NOTE: These Frequently Asked Questions are consistent with the 2018 Requirements (i.e., the revised Common Rule). Draft This guidance document represents the current thinking of the Office for Human Research Protections (OHRP) on this topic. This guidance does not create or confer any rights for or on any person and does not operate to bind OHRP or the public. OHRP guidance should be viewed as recommendations unless specific regulatory requirements are cited. The use of the word “must” in OHRP guidance means that something is required under the Department of Health and Human Services (HHS) regulations at 45 CFR part 46. The use of the word “should” in OHRP guidance means that something is recommended or suggested, but not required. An institution may use an alternative approach if the approach satisfies the requirements of 45 CFR part 46. OHRP is available to discuss alternative approaches by telephone at 240-453-6900 or 866-447-4777, or by email at firstname.lastname@example.org. Date: July 1, 2022 Scope: This guidance document applies to nonexempt human subjects research activities that are conducted or supported by HHS. It applies to cooperative research projects that involve more than one institution for which the 2018 Requirements, including the single IRB review requirement, apply. It provides guidance on the 2018 Requirements set forth in 45 CFR 46.114(b)(1) that require any institution located in the United States engaged in cooperative research to rely on approval by a single institutional review board (IRB) for that portion of the research that is conducted in the United States, with some exceptions as described at § 46.114(b)(2). The single IRB is the IRB that would be held responsible for compliance with the relevant provisions of 45 CFR part 46 in a cooperative research project. This IRB would perform review on behalf of multiple institutions. The single IRB may also be referred to as the “reviewing IRB,” the “IRB of record,” or the “central IRB.” Target Audience: Institutional review boards, institutions, investigators, HHS funding agencies, and others that may be responsible for the review, conduct, or oversight of cooperative research conducted or supported by HHS. Regulatory Background: In this document, the term “pre-2018 Requirements” refers to subpart A of 45 CFR part 46 as published in the 2016 edition of the Code of Federal Regulations. The pre-2018 Requirements were originally promulgated in 1991 and subsequently amended in 2005. For purposes of this document, the term “2018 Requirements” refers to subpart A of 45 CFR part 46 as published in the July 19, 2018 edition of the Code of Federal Regulations. The 2018 Requirements were originally published on January 19, 2017 and further amended on January 22, 2018 and June 19, 2018. More information about implementing the 2018 Requirements is available on the OHRP website. The compliance dates and transition provisions at 45 CFR 46.101(l)(2) require compliance with § 46.114(b) after January 19, 2020. This means that a single IRB of record must be used for any U.S. institutions engaged in cooperative research that is subject to the 2018 Requirements, unless the research meets the conditions to be exempt under § 46.104(d), or an exception to the single IRB requirement applies as outlined in § 46.114(b)(2). Guidance A. General What is cooperative research? The HHS protection of human subjects regulations at 45 CFR 46.114 refer to “cooperative research projects” as non-exempt human subjects research to which the regulations apply that involves more than one institution engaged in cooperative research. Note that each institution that is engaged in the human subjects research does not have to be conducting the same activities in a protocol to be subject to the mandate for review by a single IRB. For example, an institution could be an awardee institution or responsible for seeking consent from participants, another could be performing research procedures, and another could be conducting laboratory analyses for a key study endpoint. Note that only those institutions that are “engaged” in the cooperative research need to comply with the regulations (see OHRP’s guidance and correspondence on engagement). When must an institution rely on a single IRB for approval of cooperative research? The regulation at 45 CFR 46.114(b)(1) requires that any U.S. institution that is engaged in cooperative research rely on a single IRB for approval of the portion of the research conducted in the U.S. There are two regulatory exceptions to this requirement provided at 45 CFR 46.114(b)(2). The first exception is for 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) (45 CFR 46.114(b)(2)(i)). The second exception is for 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 (45 CFR 46.114(b)(2)(ii)). OHRP has the authority to determine whether to issue a 45 CFR 46.114(b)(2)(ii) exception for HHS-supported or -conducted research., OHRP currently provides exception determinations for classes of research as opposed to single studies. OHRP’s exception determinations, thus far, can be found through the Single IRB Exception Determinations webpage. For a cooperative research project supported or conducted (e.g., jointly funded) by both HHS and one or more other