Approved July 21, 2022
Background
On June 21, 2016, the National Institutes of Health (“NIH”) issued a policy requiring single institutional review board (“IRB”) review for multi-site research funded by the NIH. This policy became effective January 25, 2018. A Final Rule was issued on January 19, 2017, revising the Federal Policy for the Protection of Human Subjects in Research (“Common Rule”), and this revision also included a requirement of single IRB review for federally funded multi-site research1 with a compliance date of January 20, 2020. 45 C.F.R. 46.114.
The revised Common Rule provides for two exceptions for the requirement of single IRB review:
(i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or
(ii) Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.
In response to a request from the Office for Human Research Protection (“OHRP”) that the HHS Secretary’s Advisory Committee on Human Research Protection (“SACHRP”) advise on the criteria that departments and agencies might consider when determining that a single IRB is not appropriate for particular context under 45 C.F.R. 46.114(b)(2), SACHRP adopted relevant recommendations, “Attachment D – Granting Exceptions or Single IRB Review for Multi-Site Research,” on March 13, 2018 (Exhibit A).
Discussion
SACHRP is pleased that OHRP is considering publishing additional guidance on the use of single IRB review, “Use of Single Institutional Review Board for Cooperative Research” (“Draft Guidance”), and below, SACHRP offers its commentary and recommendations for OHRP’s consideration.
There are two key historical considerations surrounding IRB infrastructure. First, IRBs were established to function as ethics review committees within an institution, which most often have close ties to the community where the institution is located, and IRB members typically are very knowledgeable of the local context and local community values that should inform an IRB’s consideration of proposed research. Further, an institution-based IRB is often very familiar with the institutional infrastructure and the research practices of specific institutional investigators. Institutional IRBs often have repeated interactions with each of the institution’s investigators and thereby are well-positioned to keep track of any ongoing institutional needs with respect to ongoing studies (e.g., the need for increased human research training or enhanced research monitoring).
Second, institution-based IRBs are well-situated to monitor any local study-related concerns and to investigate protocol deviations and adverse events. Although there are variations in the compliance infrastructure at each institution, an institutional IRB most often has immediate access to investigators, research team members, and study records, allowing the IRB immediately to investigate problems in the conduct of research and to resolve and remediate the issues.
Such historical considerations underlie the groundwork for the IRB review infrastructure and illustrate the strengths that can characterize an institution-based IRB. This is not to say that a central, or single, IRB would be unable to achieve the same advantages, but to do so requires forethought and constructive engagement with institutions that have ceded review to that single IRB. It is in these respects that, SACHRP submits, the proposed guidance offered by OHRP in its current form lacks specificity and offers inadequate assistance to single IRBs seeking to achieve the twin goals of (1) being informed by local conditions and attitudes and (2) being equipped readily to find facts regarding serious problems in study conduct. The draft guidance, in its present form, also lacks any indication of appropriate processes that could be followed by single IRBs and their relying institutions regarding how to resolve differences in judgment about essential features of a proposed study.
Local Context
The revised Common Rule provisions pertaining to single IRB review in cooperative research already acknowledge the importance of accounting for local context in specific circumstances. First, the single IRB requirement set forth in 45 C.F.R. 46.114(b) applies only to institutions located in the United States and not to any international institutions, presumably at least in part because of complexities in ensuring a central U.S.-based IRB’s adequate knowledge of local contexts. Second, the revision incorporates an exception under 45 C.F.R. 46.114(b)(2)(i) for research governed by tribal law (i.e., passed by the official governing body of an American Indian or Alaska Native tribe).
Acknowledging therefore that OHRP, in revising the Common Rule, was aware of the importance of specific local contexts, SACHRP recommends that the Draft Guidance should include additional commentary on how a single IRB ought to take local context into account and when the local context should prevail as a determinant in the approval decision for a proposed study. For example, in a multi-site social behavioral study on psychological counseling interventions for transgender teenagers, the issues and implications likely are to differ substantially in a city or state whose population heavily favors more traditional gender roles and where access to resources is limited, when compared to a community with a high level of acceptance of gender diversity and greater availability of support services. The scenario is further complicated if the study is to occur simultaneously in multiple locations with widely varying community standards. Issues of how to recruit, how to obtain consent, how to gain parental consent, how to respond to participant distress (particularly for those in communities with limited support services) – the appropriate resolution of these and other issues may differ among the study locations. The Draft Guidance is an opportunity to elaborate further on whether the IRB should approve such a study for some communities and require further adaptations or protections in other communities. This would be consistent with the revised Common Rule and with the values embodied in the existing specific exceptions to single IRB review.
