Approved October 19, 2022 On September 28, 2022, the U.S. Food and Drug Administration (“FDA”) issued two Notices of Proposed Rule Making to harmonize FDA’s regulations pertaining to human subjects research (the “HSR NPRM”)1 and the review of cooperative research by a single institutional review board (“IRB”) (the “sIRB NPRM”)2 with those of the Federal Policy for the Protection of Human Subjects (the “Common Rule”). In 2018, U.S. Department of Health and Human Services Secretary’s Advisory Committee on Human Research Protection (“SACHRP”) had commented and provided its recommendations on single IRB review.3 In 2022, SACHRP followed up with a second set of recommendations, in response to a request from the Office for Human Research Protection (“OHRP”) that SACHRP advise on the criteria that departments and agencies might consider when determining that a single IRB is not appropriate for the particular human subjects research context under 45 C.F.R. Section 46.114(b)(2).4 This document presents SACHRP’s recommendations in response to FDA’s request for comments in the sIRB NPRM. SACHRP’s Response to FDA’s Request for Comment “FDA is requesting comment on whether it is appropriate to include an exception for cooperative research for which use of a single IRB is unable to meet the needs of specific populations.” 87 Fed. Reg. 58,759. SACHRP believes it would be appropriate to include an exception for cooperative research for which a single IRB is unable to meet the needs of specific populations, although there should be a high standard applied to enable access to this exception, so that the exception does not become so heavily used that it undermines the efficiencies of a single IRB mechanism. A local, institutional IRB may be better positioned to ensure the welfare and protection of subjects, such as when there are special needs of the subject population or when the research topic involves political, controversial, or sensitive issues. For example, in a multi-site study on pre-exposure HIV prophylaxis for adolescent men who have sex with men (including transgender women), the issues and implications likely are to differ substantially in a city or state whose population heavily favors more traditional gender roles. In such communities, access to resources and support services is likely more limited when compared to a community with a higher level of acceptance of diversity in sexual orientation and gender. The scenario is further complicated if the study is to occur simultaneously in multiple locations with widely varying community standards. The appropriate resolution 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) and other issues may differ among the study locations. Further, FDA’s incorporation of an exception for which the single IRB is unable to meet the needs of specific populations would be consistent with the Common Rule’s single IRB review exceptions and the values embodied in those exceptions. The sIRB NPRM and revised Common Rule provisions pertaining to single IRB review in cooperative research acknowledge the importance of accounting for local context in specific circumstances. The sIRB NPRM incorporates two elements that harmonize with the revised Common Rule: (1) application of the single IRB review requirement only to sites located in the U.S.5; and (2) an exemption from single IRB review if “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).”6 This presumably is at least in part to account for complexities in ensuring an IRB’s adequate knowledge of local contexts and requirements of local laws. FDA’s adding an exception for which the single IRB is unable to meet the needs of specific populations would be consistent with and in furtherance of this purpose. SACHRP recommends that any single IRB requirements should not erase the historical goal of IRBs making decisions informed by local conditions and attitudes. IRBs were established initially 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. 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. “We request comment on whether a single IRB of record would generally be able to supplement its members’ knowledge and experience with additional information or expertise to account for these situations, examples of FDA-regulated research for which these circumstances would apply, and any data on the frequency of how often this situation may occur.” 87 Fed. Reg. 58,759. SACHRP notes that current FDA regulations and the Common Rule (even prior to its being revised in 2017) have provisions permitting an IRB to invite individuals with competence in special areas to assist in the review of issues that require expertise beyond or in addition to that available on the IRB.7 Inviting expert consultants to supplement its members’ knowledge is a common and long-standing practice among central/single and local institutional IRBs. Under the HSR NPRM, IRBs will be able to continue this practice and supplement their knowledge with additional information or expertise.8 However, SACHRP believes that the long-standing practice of inviting a small number of experts for consultation cannot replace a specialized IRB (i.e., an entire committee of experts); for example, in a clinical trial involving intervention with pregnant women at one site and then follow-up with