Inadequate Toxicological Risk Assessments for Leachables
Severity: majorThe sponsor has not provided adequate toxicological risk assessments for leachables over the 5 mcg/day qualification threshold. The original approach utilizing ICH M7 for genotoxicity is not acceptable for general toxicity. Additionally, compounds were only tentatively identified, and method validation is ongoing, which is not acceptable for safety assessment.
Recommended response: Submit a revised toxicological risk assessment for all leachable compounds detected above the 5 mcg/day threshold. Ensure structural identification and quantification are confirmed using validated methods. The risk assessment should be based on the maximum level of each leachable from long-term stability data. Justify all safety factors if employing a Permissible Daily Exposure (PDE) assessment as described in ICH Q3C. Provide detailed study designs for any published literature used and compare to modern toxicology endpoints. Justify safety assessments based on analogous compounds with adequate data.
Deficiencies in Prescribing Information Content and Format
Severity: majorDraft labeling will be provided in a separate communication. Upon resubmission, submit draft labeling that is responsive to that communication. Correct any formatting errors using the SRPI checklist to ensure conformance with regulations and guidances. Submit updated content of labeling in Structured Product Labeling (SPL) format as described at FDA.gov. Provide a highlighted or marked-up copy showing all changes, as well as a clean Word version, with annotations supporting proposed changes. The proposed Prescribing Information (PI) must conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57.
Recommended response: Upon resubmission, submit draft labeling responsive to the separate communication. Use the SRPI checklist to correct formatting errors and ensure conformance with regulations and guidances. Submit updated content of labeling in SPL format. Provide highlighted/marked-up and clean Word versions with annotations. Ensure PI conforms to 21 CFR 201.56(a) and (d) and 201.57.
Cited: 21 CFR 314.50(l)(1)(i), 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57
Deficiencies in Carton and Container Labeling
Severity: majorDraft carton and container labeling will be provided in a separate communication. Upon resubmission, submit draft carton and container labeling that is responsive to that communication.
Recommended response: Upon resubmission, submit draft carton and container labeling responsive to the separate communication.
Missing Medication Guide Statement on Labeling
Severity: minorAdd the bolded statement 'ATTENTION PHARMACIST: Each patient is required to receive the enclosed Medication Guide' or an appropriate alternative to the carton and container labeling per 21 CFR 208.24(d).
Recommended response: Add the required Medication Guide statement to the carton and container labeling as specified in 21 CFR 208.24(d).
Cited: 21 CFR 208.24(d)
Proprietary Name Requires Resubmission
Severity: infoThe proposed proprietary name, Combogesic IV, 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 with the response to application deficiencies.
Comprehensive Safety Update Required Upon Resubmission
Severity: majorUpon resubmission, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). This includes data from all nonclinical and clinical studies, detailed changes in safety profile, new safety data presentation, combined tabulations, comparison tables, separate tables for other indications, retabulation of premature trial discontinuations, case reports for deaths/serious adverse events, information on common adverse events, updated exposure information, worldwide experience summary, and English translations of foreign labeling.
Recommended response: Prepare a comprehensive safety update upon resubmission, adhering to all requirements outlined in 21 CFR 314.50(d)(5)(vi)(b), including data from all studies, detailed safety profile changes, new data presentation, combined tabulations, comparison tables, separate tables for other indications, retabulation of premature trial discontinuations, case reports for deaths/SAEs, information on common AEs, updated exposure, worldwide experience, and foreign labeling translations.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
