Missing Patent Certification or Statement
Severity: majorThe 505(b)(2) application relies on NDA 205029 for Epinephrine but lacks an appropriate patent certification or statement for patents 10,004,700 and 10,039,728 listed in the Orange Book. If a paragraph IV certification is elected, it must be accompanied by a statement of compliance with notice requirements to patent owners and application holders.
Recommended response: Submit a complete patent certification or statement, including a paragraph IV certification if applicable, and ensure compliance with notice requirements to patent owners and application holders as per 21 CFR 314.52(a) and (c).
Cited: 21 CFR 314.50(i)(1)(i)(A)(4), 21 CFR 314.52(a), 21 CFR 314.52(c)
Inadequate Prescribing Information and SPL Format
Severity: majorThe proposed labeling requires review and update to conform with PLR Requirements, Pregnancy and Lactation Labeling Final Rule, and the Selected Requirements for Prescribing Information (SRPI) checklist. The response must include updated content of labeling in Structured Product Labeling (SPL) format.
Recommended response: Revise prescribing information according to PLR requirements, Pregnancy and Lactation Labeling Final Rule, and SRPI checklist. Submit updated labeling in SPL format as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
Cited: 21 CFR 314.50(l)(1)(i)
Incomplete Safety Update
Severity: majorA comprehensive safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b). This includes detailing significant changes in the safety profile, presenting new safety data from studies/clinical trials for proposed and other indications, tabulating combined new and original application data, and comparing frequencies of adverse events.
Recommended response: Provide a comprehensive safety update covering all nonclinical and clinical data, including detailed analysis of adverse events, exposure, and any changes in safety profile, following 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Insufficient Clinical Safety Data Documentation
Severity: majorProvide separate tables for frequencies of adverse events occurring in clinical trials for indications other than the proposed indication. Submit case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial due to an adverse event. Additionally, provide narrative summaries for all serious adverse events.
Recommended response: Compile and submit detailed adverse event tables for all indications. Provide complete CRF and narrative summaries for all deaths, discontinuations due to AEs, and serious AEs.
Inadequate Exposure Information and Worldwide Safety Summary
Severity: majorProvide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time). Additionally, provide a summary of worldwide experience on the safety of this drug, including an updated estimate of use for drug marketed in other countries.
Recommended response: Update and submit comprehensive exposure data for all clinical trials. Prepare and submit a global safety summary, including usage estimates from other markets.
Missing English Translations of Foreign Labeling
Severity: minorProvide English translations of current approved foreign labeling not previously submitted.
Recommended response: Translate and submit all current approved foreign labeling that has not yet been provided.
