Debate around best practices for safety pharmacology continued on December 11, 2014 as global regulators, drug developers and scientists from contract research organizations gathered in Silver Spring, MD for a workshop on the Comprehensive in vitro Proarrhythmia Assay (CiPA) and the clinical QT testing initiatives that stand to create a new paradigm in cardiac safety testing and drug development.
So, what led to the proposal for this sweeping change and why the debate?
In the early 1990s, a number of FDA-approved drugs for non-cardiac indications were linked to cardiac arrhythmia and six compounds were withdrawn from the market, the most infamous being terfenadine (Seldane). This is an enormous issue for public health, and in response, international regulatory authorities released three guidance documents: two nonclinical (ICH S7A and S7B) and one clinical (ICH E14).
The nonclinical guidelines state that all drugs seeking regulatory approval in the US, EU and Japan would undergo two nonclinical tests to determine proarrhythmic potential. The first test is the in vitro hERG assay, which determines whether a drug interferes with one of the ion channels that can lead to cardiac rhythm disturbances (arrhythmias). The second test, performed in laboratory animals, is an assessment of the electrocardiogram (ECG), to look for an effect called QT prolongation. This is a biomarker for the potentially fatal arrhythmia Torsades de Pointes (TdP). Although this biomarker is not perfect, exactly the same assessment can be made in humans, which is what the ICH E14 guideline addresses. Following this paradigm, animals can be used to predict effects in humans with a high confidence and therefore manage this safety risk.
Since the introduction of these guidelines, no drugs have been withdrawn from the market for causing these rare cardiac events. Despite the apparent success of these regulations, the guidelines are under review because many safety pharmacologists believe alternative approaches can deliver reduced costs and improve speed of development, while continuing to ensure safety for patients.
Among the top reasons for change are the considerable costs and time associated with clinical studies required in the ICH E14 guideline. These specialized clinical trials add to development time and, since 2005, have cost pharma companies an estimated $1 billion.
But it's not all driven by financial benefits. Scientific advancements during the past 14 years may offer better, more efficient ways of testing for indicators of drug-induced cardiac arrhythmia. The hope, say supporters, is that newer methods will reduce both clinical and animal work, helping bring compounds to regulatory authorities, and ultimately patients, more quickly.
Further, some scientists believe that the existing guidelines are too conservative and have prevented some potentially efficacious drugs from reaching patients and providing benefit. They envision the new paradigm will stop the conservative "throwing the baby out with the bath water" behavior and may reopen opportunities for some drugs that were previously halted in development allowing them to be reconsidered for approval.
Since July 2013, the solution up for debate has been to move away from the existing, relatively simple testing paradigm that relies upon one cardiac ion channel (hERG) before progressing into animal studies in favor of CiPA. The proposed CiPA assessment has three components:
As was evident at the December workshop, which was sponsored by HESI, CSRC and the FDA, many unanswered questions remain about CiPA despite the proposed July 2015 deadline. These include the use of standards, protocol design and, most importantly, translation and predictive value to humans, as well as whether, CiPA and the newly proposed clinical testing paradigm will be accepted by regulatory agencies.
The key question, however, is if a suitable CiPA profile, together with an appropriate outcome in a Phase I clinical ECG study, will provide a waiver for the expensive ICH E14 study? An impressive study sponsored by IQ-CSRC, designed and analyzed by iCardiac and performed by Covance, gives confidence that this is possible. This study assessed six reference drugs in a typical Phase I clinical study design to show the expected results with high statistical power. This study sets the scene for an improved testing paradigm to test patient safety and business risk and support a more efficient approach to drug development.
For now, it seems certain that change - in some form - will come, and with it, a potential revolution in how drugs come to market. If the initiative delivers on what its supporters tout, an earlier, more precise study may open doors for more significant therapeutic advances and fewer drugs being needlessly discarded.
Until then, we are keeping a watchful eye and anticipating the wide-reaching impact of CiPA on drug development in the not-too-distant future. We are already seeing a number of large pharma companies building their capabilities to address the objectives of CiPA, so we predict that it may not affect their preclinical work significantly. However, small- and medium-sized companies, which may not have the resources to conduct these tests in-house, may soon find themselves needing help to create strategies and drug development plans to address the initiative's objectives. Drug development partners like Covance may play a part in that. It's just one more question that needs to be thoughtfully answered.
What do you think about the CiPA and clinical QT debate and its long-term influence on drug development? Join the conversation.