Drug developers must demonstrate that new medications are safe and effective in order to win regulatory approval. The gold standard in cardiac safety testing has been the Thorough QT study, a separate, expensive trial that is typically conducted late in the clinical development process.
The international body that informs drug development standards has just revised its stance to support definitive QT testing based on ECGs collected during existing early-stage trials. iCardiac Technologies, where I’m a board member, pioneered this approach in conjunction with the FDA. I asked iCardiac’s CEO Alex Zapesochny to explain what is happening.
- What is the ICH and why does it matter for clinical trials?
The International Council for Harmonisation is an international forum for regulators to harmonize drug approval practices. The group includes pharmaceutical industry representatives and regulators from the United States, Canada, the European Union, Japan and Switzerland.
As for the clinical trials process, the ICH aims to make recommendations toward achieving greater harmonization in the interpretation and application of technical guidelines and requirements related to research and development of new drugs. These guidelines can assist with pharmaceutical product registration and help reduce or avoid duplication of testing carried out during R&D.
- ICH has issued a regulatory revision for cardiac safety testing. What specifically has it done?
Currently, the FDA and other regulators expect nearly all new drugs to be tested using a costly, stand-alone Thorough QT (TQT) study to assess a drug’s effect on the QT interval before market approval. This is an important step, since a prolonged QT interval is associated with a heightened risk for arrhythmias and possible sudden cardiac death. The latest revision adopted by the ICH states that data from ECGs collected during routine Phase I or other early clinical trials may be used to conclusively demonstrate a drug’s QT effect. This approach relies on intensive, high quality ECG analysis and the use of exposure response modeling.
- What led to the change?
Regulators around the world want to make the drug development process as safe, precise and efficient as possible. The ICH revision emerged a year after the U.S. Food and Drug Administration helped to organize a meeting of thought leaders to discuss the results of a successful prospective validation study demonstrating the ability to determine cardiac safety much earlier in the development process. This revision is likely the most significant regulatory shift in cardiac safety since the original E14 guidance was adopted by the ICH in 2005.
- What role did iCardiac play? The FDA?
iCardiac has been championing this alternative approach for several years, including collaborating with thought leaders from the FDA and from industry to help organize a prospective validation study to definitively test this new approach. Ultimately iCardiac sponsored that definitive validation study, and it was overseen by iCardiac personnel and used our proprietary High Precision QT methodology to perform the critical data analysis. Leaders from the FDA have been involved in multiple key ways, including decisions around the validation study design and co-authoring publications about the validation study and its implications. Of course, the FDA is also a participant in the ICH and played a direct role in the new regulatory revision.
- What will be the practical implications?
This development provides an alternative path for sponsors with regard to demonstrating the effect of their drug on QT, which is a critical part of gaining market approval for a new drug. By analyzing ECG data from a Phase I or other early clinical study, sponsors can choose to seek a waiver from regulators from having to do a TQT study. The FDA granted the first TQT waiver based on this alternative approach earlier in 2015. So apart from saving time and money, this approach gives drug developers insight into their compound’s QT liability much earlier in the clinical trials process.