US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter BLA 761027 (Jun 26, 2025)

Issued June 26, 2025

Issued

June 26, 2025

Application

BLA • 761027

Review center

CBER

Stage

Final Decision

Letter type

Complete Response Letter

Response due June 26, 2026Requires resubmission addressing deficiencies.

Summary

This letter from the FDA outlines deficiencies in Biologics License Application (BLA) 761027, requiring the applicant to revise labeling, resubmit the proprietary name, and provide a comprehensive safety update. It also specifies the timeline and format for resubmission.

Key points

Use the Selected Requirements for Prescribing Information (SRPI) checklist to ensure Prescribing Information conforms with format items in regulations and guidances if labeling is revised.
Include updated content of labeling in structured product labeling (SPL) format as described at FDA.gov.
Resubmit the proposed proprietary name after addressing all application deficiencies.
Include a safety update when responding to deficiencies, incorporating data from all nonclinical and clinical studies.
Describe in detail any significant changes or findings in the safety profile and their relevance to clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.
Incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events.
Present new safety data from clinical studies for the proposed indication using the same format as the original BLA submission.
Present tabulations of new safety data combined with the original BLA data.

Cited reasons

Proprietary Name Resubmission Required
Comprehensive Safety Update
Incomplete Clinical Data for Deaths and Serious Adverse Events
Insufficient Clinical Exposure Data
Missing Worldwide Safety Experience Summary
Untranslated Foreign Approved Labeling
Labeling Content and Format Non-Compliance
The FDA issued a Complete Response Letter for BLA 761027, primarily due to significant deficiencies in the clinical safety data package, including incomplete reporting of adverse events, insufficient exposure information, and lack of a comprehensive worldwide safety summary. Additionally, the agency identified issues with the proposed labeling's format and content, requiring adherence to regulatory guidance and submission in SPL format, along with the need for foreign labeling translations and resubmission of the proprietary name.

Recommended actions

Use the Selected Requirements for Prescribing Information (SRPI) checklist to ensure Prescribing Information conforms with format items in regulations and guidances if labeling is revised.
Include updated content of labeling in structured product labeling (SPL) format as described at FDA.gov.
Resubmit the proposed proprietary name after addressing all application deficiencies.
Include a safety update when responding to deficiencies, incorporating data from all nonclinical and clinical studies.
Describe in detail any significant changes or findings in the safety profile and their relevance to clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.
Incorporate new safety data into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events.
Present new safety data from clinical studies for the proposed indication using the same format as the original BLA submission.
Present tabulations of new safety data combined with the original BLA data.

Deficiency summary

The FDA issued a Complete Response Letter for BLA 761027, primarily due to significant deficiencies in the clinical safety data package, including incomplete reporting of adverse events, insufficient exposure information, and lack of a comprehensive worldwide safety summary. Additionally, the agency identified issues with the proposed labeling's format and content, requiring adherence to regulatory guidance and submission in SPL format, along with the need for foreign labeling translations and resubmission of the proprietary name.

Findings

Proprietary Name Resubmission Required

Severity: minor

The proposed proprietary name was found conditionally acceptable but must be resubmitted concurrently with the complete response to all other application deficiencies.

Recommended response: Resubmit the proprietary name application as part of the comprehensive response to all deficiencies.

Comprehensive Safety Update

Severity: major

A comprehensive safety update is required, including data from all nonclinical and clinical studies of the product, regardless of indication, dosage form, or dose level, with detailed descriptions of significant changes or findings in the safety profile and their relevance to biosimilarity.

Recommended response: Prepare and submit a detailed safety update that integrates all new nonclinical and clinical safety data, highlighting any clinically meaningful differences from the reference product.

Incomplete Clinical Data for Deaths and Serious Adverse Events

Severity: critical

Provide case report forms (CRFs) and narrative summaries for all subjects who died during a clinical study or discontinued due to an adverse event. Additionally, provide narrative summaries for all serious adverse events.

Recommended response: Compile and submit all missing CRFs and narrative summaries for deaths and serious adverse events to ensure a complete safety profile assessment.

Insufficient Clinical Exposure Data

Severity: major

Provide updated exposure information for the clinical studies, including the number of subjects and person-time, and present new safety data from clinical studies using the same format as the original BLA submission, combined with original data, and comparative tables of adverse event frequencies.

Recommended response: Update and submit comprehensive clinical exposure data, ensuring consistency in presentation with the original BLA and providing comparative analyses of adverse event frequencies.

Missing Worldwide Safety Experience Summary

Severity: major

Provide a summary of worldwide experience on the safety of this product, including adverse events known to be associated with its use, immunogenicity data, and an updated estimate of product use in other countries.

Recommended response: Gather and summarize all available global safety data, including post-marketing experience and immunogenicity, along with updated usage estimates from other countries.

Untranslated Foreign Approved Labeling

Severity: minor

Provide English translations of all current approved foreign labeling that has not been previously submitted.

Recommended response: Obtain and submit certified English translations for all relevant foreign approved labeling documents.

Labeling Content and Format Non-Compliance

Severity: major

Revise labeling to conform with format items in regulations and guidances, including the Selected Requirements for Prescribing Information (SRPI) checklist. Submit updated content of labeling in structured product labeling (SPL) format.

Recommended response: Thoroughly review and revise all proposed labeling to ensure full compliance with FDA regulations and guidance, utilizing the SRPI checklist, and submit the final version in SPL format.

Cited: 21 CFR 601.14(b)

Regulatory context

Submission stage: final decision
Regulatory pathway: BLA

Impact

Impact score: 0.95
Estimated delay: 665 days
Estimated rework cost: $0
Subsequent action: resubmission

Strategic insights

The primary themes of this Complete Response Letter are the need for comprehensive and well-organized clinical safety data, including detailed adverse event reporting and global safety experience, and ensuring all labeling components meet current regulatory standards for content and format, particularly for a biosimilar product.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%

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