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WARNING LETTER

FDA Ref No: 24-HFD-45-03-01

Dear Ms. Rogers:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted between January 23 and February 2, 2023, of the New York State Psychiatric Institute (NYSPI) Institutional Review Board (IRB). Investigator Omadevi Somai, representing FDA, conducted the inspection to determine whether the IRB’s procedures for the protection of human subjects complied with Title 21 of the Code of Federal Regulations (CFR), parts 50 and 56. These regulations apply to clinical investigations of products regulated by FDA.

This inspection is 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 Somai presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of the IRB’s February 17, 2023, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and the IRB’s February 17, 2023, written response, it appears that the IRB did not adhere to applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and FDA regulations governing the protection of human subjects.

We wish to emphasize the following:

1. The IRB failed to prepare, maintain, and follow required written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the Food and Drug Administration (FDA) [21 CFR 56.108(b) and 21 CFR 56.115 (a)(6)].

An IRB is required to prepare and maintain adequate documentation of IRB activities, including written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the FDA of: (1) any unanticipated problems involving risks to human subjects or others; (2) any instance of serious or continuing noncompliance with these regulations or the requirements or determinations of the IRB; or (3) any suspension or termination of IRB approval. The IRB also must follow such written procedures [21 CFR 56.108(b) and 115(a)(6)].

The IRB failed to adhere to these requirements. Specifically, the NYSPI IRB failed to prepare, maintain, and follow such written procedures, as follows:

a. For unanticipated problems involving risks to human subjects or others, the IRB’s written procedures specify that these are promptly reported by the IRB to the head of the sponsoring Federal department or agency, if any, and to the Office of Human Research Protections (OHRP) as required by HHS regulations, and to FDA when the study is subject to FDA regulation. In addition, the IRB’s written procedures further specify that reporting to federal officials will take place within a few days for a more serious incident, but generally takes place within 7 to 10 days following the IRB’s determination that an event meets the definition of an unanticipated problem involving risks to subjects or others. However, the IRB failed to report an unanticipated problem involving risks to human subjects or others, as required by the IRB’s written procedures. On August 9, 2021, at a convened meeting, the IRB determined that a serious adverse event (SAE) of death by suicide of a subject enrolled on Protocol (b)(4), titled “(b)(4),” was an unanticipated problem involving risks to human subjects or others. However, the IRB did not report this unanticipated problem involving risks to subjects or others to the FDA.

b. For serious or continuing noncompliance by investigators with the regulations or requirements or determinations of the IRB, the IRB’s written procedures specify that the IRB has the responsibility to promptly report to appropriate institutional officials to ensure prompt reporting to federal regulatory agencies. These written procedures further specify that reports of any serious or continuing noncompliance with federal regulations, or [with] IRB requirements or determinations, will promptly be reported to FDA when research is regulated by the FDA. However, instances of serious or continuing noncompliance by clinical investigators with applicable regulations or requirements or determinations of the IRB for three clinical studies were not promptly reported to the FDA, as follows:

i. On August 9, 2021, at a convened meeting, the IRB determined that the enrollment of a subject who did not meet all eligibility criteria, and the subsequent use of a medication taper procedure for Protocol (b)(4), was serious noncompliance. However, this instance of serious noncompliance by an investigator was not promptly reported to the FDA.

ii. On February 7, 2022, at a convened meeting, the IRB reviewed and discussed serious noncompliance by an investigator related to medication tapers being conducted without being part of the IRB-approved protocol for Protocol (b)(4), “(b)(4).” However, this instance of serious noncompliance was not reported to the FDA.

iii. On July 11, 2022, at a convened meeting, the IRB determined that an investigator’s failure to report an SAE to the IRB, to consistently establish or document eligibility, and to conduct all required assessments, as well as poor documentation, including missing dates/identifiers, which was consistent with findings on past monitoring reports for Protocol (b)(4), “(b)(4),” was serious and ongoing noncompliance. However, these instances of serious and continuing noncompliance by an investigator were not reported to the FDA.

c. For suspension or termination of IRB approval, the IRB’s written procedures specify that the IRB has the responsibility to promptly report to appropriate institutional officials to ensure prompt reporting to federal regulatory agencies. These written procedures further specify that IRB suspensions or terminations of approved research will be promptly reported to OHRP, institutional officials, and the department or agency head of other federal agencies when federally funded. However, the IRB’s written procedures fail to explicitly provide a procedure for reporting suspensions or terminations of IRB approval to FDA, regardless of federal funding. Further, under 21 CFR 56.113, suspensions or terminations of IRB approval of FDA-regulated research must be reported promptly to FDA. We note that on July 11, 2022, at a convened meeting, the IRB suspended IRB approval of research activities conducted under Protocol (b)(4). However, this suspension of IRB approval was not reported to FDA.

We acknowledge that the finding discussed above regarding the failure to report suspension of IRB approval for Protocol (b)(4) was not included on the Form FDA 483 you received, and therefore your written response does not address this violation.

In your February 17, 2023, written response to the Form FDA 483, you indicated that failing to report both unanticipated problems and serious or continuing noncompliance to FDA was an oversight and that, although the IRB’s Policy and Procedures Manual states that the IRB is to report serious or continuing noncompliance and unanticipated problems involving risks to human subjects or others, the IRB failed to correctly implement the process. The IRB administrative team instead directed the Principal Investigator(s) to inform FDA, while the IRB directly communicated with OHRP. You stated that the IRB staff and Co-chairs have been re-educated on proper reporting procedures at a meeting held on February 13, 2023. In addition, you stated that there are plans to develop an internal process flow that illustrates the appropriate procedures for such events that will explicitly include language about the IRB reporting directly to the FDA. Furthermore, you stated that the NYSPI policy will be updated to clarify the external reporting requirements for Principal Investigators who are subject to FDA oversight.

