Kevin R. Bender, M.D./DBC Research Corporation

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 December 5 and December 16, 2022. Investigator Angelica Chica, representing FDA, reviewed your conduct of the following clinical investigations:

Protocol (b)(4), “(b)(4),” of the investigational drug product (b)(4), performed for (b)(4) (formerly performed for (b)(4))

Protocol (b)(4), “(b)(4),” of the investigational drug product (b)(4), performed for (b)(4).

Protocol (b)(4), “(b)(4),” of the investigational drug product (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 Chica presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your January 4, 2023, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your January 4, 2023, 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:

You failed to take adequate precautions to prevent theft or diversion of an investigational drug that is subject to the Controlled Substances Act [21 CFR 312.69], and you failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].

As a clinical investigator, when handling an investigational drug that is subject to the Controlled Substances Act, you are required to take adequate precautions to prevent theft or diversion of the controlled substance into illegal channels of distribution. These precautions include the storage of the investigational drug in a securely locked, substantially constructed cabinet, or other securely locked, substantially constructed enclosure, access to which is limited. In addition, 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 you to ensure that all clinical drug supplies were stored in a secured, monitored, and limited-access area, in accordance with labeled storage conditions. Additionally, the protocol required the clinical investigator to limit access to the study drug to the named subinvestigators, or to other appropriately designated study personnel or monitoring personnel.

You failed to adhere to these requirements. Study drug was provided in metered dose pumps containing (b)(4) or matching placebo. (b)(4), an investigational drug for Protocol (b)(4), is classified by the DEA as a Schedule III controlled substance because it contains (b)(4). You failed to store the investigational drug in a secured and limited-access area in accordance with the requirements of 21 CFR 312.69 and the investigational plan. Specifically, the shipment containing the investigational drug, (b)(4), or matching placebo was received on December 2, 2021; was stored outside the designated locked cabinet in a locked room following receipt; and the room was accessible to individuals other than staff designated to oversee investigational drug for Protocol (b)(4). Reports to the study monitor on March 10, 2022, and to the DEA on April 1, 2022, stated that 110 kits of investigational drug received on December 2, 2021, were missing because of customer/nonemployee theft.

In your January 4, 2023, written response, you acknowledged that a break in your process for securely storing investigational product (IP) (that is, standard operating procedure (SOP) and DEA’s storage requirements for a Class III Controlled Substance) resulted in the loss of IP. You stated that following the discovery of the missing IP, your site performed a comprehensive investigation, including but not limited to a complete accountability and reconciliation of all available kits onsite and in the Interactive Web Response System (IWRS); however, the exact cause remains unknown.

As part of your written response, you stated that the following corrective and preventive actions have been taken or will be taken:

An electronic keypad has been installed on the door of the IP room. It is configured to lock (b)(4) after it is unlocked, whether the door is open or closed, and (b)(4).

A video camera has been installed inside the IP room. It monitors the room (b)(4), with immediate motion notification being sent to the clinical investigator and the Site Director.

Manual IP inventory will be carried out once a week. This process will be added to the SOP.

Constructed a larger IP room with a closet to store new and used IP, which will remain secure and inaccessible to all non-study staff.

While we acknowledge the actions that your site has taken and plans to take, your response is inadequate because you did not include sufficient details about your corrective action plan. For example, you did not provide sufficient details about how you will limit access to secure areas that store investigational product subject to the Controlled Substances Act. While you noted several measures to secure access to the IP room, you did not provide details concerning how you will ensure access is limited to the appropriate personnel. Also, you did not provide details concerning any planned or completed training on the responsible conduct of clinical trials or compliance with FDA regulations. Without this information, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.

We emphasize that as the clinical investigator, it was your responsibility to ensure that this study was conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of study subjects and to ensure the integrity of study data. Your failure to ensure that investigational product subject to the Controlled Substances Act was stored in a secured and limited-access area, as required by FDA regulations and the protocol, raises significant concerns about the protection of study subjects enrolled at your site, and raises 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 described 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 adequately address this matter 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.

If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may e-mail FDA at CDER-OSI-Communications@fda.hhs.gov.

Your written response and any pertinent documentation should be addressed to:

Miah Jung, Pharm.D., M.S. Branch Chief 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