Fennec Pharmaceuticals, Inc.PEDMARK (sodium thiosulfate injection), for intravenous use

NDA 212937 COMPLETE RESPONSE

Fennec Pharmaceuticals, Inc. Attention: Anne McKay

Regulatory Affairs Agent

P.O. Box 13628

68 T.W. Alexander Drive

Research Triangle Park, NC 27709

Dear Ms. McKay:

Please refer to your new drug application (NDA) dated February 10, 2020, received February 10, 2020, submitted under pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA), for PEDMARK (sodium thiosulfate injection), for intravenous use, 12.5 grams/100 mL.

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.

PRODUCT QUALITY

1. Test PEDMARK registration batches in accordance to the USP monograph for Sodium Thiosulfate Injection. You may use an alternative test method for assay, however, the USP method will be considered the regulatory method. Refer to USP General Notices and Requirements: 6.30 Alternative and Harmonized Methods and Procedures for more details.

2. Submit a new assay test method, intended for commercial use, that expresses assay in terms of the pentahydrate. Alternatively, you may revise the calculations for the currently proposed non-compendial ion chromatography assay method so that the drug product assay is calculated based on the sodium thiosulfate pentahydrate form.

3. If you plan to use the currently proposed non-compendial assay test method, provide comparative data to show that the method is comparable to the compendial test method. Per the USP monograph, the assay must be calculated based on sodium thiosulfate pentahydrate.

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NDA 212937 Page 2

FACILITY INSPECTIONS

4.

During a recent inspection of aa

anufacturing facility for this NDA, our field investigators conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this NDA may be approved.

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 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(I)(1)(i)] in structured product labeling (SPL) format as described at FDA.gov.?

Submit draft labeling that incorporates the proposed revisions identified in the attached labeling. In addition, submit updated content of labeling [21 CFR 314.50(I)(1)(i)] in structured product labeling (SPL) format as described at

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

When responding to this letter, submit labeling that includes all previous revisions, as reflected in the most recently approved package insert. To facilitate review of your submission, provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy should include annotations that support any proposed changes. Prior to resubmitting the labeling, use the SRPI checklist to correct any formatting errors to ensure conformance with the format items in regulations and guidances. In addition, submit updated content of labeling [21 CFR 314.50(I)(1)(i) in structured product labeling (SPL) format as described at FDA.gov.4

1 http:/Iwww.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm08415

g.htm

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

Z.htm

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

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

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NDA 212937 Page 3

CARTON AND CONTAINER LABELING

7. Submit draft carton and container labeling revised based on the final determination of product strength.

a. Change ©® to “12.5 grams/100 mL (125 mg/mL)” on both container and carton labeling to be consistent with the USP drug product monograph, where the strength is expressed as that of the pentahydrate. The Agency does not agree with the justification provided in your response dated July 27, 2020 to continue calculating the strength as ©® as it does not comply with Section 502(g) of the FD&C Act.

b. On the container and carton labeling, replace a]

with “each mL contains the equivalent of sodium thiosulfate pentahydrate 125 mg (provided as sodium thiosulfate anhydrous 80 mg),

0.25 mg boric acid, NF and water for injection, USP. May contain sodium

hydroxide and hydrochloric acid for pH adjustment”.

c. The proposed carton labeling submitted on July 27, 2020 indicates the product is ©® Remove the boxed statement that reads |

PROPRIETARY NAME

Please refer to correspondence dated, April 14, 2020 which addresses the proposed proprietary name, Pedmark. This name was found conditionally acceptable pending approval of the application in the current review cycle. Please submit a new request for name review for your proposed proprietary name when you respond to the application deficiencies.

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) Describe in detail any significant changes or findings in the safety profile. (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 studies/clinical trials for the proposed indication using the same format as in the original submission.

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

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NDA 212937 Page 4

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.

(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, but less serious, adverse events between the new data and the original/supplemental 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/product 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. 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.

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

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NDA 212937 Page 5

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 guidance for industry Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products.

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

If you have any questions, call Anuja Patel, Lead Regulatory Project Manager, at 301- 796-9022.

Sincerely, {See appended electronic signature page}

Harpreet Singh, M.D.

Director

Division of Oncology 2

Office of Oncologic Diseases

Center for Drug Evaluation and Research

ENCLOSURE(S): e Labeling with FDA proposed revisions

13 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page

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.

B HARPREET SINGH 08/10/2020 04:20:23 PM

Reference ID: 4654300