Issued January 1, 2018
Issued
January 1, 2018
Application
Other • 208313
Review center
Other
Stage
Final Decision
Letter type
Approval Letter
The FDA issued a Complete Response letter to Sun Pharmaceutical Industries Limited for their New Drug Application (NDA) for INFUGEM (gemcitabine injection), indicating that the application cannot be approved in its present form due to deficiencies identified during facility inspections and issues related to clinical data presentation and labeling.
The application cannot be approved in its current form due to unresolved manufacturing facility deficiencies and significant issues with the completeness and presentation of clinical safety data. Specific concerns include inadequate presentation of new and combined safety data, missing adverse event tables for other indications, incomplete retabulation of premature trial discontinuations, missing case report forms and narrative summaries for deaths and serious adverse events, insufficient description of changes in common adverse events, outdated exposure information, and an incomplete summary of worldwide safety experience. Labeling comments are reserved until these core issues are addressed.
During recent inspections of the Sun Pharmaceutical Industries Limited manufacturing facility, deficiencies were conveyed to the facility representative. Satisfactory resolution of these deficiencies is required before this NDA may be approved.
Recommended response: Address and resolve all deficiencies identified during the manufacturing facility inspection to the satisfaction of the agency.
The agency reserves comment on the proposed labeling until the application is otherwise adequate. The sponsor is encouraged to review FDA labeling review resources, including PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, regulations, guidance documents, and the Selected Requirements for Prescribing Information (SRPI).
Recommended response: Review FDA labeling resources and guidance documents in preparation for future labeling submissions once other deficiencies are resolved.
New safety data from clinical trials for the proposed indication must be presented using the same format as the original submission. Tabulations of new safety data combined with original application data are required, including tables that compare frequencies of adverse events between the original application and the retabulated frequencies.
Recommended response: Provide clear, consistent, and comparative tabulations of new safety data, combined with original application data, ensuring consistent formatting and direct comparison of adverse event frequencies.
Separate tables for the frequencies of adverse events occurring in clinical trials for indications other than the proposed indication must be provided.
Recommended response: Compile and submit separate tables detailing adverse event frequencies for all clinical trials related to indications other than the proposed one.
A retabulation of the reasons for premature trial discontinuation, incorporating drop-outs from newly completed trials, is required. Any new trends or patterns identified must be described.
Recommended response: Update the retabulation of premature trial discontinuations to include all new trial data and analyze for any emerging trends or patterns.
Case report forms and narrative summaries are required for each patient who died during a clinical trial or who did not complete a trial due to an adverse event. Additionally, narrative summaries for all serious adverse events must be provided.
Recommended response: Submit all requested case report forms and comprehensive narrative summaries for patient deaths, trial discontinuations due to AEs, and all serious adverse events.
Information suggesting a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data must be described.
Recommended response: Analyze and report any significant changes in the incidence of common, less serious adverse events when comparing new and original application data.
Updated exposure information for the clinical studies/trials (e.g., number of subjects, person time) must be provided.
Recommended response: Submit current and complete exposure information, including subject numbers and person-time, for all clinical studies/trials.
A summary of worldwide experience on the safety of this drug is required, including an updated estimate of use for the drug marketed in other countries.
Recommended response: Compile and submit a comprehensive summary of worldwide safety experience, including updated usage estimates from all countries where the drug is marketed.
English translations of current approved foreign labeling not previously submitted must be provided.
Recommended response: Submit English translations for all current approved foreign labeling that has not yet been provided to the agency.
The primary issues preventing approval are unresolved manufacturing site deficiencies and significant gaps in the clinical safety data presentation and completeness, requiring a comprehensive resubmission addressing both facility compliance and detailed clinical data analysis.
Regulatory change impact: Pending sponsor mitigation plan
Approval likelihood after response: 5%
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