AuroMedics Pharma LLCCyclophosphamide Solution, 500 mg/2

NDA 210735 COMPLETE RESPONSE

AuroMedics Pharma LLC Attention: Vincent P. Andolina Vice President, Regulatory Affairs 279 Princeton-Hightstown Road East Windsor, NJ 08520

Dear Mr. Andolina:

Please refer to your New Drug Application (NDA) dated June 28, 2017, received June 28, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Cyclophosphamide Solution, 500 mg/2.5 mL, 1 g/5 mL “7%

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.

NONCLINICAL AND PRODUCT QUALITY

The proposed specified levels of Related Compound and Related Compound ©® exceed the ICH Q3B qualification threshold. The safety of the proposed levels of © or the proposed combined levels of © were not adequately justified. We note that the submitted reference ©® provided an LDS0 after a single intraperitoneal injection of ©@ with no corresponding line listed data (i.e., hematology, clinical

chemistry, histopathology). The published data are inadequate to assess the safety of the specified impurities or to set a permissible daily exposure due to evaluation of a single dose, lack of details about the study design and conduct, lack of data (i.e., standard toxicological endpoints), and a different route of administration. In addition, using a severely toxic dose (i.e., LDso) of © i; inappropriate to determine the safety of the specified impurities.

Provide an adequate justification for the safety of the proposed shelf life specification levels of » or the proposed combined levels of

Submit a final study report from a GLP repeat-dose toxicology study in rodents to qualify the proposed specified levels of © or the proposed combined levels of

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NDA 210735

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9 in Cyclophosphamide Injection Concentrate at the

recommended maximum dose of 25 mg/kg/day (50 mg/kg in divided doses over two days).

PRESCRIBING INFORMATION

6. 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.

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 314.50(1)(1)(i)] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.

CARTON AND CONTAINER LABELING

7.

We reserve comment on the proposed labeling until the application is otherwise adequate. Submit draft carton and container labeling with your resubmission.

SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at

21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

1.

2.

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Describe in detail any significant changes or findings in the safety profile.

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 studies/clinical trials for the proposed indication using the same format as in the original submission.

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

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

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

NDA 210735 Page 3

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

4. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial 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, ut less serious, adverse events between the new data and the original application data.

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

7. Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

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

OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. 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 314.65. 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 this 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 take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” March 2015 at http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 43743 L.pdf.

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

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If you have any questions, call Sherry Hou, PharmD, Regulatory Project Manager, at (240) 402-1813.

Sincerely,

{See appended electronic signature page}

Amna Ibrahim, MD

Deputy Director

Division of Oncology Products |

Office of Hematology and Oncology Products Center for Drug Evaluation and Research

This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

AMNA IBRAHIM 04/26/2018

Reference ID: 4253991