We are unable to perform an informed evaluation of the IRB’s written response because you did not provide a corrective action plan that, if properly carried out, would prevent the recurrence of this type of violation in the future. Specifically, you did not provide documentation of the training conducted with IRB staff and Co-chairs on proper reporting procedures at the February 13, 2023, meeting. In addition, you did not provide sufficient details on the procedures or IRB policy you are proposing to develop, and how you will ensure that these written procedures or this IRB policy will be followed to prevent repeat violations.

Please submit copies of the training provided to IRB staff and members on the reporting procedures, a list of IRB staff and members trained, or a projected timeline of planned training. In addition, please submit a copy of the IRB policy and any revised written procedures, or draft IRB policy and any written procedures in development, and a projected timeline for the implementation of the IRB policy and written procedures.

Failure of the IRB to prepare, maintain, and follow required written procedures raises concerns about the adequacy of the IRB's review processes for ensuring the protection of the rights and welfare of human research subjects.

2. The IRB failed to review proposed research at convened meetings at which a majority of the members of the IRB were present, including at least one member whose primary concerns are in nonscientific areas [21 CFR 56.108(c)].

Under 21 CFR 56.108(c), except when an expedited review procedure is used, the IRB may review proposed research only at convened meetings at which a majority of the IRB members are present, including at least one member whose primary concerns are in nonscientific areas. The IRB failed to adhere to this requirement.

Specifically, the IRB reviewed and approved FDA-regulated research at a convened IRB meeting without at least one nonscientific member being present.

IRB meeting minutes for a meeting held on June 17, 2019, between 12:05 p.m. and 2:15 p.m., indicate that no member whose primary concerns were in nonscientific areas attended the meeting between 1:00 p.m. and 2:15 p.m. During this time, the convened IRB reviewed ten research protocols, including protocols for FDA-regulated research, without a nonscientific member present. Specifically, the nonscientific member present at the beginning of the meeting, (b)(6), J.D., left the meeting at 1:00 p.m. and was replaced by (b)(6), Ph.D. (biology/pharmacology), as an alternate voting member in Ms. (b)(6)’s absence. However, as identified on the IRB’s membership roster, Dr. (b)(6)’s primary concerns are in scientific areas, and therefore Dr. (b)(6) was not a nonscientific IRB member.

The IRB should not have reviewed or approved the proposed FDA-regulated research, because the IRB did not have a member present whose primary concerns are in nonscientific areas during the above-noted time frame at this IRB meeting.

In your February 17, 2023, written response to the Form FDA 483, you stated that the absence of a nonscientific member during the June 17, 2019, meeting was an error. You noted that during the June 17, 2019, meeting, there were two community members, one whose primary concerns were in nonscientific areas, and the other who did have primary concerns in scientific areas. You stated that when the nonscientific member left the June 17, 2019, meeting, the IRB mistakenly replaced her with the unaffiliated scientific member as an alternate. You stated that going forward, the IRB roster will identify all nonscientific members with a bold font, so that the designation as a nonscientific member will be clearer to all, to prevent another such reoccurrence. In addition, you stated that the NYSPI IRB will review the minutes from the June 17, 2019, meeting at the next available IRB meeting, to document the occurrence for the convened committee.

We are unable to perform an informed evaluation of the IRB’s written response, because you did not provide a corrective action plan that, if properly carried out, would prevent the recurrence of this type of violation in the future. Specifically, you did not provide sufficient
details on how you intend to update your procedures to ensure that the revision of the membership list to identify all nonscientific members in bold font will continue to be maintained, and how the IRB Chair, who is listed in your procedures as being responsible for ensuring that IRB meetings remain appropriately convened, will ensure that a majority of the IRB members, including at least one member whose primary concerns are in nonscientific areas, will be present at convened meetings when proposed FDA-regulated research is under review. Please submit any corrective or preventive actions that the IRB plans to take to address the violation described above. With these corrective or preventive actions, please provide a copy of any revised written procedures, or any draft written procedures in development, and a projected timeline for the implementation of these written procedures. In addition, please provide a description of any training provided to IRB staff and members on the revisions to the membership list or any new written procedures, and a list of staff and members trained, or a projected timeline of planned training.

As an IRB, the review of proposed research at convened meetings at which a majority of the IRB members are present, including at least one member whose primary concerns are in a nonscientific area, is important to ensure that the IRB’s review and approval of research is fair and equitable.

This letter is not intended to be an all-inclusive list of deficiencies related to the IRB’s procedures or to the IRB’s review and approval of protocols and informed consent documents. It is the IRB’s responsibility to ensure adherence to each requirement of the law and relevant 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 that the IRB has taken or plans to take to address any violations and to prevent the recurrence of similar violations in the future. Failure to address this matter adequately may lead to regulatory action. If you believe that the IRB has complied with the FD&C Act and FDA regulations, include your reasoning and any supporting information for our consideration.

We recommend that the IRB visit the following FDA Web page for information on human subject protections that may assist the IRB in its efforts to come into compliance with FDA regulations: http://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/default.htm.

If the IRB has 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. The IRB’s 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
Food and Drug Administration
Building 51, Room 5352
10903 New Hampshire Avenue
Silver Spring, MD 20993

Sincerely,
{See appended electronic signature page}
David C. Burrow, Pharm.D., J.D.
Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration

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This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.
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/s/
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DAVID C BURROW
03/21/2024 12:05:43 PM