Incomplete Container Closure Integrity Test (CCIT) Method Validation
Severity: majorThe non-compendial CCIT method used for drug product stability testing was validated for specificity and detection limit but lacks validation for precision (repeatability, intermediate precision, and reproducibility) and robustness. Complete validation results for the proposed dye ingress method are required.
Recommended response: Conduct full validation studies for the CCIT method, including precision and robustness, as per FDA guidance. Update relevant sections of the BLA with complete validation results.
Cited: FDA Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics, 2015
Lack of Data for Manufacturing Reproducibility
Severity: majorAdditional data and/or information are required to support that the manufacturing process is capable of producing IMAB362 drug product reproducibly.
Recommended response: Provide comprehensive data demonstrating manufacturing process reproducibility, potentially including process validation data, batch consistency data, and relevant statistical analyses.
Proprietary Name Resubmission Contingent on Deficiency Resolution
Severity: minorThe proposed proprietary name, VYLOY, was conditionally acceptable pending approval. Resubmission of the proprietary name is required only after all application deficiencies identified in this letter have been addressed.
Recommended response: Focus on resolving all other deficiencies first. Once resolved, resubmit the proprietary name proposal.
Incomplete Safety Update
Severity: majorA comprehensive safety update is required as described in 21 CFR 314.50(d)(5)(vi)(b), including data from all nonclinical and clinical studies/trials. This involves detailing significant changes, presenting new and combined safety data, comparing frequencies of adverse events, providing separate tables for other indications, narrative summaries for deaths and serious adverse events, updated exposure information, and a summary of worldwide safety experience.
Recommended response: Compile and present a complete safety update following the detailed requirements of 21 CFR 314.50(d)(5)(vi)(b), ensuring all new and existing safety data are integrated and analyzed.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Insufficient Detail in Adverse Event Reporting
Severity: majorProvide case report forms and narrative summaries for each subject who died or discontinued due to an adverse event during clinical trials. Additionally, provide narrative summaries for all serious adverse events.
Recommended response: Extract and compile detailed case report forms and narrative summaries for all specified adverse events and deaths, ensuring thorough documentation.
Outdated Clinical Exposure Information
Severity: minorProvide updated exposure information for the clinical studies/trials, including details such as the number of subjects and person-time.
Recommended response: Update all relevant clinical study reports and summaries with the most current exposure data.
Missing Worldwide Safety Experience Summary
Severity: majorProvide a summary of worldwide experience on the safety of this drug, including an updated estimate of use for the drug marketed in other countries.
Recommended response: Gather and summarize all available worldwide safety data, including post-marketing experience and usage estimates from other countries.
