Jose M. Carpio, 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 May 1 and May 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 June 3, 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 June 3, 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 that subjects were dispensed and administered the investigational product (IP) (b)(4) or the control product (CP) (b)(4) for a treatment duration of five days. Specifically, subjects assigned to Cohort 2 (the outpatient cohort) were to receive IP or CP during each outpatient visit on Days 1, 2, and 4, to ensure sufficient daily IP or CP self-administration between Day 1 and Day 5.

You failed to adhere to this requirement. Specifically, Subjects (b)(6), and (b)(6), who were assigned to outpatient treatment in Cohort 2, were dispensed IP or CP only on Day 1 (April 4, April 7, and April 11, 2023, respectively). However, IP or CP was not dispensed to these subjects during their outpatient visits on Day 2 or Day 4. As a result, Subjects (b)(6), and (b)(6) were not dispensed the required amount of IP or CP and subsequently self-administered less than the protocol-specified dose of study drug during the five-day treatment period.

In your June 3, 2025, written response to the Form FDA 483, you stated that resulting from a misunderstanding of the protocol, these three subjects’ source records did not include Interactive Response Technology (IRT) registration for Day 2 through Day 5, and this registration was required to initiate IP dispensation. You stated that the Contract Research Organization discovered these violations and noted that Day 2 through Day 5 were not registered in the IRT; however, these subjects had already completed five days of study participation. As part of your corrective and preventive actions, you stated that Subjects (b)(6), and (b)(6) were monitored for adverse events during their follow-up visits. You also stated that the violations were reported to the Institutional Review Board, and that Protocol (b)(4)’s source records for Day 2 and Day 4 were updated to include IP registration under Amendment 4 of the protocol.

Furthermore, you stated in your written response that the following additional actions have been or will be taken: (1) training on protocol requirements and on IP dispensation and administration procedures; (2) conducting an internal audit of recent cases to identify gaps, and reviewing current subject records for compliance; and (3) implementing a dual verification process of IP system registration for IP dispensing and administration, to verify correct dosing, timing, and documentation (this process has been implemented in a new site SOP).

While we acknowledge the corrective and preventive actions that your site has taken, your written response is inadequate because you did not provide sufficient details about how you, as the clinical investigator, will ensure adequate oversight of the study procedures and will prevent similar violations in the future. For example, your written response does not provide sufficient details about the newly created SOP for IP dispensing and administration, nor does it specify how the new SOP will be implemented to ensure that the IP is dispensed and administered in accordance with protocol requirements. Without this information, we are unable to determine whether your corrective actions appear adequate to prevent similar violations in future clinical investigations.

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. The primary objective of the study was to assess the microbiological efficacy of the study drug, administered according to the five-day dosing duration required by the protocol, in subjects with (b)(4). Your failure to conduct the clinical investigation in accordance with the investigational plan resulted in subjects’ not receiving sufficient IP or CP dosing to support the primary objective of the study. Additionally, subjects who received less than the protocol required dose of the IP or CP may have experienced inadequate treatment of the original (b)(4), thereby increasing their risk of complications, such as a recurrent (b)(4) and associated clinical symptoms (for example, dysuria, frequency, urgency, or lower abdominal pain). This conduct 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 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, 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.