As one of the most crucial phases in early research of innovative drugs, cardiac safety assessment is an issue that needs attention. In Europe and America, cardiac safety events are also a leading cause of many therapeutic drugs being withdrawn from the market. In July this year, the "E14: Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs" guideline issued by the National Medical Products Administration will be implemented, signifying that cardiac safety assessment during clinical trials may become a necessary task.

At the Seminar on Cardiac Safety Assessment in Clinical Trials hosted by DIA, Ms. Xiaomei Qi, Vice President of Elixir Clinical Research, delivered a presentation titled "Central Evaluation of Cardiac Safety Assessment in Clinical Trials" from the perspective of IRC, in which she shared the challenges of independence and data bias in cardiac safety assessment during clinical trials and Elixir Clinical Research's solutions to these issues.

Why is Cardiac Safety Assessment So Crucial?

In terms of the mechanism of action, series of pharmacological studies and clinical practices have revealed that the prolongation of QT/QTc interval is associated with the occurrence of arrhythmia. Therefore, it's necessary for new drugs to undergo comprehensive safety evaluations before market approval, including a detailed description of their impact on the QT/QTc interval. In terms of severity, non-antiarrhythmic drugs have adverse effect of delaying cardiac repolarization, manifesting as QT interval prolongation on electrocardiograms. This can lead to arrhythmias, most commonly Torsades de Pointes (TdP), which can evolve into ventricular fibrillation and result in sudden death, posing extremely serious consequences. In terms of correlation, the extent of QT prolongation can be considered as a relative biomarker for arrhythmogenic risk. There is a qualitative relationship between QT prolongation and TdP, although QT interval prolongation is not a perfect biomarker.

Therefore, as early as 2005, ICH officially released two guidelines, E14 and S7B, setting stringent requirements for cardiac safety assessment before drug market approval. In 2017, these two guidelines were endorsed by FDA and were formally implemented in the United States.

After China joined ICH in 2017, it has been gradually promoting and implementing the relevant requirements of ICH. In October 2020, the ICH Office issued the third-phase draft for comment on conducting cardiac safety assessment, clarifying that as an ICH member, China would accelerate the implementation of cardiac safety assessment regulations. In August 2022, NMPA officially issued a document, effective as of July 31, 2023, officially adopting the guidelines for clinical drug research, particularly highlighting E14 for the clinical evaluation of non-antiarrhythmic drugs inducing QT/QTc interval prolongation and potential proarrhythmic effects.

How is Cardiac Safety Assessment Applied in China?

Many manufacturers of innovative drugs in China have already conducted cardiac safety assessments in clinical research phases, including TQT and C-QT trials, in accordance with ICH standards, even before the requirements set by NMPA. Due to the inherent limitations of TQT studies, both in terms of methodological constraints and being the most expensive clinical pharmacological study, these trials pose significant challenges to the industry in terms of research investment, limiting their application.

With the release of the E14 Q&A R3 version by ICH in 2015, concentration-QTc (C-QTc) studies were officially recommended and recognized as an alternative to thorough QT (TQT) studies for assessing the risk of QT interval prolongation in new drugs. Based on single-dose and multiple-dose escalation trials in Phase I clinical studies, C-QTc establishes a relationship model between drug concentration and changes in heart rate-corrected QTc duration. It has been identified as an alternative method for conducting TQT studies for some drugs, reliably ruling out clinically relevant QTc effects. The promotion of C-QT study methodology greatly enhances the accessibility of cardiac safety assessment trials.

“We believe that with the updates to ICH regulations and their implementation in China, along with the continuous increase in the demand for Chinese innovative drugs to reach international markets, more and more products will conduct cardiac safety assessment trials represented by C-QT,” said Xiaomei Qi, optimistic about the future of cardiac safety assessment.

How to Address Independence and Data Bias Issues in Cardiac Safety Assessment?

Elixir Clinical Research, as an independent review center in clinical research phase, has extensive practical experience. On one hand, as a technical solution provider, it operates independently from the research centers and trial institutions, ensuring the authenticity of data. On the other hand, Elixir Clinical Research's IRC implements strict authority management between different trial participants, achieving role opposition, data independence, and process independence through a well-established SOP system and advanced information system. This ensures the reliability of evaluation data, adhering to the highest principle of "independence".

Another underlying logic of independent center evaluation is "centralization." Traditional methods often involve assessments at sub-centers using printed paper ECGs or directly adopting machine-generated measurements, which can lead to errors. Elixir Clinical Research conducts centralized interpretations through an electronic analysis system, ensuring long-term, secure, and high-quality storage of data in electronic form, which is in compliance with GCP requirements. This also guarantees the timeliness of interpretations and improves project management efficiency. Furthermore, it ensures the accuracy of interpretations, thereby addressing issues of independence, data bias, and variability in clinical trials.

Elixir Clinical Research's Department of Cardiac Safety

To guard every heartbeat, Elixir Clinical Research proudly introduces its newly established Department of Cardiac Safety, offering a comprehensive cardiac safety solution for early clinical trials to benefit more patients. This Department integrates medical knowledge, pharmacovigilance (PV), and statistical analysis to provide a complete cardiac safety solution for early clinical trials. From the source, namely the protocol design of clinical trials, to centralized review services, to demonstrating a target drug's cardiac safety through statistical modeling, as well as collecting and processing safety information throughout the research cycle, Elixir Clinical Research offers an end-to-end solution. It is one of the few providers capable of delivering such a comprehensive range of services.

While Elixir Clinical Research strives for excellence, our solutions are equally outstanding:

With mature project experience, Elixir's independent review center has conducted centralized clinical data assessments at a leading level domestically, with over 10 IRC projects receiving NMPA approval for marketing.

A high-quality expert team consisting of clinical pharmacology and statistical experts, with top-notch experts capable of ECG reading. Maintaining close collaboration with clinical institutions, our expert team skillfully manages technical processes including data transmission, blinding, reader management, and quality control of readings.

Possessing an FDA-approved ECG transmission and central evaluation analysis system, Elixir ensures the quality of assessments through the digital, automated, and intelligent system.

Furthermore, cardiac safety is a part of drug safety and also an integral component of the broader range of PV. In the field of PV, Elixir not only offers information systems that meet regulatory requirements and align with PV workflows of enterprises, but also provides more insightful recommendations and references to sponsors, drawing from its extensive experience in this field.

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