Dow Pharmaceutical Sciences, Inc.halobetasol propionate and tazarotene lotion

NDA 209354 COMPLETE RESPONSE

Dow Pharmaceutical Sciences, Inc.

c/o Valeant Pharmaceuticals North America, LLC Attention: Sean Humphrey

Sr. Manager, Regulatory Affairs

330 Redwood Way, Suite C

Petaluma, CA 94954

Dear Mr. Humphrey:

Please refer to your New Drug Application (NDA) dated and received August 18, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for halobetasol propionate and tazarotene lotion, 0.01%/0.045%.

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

Per 21 CFR 314.125(b)(4), there is insufficient information about the drug to determine whether the product is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling.

Specifically, you did not provide sufficient nonclinical toxicology data to support NDA approval as it was determined that an adequate bridge to the listed drugs, Ultravate (halobetasol propionate) Cream, 0.05% and Tazorac (tazarotene) Cream, 0.05%, was not established based on the information submitted in the NDA.

In particular, the relative bioavailability assessment showed that the bioavailability of the proposed combination product, halobetasol propionate and tazarotene lotion, 0.01%/0.045%, was higher than each of the listed drugs for the individual monads.

Information Needed to Resolve the Deficiency

1. Adequate data from a complete battery of genetic toxicology studies for both monads. 2. Adequate data from systemic embryofetal development studies in a rodent and a nonrodent

species for both monads. It is recommended that embryofetal development studies involve systemic dosing to ensure adequate exposure to the drug substances.

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3. Adequate data from a study or studies in male and female rodents for effects upon fertility, reproductive function, or early embryonic development for both monads.

4. Adequate data from a study in rodents for effects on pre- and postnatal development for both monads.

5. Potential of your drug product or drug substances to induce carcinogenicity should be evaluated in two species for both monads. One study should be conducted using a systemic route of administration and the other by the dermal route of administration. It is recommended that protocols for carcinogenicity studies be submitted to the Division for evaluation by the Executive Carcinogenicity Assessment Committee of CDER.

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.

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

PROPRIETARY NAME

Please refer to correspondence dated, November 17, 2017 which addresses the proposed proprietary name, Duobrii. 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.

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.

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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, 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,” December 2017 at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM59054 1.

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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 Strother D. Dixon, Senior Regulatory Project Manager, at (301) 796-1015.

Sincerely,

{See appended electronic signature page}

Jill A. Lindstrom, MD, FAAD Deputy Director

Division of Dermatology and Dental Products Office of Drug Evaluation III

Center for Drug Evaluation and Research

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

JILL A LINDSTROM 06/15/2018

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