Gazyva: what flexibility did regulators accept, and why?

“In a 26 week cynomolgus monkey study, hypersensitivity reactions were noted and attributed to the foreign recognition of the humanised antibody in cynomolgus monkeys (0.7-6 times the clinical exposure based on Cmax and AUC at steady state after weekly administration of 5, 25, and 50 mg/kg).”

“The validations of the bioanalysis methods used for quantification of obinutuzumab in Cynomolgus monkey serum were not performed according to GLP.”

“However, the analytical method was validated according to the guidance valid at the time of study performance, which was consistent with the FDA Guidance on Bioanalytical Method Validation and best industry practices (Kelley M et al. 2007, Viswanathan CT et al. 2007) with regards to the tested validation parameters and pre-defined acceptance criteria; thus, the lack of GLP compliance of the bioanalysis validation was considered acceptable.”

“According to ICH guidance M3(R2), the results of these studies are considered appropriate to address acute toxicity aspects. Therefore, the lack of dedicated single-dose toxicity studies was considered acceptable.”

“Reviewer’s comment: This assay did not include a set of experiments using immobilized antibodies. By not doing, the assay may not adequately mimic the in vivo conditions that may give rise to cytokine release.”