June 23, 2023 – New York State Psychiatric Institute

Dear Dr. Smith:

The Office for Human Research Protections (OHRP) received an allegation of noncompliance with Department of Health and Human Services (HHS) regulations for the protection of human research subjects (45 CFR part 46) (hereinafter referred to as the “HHS regulations”) involving the study titled: “L-DOPA vs. Placebo for Depression and Psychomotor Slowing in Older Adults” 7733 (Award R33MH110029), other research conducted by the principal investigator for this study, and the New York State Psychiatric Institute (NYSPI) human research protections program (HRPP). This letter outlines OHRP’s significant observations, concerns, and actions to date that are related to the conduct of human subject research at NSYPI.

OHRP, in collaboration with the National Institute of Mental Health (NIMH), conducted an on- site for-cause investigation of the above investigator’s studies and the NYSPI HRPP from November 29, 2021, to December 3, 2021. Following that on-site period, OHRP has continued its investigation of NYSPI’s HRPP remotely. This investigation was begun in response to concerns that NIMH raised with OHRP related to the initial incident reports that NYSPI submitted about the above-referenced study and other indications of possible non-compliance with the HHS regulations.

The NIMH funded study titled “L-DOPA vs. Placebo for Depression and Psychomotor Slowing in Older Adults” (“L-DOPA study”) was a double-blinded randomized clinical trial with a central hypothesis that the administration of carbidopa/levodopa (L-DOPA), by enhancing dopamine functioning in the brain and improving cognitive and motor slowing, would improve depressive symptoms in older adults with mild to moderate depression. This study sought to enroll 90 adults aged 59 years or older with (1) a DSM-5 depressive disorder, (2) significant depressive symptoms, and (3) decreased thinking or walking speed. According to the protocol, subjects could only enroll if they were not currently taking medication for their depression. Study subjects were randomized to either a placebo arm or to receive 8 weeks of treatment with L-DOPA with doses up to 450mg/day. The study tested whether L-DOPA increased brain dopamine release using neuroimaging and whether it increased thinking and walking speed.

On October 26, 2021, NIMH contacted OHRP after reviewing a report of an unanticipated problem submitted by NYSPI to OHRP (dated August 23, 2021) detailing the death by suicide of one of this study’s subjects. NIMH raised concerns that the report failed to include sufficient details regarding NYSPI’s review of the study and the circumstances surrounding the subject’s death. Specifically, the report did not mention that the actual conduct of this study included a psychiatric medication tapering procedure for ten participants, who otherwise would have been ineligible to enroll if their psychiatric medication was not discontinued. Further, this psychiatric medication tapering procedure was neither IRB approved nor did the research informed consent document describe the risks of the washout process.

In addition to examining the IRB records associated with this study, OHRP’s investigation included an assessment of NYSPI’s HRPP and other studies conducted by NYSPI investigators. OHRP’s site visit team also reviewed IRB meeting minutes for the previous six months and IRB written standard operating procedures, and the team observed an IRB meeting and interviewed multiple NYSPI officials, IRB chairpersons, IRB members, and staff. The OHRP site visit team conducted interviews with the study investigator and members of his research team, which revealed multiple areas of concerns related to how this study was conducted. OHRP presented preliminary observations and related concerns to NYSPI officials on the last day of the site visit and stated that OHRP’s investigation and review of other studies conducted by NYSPI would continue. Details regarding the L-DOPA Study, OHRP’s site visit, and further observations are described below.

I. Background

On July 26, 2021, the NYSPI IRB received notice of a serious adverse event involving the death by suicide of a subject ████ enrolled in the study. Consent of this subject was obtained on ███████. At the time of consent, the subject was taking antidepressant and mood stabilizing medications; according to the IRB-approved protocol, individuals taking these types of medications were not considered eligible for enrollment in this study. Despite this condition, the study team tapered the subject off the antidepressant medications and followed the taper with a three-week medication washout period -- a procedure that was not included in the IRB- approved protocol or consent form, and which involved the risks of antidepressant medication withdrawal.

