Issued January 1, 2021
Issued
January 1, 2021
Application
Other • 213072
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This is a Complete Response Letter from the FDA to Althera Life Sciences, LLC, for their New Drug Application (NDA) 213072 for rosuvastatin and ezetimibe tablet. The FDA has determined that the application cannot be approved in its present form due to deficiencies related to product quality, facility inspections, and pediatric assessment requirements.
The application cannot be approved in its current form due to critical manufacturing facility deficiencies identified during a pre-approval inspection, resulting in unreliable method validation data. Additionally, the submission lacks a comprehensive safety update with detailed clinical data and does not adequately address Pediatric Research Equity Act (PREA) requirements for the ezetimibe component.
Satisfactory resolution of deficiencies conveyed by the field investigator during a recent inspection of the manufacturing facility is required before this application may be approved.
Recommended response: Address all outstanding deficiencies identified during the pre-approval inspection of the manufacturing facility and provide evidence of satisfactory resolution.
Due to the impact of testing data deficiencies identified at the manufacturing facility during pre-approval inspection (PAI), the method validation information provided in the NDA application is not considered reliable.
Recommended response: Revalidate analytical methods for assay, chromatographic purity, content uniformity, and dissolution using suitable reference standards/working standards, ensuring data integrity and reliability.
The proposed proprietary name, Roszet, was found acceptable pending approval of the application in the current review cycle. It must be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name 'Roszet' along with the complete response to other deficiencies.
A comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), is required. This update must include data from all nonclinical and clinical studies/trials of the drug/product, regardless of indication, dosage form, or dose level.
Recommended response: Provide a comprehensive safety update as per 21 CFR 314.50(d)(5)(vi)(b), including all nonclinical and clinical study data, significant changes in safety profile, and updated adverse event tabulations.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Specific requirements for clinical safety data include: describing significant changes in safety profile; presenting new safety data in the same format as the original submission; tabulating new safety data combined with original data; comparing frequencies of adverse events; providing separate tables for adverse events in other indications; retabulating reasons for premature trial discontinuation; providing case report forms and narrative summaries for deaths, discontinuations due to adverse events, and serious adverse events; describing changes in common, less serious adverse events; providing updated exposure information; summarizing worldwide safety experience; and providing English translations of current approved foreign labeling.
Recommended response: Compile and present all requested detailed clinical safety data, including adverse event tabulations, case report forms, narrative summaries, exposure information, worldwide experience, and foreign labeling translations, ensuring consistency and completeness.
Insufficient evidence was provided to support the safety and efficacy of the ezetimibe component in pediatric homozygous familial hypercholesterolemia (HoFH), ages to 17 years. This evidence gap must be addressed with data from published literature or a completed pediatric trial.
Recommended response: Address the PREA requirement for ezetimibe in pediatric HoFH by providing sufficient evidence from published literature or a completed pediatric trial. If adult data is sufficient for approval, anticipate postmarketing study requirements.
The application faces significant hurdles to approval, primarily stemming from critical manufacturing quality control and data integrity issues, compounded by substantial deficiencies in the presentation and completeness of clinical safety data, and unfulfilled pediatric assessment obligations under PREA.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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