Insufficient evidence of effectiveness due to missing EFS data
Severity: criticalSubstantial evidence of effectiveness for treosulfan as a preparative regimen for allogeneic hematopoietic stem cell transplantation for adult and pediatric AML or MDS was not provided. Specifically, complete blood cell (CBC) and marrow results were not submitted for Study MC-FLudT-14/L Trial II, preventing independent confirmation of the event-free survival (EFS) primary endpoint analysis and assessment of support for proposed indications.
Recommended response: Submit complete CBC and marrow results through the entire assessment period for EFS for Study MC-FLudT-14/L Trial II to allow independent confirmation of primary endpoint analysis and assessment of indication support.
Overall Survival (OS) cannot be used as sole basis for approval due to statistical plan deficiencies
Severity: criticalOverall Survival (OS) cannot be used as the sole basis for approval because the statistical plan for Study MC-FLudT-14/L Trial II lacked control of Type 1 error and had no prespecified boundary or alpha allocation for interim OS analyses, rendering p-values nominal and OS analysis exploratory.
Recommended response: Submit data from an adequate and well-controlled trial comparing treosulfan vs busulfan with a prespecified analysis of OS for each indication, including control of Type 1 error.
Labeling comments reserved until application is otherwise adequate
Severity: minorComments on the proposed labeling are reserved until the application is otherwise adequate. The sponsor is encouraged to review labeling resources and guidance documents, and any revised labeling must conform to format items using the SRPI checklist and be submitted in structured product labeling (SPL) format.
Recommended response: Review labeling resources and guidance documents. Ensure any revised labeling conforms to format items using the SRPI checklist and submit updated content in SPL format once clinical deficiencies are resolved.
Cited: 21 CFR 314.50(l)(1)(i)
Resubmit proposed proprietary name after addressing application deficiencies
Severity: infoThe proposed proprietary name, Grafapex, 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, Grafapex, with the complete response to the application deficiencies.
Required comprehensive safety update with response to deficiencies
Severity: majorA comprehensive safety update, as described at 21 CFR 314.50(d)(5)(vi)(b), must be included with the response to deficiencies. This update should incorporate all new nonclinical and clinical safety data, including detailed analyses of adverse events, discontinuations, exposure information, worldwide experience, and English translations of current approved foreign labeling.
Recommended response: Prepare a comprehensive safety update as per 21 CFR 314.50(d)(5)(vi)(b), incorporating all new nonclinical and clinical safety data, including detailed analyses of adverse events, discontinuations, exposure, worldwide experience, and foreign labeling translations.
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Missing clinical pharmacology data for treosulfan and its metabolites
Severity: majorThe application lacks essential clinical pharmacology data, specifically: in vitro data evaluating treosulfan and its epoxide metabolites as substrates of metabolizing enzymes, pharmacokinetics (PK) data of treosulfan active metabolites in adult patients, and data evaluating the effects of race and ethnicity on treosulfan PK.
Recommended response: Conduct and submit in vitro studies on treosulfan and its epoxide metabolites as enzyme substrates, provide PK data for active metabolites in adult patients, and evaluate the effects of race and ethnicity on treosulfan PK.
Inadequate nonclinical characterization of genotoxicity and alkylating properties
Severity: majorPrior to resubmission, an in vitro study demonstrating DNA alkylation and breakage with treosulfan is required to adequately characterize its alkylating and genotoxicity properties and to determine the potential serious risk of reproductive and developmental toxicity and carcinogenicity.
Recommended response: Conduct and submit an in vitro study demonstrating DNA alkylation and breakage with treosulfan to fully characterize its genotoxicity and alkylating properties prior to resubmission.
