Approval Letter Other 209471 (Jan 1, 2024)

The application has not adequately described the exposure to the product. Specific and accurate exposure information is needed, including distribution of patients versus doses, exposure during the open-label extension stage in multiple-dose studies, and clarification for single-dose pharmacokinetic studies (MX-9, 10, 11, 13b, 14a, 14b). Information on the number of patients exposed per number of doses for Study MX-1 and a summary of exposure during the open-label extension stage of the two 24-hour studies are also required.

Recommended response: Provide detailed and accurate exposure data, including patient and dose distribution, for all relevant clinical studies and phases, ensuring clarity and completeness.

The datasets provided for Study AFT-MX-6 were not of sufficient quality to allow for a thorough review of efficacy. The agency was unable to confirm primary and secondary analyses, thus could not conclude that the study provided sufficient evidence of efficacy. The sponsor acknowledged errors due to manual data generation in Microsoft Excel. A third party should produce SAS programs to reproduce primary/secondary analyses from ADaM domains and derive new ADaM datasets from SDTM domains for complete traceability.

Recommended response: Re-generate and validate all efficacy datasets using robust statistical programming (e.g., SAS) from SDTM domains to ensure accuracy and traceability, and resubmit for review.

Inadequate justification for the proposed drug substance specification for an unnamed impurity. Because this impurity has been reported to produce chromosomal aberrations in human lymphocytes, its specification should be reduced to as low as technically feasible.

Recommended response: Provide robust justification for the drug substance specification or reduce the specification for the genotoxic impurity to the lowest technically feasible level.

The application does not address the potential presence of elemental impurities in the drug product in accordance with ICH guidance document: Q3D Elemental Impurities. The final drug product must be analyzed for elemental impurities, considering the maximum daily dose of 12 tablets per day, and safety justification provided for any impurity exceeding ICH permissible daily exposures.

Recommended response: Analyze the final drug product for elemental impurities per ICH Q3D, considering the maximum daily dose, and provide safety justification for any impurities exceeding permissible daily exposures.

Cited: ICH guidance document: Q3D Elemental Impurities

The chromatograms example included in the analytical procedure document are illegible and cannot be used to assess the methods.

Recommended response: Resubmit clear and legible chromatograms as part of the analytical procedure documentation.

The application refers to four exhibit batches, which are smaller than the proposed commercial batch size, as validation batches. Process validation must be performed on three commercial-scale validation batches using the approved commercial process, per current FDA Guidance “Process Validation: General Principles and Practices.”

Recommended response: Confirm and commit to performing process validation using three commercial-scale batches according to FDA guidance, and provide the updated validation plan.

Cited: FDA Guidance “Process Validation: General Principles and Practices.”

During a recent inspection of an unnamed facility, product/process controls, lab controls, and QA functions for the facility were found unacceptable for this NDA. The field investigator observed issues and conveyed this information to the facility representative.

Recommended response: Address all observations from the facility inspection, implement comprehensive corrective and preventive actions, and ensure the facility's quality systems are compliant and acceptable for manufacturing.

The response must include updated content of labeling [21 CFR 314.50(l)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.

Recommended response: Update the content of labeling to conform to SPL format requirements and resubmit.

Cited: 21 CFR 314.50(l)(1)(i)

1. It is unclear if the placeholders for 'barcode space' are intended to be linear barcodes. Revise the container label and carton labeling to include the graphical representation of the linear barcode, ensuring sufficient white space per 21 CFR 201.25(c)(i). 2. The format for the expiration date is not defined. Identify the intended format, recommending YYYY-MM-DD or YYYY-MMM-DD, with a hyphen or space, and year/month if space is limited.

Recommended response: Revise carton and container labeling to include clear linear barcodes with adequate white space and define the expiration date format according to FDA recommendations.

Cited: 21 CFR 201.25(c)(i)

A comprehensive safety update is required as described at 21 CFR 314.50(d)(5)(vi)(b). This includes: detailed description of significant changes/findings in the safety profile; incorporation of new safety data into discontinuations, serious adverse events (AEs), and common AEs sections; separate tables for AEs in clinical trials for non-proposed indications; retabulation of premature trial discontinuations; case report forms and narrative summaries for deaths/discontinuations due to AEs and for serious AEs; information on substantial changes in incidence of common, less serious AEs; updated exposure information; a summary of worldwide safety experience; and English translations of current approved foreign labeling.

Recommended response: Provide a comprehensive safety update addressing all requested data points, including detailed analyses, comparisons, narratives, and worldwide experience, in accordance with regulatory requirements.

Cited: 21 CFR 314.50(d)(5)(vi)(b)