Kashiv BioSciences, LLCTheragrastim

BLA 761082 COMPLETE RESPONSE

Kashiv BioSciences, LLC

Attention: John Pakulski

Senior, Vice President, 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 8, 2017 and your amendments, submitted under section 351(k) of the Public Health Service Act for Theragrastim.

We acknowledge receipt of your amendment dated December 11, 2018, which constituted a complete response to our May 10, 2018, action letter.

We also refer to our complete response letter dated June 11, 2019, which contained the following errors: The company name and FEI number on page 1 under FACILITY INSPECTIONS is incorrect.

This replacement complete response letter incorporates the correction of the error. The effective complete response date will remain June 11, 2019, the date of the previous complete response 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.

We also acknowledge receipt of an amendment to a supportive DMF, which was not reviewed for this action. You may cite the DMF by specific reference as part of your response to the deficiencies cited in this letter.

FACILITY INSPECTIONS:

1. During a recent inspection of the Kashiv BioSciences, LLC (FEI 3011289655) manufacturing facility for this BLA, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

U.S. Food and Drug Administration

Silver Spring, MD 20993 www.fda.gov

Reference ID: 4962624

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PRODUCT QUALITY:

2.

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A pre-license inspection of the drug substance (DS) manufacturing facility identified significant deficiencies regarding quality control (QC) documentation that may have negatively impacted the accuracy and reliability of the analytical data provided to demonstrate that Theragrastim is highly similar to US-licensed Neupogen. Furthermore, the data provided in the submission do not support process validation and DS and drug product (DP) quality at release and on stability. In addition, the Agency is concerned about the repeated Quality Assurance (QA) failures at Kashiv Biosciences manufacturing site. For the Agency to make a meaningful assessment of the application, it is critical that product quality information provided in the BLA be accurate, reliable, and complete. In the absence of an adequately functioning QA unit, the Agency does not have sufficient assurance that the Applicant will be able to perform an appropriate retrospective review of all analytical data to ensure their accuracy. The retrospective review is necessary to support a determination that Theragrastim is highly similar to U.S.-licensed Neupogen and the adequacy of process validation, release, and stability data. To address this deficiency, identify an appropriately qualified, external third party to perform an independent and thorough audit of all the product quality data provided in your 351(k) BLA for accuracy and completeness. The Agency recommends that, prior to initiating the external third party audit, you submit a detailed audit protocol with the following information to obtain Agency’s agreement on the protocol design and content:

a. Purpose and scope of the audit,

b. Adescription of the qualifications and experience of audit team members with regards to the intended purpose and scope of the audit,

c. Roles and responsibilities of the external third party and Kashiv Biosciences,

d. | Adescription of how the external third party and Kashiv Biosciences would address any disagreements or differences in opinion that may arise during the audit process, and

e. Adescription of the nature and extent of information that will be included in the final audit report.

Depending on the final audit results, as appropriate, additional studies may be needed to generate new information and data to support the product quality content in your 351(k) BLA resubmission. The Agency will not be able to perform a meaningful review of your 351(k) BLA until the final audit report provides assurance that all analytical similarity and other product quality information provided in the 351(k) BLA application is accurate and complete.

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Analytical Similarity

The CEX-HPLC analytical similarity data indicate differences in charge variants between Theragrastim and US-licensed Neupogen. For example,

a.

Figure 19 from report RPT-1076 “Analytical Testing Report to Demonstrate Similarity of Theragrastim (Adello Product) to Neupogen (Reference Product)” shows that out of the 8 Theragrastim DP lots, lots 180136, 170086, 3- FIN2479, and 3-FIN-2897 have total charge impurity variants levels of 1.0- 1.3%, which exceed the US-licensed Neupogen range of < 1.0% for total charge impurity variants levels.

. Figure 4 from the new forced degradation report PTL-2169-R “Force

Degradation Study Report of Theragrastim and Neupogen” shows peaks eluting at ~ 12.5 min and ~18.5 min by CEX-HPLC for Theragrastim. These peaks were not observed in US-licensed Neupogen under the same light- induced stress conditions. In addition, data provided in Figure 15 show that Theragrastim has lower purity than US-licensed Neupogen (~82% vs. ~95%) after 2 cycles of light exposure for 0.3 mg/mL vial presentation.

In the absence of additional data and appropriate justification, these differences preclude a determination that Theragrastim is highly similar to US-licensed Neupogen. To address this deficiency, provide appropriate information in your 351(k) BLA resubmission to demonstrate why these differences do not preclude a determination that Theragrastim is highly similar to US-licensed Neupogen.

