Inadequate Safety Qualification of Leachables
Severity: criticalThe safety (i.e., general toxicity) of several leachables detected with the drug product has not been adequately qualified. Inadequate safety information was provided to support the qualification of identified leachables, leading to insufficient data for an independent safety review of these compounds.
Recommended response: Submit additional nonclinical qualification studies, including repeated-dose toxicology studies for leachables exceeding the qualification threshold (5 mcg/day). Submit a draft study protocol for agency review prior to initiating studies. Provide justification for species selection and ensure qualitative and quantitative similarity of leachables in test articles. Conduct additional (Q)SAR evaluations for bacterial mutagenicity for new leachables exceeding 20 mcg/day, and follow-up Ames tests for genotoxic potential.
Prescribing Information (PI) Non-Compliance
Severity: majorThe proposed Prescribing Information (PI) does not conform to the content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57. Draft labeling needs to address proposed revisions provided by the agency.
Recommended response: Submit draft labeling that addresses the agency's proposed revisions, reviewing resources on PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites.
Cited: 21 CFR 201.56(a), 21 CFR 201.56(d), 21 CFR 201.57
Carton and Container Labeling Non-Compliance
Severity: majorDraft carton and container labeling must be submitted based on the agency's proposed revisions dated February 22, 2021.
Recommended response: Submit draft carton and container labeling based on the proposed revisions dated February 22, 2021.
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name, DAPZURA RT, 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, DAPZURA RT, when responding to the application deficiencies.
Comprehensive Safety Update Required
Severity: majorUpon responding to the deficiencies, a comprehensive safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b). This includes detailing significant changes in safety profile, presenting new and combined safety data, comparing adverse event frequencies, providing separate tables for other indications, retabulating trial discontinuations, providing case reports for deaths/serious adverse events, describing changes in common adverse events, updating exposure information, summarizing worldwide experience, and providing English translations of foreign labeling.
Recommended response: Include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b) when responding to deficiencies, covering all nonclinical and clinical data, significant changes, adverse event frequencies, trial discontinuations, case reports, exposure, worldwide experience, and foreign labeling translations.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
