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Changes to cardiac safety assessments could equal more drugs in the pipeline and cost savings to sponsors.
Changes to cardiac safety assessments could equal more drugs in the pipeline and cost savings to sponsors
In December 2015, the ICH updated its E14 Guideline Q & A to define an alternative path for identifying the cardiac safety issue of QT prolongation in non-cardiac drugs. This is the most considerable revision to the Q&A of “The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs”1 since its implementation in 2005 and is based on a study conducted with the Cardiac Safety Research Consortium (CSRC).2 The adopted alternative describes how data from ECGs collected during Phase I or other early clinical trials can be used to demonstrate a drug’s QT effect. What it represents for sponsors is earlier collection of QT data, which could represent a savings of over 80% as compared to the most recently sanctioned Thorough QT (TQT) studies, which hover in the $2M to $4M range.
Cardiologists and clinical trialists had long been discussing ways to address cost challenges surrounding TQT studies when they started to emerge, soon after the Guideline was issued in May 2005. The guideline basically states that drugs in clinical trials for non-CV conditions should undergo TQT studies to ensure that the drugs did not cause QTc interval prolongation. These longer intervals predispose a patient to Torsade de Pointes, a life threatening arrhythmia. Sponsors quickly adopted TQT studies, and have ensured their conduct for the past 10 years.
Published reports show that ICH E14 has had an impact on FDA regulatory decisions on drugs. Of 205 NDA submissions, 46 drugs were identified as QT prolonging. Of the 46, 41 were approved with labeling restrictions to inform of the QT-related issues.3 More importantly, no new drug has resulted in TdP and unexpected death since the guidance went into effect. No one disputes these successes, but the downside-risk aversion by pharma has discontinued approximately 60% of new molecular entities for suspected proarrhythmia3 and the high costs of TQT studies, which are traditionally conducted in stand alone trials, after proof of concept, in randomized arms of healthy volunteers with a positive control.
In 2012, the CSRC members began their own discussions around E14 and initiated the IQ-CSRC study in 2014. CSRC members were invited to participate in the study and iCardiac Technologies signed on as the core ECG lab to analyze the data and, based on the results of the study, ICH made its revision to allow the alternative approach.
The new approach relies on intensive, high quality ECG analysis and the use of exposure response modeling. This type of data-driven approach was actually the premise for iCardiac’s establishment 10 years ago and has led to the development of High Precision QT methodology. Although that was the method used in the study, the CSRC has made it clear that it does not formally endorse any particular method over another, and there are other core ECG labs that can produce the data needed for detecting the changes noted in this study.
From the FDA’s perspective, iCardiac CEO Alex Zapesochny explained, if a sponsor submits QT data to a regulator, which meets certain defined standards, as described in the ICH revision document, it may seek a waiver from having to conduct a TQT study. The FDA granted the first TQT waiver based on this alternative approach earlier in 2015.
Zapesochny told Applied Clinical Trials that the lower costs for sponsors are important, but also to the earlier de-risking and more confident decision-making relative to QT liability for a drug in development. “We were hearing from various large pharma companies if they saw any hint of a QT signal, they would sometimes discontinue the drug. That’s the big outcome from this. Drugs that may not see the light of day are being tested earlier and more cost-effectively for QT liability.”
Because iCardiac conducted the study, its Chief Scientific Officer and cardiologist Dr. Borje Darpo has authored on the many resulting papers that came out of the study, along with other CRSC participants. Darpo said in a release, “The significance of the change in regulations is that is it gives sponsors a choice. You can either perform a careful assessment of the drug’s effect on ECG parameters as part of your standard early clinical trials, or you can later on conduct a formal TQT study. Both options are now viable alternatives, provided you do things right.”