FDA CRL - Delcath Systems, Incorporated

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter (CRL) to Delcath Systems, Incorporated, for its New Drug Application (NDA 201848) concerning the Melblez Kit, a melphalan-based hepatic delivery system. The FDA determined the application could not be approved in its present form. Key issues centered on a lack of substantial evidence of effectiveness for the claimed indications. The agency concluded that the risks associated with an earlier version of the Melblez Kit, including toxic death and severe cardiovascular, hepatic, gastrointestinal, and bone marrow toxicities, outweighed its benefits. Furthermore, the application lacked adequate safety and efficacy data for the *proposed commercial product*, as data from prior device versions could not be extrapolated.

Additional deficiencies included insufficient information to characterize melphalan's pharmacokinetic profile for the proposed dose and route of administration, particularly for special populations. Product quality concerns were also cited for both the drug and device components, specifically inadequate testing for extractables, leachables, drug interaction with the delivery system, and an incomplete toxicological risk assessment of device leachables.

To address these issues, Delcath Systems must conduct new, adequate, and well-controlled clinical trials demonstrating substantial evidence of effectiveness and safety with the *intended-to-market* combination product, preferably using overall survival as a primary endpoint. The company is also required to provide comprehensive pharmacokinetic data, detailed analytical method descriptions and validations for product quality testing, and a complete toxicological risk assessment for all device leachables. The regulatory framework for these requirements largely stems from the Federal Food, Drug, and Cosmetic Act concerning evidence for drug safety and efficacy.