Streamlining Analysis of Ion Channel In Vitro Assays Data to Support Clinical Decisions

The Center for Drug Evaluation and Research (CDER) researchers have been pioneering methods for sharing and analyzing extensive volumes of cardiac electrophysiology in vitro data. This initiative aims to enhance the analysis and interpretation of nonclinical data, thereby supporting vital clinical cardiac safety decision-making processes.

Since 2005, evaluating the risk of a potentially dangerous heart rhythm known as Torsade de Pointes (torsade) has been mandatory for nearly all new drugs. This heart rhythm issue is typically tied to a prolonged QT interval in the electrocardiogram (ECG) due to delayed cardiac repolarization. This is commonly caused by the blockage of the ion channel encoded by the human ether-a-go-go gene (hERG) in heart cells. The International Conference on Harmonisation (ICH) E14 guidance outlines a dedicated clinical study to assess the risk of QT prolongation and other proarrhythmic concerns, referred to as a thorough QT (TQT) study.

With significant advancements since 2015, the ICH E14 questions and answers document (ICH E14 Q&As) R3 suggests using drug concentration and QT changes from non-dedicated QT studies. More recent updates from 2022 further indicate how in vitro hERG studies can support integrated nonclinical risk assessments, potentially eliminating the need for a separate clinical QT study for ICH E14 compliance.

As parallels develop between clinical QT study data and FDA’s anticipated reception of raw data from ion channel experiments, the need for a standardized data exchange format became evident. Such data exchange is crucial for independently evaluating best practices in submitted assays, irrespective of whether they occurred before or after new guidance releases. However, there wasn’t an open data standard available for sharing cardiac electrophysiology in vitro data, which presented a challenge to comprehensive risk assessments.

To bridge these gaps, CDER researchers collaborated with external stakeholders through initiatives like the Comprehensive in vitro Proarrhythmia Assay (CiPA). Since its inception in 2013, CiPA has evolved into a global effort, incorporating regulators, industries, and academia with various public-private partnerships. This collective thrust under CiPA sprouted a modern, model-informed methodology for cardiac safety assessment of new pharmaceuticals, grounded on a robust understanding of ionic currents affecting QT prolongation and torsades development.

However, the exchange of raw data for CiPA-related research encounters hurdles due to proprietary data formats needing transformation into various files for further analysis in different tools. An imminent need to establish an open data format was recognized, resulting in the creation of the CiPA Open Data (COD) format. Developed collaboratively by industry, academic, and FDA CDER researchers, the COD format aids in sharing cardiac electrophysiology data generated through both manual and automated high-throughput patch clamp systems.

Alongside the COD format, the Tabulated Experimental Data (TED) format was crafted to allow easier export of existing manual patch clamp data, further simplifying data sharing and interpretation. Both formats were built considering several data handling standards and recommendations, such as the Minimum Information of Cardiac Electrophysiology Experiments (MICEE) and FDA-supported file types.

The CDER team also invested in means for analyzing and presenting ion channel pharmacology experiment outcomes. The development of an automatic analysis and reporting pipeline for COD and TED datasets marked a significant advancement. It enabled an expedited analysis, converting previously time-consuming analyses into a streamlined process, producing interactive HTML reports and comprehensive numerical data tables.

This automation allows CDER scientists and reviewers to efficiently evaluate the reproducibility of assay results or to verify adherence to best practices such as recording quality, as specified in ICH S7B guidelines. A notable application of TED format and this analytical pipeline was documented in Alvarez-Baron et al. (2022), exemplifying hERG block potencies across different temperature settings.

To combat the variance seen in hERG and other cardiac ion channel in vitro assays, an international undertaking, funded via a Broad Agency Announcement (BAA) from the FDA and awarded to HESI, was chartered in 2019. This ambitious project has engaged multiple laboratories to generate extensive in vitro cardiac multi-ion channel data over several phases, using both manual and automatic systems adhering to COD and TED formats.

As the HESI BAA project nears completion, the data compilation strategy effectively minimizes earlier challenges encountered during the CiPA initiative, facilitating meta-analysis and data transparency. This approach, leveraging standardized formats and automatic tools, ensures higher efficiency and accuracy while enabling substantial understanding of the variability surrounding cardiac electrophysiology results.

To summarize, CDER’s pioneering research into data sharing and automatic analytics for cardiac electrophysiology data not only highlights innovative methodologies for nonclinical risk assessments but also aligns with global standards under ICH E14/S7B guidelines. By collaborating with international partners and using formats like COD and TED, significant progress is evident in supporting clinical cardiac safety decisions through enhanced data reliability and transparency.

This project exemplifies a joint effort supported through the Research Fellow Program at the FDA, showcasing interdisciplinary engagement between governmental, industrial, and academic spheres, thereby fostering advancements in cardiac safety science.