04/23/2024
Photo by CharlesDeluvio on Unsplash
On March 21, 2024 the Centre for Drug Evaluation and Research (CDER) of the US Food and Drug Administration (FDA) issued a warning letter to the New York State Psychiatric Institute (NYSPI) institutional review board (IRB). The FDA’s inspection resulted in six major observations, all of which occurred during convened IRB meetings.
The first five observations were all violations of 21 CFR 56.108(b) and 56.115(a)(6), the requirement for IRBs to prepare, maintain, and follow required written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the FDA.
In FDA regulated studies, the IRB’s written procedure details that instances of unanticipated problems involving risks to human subjects or others are to be reported by the IRB to federal officials following the IRB’s determination that such an instance fits the criteria. Generally, this reporting takes places within the following 7 to 10 days of the IRB’s determination, however, in more serious instances this reporting should be done within the following few days.
The following observations were related to the IRB not reporting to the FDA per the IRB’s written procedures.
21 CFR 56.108(b) and 21 CFR 56.115 (a)(6)
The NYSPI IRB determined that a serious adverse event (SAE) resulting in the death of a participant was considered an unanticipated problem involving risk to human subjects or others, which would require reporting within a few days per their written procedures.
The IRB determined that an Investigator’s enrollment of a participant who did not meet eligibility criteria and subsequent use of the investigational product taper procedure was a serious noncompliance.
The IRB determined another serious noncompliance by an Investigator related to medication tapers being conducted without being part of an IRB approved protocol.
The IRB determined both a serious and ongoing noncompliance from an Investigator. The Investigator:
did not report an SAE to the IRB.
was not consistently establishing or documenting subject eligibility.
was not conducting all required assessments.
as observed in the previous monitoring report, was missing dates/identifiers in their documentation making this noncompliance ongoing.
The fifth observation is a regulatory responsibility for the IRB to report to the FDA per 21 CFR 56.108(b)(3) & 21 CFR 56.113. The IRB suspended IRB approval on FDA-regulated research activities but did not report this to the FDA.
The sixth observation was a violation of 21 CFR 56.108(c), the requirement that at convened IRB meeting, during which FDA-regulated proposed research is reviewed, a majority of the IRB members must be present including at least one member whose primary concerns are in nonscientific areas.
During a full IRB meeting, the member of the IRB whose primary concerns are in nonscientific areas left and was replaced by a member whose primary concerns are in scientific area.
The NYSPI IRB’s response acknowledged their mistakes and stated that they had re-educated the IRB staff and Co-chair on the requirements for IRB reporting to the FDA and are updating the procedures and policies to meet the requirements of the listed CFRs for the first 5 observations. They also stated that going forward the IRB roster would identify the nonscientific members in bold font to prevent another reoccurrence of the sixth observation. However, the FDA determined the IRB’s response was inadequate since they did not provide a corrective or preventive action plan for any of the observations. Furthermore, sufficient details on the procedures and policies they were proposing to develop was not provided, or how the IRB chair would ensure that the required members are present when reviewing proposed FDA-regulated research in the future.
The full warning letter can be found on the FDA website. FDA warning letters to IRBs are relatively rare compared to investigator warning letters (examples can be found in our previous blogs from 8/17/2021, 2/1/2022, and 7/5/2022). However, IRB warning letters are not unheard of, in 2023 a different IRB received a letter for the similar reason of reviewing FDA regulated research without a nonscientific member present (see our blog on this warning letter here). The response, also similarly, did not contain a corrective action plan and therefore could not be fully evaluated by the FDA.
The NYSPI IRB did not follow their written procedure on multiple accounts by not reporting the CFR violations to the federal officials. The first listed observation was particularly egregious where not only was the death of a participant not reported but the IRB was aware of the event and determined it to be an unanticipated problem involving risk to human subjects or others. Furthermore, by not providing an adequate response about how the IRB would prevent the observations from recurring, this may influence the FDA’s decision on whether the NYSPI IRB should be allowed to continue to oversee clinical studies in the future.
- The Clinical Pathways Team
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