Trials in Healthy Subjects and Patients
CRS accomplish excellent and fail-safe cardiac safety assessments
Delays in ventricular repolarization during electrical cardiac activity – mapped as QT prolongation on the electrocardiogram (ECG) – can lead to life-threatening arrhythmias, in particular to Torsade de Pointes (TdP) tachycardia. Since the QT interval is strongly influenced by heart rate, it is often expressed as a “corrected” value (QTc) that takes heart rate into account.
For most drugs, the potential for drug-related QTc prolongations involves performing a standalone thorough QT/QTc (TQT) clinical trial, including pharmacokinetics (PK) and pharmacodynamics (PD) as integral parts. Characterization of the PK/PD concentration-response relationship for QT/QTc prolongation is essential during these investigations.
As such, careful consideration must be given to the timing of ECG acquisition, the PK sampling schedule, and other study design elements. Depending upon the depth of existing knowledge around the PK behavior of the investigational drug, pre-study simulations may be helpful for selecting the study design and optimizing PK/PD sample collection time pointes.
The New Approach – an alternative to TQT studies
IDENTIFYING THE CARDIAC SAFETY ISSUE OF QT PROLONGATION IN NON-ANTIARRHYTHMIC DRUGS
To optimize and streamline the clinical drug development, an alternative path to TQT clinical trials was implemented in ICH Guidelines.
To define the alternative path for identifying the cardiac safety issue of QT prolongation in non-antiarrhytmic drugs, ICH has updated its E14 Guideline on Questions & Answers in December 2015. The adopted alternative evaluation describes how data from ECGs collected during Phase I or other early clinical trials can be used to demonstrate a drug’s QT safety .
ICH E14 has had also an impact on the U.S. Food and Drug Administration’s (FDA) regulatory decisions on drugs. More importantly, no new drug has resulted in TdP tachycardia and unexpected death since the guidance was effective.
THE NEW APPROACH RELIES ON INTENSIVE, HIGH QUALITY ECG ANALYSIS AND EXPOSURE RESPONSE MODELING
The new approach relies on intensive, high quality ECG analysis and exposure response modeling in early clinical development.
CRS exploits state-of-the-art techniques and procedures
CRS provides the important consideration to accumulate the specialized requirements for cardiac safety assessments in early clinical trials or in stand-alone TQT studies.
For that CRS has fully trained and qualified staff available, working with the best and latest monitoring equipment, and running the investigations in a quiet, comfortable, and spacious study environment.
Furthermore, CRS provides a wide range of services to support your TQT study and overall development program, including:
- Strategic advice
- PK/PD modeling and simulation (exposure-response)
- Concentration QT analysis as per ICH E14
- Medical writing
- Regulatory affairs
In particular cases CRS cooperates with a central ECG provider.
CRS is conducting approximately 3–5 cardiac safety trials each year, all in all 19 trials with cardiac safety monitoring and central ECG evaluation. 12 of these trials have been TQT trials pursuant to ICH E14.
CRS has cooperated with all relevant core labs (eRT, Ganimed, Nabios, MDS, CardiaBase, Biomedical System, iCardiac) and has implemented state-of-the-art technologies. CRS’s expertise covers all kinds of recording equipment (stationary/Holter), trial designs (ambulatory, hospitalized, mixed) and various blinding and dummy procedures. As already mentioned above, TQT studies are handled in specially arranged clinic surroundings separated from other clinical activities, which ensures a controlled environment with minimal sources of errors.
 ICH E14 Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs – Questions & Answers (R3).