We noted several deficiencies in the impurity characterization report RPT-1055

provided in Section 3.2.S.3.2. For example,

a. The labels for chromatographic plots in the report indicate that the study was performed in August 2018. It appears that some study samples, e.g., US-licensed Neupogen lot 1062643 with an expiration date of April 2018, were tested after expiry in this study. In addition, you did not provide the storage conditions and dating periods for samples from Hydrophobic Interaction Chromatography (HIC) load and Tangential Flow Filtration (TFF) retentate + rinse. Therefore, it is not clear whether samples from HIC load and TFF retentate + rinse were of good quality when tested in this study. It is not appropriate to use expired products in the impurity characterization studies because the impurity results from expired products may not be representative of the impurities profiles from unexpired material. To address this deficiency, provide the ages of the Theragrastim materials used in the study and the study execution dates in your report. Ensure that Theragrastim and US-licensed Neupogen lots

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used in this study are within expiry dates. As appropriate, perform additional studies to characterize the impurities in Theragrastim and compare against US-licensed Neupogen.

It is not clear whether you used the baseline drop integration method to quantify the chromatographic peaks observed in the RP-HPLC and CEX- HPLC chromatograms. Clarify the peak integration method used to quantify RP-HPLC and CEX-HPLC chromatographic peaks for Theragrastim and US-licensed Neupogen. Integration of RP-HPLC and CEX-HPLC chromatograms should be conducted using the baseline drop integration method because the original valley-to-valley peak integration method resulted in underestimation of impurities. Reanalyze any peaks not analyzed using the baseline drop integration method and provide the updated results.

We do not agree with your statement that “All species are product-related substances”. For example, several CEX-HPLC peaks have < 50% potency, indicating that these peaks likely represent product-related impurities. Per ICHQ6b “Test Procedures and Acceptance Criteria for Biotechnological/Biological Products” product-related substances have “properties comparable to those of the desired product with respect to activity, efficacy, and safety...”. Provide a rationale for designating the various charge variants observed by CEX-HPLC as product-related substances or product-related impurities.

You did not state whether the Theragrastim peaks separated by RP-HPLC are product-related substances or product-related impurities. In addition, you did not provide potency values for Theragrastim peaks separated by RP-HPLC. Clarify which variants observed by RP-HPLC are product related substances and which are product related impurities and explain your rationale for those categorizations.

You stated that the peak CEX-4 is characterized as primarily comprised of a pentose adduct species when Theragrastim is stored under the recommended storage conditions, and is primarily comprised of an M127 oxidized species in oxidation-stressed materials. The difference in CEX-4 species identified for material stored under recommended and stress conditions suggests that the identity for fractions enriched under stressed conditions may not represent the species existing under recommended storage conditions. Provide data on the identity of species in corresponding chromatography peaks observed by CEX-HPLC, RP- HPLC, and SE-HPLC, for Theragrastim and US-licensed Neupogen samples stored at the recommended and stressed storage conditions.

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5.

f. The Theragrastim lot used for characterization of SEC-P1 aggregate peak was not listed in the material table in RPT-1055. The Theragrastim lot used for characterization of SEC-P2 dimer peak was also not listed. Provide a description of the identity and suitability of the Theragrastim samples used in characterization of SEC-HPLC fractions.

g. You did not characterize some chromatographic peaks observed by RP- HPLC and CEX-HPLC in US-licensed Neupogen samples, for example, RP-2, RP-4, and CEX-3. Clarify whether the identity of the species in the uncharacterized peaks from US-licensed Neupogen is the same as in the same peaks observed in Theragrastim samples.

In your 351(k) BLA resubmission, you stated that the conditions used in the original forced degradation study under protocol PTL-1192-R were too extreme. For this reason, you performed a new forced degradation study under protocol PTL-2169 and provided the relevant data in the report PTL-2169-R in the 351(k) BLA resubmission. However, you did not provide a justification for the stress conditions and the time points used in this new forced degradation study. To address this deficiency, provide detailed information in your 351(k) BLA resubmission to justify how these study conditions are appropriate to help evaluate meaningful degradation rates for Theragrastim and US-licensed Neupogen.

Regarding analytical similarity report RPT-1076 for Theragrastim and US- licensed Neupogen, it is not clear whether you used the baseline drop integration method to quantify the chromatographic peaks observed in the RP-HPLC and CEX-HPLC chromatograms, refer to comment 4b. Reanalyze any peaks not analyzed using the baseline drop integration method and provide the updated results.

Control Strategy

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Stability Protocol

In your response to CR item #52 regarding annual stability protocol, you proposed to place (i) one lot from each of all four presentations on stability in the first year of commercialization, and (ii) one lot of vials and one lot of PFSs on stability each year following the first year of commercialization, with alternating high and low dose forms for the vial and PFS presentations. Your proposed approach for annual stability program is not acceptable because you did not provide sufficient stability data to demonstrate that the high and low dose forms in vials versus PFSs have the same stability profiles. For example, data provided in Figure 26 in report PTL-2169-R “Force Degradation Study Report of Theragrastim and Neupogen” show differences in the degradation rates between high and low dose forms of Theragrastim DP. Moreover, the proposed stability strategy carries the inherent risk that changes to product quality will go undetected for 2 years because you will not test the low and high dose products in both container closure systems every year. To address this deficiency, revise

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your annual stability protocol to place one lot from each of all four presentations on stability at the intended storage condition of 5°C after commercialization.

