Alvotech USA, Inc. – FDA CRL

The FDA issued a Complete Response Letter (CRL) to Alvotech USA Inc. for its biologics license application (BLA 761343) for AVT04, submitted under section 351(k) of the Public Health Service Act. The agency determined it could not approve the application in its current form due to several deficiencies. A primary concern stems from an inspection of Alvotech hf in Reykjavik, Iceland, where unsatisfactory deficiencies were observed, requiring satisfactory resolution before approval. Additionally, the FDA requires updates to the carton and container labeling to include a bolded statement regarding the enclosed Medication Guide, as per 21 CFR 208.24(d). A comprehensive safety update is also mandated, including detailed changes in the safety profile, retabulation of clinical study data, case report forms for serious adverse events or deaths, updated exposure information, and a summary of worldwide safety experience. While not direct approvability issues, the FDA also provided comments on product quality, requesting justification for large variability in FcyRilla 158F and FcyRilla 158V binding assays and data supporting method fitness. Microbial quality comments included requirements for method qualification data, endotoxin detection hold time studies, and continuous in-line pressure monitoring during sterile filtration. Alvotech is required to address all identified deficiencies in a complete resubmission within one year, or take other available actions.