Inadequate data to support waiver of reproductive and developmental studies for triacetin
Severity: majorYou have not provided adequate data to support your request for a waiver of reproductive and developmental studies for triacetin. No data supports the conclusion that triacetin instilled into a wound at the maximum daily dose will not result in systemic exposure to the triacetin molecule, nor is there justification for relying on a cited oral rat reproductive and developmental study.
Recommended response: Provide data to support the conclusion that triacetin levels are not present in systemic circulation via your drug product, or conduct reproductive and developmental toxicology studies with triacetin via a route that mimics clinical exposure. Alternatively, justify that animals in the cited oral rat study were exposed to triacetin at comparable levels to those that will occur clinically.
Inadequate data to support safety of DMSO or triacetin due to levels exceeding CDER IID maximum potency
Severity: majorYou have not provided adequate data to support the safety of DMSO or triacetin in your drug product. The levels exceed the maximum potency listed in the CDER Inactive Ingredient Database (IID) and are, therefore, considered novel. Your NDA did not include any discussion of the impact of these two excipients on the standard reproductive and developmental battery of studies.
Recommended response: Submit adequate data to fully characterize the impact of the proposed doses of DMSO and triacetin on all endpoints normally characterized via the standard battery of reproductive and developmental toxicology studies. If addressing via literature, justify its adequacy based on current standard study protocols and provide copies of all referenced literature. In the absence of adequate published data, GLP nonclinical toxicology studies should be completed.
Inadequate toxicological risk assessment for maleic acid regarding embryo-fetal development in a second species
Severity: majorYour toxicological risk assessment for the excipient maleic acid, which exceeds the maximum potency listing in the CDER Inactive Ingredients Database (IID), does not address the potential impact of maleic acid on embryo-fetal development in a second species (typically rabbit).
Recommended response: Submit adequate justification for the safety of the proposed maximum daily dose of maleic acid, specifically with respect to the effects of this compound on rabbit embryo-fetal development.
Inadequate data to qualify proposed drug product degradant exceeding ICH Q3B(R2) qualification threshold
Severity: majorYou have not provided adequate data to qualify the proposed drug product degradant which exceeds the ICH Q3B(R2) qualification threshold.
Recommended response: Either tighten the drug product specification to NMT % or provide adequate qualification in accordance with ICH Q3B(R2), including a minimal genetic toxicology screen (two in vitro genetic toxicology studies, e.g., one point mutation assay and one chromosome aberration assay) with the isolated impurity, tested up to the limit dose for the assay.
Cited: ICH Q3B(R2)
Prescribing Information not adequate
Severity: minorFDA reserves comment on the proposed labeling until the application is otherwise adequate. The response must include updated content of labeling in structured product labeling (SPL) format.
Recommended response: Review labeling review resources (PLR Requirements, Pregnancy and Lactation Labeling Final Rule, SRPI checklist) and submit updated content of labeling in SPL format with the complete response.
Cited: 21 CFR 314.50(l)(1)(i)
Resubmit proposed proprietary name
Severity: minorThe proposed proprietary name, Zynrelef, was found acceptable pending approval of the application in the current review cycle. It needs to be resubmitted when responding to the application deficiencies.
Recommended response: Resubmit the proposed proprietary name when responding to the application deficiencies.
Include a comprehensive safety update with the response
Severity: majorA safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b), including detailed changes in safety profile, new safety data from studies, tabulations, comparisons, separate tables for other indications, retabulation of discontinuations, case reports for deaths/SAEs, information on common adverse events, updated exposure, worldwide experience, and foreign labeling translations.
Recommended response: Provide a comprehensive safety update as per 21 CFR 314.50(d)(5)(vi)(b) with the complete response, incorporating all new nonclinical and clinical safety data.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
