Santen, Inc.Omlonti (omidenepag isopropyl ophthalmic solution)

NDA 215092 COMPLETE RESPONSE

Santen, Inc. Attention: Raul Brena, RAC Global Regulatory Affairs Manager 6401 Hollis Street, Suite 125 Emeryville, CA 94608

Dear Mr. Brena:

Please refer to your new drug application (NDA) dated November 19, 2020, received November 19, 2020, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA), for Omlonti (omidenepag isopropyl ophthalmic solution), 0.002%.

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.

1. The methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product do not comply with the current good manufacturing practice regulations in parts 210 and 211, and the methods to be used in, and the facilities and controls used for, the manufacture, processing, packing, or holding of the drug substance or the drug product are inadequate to preserve its identity, strength, quality, purity, stability, and bioavailability. During a recent inspection of the of the | manufacturing facility for this application, our field investigator conveyed deficiencies to the representative of the facility. Satisfactory resolution of these deficiencies is required before this application may be approved.

Following an evaluation of an inspection performed at the OEY

Woodstock Sterile Solutions (FEI 1419377) manufacturing facility, our field investigator observed objectionable conditions at the facility and conveyed that information to the representative of the facility at the close of the inspection. Satisfactory resolution of the remaining objectionable conditions, and verification by FDA, is required before this application may be approved. We recommend you contact your manufacturing facility if more information is needed.

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 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 https://www.fda.gov/emergency- preparedness-and-response/coronavirus-

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disease-2019-covid-19/covid-19-related-guidance-documents-industry-fda-staff-and- other-stakeholders.

2. The investigations required under section 505(b) of the Federal Food, Drug, and Cosmetic Act do not include adequate tests by all methods reasonably applicable to show whether or not the drug is safe for use under the conditions prescribed, recommended, or suggested in its proposed labeling. Study 1171504 demonstrated significant endothelial cell loss in both omidenepag isopropyl ophthalmic solution monotherapy arms particularly between Weeks 12 and 26. In the absence of a control arm without omidenepag isopropyl treatment, the trial is suggestive of potential harm to the corneal endothelial cells. A concurrently controlled, randomized, 12-month clinical study in which omidenepag isopropyl ophthalmic solution is dosed as monotherapy and corneal endothelial cell counts are compared to a concurrent control without omidenepag isopropyl should be conducted and submitted.

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.

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.

CARTON AND CONTAINER LABELING We reserve comment on the proposed labeling until the application is otherwise adequate.

PROPRIETARY NAME

Please refer to correspondence dated, October 21, 2021, which addresses the proposed proprietary name, Omlonti. This name was found conditionally 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.

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

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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.

In the Genus decision issued on April 16, 2021, the U.S. Court of Appeals for the District of Columbia Circuit held that articles that meet the device definition in section 201(h) of the FD&C Act must be regulated as devices and not as drugs. In implementing this decision, FDA has determined that the language in 21 CFR 200.50(c) indicating that eye cups, eye droppers, and ophthalmic dispensers are regulated as drugs when packaged with other drugs is now obsolete, as these articles meet the “device” definition. FDA will be regulating these products, including your product, as drug-led combination products composed of a drug constituent part that provides the primary mode of action (PMOA) and a device constituent part (an eye cup, dropper, or dispenser). As the drug constituent part provides the PMOA, CDER will have primary jurisdiction over these products, including your product.

For each submission for this application, indicate that the product is a combination product in field #24 of the FDA Form 356h. Additionally, please refer to the Guidance for Industry, Identification of Manufacturing Establishments in Applications Submitted to CBER and CDER, Questions and Answers, from Oct 2019. For combination products, facilities manufacturing a constituent part of a co-package or single entity combination product, or drug-device combination product that are proposed to be involved in the disposition of commercial product should be included on Form 356h. This includes final kitting facilities and facilities that conduct design control activities, including verification and validation, of a device constituent part.

Combination products are subject to the current good manufacturing practices (CGMP) requirements applicable to each constituent part (drug, device, biological product) of the combination product. However, as reflected in the final rule on CGMPs for combination products (21 CFR part 4), manufacturers have the option to demonstrate compliance both with the drug CGMP regulations (21 CFR parts 210, 211) and with the device quality system (QS) regulation (i.e., 21 CFR part 820) through a streamlined approach.

If utilizing a streamlined approach, you must demonstrate compliance (i) with either the drug CGMP regulations or the QS regulation in their entirety and also (ii) with those provisions specified in part 4 from the other of these two sets of requirements. Alternatively, you may demonstrate compliance with both the drug CGMPs and QS regulation in their entirety (non-streamlined approach). For further information on 21 CFR part 4, see guidance for industry and FDA staff Current Good Manufacturing Practice Requirements for Combination Products (January 2017), available at http:/Awww.fda.gov/RegulatoryInformation/Guidances/ucm126198.htm

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

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Based on an assessment of the risk profile of your proposed combination product, FDA has determined that information to demonstrate compliance with the device QS regulation is most appropriately assessed during inspection, and this information must be available upon inspection to demonstrate your compliance with 21 CFR part 4. Please ensure that the information you have available on-site describes how your firm has implemented each applicable regulation in your manufacturing processes, and that it includes descriptions of the specific procedures and activities conducted by your firm and the protocols used by your firm for each activity.

We acknowledge your proposal, dated August 31, 2021, to withdraw the analytical testing site, © from the application and commit to a post-approval supplement for a new analytical laboratory. However, your proposal is not acceptable. The application needs a facility to perform drug product release and stability testing prior to approval of the application. We therefore recommend proposing an alternative facility to handle those responsibilities in the application prior to withdrawing the | facility.

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 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 Jacquelyn Smith, MA, Senior Regulatory Project Manager, at (301) 796-1002.

Sincerely, {See appended electronic signature page}

Charles J. Ganley, M.D.

Director, Office of Specialty Medicine (OSM) [Division of Imaging and Radiation Medicine (DIRM), Division of Ophthalmology (DO); OND Compounding Review Team]

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.

CHARLES J GANLEY 11/09/2021 03:40:03 PM

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