As part of the study’s screening procedures and while the subject was still taking psychiatric medications (an exclusion criteria), the subject’s depression was assessed using the Hamilton Rating Scale for Depression (HRSD), a commonly used instrument for assessing symptoms of depression. Although at the time of screening the subject was ineligible for the study per the criteria listed in the IRB-approved protocol, subsequently the subject provided consent and was enrolled in the study.

This subject started taking the placebo (i.e., “sugar pill”), on ███████. The study was a double-blinded randomized trial, and thus neither the subject nor the study team knew which subjects received the psychiatric medication being studied or a placebo. After the subject died pharmacy unblinding revealed that the subject had been assigned to a placebo.

II. Timeline of Events

The following table provides a timeline of events and includes information obtained from NIMH regarding studies for which the investigator referred to above was the principal investigator:

We note that all of the original investigator’s HHS-supported research is suspended, terminated, or closed, and that the investigator is no longer employed at NYSPI.

III. OHRP’s Initial Observations

During the exit meeting on December 3, 2021, OHRP presented the following concerns:

1. We were concerned that certain non-exempt human subjects research procedures were conducted without IRB review and approval. The IRB must review and approve all non- exempt human subject research covered by an assurance before the research can be conducted, as required by the HHS regulations at 45 CFR 46.103(b) and 46.109(a). Specifically, we noted the following:
   • As reported to OHRP on August 23, 2021, a subject who did not meet eligibility criteria at the time informed consent occurred was enrolled in the L-DOPA Study.
   • As confirmed by NYSPI, the L-DOPA Study did not include medication tapering in the IRB-reviewed and approved protocol or consent form.
   • For protocol 7976, OHRP notes that while the protocol included medication tapering, the IRB-approved consent form for 7976 did not discuss medication tapering or its associated risks.
2. Regarding clinical trials conducted by NYSPI involving individuals who consent to participate in the research and subsequently have their medication tapered and discontinued before they will be assigned to a study arm, OHRP understands that NYSPI considers these individuals to be research subjects during the tapering procedures. OHRP noted that when research subjects undergo medication tapering procedures, the IRB is responsible for ensuring that its oversight of these medication tapering procedures is adequate with respect to minimizing the risks to subjects, as required by 45 CFR 46.111(a)(2). OHRP further noted that for studies that include medication tapering as a research procedure, the IRB should receive sufficient information from investigators about the medication tapering procedures to provide adequate oversight.
3. For some NYSPI studies involving medication tapering as part of the research, such as the L- DOPA study (7733), information about how subjects’ medication tapering was to be managed and how safety monitoring was to be performed were not described in the protocol reviewed and approved by the IRB. Consequently, the IRB did not review and approve medication tapering procedures. During OHRP’s interviews with NYSPI IRB members and researchers, there appeared to be confusion about whether research subjects’ medications could be manipulated by the research as part of their participation in research without providing this information in the protocol or consent form. Without the inclusion of this information in protocols and consent forms presented to the IRB, and in the absence of the IRB’s inquiring about this potential process, it appeared that the IRB may not have had sufficient information about studies that include medication tapering as a research procedure to ensure that risks to subjects are minimized in compliance with 45 CFR 46.111(a)(2).
4. The regulations at 45 CFR 46.116 require that legally effective informed consent be obtained from prospective subjects before they become involved in research. However, based on our interviews with the investigator’s research team, and specifically those team members who enrolled subjects in the L-DOPA study, the study team did not appear to be aware of discrepancies between research procedures described in the IRB-approved protocol and the procedures described in the consent document. In fact, a member of the research team who enrolled subjects in the L-DOPA study stated they were unaware that the L-DOPA consent form did not include information about the risks associated with medication tapering or the exclusion of subjects on depression medications. OHRP is concerned that some research staff who obtained informed consent did not have sufficient expertise (e.g., background, training, experience, or understanding of the protocols) to adequately obtain informed consent for the studies. Specifically, the study team appeared unaware that at least some of the subjects they were enrolling in the study did not meet the eligibility criteria listed in the IRB-approved study protocol.
5. While on site, OHRP was told that NYSPI was requiring monitoring of greater than minimal risk studies, with the results of that monitoring being used by the IRB during the conduct of the continuing review. We interviewed several NYSPI staff who stated that they believed it may not be sufficient to have a ███████ staff member assigned to carry out that responsibility.
6. Regarding NYSPI’s resources and staff, we had a few observations:
   • OHRP heard from staff and IRB members that the electronic IRB submission and processing system lacked functionality that would facilitate the work of the IRB and IRB staff.
   • OHRP heard that the institution does not have the same number of IRB Analysts as previously, and that the IRB Director was currently performing responsibilities that were previously divided between two Director-level positions.
   • Several persons we interviewed recommended additional resources be provided for training of all members of certain research teams, including investigators, clinicians, program managers, research assistants, and research staff. Specifically, they suggested that consideration be given to strengthening training regarding obtaining consent and protocol adherence.
7. Based on OHRP’s on-site interviews, it appeared that the Signatory Official had adequate authority to seek the resources needed to ensure that the IRB and the Office of Research Oversight could fulfill their responsibilities. However, neither the Signatory Official nor the Human Protections Administrator appeared to have a close and ongoing awareness about, or sufficient knowledge of, the nature and volume of the work of the IRB and the Office of Research Oversight such that they would fully appreciate their responsibility to determine whether their resources were adequate. (Later, according to the Interim Director’s June 26, 2022, email, NYSPI, along with leadership at the New York State Office of Mental Health (OMH) and the Research Foundation for Mental Hygiene (RFMH), agreed that additional staff were needed to buttress the HRPP and created a Director of the HRPP position that would report directly to the Signatory Official. Further, according to the Interim Director’s August 25, 2022, email, NYSPI, OMH, and RFMH decided to change the Signatory Official to the Chief Medical Officer of the New York State Office of Mental Health.)
8. We learned from some of the individuals we interviewed that they believed there might be benefit to adding new members to the IRB who have expertise in conducting research with geriatric populations. We also heard that it has been difficult to recruit new IRB members. We made some non-regulatory suggestions, including that some institutions address this issue by offering protected time for IRB duties or having term limits for IRB members. Additionally, in some institutions, there is an expectation that each research group will, as needed, provide a staff member to serve on the IRB.

