Cardiac safety is a critical consideration in new drug development, particularly in the safety assessment of early-phase clinical trials. It serves as a crucial basis for the continuation of subsequent trials, drug approval, market access, and the determination of risk of market withdrawal after launch. It is also a vital component of the clinical pharmacology section of new drug application (NDA). The importance of cardiac safety assessment is also recognized by drug regulatory authorities. On July 31, 2023, ICH E14 was officially implemented in China. E14 is the most important guiding document for cardiac safety assessment during clinical phases and has been widely applied by sponsors worldwide.

In this context, the recent "Learn from Each Other: Discussions on DIA Regulations" focused on "Regulatory Considerations of Cardiac Safety Assessment in New Drug Development." Ms. Xiaomei Qi, General Manager of the Department of Cardiac Safety at Elixir Clinical Research, was invited to share her insights on hot topics related to ICH E14 and cardiac safety assessment.

Based on Ms. Xiaomei Qi's presentation, the following six questions and answers have been compiled, which may address your concerns about ICH E14 and cardiac safety assessment.

1. What does cardiac safety assessment encompass?

Cardiac safety assessment encompasses the assessment of a drug's impact on ventricular function, heart rate, myocardial blood supply capacity, blood pressure, and other aspects, with a focus on Torsades de Pointes (TdP) induced by QT/QTc interval prolongation as a key indicator.

Assessment standards include monitoring and evaluation of 12-lead ECGs, testing and evaluation of cardiac serum biomarkers, and the incidence rate of cardiovascular events of special interest. In E14, there is a particular emphasis on changes in ECG data, especially the QT interval.

2. What is the purpose of cardiac safety studies?

The aim of cardiac safety studies is to ascertain whether a candidate drug has significant clinical impact on cardiac repolarization, providing a basis for electrocardiographic monitoring strategies in later clinical trials, rather than to assess the risk of Torsades de Pointes (TdP) in the target population. QT prolongation does not necessarily indicate a risk of TdP, nor does it imply that the drug cannot be approved. Regulatory authorities focus on whether there is sufficient data to demonstrate that the drug's safety is controllable.

In addition to meeting the requirements for regulatory approval, conducting cardiac safety studies enables researchers and sponsors to understand the drug's properties more comprehensively in the early research phase. Such understanding can lead to more targeted development strategies in later stages and possibly offer differentiated favorable options for clinical practice.

3. How does cardiac safety assessment differ from pharmacovigilance (PV)?

The differences between cardiac safety assessment and PV are mainly reflected in three dimensions:

Firstly, in terms of the event progression, cardiac safety assessment primarily focuses on the early stages of drug research, including animal studies and early-phase clinical trials. In contrast, PV typically covers the period after the drug is used in humans, extending to the latter part of its lifecycle when the drug has been marketed for sales.

Secondly, from the perspective of the focus, cardiac safety assessment mainly focuses on a range of vital signs, represented by the QT interval, while PV places more emphasis on adverse events.

Thirdly, regarding risk management strategies and measures, cardiac safety assessment is primarily conducted in non-clinical/clinical research, while PV mainly uses individual case reports, pooled analyses, and other methods for safety signal detection.

Both cardiac safety assessment and PV overlap in the drug lifecycle but have their distinct emphases. When applied in combination, they can help sponsors gain a more comprehensive understanding of a drug's impact on cardiac safety and engage in proactive and effective risk management.

4. The two main guidelines related to cardiac safety, E14 and S7B, have been continuously refined and improved during development. Since their issuance in 2005, there have been several updates to these guidelines. What are the key points of these updates?

Firstly, clarifications were made regarding electrocardiographic measurement methods, study designs, gender considerations and positive controls in QT studies, as well as ECG monitoring in late-stage clinical trials.

Secondly, the requirement for the Thorough QT (TQT) study for large molecules was eliminated, allowing for more flexible study designs, such as Concentration-QT (C-QT) studies, for drugs where traditional TQT studies are not feasible.

Thirdly, the updates involve comprehensive assessment of non-clinical and clinical risks to fully evaluate the potential risk of drug-induced arrhythmias.

5. What needs to be considered in the implementation of clinical trials when conducting studies related to cardiac safety assessment?

Firstly, in the preclinical phase, in vitro hERG laboratory studies and in vivo QT studies in dogs or monkeys need to be conducted according to the best practice requirements outlined in S7B. The focus of these experiments is to determine if the results are "double negative". This has important reference significance for subsequent clinical development.

Next, the focus shifts to the clinical phase. TQT studies can be conducted, while under certain conditions, C-QT studies may be nested within phase I single/multiple-dose studies as a substitute for TQT.

For CQT studies, it's necessary to collect plasma-drug concentration data and high-quality ECG data at the same time from patients in different dosage groups to perform C-QT analysis. If, at the highest clinically relevant exposure, the upper limit of the two-sided 90% confidence interval of ΔΔQTc is < 10 ms, the test result is negative; if it is greater than 10 ms, the result is positive, indicating the need for expanded, intensive ECG data collection in subsequent phase III clinical trials. Furthermore, after the product is marketed, its package insert should include warnings about QT interval prolongation and clearly state strategies to mitigate the

 risk.

6. Why does the ICH guideline consider partial alternatives to the TQT study?

The purpose of TQT study is to ascertain whether a drug has a pharmacological effect threshold on cardiac repolarization by measuring the prolongation of the QT/QTc interval. It is a double-blind, randomized study, and includes four trial groups: placebo, positive control, therapeutic dose, and supra-therapeutic dose, using either a four-arm crossover or parallel design.

From an execution standpoint, both 4-arm crossover and parallel designs are highly complex. In terms of research costs, TQT is the most expensive clinical pharmacology study. The original text of E14 also explicitly states, "Some drugs, due to tolerance issues, are not suitable for clinical trials in healthy populations (such as antipsychotic or chemotherapy drugs), and the results of TQT studies may affect the value of information obtained in subsequent trials."

On one hand, there is the possibility of false positive, and on the other hand, the design's limitations make it unsuitable for innovative drug research, particularly with anti-cancer drugs. This can lead to delays in the overall drug approval process. Consequently, both the industry and regulatory authorities have been exploring alternative approaches to TQT studies.

In the E14 Q&A R3 version issued by ICH in 2015, it was explicitly stated: C-QT is officially recommended and recognized as an alternative to TQT studies for assessing the risk of QT interval prolongation of new drugs.

The Department of Cardiac Safety of Elixir Clinical Research

The Department of Cardiac Safety of Elixir Clinical Research has developed a complete solution for cardiac safety assessment in early-phase clinical trials, which integrates medical, PV, and statistical analysis expertise. From the source, namely the protocol design of clinical trials, to centralized review services, to demonstrating the study drug's cardiac safety through statistical modeling, as well as collecting and processing safety information throughout the research cycle, it offers an end-to-end solution. This department is one of the few providers capable of offering such comprehensive solutions.

The Department of Cardiac Safety boasts a team of high-quality experts, including clinical pharmacology and statistical experts, with top-notch ECG interpretation expert resources. Additionally, it possesses an FDA-approved system for ECG transmission and central evaluation and analysis.

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