September 7, 2022 - Leland Stanford Junior University

Dear Dr. Moler,

The Office for Human Research Protections (OHRP) conducted a not-for-cause virtual site evaluation of Leland Stanford Junior University’s (“Stanford”) Human Research Protections Program (HRPP) from August 24, 2021 through September 17, 2021. The evaluation was conducted as part of OHRP’s program to evaluate institutions and institutional review boards (IRBs) that review research receiving Department of Health and Human Services (HHS) support for compliance with 45 CFR part 46, as amended (“2018 Common Rule”).

This evaluation was conducted by an OHRP team of ten members and involved a review of study files for approximately 42 active HHS funded studies, IRB written procedures and checklists, IRB meeting minutes, and reliance agreements. The site visit team observed three IRB meetings that were held on August 24, 2021, August 27, 2021, and September 7, 2021, and were pleased to observe that continuing education was provided during the IRB meetings.

Multiple interviews were conducted with Stanford’s IRB officials, IRB Chairs, IRB members, researchers, Quality Assurance (QA) staff, and support staff with a variety of responsibilities that are key to Stanford’s HRPP operations. The IRB staff, members, and researchers we interviewed displayed a sincere commitment to the work of Stanford’s HRPP. We particularly noted the extensive engagement across multiple roles of the IRB support staff who serve as an essential resource to both the IRB members and researchers. We noted that there are multiple IRB staff vacancies, and that Stanford is adapting to a changing environment affected by the pandemic and is committed to re-staffing key positions.

The following concerns we expressed in our May 2, 2022 letter have been adequately addressed by Stanford; we note these are not violations of the HHS regulations at 45 CFR part 46:

Resolved Concerns

1. The 2018 Common Rule requires that for any clinical trial conducted or supported by a Federal department or agency, one IRB-approved consent form used to enroll subjects must be posted by the awardee or the Federal department or agency component conducting the trial on a publicly available Federal website after recruitment closes and no later than 60 days after the last study visit by any subject (45 CFR 46.116(h)). OHRP requested clarification of the process used by Stanford to ensure this regulatory requirement is satisfied.
   
   Response: According to your response, Stanford ensures consent form posting requirements are met in several ways, including reminders to the investigators from the IRB’s eProtocol system, reminders to the investigators from the School of Medicine office of Continuous Research Quality (CRO) and posting consent forms for cancer studies by the Cancer Clinical Trials Office on behalf of all Stanford Cancer Institute (SCI) investigators.

2. Based on our discussions with IRB members and staff along with our review of Stanford’s written procedures, it was unclear whether the IRB could distinguish which incident reports need to be submitted to the FDA, to OHRP, or to both agencies. OHRP requested an explanation of the process for reviewing and reporting incidents to OHRP.
   
   Response: According to your response, IRB members and staff follow Stanford’s HRPP Manual in Chapters 3.9, 3.10, and 3.11 regarding reporting incidents internally and to federal agencies such as OHRP. This policy is consistent with the 2011 Guidance on Reporting Incidents to OHRP. The IRB determines whether the incident occurred in non-exempt human subjects research and is an unanticipated problem involving risks to subjects or others, serious or continuing noncompliance, suspension, and/or termination of IRB approval. The HRPP Policy Manual has been updated to be more explicit about Stanford’s process for reporting incidents to OHRP.

3. During our evaluation, it appeared your processes were generally compliant with the 2018 Common Rule requirements. However, OHRP noted that Stanford’s IRB written procedures and guidance documents did not appear to reflect the 2018 Common Rule requirements, such as the waiver or alteration of consent requirements, the waiver of documentation of consent requirements, the reporting requirements, and the exempt research criteria.
   
   Response: Stanford has made the noted updates to the HRPP Policy Manual, guidance documents and the IRB’s eProtocol system to reflect the 2018 Common Rule requirements.

4. During the IRB meetings that OHRP observed, some discussions of risk appeared to rely on a “low, medium or high” risk categorization, the relationship of which was unclear to the Common Rule’s definition of minimal risk (45 CFR 46.102(j)). A similar observation was noted for assessments and documentation of risk within eProtocol.
   