the neonates at another. Unless a single IRB has 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 a specialized IRB that has extensive expertise with that area, and the elements relevant to the neonates reviewed by a specialized pediatric IRB. Similarly, another example would be in a clinical trial involving surgical placement of a deep brain stimulator in patients with obsessive compulsive disorder who are treatment refractory, drawn from a single site and evaluated by psychiatrists at that site for capacity to consent, treatment refractoriness, and follow-up, with surgery conducted at a different location. Given the vastly different research activities conducted at each site, each site’s IRB may be best suited to conduct its own review of this research. In addition, with only two sites, the logistics of organizing single IRB review may be inefficient and unnecessary for participant protection. Accordingly, an exception from the single IRB review requirement would be appropriate in this context. “FDA is also requesting comment on including an exception for cooperative research with a small number of investigational sites. SACHRP recommended that research involving five or fewer investigational sites should be considered as potentially appropriate for exception to the single IRB review requirement.” 87 Fed. Reg. 58,759. SACHRP supports the goals of single IRB review for multi-site research in improving efficiency and protecting human subjects in research. At the same time, SACHRP continues to believe that studies with five or fewer sites should be excepted from the single IRB review requirement, including with respect to FDA-regulated research. The criterion of five or fewer sites forms a quantifiable and easily understandable threshold that would not be a mandatory exception but can be invoked as needed. Should FDA choose to adopt an exception based on a small number of study sites, then SACHRP urges FDA to make clear that single IRB review would be required only for U.S. sites, and only when the number of U.S. sites exceeds a certain threshold. (For example: If the single IRB exception threshold were set at five or fewer sites, then in a trial with 10 international sites and six U.S. sites, the single IRB review requirement would apply only to the six U.S. sites. Under the same exception threshold, if there were 10 international sites and four U.S. sites, then none of the sites would be required to undergo single IRB review.) Under the sIRB NPRM, single IRB review is required only for study sites located in the U.S., and SACHRP believes that additional clarification would benefit the regulated community. “FDA is requesting feedback on whether an exception from single IRB review might be warranted for a multisite study with a small number of sites, what the benefits and burdens are for a multisite study with a small number of sites, and what the appropriate threshold should be for the number of sites involved. In addition, we request any specific data that can be provided on the relationship between the number of sites and the value of single IRB review.” 87 Fed. Reg. 58,759. As noted above and in previous recommendations, SACHRP has proposed using five or fewer sites as a quantifiable threshold for an exception to single IRB requirements.9 SACHRP recognizes that single IRB review might not be too burdensome for studies with a small number of sites if the study is not likely to implicate any unique needs of, or any political, controversial, or sensitive issues in, the local community (e.g., an investigation on a diagnostic device related to heart valves, which is unlikely to implicate controversial issues). However, single IRB review may be less beneficial for studies with fewer sites, especially if the study is likely to implicate sensitive issues in one or more of the local communities (e.g., a study testing pre-exposure HIV prophylaxis use in young men who have sex with men). In such scenarios, it may be more efficient for study sites to coordinate with one another and resolve complex ethical issues with their respective local IRBs. Coordinating through a single IRB may just add an additional layer of complexity. SACHRP does not have data regarding the relationship between the number of sites and the value of single IRB review. However, SACHRP notes that while “five or fewer sites” forms a quantifiable threshold, a slightly lower threshold number could also be appropriate. “Both the revised Common Rule and FDA’s proposed rule still permit use of a single IRB for review and approval of cooperative research even if an exception applies. However, we are requesting public comment on any impact that such differences in exceptions from the single IRB review requirement may have on stakeholders, and on possible approaches to avoid or minimize any potential negative effects of such differences for stakeholders, such as whether additional exceptions from the proposed single IRB review requirement should be included or whether providing guidance on the application of FDA’s proposed exceptions might help avoid or minimize any differences in exceptions.” 