IV. Additional Observations:

As our investigation progressed, OHRP identified the following additional concerns:

1. According to NIMH’s audit report, of the 46 L-DOPA enrolled subjects, one subject withdrew from the study, and all of the 45 available subject files were audited. NIMH auditors were unable to confirm the eligibility for 41 of the subjects enrolled in that study.

2. Another concerning observation is that the IRB, which is constituted largely of long-term members who reviewed a wide variety of psychiatric research studies, seemed to generally fail to inquire about how researchers would identify subjects with mild to moderate depression (who were not on antidepressants as specified in the protocol), manage subjects with worsening depression, and implement stopping rules for study subjects. Also, the IRB did not appear to detect discrepancies between protocols and consent forms.

   For example, in another study that the IRB reviewed (study 7976, entitled “Dopaminergic Dysfunction in Late Life Depression”), as part of the initial review the IRB asked the investigator to add a medication tapering phase to the protocol and the consent form. The investigator responded that the “[w]ashout procedures have been added as point 7 of the Study Procedures section” of the protocol. However, nothing related to the washout procedures was added to the consent form, and the IRB approved the form without that information. The IRB went on to review and approve the form several times after the initial review, as follows:

   • The IRB approved the consent form for the period October 27, 2020 - May 3, 2021, which included various changes to the consent form, but again did not include a tapering procedure or the accompanying risks.
   • The IRB-approved amendment memo (dated January 14, 2021) for recruiting from studies 7733 and 8065 included changes to the consent form in the risks section for the study drug but again did not include a tapering procedure or any accompanying risks.
   • The IRB memo with the approved continuation application (April 8 memo for April 5, 2021 meeting) included the same language in the protocol for procedures and risks related to tapering, but again this was not included in the approved consent form for the period May 4, 2021, to May 3, 2022.

