The Importance of Reproducibility

The CIPA assay is an early screening tool for the detection of arrhythmic potential in animals. During the development phase, the assay was tested on nine different animal strains, four of which had myocardial infarction and two did not. These initial tests established the assay’s safety and efficacy. After the validation phase, an improved protocol was applied to a subset of three animals, two of which had myocardial infarction and one of which was normal. The CIPA assay improved cardiac function in these patients and proved to be effective for early screening tests.

Mechanistic Assessment Of Proarrhythmic Potential

The Comprehensive in vitro Proarrhythmic Assay (CiPA) is an experimental model of the human ventricular myocyte that integrates multiple cardiac ionic currents. This method is being developed to identify, and characterise drug effects on cardiac ion channels, as well as to assess the potential for proarrhythmic. Currently, data from ion-channel assays are typically stored in proprietary formats and exported to spreadsheets with a specific layout. By integrating multiple cardiac ion currents into one assay, this new method will make it easier to share data in a research environment and facilitate review of datasets.

In order to create a robust model, the CIPA assay employs an in-silico model qualification procedure designed by the CiPA Steering Committee. This procedure includes model optimisation and metric development. The datasets are evaluated against a predefined list of twelve training compounds to ensure that the model can adequately represent the proarrhythmic properties of each drug.

Reproducibility Of Results

Reproducibility is the ability of a method to reproduce results. The method must use a different experimental setup, measuring device, dataset, and methodology to produce the same results. Reproducibility is essential for a variety of reasons. It reinforces findings and prevents fraud or human error.

 In this study, the HESI Cardiac Safety Committee’s Myocyte Sub team evaluated the electrophysiologic responses across eight compounds. The team looked for reproducibility and variability across the different platforms and compounds. The results showed that there was an overall lack of reproducibility, but there were some areas of high reproducibility.

Regulatory Authority

The Regulatory Authority for the CiPA Assay (CIPA) is a multinational group of experts from the pharmaceutical industry and academic institutions that have come together to develop a novel, nonclinical assay for proarrhythmic risk assessment. This collaborative effort is the result of a comprehensive, mechanistic approach to integrate different components in a single assay. The objective of the CIPA is to facilitate a new paradigm for TdP assessment, which is not driven by hERG block potency or QT prolongation, but by a suite of mechanistically based in vitro assays and in silico reconstructions of cardiac electrophysiologic activity. The resulting assays will be validated with the aid of human-derived cardiac myocytes.