit of any drug must be weighed against
the risk. It is particularly important for new drugs for which a viable, safe alternative already is available in the market.
For example, the risk-benefit analysis for a drug that treats schizophrenia would be very different from the risk-benefit
analysis for an analgesic or an antihistamine. Obviously, the risk-benefit profile will differ if a viable safe alternative
already exists for a new drug.
Given what we know now, is there already an effective strategy for assessing the cardiac safety of drugs?
In general, manufacturers need to be proactive about cardiac-safety analysis for any drug, since this is a prerequisite for
approval. By planning a thorough QT study early in development, researchers can achieve proof of concept early in the development
life cycle; the investment is well worth the initial expenditure.
Compliance with regulatory authorities in data collection and submission is a cost-cutter; having digital ECGs analyzed by
a core group of readers and submitted in XML format is recommended. Finally, top managers must assess the risks of a compound
in a holistic risk-benefit framework, keeping in mind the preclinical results, the thorough QT study results, and the class
of the compound.
Jogin Desai, MD (firstname.lastname@example.org
is executive director and Sheetal Shetty, MD (email@example.com
) is a medical writer, both with Quintiles ECG Services, based in Mumbai, India.