FDA CRL - INNOCOLL PHARMACEUTICALS

The FDA issued a Complete Response letter to Innocoll Pharmaceuticals regarding its New Drug Application (NDA 209511) for bupivacaine hydrochloride collagen-matrix implants, submitted under Section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act. Following an initial submission on October 31, 2016, and a resubmission on February 2, 2018, the application cannot be approved in its current state due to significant nonclinical and product quality issues.Key nonclinical deficiencies include an inadequate characterization of the drug's systemic safety, as the product resulted in bupivacaine exposures twice that of the reference product without sufficient supportive toxicology data. The company also failed to provide a valid in vivo micronucleus assay and an adequate extractables/leachables evaluation for the container closure system, with several compounds detected above safety thresholds remaining unidentified. Justification for a proposed impurity specification was also deemed insufficient.Product quality concerns centered on an incomplete leachables assessment, specifically the absence of an analytical method to detect leachables and correlate them with extractables. To resolve these issues, Innocoll must conduct additional toxicology studies or provide clinical safety data, repeat the micronucleus assay with appropriate dosing, identify all extractables, perform toxicological risk assessments for leachables, and develop robust analytical methods for leachables testing across multiple batches. A comprehensive safety update and updated prescribing information are also required.