Holoclar: what flexibility did regulators accept, and why?

“Overall, the omission of classical toxicology animal studies, including single and repeat dose studies as well as immunogenicity studies, was considered by the CAT to be justified due to the lack of suitable animal models and in light of the available clinical safety data.”

“While conventional carcinogenicity studies have not been performed, the potential for transformation and formation of tumours by the human corneal epithelial cells in Holoclar was investigated in in vitro assays.”

“tumourigenicity of Holoclar drug substance and product was investigated in three different in vitro approaches, all of which pointed towards a low risk of tumour formation.”

“As no systemic exposure was to be expected and since the product was autologous in nature, the risk for product-related toxicity to the reproductive system was considered to be negligible and therefore omission of reproductive toxicity testing was deemed acceptable.”

“Therefore, and in light of the availability of clinical data (see section 2.5. ), in vivo studies in a homologous animal model were considered by the CAT not to be necessary and the absence of non-clinical PD data was accepted.”

“The main support for a lack of biodistribution, however, was provided by clinical data including an immunohistological analysis of corneal sections derived from Holoclar-treated patients who had perforating keratoplasty.”

“In light of the available clinical data, the CAT agreed that no additional non-clinical biodistribution data were needed.”