Ea Annual Review Notes Of Guidance

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Liliane Hubright

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Aug 3, 2024, 10:19:18 AM8/3/24

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Scope: This guidance document applies to research involving human subjects that is conducted or supported by HHS. It provides guidance on the HHS regulations for the protection of human research subjects at 45 CFR part 46 related to institutional review board (IRB) continuing review of research. In particular, the guidance addresses the following topics:

Target Audience: IRBs, investigators, HHS funding agencies, and others that may be responsible for the review, conduct, or oversight of human subjects research conducted or supported by HHS.

This guidance is intended to assist IRBs in carrying out their continuing review responsibilities under 45 CFR part 46 by providing recommendations regarding, among other things, the approval criteria, process, and frequency for continuing review to assure the protection of the rights and welfare of human subjects participating in research. The guidance also is intended to help investigators and others involved in the review, conduct, or oversight of research better understand their responsibilities related to continuing review.

It also may be appropriate for the IRB at the time of continuing review to confirm that any provisions under the previously approved protocol for monitoring the research data to ensure safety of subjects (45 CFR 46.111(a)(6)) have been implemented and are working as intended (e.g., the IRB could require that the investigator provide a report from the monitoring entity described in the IRB-approved protocol).

At the time of continuing review, the IRB should review a copy of the sample informed consent document submitted by the investigator to verify that the investigator is using the most recently approved version and that the document contains the most accurate, up-to-date information about the research. OHRP recommends that IRBs consider using methods that will allow the IRB to readily recognize the most current version of the IRB-approved informed consent document, for example, using date stamps, version numbers, or initialing and dating documents to indicate when a version was approved.

Likewise, if the IRB waived the requirement for the investigator to obtain a signed consent form for some or all subjects (45 CFR 46.117(c)), the IRB should assess the accuracy of the content of the information being provided to subjects orally and of any written statement regarding the research that is being provided to subjects.

When reviewing an informed consent document, the IRB must ensure that the currently approved or proposed consent document adequately addresses the elements of informed consent required under 45 CFR 46.116(a) and (b). The IRB should be particularly attentive to whether the informed consent document provides an accurate and up-to-date description of the reasonably foreseeable risks and discomforts of the research to the subjects (45 CFR 46.116(a)(2)) and any appropriate alternative procedures or courses of treatment that might be advantageous to the subject (45 CFR 46.116(a)(4)).

The IRB should confirm that the information provided by the investigator at the time of continuing review is consistent with the research protocol previously approved by the IRB. If this information suggests that the investigator is not conducting the research in accordance with either the IRB-approved protocol or the requirements or determinations of the IRB, the IRB should either defer re-approving the research or re-approve the research for a limited period of time (e.g., one month) and seek an explanation from the investigator regarding the apparent discrepancies.

As part of its initial review of a research project, the IRB typically will have approved a protocol that includes the expected total number of subjects to be enrolled by the investigator and the expected rate of enrollment. Evaluating information about the number of subjects enrolled in the research at the time of continuing review may allow the IRB to ascertain whether enrollment is consistent with the planned number of subjects described in the IRB-approved protocol. A marked difference between the actual and expected rates of enrollment may indicate a problem with the research project that requires further evaluation, including whether the research project is likely to provide sufficient data to answer the scientific question(s) being posed.

IRB review of this information may shed light on problems related to the conduct of the research. For example, a high rate of subject withdrawal secondary to serious adverse events may indicate that the risks of the research are greater than expected and may lead the IRB to conclude that the research should not be approved for continuation because the risks to subjects are not being minimized or are not reasonable in relation to the anticipated benefits to the subjects and the importance of the knowledge that may reasonably be expected to result (45 CFR 46.111(a)(1) and (2)).

Continuing review must take place at a convened meeting at which a majority of the IRB members are present, including at least one member whose primary concerns are in nonscientific areas, unless the research qualifies for review under an expedited review procedure (45 CFR 46.108(b)). In order for research undergoing continuing review to be approved by the IRB at a convened meeting, it must receive the approval of a majority of those members present at the meeting (45 CFR 46.108(b)). Should the quorum fail during a meeting (e.g., loss of a majority through exclusion (i.e., recusal) of members with conflicting interests or early departures of members, or absence of a nonscientist member), the IRB may not take further actions or votes for research projects undergoing continuing review unless the quorum can be restored (45 CFR 46.108(b)).

For each research project undergoing continuing review, the minutes of IRB meetings must be in sufficient detail to show actions taken by the IRB; the vote on these actions, including the number of members voting for, against, and abstaining; the basis for requiring changes in or disapproving the research; and a summary of the discussion of controverted issues and their resolution. (45 CFR 46.115(a)(2)). OHRP recommends that the recusal of IRB members because of a conflicting interest also be documented when recording votes on IRB actions. The following examples demonstrate one acceptable format for documenting in the minutes the votes on actions taken by the IRB on research projects undergoing continuing review:

When continuing review of research is conducted under an expedited review procedure, the review must be conducted by the IRB chairperson or one or more experienced reviewers designated by the IRB chairperson from among the IRB members (45 CFR 46.110(b)). The IRB must have procedures in place to ensure that no IRB member participates in the expedited review of research in which the member has a conflicting interest, except to provide information requested by the chairperson or his/her designee(s) (46 CFR 46.107(e)). The IRB chairperson or IRB members designated by the chairperson only can approve or require modification in (to secure approval of) research, but may not disapprove research using the expedited procedures (45 CFR 46.110(b)). Disapproval of a research project at the time of continuing review can only occur after review by the IRB at a convened meeting, not by the expedited review process. All IRB members must be advised of research that has been approved under an expedited review procedure (45 CFR 46.110(c)).

In developing procedures for continuing review, the IRB might consider use of templates, checklists, or other tools to standardize the request for information or list of materials to be provided to the IRB by investigators at the time of continuing review.

An IRB that is conducting continuing review of research should be familiar with, and have access to, all IRB records related the research, including those associated with the initial review and approval and any other previous reviews, including ad hoc and scheduled continuing reviews and any reviews of amendments to the research or unanticipated problems. For continuing review of research at a convened meeting, IRB members should receive appropriate materials sufficiently in advance of the meeting to allow adequate time for review.

When conducting continuing review of research under an expedited review procedure, the IRB chairperson (or designated IRB member(s)) should receive and review copies of the progress report described in the preceding section, the current IRB-approved informed consent document, and any newly proposed consent document, and have available, for review as needed, all of the above-referenced documentation, including the complete IRB protocol file.

Appropriately trained IRB staff members, regardless of whether they are members of the IRB, may perform preliminary reviews of continuing review documents and complete IRB files in order to facilitate the continuing review of research by the IRB. As part of this preliminary review, IRB staff may perform the following functions, among others:

IRB staff members who are not IRB members may not be delegated responsibility for making the determinations that must be made by the IRB at the time of continuing review (see sections B, C.1 and C.2 above) and may not approve research on behalf of the IRB (45 CFR 46.109).

The amount of time the IRB spends on the continuing review of a particular research project at a convened meeting will vary depending on the nature and complexity of the research, the amount and type of new information presented to the IRB by the investigator, and whether the investigator is seeking approval of substantive changes to the research protocol or informed consent document. For many research projects, continuing review can be fairly straightforward, and the IRB should be able to complete its deliberations and approve the research within a brief period of time.

In the absence of any concern about the research being raised by the IRB member assigned to be the primary reviewer or by any other IRB member present at the IRB meeting, the IRB should be able to complete its continuing review deliberations for such a research project within a brief period of time. In this example, deliberations that included the following brief series of steps would be sufficient: