Novo Nordisk Inc. – FDA CRL

The FDA has issued a Complete Response Letter (CRL) to Novo Nordisk regarding its Biologics License Application (BLA 761315) for NNC0172-2021 injection, submitted under section 351(a) of the Public Health Service Act. The application, initially received August 24, 2022, cannot be approved in its current form due to several clinical, device, and product quality deficiencies. Clinically, the FDA noted significant fluctuations in drug concentrations and a relatively short half-life, leading to subtherapeutic levels if doses are missed. Novo Nordisk must provide a comprehensive plan for dosing after missed doses, potentially including additional pharmacokinetic monitoring or repeat loading doses, and enhance patient education on adherence. The proposed single pharmacokinetic monitoring after four weeks was deemed insufficient. Regarding the associated device, the NNC0172-2021 ELISA assay validation was inadequate. Issues included insufficient evaluation of native patient samples across critical concentration ranges, a lack of instrument and lot-to-lot precision assessment, and unaddressed interference from various substances. A root-cause analysis for underestimation of drug concentrations in specific studies is also required. Product quality concerns involve an inadequate control strategy for a specific drug product component impacting safety and efficacy. Additionally, the drug substance and drug product release and stability specifications, as well as the cell bank and reference material stability protocols, were deemed insufficient to ensure batch-to-batch consistency and long-term stability. Novo Nordisk must revise these protocols and justifications to meet regulatory standards. The FDA recommends a post-action meeting to discuss these issues.