87 Fed. Reg. 58,760 SACHRP supports the goals of single IRB review for multi-site research in improving efficiency and protecting human subjects in research. However, SACHRP urges FDA to favor harmonization when creating single IRB review exceptions to reduce confusion and administrative burden among the regulated community. In the interest of harmonization, SACHRP therefore continues to recommend that both FDA and OHRP consider the following three categories as potentially appropriate for exception to the single IRB review requirement: Research involving five or fewer sites; Research for which review by a single IRB is unable to meet the needs of specific populations; and Research involving political, controversial, or sensitive issues such that review by local IRBs would better address those concerns.10 “We also specifically request comment on whether there are unique challenges to use of a single IRB review model for FDA-regulated cooperative research that could not be addressed by FDA’s proposed exceptions. For any challenges identified, we seek comment on whether additional exceptions should be included to address them. For example, should FDA consider including an exception analogous to the revised Common Rule’s exception at 45 CFR 46.114(b)(2)(ii)?” 87 Fed. Reg. 58,760 SACHRP agrees that an exception requiring FDA to document and determine that single IRB is not appropriate for the particular context (i.e., an exception analogous to 45 C.F.R. Section 46.114(b)(2)(ii)) is likely to increase administrative burden and delay the initiation of research. In the sIRB NPRM, FDA stated that it did not include an exception analogous to 45 C.F.R. Section 46.114(b)(2)(ii) because such an approach would be impractical under FDA regulations and because there are many FDA-regulated studies for which there is no interaction with or submission to FDA prior to the study beginning. SACHRP agrees with FDA’s reasoning but urges FDA to take a different approach. Instead, SACHRP recommends adding an exception for research funded or conducted by a federal agency under which FDA defers to the federal funding agency’s determination that a single IRB would not be appropriate for the particular context (as set forth under 45 C.F.R. Section 46.114(b)(2)(ii)). Proposing an exemption that defers to a federal funding agency’s determination is likely to promote consistency, reduce administrative burden, and would not require any additional submissions to FDA. Presumably, this exception would apply only when a study falls under both FDA regulations and the revised Common Rule (e.g., a federally funded multi-site study involving an FDA-regulated investigational product). As thus, SACHRP recommends incorporating the exception for FDA-regulated research subject to the Common Rule, when the 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 under 45 C.F.R. Section 46.114(b)(2)(ii). “However, we seek comment on whether including an exception that provides for FDA to determine and document that single IRB review is not appropriate for the particular context, in addition to the exceptions FDA has proposed, could help address any such situations and any negative impacts of differences between FDA’s proposed exceptions and exceptions available under the revised Common Rule to a Common Rule Department or Agency.” 87 Fed. Reg. 58,760 SACHRP recommends incorporating an exception that permits the cognizant IRB, and/or the institution engaged in the research, presumably in consultation with the investigator, to determine on a case-by-case basis that single IRB review would not be in the best interests of research subjects; or that single IRB review would be significantly detrimental to the data integrity or the health and safety of subjects. Such an exception should (1) allow only for anomalies, (2) have a high standard, and (3) require a rationale that single IRB review would not be in the best interests of research subjects, or that single IRB review would be significantly detrimental to data integrity or the health and safety of subjects. “Lastly, FDA is requesting comment on the proposed exceptions and any other criteria that should be considered when assessing whether an exception to the use of single IRB review might be warranted. We also encourage the public to provide examples of any additional types of FDA-regulated clinical investigations that they believe should qualify for such an exception.” 87 Fed. Reg. 58,760. Under the sIRB NPRM, FDA proposes to require single IRB review for FDA-regulated multi-site clinical investigations, which would apply to any institutions located in the U.S. The proposed rule allows for the following exceptions: 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); Cooperative research involving a highly specialized FDA-regulated medical product for which unique, localized expertise is required; Cooperative research on drugs that meets the exemptions from an investigational new drug application (“IND”) under 21 C.F.R. Section 312.2(b); or Cooperative research on medical devices that meets the abbreviated requirements under 21 C.F.R. Section 812.2(b) (i.e., studies that are determined to be non-significant risk (“NSR”)) or the requirements for exempted investigations under 21 C.F.R. Section 812.2(c) (i.e., studies determined to be exempt from an investigational device exemption (“IDE”)).11 a. Comment on the proposed exceptions. SACHRP urges FDA to omit the proposed exceptions