Devalingam Mahalingam, M.D., Ph.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 October 7 and October 18, 2024. 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 drugs (b)(4) and (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 November 6, 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 written response dated November 6, 2024, 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 the investigational drug, (b)(4), to be administered to subjects in accordance with the dose-level cohort to which subjects were assigned. The protocol also required that (b)(4) be prepared and administered in accordance with the (b)(4) Pharmacy Manual, which included specific dilution procedures to be followed during dose preparation.

You failed to adhere to these requirements. Specifically, Subject (b)(6) was assigned to the Part 1: Group C dose cohort, and was to receive 0.18 mcg/kg of the investigational drug on Cycle 1 Day 1. Based on the subject’s assigned dose-level (0.18 mcg/kg) and body weight (59.3 kg), Subject (b)(6) should have received a total intravenous (IV) infusion dose of 10.674 mcg of (b)(4) from a final drug concentration of 2 mcg/mL. However, during dose preparation, the dilution procedures specified in the pharmacy manual were not correctly followed, resulting in the subject’s (b)(4) IV infusion containing a final drug concentration of 200 mcg/mL, instead of the intended 2 mcg/mL. On April 22, 2024 (Cycle 1 Day 1), Subject (b)(6) was administered an IV infusion dose of approximately 1060 mcg, instead of 10.674 mcg, of the investigational drug. As a result, the subject was administered an IV infusion containing approximately 100 times the protocol-required dose of (b)(4). Subsequently, Subject (b)(6) was hospitalized and experienced multiple serious adverse events, including cardiac arrest, and death on (b)(6).

In your November 6, 2024, written response to the Form FDA 483, you stated that because of a compounding error, Subject (b)(6) received a larger than intended dose of study drug, which resulted in a prepared total dose of 1067 mcg of (b)(4) that was added to the IV bag for infusion. You stated that once the dosing error was confirmed, site personnel immediately contacted the subject’s nurse and the pharmacist in the clinic to stop the drug infusion.

In addition, in your written response, you stated that the following corrective and preventive actions have been implemented, including but not limited to: (1) study-specific training, attended by you and all oncology Investigational Drug Services (IDS) pharmacists and compounding technicians; (2) the updating of several IDS standard operating procedures (SOPs) and training on these procedures, which included updated observation and verification dose preparation procedures for certain investigational medications, and protocol training for compounding technicians and pharmacists for studies that include certain investigational medications; and (3) sponsor updates to the pharmacy manual, to include additional clarification for dilution steps, with illustrations, and pharmacist verification dosing requirements.

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 study procedures. For example, while your written response notes that you attended training on Protocol (b)(4), the written response states that only site pharmacists and technicians attended or will attend trainings on revised SOPs, pharmacy manual updates, and future protocols that include certain investigational medications. Therefore, your written response does not provide sufficient details concerning how you, as the clinical investigator, will prevent similar violations from occurring in the future. 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. Your failure to conduct the clinical study in accordance with the protocol resulted in an overdose of investigational drug to a subject, who subsequently experienced several serious adverse events, including death. This conduct raises significant concerns about your protection of the study subjects enrolled at your site, and 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, 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