Lack of Substantial Evidence of Effectiveness
Severity: criticalThe clinical data submitted from Study 301 do not provide substantial evidence of effectiveness for the proposed indication of treatment of adult women with uncomplicated urinary tract infections (uUTI) caused by designated susceptible microorganisms proven or strongly suspected to be nonsusceptible to a quinolone. The results are not sufficient as a single trial without a second adequate and well-controlled trial. Other trials conducted with sulopenem failed to meet their primary endpoint, calling into question the effectiveness.
Recommended response: Conduct at least one additional adequate and well-controlled study in uUTI and consider using a different active comparator drug that is more reflective of currently recommended treatment. Conduct further investigation to determine the optimal sulopenem dosing regimen.
Cited: 21CFR §314.126, 21 CFR §314.125(b)(5)
Inadequate Prescribing Information
Severity: majorThe agency 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, regulations, and guidance documents. Use the SRPI checklist to ensure format compliance. Include updated content of labeling in SPL format.
Cited: 21 CFR 314.50(l)(1)(i)
Incomplete/Incorrect Container and Carton Labeling
Severity: majorEnsure consistency with Prescribing Information (dosage statement). Include linear barcodes on bottle and blister cell in accordance with 21 CFR 201.25(c)(2), ensuring proper orientation and sufficient white space. Add linear barcode to unit-dose carton labeling. Ensure human-readable and machine-readable product identifier (2D data matrix barcode) is included on carton labeling, with sufficient white space between barcodes.
Recommended response: Revise dosage statement, add/correct barcodes with proper placement and white space, include product identifiers.
Cited: 21 CFR 201.25(c)(2), 21 CFR 201.25(c)(i)
Proprietary Name Resubmission Required
Severity: minorThe proposed proprietary name, Orlynvah, was found acceptable pending approval of the application. It needs to 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
Severity: majorA comprehensive safety update is required when responding to deficiencies, as described at 21 CFR 314.50(d)(5)(vi)(b). This includes detailed changes in safety profile, new safety data from studies/trials, tabulations of new data combined with original, comparison tables, separate tables for other indications, case report forms/narrative summaries for deaths/serious adverse events, information on substantial changes in common adverse events, updated exposure information, summary of worldwide experience, and English translations of foreign labeling.
Recommended response: Provide a comprehensive safety update following 21 CFR 314.50(d)(5)(vi)(b) guidelines, including all specified data and analyses.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Inconclusive Nonclinical PK/PD Studies
Severity: infoResults of the nonclinical PK/PD studies are inconclusive, providing insufficient evidence to support the use of T>MIC as the PK/PD index. Deficiencies were noted in the analysis and interpretation of dose-fractionation study results and the approach used for PK/PD target determination. (Note: This was listed as 'not approvability issues' but recommendations were provided.)
Recommended response: Conduct additional nonclinical PK/PD studies to better understand PK/PD behavior and appropriately determine PK/PD targets. Submit study plans and protocols for review.
