Lack of Substantial Evidence of Effectiveness (PK/PD for Repeat Dosing)
Severity: majorThe submitted data do not provide substantial evidence of effectiveness for the use of ARS-1 (epinephrine nasal spray) for its proposed indication, the treatment of allergic reactions (Type I), including anaphylaxis, in adult and pediatric patients who weigh ≥ 30 kg, under conditions likely to be encountered by the target population. Concerns exist regarding the durability of effect from a single dose and the need for repeat dose PK/PD data under allergen-induced acute rhinitis conditions, including administration in ipsilateral and contralateral naris, to demonstrate sustainability and strength of PK/PD for patients who may require a repeat dose.
Recommended response: Conduct a repeat dose trial to provide PK/PD data assessing repeat doses of ARS-1 compared to repeat doses of epinephrine injection product(s) under allergen-induced allergic rhinitis conditions. Include an assessment of PK/PD findings when the second dose of ARS-1 is administered in the ipsilateral and contralateral naris.
Inadequate Nitrosamine Impurity Assessment and Mitigation
Severity: majorFDA expects manufacturers to ascertain the presence of Nitrosamine Drug Substance-Related Impurities (NDSRIs) and implement a 3-step mitigation strategy (risk assessment, confirmatory testing, reporting changes). The applicant needs to investigate the root cause and implement changes to eliminate, mitigate, or reduce nitrosamine impurity consistent with recommendations in the NDSRI Guidance, or provide a scientifically justified rationale for a different AI limit for N-nitroso-epinephrine.
Recommended response: Conduct a comprehensive risk assessment for nitrosamines, perform confirmatory testing, and implement changes in the manufacturing process or product formulation to eliminate, mitigate, or reduce nitrosamine impurities. Alternatively, provide a scientifically justified rationale for an acceptable intake (AI) limit different from FDA recommendations for N-nitroso-epinephrine.
Missing Irritation Testing for Device Constituent Part
Severity: majorWhile cytotoxicity and sensitization testing were provided for the device constituent part, irritation testing was not. An adequate irritation assessment is important due to potential localized non-specific inflammatory responses. Methods and results from irritation testing of the device constituent part are required.
Recommended response: Provide methods and results from irritation testing of the device constituent part of the proposed combination product, potentially following recognized standards such as ISO 10993-10.
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name, Neffy, 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.
Comprehensive Safety Update Required
Severity: minorA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included when responding to the deficiencies. This includes detailed changes in safety profile, updated tabulations of adverse events, comparison of frequencies, case reports for deaths/serious adverse events, updated exposure information, and worldwide experience summary.
Recommended response: Prepare and submit a comprehensive safety update in accordance with 21 CFR 314.50(d)(5)(vi)(b) when resubmitting the application.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
