Recommendations on the measurement of electrocardiogram and hemodynamic parameters in restrained non-rodent species in regulatory safety assessment studies

Abstract

Life supportive cardiovascular (CV) parameters [e.g., arterial blood pressure (BP), electrocardiogram (ECG), heart rate (HR)] are recorded in non-rodent safety pharmacology and toxicology studies and data are used to support pharmaceutical drug development in accordance with several guidelines (e.g., ICH M3, S6, S7, S9). Various methodological approaches are used to collect CV parameters on toxicology studies, including fully implantable telemetry, non-invasive jacket telemetry, and short-duration restraint-based measurement from surface ECG leads and a blood pressure cuff, but their robustness and applicability domain differ widely. The challenge of using conscious animals, especially non-human primates, is that arousal behavior, locomotion, body temperature, and sympathetic activation are significant sources of variability that impact CV parameters, thus telemetry methods are the preferred approach. Historically, toxicology studies have incorporated short-duration restraint methods (manual; chemical sedation) to collect brief periods (“a snapshot at one timepoint”) of CV endpoints in a large number of non-rodents (N ≥ 24) after repeat dosing. Non-rodent species, however, demonstrate increased BP and HR in response to room entry and/or manual restraint, which confounds the interpretation of drug-related effects. Published case examples and company experiences indicate that CV waveforms collected under restraint are of low quality, can vary based on body position and sensor placement (skin electrode; pressure cuff), as well as the type of sedative and dose used. In addition, the data captured can be misleading or incongruent with CV safety pharmacology findings in the same animal species. As a result, restraint-induced stress lowers the sensitivity to detect CV changes as measured over a short-duration and has a higher probability for false negative findings. Although functional CV evaluations in restrained animals have been included in toxicology studies for decades, there is no industry consensus on methods, assay performance, or value (translation) for risk assessment. This communication will review the available literature and leverage pharmaceutical and Contract Research Organization (CRO) experiences, and propose recommendations, with an emphasis on short-duration techniques, from the ICH E14/S7B Industry Support Group with the aim to identify how, when, and if short term restraint-based CV data are valuable for nonclinical safety assessment.