SACHRP cautions against an emphasis on relying on the IRB’s diversity in membership to assess the local context. Section A.8. of the Draft Guidance states that the single IRB may rely on the diversity of its membership to consider the local context (e.g., race, gender, cultural background, and sensitivity to issues such as community backgrounds). However, as demonstrated by the above scenario (i.e., the single IRB is reviewing a multi-site study on transgender teenagers in multiple communities with significant variations in acceptance and support services among those communities), it is unlikely that any single IRB can expect the representativeness of its own membership to reflect sufficiently the diversity of each conceivable study and study site.2 Nonetheless, SACHRP agrees that the relying institution can and should, as a matter of course, provide to the single IRB additional information regarding the local context. This might be done by, among other things, the single IRB’s utilizing its own standardized “local conditions” form to solicit a consistent set of “local conditions” information from relying sites.
Local Site Review and Approval
SACHRP would like to emphasize the distinction between IRB review of a research study and review by the relevant components of an institution’s human research protection program (“HRPP”). At large institutions, an HRPP may consist of various regulatory, compliance, or training functions (e.g., departmental units that monitor and audit ongoing research, services to assist researchers with preparing regulatory submissions, or institutional approval requirements for research that are in addition to IRB review). Although there are variations in each institution’s HRPP, including in infrastructure and processes, the IRB review process is only a subset of activities within a research institution’s HRPP. The Draft Guidance reference to relying institution IRBs reviewing studies whose approval is actually in the jurisdiction of a single IRB is misplaced, and ideally, not local IRBs, but local HRPPs, should perform the “review and advise” function. SACHRP recommends that the Draft Guidance refrain from advising that institutions may conduct additional internal IRB review, but instead leave to the research institutions any decision about conducting any additional local IRB and/or HRPP review for a study with a single IRB. Further, SACHRP recommends that the guidance be amended to include mechanisms for resolving differences in judgment between the single IRB and the relying institution on critical features of a proposed study. SACHRP would suggest, for example, that in cases of such disagreement, there be a colloquy between those entities, including in that discussion the lead PI and site PI. In extreme circumstances, a relying institution that disagrees with important features of a protocol or with the single IRB’s judgment regarding that protocol has the option of not being a site in the study or requesting an exception to the single IRB requirement to allow for local review and modifications as appropriate.
Advising that relying institutions may conduct additional internal IRB review will likely undermine and conflict with the overall recommendation that institutions should aspire to use a single IRB review process to the extent it is feasible and that it sufficiently protects the welfare of research participants. The Draft Guidance should instead advise that purely duplicative IRB review is inconsistent with best practices, with some exceptions (e.g., in situations where local community values or risk concerns warrant review by the institutional IRB) and runs counter to intent of the single IRB requirement.
SACHRP recommends using this Draft Guidance as an opportunity to delineate the respective roles of the single IRB and the role of the relying institution’s HRPP. Guidance can emphasize the benefits associated with the local HRPP’s providing information at the time the single IRB conducts its initial review of a protocol. In most cases, for example, the relying institution’s HRPP will be familiar with its research personnel and institutional resources and will be able to offer this information to the single IRB that is responsible for reviewing and approving the research.
Compliance Investigations at Local Sites
OHRP should clarify what role single IRBs are to play when issues in study conduct arise requiring further investigation and which responsibilities should be reserved to the institution’s HRPP. In general, SACHRP recommends that reliance agreements should make clear that a single IRB must have the authority to investigate local study issues and to receive relevant documentation. Ideally, the relying HRPP would direct, or if it wishes, collaborate, with the single IRB in the fact-finding in these cases, but if the relying HRPP declines to do so, or unduly delays doing so, the single IRB must have the authority to fulfill its mission by making a factual determination about possible noncompliance, and should have access to witnesses to do so, hopefully with the involvement of the relying HRPP and its legal counsel The Draft Guidance should also identify the circumstances under which the single IRB should give advance notice to the relying HRPP of problems at that site before they are reported to a federal or accreditation agency. The guidance should also delineate the responsibilities of reporting to government agencies in the case of a reportable event (i.e., whether the responsibility falls on the single IRB, the relying site HRPP, or both). Providing institutions with recommendations on each party’s responsibilities will help promote coordination and accuracy, prevent duplicated reporting to government agencies, establish a standard industry expectation, and prevent confusion amongst the various parties involved.
