Julio R. Flamini, M.D./Clinical Integrative Research Center of Atlanta

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 28 and March 11, 2024. Investigator Koffi Amegadje, 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, Investigator Amegadje presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your March 25, 2024, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your March 25, 2024, written response, 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 studies are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4) required the investigational drug (b)(4) to be administered to subjects according to their weight and in accordance with the protocol’s titration schedule for the 20-week Titration Phase. During the 20-week Titration Phase, the protocol required a daily dose of (b)(4), with the dose of (b)(4) to increase according to the titration schedule at each study visit, which occurred every two weeks. According to the protocol’s titration schedule, subjects at Visit 2 who were 12 to <18 years old were to receive an (b)(4) of (b)(4) at a daily dose of 0.2 mg/kg, not to exceed 12.5 mg per day.

You failed to adhere to these requirements. Specifically, at Visit 2 (on May 15, 2023), Subject (b)(6), a 15-year-old female, weighed 59.1 kg. According to the protocol, this subject should have received a dose of 1.2 mL (~12 mg) per day. However, on May 16, 2023, Subject (b)(6) was dispensed a bottle of (b)(4) of (b)(4) with a dosing instruction of 12.0 mL per day, and she received a total dose of 120 mg of (b)(4) per day for 7 days (from May 17, 2023, to May 23, 2023). As a result, Subject (b)(6) received doses of (b)(4) that exceeded the weight-based dose required by the protocol-specified titration schedule. Subject (b)(4) received approximately 10 times the maximum daily dose and was exposed to an increased risk of adverse events, such as Drug Reaction with Eosinophilia and Systemic Symptoms syndrome.

In your March 25, 2024, written response to the Form FDA 483, you stated that no adverse events were reported during or following this incident. You stated that once the site became aware of the overdose, immediate action was taken to address safety concerns. The subject’s Legally Authorized Representative was promptly contacted and confirmed that the subject was doing well, without experiencing any adverse events. You stated that instructions were provided to reduce the drug dosage to the correct amount, and an unscheduled visit was conducted the following day to ensure compliance. You further stated that at the time of the occurrence, no electronic dose calculator was provided by the sponsor, and the electronic dispensing algorithm lacked safety guards to prevent errors.

As a Corrective and Preventive Action plan (CAPA), you stated that a Standard Operating Procedure (SOP) has been established to address medication dispensation procedures, which includes components such as: (1) collaboration between clinical investigator(s) and clinical research coordinators to ensure accurate dose calculations based on weight; (2) verification that the recommended dose adheres to protocol guidelines; and (3) provision of detailed instructions and written documentation of dosing instructions to patients. You stated that these measures are designed to enhance the accuracy and integrity of medication dispensation processes, to minimize the risk of dosage errors, and to ensure the safety and well-being of study participants.

While we acknowledge the corrective and preventive actions that your site has taken, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, you did not provide sufficient details regarding the procedures implemented at your site to prevent similar violations in the future. Given the significance of the protocol violation involving a pediatric subject, we request follow-up documentation regarding the procedure implemented at your site to ensure compliance with study protocol dosing procedures. Without this information, we are unable to determine if 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, 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 resulted in an overdose of (b)(4) to a pediatric subject. This conduct raises significant concerns about your protection of the study subjects enrolled at your site, and also raises concerns about the validity and integrity 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. 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 regarding 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-Colón, M.P.H. Branch Chief (Acting) Compliance Enforcement Branch Division of Enforcement and Postmarketing Safety Office of Scientific Investigations Office of Compliance Center for Drug Evaluation and Research U.S. Food and Drug Administration Building 51, Room 5352 10903 New Hampshire Avenue Silver Spring, MD 20993