What is an IRB Reliance Agreement?
An IRB reliance agreement is a document that is essential for researchers who collaborate with other institutions or entities. This agreement allows one IRB to rely on the review and oversight provided by another IRB, streamlining the process and ensuring compliance with ethical standards. When two institutions are collaborating on a research study, they may not have to duplicate all institutional requirements if they have a reliance agreement in place. Specifically, the relying institution will not need to conduct its own IRB review once it obtains assurances that the lead institution has fulfilled all of the requirements.
When an investigator at one institution collaborates with another institution , each must still comply with federal regulations (45 CFR 46; 21 CFR 56) and with the requirements of their respective institutions. These regulations require that an IRB "review and approve research at the institution" (45 CFR 46.112; 21 CFR 56.110). However, institutions can agree to skip a duplicate IRB review. The new rule on this issue is found in 45 CFR 46.114(b). This section permits the IRB chair or "designee" to make the determination that "there is an IRB authorized" at the "lead institution," and no further IRB review is required.
Advantages of IRB Reliance Agreements
The most obvious yet significant benefit to be derived from IRB reliance agreements is the reduction in duplication of effort. The IRB that is the lead reviewer of a multi-site study gains access to all the information and materials previously provided to any other IRB that has reviewed the study, and the relying investigator avoids having to submit the study to multiple IRBs. An IRB reliance agreement can greatly speed up a research study by minimizing the time it takes for a relying site to obtain IRB approval. It also lessens the burden on research investigators by reducing the replication of effort that can occur when local IRBs conduct individual reviews of multicenter research studies.
IRB reliance agreements significantly reduce the amount of administrative activity required. They can minimize or eliminate duplicate and unnecessary paperwork. The reliance agreement task shifts most of the administrative duties onto the lead IRB, which in turn allows relying sites to provide more time to study activities themselves. Additionally, studies have shown that IRB reliance agreements can lead to reduced overall study costs.
Every IRB involved with a research study will need to negotiate the terms of its respective IRB reliance agreement with the lead IRB, often resulting in delays before IRB review can begin. But once all the terms of an IRB reliance agreement have been negotiated, one IRB can simultaneously provide a single list of IRB requirements to all the participating sites for institutional review, which can lead to a more efficient institutional approval process.
Finally, IRB reliance agreements mean fewer adjudicatory bodies reviewing coverage analysis or budgets for clinical trials, because each participating site no longer has to negotiate a coverage analysis and budget with an IRB.
The Mechanism of IRB Reliance Agreements
IRB reliance agreements use currently acceptable approaches to reduce redundancy, enhance predictability and improve efficiency. Under these arrangements, one or more IRBs agree to review a study on behalf of other, usually cooperating parties. In the United States, cooperating parties are limited by federal regulation, including the Federal policy for the Protection of Human Subjects (Common Rule), to the three classes of IRBs and institutions described above. In this situation, the Principal Investigator or the Cooperative Research Group enters into an agreement with other participating IRBs and study sites. Well-written reliance agreements should clearly delineate the role of the IRB in its review of the study. Reviews may be performed using delegation (i.e., the cooperating IRB assumes primary responsibility and the other IRB defers to the judgment of the collaborating IRB) or by collaboration (i.e., all IRBs work together to review the study). Regardless of the approach selected, the IRB will perform its review of the study as required by law. The IRB will also attach any additional stipulations necessary to minimize institutional liability or address organizational policies or practice norms (e.g., payment for services, confidentiality, or data sharing).
As discussed above, the IRB must still perform its review of the study even if the protocol is reviewed by another IRB. The review is not limited to the protocol itself or the informed consent form, it is extended to and must include review of "any other material that is likely to be relevant to the IRB’s deliberations." (45 CFR 46.112; 21 CFR 56.111(7)). The IRB, however, is not required to receive and review redundant information (45 CFR 46.115(a); 21 CFR 56.108(a)(6)).
In practice, many IRBs will request that the collaborating IRB and the Principal Investigator agree to a set of expectations that are deemed necessary to facilitate an efficient consultation and communication between two or more IRBs. Once one or more IRBs have agreed to perform the review, the Principal Investigator is required to notify the subjects at each site of any transfer of control over the screening and recruitment in the study. It is always good practice for the Principal Investigator to explain the IRB reliance agreement to the subjects before they sign the informed consent document.
Parties Involved with IRB Reliance Agreements
Although IRB reliance agreements are contractual arrangements, the parties are not necessarily restricted to the signatories of the agreement. There are two dimensions to the approach for analyzing stakeholders to a reliance agreement: (1) the stakeholders, and (2) their responsibility. At a minimum; the research ethics review board ("IRB"), the relying institution, and the principal investigator will be stakeholders.
