Ehsan Sadri, M.D.

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between March 27 and April 16, 2025. The investigators representing FDA reviewed your conduct of the following clinical investigations:

Protocol (b)(4), “(b)(4),” of the investigational drug (b)(4) (preservative-free (b)(4)), performed for (b)(4)

Protocol (b)(4), “(b)(4),” of the investigational drug (b)(4), performed for (b)(4)

This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.

At the conclusion of the inspection, the FDA investigators presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your April 17, 2025, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated April 17, 2025, it appears that you did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 (21 CFR 312), governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:

As a clinical investigator, you are required to ensure that your clinical investigations are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4) required you to ensure that all subjects met all eligibility criteria before enrollment in the study. For example, the protocol required the following inclusion criteria to be eligible for enrollment in the study:

Central corneal endothelial cells (CEC) density of at least 2000 cells/mm in each eye at Visit 1 (Screening)

Intraocular pressure (IOP) ≥ 21 mmHg in at least one eye at 8:00 a.m. at Visit 2 (Randomization)

You failed to adhere to these requirements. Specifically:

1. Subject (b)(6)’s central CEC density measurement was not completed at Visit 1 (Screening) on August 27, 2024, as required by the protocol. However, this subject was enrolled and received study drug on September 23, 2024.

2. Subject (b)(6)’s IOP measurement at Visit 2 (Randomization) on September 23, 2024, at 8:00 a.m., was 16 mmHg in each eye, which was outside the protocol-specified range for eligibility. However, this subject was enrolled and received study drug on September 23, 2024.

We acknowledge that the finding discussed above regarding Subject (b)(6)’s IOP measurement at Visit 2 (Randomization) at 8:00 a.m. was not included on the Form FDA 483 you received, and therefore your written response does not specifically address this finding.

In your April 17, 2025, written response to the FDA 483, you acknowledged the observation and stated that the root cause was the repeated delay of site activation and the abrupt shortening of the enrollment period, which caused significant challenges, added pressure, and ultimately led to mistakes. As part of your corrective and preventive action plan, your written response stated that a checklist detailing the required assessments for each visit according to the protocol was created as part of your standard operating procedure (SOP). You stated that this checklist is reviewed by the subinvestigator during the visit and by the principal investigator at the conclusion of the visit, which provides a two-step review system to confirm eligibility and to verify that all required assessments are completed. You also stated that, upon site activation, each visit must have its checklist created, and it is the clinical research coordinator’s responsibility to ensure that each checklist and its source documents are reviewed by both investigators in a timely manner. Your response further stated that your site plans to revise its SOPs to include weekly team meetings, when you will review study status and progression.

Your written response also outlined the following ongoing efforts to address systemic issues at the site: (1) comprehensive training programs for your clinical research coordinators, to manage multiple large-scale projects better; (2) revision of your resource-allocation strategies to ensure adequate support for all ongoing studies; (3) establishment of clearer communication channels with contract research organizations and clinical research associates to prevent inconsistencies; and (4) regular internal audits and monitoring.

While we acknowledge your response that an abrupt shortening of the enrollment period led to challenges and mistakes, your response is inadequate because, regardless of the length of the enrollment period, you are still responsible for ensuring that subjects meet protocolspecified eligibility criteria before you enroll them into the study. Further, while we acknowledge the corrective and preventive actions that your site has taken or plans to take, your written response is inadequate because it does not provide sufficient details about how you, as a clinical investigator, will ensure adequate oversight of the study procedures (for example, adherence to eligibility requirements). In addition, your response is inadequate because you did not provide sufficient details about proposed changes to policies and procedures being implemented at your site to prevent similar violations in the future. Without this information, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.

We emphasize that as the clinical investigator, it is your responsibility to ensure that studies are conducted in accordance with the investigational plan, both to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data. Specifically, two of the nine subjects who were randomized and treated with investigational product at your site were ineligible for enrollment in the study. Your failure to ensure that subjects met all protocolrequired eligibility criteria before their enrollment in the study raises significant concerns about the safety of study subjects enrolled at your site, and raises concerns about the reliability of the data collected at your site.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations.

This letter notifies you of our findings and provides you with an opportunity to address the deficiencies noted above. Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to address this matter adequately may lead to regulatory action without further notice to you. If you believe that you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.

Should you have any questions or concerns about this letter or the inspection, please email FDA at CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:

Brittany L. Garr, MPHBranch ChiefCompliance Enforcement BranchDivision of Enforcement and Postmarketing SafetyOffice of Scientific InvestigationsOffice of ComplianceCenter for Drug Evaluation and ResearchU.S. Food and Drug AdministrationBuilding 51, Room 535210903 New Hampshire AvenueSilver Spring, MD 20993