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US FDA•United StatesCRL•Complete Response Letter

Complete Response Letter BLA 761303 (Jul 30, 2025)

Issued July 30, 2025

Issued

July 30, 2025

Application

BLA • 761303

Review center

CBER

Stage

Final Decision

Letter type

Complete Response Letter

Response due July 30, 2026Requires resubmission addressing deficiencies.

Summary

This FDA communication outlines specific requirements for the resubmission of Biologics License Application (BLA) 761303, focusing on updated prescribing information, safety data, and general submission procedures. It emphasizes adherence to labeling regulations and guidance, and mandates the provision of comprehensive safety information from clinical trials and worldwide experience.

Key points

  • Submit draft labeling responsive to the FDA's electronic communication.
  • Use the SRPI checklist to correct any formatting errors in the labeling to ensure conformance with regulations and guidances.
  • Submit updated content of labeling in structured product labeling (SPL) format as described at FDA.gov, in accordance with 21 CFR 601.14(b).
  • Provide a highlighted or marked-up copy showing all changes, and a clean Word version of the proposed Prescribing Information (PI).
  • Ensure the proposed PI conforms to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57.
  • Provide case report forms and narrative summaries for each subject who died during a clinical trial or who did not complete a trial because of an adverse event.
  • Provide narrative summaries for serious adverse events.
  • Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between new data and original application data.

Cited reasons

  • Inadequate Prescribing Information (PI) and SPL Format
  • Missing Clinical Case Report Forms and Narrative Summaries
  • Inadequate Analysis of Adverse Event Incidence Changes
  • Missing Updated Clinical Exposure Information
  • Missing Worldwide Safety Experience Summary
  • Missing English Translations of Foreign Labeling
  • The FDA issued a Complete Response Letter for BLA 761303, citing significant deficiencies primarily related to inadequate Prescribing Information (PI) formatting and content, missing or insufficient clinical safety data (case reports, adverse event analysis, exposure information, worldwide safety experience), and unsubmitted English translations of foreign labeling. The application cannot be approved in its current form.

Recommended actions

  • Submit draft labeling responsive to the FDA's electronic communication.
  • Use the SRPI checklist to correct any formatting errors in the labeling to ensure conformance with regulations and guidances.
  • Submit updated content of labeling in structured product labeling (SPL) format as described at FDA.gov, in accordance with 21 CFR 601.14(b).
  • Provide a highlighted or marked-up copy showing all changes, and a clean Word version of the proposed Prescribing Information (PI).
  • Ensure the proposed PI conforms to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57.
  • Provide case report forms and narrative summaries for each subject who died during a clinical trial or who did not complete a trial because of an adverse event.
  • Provide narrative summaries for serious adverse events.
  • Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between new data and original application data.

Deficiency summary

The FDA issued a Complete Response Letter for BLA 761303, citing significant deficiencies primarily related to inadequate Prescribing Information (PI) formatting and content, missing or insufficient clinical safety data (case reports, adverse event analysis, exposure information, worldwide safety experience), and unsubmitted English translations of foreign labeling. The application cannot be approved in its current form.

Findings

Inadequate Prescribing Information (PI) and SPL Format

Severity: major

Submit draft labeling that is responsive to our electronic communication dated. Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to ensure conformance with the format items in regulations and guidances. In addition, submit updated content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format as described at FDA.gov. To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Word version. The marked-up copy should include annotations that support any proposed changes. Your proposed Prescribing Information (PI) must conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57.

Recommended response: Revise the Prescribing Information (PI) and Structured Product Labeling (SPL) to comply with all cited regulations and guidance. Ensure proper formatting, content, and provide both marked-up and clean versions with annotations.

Cited: 21 CFR 601.14(b), 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57

Missing Clinical Case Report Forms and Narrative Summaries

Severity: major

Provide case report forms and narrative summaries for each subject who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

Recommended response: Compile and submit all requested case report forms and narrative summaries for subjects who died or discontinued due to adverse events, and for all serious adverse events.

Inadequate Analysis of Adverse Event Incidence Changes

Severity: major

Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

Recommended response: Conduct a thorough comparative analysis of adverse event incidence between new and original application data, and provide a detailed description of any substantial changes.

Missing Updated Clinical Exposure Information

Severity: major

Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

Recommended response: Submit comprehensive and updated exposure information for all clinical studies and trials, including metrics such as number of subjects and person-time.

Missing Worldwide Safety Experience Summary

Severity: major

Provide a summary of worldwide experience on the safety of this product. Include an updated estimate of use for product marketed in other countries.

Recommended response: Prepare and submit a comprehensive summary of the product's worldwide safety experience, along with updated estimates of product use in other countries.

Missing English Translations of Foreign Labeling

Severity: major

Provide English translations of current approved foreign labeling not previously submitted.

Recommended response: Obtain and submit certified English translations for all current approved foreign labeling that has not yet been provided to the agency.

Regulatory context

Submission stage
final decision
Regulatory pathway
BLA

Impact

Impact score
0.75
Estimated delay
545 days
Estimated rework cost
$0
Subsequent action
resubmission

Strategic insights

The application lacks critical clinical safety data and analyses, as well as compliant and complete labeling information, preventing approval. Significant data compilation, analysis, and labeling revisions are required for resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%

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