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 June 24, 2020, which constituted a complete response to our June 11, 2019, action letter.

We have completed our review of this application, 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. An inspection 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 restrictions on travel, we were unable to conduct an inspection during the current review cycle for your application. While you may respond to deficiencies in this Complete Response Letter while the travel restrictions remain in effect, please note that the application cannot be approved until the required FDA inspection is conducted and any findings are assessed with regard to your application.

For more information, please see the FDA guidances related to the Coronavirus Disease 2019 (COVID-19) public health emergency.”

! 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.

2 https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid- 19-related-quidance-documents-industry-fda-staff-and-other-stakeholders

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PRODUCT QUALITY

Audit Completeness and Data Traceability 2. We understand that you identified © as the third-party to audit your quality data and systems to support BLA 761082. However, it is unclear whether the ™® audit reviewed all the quality data submitted in the BLA because the! audit covered data mainly generated during the years 2015-2017 and the clinical DP lots 40-13013 and 45-14042 were manufactured on November 9, 2013 and July 19, 2014, respectively. Also, it is not clear whether there are source data traceability issues in the comparative analytical assessment including lots used in clinical studies submitted in the BLA. The audit team reported (see pages 596-7 of “Response to Retrospective Review of the GMP Systems and Product Quality Data of Theragrastim by! Oa».

a. some HPLC raw data and UV data were not traceable to the source, and

b. SDS-PAGE data for the clinical lot 45-14042 manufactured on July 19, 2014 were not available for review during the audit.

The Theragrastim lots for which source data are not traceable should not be included in the comparative analytical assessment. To address this deficiency:

a. Provide a table listing all lots, tests performed with those lots, and the dates of testing that were retrospectively reviewed during the | audit.

b. Identify results that were included in the comparative analytical assessment but cannot be traced back to the source.

c. Remove untraceable data from the comparative analytical assessment. If the source of the data is known but the source is unavailable for FDA inspection, then the data are considered untraceable.

Depending on the impact of removing untraceable data from the comparative analytical assessment you may need to conduct additional comparative analytical studies, repeat clinical studies, or both.

Sequence Variants

3. In your response to the June 11, 2019, complete response (CR) item # 3, you reported the detection of two sequence variants, S77-R77 and G101-R101 from a peak (CEX-P6) separated using the CEX-HPLC method. However, you did not provide an explanation for the etiology of the sequence variants or whether the sequence variants impact the conclusions reached in your comparative analytical assessment. To address this deficiency, provide an explanation for the sequence

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variants, and whether the variants impact a determination that Theragrastim is highly similar to US-licensed Neupogen. Depending on the etiology of the sequence variants and their impact on a determination that Theragrastim is highly similar to US-licensed Neupogen, you may need to develop a strategy to control or remove these sequence variants in Theragrastim.

In-House Reference Standards

4. The stability protocols PTL-1981 “Stability Protocol for Theragrastim Primary Reference Standard ™® «Stability Protocol for Theragrastim Working Reference Standard” are deficient because there are no acceptance criteria established to control for EC50 values. To address this deficiency, update the stability protocols for in-house primary and working reference standards to include adequate control over EC50. Because you have not established a working reference standard (WRS) and you have been using the primary reference standard (PRS) in QC testing, you should perform a trending analysis of the EC50 values obtained during routine release and stability testing to establish a stability acceptance criterion for the PRS. After a WRS has been established and used in QC testing, you may use a similar strategy to establish a stability acceptance criterion for the WRS. Provide a detailed description of how you propose to perform this trend analysis and how the acceptance criterion is going to be defined.

Post-Approval Stability Protocol

5. We noted deficiencies in your stability specifications and stability protocols for Theragrastim DP. The DP stability protocols listed in section 3.2.P.8.2. indicate to test for syringe break loose and glide force determination and follow specifications per SPC-0031 “Theragrastim Drug Product (DP) Specification”. However, we noted that SPC-0031 does not list stability specifications for this quality attribute. Also, we noted you schedule to test container closure integrity (CCI) only at the 12-month time-point but not at the 24-month time-point. To address these deficiencies:

a. update the DP stability specifications to assess for syringe break loose and glide force, and

b. modify the DP post-approval stability protocols to include CCI testing at the 24-month time-point.

Shipping Validation Protocol

6. We noted the following deficiencies in the shipping performance qualification protocols PTL 2079 and PTL-2080 for the DP in vials and pre-filled syringes:

a. You proposed to use the lower filling volumes in the shipping validation studies without providing adequate justification that the lower filling volumes

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represent worst-case scenarios, and it is inconsistent with your response to June 11, 2019, CR item # 25, that the higher filling volumes will be used in the shipping validation studies.

b. There is no test to examine the primary and secondary packaging systems to ensure that there is no physical damage to the packaging systems after shipment.

