Are current rat studies sensitive to detect blood pressure changes per the new FDA draft clinical blood pressure guidance?

Abstract

Released in 2022, the FDA's draft guidance “Assessment of Pressor Effects of Drugs”, proposes that a dedicated clinical study for chronic use drugs should be powered to rule out a potential systolic arterial blood pressure (BP) increase of 3 mmHg over 24 h. Given the resource commitment of clinical studies, sensitive nonclinical prediction of potentially meaningful BP increases would be valuable. This study aimed to determine the utility of long-term rat studies for detecting acute and chronic blood pressure changes. We hypothesized that studies using rats have adequate stability and variability to detect BP changes ≥3 mmHg over several weeks. Available data from a historic rodent assessment of 80 days duration (N = 9) in vehicle treated Sprague Dawley rats was used. The data were assessed for minimal detectable differences (MDDs), least significant differences (LSDs), and changes from baseline for all BP measures in light and dark 12 h, days, and weeks. Day 15 was used as the reference day and Day 43 as the comparison for day-to-day and light and dark changes from baseline to simulate a 4-week study with a week-long baseline assessment. In week comparison, week 2 was compared to week 5. A one-way t-test was conducted against an assumed mean difference of 0 to evaluate for significance. Study average difference from baseline for the dark cycle were 1.80 ± 1.42 (mean ± standard deviation), 1.99 ± 1.34, and 1.86 ± 1.25 mmHg for diastolic (Dia), systolic (Sys), and mean arterial pressure (MAP), respectively. Light cycle differences were 0.54 ± 1.23, −0.04 ± 1.101, and 0.143 ± 0.91 mmHg for Dia, Sys, and MAP . Day-to-day differences of 1.21 ± 1.29, 0.89 ± 1.12, and 0.931 ± 1.01 mmHg for Dia, Sys, and MAP were seen. Week-to-week differences were − 2.55 ± 1.47 mmHg for Sys, 2.30 ± 1.29 mmHg for MAP, and 1.87 ± 1.22 mmHg for Dia. Results were not significantly different from 0. Overall, rats demonstrated small insignificant changes from baseline in their blood pressure measures across a longitudinal study. The low variability observed was sufficient to encourage further evaluation of the minimal detectable differences which is currently underway.