Insufficient PK bridge and inconsistent drug delivery
Severity: criticalThe pharmacokinetic (PK) bridge between the Gimoti 15 mg dose and the Reglan tablet 10 mg is insufficient to justify reliance on Reglan's safety and efficacy findings. Concerns exist regarding the product's inability to deliver metoclopramide reliably and consistently, evidenced by low Cmax in several subjects, suggesting very little drug delivery.
Recommended response: Investigate the root cause(s) for the variability in PK for Gimoti, including inconsistent and incomplete delivery. Provide evidence supporting conclusions from root cause analysis and mitigation strategies. May require additional in vitro and/or in vivo studies.
Inadequate drug product specification for combination product
Severity: criticalThe proposed specification for the drug product is inadequate as insufficient evidence has been provided to ensure that the quality control and essential performance characteristics of the combination product do not contribute to observed clinical variability and lack of efficacy. Specifically, the method and acceptance criterion for droplet size distribution are not robust enough or justified given the observed PK variability.
Recommended response: Upon resubmission, all proposed tests and acceptance criteria, including droplet sizes and other essential performance characteristics, for the commercial product specification should be supported by three batches of drug product using the selected commercial formulation and commercial device. Registration batches should be manufactured at the proposed commercial manufacturing site, by the proposed commercial process, and tested using validated analytical methods at the proposed analytical site.
Actuation force not considered an essential performance requirement
Severity: minorActuation force should be considered an essential performance requirement. A test and acceptance criterion for actuation force for the to-be-marketed combination product should be included in the product release and stability specification, supported by verification and validation data. Alternatively, a rationale for not considering it essential and how consistency will be assured is required.
Recommended response: Consider actuation force an essential performance requirement and include a test and acceptance criterion in product release and stability specification, supported by verification/validation data. Alternatively, provide a rationale for not considering it essential and how consistency will be assured.
Missing upper cap removal force specification
Severity: minorA specification for the lowest allowable cap removal force was provided, but not for the highest allowable cap removal force. The upper cap removal force specification is recommended to demonstrate that the cap will not be too difficult for the user to remove.
Recommended response: Define the upper cap removal force specification.
Insufficient data to support proposed shelf-life
Severity: minorThe proposed shelf-life is not supported by the submitted data. Upon resubmission, the proposed shelf-life should be supported by three batches of the drug product using the selected commercial formulation (including strength) and the proposed commercial device.
Recommended response: Support the proposed shelf-life with data from three batches of the drug product using the selected commercial formulation and proposed commercial device upon resubmission.
Premature request for reduced reporting category for facility
Severity: minorIt is premature to agree to a reduced reporting category for an additional release and stability facility as proposed in the comparability protocol.
Recommended response: Address the prematurity of the request for a reduced reporting category for the additional release and stability facility.
Recommendation for lower dosage strength development
Severity: minorA lower dosage strength is recommended to address dosage adjustment for patients who may need a lower dose.
Recommended response: Develop a lower dosage strength to address dosage adjustment for patients needing a lower dose.
Labeling comments reserved, review resources recommended
Severity: infoComments on proposed labeling are reserved until the application is otherwise adequate. Review of labeling resources (PLR, PLLR, SRPI) is encouraged, and updated content of labeling in SPL format conforming to regulations and guidances is required upon resubmission.
Recommended response: Review labeling resources (PLR, PLLR, SRPI) and update content of labeling in SPL format upon resubmission, ensuring conformity with format items in regulations and guidances.
Cited: 21 CFR 314.50(l)(1)(i)
Requirement for comprehensive safety update upon resubmission
Severity: infoA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), is required upon resubmission. This update must include data from all nonclinical and clinical studies/trials, detailed changes in safety profile, retabulated adverse events, reasons for discontinuation, case reports for deaths/serious AEs, updated exposure information, and worldwide experience.
Recommended response: Provide a comprehensive safety update upon resubmission, including data from all nonclinical and clinical studies/trials, detailed changes in safety profile, retabulated adverse events, reasons for discontinuation, case reports for deaths/serious AEs, updated exposure information, and worldwide experience.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