for IND-exempt studies, NSR studies, and IDE-exempt studies. The sIRB NPRM proposes two new exceptions from the mandate for single IRB review if: (1) the study meets the IND exemptions under 21 C.F.R. Section 312.2(b); or (2) if a device study is determined to be NSR under Section 812.2(b) or IDE-exempt under Section 812.2(c). SACHRP believes that such exceptions are likely to create new areas of confusion. The regulated community would benefit from as much consistency as possible in the regulations. Further, SACHRP is skeptical of FDA’s reasoning that studies conducted under INDs or IDEs are more likely to benefit from the increased efficiencies of the single IRB process than studies not requiring a submission to FDA (i.e., IND-exempt studies, NSR studies, and IDE-exempt studies). FDA reasons, for example, that “[u]nlike clinical investigations that are conducted under the IND requirements, increased efficiencies leading to earlier initiation of clinical investigations exempt from the IND requirements generally would not provide the benefit of bringing new drugs or new uses of drugs to patients sooner.”12 FDA also states that “[t]he proposed exception would also encompass research that is not focused on bringing new devices to the market for patients. Therefore, the initial administrative burden of establishing cooperative review agreements may not be offset by the anticipated benefits of single IRB review efficiencies, such as improvement in the review and handling of safety reports and faster initiation of research that facilitates the development of new medical products.”13 SACHRP, however, believes that the requirements for mandating single IRB should not be based on whether an IND or IDE application will be submitted to FDA. For example, studies such as FDA-regulated research on mobile medical device applications may or may not require an IDE.14 These mobile medical device application studies, even if an IDE is not required, can involve numerous study sites and might still benefit from the increased efficiency and earlier study initiation associated with single IRB review. SACHRP nonetheless agrees with FDA’s rationale that permitting local IRB review for IND-exempt studies, NSR studies, and IDE-exempt studies will benefit many studies originating from academic institutions (i.e., investigator-initiated research). Unlike industry-sponsored trials, many investigator-initiated studies are conducted without the intention of bringing new drugs or new uses to the market. Such investigator-initiated studies often have fewer study sites and limited resources to manage a centralized single IRB review process. SACHRP notes that this category of studies would in most cases already be covered by other exemption criteria regarding which FDA has requested comment (e.g., for research involving five or fewer sites or studies for which a single IRB is unable to meet the needs of specific populations). Therefore, SACHRP urges FDA to omit specific exceptions for IND-exempt studies, NSR studies, and IDE-exempt studies, and instead adopt the single IRB exemption categories recommended by SACHRP. b. Other examples of scenarios that should be exempt from single IRB requirements. SACHRP provides the below additional examples of studies that should qualify for an exception from single IRB requirements. SACHRP notes that the below scenarios would likely be captured by one of SACHRP’s three recommended exceptions noted above (e.g., research “involving political, controversial or sensitive issues such that review by local IRBs would better address those concerns”). FDA-regulated study evaluating an investigational assay for the detection of monkeypox among a stigmatized group (e.g., men who have sex with men, people with HIV, or people who use or inject drugs, or sex industry workers). Studies in which participation, by virtue of the eligibility criteria, could identify subjects as violating applicable laws (e.g., users of illegal drugs, sex industry workers) or as members of a stigmatized population. A study of pre-exposure HIV prophylaxis use among adolescent men who have sex with men (including transgender women), in a state with laws permitting minors to consent to participating in research. Ethical concerns may be further heightened if the local community disagrees with the state law and believes that consent should be granted by a parent or guardian. Such scenarios may require local ethics and legal consultation. In this example, local IRB review may better serve the needs of the proposed subject population.15 “The Regulatory Flexibility Act requires us to analyze regulatory options that would minimize any significant impact of a rule on small entities. Because small entities affected by this proposed rule would incur net cost savings, we propose to certify that the rule, if finalized, will not have a significant economic impact on a substantial number of small entities. However, as discussed in the Preliminary Economic Analysis of Impacts (Ref. 5), there is a lack of high quality, comprehensive data regarding the number of small and very small institutions associated with IRBs, as defined by revenue. We have prepared an initial regulatory flexibility analysis and are seeking comment on the data and assumptions used in that analysis.” 