Issued January 1, 2024
Issued
January 1, 2024
Application
Other • 761248
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This letter from the FDA's Center for Drug Evaluation and Research outlines deficiencies in Biologics License Application (BLA) 761248 for Kisunla and provides detailed requirements for a resubmission. Key areas addressed include long-term safety characterization, prescribing information, carton and container labeling, proprietary name, a comprehensive safety update, and product quality specifications. The applicant is required to address all deficiencies within one year to avoid withdrawal of the application.
The application for Kisunla received a Complete Response Letter primarily due to significant deficiencies in the long-term safety data presentation, particularly regarding adverse events like ARIA, and the overall safety profile. Additionally, the Prescribing Information (PI) requires substantial revisions to meet formatting and content regulations, including submission in SPL format. Administrative items such as proprietary name resubmission and foreign labeling translations are also pending.
The submitted draft labeling is not responsive to the electronic communication dated January 18, 2023.
Recommended response: Revise the Prescribing Information to fully address all points raised in the agency's electronic communication from January 18, 2023.
The Prescribing Information (PI) does not conform to the SRPI checklist, contains formatting errors, and the content of labeling (21 CFR 601.14(b)) is not in structured product labeling (SPL) format. The PI must also conform to 21 CFR 201.56(a), (d), and 201.57.
Recommended response: Ensure all Prescribing Information formatting and content strictly adhere to the SRPI checklist, SPL format, and the specified CFR regulations.
Cited: 21 CFR 601.14(b), 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57
To facilitate review, a highlighted or marked-up copy showing all changes, as well as a clean Word version of the Prescribing Information, must be provided.
Recommended response: Prepare and submit both a marked-up version indicating changes and a clean Word version of the revised Prescribing Information.
The proposed proprietary name, Kisunla, must be resubmitted when responding to the application deficiencies, despite previous acceptance pending approval.
Recommended response: Resubmit the proprietary name application concurrently with the complete response to the application deficiencies.
A comprehensive safety update is required, including data from all nonclinical and clinical studies/trials of the product under consideration, regardless of indication, dosage form, or dose level.
Recommended response: Compile and submit a complete safety update encompassing all nonclinical and clinical study data for the product.
Failure to describe in detail any significant changes or findings in the safety profile.
Recommended response: Analyze and clearly articulate any significant changes or new findings identified in the safety profile.
Insufficient incorporation and presentation of new safety data for discontinuations due to adverse events, serious adverse events, and common adverse events. This includes a lack of comparison tables between original and new data, and separate tables for adverse events in indications other than the proposed one.
Recommended response: Retabulate and present all adverse event data, combining new and original data, providing comparisons, and separating by indication as requested.
Failure to present a retabulation of the reasons for premature trial discontinuation, incorporating drop-outs from newly completed trials, and describing any new trends or patterns identified.
Recommended response: Update and retabulate premature discontinuation data, including new trial drop-outs, and analyze for new trends or patterns.
Failure to 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. Additionally, narrative summaries for serious adverse events are missing.
Recommended response: Compile and submit all requested case report forms and narrative summaries for relevant subjects and serious adverse events.
Failure to 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: Analyze and describe any substantial changes in the incidence of common adverse events between new and original data.
Failure to provide updated exposure information for the clinical studies/trials, including specific details for Kisunla 700 mg and 1400 mg dosages, and an accounting of subjects who switched to placebo based on amyloid plaque reduction at various weeks.
Recommended response: Provide detailed and updated exposure information as specified, covering all requested dosage and time points.
Failure to provide a summary and analysis of all patients who had recurrent ARIA, including frequency of subjects with multiple episodes, and information about individual patients (asymptomatic/symptomatic, radiographic severity).
Recommended response: Conduct and submit a comprehensive analysis of recurrent ARIA events, including individual patient data and detailed characteristics.
The primary themes of the Complete Response Letter revolve around the critical need for comprehensive and well-presented long-term safety data, particularly concerning adverse events like ARIA, and strict adherence to labeling content and formatting regulations. The agency emphasizes the importance of robust data integrity and clear communication of safety information to ensure patient safety and proper product use.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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