FDA CRL - DMK Pharmaceuticals Corporation (fka Adamis Pharmaceuticals Corporation)

Adamis Pharmaceuticals Corporation received a Complete Response Letter (CRL) from the FDA concerning its New Drug Application (NDA 212854) for Naloxone HCl Injection, 5 mg/0.5 mL (ZIMHI). The NDA, initially submitted in December 2018, was not approved following the FDA's review of the company's complete response to a November 2019 action letter and subsequent amendments. The agency identified critical deficiencies related to both clinical safety and device reliability.

From a clinical perspective, the FDA found inadequate data to support the safe use of the ZIMHI pre-filled syringe in community settings, especially by laypersons. Specific concerns include the current user interface's difficulty in deploying the needle safety guard, increasing the risk of needlestick injuries and potential transmission of bloodborne pathogens. Adamis must redesign the device to include an automatically deploying needle safety element, submit an updated comprehensive use-related risk analysis, and conduct a human factors validation study under simulated conditions with representative users.

Regarding the device's reliability, the FDA determined that the submitted Fault Tree Analysis (FTA) failed to adequately demonstrate the required 99.999% reliability for successful activation and dose delivery. The analysis lacked a comprehensive consideration of all basic design and manufacturing failure modes, and explanations linking process capability index (Cpk) to failure rates were unsubstantiated. Adamis is required to revise the FTA to incorporate all relevant failure modes and provide clear, evidence-backed justifications for its reliability claims.