Naseem A. Jaffrani, 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 February 24 and March 13, 2025. The investigator representing FDA reviewed your conduct of the following clinical investigations:

Protocol (b)(4), “(b)(4),” of the investigational drug (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 investigator presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your March 31, 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 March 31, 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 plans for Protocol (b)(4) and Protocol (b)(4) required you to report all serious adverse events (SAEs) to the sponsor within 24 hours of your knowledge of the occurrence.

You failed to adhere to this requirement. Specifically:

1. The investigational plan for Protocol (b)(4) required every SAE, regardless of causality, occurring after the subject has provided informed consent and until 16 weeks after the last dose of study drug, to be reported to (b)(4) safety team immediately, without undue delay, but under no circumstances later than 24 hours after your learning about the events1.

Specifically, Subject (b)(6) was consented on July 6, 2020, and the last dose of study drug occurred on July 8, 2024. This subject experienced the following SAEs, which were not reported to the sponsor’s safety team within the required time frame:

a. The subject experienced an SAE of non-ST elevation myocardial infarction (NSTEMI) between September 1 and 3, 2022, which you became aware of on September 2, 2022. However, this SAE was not initially reported to the sponsor’s safety team until September 26, 2022.

b. The subject experienced SAEs of COVID-19 pneumonia, chronic obstructive pulmonary disease exacerbation, and hospitalization for congestive heart failure between January 5 and 9, 2023, which you became aware of on January 5, 2023. However, these SAEs were not initially reported to the sponsor’s safety team until February 21, 2023; April 3, 2023; and May 1, 2023, respectively.

c. The subject experienced SAEs of pulmonary embolism and deep vein thrombosis post-COVID-19 pneumonia between January 13 and 17, 2023, which you became aware of on January 13, 2023. However, these SAEs were not initially reported to the sponsor’s safety team until May 1, 2023.

d. The subject experienced an SAE of worsening ischemic cardiomyopathy between October 3 and November 16, 2024, which you became aware of on November 13, 2024. However, this SAE was not initially reported to the sponsor’s safety team until November 24, 2024.

2. The investigational plan for Protocol (b)(4) required all SAEs occurring from the time of informed consent until End of Study to be reported to Medpace Clinical Safety within 24 hours of knowledge of the occurrence, regardless of the investigator’s determination as to relatedness. The IRB suspended enrollment and dosing for Protocol (b)(4) on November 27, 2024. Specifically:

a. Subject (b)(6) was consented on January 18, 2023. This subject experienced an SAE of post-operative neck hematoma, after a right carotid endarterectomy, between August 29 and September 2, 2023, which you became aware of on September 11, 2023. However, this SAE was not initially reported to the safety team until September 15, 2023.

b. Subject (b)(6) was consented on July 17, 2023. This subject was hospitalized for hypotension between (b)(6), which you became aware of on January 30, 2025. However, this SAE was not initially reported to the safety team until February 7, 2025.

In your March 31, 2025, written response to the Form FDA 483, you acknowledged that you failed to meet your responsibilities as a clinical investigator by relying on the clinical research coordinators to comply with all research requirements without sufficiently overseeing their day-to-day activities to ensure compliance. As corrective and preventive actions, you plan to participate with the new site management in the review of all studies for which you were the clinical investigator, and you plan to implement internal corrective action plans for future studies. You also stated that you attended mandatory training sessions related to, among other things, Good Clinical Practice for clinical trials. You further stated that you plan to develop and implement a system to determine at each subject’s visit whether an SAE has occurred. You plan to use this system to receive notifications from other health care professionals if an SAE has occurred, and to notify the study sponsor and IRB when an SAE occurs, no more than 12 hours (or as provided by the applicable protocol) after becoming aware of its occurrence.

While we acknowledge the corrective and preventive actions that you have taken and plan to take, your response is inadequate because you have not provided sufficient details on how you, as a clinical investigator, will ensure adequate supervision and oversight of study personnel to whom you have delegated study procedures and tasks (for example, verifying that study activities performed by study personnel adhere to the protocol requirements), and how you plan to prevent similar violations from occurring in the future. You also did not provide sufficient details about how you will implement a system for reporting SAEs to ensure that the SAEs are reported in accordance with protocol requirements. Without these details, we are unable to determine whether your preventive 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. Your failure to conduct the clinical investigation in accordance with the investigational plan, and specifically, your failure to report all SAEs to the sponsor within 24 hours of your knowledge of their occurrence, raises significant concerns about your protection of the 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 studies 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 receiving 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.

Your written response, and any questions or concerns about this letter or the inspection, should be sent via email to the FDA at CDER-OSI-Communications@fda.hhs.gov.