Product Quality - Assay Method Compliance with USP
Severity: major1. Test PEDMARK registration batches in accordance to the USP monograph for Sodium Thiosulfate Injection. You may use an alternative test method for assay, however, the USP method will be considered the regulatory method. Refer to USP General Notices and Requirements: 6.30 Alternative and Harmonized Methods and Procedures for more details. 2. Submit a new assay test method, intended for commercial use, that expresses assay in terms of the pentahydrate. Alternatively, you may revise the calculations for the currently proposed non-compendial ion chromatography assay method so that the drug product assay is calculated based on the sodium thiosulfate pentahydrate form. 3. If you plan to use the currently proposed non-compendial assay test method, provide comparative data to show that the method is comparable to the compendial test method. Per the USP monograph, the assay must be calculated based on sodium thiosulfate pentahydrate.
Recommended response: Revise the assay method to comply with USP monograph requirements, either by adopting the USP method, submitting a new pentahydrate-based method, or providing comparability data for the current method with revised calculations.
Cited: USP General Notices and Requirements: 6.30 Alternative and Harmonized Methods and Procedures
Comprehensive Safety Update Required
Severity: majorWhen you respond to the above deficiencies, include a safety update as described at 21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.
Recommended response: Prepare a comprehensive safety update covering all nonclinical and clinical data as per 21 CFR 314.50(d)(5)(vi)(b).
Cited: 21 CFR 314.50(d)(5)(vi)(b)
Clinical Safety Data Presentation Deficiencies
Severity: majorPresent new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission. Present tabulations of the new safety data combined with the original application data. Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above. For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original/supplemental application data. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).
Recommended response: Re-analyze and present clinical safety data, including adverse event frequencies, discontinuation reasons, and exposure information, in the requested comparative and tabulated formats.
Missing Case Report Forms and Serious Adverse Event Narratives
Severity: criticalProvide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.
Recommended response: Compile and submit all requested case report forms and narrative summaries for deaths and serious adverse events.
Worldwide Safety Experience and Foreign Labeling Translations
Severity: majorProvide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug/product marketed in other countries. Provide English translations of current approved foreign labeling not previously submitted.
Recommended response: Gather and summarize worldwide safety data and provide English translations of all current approved foreign labeling.
