Approval Letter Other 761161 (Jan 1, 2023)

Summary

This document is a Complete Response Letter from the FDA to Chiesi USA regarding their Biologics License Application (BLA) 761161 for PRX-102. The FDA has determined that the application cannot be approved in its present form due to several deficiencies, including issues with manufacturing facilities, questions regarding the accelerated approval pathway given the availability of other therapies, non-conformity of proposed Prescribing Information, and requirements for a comprehensive safety update. The letter also notes that an inspection of a manufacturing facility is required but was not possible due to travel restrictions.

Key points

• Satisfactorily resolve outstanding issues with the manufacturing facility named in the application.
• Discuss the appropriateness of the accelerated approval pathway for PRX-102, including its therapeutic advantage over available therapy and the status of the confirmatory postmarketing trial, at an End-of-Review meeting.
• Consider an alternative approach for full approval by establishing that the reduction in renal Gb3 inclusions with PRX-102 predicts clinical benefit, supported by specific data points.
• Ensure the proposed Prescribing Information (PI) conforms to 21 CFR 201.56(a) and (d) and 201.57, using the SRPI checklist for formatting, and submit updated content of labeling in SPL format.
• Resubmit the proposed proprietary name, Elfabrio, when responding to the application deficiencies.
• Include a comprehensive safety update as described at 21 CFR 314.50(d)(5)(vi)(b), detailing significant changes, presenting new and combined safety data, providing case report forms for deaths/serious adverse events, and summarizing worldwide safety experience.
• Acknowledge that an inspection of the Protalix Ltd. manufacturing facility is required before the application can be approved, and that this inspection was not possible during the current review cycle due to travel restrictions.
• Provide a dataset and assessment of all infusion-related reactions that occurred within 24 hours of PRX-102 administration.

Cited reasons

• Unresolved Manufacturing Facility Issues and Pending Inspection
• Appropriateness of Accelerated Approval Pathway
• Deficiencies in Prescribing Information (Labeling)
• Proprietary Name Resubmission
• Comprehensive Safety Update Requirements
• Inadequate Assessment of Infusion-Related Reactions
• The application for PRX-102 cannot be approved in its current form due to unresolved manufacturing facility issues, questions regarding the continued appropriateness of the accelerated approval pathway given the availability of an approved therapy (Fabrazyme), deficiencies in the proposed prescribing information, and outstanding safety data requirements. A required manufacturing facility inspection could not be conducted due to travel restrictions.

Recommended actions

• Satisfactorily resolve outstanding issues with the manufacturing facility named in the application.
• Discuss the appropriateness of the accelerated approval pathway for PRX-102, including its therapeutic advantage over available therapy and the status of the confirmatory postmarketing trial, at an End-of-Review meeting.
• Consider an alternative approach for full approval by establishing that the reduction in renal Gb3 inclusions with PRX-102 predicts clinical benefit, supported by specific data points.
• Ensure the proposed Prescribing Information (PI) conforms to 21 CFR 201.56(a) and (d) and 201.57, using the SRPI checklist for formatting, and submit updated content of labeling in SPL format.
• Resubmit the proposed proprietary name, Elfabrio, when responding to the application deficiencies.
• Include a comprehensive safety update as described at 21 CFR 314.50(d)(5)(vi)(b), detailing significant changes, presenting new and combined safety data, providing case report forms for deaths/serious adverse events, and summarizing worldwide safety experience.
• Acknowledge that an inspection of the Protalix Ltd. manufacturing facility is required before the application can be approved, and that this inspection was not possible during the current review cycle due to travel restrictions.
• Provide a dataset and assessment of all infusion-related reactions that occurred within 24 hours of PRX-102 administration.

Deficiency summary

The application for PRX-102 cannot be approved in its current form due to unresolved manufacturing facility issues, questions regarding the continued appropriateness of the accelerated approval pathway given the availability of an approved therapy (Fabrazyme), deficiencies in the proposed prescribing information, and outstanding safety data requirements. A required manufacturing facility inspection could not be conducted due to travel restrictions.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

Biologics License Application (BLA) under section 351(a) of the Public Health Service Act, with a request for accelerated approval

Impact

Impact score

0.95

Estimated delay

270 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The application faces significant hurdles to approval, primarily stemming from critical manufacturing compliance issues, a challenged accelerated approval strategy due to new market dynamics, and substantial deficiencies in the submitted labeling and clinical safety data presentation. Resolution of these issues, including a pending facility inspection, is required for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%