Bret R. Rutherford, 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 December 19, 2022, and January 10, 2023. Investigators Omadevi Somai and Eileen Monaghan, representing FDA, reviewed your conduct of the following clinical investigations:

Protocol (b)(4), “(b)(4),” of the investigational drugs (b)(4), which you performed as a sponsor-investigator.

Protocol (b)(4), “(b)(4),” of the investigational drugs (b)(4), which you performed as a clinical investigator for Columbia University Medical Center Kreitchman (b)(4) Center.

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, Investigators Somai and Monaghan presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your January 27, 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 27, 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:

As a clinical investigator, you are required to ensure that your clinical investigations are conducted in accordance with the investigational plan. The investigational plans for Protocols (b)(4) and (b)(4) required you to ensure subjects met all eligibility criteria before enrollment in the studies. Specifically, both Protocol (b)(4) and (b)(4) required you to exclude subjects on current or recent (within the past 4 weeks) treatment with antidepressants, antipsychotics, or mood stabilizers. However, subjects were eligible to participate in the studies and undergo a medication washout if subjects were taking antidepressants but had not responded to an adequate trial of the medication (at least 6 weeks at a therapeutic dose) at the time of their screening assessment. The protocols required these subjects to be tapered off their current antidepressant medication and remain off medication for 5 elimination half-lives or 2 weeks, whichever is longer. You failed to adhere to these requirements.

Specifically, for example, the following enrolled subjects were on antidepressant treatment at the time of the screening assessment and did not undergo the protocol-required medication tapering and washout period (i.e., subjects did not remain off the antidepressant medication for 5 elimination half-lives or 2 weeks (whichever is longer)) before randomization:

a. Protocol (b)(4):

i. Subject (b)(6)’s last dose of antidepressant medication, bupropion extended release, was on (b)(6). However, this subject was randomized and received study drug on (b)(6).

ii. Subject (b)(6)’s last dose of antidepressant medication, sertraline, was between February 26 and (b)(6). However, this subject was randomized and received study drug on (b)(6).

iii. Subject (b)(6)’s last dose of antidepressant medication, escitalopram, was between (b)(6). However, this subject was randomized and received study drug on (b)(6).

iv. Subject (b)(6)’s last dose of antidepressant medication, duloxetine, was on (b)(6). However, this subject was randomized and received study drug on (b)(6).

b. Protocol (b)(4):

i. Subject (b)(6)’s last dose of antidepressant medication, fluoxetine, was between (b)(6). However, this subject was randomized and received study drug on (b)(6). In this instance, the protocol-required washout period would have been at least 20 to 30 days based on the fluoxetine’s elimination half-life.

ii. Subject (b)(6)’s last dose of antidepressant medication, escitalopram, was between (b)(6). However, this subject was randomized and received study drug on (b)(6).

iii. Subject (b)(6)’s last dose of antidepressant medication, venlafaxine extended release, was between (b)(6). However, this subject was randomized and received study drug on (b)(6).

iv. Subject (b)(6)’s last dose of antidepressant medication, sertraline, was on (b)(6). However, this subject was randomized and received study drug on (b)(6).

v. Subject (b)(6)’s last dose of antidepressant medication, fluoxetine, was between (b)(6). However, this subject was randomized and received study drug on (b)(6).

In your January 27, 2023, written response, you acknowledged the observation, and attributed the inclusion of these subjects to your insufficient oversight of the study protocols. You also stated that these errors should not have occurred, and you need to provide stronger oversight over the conduct of studies for which you are responsible.

You stated that you had full confidence that the study clinicians monitoring the subjects in these studies were skilled, responsible clinicians who closely monitored the safety of all subjects during participation in the study and would have not begun study procedures if there was increased risk to subjects. Further, you stated that the medication-free period called for in the study exclusion criteria was not intended primarily to protect subject safety, but rather to protect data validity of the neuroimaging data, among other study measurements. While we acknowledge that the protocol rationale for excluding individuals currently taking antidepressant or other psychotropic medications was to measure the effect of (b)(4) alone as a treatment for cognitive/motor slowing and depressive symptoms, we note that because of this rationale, failure to follow the medication-free period had a significant impact on data integrity. We also note that subjects who did not undergo the protocol-required medication tapering and washout or were unable to tolerate this tapering or washout, were ineligible for enrollment and were to be referred for clinical treatment. As a result, failure to follow the tapering and washout requirements in the protocol significantly impacts the safety of study subjects.

