Maria E. De La Torre Silva, 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 June 26 and July 15, 2025. The investigators 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 investigators presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your August 4, 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 August 4, 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. Specifically, Protocol (b)(4) required you to exclude subjects from the study if they were participating in another investigation (clinical trial) during the study. The protocol also prohibited the use of any other investigational product (IP) for the duration of the study.

You failed to adhere to these requirements. Specifically, Subject (b)(6) Visit 1 Screening for Protocol (b)(4) occurred on November 6, 2024, and the subject was randomized on the study on November 13, 2024. The subject was dispensed study drug for Protocol (b)(4) between November 13 and December 16, 2024, and completed the study on January 14, 2025. However, this subject was simultaneously enrolled and randomized as Subject (b)(6) in another clinical investigation, Protocol (b)(4), on June 24, 2024. Specifically, this subject was administered study drug for Protocol (b)(4) between August 7 and December 23, 2024, and completed the study on January 6, 2025. Therefore, Subject (b)(4) was participating in another clinical investigation, Protocol (b)(4), while simultaneously participating in Protocol (b)(4), and the subject received the IP for Protocol (b)(4) while enrolled in and receiving study drug for Protocol (b)(4).

In your August 4, 2025, written response to the Form FDA 483, you acknowledged that the subject was enrolled in both Protocol (b)(4) and Protocol (b)(4). You stated that you understand that this constitutes a regulatory violation. You also stated that the exclusion criterion in Protocol (b)(4) was not followed for this subject.

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. Yourfailure to ensure that subjects met all protocol-required eligibility criteria before their enrollment in the study, and your failure to ensure that subjects were not taking prohibited medications during the study, raise significant concerns about the safety of study subjects enrolled at your site, and raise concerns about the reliability of the data collected at your site.

As a clinical investigator, you are required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects.

You failed to adhere to these requirements. Specifically, for six subjects enrolled on Protocol (b)(4), the following discrepancies were observed between the quantity of drug used by the subjects and the quantity of drug returned, as recorded on the site IP accountability record; the EDC records of subjects’ self-reported doses; and the EDC records of site-reported IP returned (used and unused):

Subject ID #&Assigned IP Kit #Self-Reported IPDoses & DatesAdministeredSite IP MasterAccountabilityEDC IPAccountability

ID #(b)(6) Kit #34_MFWEMarch 6-19, 2025March 21-24, 202518 doses administered35 sachets returned(1 used & 34 unused)No sachets returned

ID #(b)(6) Kit #34_PNBTMarch 6-17, 2025March 19-24, 202518 doses administered35 sachets returned(19 used & 16 unused)35 sachets returned(0 used & 35 unused)

ID #(b)(6) Kit #34_RJRFMarch 6-17, 2025March 19-20, 2025March 22-24, 202517 doses administered35 sachets returned(0 used & 35 unused)No sachets returned

ID #(b)(6) Kit #34_PUVNMarch 6-24, 202519 doses administered35 sachets returned(19 used & 16 unused)No sachets returned

ID #(b)(6) Kit #34_AHRGMarch 11-24, 202514 doses administered35 sachets returned(14 used & 21 unused)No sachets returned

ID #(b)(6) Kit #34_HPOPMarch 20-24, 20255 doses administered35 sachets returned(5 used & 30 unused)No sachets returned

In your August 4, 2025, written response to the Form FDA 483, you stated that sealed kits were provided to the subjects, and that the subjects were responsible for using them at home and returning them afterwards. You also stated that the kits were not used at the study site.

While we acknowledge that the study drug was not administered at the study site and that subjects were to administer the study drug at home and return unused study drug to the study site, your response is inadequate because, as the clinical investigator, you are responsible for maintaining adequate records of the disposition of the drug, including dates, quantity, and use by subjects, in accordance with FDA regulations. Additionally, Protocol (b)(4) specifically stated that it is the investigator’s responsibility to ensure that accurate records of study-medication issuance and return are maintained. Finally, we note that in correspondence from the sponsor dated May 21, 2025, regarding a remote close-out visit, the sponsor observed that the above-referenced IP kits dispensed to subjects contained the tamper-resistant seals on both ends of the kits, although the kits were shown to have been dispensed in the EDC records, and the completed medication questionnaires document that nightly study doses were taken by the subjects. The sponsor further stated that they did not see how the dispensing records could be accurate, given that the IP kits had not been opened. Therefore, based on these observed discrepancies and the sponsor’s report concerning the physical condition of the IP kits and inaccurate dispensing records, the records of the disposition of the study drug at your site are inadequate.

Your failure to maintain adequate drug-accountability records, including documents recording study drug used, unused, and returned, raises significant concerns about the adequacy of your oversight and control of investigational drug, and raises concerns about the validity and integrity of the data collected at your site.

In addition, in your written response, you stated that the following corrective actions have been taken: (1) the study was closed; (2) the sponsor agreed not to use the clinical site’s data; and (3) all funds made to the site were returned. You further stated that no subjects were harmed. Finally, you stated that following the conclusion of the investigation, the site will be permanently closed, and you will no longer engage in any investigative activities, now or in the future.

While we acknowledge the corrective actions that your site has taken and your statement that you do not intend to perform clinical investigations in the future, your written response is inadequate because you did not provide sufficient details about how you, as the clinical investigator, will prevent similar violations from occurring if you should change your mind and decide to conduct clinical investigations in the future. Without this information, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in future clinical investigations.

We emphasize that as the clinical investigator, you are ultimately responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, both to protect the rights, safety, and welfare of subjects and to ensure the integrity of study data. Your failure to conduct the clinical study in accordance with the protocol, and your failure to maintain adequate drug-accountability records, raise significant concerns about your protection of study subjects enrolled at your site and raise concerns about the reliability of the data generated 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.

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