Approval Letter Other 761091 (Jan 1, 2018)

During a recent inspection of the Celltrion, Inc. (FEI 3005241015) manufacturing facility, the field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of the deficiencies is required before this BLA may be approved.

Recommended response: Address all outstanding observations from the manufacturing facility inspection and provide evidence of satisfactory resolution.

Per the “Guidance for Industry: Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products”, the product should be designed to meet the label claim and acceptable overfill, and allow for correct dosing. Adjust the Drug Product (DP) release specification of mg/ml to ensure that the recoverable protein content at the lower limit of the acceptance criterion will consistently meet the label claim of 420 mg.

Recommended response: Revise DP release specifications and provide data demonstrating consistent deliverable volume and protein concentration to meet label claim, referencing the FDA guidance on allowable excess volume.

To support the licensure of CT-P6 420 mg/vial, the CT-P6 DP manufacturing process and controls should be set to ensure the appropriate deliverable volume and protein concentration after reconstitution in each DP vial to meet the label claim. Insufficient information and data on the approach and method used to derive the overfill volume.

Recommended response: Provide comprehensive data and justification for the derived overfill volume to ensure consistent deliverable volume and protein concentration.

Please refer to correspondence dated February 14, 2018, which addresses the proposed proprietary name, Herzuma. This name was found acceptable pending approval of the application in the current review cycle. Please resubmit the proposed proprietary name when you respond to the application deficiencies.

Recommended response: Resubmit the proposed proprietary name 'Herzuma' with the complete response.

When you respond to the above deficiencies, include a safety update. The safety update should include data from all nonclinical and clinical studies of the product under consideration regardless of indication, dosage form, or dose level.

Recommended response: Prepare a comprehensive safety update incorporating all nonclinical and clinical study data, regardless of indication or dosage, as part of the complete response.

Describe in detail any significant changes or findings in the safety profile and their relevance, if any, to whether there may be clinically meaningful differences between the proposed biosimilar product and the U.S.-licensed reference product.

Recommended response: Analyze and describe any significant changes in the safety profile, specifically addressing potential clinically meaningful differences from the reference product.

When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows: Present new safety data from the clinical studies for the proposed indication using the same format as the original BLA submission. Present tabulations of the new safety data combined with the original BLA data. Include tables that compare frequencies of adverse events in the original BLA with the retabulated frequencies described in the bullet above.

Recommended response: Integrate and present new safety data from clinical studies, including discontinuations and adverse events, in a consistent format, combining with original BLA data and providing comparative tables.

Present a retabulation of the reasons for premature study discontinuation by incorporating the drop-outs from the newly completed studies. Describe any new trends or patterns identified.

Recommended response: Retabulate and analyze reasons for premature study discontinuations, including new study data, and identify any emerging trends.

Provide case report forms and narrative summaries for each patient who died during a clinical study or who did not complete a study because of an adverse event. In addition, provide narrative summaries for serious adverse events.

Recommended response: Submit all requested case report forms and narrative summaries for patient deaths and serious adverse events.

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 BLA data.

Recommended response: Analyze and describe any substantial changes in the incidence of common adverse events between new and original BLA data.

Provide updated exposure information for the clinical studies (e.g., number of subjects, person time).

Recommended response: Submit updated clinical study exposure information, including subject numbers and person-time data.

Provide a summary of worldwide experience on the safety of this product, including adverse events known to be associated with the use of the product and immunogenicity. Include an updated estimate of use for this product marketed in other countries.

Recommended response: Compile and submit a comprehensive summary of worldwide safety experience, including adverse events, immunogenicity, and updated usage estimates from other countries.