Changing Heart Rhythms
Safety Assessment
Regina Kelder

Changing Heart Rhythms

An interview with cardiology expert Philip Sager on regulatory changes that are transforming cardiac safety testing.

In December, U.S. and international regulators made critical changes to a guidance document known as ICH E14, commonly referred to as the "QT guidance," that pharmaceutical manufacturers have long treated as gospel. Most drugs will not make it to market without satisfying it by performing a Thorough QT study (TQT study).

The guidance was originally created to provide guidance to sponsors concerning the "design, conduct, analysis, and interpretation of clinical studies to assess the potential of a drug to delay cardiac repolarization." Since its adoption in 2005, the E14 Guidance has been tweaked several times, but this latest amendment is inarguably the most significant. In a nutshell, sponsors will be able to trade the expense of a TQT study, which normally is conducted during the latter stages of drug development, with a more built-out but nevertheless cheaper ECG assessment during a routinely performed first-in-human Phase 1 trial.

This naturally raises questions about the future of the TQT and the E14 guidance. To put these changes in perspective, Senior Scientific Writer Regina McEnery talked with Dr. Philip Sager, an internationally recognized cardiologist who chairs the FDA Cardio-Renal Advisory Committee and the Scientific Programs Committee of the Cardiac Safety Research Consortium (CSRC). He is also a member of the ICH E14 Discussion Group and consults on CV safety and QT issues. Dr. Sager spoke about the genesis of E14—and this latest change—and how it ties into the Comprehensive in vitro Proarrhythmia Assay (CiPA) Initiative that is currently in development.

Q: Why was the E14 guidance created?Dr. Philip Sager

PS: There was growing concern that many drugs were being either removed from the market because of QT increases or torsades de pointes, or had had warnings added to their labels. This was seen as a major public health problem, with a number of drugs being linked to the development of sudden cardiac death. Since we completed the guidance in 2005, there have been a few revisions to the guidance, the most recent being this past December.

Q: What helped push this latest revision out the door?

PS: New data that showed that carefully collect ECG data in a Phase 1 first-in- human clinical trial using exposure response modeling can be used to assess the QTc and other electrocardiographic effects of a drug with a high level of assurance. Even though the number of subjects in a Phase 1 is not large, exposure-response modeling is sufficiently powerful in a properly designed study to make excellent QT assessments. A study prospectively tested this hypothesis on a number of drugs. The study was completed a little over a year ago and it provided strong, prospectively collected scientific data to permit another pathway to assessing effects of the drug on the QT interval for regulatory purposes.

Q: Who did the study?

PS: It was done by the IQ [Consortium for Innovation and Quality in Pharmaceutical Development] and the CSRC. The FDA was also involved. The study was led by Dr. Borje Darpo, who is the Chief Scientific Officer of iCardiac Technologies, one of the core ECG labs and the financial sponsor of the study.

Q: How much does a TQT study cost?

PS: Typically, overall more than US$1 million. These are fairly involved studies. They have three to four arms, with 40 to 60 patients per arm. The studies are either done in crossover or parallel design, they use a lot of resources, and they typically are not done until later in development. By prospectively building careful ECG data collection into a Phase I study, one can, identify if there is an issue or de-risk a potential issue at a very early stage. Using the first in human studies in this manner brings significant cost savings and increased efficiency.

Q: But the E14 revision also bumps up the cost of the Phase 1 trial, right?

PS: You have the cost of having ECGs read by an ECG lab, but a lot of the other things that have to be built in are just doing things with the appropriate protocol and do not add a lot of expense. Significantly, it relieves you of the burden of having to conduct a separate TQT study.

Q: What is critical to the success of these Phase 1 studies?

PS: You have to think your study out carefully beforehand and add some necessary items. Most are simple, but you won't be able to mitigate the situation if you do not do them in the first place. So it requires a good bit of prospective thinking. For instance, you need to make sure you have the proper ECG collection protocol in place along with PK sampling time points around Cmax, assuring that the ECGs quality meets the regulatory requirements (in the US the ECGs are submitted to the FDA). In addition, it is critical to explore supratherapeutic exposures. If careful attention is not paid to such issues, one could end up having to do the TQT study anyway.

Q: Are there still sponsors who prefer the TQT study?

PS: Sure. Like anything else, people will need to gain experience in order to get comfortable with the E14 revision. The CSRC will be holding a meeting April 6 in Washington D. C. that will discuss some of these approaches in Phase 1. We'll also be talking about what kinds of human ECG assessments one would do under CiPA.

Q: What events opened the door to CiPA?

PS: Firstly, the science was evolving over the last 10 years pertaining to our mechanistic understanding of what causes torsade de pointes. Also, some of us had become quite concerned that focusing on QT and hERG [the human Ether-à-go-go-Related Gene] related current (IKr) was having a negative effect on drug development. Drugs that have a significant effect on hERG or, in humans, the QT interval, are commonly terminated from further development. Yet we know that drugs like verapamil, which affects hERG, or those that prolong QT, like phenobarbital and ranolazine, are not actually proarrhythmic. So the concern was that there are many potentially important drugs being prematurely discontinued, on the basis of biomarkers that are not very specific. So a group of us met at the FDA in 2013 to discuss a new approach. This led to the CiPA proposal, which is detailed in a paper we published about two years ago. It is expected that CiPA will make drug development more efficient, increase the development pipeline, and provide a model of a mechanistic approach that can be used in other safety areas (e.g., drug-induced myocardial damage).

Q: How many drugs were getting discontinued due to QT or hERG?

PS: A lot. De Ponti and colleagues estimated that as many as 60% of new molecular entities, when assayed for hERG, test positive and are thus routinely abandoned early during development.

Q: Is the E14 revision as significant as CiPA?

PS: The latest E14 revision makes the evaluation of the QT interval much more efficient and cost-effective and provides data at an earlier development stage informing if a drug meaningfully affects the QTc. This is important. But CiPA, which will assess not whether a drug prolongs the QT interval—a rather imperfect biomarker—but whether it is actually proarrhythmic, is more revolutionary. CiPA is going to allows us to say, even before a drug gets into humans, what the likelihood is that a drug is proarrhythmic, even if it prolongs the QT interval. Drugs that prolong the QT interval, but are not thought to be proarrhythmic based on the CiPA evaluation, will be able to move forward in development without an expectation of deleterious labeling related to arrhythmias (assuming no unexpected issues arose during clinical development).

Feel free to email Dr. Sager at [email protected] if you have specific questions regarding the E14 guidance, CiPA, or performing the described first in human studies. Also, check out these recent Eureka blog posts found herehere, and here on CiPA.

How to cite:

McEnery, Regina. Changing Heart Rhythms. Eureka blog. Jan 28, 2016. Available: