Fennec Pharmaceuticals, Inc.PEDMARK (sodium thiosulfate injection)

NDA 212937 COMPLETE RESPONSE

Fennec Pharmaceuticals, Inc. Attention: Robert McCormack, Ph.D. Regulatory Affairs Agent

PO Box 13628

68 T.W. Alexander Drive

Research Triangle Park, NC 27709

Dear Dr. McCormack:

Please refer to your new drug application (NDA) dated February 10, 2020, received February 10, 2020, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for PEDMARK (sodium thiosulfate injection).

We acknowledge receipt of your amendment dated May 27, 2021, which constituted a complete response to our August 10, 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 AND MANUFACTURING PROCESSES

1) During a recent inspection of | manufacturing 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 can be approved.

2) In your May 27, 2021 amendment, you removed |

previously proposed in the application from 3.2.P.3.4. During review of your amendment, we asked you to confirm if you were proposing no commercial production a] , and if so, to revise your master batch records accordingly. You confirmed

that there will be ©® specified for commercially manufactured drug product and that the commercial master batch record for the drug product has © listed.

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NDA 212937 Page 2

We note that your registration batch records all include aa

(b) 4)

CLINICAL

3)

There is an increased incidence of Grade 3 — 4 hypophosphatemia (in SIOPEL6 and ACCL0431) and Grade 3 — 4 hyponatremia (in ACCL0431) in patients receiving sodium thiosulfate injection with cisplatin compared to patients receiving cisplatin alone. Your November 3, 2021 response to our information request provided insufficient information to rule out a causal role for sodium thiosulfate injection in these events. Provide an analysis of hypophosphatemia and hyponatremia in your safety database to support your conclusion that these treatment-emergent adverse events are not related to sodium thiosulfate injection to inform our decision-making regarding whether hypophosphatemia and hyponatremia should be described in Section 5 (Warnings and Precautions) of product labeling for sodium thiosulfate injection. Include an assessment of whether patients experienced recurrent hyponatremia or hypophosphatemia with subsequent administration of sodium thiosulfate injection following initial occurrence of one of these events.

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 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.

1 https:/www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources

2 https://www.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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NDA 212937 Page 3

CARTON AND CONTAINER LABELING

We reserve comment on the proposed labeling until the application is otherwise adequate.

PROPRIETARY NAME

Please refer to correspondence dated, August 24, 2021 which addresses the proposed proprietary name, PEDMARK. 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 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.

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

b. 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.

c. 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.

d. 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. U.S. Food and Drug Administration

Silver Spring, MD 20993 www.fda.gov

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NDA 212937 Page 4

e. 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

application data.

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

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

h. 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

under21 CFR 314.65. You may also request an extension of time in which to resubmi

he 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 Sponsors or Applicants of PDUFA Products.

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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NDA 212937 Page 5

If you have any questions, call Idara Ojofeitimi, Chief, Project Management Staff, at 301-796-3074.

Sincerely, {See appended electronic signature page}

Martha Donoghue, M.D.

Deputy Director

Division of Oncology 2

Office of Oncologic Diseases

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.

MARTHA B DONOGHUE 11/26/2021 04:17:40 PM

Reference ID: 4894961