Review of the statistical analysis of the dog telemetry study

Abstract

In 2008, the PSI Toxicology Special Interest Group met to discuss the design and analysis of dog telemetry studies. The dog telemetry study is one component of the integrated cardiovascular assessment required by regulatory bodies. Although there are guidelines for these studies, little is said about the statistical analysis. With parameters of interest measured continually over time, in studies typically involving four dogs, the analysis is not straightforward. This has led to many different types of analysis being proposed in the literature, with many different methods applied within the pharmaceutical industry itself. This paper summarizes the PSI Toxicology group's discussions and recommendations around these issues.

Inter‐study variability of preclinical in vivo safety studies and translational exposure–QTc relationships – a PKPD meta‐analysis

“…On a relative scale (% ΔQTc from baseline), K v 11.1 channel (hERG)‐induced QTc prolongation seems thus consistent between dogs and humans, similar to recent reports (Holzgrefe et al ., ; Sparve et al ., ). This confirms with increased evidence that the conscious dog is an appropriate model to detect clinically relevant QTc prolongation and highlights the importance of adequate sensitivity – of both the study design (Leishman et al ., ) and the statistical analysis (Aylott et al ., ; Gotta et al ., ) – for detecting clinically relevant QTc prolongation of 10 ms (≈2.6% from baseline in human) in the preclinical setting. Usually supra‐therapeutic doses are studied preclinically making the detection of small effects at therapeutic levels possible (Gotta et al ., ).…”

“…This highlights the necessity to define best practice analysis standards (e.g. Snelder et al ., ), similar to those proposed for dose‐effect analysis (Aylott et al ., ), especially if such models are used for regulatory decisions. An integration of PKPD models to assess drug effects on the QTc interval and other CV biomarkers (Snelder et al ., ) simultaneously would also be desirable.…”

“…The difficulty in comparing heterogeneous studies quantitatively can be overcome by comparing concentration –effect relationships over time [i.e. by pharmacokinetic‐pharmacodynamic (PKPD) analysis], instead of dose –effect relationships at pre‐defined time points (as assessed by conventional analysis of covariance, ANCOVA; Aylott et al ., ). Therefore, PKPD modelling is also a method advocated for translating drug effects from preclinical species to humans (Leishman et al ., ; Caruso et al ., ; Parkinson et al ., ).…”

Social housing of non-rodents during cardiovascular recordings in safety pharmacology and toxicology studies

“…The standard study design for safety pharmacology studies is the Latin-square cross-over design ( Guth, Chiang, Doyle, Engwall, Guillon, Hoffmann, Koerner, Mittelstadt, Ottinger, Pierson, Pugsley, Rossman, Walisser, & Sarazan, 2015 ), which is widely accepted as conferring the best statistical power (sensitivity to detect changes in cardiovascular parameters of interest; Aylott et al, 2011 , Leishman et al, 2012 ). Some facilities performing studies with socially housed animals have retained the Latin-square design, whereby each animal within the pen receives a different dose level, with no reports of cross-contamination in over 15 years of using this approach, based on drug exposure confirmation with each study (Guth, 2015, personal communication).…”

EEG Radiotelemetry in Small Laboratory Rodents: A Powerful State-of-the Art Approach in Neuropsychiatric, Neurodegenerative, and Epilepsy Research

“…Within the last decades radiotelemetry became a widely used and highly recognized methodological in vivo approach for measuring a variety of behavioral and physiological parameters in conscious, unrestrained animals of various sizes, for instance, in the context of electroencephalogram (EEG), electrocardiogram (ECG), electromyogram (EMG), blood pressure, body core temperature, or activity measurements [ 1 – 7 ]. Virtually any species can be analyzed using radiotelemetry from laboratory rodents such as mice and rats to cats, dogs, pigs, and primates [ 3 , 8 ]. Even fish, reptiles, and amphibians are subject to radiotelemetric investigation [ 9 ].…”