Complete Response Letter BLA 761433 (Dec 13, 2024)

Summary

This FDA letter outlines deficiencies and requirements for the resubmission of Biologics License Application (BLA) 761433, providing instructions for updated labeling, clinical data, safety information, and product quality assessments.

Key points

• Submit updated content of labeling in structured product labeling (SPL) format as described at FDA.gov.
• Provide a 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.
• Submit draft carton and container labeling based on FDA's proposed revisions in the resubmission.
• Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
• Provide a summary of worldwide experience on the safety of this product, including an updated estimate of use for product marketed in other countries.
• Provide English translations of current approved foreign labeling not previously submitted.
• Re-analyze the incidence of anti-amivantamab antibodies from PALOMA using the drug tolerance limit enhanced method prior to resubmitting the application.

Cited reasons

• Prescribing Information (PI) Content and Format Non-Compliance
• Carton and Container Labeling Revisions Required
• Incomplete Clinical Exposure Information
• Insufficient Worldwide Safety Experience Summary
• Missing English Translations of Foreign Labeling
• Immunogenicity Assay Re-analysis Recommended (Non-Approvability Comment)
• Acceptability of PK/Immunogenicity Data Contingent on Site Inspection (Non-Approvability Comment)
• The application received a Complete Response Letter due to significant deficiencies in labeling, clinical data submission, and a pending site inspection. Key issues include non-compliant Prescribing Information format, incomplete clinical exposure and worldwide safety data, and missing foreign labeling translations. Additionally, recommendations were made for immunogenicity assay re-analysis and the acceptability of PK/immunogenicity data is contingent on a site inspection.

Recommended actions

• Submit updated content of labeling in structured product labeling (SPL) format as described at FDA.gov.
• Provide a 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.
• Submit draft carton and container labeling based on FDA's proposed revisions in the resubmission.
• Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
• Provide a summary of worldwide experience on the safety of this product, including an updated estimate of use for product marketed in other countries.
• Provide English translations of current approved foreign labeling not previously submitted.
• Re-analyze the incidence of anti-amivantamab antibodies from PALOMA using the drug tolerance limit enhanced method prior to resubmitting the application.

Deficiency summary

The application received a Complete Response Letter due to significant deficiencies in labeling, clinical data submission, and a pending site inspection. Key issues include non-compliant Prescribing Information format, incomplete clinical exposure and worldwide safety data, and missing foreign labeling translations. Additionally, recommendations were made for immunogenicity assay re-analysis and the acceptability of PK/immunogenicity data is contingent on a site inspection.

Findings

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 Complete Response Letter highlights critical deficiencies primarily in labeling compliance and the completeness of clinical data, specifically regarding patient exposure and global safety information. There are also administrative issues with foreign labeling translations. While not approvability issues, concerns were raised about immunogenicity assay consistency and data integrity pending a site inspection, indicating a need for comprehensive data and process review prior to resubmission.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%