Common Rule departments or agencies, 45 CFR 46.114(b)(2)(ii) allows that any of these departments or agencies can issue a single IRB exception applicable to the research study. When issued by a department or agency that is acting independently, the single IRB exception would apply to any research institution over which that department or agency has jurisdiction, unless the terms of that department or agency’s exception limits it to only some of the institutions to which that department or agency has jurisdiction. A department or agency may not independently issue a single IRB exception for institutions over which it does not have jurisdiction. For example, assume that Agency X and Agency Y are involved in a cooperative research study. Agency X has jurisdiction over only one institution (e.g., it owns a hospital); Agency Y is funding all involved institutions (and, therefore, has jurisdiction with respect to the cooperative research provision of the Common Rule over all the institutions). Agency X issues an exception to the single IRB mandate for its institution. This exception would apply only to the one institution over which Agency X has jurisdiction. Alternatively, Agency Y could issue an exception applicable to all institutions over which it has jurisdiction, including the one institution which has shared jurisdiction with Agency X. Finally, research that is not supported or conducted by any Common Rule agency is not subject to the single IRB requirement even if one (or more) of the institutions engaged in the research has “checked the box” on its Federalwide Assurance (FWA). Who decides which IRB will be the single IRB for the purposes of regulatory compliance? Per the requirement at 45 CFR 46.114(b)(1), the single IRB will be identified by the Federal department or agency supporting or conducting the research or proposed by the lead institution subject to the acceptance of the Federal department or agency supporting the research. For HHS conducted or supported research this determination would come from an HHS division such as NIH or CDC. If the research is supported or conducted by more than one Federal department or agency, those departments and agencies should collaborate to determine the single IRB Can an institution that is not required to comply with 45 CFR 46.114(b)(1) for a particular study still choose to rely on a single IRB for review of cooperative research? Yes. For cooperative research not subject to 45 CFR 46.114(b)(1), an institution participating in a cooperative project may enter into a joint review arrangement, rely on the review of another IRB, or make similar arrangements for avoiding duplication of effort, as is provided for in § 46.114(c). This is also the case for institutions participating in cooperative research under the pre-2018 Requirements. Can an institution involved in cooperative research choose to conduct its own IRB review of the research even though review is required by a single IRB that is located elsewhere? Yes. An institution may conduct additional internal IRB reviews of the research activities in which the institution is engaged, although such reviews would not have any regulatory status in terms of compliance with the 2018 Requirements. OHRP recommends that the institution conducting the additional internal IRB review inform the single IRB of such a decision and of the internal IRB’s determinations. Are there documentation requirements for use of a single IRB in cooperative research? Yes. The relying institution and the organization operating the single IRB must document the institution’s reliance on the single IRB and the responsibilities of each entity with respect to ensuring compliance with the 2018 Requirements (45 CFR 46.103(e)). However, the regulations do not prescribe how such documentation must be accomplished. There is flexibility in how this might be done: for example, through a written agreement between the institution and the single IRB, through implementation of an institution-wide policy directive outlining the allocation of responsibilities between the single IRB and the institution, or through a description in the IRB-approved research protocol (§ 46.103(e)). Reliance agreements may cover one protocol, multiple protocols, or all research within a certain set of parameters. They might address, for example, some or all of the following regulatory requirements and/or other considerations: prompt reporting of incidents to OHRP and to the department or agency supporting the research; monitoring and auditing responsibilities; management of response to complaints or concerns of research subjects; the process for ensuring investigator qualifications; recordkeeping and access to records; communications; dealing with conflicts of institutional or individual interest; indemnification and liability provisions; and managing investigations related to protocol deviations, noncompliance, or unanticipated problems. What are some of the operational capacities an IRB should have in order to serve as a single IRB? An IRB designated as the single IRB for review of cooperative research should have the capacity to manage review and oversight of multiple research institutions and site investigators. The following are some, but not all, of the activities