Issued January 1, 2024
Issued
January 1, 2024
Application
Other • 761299
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
The FDA issued a Complete Response letter for Biologics License Application (BLA) 761299 for AVT02, indicating that the application cannot be approved in its current form due to deficiencies. The letter outlines specific requirements for resubmission, including resolving facility inspection issues, updating labeling, resubmitting the proprietary name, and providing a comprehensive safety update.
The application cannot be approved in its present form due to unresolved deficiencies from a facility inspection, several issues related to the presentation and completeness of clinical safety data, and minor labeling and administrative requirements. A comprehensive safety update and resubmission of the proprietary name are also required.
Satisfactory resolution of deficiencies identified during the inspection of the Alvotech hf, Reykjavik, Iceland facility (FEI: 3013702557) is required before this application may be approved.
Recommended response: Address all outstanding deficiencies identified during the facility inspection at Alvotech hf, Reykjavik, Iceland, to ensure compliance with cGMP regulations and facilitate approval.
The carton and container labeling must include the bolded statement or appropriate alternative: 'ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide,' as required by 21 CFR 208.24(d).
Recommended response: Revise carton and container labeling to include the specified Medication Guide statement in compliance with 21 CFR 208.24(d).
Cited: 21 CFR 208.24(d)
The proposed proprietary name, Simlandi, was found acceptable pending approval. It must be resubmitted with the response to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name, Simlandi, as part of the complete response to the application deficiencies.
Provide a detailed description of any significant changes or findings in the safety profile and their relevance, if any, to whether there may be clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.
Recommended response: Conduct a thorough analysis of the safety profile, identifying and detailing any significant changes, and clearly articulate their relevance to biosimilarity with the reference product.
Incorporate new safety data from clinical studies into sections describing discontinuations due to adverse events, serious adverse events, and common adverse events. This includes presenting new data in the original BLA format, tabulating combined new and original BLA data, and providing comparative tables of adverse event frequencies.
Recommended response: Reformat and present all new clinical safety data, ensuring consistency with the original BLA submission, and provide comprehensive tabulations and comparative analyses of adverse event frequencies.
Provide a retabulation of reasons for premature study discontinuation, incorporating drop-outs from newly completed studies, and describe any new trends or patterns identified.
Recommended response: Update the analysis of premature study discontinuations to include data from all completed studies and identify any emerging trends or patterns.
Submit case report forms and narrative summaries for all subjects who died or discontinued a clinical study due to an adverse event, and provide narrative summaries for all serious adverse events.
Recommended response: Compile and submit all required case report forms and narrative summaries for deaths, study discontinuations due to AEs, and serious adverse events.
Describe any information indicating a substantial change in the incidence of common, but less serious, adverse events when comparing new data with the original BLA data.
Recommended response: Perform a comparative analysis of common adverse event incidence between new and original BLA data, highlighting any substantial changes.
Submit updated exposure information for all clinical studies, including details such as the number of subjects and person-time.
Recommended response: Provide comprehensive and updated exposure data for all clinical studies to support the safety assessment.
Submit a comprehensive summary of worldwide safety experience for the product, including adverse events known to be associated with the use of the product and immunogenicity. Include an updated estimate of use for this product marketed in other countries.
Recommended response: Compile and present a global safety summary, incorporating all available post-marketing data, adverse events, immunogenicity, and usage estimates from other countries.
Submit English translations of all current approved foreign labeling that has not been previously provided.
Recommended response: Provide English translations for all relevant foreign approved labeling documents.
The primary themes for this Complete Response are critical manufacturing compliance issues, significant deficiencies in the clinical safety data analysis and presentation, and outstanding administrative and labeling requirements. The agency requires a comprehensive resubmission addressing all points.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
Document viewer
Read the FDA letter and send context to the co-pilot at any time.