Stability

24.Real time stability data provided in the BLA submission do not support the proposed 24 months dating period for Theragrastim PFS and vial presentations. Specifically: a. DP stability data show many out-of-specification (OOS) results by RP-HPLC.

For examp! i.

iii. Lo iv. v. vi. Loi

e,

Lot 400-16014 (vial): Multiple OOS failures for purity by RP-HPLC occurred at 6 months, 12 months, and 18 months inverted; as well as 12 months, 18 months, and 24 months upright.

Lot 400-16015 (vial): OOS for purity by RP-HPLC happened at 24 months upright; as well as 12 months, 18 months, and 24 months inverted.

450-16017(vial): OOS for purity by RP-HPLC at 24 months. Lot 300-16009 (PFS): OOS for purity by RP-HPLC at 18 months. Lot 300-16011(PFS): OOS for purity by RP-HPLC at 6 months. 350-16012(PFS): OOS for purity by RP-HPLC at 18 months.

You did not provide a scientifically sound justification for proposing a 24-month dating period for Theragrastim DP despite the above-mentioned stability failures

for multiple lots. b.

Therefore, these data are insufficient to support tl period for DP PFS and vial presentations when s conditions of 5°C. To address this deficiency, pro}

In addition, there are missing data at many stabi specifications. For example, missed testing for p;

ity timepoints for various articulate matter at 6 months

or 12 months, as well as missed testing for polysorbate 80 at 6 month and 12

months for several lots. Justify these missing da

‘a. You should follow the

stability protocol to test particulate matter and polysorbate 80 at all proposed

timepoints.

several lots by UV absorbance and was tested b:

. Protein concentration was not tested at 18-month and 24-month timepoints for

y RP-HPLC instead. Provide

appropriate information to demonstrate that the two different methods will produce comparable results for protein concentration.

he proposed 24-month dating ‘ored at recommended storage pose a revised dating period

that is supported by appropriate real-time stability data for Theragrastim DP along with a scientifically sound justification to support the proposed dating period.

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Shipping Validation

25.We noted the following deficiencies in shipping performance qualification protocols PTL 2079 and PTL-2080:

a. You did not fully address CR item #30(a) with regards to assessment of the qualification of the shipping container to maintain the product temperature when exposed to worst-case conditions of temperatures (e.g., different climatic zones and seasons).

b. You did not fully address CR item #30(b) with regards to a description of the batches used in the study and criteria for selection.

c. The proposed product quality assessment strategy for shipping qualification does not include a test for appearance. Include appearance testing in your assessment to help evaluate changes in product quality before and after shipping.

Provide appropriate information in your 351(k) BLA resubmission to address the

above deficiencies.

PRODUCT QUALITY MICROBIOLOGY:

26. Your application referenced the Drug Master File (DMF)! This DMF was found inadequate to support your submission and a deficiency letter was sent to the DMF holder on May 16, 2019. These deficiencies must be adequately addressed before this application can be approved. As part of your response to this CR letter, include the date the DMF holder amended their DMF to address the deficiencies.

27.Numerous discrepancies were noted between the media fill reports, the media fill summary report (CMO-1041), and Section 3.2.P.3.5 of the BLA (Tables 67 and 68). Clarify these discrepancies and provide the corrected information in the BLA resubmission.

CMC STATS:

28.Regarding the biological potency results of the M-NFS-60 cell proliferation assay, we found inconsistencies in the reported potency values and the Theragrastim DP lots included in the analysis between multiple submissions. Refer to Exhibit III of the report RPT-0987 in response to IR received by FDA on 01/23/2018 and Table 3 of the report PRT-1077 in current submission. Specifically, differences are found for:

e The relative potency data provided for DP lots 35-15013-RND, 40-15046, 3- FIN-2897 and 45-14042 are different in RPT-0987 and PRT-1077.

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e Lots 30-15018, 30-15019 and 45-15025 are not included in report PRT-1077 while they were included in report RPT-0987.

e DP lots 17-0086 and 180136 are included in report PRT-1077 while these two lots were not in report RPT-0987.

To allow for a proper evaluation of the results, provide scientific justifications or explanations for these differences and any other differences identified during the audit described in CR item #2 above.

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 draft 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 March 20, 2019.

PROPRIETARY NAME

Please refer to correspondence dated, March 13, 2019, 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.

1 http://www.fda.gov/Drugs/GuidanceComplianceRegulatory|nformation/LawsActsandRules/ucm08415 9.htm

2 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330 7.htm

3 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/Regulatorylnformation/Guidances/default.htm.

4 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm

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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.

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 drop-outs 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.

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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 should request a meeting or teleconference with us to discuss what steps you need ‘0 take 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, contact Kris Kolibab, Senior Regulatory Project Manager, at 240) 402-0277.

Sincerely, {See appended electronic signature page}

Albert Deisseroth, MD, PhD

Supervisory Associate Division Director Division of Hematology Products

Office of Hematology and Oncology Products 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 06/11/2019 12:00:00 AM

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