Nobelpharma Co., Ltd.sirolimus topical gel

NDA 213478 COMPLETE RESPONSE

Nobelpharma Co., Ltd.

c/o Dunn Regulatory Associates, LLC Attention: Dana Dunn

2709 Silkwood Court

Oakton, VA 22124

Dear Ms. Dunn:

Please refer to your new drug application (NDA) dated and received February 18, 2020, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for sirolimus topical gel, 0.2%.

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. The Agency acknowledges the statement that if the active pharmaceutical ingredient (API) assay result is outside of | We remind you that if the API assay for a batch of sirolimus falls outside of @e, it fails to meet the drug substance specification and cannot be used in the manufacture of the commercial drug product.

2. You acknowledged in your response to Information Request 5 that, |

a. Revise all manufacturing process parameters for commercial production to be either a set point or range with lower and upper limits. Those parameters should be supported by data collected from manufacturing process used for development and/or registration batches, and by adequate discussion of potential scalability issues for scale dependent parameters.

b. Revise the pertinent section of P.3 and master batch record accordingly.

2 Page(s) have been Withheld in Full as b4 (CCI/TS) immediately following this page

Reference ID: 4656003

NDA 213478 Page 4

(©) (4)

PRESCRIBING INFORMATION

9. 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.

10. 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.?

PROPRIETARY NAME

11.Please refer to correspondence dated, May 6, 2020 which addresses the proposed proprietary name, Hyftor. 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.

FACILITY INSPECTIONS

12.An inspection of the TOYO PHARMACEUTICAL CO. LTD. facility (FEI 3016419927) located in Tsurumi-Ku, Osaka, Japan; is required before this application can be approved. 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. You may respond to deficiencies in this Complete Response Letter while the travel restrictions remain in effect. However, even if these deficiencies are addressed, the application cannot be approved until the required FDA inspection is conducted and any findings are assessed with regard to your application. We will continue to monitor the public health situation as well as travel restrictions. We are actively working to define an approach for scheduling outstanding inspections, once

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

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

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

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

Reference ID: 4656003

NDA 213478 Page 5

safe travel may resume and based on public health need and other factors. For more information, please see the FDA guidances related to COVID 19. These guidances can be found at htips://www.fda.gov/emergency-preparedness-and- response/coronavirus-disease-201 9-covid-19/covid-19-related-quidance-documents- industry-fda-staff-and-other-stakeholders

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.

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 application data.

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

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

Reference ID: 4656003

NDA 213478 Page 6

(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

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.

If you have any questions, call Strother D. Dixon, Senior Regulatory Project Manager, at (301) 796-1015.

Sincerely, {See appended electronic signature page}

Kendall A. Marcus, MD

Director

Division of Dermatology and Dentistry Office of Immunology and Inflammation Center for Drug Evaluation and Research

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

Reference ID: 4656003

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.

KENDALL A MARCUS 08/13/2020 12:43:53 PM

Reference ID: 4656003