The term ‘relying institution’ refers to the local institution where the research is being conducted. It is the administering and institutional signatory that is entering into the reliance agreement with a central or coordinating IRB. The relying institution may have an IRB but typically does not; it does not make a difference either way. It is important to note: your institution must have an IRB, before you may begin submitting on studies under one of the IRBs at your institution. For that reason, institutions with an IRB are call ‘IRB-indexed.’ When no local IRB is possible, small institutions without an IRB must do due diligence when using an outside IRB. This diligence may include inquiry to ensure that the coordinating or central IRB follows the required protocols for disclosure and material change in teams, as discussed later in our post.
The principal investigator delayed courses of action, such as enrolling research participants, until the local institution has an adequate understanding of the IRB and its policies; absent the institution, agreeing to or not objecting to the research. For example, institutional IRB approval cannot be substituted by approval from a centralized or coordinating IRB or its institutional signatory. Noncompliance can be avoided; however, through adequate and timely communication between the principal investigator and the local institution.
Like the principal investigator and relying institution, the local Institutional Review Board also needs to be informed of unusual situations, in order to avoid possible compliance issues. For example, if the protocol approval relies on making material changes in the following 12 months of the study, the institution and Institutional Review Board should be notified. Many Institutional Review Boards have material change guidelines that must be followed; others, such as the National Cancer Institute Institutional Review Board have different guidelines.
Disclosure of the institution’s involvement with the study requires additional communication; otherwise, there may be noncompliance with federal grant and contract rules. This may include not submitting a copy to the National Institutes of Health or the National Health Institute, in which case obligations and conditions may be violated. Since this is the same for the principal investigator and the local Institutional Review Board, therefore, they should communicate with each other in all situations, and where applicable, institutional contact, to obtain the necessary approvals.
In addition to the above, creating a comprehensive plan that addresses coordination issues, such as transportation, scheduling, and patient safety, may enhance the local institution’s practical ability to implement the study.
Considerations and Challenges with IRB Reliance Agreements
In addition to the logistical and regulatory considerations, there are potential ethical issues that must be acknowledged. When a study engages multiple institutions, each typically has its own Institutional Review Board ("IRB") that oversees the protection of the rights and welfare of potential research subjects. In order to manage costs and efficiency, some institutions may enter into agreements to rely on the review and oversight of another institution’s IRB. This is known as an "IRB reliance agreement" or "Single IRB agreement" (which may also be called a "Master Agreement"). However, while IRBs may enter into such agreements, they must be aware that the primary institution that is relying on another institution’s IRB must still review the informed consent document(s) for a study, even if the other IRB is the one overseeing the study. Investigators should be aware of the current requirements under FDA regulations and the Common Rule and ensure compliance regarding the informed consent process.
In addition to the legal considerations, there are many questions that arise as institutions contemplate whether to rely on each other’s IRB for a specific clinical trial. For example, the institutions need to agree on the logistics of how a subject’s information will be shared and transferred from one institution to the other , such as how enrollment lists and consent forms will be stored, and how concerns about breaches of confidentiality or privacy will be handled. Additionally, the IRB reliance agreement also needs to address how deviations from a protocol will be reported if one study site becomes aware of a problem that another study site misses. The main institution also has to consider what is needed to demonstrate awareness of any problems. For example, if a noncompliance issue arises, how much oversight is the primary institution going to retain to ensure the problems are resolved?
In cases where one institution replaces the IRB of another, the institutions need to consider the issues that might arise when subjects who consent to participate in a study do not understand that their consent extends beyond the physical location of the institution where they are enrolling in the study. Thus, some institutions include a statement in the informed consent documents indicating that the person being asked to consent understands that his/her consent is being given in connection with a study that is being conducted at other participating sites (and thus may be sharing information among sites).
These are just a few of the issues that institutions need to consider when contemplating entering into an IRB reliance agreement.
Implementing a Robust IRB Reliance Agreement
The success of an IRB reliance agreement largely rests on the IRBs’ ability to understand and follow the procedures outlined in the agreement itself. This is key for not only understanding which regulations and policies apply to a specific study, but also implementing necessary oversight by both IRBs.
To successfully implement a reliance agreement, each institution’s process should involve the creation and retention of a study-specific binder with supporting documents in accordance with the agreement. The binder should include:
– Study protocol and synopsis – to ensure that both IRBs have reviewed and assessed the same version of the protocol and the basis for approval;
– Ethics committee approvals – copies of supporting documents (e.g. minutes, correspondence):
• All ethics committee approval letters;
• Ethics committee request for information or modifications;
• Correspondence between ethics committees and the investigator regarding approval and any deficiencies;
• Correspondence between IRB administrators (regarding protocol with multiple sites); and
• Approval letters to the investigators from the ethics committees.
– Sponsor correspondence or contracts – in order to keep track of the agreements, whether upfront contract or between the sponsor and investigator; and
– Investigator correspondence – all correspondence between the investigator and both IRBs for tracking and archive purposes.
