Issued January 1, 2024
Issued
January 1, 2024
Application
Other • 761343
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
The FDA issued a Complete Response letter for Biologics License Application (BLA) 761343 for AVT04, indicating that the application cannot be approved in its present form due to outstanding deficiencies related to facility inspections, labeling, safety updates, product quality, and microbial quality.
The application received a Complete Response Letter due to unresolved facility inspection deficiencies, comprehensive safety data update requirements, and significant product quality and microbial control issues related to analytical methods and manufacturing process controls. Labeling comments are reserved pending resolution of these core issues.
Satisfactory resolution of deficiencies identified during the inspection of Alvotech hf, Reykjavik, Iceland (FEI: 3013702557) is required before this application may be approved.
Recommended response: Address all outstanding deficiencies identified during the facility inspection and provide evidence of satisfactory resolution to the agency.
Add the following bolded statement or appropriate alternative to the carton and container labeling per 21 CFR 208.24(d): 'ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide.'
Recommended response: Revise carton and container labeling to include the required Medication Guide statement as per 21 CFR 208.24(d).
Cited: 21 CFR 208.24(d)
The proposed proprietary name, Selarsdi, was found conditionally acceptable. Please resubmit the proposed proprietary name when you respond to all of the application deficiencies identified in this letter.
Recommended response: Resubmit the proposed proprietary name, Selarsdi, concurrently with the response to all other application deficiencies.
Include a safety update with data from all nonclinical and clinical studies, regardless of indication, dosage form, or dose level. Describe in detail any significant changes or findings in the safety profile and their relevance to potential clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.
Recommended response: Provide a comprehensive safety update incorporating all new nonclinical and clinical data, highlighting any significant changes or differences from the reference product.
Present new safety data from clinical studies using the same format as the original BLA, including tabulations of new data combined with original BLA data, and tables comparing frequencies of adverse events. Retabulate reasons for premature study discontinuation incorporating new drop-outs and describe new trends.
Recommended response: Reformat and retabulate clinical safety data, combining new and original BLA data, and compare adverse event frequencies and discontinuation reasons.
Provide case report forms and narrative summaries for each subject who died during a clinical study or who did not complete a study because of an adverse event. In addition, provide narrative summaries for serious adverse events.
Recommended response: Submit all requested case report forms and narrative summaries for deaths, study discontinuations due to AEs, and serious adverse events.
Provide updated exposure information for the clinical studies (e.g., number of subjects, person time).
Recommended response: Submit updated clinical exposure information, including subject numbers and person-time data.
Provide a summary of worldwide experience on the safety of this product, including adverse events and immunogenicity. Include an updated estimate of use for this product marketed in other countries.
Recommended response: Compile and submit a comprehensive summary of worldwide safety experience, including immunogenicity data and updated usage estimates from other countries.
Provide English translations of current approved foreign labeling not previously submitted.
Recommended response: Submit English translations of all current approved foreign labeling that has not yet been provided.
Provide a justification for the large data variability observed for FcγRIIIa 158F and FcγRIIIa 158V binding assays and provide data and/or information to support that the methods developed are fit for their intended purpose.
Recommended response: Provide justification for the observed variability in FcγRIIIa binding assays and submit data demonstrating the fitness-for-purpose of the analytical methods.
Update the submission with endotoxin and bioburden assay qualification data for in-process eluates with three independent process eluate lots.
Recommended response: Submit complete endotoxin and bioburden assay qualification data for in-process eluates from three independent process lots.
Determine the effect of hold time on endotoxin detection using endotoxin spiked samples to ensure the drug product formulation does not mask detectability. Refer to PDA Technical Report No. 82.
Recommended response: Conduct and submit a hold time study for the endotoxin assay using spiked samples to demonstrate that the drug product formulation does not mask endotoxin detection.
The application received a Complete Response due to significant manufacturing facility deficiencies, comprehensive safety data update requirements, and unresolved product quality and microbial control issues. Labeling comments are pending resolution of these core issues.
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.