March 21, 2022 – New York University Grossman School of Medicine

Dear Dr. Alsayed,

Thank you for your responses to OHRP following our 2015 site visit, including your August 28, 2020 and September 3, 2020 written responses to an OHRP questions and concerns.

In May of 2014, the Office for Human Research Protections (OHRP) opened a not-for-cause paper-based evaluation of the human research protections program (HRPP) at NYU Grossman School of Medicine (hereinafter referred to as NYU). Initially, that evaluation was part of OHRP’s program for assessing compliance with 45 CFR Part 46 by routinely evaluating human subjects protection programs of institutions that receive Department of Health and Human Services (HHS) support for research. Before OHRP completed that evaluation, we were informed by the National Institute of Mental Health (NIMH) of concerns related to the NIMH-funded studies referenced above, all of which were being conducted by the same principal investigator.   

According to the information provided by NIMH, on March 11, 2015, NYU reported to the NIMH that the principal investigator for these studies had been placed on administrative leave due to “significant irregularities in his management of certain research projects.” On May 1, 2015, NYU submitted reports to OHRP citing unanticipated problems involving risks to subjects or others, and serious noncompliance that occurred in each of those studies. NIMH decided to conduct an on-site audit of these studies and invited OHRP to join them on that visit. OHRP converted its paper-based evaluation of NYU’s HRPP to an on-site evaluation and accompanied NIMH on their audit visit.   

OHRP evaluated how NYU identified and managed allegations of non-compliance associated with the principal investigator as part of its broader evaluation of the HRPP. OHRP also reviewed IRB minutes for studies that were not related to the principal investigator, and obtained information about other aspects of the NYU HRPP, including NYU HRPP resources and training activities for researchers and IRB members. OHRP site team members and NIMH team members in discussion specific to the studies being audited by the NIMH team.

The following is a chronology of events associated with OHRP’s evaluation alongside the NIMH audit of the serious non-compliance in the conduct of these research studies.

I. Background

On March 23, 2014, non-compliance was reported to the NYU School of Medicine Institutional Review Board (IRB) by the principal investigator, pertaining to his protocol “Functional brain Imaging in post-traumatic stress disorder (PTSD)” (protocol 13-000313), funded by the NYU Department of Psychiatry.  The deviations cited in that report had occurred in June and July 2013. The NYU IRB determined that 8 of 37 subjects had received incorrect PET-MRI brain scans at Yale University. In follow-up communication, the IRB noted that the principal investigator had: 1) “reused medical assessments from prior year PET and MRI scans for rescans,” and 2) allowed eight months to pass before he reported these protocol deviations. The investigator argued that the delay in reporting these protocol deviations was due to a data transfer problem between Yale University (the site where scans took place) and NYU School of Medicine (the site where the investigator maintained the protocol data). The IRB developed a detailed corrective action plan (CAP) to avoid any further protocol deviations of this nature. 

In June 2014, based on these initial findings, the NYU IRB initiated an internal audit of the principal investigator’s protocols that had ongoing enrollment of research subjects. The audit included interviewing prior and current study staff. This internal audit was coordinated with and supported by a commercial IRB. The audit was conducted on four of the principal investigator’s nine protocols, including three studies funded by NIMH (12-01236, 12-01521, 12-02787).

In July 2014, the NYU HRPP Director, Associate Director, IRB Chair, and IRB members received the audit report. The audit report identified the following issues: 1) no rationale for co-enrollment of subjects in multiple protocols, 2) questionable data validity, 3) no information as to how subject radiation exposure was ascertained for research subjects who were co-enrolled in multiple protocols, 4) a total of 1,020 protocol deviations and adverse events, and 5) five deviations characterized as major risks because pregnancy test records did not exist for female subjects receiving MRI-PET scans. The IRB consulted with the NYU School of Medicine Radiation Safety Committee regarding the radiation exposure levels to co-enrolled subjects and requested that the investigator submit a new corrective action plan (CAP).