   Response: According to your response, the low/medium/high designation that prompted OHRP’s question is intended for Stanford’s internal institutional purposes, such as categorizing the study in case Risk Management needs to understand the relative risk that a study might pose for institutional coverage and liability exposure. Furthermore, Stanford has updated its approval letters and eProtocol system to reflect terms consistent with the risk levels specified in the Common Rule.

5. During the records review, OHRP noted that the eProtocol system only allowed one regulation to be selected for a waiver of documentation of consent when more than one regulation may apply. For studies under both HHS and FDA’s jurisdiction, only the FDA regulation was selected.
   
   Response: According to your response, Stanford modified eProtocol to allow selection of applicable regulatory requirements waiving documentation of consent under both FDA and HHS regulations. This change allows clearer documentation that the determinations are in fact being made under the applicable regulations for both HHS and FDA.

6. The General Requirements for Informed Consent guidance document (GUI03C41) stated, “Common Rule general requirements, basic elements, and additional elements of consent do not apply to FDA regulated research because the FDA has not yet harmonized with the revised OHRP regulations at 45 CFR 46.” This could appear to be saying that the elements of consent in the revised Common Rule were not required for FDA regulated studies, even when the research is HHS funded or supported.
   
   Response: According to your response, Stanford updated this guidance document to reflect that Common Rule requirements for consent apply to FDA regulated studies that are also subject to the Common Rule.

7. During the records review, OHRP noted that Stanford was utilizing the short form consent process. However, OHRP was unable to locate documentation of IRB review and approval of the English text of short form.
   
   Response: According to your response, the Stanford IRB received training on the short form consent process and approved the English version short form at the 9/21/2021 convened meeting.

Recommendations

We make the following recommendations regarding Stanford’s human subject protection program:

1. During the records review, OHRP noted that many approval letters included FWA numbers for Stanford Hospitals and Clinic (SHC) (FWA00000934) and Leland Stanford Junior University (FWA00000935). OHRP was previously told by Stanford officials there is no human subjects research occurring under SHC FWA00000934. However, when both FWA numbers are included on approval letters, it gives the impression that each institution is engaged in the research.
   
   Response: According to your response, Stanford has determined that it would be appropriate, for clarity, to end the hospital FWA (FWA00000934). We recommend Stanford proceed to deactivate this FWA as indicated.

2. In general, OHRP found it challenging to reconstruct the history of a study and all communication between the IRB members, IRB staff, and investigators. In addition, many necessary documents including external communications, minutes, and agendas are kept outside of the eProtocol system (the IRB’s primary repository for study submissions and associated materials).
   
   Response: According to your response, Stanford has updated its HRPP Policy Manual to clarify that some IRB records and communications are retained under the eProtocol ID number in eProtocol. Some protocol information is also maintained on the secure server. Some examples of documentation maintained outside eProtocol include minutes, agendas, and external communications pertaining to reportable events. Stanford noted that it will continue to explore best secure computing practices for the storage and retrieval of confidential IRB documents. We recommend that Stanford consider organizing its IRB records to better reflect submissions and related IRB actions.

3. Based on OHRP’s review of Stanford’s IRB approval letters, some letters did not provide sufficient information about the submission that was approved by the IRB. For example, when the IRB approved a modification to a study, it was sometimes unclear to which modification the approval letter was referring. This communication process could lead to regulatory concerns regarding noncompliance if investigators need to piece together all approval information.
   
   Response: According to your response, the eProtocol system was updated to pull existing regulatory requirements in the eProtocol system into the IRB approval letters to enhance linking to corresponding submissions. We recommend that Stanford consider including more details about submissions in its IRB correspondences.

These responses adequately address OHRP’s concerns. At this time, there should be no need for further involvement by our office in this matter. Please notify us if you identify new information that might alter this determination.

We appreciate your institution’s continued commitment to the protection of human research subjects. Please feel free to contact me if you have any questions.

Sincerely,

Crystal M. Kelly, MPH
Compliance Analyst
Division of Compliance Oversight

cc:
Ms. Kathryn McClelland, Human Protections Administrator, Stanford
Ms. Winifred Meeker-O’Connell, Director, Office of Clinical Policy, FDA
Dr. Quynh-Van Tran, Center for Drug Evaluation and Research, 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