Evaluating QTc Risk and ECG Changes in Early Clinical Development

Introduction

Cardiac safety assessment is a critical component of Phase 1 clinical trials, particularly for new chemical entities and biologics with unknown off-target effects. One of the primary concerns is QT interval prolongation—a surrogate marker for the risk of Torsades de Pointes and sudden cardiac death. Phase 1 studies typically include intensive ECG monitoring to detect such changes early. This article outlines best practices, regulatory expectations, and technical strategies for cardiac safety monitoring, with a focus on QTc evaluation, ECG scheduling, and data interpretation.

Why Cardiac Safety Is Prioritized in Phase 1

Many marketed drugs have been withdrawn due to cardiac arrhythmias linked to QT prolongation. Since Phase 1 represents first-in-human exposure, it is essential to:

• Identify QTc changes before large-scale exposure
• Understand heart rate, rhythm, and conduction effects
• Inform go/no-go decisions for dose escalation
• Mitigate regulatory risk and support thorough QT (TQT) waiver strategies

What Is QTc and Why It Matters

The QT interval on an ECG represents the time from ventricular depolarization to repolarization. Prolonged QT increases the risk of fatal arrhythmias. The QT interval is corrected for heart rate using formulas:

• QTcB (Bazett): QT / √RR
• QTcF (Fridericia): QT / (RR)^1/3 – preferred in clinical trials

Thresholds of concern:

• QTc > 450 ms in men or > 470 ms in women
• QTc increase > 30 ms from baseline is concerning
• QTc increase > 60 ms or QTc > 500 ms is high risk

Study Design Strategies for QT Assessment

1. Intensive ECG Collection in Phase 1

• 12-lead ECGs collected at pre-dose and multiple post-dose timepoints
• Triplicate ECGs preferred at each timepoint to reduce variability
• Paired ECG and PK sampling to enable exposure-response modeling

2. Thorough QT Study (TQT) Waiver Strategy

• If intensive ECGs and PK analysis in Phase 1 show no QT risk, TQT may be waived
• Preferred by FDA under ICH E14/S7B integrated risk assessment approach

3. Exposure-Response Modeling

• Model the relationship between drug concentration and QTc change
• Linear mixed-effects models used to support waiver from TQT

4. Placebo-Controlled ECG Subsets

• Use a subset of subjects dosed with placebo to establish baseline ECG variability

ECG Equipment and Data Collection

1. Digital ECG Devices

• Devices must be FDA 21 CFR Part 11 compliant
• Data exported in XML/DICOM format for core lab analysis

2. ECG Core Labs

• Independent review of QT, PR, QRS, and HR values
• Manual adjudication of automated readings
• Outlier detection, central reading, and quality assurance

3. Wearable Devices for Telemetry

• Optional in hybrid or inpatient trials for continuous rhythm tracking

Safety Monitoring and Risk Mitigation

1. Real-Time ECG Review

• On-site or remote cardiologist to review ECGs post-dose
• Predefined QTc thresholds for stopping rules

2. ECG Alerts and Medical Oversight

• Trigger medical review if QTcF > 480 ms or delta QTc > 30 ms
• Hold dose escalation pending Safety Review Committee decision

3. Concomitant Medications

• Screen for drugs that prolong QT (e.g., macrolides, fluoroquinolones)
• Document electrolyte levels (K+, Mg++, Ca++) pre- and post-dose

Regulatory Guidelines and Expectations

FDA

• Follows ICH E14 and S7B guidelines for QT risk assessment
• Supports integrated nonclinical and clinical QT strategy
• Allows TQT waiver based on robust Phase 1 data

EMA

• Requires ECG data for drugs affecting ion channels or cardiac targets
• Expects ECG monitoring in SAD/MAD studies

CDSCO (India)

• Mandates ECGs in FIH studies and for drugs with known cardiac risk

Case Studies

Case 1: Oncology Drug with HERG Inhibition

• Preclinical data showed HERG inhibition at 10 µM
• Phase 1 QTc increased 22 ms at Cmax, no clinical QT > 480 ms
• PK-QT model supported dose escalation

Case 2: Antibiotic with QT Liability

• Triplicate ECGs and TQT study required
• QTc increase of 12 ms at therapeutic dose
• Label included “use with caution in QT-prolonging conditions”

Best Practices for QT and ECG Monitoring in Phase 1

• Plan ECG collection points based on Tmax of the drug
• Use triplicate 12-lead ECGs with centralized review
• Collect paired PK and ECG samples to model concentration-QTc relationship
• Train site staff in ECG timing, positioning, and artifact minimization
• Ensure ECG core lab meets GCP and regulatory standards