On August 5, 2014, the NYU IRB reviewed these deviations, audit findings, IRB findings, expert consultation responses, supporting documents, and the responses of the investigator. In response to this information, the IRB took several actions: 1) authorized re-scanning of eight subjects after the investigator obtained new signed consent forms, 2) implemented protocol modifications for pre-imaging assessments, 3) updated assessment tools in protocols, and 4) discarded data from five subjects who did not meet the inclusion criteria. As part of the corrective action plan, the principal investigator was also directed to complete NYU’s “PI responsibility course.”

On September 8, 2014, NYU’s IRB approved two new protocols to be conducted by this principal investigator: a NIMH-funded protocol, 13-00609, a study involving PTSD; and a second protocol funded by a pharmaceutical company.   

In January 2015 a new research coordinator and a post-doctoral fellow at NYU expressed concerns related to the principal investigator’s lack of compliance with Good Clinical Practice (GCP) in HHS funded studies, including “blank signed prescriptions by a study physician...” That research physician acknowledged that he provided blank signed prescriptions and acknowledged that subject medical and laboratory records were not obtained, as required by protocols for pre-imaging assessments.

During this same month, NYU received information that the principal investigator might be misusing Federal funds by charging personal expenses to NIMH grants. The principal investigator subsequently acknowledged using grant funds for personal expenses. On January 28, 2015, NYU officials directed NYU’s Office of Internal Audit, Compliance, and Enterprise Risk Management (IACERM) to conduct an internal audit.

On February 3, 2015, the IRB reviewed the principal investigator’s appeal regarding the IRB’s August 5, 2014 decision to discard the data from five subjects who did not meet the inclusion criteria. The principal investigator noted that the “data collected was usable and that the IRB determination would deny subjects’ contribution to the study purpose after being exposed to radiation… and that this exclusion of data would result in the inability to perform a meaningful analysis on the entire dataset.”  The IRB rescinded its earlier determination, and issued a new letter authorizing the use of data from those subjects. 

On March 10, 2015, NYU’s signatory official on the FWA directed the IRB to conduct GCP audits of all the principal investigator’s research records. On the same day, the NYU School of Medicine Department Chair and Vice Dean of Faculty Affairs placed the principal investigator on administrative leave. On March 11, 2015, the IRB administratively transferred all the principal investigator’s active research studies to the Department Chair, who then suspended all study activities, but continued safety-related follow-ups. On the same day, an official from the NYU School of Medicine Sponsored Programs Administration (SPA) contacted NIMH to inform them that the principal investigator had been suspended and was on administrative leave from NYU. On March 12, 2015, the research physician who signed blank prescriptions was terminated and the principal investigator resigned from NYU. Simultaneously, NIMH suspended all six HHS-funded grants, except for subject safety protections, and placed them on freeze status to prohibit billing or drawdowns from NIMH funds. On March 13, 2015, the NYU School of Medicine IRB began GCP audits of all the principal investigator’s protocols.

A few days later, on March 17, 2015, the Institutional Official informed the Vice-Dean of Faculty Affairs of preliminary GCP audit findings related to “data fabrication or falsification.” The Vice-Dean then convened a Research Misconduct Inquiry Committee. A determination made in January 2020 by the HHS Office of Research Integrity (ORI) about data fabrication or falsification is discussed on page 14 of this letter.

On April 7, 2015, IRB auditors completed their GCP audits of eight active protocols led by the principal investigator, noting “protocol deviations across studies.” The GCP audit reports confirmed “serious protocol and regulatory violations” including no record of pregnancy testing of 11 female subjects prior to MRI-PET scans.  These audit reports were submitted to the IRB on April 22, 2015 and reviewed by the IRB on April 30, 2015. Subsequently, the Psychiatry Department Chair and others received copies of the complete GCP audit report. 

On April 29 and June 19, 2015, the NYU Research Misconduct Inquiry Committee met. The Psychiatry Department Chair requested that consulting NYU cardiologists and gastroenterologists review the medical records of study subjects. A cardiologist recommended that four subjects with abnormal electrocardiograms (ECGs) have their ECG repeated. A gastroenterologist recommended that six subjects have repeat blood tests.  The NYU research misconduct inquiry eventually led to a January 7, 2020 action by ORI, as explained below.

