Issued January 1, 2021
Issued
January 1, 2021
Application
Other • 204957
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
This document is a Complete Response letter from the FDA to B. Braun Medical, Inc. for New Drug Application (NDA) 204957 for Acetaminophen Injection. The application cannot be approved in its current form due to unresolved facility inspection deficiencies, pending labeling review, outstanding regulatory issues (including Mallinckrodt letters and Paragraph IV certification), and concerns regarding leachables and an unknown compound. The letter details requirements for a comprehensive safety update and outlines the process for resubmission.
The New Drug Application for Acetaminophen Injection cannot be approved in its present form due to unresolved manufacturing facility inspection findings, significant deficiencies in the safety data update and presentation, and pending legal review of patent-related letters from Mallinckrodt. Comments on labeling are reserved until these core issues are addressed.
During a recent inspection of B. Braun Medical Inc. (FEI 2021236), the drug product manufacturer, our field investigator conveyed deficiencies to the facility representative. Satisfactory resolution of these deficiencies is required before this application may be approved.
Recommended response: Address all observations from the facility inspection and provide evidence of satisfactory resolution to the agency.
The safety update provided is insufficient and must include data as described at 21 CFR 314.50(d)(5)(vi)(b). Specific requirements include: describing significant changes/findings in the safety profile; presenting new safety data from studies/clinical trials for the proposed indication (in the same format as the original submission); presenting tabulations of new safety data combined with original application data; including tables that compare frequencies of adverse events; providing separate tables for adverse events in clinical trials for indications other than the proposed one; retabulating reasons for premature trial discontinuation; providing case report forms and narrative summaries for patient deaths or discontinuations due to adverse events, and for serious adverse events; describing information suggesting a substantial change in the incidence of common, less serious adverse events; providing updated exposure information; providing a summary of worldwide experience; and providing English translations of current approved foreign labeling not previously submitted.
Recommended response: Compile and present comprehensive safety data updates as requested, ensuring all specified formats and content are included, and provide translations for foreign labeling.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
A previous deficiency (from the March 27, 2019, complete response letter) required updated letters from Mallinckrodt that clearly indicate a specific date upon which the application can be approved. While updated letters were provided in Module 1.3.5.2, legal review of these letters is still pending, and a determination as to whether this deficiency is resolved has not yet been made.
Recommended response: Follow up with the agency regarding the status of the legal review of the Mallinckrodt letters and provide any further requested documentation or clarification.
The agency reserves comment on the proposed labeling until the application is otherwise adequate. The sponsor is encouraged to review the labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) checklist. Any revised labeling must include updated content of labeling in structured product labeling (SPL) format.
Recommended response: Prepare for future labeling revisions by reviewing relevant guidance and regulations, and ensure compliance with SPL format.
Cited: 21 CFR 314.50(l)(1)(i)
The agency acknowledges receipt of the revised draft carton and container labeling but reserves comments on its acceptability for the next review cycle.
Recommended response: Await further agency feedback on carton and container labeling once other deficiencies are resolved.
The application faces significant hurdles primarily related to manufacturing quality systems, comprehensive clinical safety data reporting, and administrative/legal clarity concerning patent exclusivity. Labeling issues are secondary and contingent on resolving these core deficiencies.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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