Current practices on the measurement of electrocardiogram and hemodynamic parameters in non-rodent species in regulatory safety assessment studies.

INTRODUCTION: Cardiovascular (CV) parameters1 such as blood pressure (BP), electrocardiogram (ECG), and heart rate (HR) are recorded in non-rodent non-clinical safety studies to support drug development. However, measurement quality varies depending on the methodology used, including restraint-based or telemetry (implanted or jacketed) techniques. Measurement quality, in this context, refers to the sensitivity and reliability of CV measurements in affecting baseline values of measured CV parameters and in detecting pharmacological effects. This retrospective multifaceted analysis evaluated the impact of recording methods on baseline CV parameters and their statistical and pharmacological sensitivities in detecting drug-induced CV effects.

METHODS: Data were collected from three sources: (i) 495 studies from seven pharmaceutical sponsors (2015-2023), (ii) FDA-approved drugs (47 NCEs, 26 NBEs from 2022 to 2023), and (iii) two major CROs (2020-2023). Studies were conducted in dogs, non-human primates (NHP), or minipigs, with treatment durations of up to 52 weeks. Additionally, literature-based and proprietary data were analyzed to assess baseline CV values and methodology sensitivity. A survey was conducted to evaluate statistical analysis practices in these studies.

RESULTS: All 3 datasets showed that the ECG is collected in most repeat dose toxicology studies, but not BP; the findings were largely independent on the modality (i.e., NCE versus NBE) or the indication (i.e., oncology vs. non-oncology). The choice and usage of ECG and BP methods is highly sponsor-dependent, with restraint-based methods for individual sponsors ranging from 0 to 100 %. FDA data showed that telemetry-based methods are predominantly used in short, single dose toxicology/safety pharmacology studies for NCEs. Subsequent studies of longer duration employ predominantly restraint-based snapshot methods. CRO data showed that approximately 30 % of toxicology studies do not include ECGs; however, when an ECG is recorded it is primarily collected in restrained animals using a snapshot approach. BP is infrequently recorded, regardless of methodology, in repeat dose toxicology studies. The de novo analysis and literature-based search showed that baseline BP/HR values were highly variable with consistently higher means under restraint compared to telemetry methods. The root mean square errors for BP/HR were larger under restrained conditions, in both species. Under restrained conditions, the use of fixed formulae for HR-corrected QT resulted in inconsistent QTc values across sponsor and CROs. The survey showed that statistical analysis of ECG/BP data was infrequently performed under restrained conditions in contrast to telemetry-based methods. Proprietary and published case studies showed that drug-induced BP elevation or QTc prolongation observed clinically and in NHP or dog using telemetry were not reliably detected under restraint-based conditions, highlighting limitations of RB methods in CV safety evaluation. The data illustrate that animal restraint reduces the pharmacological and statistical sensitivities to detect CV effects.

CONCLUSIONS: ECG and BP recording methods vary based on sponsor preference, experience and/or institutional practices in addition to scientific rationale. Literature and case studies confirm the limitations of restraint-based methods. As ICH S7A/S7B evolve, revisiting CV assessment practices is necessary to align with scientific, technological, regulatory, and 3Rs considerations, ultimately improving best practices for regulatory safety assessment.