The Impact of being Built Into Phase I for Cardiac Safety

Photo: Marek Studzinski

When a new drug reaches its first human studies, every additional assessment has to balance two competing priorities: generating enough evidence to make sound development decisions while keeping the study operationally manageable. Cardiac safety sits squarely at that intersection.

That balance is receiving renewed attention. On September 18, 2026, the International Council for Harmonisation published revised E14/S7B Questions & Answers, providing updated implementation support for the clinical and nonclinical assessment of QT/QTc prolongation and proarrhythmic risk. The update reflects an ongoing shift toward integrating different sources of cardiac safety evidence rather than viewing each assessment as an isolated exercise.

The reason cardiac assessment carries such weight is straightforward: changes in cardiac repolarization can be associated with serious arrhythmia risk. The QT interval on an electrocardiogram provides an important measure of ventricular repolarization, and drug-induced QT prolongation has historically been a central concern in evaluating potential proarrhythmic effects. FDA and ICH guidance therefore place QT/QTc assessment within a broader framework for understanding a drug’s cardiac risk.

For sponsors, however, the challenge is not simply deciding whether cardiac safety should be assessed. It is determining how to generate meaningful evidence within the development program.

A traditional thorough QT, or TQT, study remains an important tool for characterizing a drug’s effect on QT/QTc. But regulatory thinking has evolved. The E14/S7B framework allows sponsors, in appropriate circumstances, to use data from other clinical studies—including concentration-QTc relationships from early human studies—alongside nonclinical evidence. An integrated approach can potentially reduce the need for a separate clinical QT study when the available evidence adequately addresses the relevant risk.

That flexibility does not make cardiac assessment simpler by default. It makes study design more consequential.

The decision about how to evaluate cardiac risk increasingly begins before participants enter the study. Sponsors have to consider the characteristics of the investigational drug, its expected exposure, available nonclinical findings and the design of the early clinical program. Those factors can influence when ECGs should be collected, how they should be analyzed and how cardiac findings will ultimately be interpreted alongside pharmacokinetic and safety data.

In Phase I, ECG collection has to be coordinated with dosing, pharmacokinetic sampling and the expected exposure profile of the investigational drug. ECG measurements themselves are subject to variability, making standardized collection, appropriate timing and consistent interpretation important to the quality of the resulting evidence. ICH guidance specifically addresses factors such as reader variability and ECG methodology because seemingly small differences in collection or interpretation can affect the consistency of a dataset.

This creates a practical challenge for sponsors. Phase I studies are already highly coordinated environments in which dose escalation, participant monitoring, laboratory assessments, pharmacokinetic sampling and adverse-event evaluation may all be occurring on tightly controlled schedules. Adding cardiac assessments means another layer of timing and operational coordination.

The challenge is not simply finding time to perform an ECG. The assessment has to be positioned in a way that makes the resulting data scientifically useful. If ECG collection is poorly aligned with drug exposure, for example, the resulting dataset may be less informative than a smaller but better-timed set of measurements.

The operational challenge is therefore one of integration. Cardiac monitoring is taking place alongside dose escalation, safety observations, laboratory testing and PK assessments, often within compressed Phase I timelines. The goal is not simply to collect more ECGs. It is to ensure that the right cardiac data are collected at the right time and can be interpreted alongside the other evidence generated by the study.

Data quality adds another consideration. Cardiac safety assessments can involve repeated ECG measurements, continuous Holter recordings and other cardiovascular observations, creating substantial volumes of information. Those data have to be captured, transferred, reviewed and analyzed consistently. Any gaps in that process can complicate interpretation later, particularly when sponsors need to connect ECG findings with drug exposure or other safety observations.

Technology is beginning to support that objective. FDA researchers have been developing open data formats and automated analysis tools for large volumes of cardiac electrophysiology data, with the aim of streamlining analysis and interpretation for clinical cardiac-safety decision-making. The agency has specifically noted that better integration of nonclinical and clinical data can support development decisions while potentially reducing unnecessary duplication.

This points to a broader definition of efficiency. Efficiency in cardiac safety does not necessarily mean conducting fewer assessments. It can mean designing the study so that each assessment produces information that is useful for the next development decision.

That distinction is particularly important when considering whether a dedicated TQT study is necessary. A sponsor may be able to leverage appropriately collected early-phase ECG and pharmacokinetic data as part of a concentration-QTc analysis, depending on the drug and the overall evidence package. In other programs, a dedicated study may still be appropriate. The point is that the strategy should follow the scientific and regulatory questions rather than assuming that every compound requires an identical pathway.

For CROs, that makes operational coordination part of the scientific equation. AXIS Clinicals, for example, conducts cardiac safety and TQT studies using ECG and cardiovascular monitoring capabilities, while its February 2026 announcement of ERT certification highlighted its ability to support the design, conduct, analysis and interpretation of continuous Holter recordings. Its clinical and bioanalytical operations are housed within the same purpose-built facility, allowing study teams to coordinate cardiac monitoring, clinical operations and sample analysis within an integrated Phase I environment.

That kind of integration matters because sponsors are managing more than an individual cardiac endpoint. They are trying to build a coherent evidence package while maintaining participant safety, protocol adherence and operational consistency. A CRO that can coordinate the different components of an early-phase program can help reduce the handoffs that otherwise create delays or inconsistencies.

It also reinforces why cardiac safety planning should happen early. Decisions about ECG methodology, monitoring schedules, equipment, staffing, data workflows and analysis cannot always be made independently of the broader protocol. Addressing those considerations during study design can make it easier to preserve both scientific rigor and operational flexibility once the study begins.

The direction of the field is increasingly clear: cardiac safety assessment is becoming an exercise in integrated evidence, thoughtful study design and better data handling.

For sponsors, the opportunity is to build that strategy into Phase I from the beginning rather than treating cardiac safety as a separate requirement to solve later. The most efficient assessment is not necessarily the one with fewer measurements. It is the one designed to produce the right evidence, at the right time, in a form that can support confident development decisions without compromising the quality or interpretability of the data.