Unfunded Collaborators
OHRP also should include guidance regarding how the single IRB requirement should apply to unfunded research collaborators. The single IRB likely will encounter scenarios in which some sites are funded or supported by a federal agency and others are not. Section A.4. of the Draft Guidance notes that institutions conducting research not subject to 45 C.F.R. 46.114(b)(1) may enter into a single IRB arrangement. However, OHRP should expand upon this guidance to clarify the expectations with regard to single IRB review when different sites might have different sources of funding – i.e., whether single IRB review must be used for all sites whenever one collaborator is supported or funded by a federal agency, or if the single IRB review requirement applies only to the subset of collaborators that are funded or supported by a federal agency. In SACHRP’s view, a reasonable approach to this issue would be to allow the single IRB requirement to apply to a study when the lead site in the study is supported in the research activity by federal funds. Importantly, funders or sponsors of a study, whether federal or non-federal, might require, as part of grant or contract terms or conditions, that a single IRB be used for the funded study.
Compliance with Local Laws
SACHRP encourages OHRP to offer more commentary regarding the party that ought to be responsible for reviewing and ensuring that a given research study’s design and implementation is consistent with local laws. The Draft Guidance emphasizes in Section A.9. that the single IRB must have the ability to assess local laws that are relevant to the required IRB determinations under 45 C.F.R. 46.111. However, it stops short of delegating to any entity or party the responsibility for assessing and reviewing local laws.
One example of local laws relevant to IRB determinations is state privacy laws. In some circumstances, these new laws can also affect research processes and the rights and protections of research participants. Various states have enacted new, comprehensive privacy legislation that create new obligations and rights for state residents. The California Consumer Privacy Act went into effect in 2020, and several states, such as Colorado, Virginia, Utah, and Connecticut, each have enacted unique privacy legislation that will each take effect in 2023. A single IRB likely will need a proper assessment of state privacy laws to ensure that a study has adequate processes in place to protect the privacy of subjects and to ensure that any informed consent statements pertaining to the collection and use of private information is proper, as required under 45 C.F.R. 46.111(7) and 45 C.F.R. 46.116(b).
The Draft Guidance should elaborate further on the single IRB’s responsibility and the scope of that responsibility with regards to assessing state and local laws applicable to the research it reviews and approves. Ultimately, the single IRB should seek to review local law information from relying sites’ HRPPs and from site investigators, but at the end of the day, the single IRB is approving the research and must take some responsibility for ensuring that the study approved may be conducted lawfully, or must expressly impose that burden on the relying HRPP – including with reference to applicable state and local laws.
To assist single IRBs, as well as investigators who are planning multi-site studies using federal funding, SACHRP recognizes that a useful resource – whether supported by private or public funds, or both – would be a compilation, with updates with a defined periodicity, of a set of the state and local laws inside the U.S. that should be of most concern in domestic human subjects research. Such a compilation would need to be narrowly defined, in order even to be feasible, and could not cover all permutations of research design and subject matter. SACHRP recognizes the enormity of this task and the difficulty of creating and maintaining a listing of all laws that are relevant to IRB determinations under 45 C.F.R. 46.111. Nonetheless, given the regulatory requirements for single IRB review, such a resource is advisable, for the same reasons that OHRP now maintains such a resource for trans-national research.
Exception Criteria
SACHRP also recommends that OHRP should consider offering in the Draft Guidance, additional criteria for exceptions to the single IRB requirement. In its 2018 recommendations (Exhibit A), SACHRP recommended the following categories as potentially appropriate exceptions to the single IRB requirement, any one of which would be an appropriate exception to the single IRB requirement:
- Research involving five or fewer sites
- Research for which review by a single IRB is unable to meet the needs of specific populations
- Research involving political, controversial or sensitive issues such that review by local IRBs would better address those concerns.
When a research study involves a small number of sites, there may be occasions where single IRB review increases the complexity of the initial review and the subsequent oversight. In such scenarios, using a single IRB review process might only lead to marginal increase in efficiency, but without a significant improvement in research participant protection.