In early May 2015, NYU sent the first report to OHRP related to findings in three-audits (one in June 2014 and two in March 2015) of the principal investigator’s studies that documented continued non-compliance, serious protocol deviations, multiple unanticipated problems, increased risks to subjects, data fabrication or falsification, and serious adverse events.

II. The Site Visit

On May 26, 2015, NIMH informed the NYU SPA that they would conduct a site visit, and NIMH requested information on protocols funded by NIMH. On June 2, 2015, OHRP informed NYU that OHRP would be converting its paper-based not-for-cause evaluation of the NYU HRPP to an on-site evaluation with NIMH to assess the alleged non-compliance related to the principal investigator’s studies referenced above.

Over the June 23-25, 2015 site visit, OHRP reviewed IRB files for over 34 HHS-supported research studies, IRB meeting minutes for the previous six months, and IRB written standard operating procedures. The team also observed an IRB meeting. Part of OHRP site visit team participated in NIMH’s discussions related to the principal investigator’s conduct of the research. OHRP and NIMH reviewed their preliminary findings and presented them to NYU officials on the last day of the site visit.

III. Post Site Visit Actions

After obtaining information during the June 23-25, 2015 site visit, OHRP evaluated the entire NYU HRPP, including human subjects protection concerns associated with this principal investigator. OHRP noted that the NYU officials, IRB chairpersons, staff, and members conveyed a sincere commitment and concern for the protection of human research subjects. Furthermore, OHRP noted that the NYU HRPP, made a continuous and successful effort to improve their HRPP, most recently with the implementation of an electronic system for protocol submission, review, and approval by their IRBs and staff. OHRP concluded that NYU had a robust HRPP.

OHRP determined that the NYU HRPP appropriately identified and managed the serious human subject protections problems involving the principal investigator, including development of a corrective action plan. In order to assess those issues, OHRP posed questions and shared many concerns with NYU about the six NIMH protocols led by the principal investigator. The topics included informed consent, changes in the protocol without IRB approval, failure to follow OHRP reporting requirements of unanticipated problems, and altering of records to minimize the seriousness of certain study problems.  

1. In 2017, OHRP asked NYU to provide the status of all the principal investigator protocols, research data, and research files, including but not limited to, what information and guidance was provided to subjects that were involved in these protocols; and
2. A detailed report of corrective actions or improvement efforts to NYU’s Human Research Program derived from OHRP’s site visit observations and NIMH audit findings.  This report should include, but not be limited to, NYU’s investigator audit or monitoring program, investigator training, IRB member training, procedures to ensure that investigator-initiated protocol changes are reviewed and approved by NYU IRB, procedures to ensure that consent was property obtained from subjects as part of approved research protocols, and procedures for reporting unanticipated problems involving risks to subjects or others and non-compliance.

IV. OHRP’s Resolved Concerns

Corrective actions taken by NYU after the June 2015 site visit as described in their letter to OHRP dated March 1, 2017 are outlined below:

1. After the principal investigator resigned from NYU, all his protocols were suspended for new enrollment by the NYU IRB. The Chair and Research Vice-Chair of the NYU Department of Psychiatry assumed principal investigator responsibilities for all these protocols. By assuming direct oversight of these protocols, they became responsible for all follow-up with subjects and reporting to the NYU IRB of any newly discovered protocol deviations and potential safety issues. Simultaneously, the NYU IRB directed for-cause audits for all these protocols, then reported to and reviewed by the NYU IRB as reportable new information, which in turn was reported to OHRP, NIMH, and (when applicable) FDA. The NYU IRB also required that subjects in affected studies be notified about the non-compliance, the principal investigator’s departure, and the new principal investigators.

   Updated NYU Policies and Tools

   Several NYU IRB policies and tools were updated to enhance protection for human subjects.

   NYU ensured that their policies were consistent with the June 20, 2011, “Guidance on Reporting Incidents to OHRP.” Additionally, NYU developed and implemented training materials for this policy, including a checklist to reflect updated definitions of terms pertaining to the reporting of unanticipated problems. This checklist was then used as a reference tool during all IRB meetings.