that might be performed by the single IRB: track the status of research at multiple institutions; manage multiple consent forms and versions of consent forms from different institutions; communicate notifications of IRB actions to an individual institution or across all institutions as needed; store institution-specific information (e.g., approval documentation, informed consent documents approved by the IRB, and other study-specific materials); access and apply relevant State and local law; maintain written IRB procedures that are available to relying institutions; and monitor and/or audit research at the relying institutions. What are the responsibilities of the single IRB with respect to information pertaining to sensitivity to community attitudes and the local context for proposed research? While the phrase “local context” is not a regulatory term nor is it defined by the 2018 or the Pre-2018 Requirements, OHRP regards “local context” for proposed research as generally referring to local circumstances, preferences, and variability, and could include such factors as culture and language, geography, socioeconomic factors, the professionals conducting the research, the institutions where the research will be conducted, or local standards of care. For example, local context may refer to a geographic region that is predominantly Native American; or, local context might include a research hospital that employs specific clinical procedures for the treatment of a specific pathological condition which may be unique to that hospital. Local context information may be provided by the single IRB itself, whose diverse membership may have knowledge about, for example, local community attitudes (45 CFR 46.107(a)). The single IRB membership must include members with sufficient experience and expertise (professional competence) to determine, for the portfolio of research it reviews, whether risks to subjects are minimized, in accordance with § 46.111(a)(1), and whether those risks are reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may reasonably be expected to result (§ 46.107(a), § 46.111(a)(2)). The single IRB membership must also include sufficient diversity of race, gender and cultural backgrounds and sensitivity to such issues as community attitudes, to promote respect for its advice and counsel in safeguarding the rights and welfare of the research subjects, which may be part of local context (§ 46.107(a)). The single IRB must have sufficient expertise to adequately assess the equitable selection of subjects—taking into account the purposes of the research and the research setting—which is also related to local context (§ 46.107(a), § 46.111(a)(3)). The single IRB must assess the inclusion of additional safeguards in studies where some or all of the subjects are likely to be vulnerable to coercion or undue influence or are economically or educationally disadvantaged (§ 46.111(b)), which may also vary by local context. If a single IRB needs specific information on local context to make the required determinations for approval under 45 CFR 46.111, the single IRB must have access to such information in order to meet the regulatory requirements. In general, the relying institution should provide information on local context, as appropriate, consistent with the responsibilities that the relying institution and the single IRB have agreed upon and documented (e.g., reliance agreements might include provisions relating to informing the single IRB about such local contextual issues). The single IRB also has the discretion to invite individuals who have knowledge of the local context to their meetings (45 CFR 46.107(e)). The single IRB is not required to have local contextual and institutional information that does not directly impact the single IRB’s 45 CFR 46.111 determinations. What are the responsibilities of the single IRB pertaining to applicable state and local laws? Some states have laws that might affect research, such as legal age of majority, additional informed consent requirements, and/or additional privacy notification requirements. The single IRB must have the ability to ascertain the acceptability of proposed research in terms of institutional commitments, regulations, applicable law, and standards of professional conduct and practice, including local differences in those items (45 CFR 46.107(a)). While there are multiple approaches single IRBs can use to facilitate acquisition of such information, single IRBs should have flexibility to obtain this information in the most efficient manner (for example, through an application process and standard IRB procedures, or through consultation with other parties). The single IRB must have the ability to access information regarding state and local law that is necessary for the single IRB to make the determinations required by 45 CFR 46.111 when it is necessary. However, the single IRB is not required to have information regarding state and local laws that does not directly impact the § 46.111 determinations. For example, in order to make a 45 CFR 46.111 determination in a particular protocol, a single IRB may not need specific information about state law or institutional policy concerning who may serve as a legally authorized representative.