Approval Letter Other 201848 (Jan 1, 2024)

Summary

This is a Complete Response Letter from the FDA to Delcath Systems, Incorporated, for their New Drug Application (NDA) 201848 for Melblez Kit. The FDA has determined that the application cannot be approved in its present form due to deficiencies related to clinical effectiveness, clinical pharmacology, and product quality. Key issues include a lack of substantial evidence of effectiveness where benefits outweigh risks, insufficient pharmacokinetic characterization for the proposed commercial product, and an inadequate toxicological risk assessment of leachables and extractables from the device components of the commercial configuration.

Key points

• The applicant must conduct and provide the results of adequate and well-controlled clinical trial(s) which demonstrate substantial evidence of effectiveness on an endpoint where the clinical benefits of Melblez Kit outweigh its risks.
• The applicant should perform an adequate and well-controlled randomized trial(s) to establish the safety and efficacy of the Melblez Kit using overall survival as the primary efficacy outcome measure, ensuring applicability to the US population.
• The applicant must provide data demonstrating substantial evidence of effectiveness where these benefits outweigh its risks using the combination product that they intend to market.
• The applicant must provide data from clinical trials using the combination product that they intend to market, with sufficient melphalan pharmacokinetic samples to adequately characterize the systemic exposure to melphalan and its major metabolites and to characterize the pharmacokinetic profile in special populations.
• The applicant must provide a complete description of the Gas Chromatography (GC) and High Performance Liquid Chromatography (HPLC) Standard Test Methods used to analyze for extractables of the Melblez Kit.
• The applicant must submit method validation summaries demonstrating that the analytical methods are suitable for their intended use for leachables of the Delcath Hepatic Delivery System, melphalan simulated in-use stability, and melphalan interaction (adsorption) testing with components of the device.
• The applicant must provide a new toxicological risk assessment of the commercial configuration of the Delcath Hepatic Delivery System.
• The applicant must determine the leachable profile of the device components in the proposed commercial product in nonpolar solvents (e.g., alcoholic solution) under simulating extraction conditions.

Cited reasons

• Lack of Substantial Evidence of Effectiveness (Clinical Trial Configuration)
• Lack of Substantial Evidence for Proposed Commercial Product
• Insufficient Pharmacokinetic Profile Characterization
• Inadequate Product Quality Testing (Melblez Constituent Part)
• Inadequate Toxicological Risk Assessment (Delcath Hepatic Delivery System)
• The application for Melblez Kit was not approved due to a lack of substantial evidence of effectiveness, where the risks of the product were deemed to outweigh its benefits. Key issues included insufficient clinical data for the commercial product configuration, inadequate pharmacokinetic characterization, and significant deficiencies in the toxicological risk assessment of the device components, particularly regarding leachables and extractables.

Recommended actions

• The applicant must conduct and provide the results of adequate and well-controlled clinical trial(s) which demonstrate substantial evidence of effectiveness on an endpoint where the clinical benefits of Melblez Kit outweigh its risks.
• The applicant should perform an adequate and well-controlled randomized trial(s) to establish the safety and efficacy of the Melblez Kit using overall survival as the primary efficacy outcome measure, ensuring applicability to the US population.
• The applicant must provide data demonstrating substantial evidence of effectiveness where these benefits outweigh its risks using the combination product that they intend to market.
• The applicant must provide data from clinical trials using the combination product that they intend to market, with sufficient melphalan pharmacokinetic samples to adequately characterize the systemic exposure to melphalan and its major metabolites and to characterize the pharmacokinetic profile in special populations.
• The applicant must provide a complete description of the Gas Chromatography (GC) and High Performance Liquid Chromatography (HPLC) Standard Test Methods used to analyze for extractables of the Melblez Kit.
• The applicant must submit method validation summaries demonstrating that the analytical methods are suitable for their intended use for leachables of the Delcath Hepatic Delivery System, melphalan simulated in-use stability, and melphalan interaction (adsorption) testing with components of the device.
• The applicant must provide a new toxicological risk assessment of the commercial configuration of the Delcath Hepatic Delivery System.
• The applicant must determine the leachable profile of the device components in the proposed commercial product in nonpolar solvents (e.g., alcoholic solution) under simulating extraction conditions.

Deficiency summary

The application for Melblez Kit was not approved due to a lack of substantial evidence of effectiveness, where the risks of the product were deemed to outweigh its benefits. Key issues included insufficient clinical data for the commercial product configuration, inadequate pharmacokinetic characterization, and significant deficiencies in the toxicological risk assessment of the device components, particularly regarding leachables and extractables.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

505(b)(2) NDA

Impact

Impact score

0.95

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The application was rejected primarily due to a fundamental lack of substantial evidence of effectiveness, particularly concerning the risk-benefit profile of the Melblez Kit and the inability to bridge data from earlier device configurations to the proposed commercial product. Significant gaps in pharmacokinetic characterization and a deficient toxicological risk assessment for device leachables and extractables further contributed to the unapprovable status, necessitating extensive additional clinical, nonclinical, and CMC studies.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%