   NYU also updated policies and training materials pertaining to new protocol submissions, annual continuing reviews, and protocol amendments. The purpose was to ensure that investigators adhere to 45 CFR 46.103(b)(4)(iii) and that they submit protocol changes to the IRB for review and approval, prior to implementing any proposed protocol changes.

   Furthermore, the IRB developed new training materials, forms, and tools with respect to a) qualifications for studies led by principal investigators who are not licensed physicians, b) delegation logs, c) study record management, d) HIV testing consent, and e) other authorization forms.

   Finally, NYU strengthened its general human subjects training requirements.  All study team members conducting human subjects research were required to complete and maintain certification in a) human subjects protections training, b) training for biomedical research, and c) training in GCP standards. Such training would be done online, as provided by the Collaborative Institutional Training Initiative (CITI). All new clinical research coordinators (CRC) must complete a foundational training program consisting of a two-day immersion workshop and interactive problem-solving focused on GCP standards, key CRC responsibilities, and research integrity. In June 2016 NYU created a six-hour course for principal investigators called “Principal Investigators Development and Resources” (PINDAR), discussed in detail below.

   1. Internal Quality Assurance Capacity

   NYU expanded its internal audit capacity by creating a central administrative office known as Human Research Regulatory Affairs (HRRA). HRRA included the IRB office and the new office responsible for quality assurance and quality improvement in NYU clinical research known as Research Regulatory Services (RRS). RRS added four new auditors, including a quality assurance/quality improvement manager, with a focus on proactively identifying and correcting any non-compliance.

   HRRA started to regularly conduct routine and directed audits. Studies were selected based on risk level, inclusion of vulnerable populations, rapid or high enrollment, new investigator or research coordinator, unlicensed physicians serving as principal investigators, multi-site coordination responsibility, etc. HRRA was required to conduct audits of studies conducted. pursuant to an Investigational New Drug (IND) or Investigational Device Exemption (IDE), or studies requiring IRB continuing review cycles of less than one year. Audit findings were categorized for administrative review, expedited review, or full board review. Audit reports were sent directly to the principal investigator, department/division chairs, and the IRB for further review. The RRS also assisted investigators with the development of corrective and preventive action (CAPA) plans for IRB review and approval. RRS also followed up with investigators to support compliance with the IRB-approved CAPA plans, including plans for re-audits.

   On July 13, 2020 OHRP wrote to NYU to determine whether the corrective action measures identified above have been effective in preventing additional HRPP problems, similar to the problems that emerged while the principal investigator worked at the NYU School of Medicine.

   On August 28, 2020 and Sept. 3, 2020, NYU provided additional information to OHRP as follows:

   “NYU Grossman School of Medicine continuously reviews and updates its HRPP policies to ensure that policies remain relevant, consistent with current requirements and best practices, and accessible to NYU’s research community. Please see Appendix A for a list of relevant policies that have been updated and/or implemented since 2017.

   NYU requires all study team members conducting human subjects research to complete extensive training in and to maintain certification related to human subjects’ protections, biomedical research requirements, and Good Clinical Practice (GCP) standards. Mandatory training is offered online, through the Collaborative Institutional Training Initiative (CITI), and is augmented by topic- and role-specific online, webinars, and live training sessions offered to researchers throughout the year.

   All new clinical research coordinators (CRC) complete a foundational multi-day immersion workshop that incorporates interactive problem-solving focused on GCP standards, key CRC responsibilities, and research integrity. Since 2018, more than 440 NYU clinical research coordinators have completed this course.”

   PINDAR, a training program developed in 2016, is still provided to first-time principal investigators conducting non-exempt human research. NYU officials stated:

   “The PINDAR course is also mandated for principal investigators who are required to complete training in fulfillment of an IRB-approved CAPA plan. PINDAR is accredited by TransCelerate as meeting the GCP education requirement, and PIs who complete PINDAR are certified for three years. Since 2018, more than 90 NYU clinical research principal investigators have completed PINDAR.

   NYU consistently reevaluates its current needs and specific research risk areas to determine appropriate staffing levels, and where HRPP staff, and, more specifically, the NYU HRPP’s dedicated RRS Audit Team resources and reviews, are most efficiently deployed at any given point in time. RRS works closely with NYU’s Institutional Official, as well as with the Legal, Compliance, and Internal Audit functions, to audit and monitor compliance with human subjects research regulatory and policy requirements. RRS also works with the IRB, researchers, and other stakeholders to educate and operationalize clinical research best practices.

