Approval Letter Other 761183 (Jan 1, 2023)

Summary

This is a Complete Response Letter from the FDA to Provention Bio, Inc. regarding their Biologics License Application (BLA) 761183 for PRV-031. The FDA has determined that the application cannot be approved in its present form due to various deficiencies across clinical pharmacology, product quality, facility inspections, prescribing information, and safety updates. The letter outlines specific issues and provides recommendations for addressing them.

Key points

• Establish pharmacokinetic (PK) comparability between the intended commercial product and the clinical trial product for PRV-031.
• Provide data and information to support that any changes to the CEX-HPLC assay do not impact the data supporting the application, including batch release, stability, in-process testing, process characterization, and comparability assessment.
• Provide cell bank requalification protocols for the Master Cell Bank (MCB) and Working Cell Bank (WCB), including frequency, justification, number of vials, tests, and acceptance criteria.
• Address deficiencies in the primary reference standard (PRS) requalification protocol to ensure stability and suitability.
• Provide sufficient data from a leachable study to evaluate filled drug product container closure systems, including testing at regular intervals through shelf-life for organic non-volatile, volatile, semi-volatile species, and metals.
• Ensure satisfactory resolution of deficiencies identified during the manufacturing facility inspection.
• Review labeling review resources, ensure proposed labeling conforms with format items in regulations and guidances, and include updated content of labeling in structured product labeling (SPL) format.
• Resubmit the proposed proprietary name, Tzield, when responding to application deficiencies.

Cited reasons

• Lack of PK comparability between clinical and commercial product
• CEX-HPLC assay investigation and data impact
• Insufficient information on Master and Working Cell Bank stability monitoring
• Deficient Primary Reference Standard requalification protocol
• Insufficient information on leachables from container closure system
• Unresolved manufacturing facility inspection deficiencies
• The application received a Complete Response due to significant deficiencies across clinical pharmacology, product quality (CMC), and manufacturing facility compliance. Key issues include a lack of pharmacokinetic comparability between clinical and commercial products, inadequate information on cell bank stability, deficient primary reference standard requalification, insufficient leachables data, and unresolved manufacturing facility inspection findings.

Recommended actions

• Establish pharmacokinetic (PK) comparability between the intended commercial product and the clinical trial product for PRV-031.
• Provide data and information to support that any changes to the CEX-HPLC assay do not impact the data supporting the application, including batch release, stability, in-process testing, process characterization, and comparability assessment.
• Provide cell bank requalification protocols for the Master Cell Bank (MCB) and Working Cell Bank (WCB), including frequency, justification, number of vials, tests, and acceptance criteria.
• Address deficiencies in the primary reference standard (PRS) requalification protocol to ensure stability and suitability.
• Provide sufficient data from a leachable study to evaluate filled drug product container closure systems, including testing at regular intervals through shelf-life for organic non-volatile, volatile, semi-volatile species, and metals.
• Ensure satisfactory resolution of deficiencies identified during the manufacturing facility inspection.
• Review labeling review resources, ensure proposed labeling conforms with format items in regulations and guidances, and include updated content of labeling in structured product labeling (SPL) format.
• Resubmit the proposed proprietary name, Tzield, when responding to application deficiencies.

Deficiency summary

The application received a Complete Response due to significant deficiencies across clinical pharmacology, product quality (CMC), and manufacturing facility compliance. Key issues include a lack of pharmacokinetic comparability between clinical and commercial products, inadequate information on cell bank stability, deficient primary reference standard requalification, insufficient leachables data, and unresolved manufacturing facility inspection findings.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

Biologics License Application (BLA) under section 351(a) of the Public Health Service Act

Impact

Impact score

0.95

Estimated delay

300 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The Complete Response highlights critical gaps in demonstrating product comparability, robust quality control systems for manufacturing, and unresolved facility inspection issues. These deficiencies collectively prevent approval and necessitate substantial data generation and procedural improvements.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%