As a corrective action, you stated that you reviewed every involved subject to determine any potential risk for harm and compiled your findings, which were reviewed by the New York State Psychiatric Institute (NYSPI), Office of Research Compliance and Integrity (ORCI), and other senior institutional officials. A summary report was created, confirming that none of the subjects identified in the Form FDA 483 experienced harm due to participation in the study.

Furthermore, you stated that Protocol (b)(4) is currently closed, and that Protocol (b)(4) is in the process of being closed, noting that participant enrollment for Protocol (b)(4) was suspended in September 2021 and a request for withdrawal of the associated IND was submitted in January 2023.1 You also stated that no further research under these protocols will be conducted, and due to data validity concerns, data from these protocols will not be used in any future publications or grant proposals for which you would serve as “senior or corresponding author or as principal investigator.” You also noted that existing publications will be retracted and/or corrected.

You stated in your written response that you and your study staff have participated in retraining and began implementing a corrective action plan (CAP) for the Clinic for Aging, Anxiety, and Mood Disorders (CAAM clinic) at NYSPI. However, you stated that because no protocols in the CAAM clinic have reopened, you are unable to fully implement your CAP. In addition, the NYSPI Institutional Review Board (IRB) will not approve any new clinical investigations that involve you as clinical investigator or coinvestigator without the full implementation of your CAP.

You stated that you and your site have taken and/or plan to take the following additional corrective and preventive actions, including but not limited to:

Re-trained all investigators, clinicians, research assistants, and other team members in your research group in January 2022 on Collaborative Institutional Training initiative (CITI) Human Subject Research for Biomedical Researchers, CITI Good Clinical Practice Course (GCP) - GCP for Clinical Trials with Drugs and Medical Devices (US FDA Focus), and CITI Clinical Research Coordinator course.

Re-trained study team members on the specific assessments they perform.

Implemented training logs to document staff training on all study responsibilities, as described in the delegation of authority logs for each study.

Hold a half-day or full-day study launch meeting prior to initiating enrollment in any new study approved by the NYSPI IRB, during which, for example, the IRB-approved protocol summary form (PSF) and informed consent form will be presented and reviewed in detail.

Conduct annual study-specific summer workshops covering the study start-up meeting, any amendments made to the approved protocol, and review study progress to-date.

Provide training plans for all new protocols submitted to NYSPI IRB, which describe components, including all required training for all study team members, a protocol initiation meeting, which includes, but is not limited to, a thorough review of study protocol procedures, consent, SOPs, and the Quality Assurance Plan; and an annual protocol meeting for re-training of all study team members.

We acknowledge your statements in your written response that you have taken and plan to take the above-mentioned corrective and preventative actions. However, we are unable to undertake an informed evaluation of the adequacy of your response because you did not provide sufficient details about your plan for implementing additional measures and procedures to address the inspection findings regarding enrollment of ineligible subjects. In addition, your written response does not provide sufficient details about how you, as a sponsor-investigator and clinical investigator, will ensure adequate oversight of study procedures (for example, adherence to eligibility requirements). We are also concerned that most of the corrective actions taken, appear to represent the actions of NYSPI and do not reflect corrective actions that you have personally taken to prevent similar violations in the future.

Without these details, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future. Your explanation, when taken into consideration with the violations described above, suggests systemic failures in your conduct of these clinical investigations.

We emphasize that as the sponsor-investigator and clinical investigator, it was ultimately your responsibility to ensure that these studies were 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 subjects met protocol-required eligibility criteria by not following the protocol-required tapering and medication washout requirements, raises significant concerns about the safety of the study subjects enrolled at your site and raises concerns about the reliability of the data collected at your site. Multiple subjects were randomized and received the investigational product at your site that were ineligible for enrollment in the study. As the sponsor-investigator for Protocol (b)(4) and as the clinical investigator for Protocol (b)(4), you were responsible for ensuring that these studies were conducted in accordance with the protocol-required eligibility criteria and in compliance with FDA regulations.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical investigations of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law, including 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 an opportunity to address the deficiencies specified 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 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 5253 10903 New Hampshire Avenue Silver Spring, MD 20993