Although the IRB reliance agreement contains details as to the terms of the agreement, it is important that each institution understands that it can modify the non-FDA regulated study to the extent permitted.(1) This may include how to review study-related corrective actions necessary to protect human subjects who may be affected. But IRBs should bear in mind that the FDA does not permit an IRB to affiliate with any other IRB or organization for the purpose of fulfilling its duties, regardless of such organization’s status, accreditation status, or formation for such purpose.(2) The FDA concludes that, even when the IRBs render their decisions independently, affiliation would create an impermissible conflict.
While it is clear that an IRB may delegate its authority to another IRB, it is unclear whether an IRB may delegate its authority to an ethics committee that is not an IRB. While the FDA regulations only discuss delegation of authority to another IRB, the OHRP permits limited delegation to an ethics committee that is not an IRB, when appropriate, to undertake responsibilities for expedited review, but notes that the IRB retains ultimate authority and responsibility.(3)
Still, IRBs may enter into "cooperative agreements" with other IRBs that operate in accordance with the requirements of both the FDA regulations and OHRP regulations, provided that one or the other (or both) IRBs reviews the research proposal. These agreements may permit one IRB to undertake some administrative functions, which may include reviewing research proposals, maintaining correspondence with principal investigators and sponsors, obtaining informed consent from human subjects. Any cooperative agreement must address how the IRBs will ensure compliance with all applicable laws and regulations.
Implementing a new procedure and/or forms to facilitate compliance with an IRB reliance agreement may help IRBs that have never had the experience. For example, the Office for Human Research Protections (OHRP) has developed an IRB assurance template and guidance for sharing IRB oversight responsibilities among institutions. The guidance is to be used with the OHRP IRB reliance assurance template that outlines policies that are expected to be in place by a domestic institution intending to rely on an IRB on behalf of a domestic investigator. OHRP also provides guidance on IRB single-point review, oversight and reliance, and the IRB reliance model:
- A prospective agreement: This approach is generally the most beneficial to study subjects and sponsors. (4)
- A retrospective agreement: This approach is generally reserved for use with studies that were initiated before the IRB(s) agreed to the reliance. (4)
- A conceptual agreement: In cases where an IRB and investigator cannot reach an understanding on the terms of a reliance agreement, the IRB may offer the investigator the opportunity to propose a conceptual agreement that meets regulatory standards. (4)
Regardless of the method, if an IRB and an investigator cannot agree on the approach, the investigator may ask OHRP to make a final determination. (4)
OHRP also has specific guidance for implementing a multi-site clinical trial democratically, including the following:
- Tell the investigators the issues that need addressing;
- At minimum, the study should involve studies that are not subject to FDA jurisdiction, that are comparable in size and for which the benefit-to-risk ratio is similar;
- Submit the agreement at least 30 to 60 days before the study begins and the first research subject is enrolled in a study; and
- Identify each human subject study represented by the IRB-based system beyond what is included in the IRB assurance assurance submission.(5)
OHRP suggests that study teams should consider including:
- A description of the quality assurance procedures that will be utilized throughout the study;
- A process by which all IRBs will be notified of participant withdrawals, conditions that might affect their consent decisions, and/or deadlines for when such conditions may apply;
- A description of medical care that will be provided should study-related injuries occur; and
- A plan to notify participating IRBs in cases where any adverse event must be reported.(5)
If you have more questions about the IRB reliance agreement, join us for the "IRB Reliance Agreement Workshop" on November 18, 2014.
- (1) 45 CFR 46.114(c)(1) (OHRP)
- (2) 21 CFR 56.107
- (3) 45 CFR 46.107
- (4) OHRP IRB internet site, Share IRB Oversight Responsibility: Information about a Cooperative IRB Agreement.
- (5) OHRP IRB internet site, Developing an IRB-Reliance Model: Information for Reviewing IRB/ethics Committees.
The Future of IRB Reliance Agreements
One of the most interesting predictions for the future of IRB reliance agreements is the possibility of the universal IRB, whereby a centralized IRB could oversee all research activities for an organization. However, given the individuality of various institutions and organizations, there will still likely be a need for individual reliance agreements in some cases. Some of the strongest arguments for moving toward a Universal IRB model have been the reduction of administrative burden on IRBs and the cost when conducting multi-site studies. While the movement toward a Universal IRB will require additional work by the federal government, as it will entail revising federal regulations, etc., it is clear that the current trend of a significantly increased rate of reliance agreement usage will continue into the future .
Technology will continue to play a part in improving the utilization of IRB reliance agreements. For instance, the utilization of electronic environments and the use of a central repository for these agreements could improve efficiency. Additionally, the use of technology in more than one location could allow researchers to access IRB policies, procedure and forms online. One such ready-made online system is SMART IRB, which is a shared IRB submission and review platform for researchers conducting multisite studies recently developed by Biomedical Research Integrated Risk Administration (BRiTA). The system was created to assist institutions with meeting the requirements of the Revised Common Rule.