To address the above deficiencies, revise the DP shipping validation protocols to:

a. provide adequate justification that the lower filling volumes represent worst- case scenarios,

b. update the protocols to include examination of the primary and secondary packaging systems for physical damage.

PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information? 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.

If you revise labeling, use the SRPI checklist to ensure that the Prescribing Information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 601.14(b)] in structured product labeling (SPL) format as described at FDA.gov.®

CARTON AND CONTAINER LABELING

Submit draft carton and container labeling that are identical to the carton and immediate container labels submitted on September 11, 2020.

3 http:/www.fda.gow/Drugs/GuidanceComplianceRequlatoryInformation/LawsActsandRules/ucm08415 g.htm

4 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 Zhtm

5 http:/Awww.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

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PROPRIETARY NAME

Please refer to correspondence dated, September 29, 2020, 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.

. 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.

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.

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.

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.

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.

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

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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

In addition, there are several comments that are not approvability issues, but need to be

addressed.

1. You did not provide appropriate information to support that there is no impact on the RP-HPLC (STM-0076) and CEX-HPLC (STM-0042) method validation after replacing the United States Pharmacopeia reference standard (USP RS), FOL526, with in-house © as a reference standard for the methods. Specifically,

a.

Figure 6.6b in PTL-1193-R indicates that USP RS FOL526 and in- house © showed differences in RP-HPLC chromatographic patterns, specifically, the reduced peaks did not align.

We cannot locate data showing that CEX-HPLC chromatogram profiles for USP RS FOL526 and in-house © are comparable.

To address this concern, provide appropriate information supporting the suitable performance of in-house © in these methods.

2. We noted deficiencies in the stability protocols for the in-house reference

standards:

a.

PTL-1981 “Stability Protocol for Theragrastim Primary Reference Standard ™» does not include adequate replicate runs to robustly test potency. For the primary reference standard, a sufficient number of tests should be performed at the time of stability testing to achieve a statistically significant mean EC50 value. To address this deficiency, update the stability protocol to include sufficient replicates for potency testing.

In PTL-2305 “Stability Protocol for Theragrastim Working Reference Standard”, your Table 11.1a is entitled “Theragrastim in-house Primary Reference Standard ° Stability Specifications’. It is our

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understanding that Table 11.1a refers to WRS rather than PRS. Provide the correct reference standard for that table.

3. We noted deficiencies in the protocols for qualification of new cell banks.

a. We noted the following deficiencies in protocol PTL-2168 “Protocol for generation and characterization of new Theragrastim master cell bank and working cell bank”:

i. The protocol does not include alert limits, action limits, or criteria for trend analysis of quantitative in-process and release data from the Theragrastim DS lots produced using the new working cell banks (WCB) against historical DS lots manufactured using previous WCBs.

ii. |The protocol does not include acceptance criteria for cell growth kinetics from fermentation process, including doubling time, growth rate, age at harvest, and percent cell viability and viable cell concentration; and productivity, such as titer.

To address these deficiencies, update the protocol to include adequate acceptance criteria to ensure that new WCB perform comparably to previous WCBs.

4. In your response to June 11, 2019, CR item #24c, you concluded that methods STM-0078 (UV) and STM-0076 (RP-HPLC) produce comparable results for protein concentration by showing a difference of less than in protein concentration values measured by these two methods in the real-time stability studies. However, your justification is not adequate because the stability data in report file PTL-1088-R for the previous in-house indicate that protein concentration values measured by these two methods showed up om difference: using STM-0076 (RP-HPLC) at the 26-month time-poin vs. using STM-0078 (UV) at the 49-month time-point. To address

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this deficiency, provide an appropriate justification to demonstrate that the two methods STM-0078 (UV) and STM-0076 (RP-HPLC) will produce comparable results for protein concentration.

We acknowledge that you provided data to support that the removal of kanamycin in tel nae fermentation processes does not have an impact on manufacturing process and product quality. However, the final

conclusion will be made after the review of the final report that you committed to submit.

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.

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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.

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

Sincerely, {See appended electronic signature page}

Ann Farrell, MD

Director

Division of Nonmalignant Hematology

Office of Cardiology, Hematology, Endocrinology, and Nephrology

Center for Drug Evaluation and Research

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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 12/22/2020 12:18:04 PM

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