QTc least significant difference in stand-alone implanted telemetry safety pharmacology and jacketed external telemetry regulatory toxicology studies in dogs

The use of least significant difference (LSD) as the metric for variability of specific study, especially in the context of ICH E14/S7B Q&As studies, is considered as part of best practice. This parameter represents not only the threshold of statistical significance for a given parameter, but also reflects the intrinsic study variability. LSD is commonly used to evaluate the variability of QTc changes in standalone 4 × 4 cross-over (XO) Q&As studies. To our knowledge, LSD evaluations are not commonly performed when jacketed external telemetry (JET) in parallel groups is used during safety pharmacology studies integrated in regulatory toxicology studies, despite the complementarity between this approach and standalone XO safety pharmacology studies. The use of one and/or the other approach could prove necessary depending on the nature and/or the PK/PD of the drug candidate. Therefore, we calculated LSDs for QT and QTc in 7 randomly selected telemetry investigations, including 3 XO design studies and 4 JET studies in a parallel design. Four male dogs and 32 dogs (16 males and 16 females) were used in each XO and JET investigation, respectively. Animals received vehicle with no impact on ECG parameters and/or 3 doses of test items. LSD is calculated using repeated measure ANOVA over 24 h in several intervals. LSDs for QT interval per study were 5 ± 2, 12 ± 5 and 8 ± 3 msec in XO and 11 ± 6, 8 ± 3, 13 ± 6 and 8 ± 4 msec in JET. LSDs for QTc (with Miyazaki correction) per study were 4 ± 2, 5 ± 2 and 5 ± 2 msec in XO and 3 ± 1, 6 ± 3, 12 ± 6 and 2 ± 1 msec in JET. Mathematical sensitivity comparisons between both approaches might be difficult. However, the threshold for detecting statistically significant increases in QT/QTc from JET cardiovascular studies was close to that shown in XO studies. This investigation shows that jacketed ECG can be as adequate as cross-over implanted cardiovascular studies to support an integrative risk assessment of QT prolongation in the dog. However, this first set of LSD values will need to be completed with the same analysis, based on a larger cohort of studies.