US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter BLA 125845 (Jul 7, 2025)

Issued July 7, 2025

Issued

July 7, 2025

Application

BLA • 125845

Review center

CBER

Stage

Final Decision

Letter type

Complete Response Letter

Response due July 7, 2026Requires resubmission addressing deficiencies.

Summary

The U.S. Food & Drug Administration (FDA) issued a Complete Response Letter to Ultragenyx Pharmaceutical Inc. for their Biologics License Application (BLA) for rebisufligene etisparvovec. The FDA concluded that final approval cannot be granted due to deficiencies primarily related to Chemistry, Manufacturing, and Controls (CMC) and outstanding clinical data requirements.

Key points

Address deficiencies noted during the pre-license inspection (PLI) and Form FDA 483 observations, ensuring corrective actions are comprehensive and address systemic issues.
Ensure the product and establishment comply with standards established in the BLA and FDA regulations, including Current Good Manufacturing Practice (CGMP) requirements.
Address additional CMC comments provided in the letter.
Provide updated safety and efficacy clinical data, including Bayley Scales of Infant and Toddler Development-Third Edition (BSITD-III) and Vineland Adaptive Behavioral Scales-Second Edition (VABS-II) raw scores, brain MRI results, and cerebrospinal fluid (CSF) biomarkers (heparan sulfate [HS], ganglioside type 2 [GM2], and ganglioside type 3 [GM3]) from 30 days prior to resubmission for all treated patients.
Resubmit or withdraw the application within one year from the date of the letter (21 CFR 601.3(b)).
Ensure any resubmission fully addresses all listed deficiencies; partial responses will not be processed.
May request an extension of time for resubmission.
May request a meeting or teleconference to discuss steps necessary for approval.

Cited reasons

Unresolved Pre-License Inspection (PLI) Findings and Insufficient Corrective Actions
Lot Release Protocol Template Review Pending Resolution of Other Issues
Clinical Data Adequacy Under Evaluation; Updated Safety and Efficacy Data Required
Labeling Review Pending Resolution of Other Concerns
The Biologics License Application for rebisufligene etisparvovec received a Complete Response due to unresolved manufacturing quality system deficiencies identified during pre-license inspections, requiring comprehensive corrective actions and potential re-inspection. Additionally, the adequacy of clinical data to support the proposed indication is under evaluation, necessitating updated safety and efficacy information. Labeling review is contingent on resolving these core issues.

Recommended actions

Address deficiencies noted during the pre-license inspection (PLI) and Form FDA 483 observations, ensuring corrective actions are comprehensive and address systemic issues.
Ensure the product and establishment comply with standards established in the BLA and FDA regulations, including Current Good Manufacturing Practice (CGMP) requirements.
Address additional CMC comments provided in the letter.
Provide updated safety and efficacy clinical data, including Bayley Scales of Infant and Toddler Development-Third Edition (BSITD-III) and Vineland Adaptive Behavioral Scales-Second Edition (VABS-II) raw scores, brain MRI results, and cerebrospinal fluid (CSF) biomarkers (heparan sulfate [HS], ganglioside type 2 [GM2], and ganglioside type 3 [GM3]) from 30 days prior to resubmission for all treated patients.
Resubmit or withdraw the application within one year from the date of the letter (21 CFR 601.3(b)).
Ensure any resubmission fully addresses all listed deficiencies; partial responses will not be processed.
May request an extension of time for resubmission.
May request a meeting or teleconference to discuss steps necessary for approval.

Deficiency summary

The Biologics License Application for rebisufligene etisparvovec received a Complete Response due to unresolved manufacturing quality system deficiencies identified during pre-license inspections, requiring comprehensive corrective actions and potential re-inspection. Additionally, the adequacy of clinical data to support the proposed indication is under evaluation, necessitating updated safety and efficacy information. Labeling review is contingent on resolving these core issues.

Findings

Unresolved Pre-License Inspection (PLI) Findings and Insufficient Corrective Actions

Severity: critical

CBER conducted a pre-license inspection (PLI) and issued a Form FDA 483. The responses to the Form FDA 483 were insufficient, and corrective actions were not comprehensive enough to address systemic issues observed during the inspection. Represented corrections may require additional review and verification during a follow-up inspection. CBER cannot determine that the product and establishment comply with BLA standards and Current Good Manufacturing Practice requirements.

Recommended response: Address all outstanding Form FDA 483 observations with comprehensive corrective and preventive actions (CAPAs), including a thorough root cause analysis for systemic issues. Provide evidence of effective implementation and verification of these CAPAs, potentially requiring a re-inspection.

Cited: 21 CFR 601.20(a), 21 CFR 601.20(d), Current Good Manufacturing Practice requirements

Lot Release Protocol Template Review Pending Resolution of Other Issues

Severity: major

The review of the Lot Release Protocol template will be completed only when the issues identified in the complete response letter have been addressed.

Recommended response: Ensure all CMC deficiencies, particularly those related to manufacturing and quality systems, are fully resolved before expecting review of the Lot Release Protocol template.

Clinical Data Adequacy Under Evaluation; Updated Safety and Efficacy Data Required

Severity: critical

CBER is evaluating the clinical data to determine if it adequately supports the proposed indication. Updated safety and efficacy data, including specific raw scores (Bayley Scales of Infant and Toddler Development-Third Edition (BSITD-III) and Vineland Adaptive Behavioral Scales-Second Edition (VABS-II)), brain magnetic resonance imaging (MRI) results, and cerebrospinal fluid (CSF) biomarkers (heparan sulfate [HS], ganglioside type 2 [GM2] and ganglioside type 3 [GM3]), from 30 days prior to resubmission for all patients treated across studies, are required with the resubmission.

Recommended response: Provide a comprehensive update of all requested clinical safety and efficacy data, ensuring all specified metrics and raw scores are included for all patients. Justify the adequacy of the clinical data to support the proposed indication.

Labeling Review Pending Resolution of Other Concerns

Severity: minor

CBER acknowledges receipt of proposed labeling but anticipates conducting a detailed labeling review only once the other concerns (CMC, Clinical) have been fully addressed.

Recommended response: Address all underlying CMC and Clinical deficiencies to enable the agency to proceed with a detailed review of the proposed labeling.

Regulatory context

Submission stage: final decision
Regulatory pathway: Biologics License Application

Impact

Impact score: 0.95
Estimated delay: 365 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The application faces significant hurdles primarily due to unresolved manufacturing quality control issues stemming from inspection findings and the need for more robust clinical data to substantiate the proposed indication. These core deficiencies are preventing the final approval and subsequent labeling review.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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