87 Fed. Reg. 58,761. SACHRP does not have comment or data on these topics. “FDA invites comments on these topics: (1) whether the proposed collection of information is necessary for the proper performance of FDA’s functions, including whether the information will have practical utility; (2) the accuracy of FDA’s estimate of the burden of the proposed collection of information, including the validity of the methodology and assumptions used; (3) ways to enhance the quality, utility, and clarity of the information to be collected; and (4) ways to minimize the burden of the collection of information on respondents, including through the use of automated collection techniques, when appropriate, and other forms of information technology.” 87 Fed. Reg. 58,762. SACHRP does not have comment or data on these topics. Procedural Considerations SACHRP urges FDA to adopt regulations clarifying the procedural steps and vesting the authority in the cognizant IRB and institution engaged in the research, presumably in consultation with the investigator, to make a final determination regarding whether single IRB review is apprrpriate for a given study. The sIRB NPRM does not require any individual or entity to identify the single IRB.16 This departs from the Common Rule, which states that either the IRB is to be identified by the federal agency supporting or conducting the research, or the lead institution should propose the single IRB for acceptance by the federal agency. Unlike studies that are subject to the Common Rule (i.e., conducted or supported by a federal agency), not all studies that are FDA-regulated will interact with FDA. For example, NSR device studies do not require a submission to FDA. However, such studies will still require a sponsor or investigator to interact with an IRB. Conclusion SACHRP supports the goals of single IRB review for multi-site research in improving efficiency and protecting human subjects in research. SACHRP encourages FDA to adopt provisions to harmonize with the Common Rule, deferring to the federal funding agency’s determination that a single IRB would not be appropriate for the particular context. However, SACHRP recommends that FDA exclude the proposed exception for IND-exempt studies, NSR studies, and IDE-exempt studies and instead consider the following categories as potentially appropriate for exception to the single IRB review requirement: Research involving five or fewer sites; Research for which review by a single IRB is unable to meet the needs of specific populations; and Research involving political, controversial, or sensitive issues such that review by local IRBs would better address those concerns. SACHRP further urges FDA to delineate procedural expectations and vest in the cognizant IRB and institution engaged in the research, presumably in consultation with the investigator, the ultimate responsibility for determining whether single IRB review is appropriate. Endnotes 1 Protection of Human Subjects and Institutional Review Boards, 87 Fed. Reg. 58,733 (Sep. 28, 2022) (to be codified at 21 C.F.R. Parts 50, 56, and 812). 2 Institutional Review Boards; Cooperative Research, 87 Fed. Reg. 58,752 (Sep. 28, 2022) (to be codified at 21 C.F.R. Part 56). 3 SACHRP, Attachment A: Initial Considerations for Single IRB Review: Points to Consider (2016), available at: https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-a-november-2-2016-letter/index.html. 4 SACHRP, Recommendations on the Draft Guidance for Use of Single Institutional Review Board for Cooperative Research (2022), available at: https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-a-july-25-2022-letter/index.html. 5 45 C.F.R. § 46.114(b). 6 45 C.F.R. § 46.114(b)(2)(i). 7 45 C.F.R. § 46.107(f); 21 C.F.R. 56.107(f). FDA regulations state that individuals may be invited to assist with “complex issues” whereas the Common Rule excludes the word “complex.” 8 See e.g., 21 C.F.R. 56.107(f). 9 See e.g., SACHRP, Recommendations on the Draft Guidance for Use of Single Institutional Review Board for Cooperative Research (2022), available at: https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-a-july-25-2022-letter/index.html. 10 Id. 11 87 Fed. Reg. 58,763. 12 87 Fed. Reg. 87,758. 13 87 Fed. Reg. 87,759. 14 See e.g., U.S. Food and Drug Administration, Policy for Device Software Functions and Mobile Medical Applications (2022), available at: https://www.fda.gov/media/80958/download. 15 In a study involving minors at risk of acquiring HIV infection (i.e., adolescent men who have sex with men), the researchers relied on local regulations, which included a provision for mature minors to be considered medically emancipated for treatment of certain conditions (e.g., seek care for HIV/STIs without parental permission). Researchers in this study engaged an ethics advisory panel, sought local IRB review, and consulted with OHRP. Researchers obtained a response from OHRP and concurrence from FDA that the proposed consent procedures were reasonable and consistent under the Common Rule. See Sybil G. Hosek et al., Safety and Feasibility of Antiretroviral Preexposure Prophylaxis for Adolescent Men Who Have Sex With Men Aged 15 to 17 Years in the United States, 171(11) JAMA Pediatrics 1063 (2017). 16 See 87 Fed. Reg. 58,757.