Exblifep: what flexibility did regulators accept, and why?

“For the NOAELs in the combination studies of enmetazobactam given together with cefepime, the margin to the exposure at the MRHD was 0.71 in dogs and 0.86 or lower in rats.”

“Anyway, as there is no margin to the clinical exposure for any of the dose levels in rats or for the NOAELs for corresponding effects in dogs, and risk for increased liver enzymes and liver effects has been observed in the clinic, information on the non-clinical liver effects have been included in the SmPC.”

“Note: The study design for this study deviated from recommendations in the ICH S5(R3) Guideline. Males in the study were administered vehicle or test article for 1-month during the premating period, but dosing was not continued during the mating period at least until verification of conception as recommended in the Guideline.”

“Conception for untreated females mated with treated males occurred over a range of 2.0 to 2.7 days after the start of mating, so the deficiency in dosing duration was less than 3 days. This minor deviation was considered unlikely to produce a different study outcome with regard to male fertility.”