We acknowledge that after the on-site part of our investigation, NYSPI began taking steps to investigate and address the concerns raised during our site visit. The following are the most notable changes:

• Developed IRB Guidelines for Medication Discontinuation policy to ensure that researchers and IRB members are informed of NYSPI’s requirements when research subjects undergo medication discontinuation as a research procedure.
• Implemented a PIs Self-Audit Program: Researchers are now required to prepare and adhere to a protocol-specific quality assurance plan, training plan and data management plan (collectively, “PSPs”) that includes templates and guidelines. By January 1, 2023, the Institute planned to require PSPs for all HHS and non-HHS- funded more than minimal risk studies.
• Evaluated and submitted to OHRP complete reports of serious noncompliancen discovered for protocols 6836, 7270, and 7733, as well as serious noncompliance discovered in another investigator’s study (7284R).
• Created the Office of Research Compliance and Integrity with three full-time staff persons.
• NYSPI updated its FWA to change its Signatory Official from the Managing Director to the Chief Medical Officer.
• In addition, in response to a requirement by NIH, NYSPI retained an independent, outside entity to audit all NIH-funded research (NIH letter to NYSPI dated April 28, 2022). OHRP has received and reviewed NYSPI’s proposed audit plan (dated May 27, 2022), and NYSPI agreed to send OHRP its audit reports as they are completed.

V. Additional Information Demonstrating Serious and Continuing Concerns related to NYSPI’s HRPP

While this investigation was initiated by OHRP in November 2021 in response to concerns related to the suicide of a research subject and focused initially on the studies of a specific investigator, a growing amount of new information became available that appears to indicate systemic and serious noncompliance with the HHS regulations.

Based on the information that OHRP has received from NYSPI, most recently in May and June of 2023, OHRP has identified a general concern that multiple NYSPI investigators have been, and presently are, conducting research in a manner that is inconsistent with IRB-approved protocols. As a result of NYSPI’s audits and routine monitoring, NYSPI has submitted to OHRP incident reports regarding events NYSPI has identified as noncompliance in studies #7519 (June 2022 and February 2023) #7409, #8092, and #767645 (May, 2023) involving four different investigators. NYSPI reported that investigators enrolled subjects who either did not meet eligibility criteria, or subjects for whom eligibility could not be confirmed, or who performed research procedures in a manner that failed to implement the safeguards in the approved protocols and required by the IRB. OHRP considers this concern to be both serious and continuing, as the identified noncompliance is regarding multiple NYSPI investigators, and occurring in multiple NYSPI research studies that are supported by HHS. Further, OHRP’s serious and continuing concern applies to the current operation of NYSPI’s human research protections program, which in OHRP’s estimation may be placing research subjects at risk of harm.

Further confirmation of OHRP’s concerns is reflected in NYSPI’s draft safety proposal dated June 5, 2023, in which NYSPI stated that “[i]nternal and external research monitoring reports completed over the past year indicate significant deficiencies in practices to ensure the safety and protection of human subjects participating in research studies at the New York State Psychiatric Institute (NYSPI).”

This acknowledgement by NYSPI, and the numerous instances of serious or continuing noncompliance identified by NYPSI’s internal and external audits, raise concern that NYSPI’s overall culture does not promote compliance with the HHS regulations to ensure the appropriate protection of human subjects.

We understand that the National Institutes of Health (NIH) has also expressed its concerns about the safety and well-being of research subjects in NIH-funded studies beyond the research studies of the investigator whose studies initially precipitated the investigation.

VI. Restriction of New York State Department of Mental Hygiene’s Federalwide Assurance (FWA)

Based on the progressive and serious nature of our human subject protections concerns that go well beyond the original allegations specific to an individual investigator, OHRP finds that an immediate restriction of New York State Department of Mental Hygiene’s FWA under 45 CFR 46.103(c) is warranted to ensure that the rights and welfare of human research subjects are protected. This restriction of New York State Department of Mental Hygiene’s FWA applies only to NYSPI, which is identified as a component covered by New York State Department of Mental Hygiene’s FWA.