In many cases, and as discussed above, a local institutional IRB likely is better positioned to ensure the welfare and protection of subjects—especially when there are special needs of the subject population or when the research topic involves political, controversial, or sensitive issues. As a matter of process, both the investigator proposing the study, as well as their institution’s HRPP or IRB, and in consultation with other proposed sites, first could assess whether such an exception is indicated for one or more sites in the study. If it is determined to be so indicated, then the prime awardee institution should be the entity to request that the exception be allowed by the cognizant funding agency. Such an exception might, for example, be included in the investigator’s grant application.
Conclusion
SACHRP continues to support the goals of single IRB review for multi-site research in improving efficiency and protecting human subjects in research. SACHRP therefore recommends that OHRP’s Draft Guidance delineate more precisely the elements noted above to account for the local context, monitoring and oversight, multi-site research with various funding sources, compliance with local laws, and other possible exceptions to the single IRB review requirement.
Exhibit A
Attachment D - Granting Exceptions for Single IRB Review for Multi-Site Research
SACHRP recommendation approved March 13, 2018
Points to Consider: Granting Exceptions to Requirements
for Single Institutional Review Board Review for Multi-Site Research
Introduction
Recent initiatives, geared towards both improving efficiency as well as better protecting human subjects in research, have focused on a requirement for single Institutional Review Board (sIRB) review of multi-site research. On June 21, 2016 NIH issued a policy requiring single IRB review for multi-site research funded by the National Institutes of Health, which became effective January 25, 2018. Revisions to the Federal Policy for the Protection of Human Subjects in Research (commonly referred to as the “Common Rule”) were issued as a Final Rule on January 19, 2017, including a requirement of single IRB review for federally funded multi-site research slated to take effect January 20, 2020. At the present time, there is no existing or pending FDA regulation requiring single IRB review of FDA regulated multi-site research.
Exceptions to the Requirement for Single IRB Review of Multi-Site Research
Both the NIH policy and the Final Rule permit certain exceptions to the requirement for single IRB review.
The NIH policy provides:
Exceptions to this policy will be made where review by the proposed sIRB would be prohibited by a federal, tribal, or state law, regulation, or policy. Requests for exceptions that are not based on a legal, regulatory, or policy requirement will be considered if there is a compelling justification for the exception. The NIH will determine whether to grant an exception following an assessment of the need.
The provision in the Final Rule states:
(i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or
(ii) Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.
The Final Rule permits the Federal department or agency discretion in requiring single IRB review of multi-site research but does not include the language in the NIH policy that refers to a “compelling justification for the exception.”
Request from OHRP
OHRP has requested that SACHRP consider the criteria that departments and agencies might consider when determining that single IRB review is not appropriate for a particular context in accordance with ___114 (b)(2)(ii) of the Final Rule. OHRP noted that the NPRM utilized the word “study” for this exception, but that the word “study” was changed to “context” in the Final Rule. This topic has been discussed in depth at several SACHRP subcommittee meetings as well as at two SACHRP meetings, and the committee has repeatedly struggled with the intrinsic variability of study designs and populations, and the difficulty of establishing clear criteria which could unambiguously determine the appropriateness of single IRB review. As an alternative, the committee determined that a Points to Consider guidance document would better capture the complexity of the “context” that should determine whether or not single IRB review would decrease regulatory burden while preserving or enhancing participant protections.
Discussion
In comments offered on the proposed revisions to the Common Rule, SACHRP opined on the use of a sIRB in multi-site research and suggested the following exceptions:
- review by a single IRB is unable to meet the needs of specific populations,
- where local IRB review is required by federal, tribal or state laws or regulations,
- research that does not meet the definition of clinical trial,
- research that is not federally funded research,
- research with fewer than 5 sites, and,
- where the funding agency determines that single IRB review is not appropriate.
Two of these suggestions were included in the NIH policy and the Final Rule, which both allow exceptions to the single IRB requirement where local IRB review is required by federal, tribal or state laws or regulations, as well as where the funding agency determines that single IRB review is not appropriate. A third suggestion offered by SACHRP goes without saying: if research is not federally funded, it would not be subject to the Common Rule or NIH policy. After re-review of the proposed exceptions, SACHRP also believes that there is no reason to exempt research that does not meet the definition of clinical trial.
