Complete Response Letter BLA 761308 (May 16, 2024)

Summary

This document is a Complete Response Letter (CRL) from the U.S. Food and Drug Administration (FDA) to an applicant regarding Biologics License Application (BLA) 761308. It outlines deficiencies found in the application and specifies additional information and actions required for potential approval, particularly focusing on safety data, clinical trial information, and administrative procedures for resubmission.

Key points

• Present a retabulation of the reasons for premature trial discontinuation by incorporating drop-outs from newly completed trials and describe any new trends or patterns identified.
• 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, and 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.
• 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 drug, including an updated estimate of use for drug marketed in other countries.
• Provide English translations of current approved foreign labeling not previously submitted.
• Resubmit the application or take other actions available under 21 CFR 601.3(b) within one year after the date of this letter.
• Clearly mark any resubmission with 'RESUBMISSION' in large font, bolded type at the beginning of the cover letter.

Cited reasons

• Retabulation of premature trial discontinuation
• Missing Case Report Forms and Narrative Summaries for Deaths/SAEs
• Analysis of changes in incidence of common adverse events
• Updated clinical exposure information
• Worldwide safety experience summary
• English translations of foreign labeling
• The FDA issued a Complete Response Letter for BLA 761308, citing significant deficiencies primarily related to the completeness and analysis of clinical safety data. Key issues include insufficient reporting and analysis of premature trial discontinuations, missing case report forms and narrative summaries for deaths and serious adverse events, lack of updated clinical exposure information, and an incomplete summary of worldwide safety experience. Additionally, English translations of foreign labeling were requested.

Recommended actions

• Present a retabulation of the reasons for premature trial discontinuation by incorporating drop-outs from newly completed trials and describe any new trends or patterns identified.
• 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, and 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.
• 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 drug, including an updated estimate of use for drug marketed in other countries.
• Provide English translations of current approved foreign labeling not previously submitted.
• Resubmit the application or take other actions available under 21 CFR 601.3(b) within one year after the date of this letter.
• Clearly mark any resubmission with 'RESUBMISSION' in large font, bolded type at the beginning of the cover letter.

Deficiency summary

The FDA issued a Complete Response Letter for BLA 761308, citing significant deficiencies primarily related to the completeness and analysis of clinical safety data. Key issues include insufficient reporting and analysis of premature trial discontinuations, missing case report forms and narrative summaries for deaths and serious adverse events, lack of updated clinical exposure information, and an incomplete summary of worldwide safety experience. Additionally, English translations of foreign labeling were requested.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

BLA

Impact

Impact score

0.95

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme of the Complete Response Letter is the inadequacy and incompleteness of clinical safety data, particularly regarding adverse event reporting, patient exposure, and global safety surveillance. There is also an administrative deficiency related to foreign labeling translations.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%