Translatability of the S7A core battery respiratory safety pharmacology studies: Preclinical respiratory and related clinical adverse events.

INTRODUCTION: Before entering into first-in-human studies, most new chemical entities must undergo a series of preclinical evaluations. ICH S7A safety pharmacology (SP) guidelines, adopted in 2001, include respiratory assessments as part of the core battery. Despite these safety measures being in place for nearly two decades, studies examining the relationship between preclinical findings captured in respiratory SP studies and clinical respiratory adverse events (AEs) are sparse. Therefore, the aim of this study is to evaluate the predictive value of preclinical respiratory observations to identify clinical respiratory AEs for both investigational products in early drug development and approved drugs. METHOD: Three independent databases were interrogated to evaluate the concordance between preclinical and clinical respiratory AEs. Two databases stem from early clinical phase studies, evaluating 52 and 128 investigational products respectively. The third database was derived from a large repository of nearly 4000 FDA and EMA drug approval documents. RESULTS: Analysis of early phase clinical studies revealed little to no predictive risk for clinical respiratory adverse events when respiratory findings were observed in preclinical studies, with a positive predictive value (PPV) of 27% and 36% for each dataset respectively. In addition, the likelihood ratio, which reflects the shift in predictability of human risk, was 1.02 and 0.76 respectively, indicating no change in liability. Evaluation of approved drugs revealed a small shift in predictability for preclinical respiratory findings to translate into respiratory clinical AE, with likelihood ratios ranging from 2.5-3.4 and PPV of 18-29% for severe AEs such as lung disorder, respiratory depression and respiratory failure. DISCUSSION: Altogether the translatability of preclinical respiratory findings into clinical AEs is low. Mandating dedicated respiratory SP studies as part of the core battery should be reconsidered in light of the low translatability of respiratory risk clinically and can be effectively incorporated into toxicology investigations.