Delcath Systems, Incorporated: Melblez

1. The NDA does not contain data demonstrating substantial evidence of effectiveness for the claimed indications for the clinical trial configuration of the Melblez Kit.

The Melblez Kit cannot be approved because the results of clinical investigations do show that the product is not safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling since the ris outweigh its benefits [21 CFR 314.125(b)(3)].

Because of the differences in the dose and route of administration for melphalan as proposed in product labeling and as studied in clinical trials of Melblez Kit to that in the approved labeling for melphalan, FDA cannot rely on the prior findings for Alkeran (melphalan hydrochloride) for Injection (NDA 020207), for all aspects of the characterization of pharmacokinetics of melphalan.

15. The NDA cannot be approved because the methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product are inadequate to preserve its identity, strength, quality, purity, stability, and bioavailability [21 CFR 314.125(b)(1)].

16. | The Human Factors engineering summary report indicated that the product design and labeling were modified after completion of clinical studies in order to address six userelated hazards observed.

The purpose of a human factors validation study is to demonstrate that the device can be used by representative users under simulated use conditions without producing patterns of failures that could result in negative clinical impact to patients or injury to device users.

In accordance with section 505-1 of the FDCA, we have determined that a REMS is necessary for Melblez Kit, if it is approved for ocular melanoma metastatic to the liver, to ensure that the benefits of the drug outweigh the serious risks of hepatic failure, gastric ulceration or perforation, hemorrhage, and procedural complications.

Please identify your plan for conducting an assessment of the exposure-response relationships between melphalan concentration and adverse drug reactions based on complete pharmacokinetic profile obtained in clinical trials using the version of the product you intend to market.

For example, 3.0 mg/kg may be misinterpreted as 30 mg/kg.