From the 10Q:
In order to address the clinical hold, the FDA has requested that we:·
Provide additional sequencing data and genetic stability studies;
·Conduct a stability study on the final formulated drug product as well as the cells from the Master Cell Bank;
·
Evaluate the compatibility of the delivery devices (i.e., the prefilled syringe and microcatheter) with the drug product;
·
Provide additional detailed description of the manufacturing process;
·Provide additional product release specifications for the encapsulated cells
·Demonstrate comparability between the 1st and 2nd generation products and ensure adequate and consistent product performance and safety between thetwo generations;
·Conduct a biocompatibility assessment using the final finished capsules after the entire drug product manufacturing process (but without cells);·
Address insufficiencies in Chemistry, Manufacturing and Controls information in the cross-referenced Drug Master File;
·Conduct an additional nonclinical study to assess the safety, activity and distribution of the drug product;
·Revise the Investigators Brochure to include any additional preclinical studies conducted in response to the clinical hold and remove any statements notsupported by the data;
and·Provide data from a new pig study.
The FDA also requested that we address several issues not related to the clinical hold in an amendment to the IND, including:·
Provide a Certificate of Analysis for pc3/2B1 plasmid that includes tests for assessing purity, safety, and potency;
·
Perform qualification studies for the drug substance filling step to ensure that the product remains sterile and stable during the filling process;
·Submit an updated batch analysis for the drug product for the specific lot that will be used for manufacturing all future drug product;·
Provide additional details for the methodology for the Resorufin (CYP2B1) potency and the PrestoBlue cell metabolic assays;
·
Provide a few examples of common microcatheters that fit the specifications in the Angiography Procedure Manual;
·Clarify the language in the Pharmacy Manual regarding proper use of the syringe fill with the drug product;
and·Provide a discussion with data for the potential for cellular and humoral immune reactivity against the heterologous rat CYP2B1 protein and potential forinduction of autoimmune-mediated tox