   Until 2019, the RRS Audit Team maintained a staff of four full-time auditors who, in 2018, conducted 45 audits, of which 23 were routine and 22 were for-cause. In 2019, the RRS Audit Team began to focus on broader HRPP initiatives. In 2019, two full-time auditors conducted 11 audits, of which 6 were routine and 5 were for-cause. Further, RRS recently developed a CAPA “library,” which is used to ensure NYU’s uniform response to issues identified in audits and updated its internal audit tools and templates to reflect the revised Common Rule.”

   As a result of the RRS audit the following has made the following findings and determinations responsive to the specific areas identified in OHRP’s July 13, 2020 letter:

   • “RRS rarely identified problems with timely reporting of unanticipated problems (UAPs) and timely reporting of non-compliance.
   • RRS identified a small number of issues involving changes in protocols without IRB approval; examples include cases where: NYU employees were enrolled without prior IRB approval, the number of enrolled subjects exceeded the number approved by the IRB, there was failure to obtain prospective IRB approval of enrollment deviations, and there was performance of assessments not specifically identified in the approved protocol.
   • RRS identified a small number of issues with PIs’ failure to obtain documentation of informed consent as required by the Common Rule; examples include use of incorrect consent form versions, missing dates or signatures of study team, lost/misplaced consent forms, and infrequent cases of optional procedures conducted on subjects who had not opted-in to the research procedures.
   • RRS identified a small number of issues involving failure of PIs to follow protocol requirements, including audit findings around PI non-adherence to inclusion/exclusion criteria, incomplete, unsigned, or delayed signature of eligibility checklists; unreported protocol deviations; discrepancies between source, case report forms, and other study documentation; enrollment of subjects with unmet or undocumented eligibility criteria; and failure to conduct all protocol-mandated tests/procedures and/or study visits.”

   Additionally, NYU stated:

   “When any non-compliance impacting subject safety is discovered, this must be reported to the IRB Director and IRB Chair as immediately as possible, but, in all cases, within no more than one (1) business day of discovery of the issue.

   When any non-compliance with the potential of impacting subject safety is discovered, this must be reported to the IRB Director and IRB Chair within no more than one (1) business day of investigation conclusion (and such investigation must commence within no more than two (2) business days of discovery).

   Further, any audit with major findings of non-compliance and/or any for-cause audit must be reported to the IRB Director within no more than one (1) week of audit conclusion.
   Any routine audits with major findings of non-compliance must be reported to the IRB Director within no more than three (3) weeks of the audit conclusion.”

   Finally, OHRP asked:
   “For HHS-funded studies, does the IRB manage the reporting of events to OHRP that are required by the federal regulations at 45 CFR part 46?”

   NYU stated:
   “Yes. For HHS funded studies—and for other human subjects research events triggering reporting obligations, regardless of sponsor or funding—the IRB manages all regulatory reporting requirements of events to OHRP. The IRB also coordinates with other institutional stakeholders to timely report events as is required by state or Federal regulations, contracts with sponsors, and/or as NYU otherwise deems appropriate.”

V. Conclusion

OHRP has determined that the corrective actions implemented by NYU described in this letter adequately address the concerns identified during the 2015 OHRP site visit.

At this time, there should be no need for further involvement by our office in this matter. We appreciate your institution’s continued commitment to the protection of human research subjects.

Please do not hesitate to contact me should you have any questions.

Sincerely,
Lisa Buchanan, MAOM, CIP
Director
Division of Compliance Oversight

cc:
Ms. Helen Panageas, Human Protections Administrator, NYU
Dr. Tracy Waldeck, Director, Division of Extramural Activities, National Institute of Mental Health, NIH
Ms. Ann Meeker-O’Connell, Director, Office of Clinical Policy, Food and Drug Administration (FDA)
Dr. Quynh-Van Tran, FDA
Dr. Michelle Bulls, Director, OPERA, Office of Extramural Research, National Institutes of Health (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