As the evolution to a new approach in assessment of repolarization liability of new chemical entities continues, it is necessary to expand the usefulness of early human-phase testing to systematically confirm the preclinical assessments and to allow the exploration findings uniquely available from human subjects. The most productive path in these efforts will be to fully utilize enhanced analysis of technologies already established, primarily the collection of continuous 12-lead Holter recordings. This will not only support robust QT metrics, but can bring additional focus to underutilized data elements including arrhythmia, conduction, and morphology. Most importantly, continuous data analysis, collected during both rest and ambulation, can be incorporated in dynamic QT beat-to-beat repolarization analysis, examining the ability of the heart to recover from one beat to the next (restitution) in the face of prolongation of the QT interval during rapid heart rates or changes in heart rate (impaired hysteresis).
The FDA and prominent clinical and academic thought leaders have initiated efforts to find preclinical methods for “Rechanneling”, the Thorough QT (TQT) Study. Nevertheless, there was no expectation that clinical studies will be eliminated entirely. “ECG evaluation and the careful assessment of drug effects on intervals (PR, QRS, QT), heart rate, and QT morphology will be utilized to demonstrate that there are no effects in humans that were not predicted based on the preclinical evaluation.” In fact, results have now been reported based on collaboration among many of the same experts whereby “a clinical study in healthy subjects demonstrating that the thorough QT (TQT) study could be replaced by robust ECG monitoring and exposure–response (ER) analysis of data generated from First-in-Man single ascending dose (SAD) studies.”
This marks the start of a time for creative innovation in the appropriate, efficient and validated use of electrodiagnostics. Researchers have generally not even taken advantage of the potential of continuous data, automated analysis, and beat-to-beat approaches.
The standard QTc measure is almost exclusively obtained under resting supine conditions when heart rates are very stable. Dynamic assessment takes into account all normal states of physiology and the full range of heart rates during normal rest and activity.
Continuous ECG data with continuous, automated analysis of interval values would allow a QTc response profile to be developed. This would focus attention on where findings emerge. These periods can be further analyzed according to a prospective strategy to validate abnormal findings, eliminate technical error and to plan adaptive strategies for future cohorts or studies.
There is increasing confidence in ER modeling analysis in the assessment of repolarization effects of new compounds, in lieu of endpoints limited solely to mean responses at selected time points. The statistical approach used in ER analysis, regression modeling of changes from baseline in QTc as a function of concentration findings, allows robust repolarization effects to be characterized with fewer subjects and fewer ECGs than even the most limited TQT study.
With continuous ECG collection there is no need to ignore the heart rate and arrhythmia data inherent in the data being collected. Likewise, full analysis of PR and QRS findings can be accomplished using automation.
Morphology characteristics of the ST segment, and T and U wave can be digitally characterized and changes from baseline delineated. Novel metrics of sub-intervals of the T wave are receiving attention. Selective prolongation of the time from T peak to the end of the T wave (Tp-Te) holds promise as a measure of multi-ion channel blockage and an indication of more benign proarrhythmic profile for QT prolonging drugs.
Continuously collected RR, QT and TQ (diastolic period) intervals can be further analyzed using dynamic QT beat-to-beat (QTbtb) and restitution analyses to provide information for individual adaptation of the QT interval to heart rate and impact of changes in autonomic state. QTbtb assesses the QT interval changes without use of correction factors by directly comparing treatment related beats to all normal beats occurring at the same heart rate under baseline conditions. As research progresses, it is expected that there will be the ability to better qualify pharmacological elevations of QT intervals in the settings HR and autonomic variation, and to differentiate between drugs that are “torsadogenic” and those that are not.
Based on the various rationales outlined above, BioTelemetry Research is proposing a service offering for evaluation of cardiac repolarization in early human trials, novel to the industry, called Dynamic Repolarization Analysis.
The data collection would be during either a typical SAD and/or MAD study. Continuous 12-lead Holter would be used to collect ECG signals with the subjects quiet during the 10 minutes prior to and 5 minutes after each concentration blood sampling timepoint BUT fully ambulatory, ad libitum, the remainder of the time. Once received at BioTelemetry Research, signal processing would provide:
- Complete beat-to-beat QT and RR data
- A continuous QTc profile
- The HR, PR and QRS profiles over time
- Beat-to-beat QT-RR interval relationship and restitution (QT/TQ vs RR interval)
- Scatter plots of QT vs RR at baseline and during selected times of treatment (e.g., Cmax)
- Calculation of % of beats exceeding the upper 97.5% reference bounds for QT interval at baseline
- Tp-Te values
- T wave morphology characterization
Anthony A. Fossa, PhD, Consultant
Dr. Fossa is an independent scientific consultant with over 30 year experience in preclinical and clinical cardiovascular safety. Prior to consulting, Dr. Fossa was a Research Fellow at Pfizer for over 22 years and VP of Cardiovascular Safety at iCardiac Technologies for over 7 years. Dr. Fossa is one of four original founding members of the General Pharmacology/Safety Pharmacology Steering committee that is known today as the Safety Pharmacology Society. His research has focused on the use of the beat-to-beat dynamics and the ECG QT – TQ interval relationship in humans and conscious dogs, to assess arrhythmia liability related to human QT prolongation. Dr. Fossa received his Ph.D. in Pharmacology and Toxicology from Purdue University in 1983.
Daniel B. Goodman, MD, Vice President and Medical Director, BioTelemetry Research
Dr. Goodman directs all aspects of protocol planning and development for Sponsors, and for analysis of cardiac safety results. He is materially involved in innovations in medical technology and novel analyses, as well as in implementing the latest regulatory initiatives. He has direct interactions with key sponsor personnel and with academic experts to provide expert consulting solutions. Dr. Goodman received his training at Yale University and Cornell University Medical School. In the early 1990s, he founded Cardiology for Clinical Trials, one of the world’s first cardiac core labs. Dr. Goodman went on to direct medical affairs for Covance Cardiac Safety Services from 1994 until 2007. After this post, Dr. Goodman worked closely with the medical team as a senior scientific consultant for several years, while practicing medicine intermittently. Dr. Goodman is an international thought leader in cardiac safety testing, developing protocols, producing scientific reports, conferring with regulators and publishing extensively.
Who Should Attend?
This webinar will benefit professionals within biopharmaceutical research and medical device organizations, specifically those in the following roles:
- Chief Medical Officer
- VP Clinical Operations
- VP Clinical Development
- Director Clinical Operations
- Director Clinical Development
- Medical Writers
As the research division of BioTelemetry Inc. (Nasdaq: BEAT), BioTelemetry Research, formerly Cardiocore, provides one of the world’s largest clinical data networks. Our broad range of Cardiac and Imaging services support both safety assessments and efficacy evaluations across all major therapeutic areas, through all phases of clinical trials, in every global region.
BioTelemetry Research offers a full range of centralized clinical trial testing modalities for both safety and endpoint evaluation. Cardiac includes ECG, Holter, TTM, MCOT, ECHO, and ABPM/BP. BioTelemetry Research provides Imaging services across therapeutic areas, including Oncology, CNS, Musculoskeletal, and Cardiovascular. Supported Imaging modalities include MRI, X-Ray, PET/CT, Bone Scintigraphy, and others.