Nonclinical Advances in Proarrhythmia Risk Assessment
There have been remarkable advancements in the nonclinical evaluation of the potential for drugs to have ventricular proarrhythmic effects. In 2013, the FDA and a consortium of scientists and drug developers initiated the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative to further inform internal company and regulatory decision making, primarily putting additional focus on preclinical assays.
In the past 10 years, the CiPA initiative has led to refinements in the evaluation of a drugs effect on the human ether-a-go-go related gene (hERG) and QT measurements in non-rodent animals (principally in dogs and monkeys), direct human ventricular action potential measurements, human induced pluripotent stem cell-derived cardiomyocytes (IPS-CM) testing and in silico modeling.
Electrophysiologic drug evaluation using cardiomyoctyes –IPS-CM or actual human ventricular trabeculae derived from donors has played a major role in arrhythmia risk assessment. Their use can also reduce the need for additional animal studies beyond the ICH S7B CV non-rodent safety study.
IPS-Derived Cardiomyocytes Are Imperfect
IPS-derived cardiomyocytes are imperfect in that their generation leads to a variable population of cells of mixed maturity and myocytes of atrial, ventricular, and nodal-like cells.
An advantage of actual human ventricular cells and trabeculae is that these non-diseased cells have the full electrophysiologic profile of adult ventricular myocytes. In addition, ventricular trabeculae preparations have cell to cell coupling closely recapitulating the human situation and their evaluation uses direct action potential measurements, increasing their clinical relevance.
These cellular-based studies play important roles for early (pre-IND) internal decision making and candidate selection when the hERG assay or the animal CV safety study results are ambiguous or raise unresolved questions. Thus these assays play an important role in the ICH S7B integrated arrhythmia risk assessment.
IPS-Derived Cardiomyocytes Are Imperfect
The ICH E14/S7B questions and answers (Q&A) document was significantly revised in 2022 (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/e14-and-s7b-clinical-and-nonclinical-evaluation-qtqtc-interval-prolongation-and-proarrhythmic), increasing the role of non-clinical assays.
When negative hERG and non-rodent CV safety studies meet the ICH requirement for best practices, these studies can be used to meet regulatory requirements in new ways. Q&A Section 5.1 permits the exposures required in humans to demonstrate a QTc effect < 10 ms to be reduced; Section 6.1 stipulates that drugs that cannot be given with the quality and high exposures required in ICH E14 (e.g., a placebo control is not possible, side effects limit supra-therapeutic exposures, etc.), an integrated nonclinical/clinical risk assessment is particularly valuable.
The nonclinical studies can be used to make the case that a QTc effect < 10 ms has a low potential to be proarrhythmic. Given that the argument hinges on the totality of evidence, ventricular myocyte testing can significantly add to the integrated risk assessment, and in the case of actual ventricular human cells (vs IPS-CMs) provides direct human adult cellular data.
In summary there have been important advances in the nonclinical proarrhythmia assessments which have impacted both internal decision-making as well as regulatory requirements. As the science continues to evolve, I expect this trend to continue.
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