Fetroja: what flexibility did regulators accept, and why?

“While this is true, the use of Cynomolgus monkey should be reserved to situations where this species is the only relevant species.”

“CHMP agreed however that since the studies had already been completed in the monkey, this would not be further pursued.”

“The Applicant decided to use an additional rodent model (CD-1 mouse) and subcutaneous administration instead of intravenously administered rabbits, because repeated-dosing with intravenous administration in mice is not feasible.”

“Overall the justifications for the species use in the general toxicology and EFD studies is considered acceptable.”

“Even though the Guideline on bioanalytical method validation (EMEA/CHMP/EWP/192217/2009) states that all the bioassays should be conducted with GLP validated methods, CHMP agreed that the high-quality standards of the bioanalytical methods used here can be considered adequate for the non-clinical analyses.”

“However, this statement was not fully supported by CHMP, considering the low concentration tested and the applicant was asked to justify the concentration of cefiderocol used for the secondary pharmacology screen, also in the context of the convulsions seen in the repeat dose toxicity studies in rats.”

“Whilst using a higher concentration of the drug in the secondary pharmacology screen would seem to have been more appropriate, taking into account the absence of secondary pharmacology targets identified in the already conducted screen and the clinical safety profile to date, CHMP agreed that the issue did not need to be further pursued.”