Kashiv BioSciences, LLCTheragrastim’

BLA 761082 COMPLETE RESPONSE

Kashiv BioSciences, LLC

Attention: John Pakulski

Senior VP, Global Regulatory Affairs 20 New England Avenue Piscataway, NJ 08854

Dear Mr. Pakulski:

Please refer to your biologics license application (BLA) dated July 8, 2017, received July 10, 2017, submitted under section 351(k) of the Public Health Service Act for Theragrastim’.

We acknowledge receipt of your amendment dated February 2, 2021, which constituted a complete response to our December 22, 2020, action letter.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

FACILITY INSPECTIONS

1. Aninspection of the Kashiv Biosciences LLC DS manufacture facility (FEI 3011289655), Chicago, Illinois, is required before this application can be approved as the FDA must assess the ability of that facility to conduct the listed manufacturing operations in compliance with CGMP. Due to U.S. Government and/or Agency-wide restrictions on travel, we were unable to conduct an inspection of the Kashiv Biosciences LLC facility during the current review cycle, and the application cannot be approved until the required FDA inspection is conducted and the findings are assessed with regard to this application. We will continue to monitor the public health situation as well as travel restrictions.

Please see the FDA’s “Resiliency Roadmap for FDA Inspectional Oversight" for more information on FDA’s plan to resume inspections (https://www.fda.gov/media/148197/download). Please also see the FDA guidances related to COVID 19. These guidances can be found at

' Your proposed proprietary name, Releuko, and proposed proper name, filgrastim-ayow, are conditionally accepted until such time that the application is approved. In this document, we refer to your proposed biosimilar product by using the descriptor Theragrastim, a developmental code name.

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2. During inspection of the manufacturing facility from , the FDA field investigation team conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

PRODUCT QUALITY

3. In-House Reference Standards

a. In response to FDA Item #4, you updated the stability protocols PTL-1981

“Stability Protocol for Theragrastim Primary Reference Standard Lot “Stability Protocol for Theragrastim Workin eference Standari r the working reference standards (WRS)

to include a trending strategy and the acceptance criterion to control for EC50 values in the potency testing. However, there are deficiencies in both stability protocols.

b. You provided PTL-2306-R “Summary Report for Qualification of Theragrastim In-House Working Reference Standard Lot ” as an update to the information request response #3 dated October 08, (BLA 761082/0053). However, the Agency noted multiple out of specification results (OOS) in this report. Specifically,

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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(b) (4)

Because of the above OOS results, we do not agree that the current in-house |

has been qualified appropriately.

To address the above issues, update the stability protocols for the in-house primary and working reference standards to:

i. Provide adequate trending analysis strategies for the EC50 values of the RSs. You should evaluate whether there is a EC50 value drift based on the absolute values generated in the potency assay.

ii. Provide an updated qualification report for the adequately qualified in-house WRS. You should use an adequately qualified WRS as the standard in the stability testing for the PRS.

Establish a stability acceptance criterion for the EC50 for the WRS based ona trend analysis of the EC50 values of the WRS obtained during routing release and stability testing.

4. Analytical methods

In section “Additional information related to Module 3”, you revised the potency method (STM-0118) based on the change control CC-20-036. However, the summary information you provided to justify the changes made to the potency assay was inadequate because no supporting data were provided to allow assessment of the appropriateness of the proposed change. To ensure that the proposed change has no impact on the potency assay method validation and test article data, provide adequate information to support the proposed change.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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PRESCRIBING INFORMATION

5. We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the Prescription Drug Labeling Resources? and Pregnancy and Lactation Labeling Final Rule? websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) — a checklist of important format items from labeling regulations and guidances. In addition, we encourage you to review the FDA guidance for industry Labeling for Biosimilar Products.

CARTON AND CONTAINER LABELING

6. Submit draft carton and container labeling. PROPRIETARY NAME

7. Please refer to correspondence dated, February 2, 2021, which addresses the proposed proprietary name, Releuko. 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.

SAFETY UPDATE

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.

(1) 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.

(2) When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the clinical studies for the proposed indication using the same format as the original BLA submission.

2 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources 3 https:/Awww.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs- final-rule

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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e Present tabulations of the new safety data combined with the original BLA data.

e Include tables that compare frequencies of adverse events in the original BLA with the retabulated frequencies described in the bullet above.

(3) Present a retabulation of the reasons for premature study discontinuation by incorporating the dropouts from the newly completed studies. Describe any new trends or patterns identified.

(4) 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.

(5) 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.

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

(7) 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.

(8) Provide English translations of current approved foreign labeling not previously submitted.

ADDITIONAL COMMENTS

We have the following comments/recommendations that are not approvability issues:

U.S. Food and Drug Administration Silver Spring, MD 20993

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(b) (4)

3. You have not provided stability data for deliverable volume to support the proposed shelf life of 24 months (accelerated or real time) for your drug product. As stated in our February 7, 2017 BPD Type 4 meeting to discuss the content of format of the BLA, we stated that you should include expellable volume testing at the end of your proposed shelf life. We recommend that you provide results for this essential performance requirement testing to support the proposed 24-month shelf life for your drug product.

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 601.3(b). If you do not take one of these actions, we may consider your lack of response a request to withdraw the application under

21 CFR 601.3(c). You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider his resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to ake before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft guidance for industry Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants.

The drug product may not be legally marketed until you have been notified in writing hat this application is approved.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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If you have any questions, call May Zuwannin, Regulatory Project Manager, at 301-796-7775.

Sincerely,

{See appended electronic signature page}

Albert Deisseroth, MD, PhD Deputy Division Director Division of Nonmalignant Hematology

Office of Cardiology, Hematology, Endocrinology, and Nephrology

Center for Drug Evaluation and Research

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

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Signature Page 1 of 1

This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.

ALBERT B DEISSEROTH 08/02/2021 09:59:50 AM

Reference ID: 4834813