This restriction is effective immediately as of the date of this letter and applies to the assurance required by HHS regulations at 45 CFR 46.103(a) and (c) for all HHS-supported research involving human subjects conducted by NYSPI.

For all HHS-supported human subject research affected by this restriction, enrollment of new subjects and existing research activities must cease immediately, except for instances where continuing participation in the research is determined by the investigator and IRB, or the Institutional Official, to be in the best interest of subjects. No HHS-supported human subject research may resume at NYSPI until the terms outlined below have been established and met by NYSPI.

VII. Required Actions for NYSPI

OHRP acknowledges that according to a June 12, 2023, email that the Institutional Official sent to NYSPI Principal Investigators, on which OHRP was copied, as of June 12, 2023, NYSPI has voluntarily implemented “…a safety review of studies involving human subjects. This review includes an immediate pause of ongoing human subjects research, except for instances where continuing the study interventions and interactions are determined to be in the best interest of subjects.” We understand that this research pause applies to all studies, regardless of funding source.

While this is a commendable start, OHRP is requiring NYPSI to carry out the following corrective actions as a function of the restriction on all HHS-supported human subjects research. These actions are designed to ensure the safe cessation of HHS-supported research studies, the continuation of studies where it is in the best interest of subjects, the resumption of suspended studies, and other appropriate responses to the circumstances. When these actions have been fully executed, OHRP will modify or remove the restriction on NYSPI’s FWA, unless additional information is identified that would compel maintaining the restriction. The required corrective actions relating to HHS-supported studies are as follows:

1. Create and submit to OHRP a Research Study List of all HHS-supported studies affected by this restriction. The list must include the study title, principal investigator’s name, IRB project number, and the HHS grant number.
2. Create and submit to OHRP a Continuing Participation Report identifying those research activities involving currently enrolled subjects where continuing the research is determined by the investigator and IRB, or the Institutional Official, to be in the best interest of subject(s). Include an explanation of the rationale(s) for continuing subjects’ participation in these research studies as being in their best interests.
3. Create and submit to OHRP a Clinical Needs of Subjects from Suspended Research Report describing how NYSPI is addressing the related clinical care needs for subjects for whom their research participation is or has been suspended. This Report should include how NYSPI will cooperate with subjects who choose to seek clinical care elsewhere.
4. Create and submit to OHRP a Subject Notification Plan Report describing how NYSPI has or will address the notification of subjects about their participation in HHS-supported research at NYSPI. The report must include how NYSPI will communicate or has communicated with subjects in the following categories:
   1. Subjects whose participation in research is being continued because of the judgment that continuing to participate is in their best interests. In light of OHRP’s concerns that led to the restriction of NYSPI’s FWA, OHRP believes these subjects ought to be informed of the judgment made by the institution that it is in their best interests to continue research participation, in case the subject wishes to elect to withdraw from the study.
   2. Subjects whose participation is being suspended because of the restriction of NYSPI’s FWA or due to NYSPI’s voluntary “pause” on human subjects research. In light of OHRP’s concerns that led to the restriction of NYSPI’s FWA and NYSPI’s voluntary “pause” on human subjects research, OHRP believes subjects whose participation in a study has been stopped ought to be informed of the study suspension and the reasons for it, so that they can consider their options, including to pursue clinical care or research participation elsewhere.
5. Inform OHRP whether NYSPI considered notifying affected subjects of NYSPI’s findings that the subjects were enrolled in protocols for which they did not meet eligibility criteria described in an IRB-approved protocol, or involved in studies in which IRB-approved research procedures related to subject safety were not followed.
6. Create and submit to OHRP a plan proposing the process for reviewing and re-starting studies suspended according to the restriction. This plan may include activities described in the draft NYSPI Human Subjects Safety Review proposal that NYSPI sent to OHRP and NIH on June 7, 2023. The plan must also include the utilization of some form of external review, which could vary depending on the type and current status of the research studies. The plan must include review and consultation with the IRB, OHRP, and the HHS study sponsor. NYSPI must review all HHS-funded human subject research studies to ensure that those studies will be conducted in compliance with the HHS regulations at 45 CFR part 46.
7. Notify all federal departments and agencies supporting research in which NYSPI is engaged of OHRP’s action to restrict the FWA for all HHS-supported research. While we are in communication with NYSPI and NIH to ensure that appropriate actions are taken to protect the wellbeing of research subjects enrolled in the studies in which lapses in the protection of human subjects have been identified, we are concerned that there may be other federally supported studies in which such noncompliance is occurring that have not yet been identified.
8. Create and submit to OHRP for approval a plan for having a comprehensive, external review and assessment of NYSPI’s HRPP that will include (1) a review and assessment of the circumstances that led to OHRP’s investigation into allegations of noncompliance related to NYSPI’s HRPP and the study titled: “L-DOPA vs. Placebo for Depression and Psychomotor Slowing in Older Adults;” (2) a review and assessment of the changes NYSPI has implemented to date to strengthen its HRPP; and (3) recommendations for additional changes or actions NYSPI should take to further strengthen its HRPP to better ensure the appropriate protection of research subjects and compliance with 45 CFR part 46. At a minimum, this external review should include consideration of the following: (1) the organizational structure of NYSPI’s HRPP; (2) staffing needs and expertise; (3) IRB membership; (4) IRB policies and practices; (5) protocol monitoring procedures, and (6) educational practices and requirements regarding the regulatory requirements for the protection of human subjects in research at 45 CFR part 46 for IRB members, all individuals who support the IRB, and all research investigators and study team members.

