Delays in cardiac repolarization can lead to life-threatening heart arrhythmias. As part of a typical drug development program, a sponsor must assess the potential for cardiac repolarization delays following administration of their investigational product. This assessment involves examination the QT interval, which is the time during the heart’s electrical cycle from the beginning of the Q wave (depolarization of the interventricular septum) to the conclusion of the T wave (ventricular repolarization). Because the QT interval is strongly influenced by heart rate, the QT interval is often expressed as a “corrected” value (QTc) that takes heart rate into account.
For most drugs, the potential for pharmacologic prolongation of the QT interval involves performing a standalone thorough QT/QTc clinical study (TQT study). Pharmacokinetics (PK) is an integral part of TQT clinical studies and characterization of the pharmacokinetic/pharmacodynamic concentration-response relationship (PK/PD) for QT/QTc prolongation is essential during these investigations. As such, careful consideration must be given to the timing of electrocardiogram (ECG) acquisition, the PK sampling schedule, and other study design elements. Depending upon the depth of existing knowledge around the PK behavior of the drug, pre-study simulations may be helpful for guiding study design and optimizing PK sample collection times.
Because TQT studies typically require a large number of study subjects, Nuventra views these studies not only as a means of assessing potential pharmacological impacts on QT/QTc interval, but also as an opportunity to obtain additional PK data and build a more robust portfolio of PK knowledge for the drug. For example, a crossover TQT study design (see section on study design below) can allow for characterization of intrinsic intra-subject PK variability, which can be applied to the design of future clinical pharmacology studies that require statistical power (e.g., bioequivalence studies to support formulation changes).
Thorough QT/QTc Study Design
A thorough QT/QTc study is typically designed as a double-blind (except for the use of a positive control such as moxifloxacin in most studies), randomized, single-site, crossover study in healthy male and female subjects. Parallel study designs for TQT investigations are also a consideration depending on the pharmacokinetics of the investigational drug. For crossover studies, subjects are randomized to 1 of 4 treatment sequences and receive each of the following treatments in random order, with appropriate washout periods determined by the drug’s pharmacokinetics:
Treatment 1: Placebo
Treatment 2: Positive Control (e.g., moxifloxacin 400 mg IV)
Treatment 3: Therapeutic dose of investigational drug
Treatment 4: Supratherapeutic dose of investigational drug
Sponsors may also wish to consider methods for assessing cardiac QT/QTc prolongation and corresponding PK/PD relationships within the context of other early phase healthy volunteer studies and/or late phase clinical trials, including the use of intensive ECG sampling and of sparse sampling of blood concentrations in a population PK approach. If investigational drugs cannot be administered to healthy volunteers (this is common for oncology drugs, which are typically cytotoxic), then other strategies can be employed to gain insight into the potential for pharmacological QT/QTc interval prolongation.
When to Execute Thorough QT Studies in Development Programs
The timing of a TQT clinical study during the development program can depend on a variety of factors such as the outcome of relevant nonclinical investigations (e.g., hERG assay results) and therapeutic class considerations related to the potential to induce heart arrhythmias, as well as sponsor-related variables like risk tolerance and budget. For example, TQT clinical studies can be conducted early in a development program (i.e., in Phase 1) to de-risk continued development of a compound, or a TQT study can be conducted later in a development program if prior proof-of-concept efficacy data is needed to justify the expense of conducting a TQT study, which often costs upwards of $5 million to conduct, interpret, and report.
Read more in the FDA Guidance “E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs.”
Nuventra’s TQT Services
Nuventra provides a wide range of services to support your TQT study and overall development program, including:
- Expert advice on study design, including protocol and analysis plan development to accommodate both conventional and nonconventional products
- PK/PD modeling and simulation (exposure-response)
- Concentration QT (C-QT) analysis, which may help avoid a TQT study altogether and at significantly reduced cost (often greater than 10-fold) and in a fraction of the time
- Regulatory affairs expertise, including TQT waivers, regulatory submissions, and client-side support during FDA interactions
- Medical writing services, including clinical protocols, clinical study reports (CSRs), and NDA/BLA eCTD sections
- Strategic advice for your overall drug development program