Of the remaining two exceptions previously suggested by SACHRP, we recommend that both continue to be considered. There may be occasions where single IRB review for a particular study involving fewer than five sites could increase the complexity of initial review and ongoing oversight without improving participant protections, and whenever a single IRB is unable to meet the needs of specific populations, additional IRB review should be permitted.
There was considerable discussion at SACHRP as to whether the inclusion of vulnerable populations in research also constituted a distinct reason to except research from the single IRB review requirement. Ultimately, the consensus is that single IRB review may be appropriate even for research with vulnerable populations, and when it is not, this can be captured under the exception for circumstances in which the IRB is unable to meet the needs of specific populations.
These two considerations – number of sites and specific population needs – are demonstrated in the following examples:
1. Research involving surgical placement of a deep brain stimulator in patients with OCD who are treatment refractory, drawn from a single site and evaluated by psychiatry at that site for capacity to consent, treatment refractoriness, and follow-up, with surgery conducted at a different location. Given different research activities at each site, each site’s IRB may be best suited to conduct its own review. In addition, with only two sites, the logistics of organizing single IRB review may be inefficient and unnecessary for participant protection. Exception from the single IRB review requirement would be acceptable in this context.
2. Research that involves an intervention with pregnant women at one site and then follow–up with the neonates at another. Unless a single IRB had adequate expertise in pregnant women, obstetrical practices, and neonatal medicine, human subject protections might best be served by having the elements relevant to pregnant women reviewed by an IRB that has extensive expertise with that area and the elements relevant to the neonates reviewed by a pediatric IRB.
3. A study conducted at multiple sites including both children and adults. For the same reasons as above, it may be most protective of subjects to have inclusion of children reviewed by a separate IRB that is completely pediatric focused. Exception from the single IRB review requirement would be acceptable in this context, as well.
These examples illustrate the difficulty of establishing exception criteria, rather than points to consider. In each of the examples above, a single IRB could also augment its review expertise through the use of consultants and local experts. Thus, the consideration of whether or not single IRB review is appropriate must take into account the full context of the proposed research, including the capabilities and flexibility of the proposed single IRB.
1. In this regard, SACHRP has considered the change from the word “study” in the NPRM to the word “context” in the Revised Common Rule as requested by OHRP. The word “study” means an investigation or analysis of a subject or situation; while the word “context” means “the circumstances that form the setting for an event, statement, or idea, and in terms of which it can be fully understood and assessed.” The use of the word “context” therefore supports consideration of the background, circumstances and factors that more broadly may surround a research study.
2. Accordingly, SACHRP recommends that it would be appropriate to include a third type of exception to the single IRB review requirement, for research that involves political, controversial or sensitive overtones or issues, such that review by local IRBs would better address these concerns or be perceived to better address local sensitivities. The institution would need to present a case that unique political or controversial issues, values or sensitivities warrant review by that institution’s IRB to provide adequate subject protections and that review by an outside IRB would be inappropriate. For example, research involving medical marijuana might best be reviewed by individual IRBs that can best attend to local concerns and attitudes. Another setting in which strong consideration might be given to providing an exception to the single IRB requirement is emergency research studies conducted under the FDA Exception from Informed Consent requirements. Such studies require intensive engagement with the community that might best be performed by a local IRB.
Conclusion
SACHRP supports the goals of single IRB review for multi-site research in improving efficiency and protecting human subjects in research. However, where those goals will not be satisfied by single IRB review, exceptions are appropriate. SACHRP therefore recommends that HHS consider the following categories as potentially appropriate for exception to the single IRB review requirement:
1. Research involving 5 or fewer sites;
2. Research for which review by a single IRB is unable to meet the needs of specific populations; and
3. Research involving political, controversial or sensitive issues such that review by local IRBs would better address those concerns.
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1. 45 C.F.R. 46.114. Note that U.S. Food and Drug Administration (“FDA”) regulations permit multi-site research under its jurisdiction to be reviewed by a single IRB. At the present time, there is no existing or pending FDA regulation requiring single IRB review of FDA-regulated multi-site research.
- back to note 1 2. It is even difficult for an institution-based IRB to have sufficient membership diversity to ensure it can assess local conditions and attitudes for every study it considers. This problem is only magnified in the single IRB paradigm.
- back to note 2
