Safety Pharmacology Study Results and their Impact on the Design of First-in-human Trials for Authorised Oncology Therapies

Abstract

Safety pharmacology studies are conducted to elucidate possible safety risks on cardiovascular (CV), central nervous system (CNS) and respiratory systems, and are usually carried out prior to first-in-human (FIH) trials. These tests are either standalone tests, or have relevant endpoints integrated in repeat-dose toxicology studies. To review safety pharmacology study results for authorised oncology therapies and to assess how these results have impacted the design of FIH trials of these agents. Bearing in mind the 3Rs principle for animal use (reduction, refinement and replacement), the design of safety pharmacology studies and their outcome for 30 new anticancer medicinal products (both small molecules and biotechnology-derived products) authorised by the European Medicines Agency (EMA) between 2011 and 2015 was reviewed. The impact of the safety pharmacology study results on the design of the FIH trials was also investigated. Our analysis shows that all CNS and respiratory safety pharmacology tests were negative, while for the CV system, 61% of small molecules had positive effects in vitro and/or in vivo and only one out of seven biotechnology-derived products had positive effects in vivo. Regarding the impact of safety pharmacology on clinical trial study design, CV safety pharmacology results for small molecules influenced FIH trial designs in 60% of cases. Based on this subset of data in the oncology therapeutic area, results indicate that the use of safety pharmacology endpoints in repeat-dose toxicology tests could be further utilised as compared with stand-alone safety pharmacology studies, in particular for the CNS and respiratory systems.