Please provide OHRP with a general progress report in six months, with any findings and proposed corrective actions to address findings of noncompliance with HHS regulations and revisions of NYSPI’s HRPP. Following this report, provide OHRP with additional progress reports every six months until the restriction is lifted. Also, please provide any other audit reports conducted in response to NIMH’s and OHRP’s requirements. NYSPI should not delay reporting to OHRP any findings that HHS regulations require to be promptly reported (i.e., serious or continuing noncompliance, unanticipated problems that involve risk of harm to subjects or others, and suspensions or terminations of research).

OHRP is available to assist in the development and implementation of these corrective action plans. Do not hesitate to contact OHRP should you have any questions.

Sincerely,

Julie A. Kaneshiro, M.A.
Acting Director, OHRP

cc:
Dr. Karya Ottey, Director of the New York State Office of Mental Hygiene, Office of Human Research Protections Program
Dr. H. Blair Simpson, Interim Director, New York State Psychiatric Institute
Dr. Rachel L. Levine, Admiral, United States Public Health Service, Assistant Secretary for Health
Dr. Michael Lauer, Deputy Director for Extramural Research, National Institutes of Health (NIH)
Dr. Tracy Waldeck, Director, Division of Extramural Activities, National Institute of Mental Health
Ms. Theresa Jarosik, Chief Grants Management Officer, National Institute of Mental Health
Dr. Anna E. Ordóñez, Director, Office of Clinical Research, National Institute of Mental Health
Ms. Winifred Meeker-O’Connell, Director, Office of Clinical Policy, FDA
Dr. Michelle Bulls, Director, OPERA, Office of Extramural Research, NIH
Dr. Pamela Kearney, Director, Division of Human Subjects Research, Office of Extramural Research, NIH
Dr. Adam Berger, Director, Division of Clinical and Healthcare Research Policy, Office of Science Policy, NIH
Ms. Lydia Kline, Team Lead, Clinical Research Policy, Division of Clinical and Healthcare Research Policy, Office of Science Policy, NIH
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Center for Biologics Evaluation and Research (CBER): CBERBIMONotification@fda.hhs.gov
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Center for Drug Evaluation and Research (CDER): BIMO-CDEROSI@fda.hhs.gov