Luis Javier Pena-Hernandez, M.D., FCCP

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 January 9 and January 23, 2023. Investigator Emily A. (Green) Baldwin, representing FDA, reviewed your conduct of a clinical investigation [Protocol (b)(4), “(b)(4) of the investigational drug products (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 Baldwin presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of the February 13, 2023, and April 12, 2023, written responses to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written responses dated February 13, 2023, and April 12, 2023, 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 you to ensure that subjects met all inclusion criteria before participating in the study. Specifically, Protocol (b)(4) required that subjects currently be on (b)(4) to be eligible for inclusion in the study. You failed to adhere to this requirement.

Specifically, although the inclusion/exclusion checklist for Subject (b)(6) notes the subject met this inclusion criterion, the subject’s study records, including the subject’s concomitant medication log, do not list a (b)(4). However, this subject was randomized to the Digital System (DS) cohort on (b)(6).

We emphasize that enrollment of subjects who do not meet eligibility criteria jeopardizes subject safety and welfare and raises concerns about the validity and integrity of the data collected at your site. As the clinical investigator, you are responsible for ensuring compliance with the protocol-required eligibility criteria.

2. You failed to ensure that an Institutional Review Board (IRB) that complies with the requirements set forth in 21 CFR part 56 was responsible for the initial and continuing review and approval of the proposed clinical study [21 CFR 312.66].

As a clinical investigator, you are required to ensure that an IRB that complies with the requirements set forth in 21 CFR part 56 is responsible for the initial and continuing review and approval of a proposed clinical investigation. You failed to ensure that an IRB that complies with 21 CFR part 56 continued to review and approve your conduct of Protocol (b)(4).

Specifically, IRB approval for Protocol (b)(4) lapsed from December 3, 2021, to January 27, 2022.

During this lapsed period, you performed the following study visits and study procedures:

a. Subject (b)(6) completed Visit 3 [Week 24; End of Treatment (ET) Visit] on (b)(6), including the (b)(4). This subject was randomized to the DS cohort on (b)(6), and was dispensed the investigational drug products (b)(4) during the treatment period.

b. Subject (b)(6) completed the early termination visit on (b)(6), including collection of vital signs and completion of the (b)(4), and the Beliefs about Medicines Questionnaire (BMQ S11). This subject was randomized to the DS cohort on (b)(6), and was dispensed the investigational drug products (b)(4) during the treatment period.

IRB review serves an important role in the protection of the rights and welfare of human research subjects. The purpose of IRB review is to ensure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. Your failure to ensure continuing IRB review and approval of Protocol (b)(4) impeded the IRB’s ability to determine the adequacy of your application to conduct Protocol (b)(4), which raises significant concerns about the extent to which subjects’ rights and welfare were protected at your site during the lapse in approval.

In your February 13, 2023, and April 12, 2023, written responses to the Form FDA 483, you stated that you were hired by a clinical research organization as the investigator for the above-referenced clinical investigation. You explained that during an initial telephone conference with the sponsor, you agreed to enroll subjects after reviewing the inclusion criteria and study protocol; however, you also stated that you were not made aware of any subject enrollment, and you were not asked to review any clinical document, medical record, or enrollment form at the time of subject enrollment. You also noted that you terminated your contract with the clinical research organization in October 2022.

In your written responses, you also acknowledged that you acted as the principal investigator for clinical investigations on behalf of the clinical research organization between March 2021 and October 2022. In addition, you stated during the inspection that you attended the Site Initiation Visit and the telephone conference discussing the inclusion/exclusion criteria and methodology for the above-referenced clinical investigation. You also acknowledged that you were responsible for overseeing the inclusion/exclusion criteria, following the protocol, ensuring accurate data entry, and providing medical care as needed during the study. During the inspection, you also acknowledged that you had been the clinical investigator since the study’s initiation, and that there was open communication between you and the site by text messaging, email, and telephone. Lastly, you acknowledged that you had provided training throughout the study, as needed. We note that as the clinical investigator for the above-referenced clinical investigation, you were ultimately responsible for the oversight and conduct of the study at your clinical site.

Your response is inadequate because you did not provide information about any completed or proposed corrective actions that would prevent similar violations in the future. In particular, you have not provided sufficient details about a corrective action plan. For example, you did not provide sufficient details about a corrective action plan to ensure that you would personally conduct or supervise future clinical investigations for which you are the clinical investigator. In addition, you have not provided sufficient details about any policies or procedures that you would institute to ensure your compliance with study protocols when conducting future clinical investigations, and your adequate oversight of the conduct of clinical studies.

We emphasize that as a clinical investigator, you had oversight of the study, and you were ultimately responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, including your adhering to the investigational plan and ensuring continuing IRB review and approval of the proposed clinical investigation. Your failure to ensure that subjects met protocol-required eligibility criteria, your failure to ensure continuing IRB review, and your lack of oversight and supervision of the clinical study raise significant concerns about the safety of study subjects enrolled at your site and the reliability of the data generated at your site. Your explanations, when taken into consideration with the regulatory violations described above, suggest systemic failures in your conduct of this clinical investigation.

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 above deficiencies. 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 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