Demystifying Reliance Agreements in the IRB Context
What is a Reliance Agreement?
Reliance agreements are formal written agreements made between two or more institutions that define and agree upon the responsibilities of each institution in a research protocol study. Specifically, at least one institution agrees to not conduct its own internal review of the protocol. Reliance agreements can be used in many different situations. For example, a researcher holding a single federal grant who is conducting only a minimal risk protocol may delegate sole review authority to an IRB by way of a reliance agreement with that one IRB . Or a researcher holding multiple federal grants and contracts may be required by a funding agency to designate one IRB of record in a multi-site study and that researcher will then execute a reliance agreement with that one IRB for the study.
Since a reliance agreement is typically a study specific document in which a lead institution of the multi-site study delegates review authority to a single IRB, relying institutions must make sure that they execute a separate written agreement with the single IRB. In addition, relying institutions must also ensure that any consent forms have been appropriately approved or modified by the IRB of record (i.e., the IRB responsible for reviewing the protocol).
The Rationale for Reliance Agreements
Reliance agreements are important because they are tools that help rationalize and simplify the process of conducting human subjects research that involves multiple cooperating institutions, and are an essential component of IRB processes. Reliance agreements are also a means of ensuring that research institutions remain in compliance with key regulations and ethical standards related to subject protection. Research partnerships can be furthered and deepened as a consequence of agreed-upon obligations set forth in a reliance agreement. Moreover, as described in this article, IRBs provide an opportunity to streamline review processes, which can ultimately result in the acceleration of human subjects research.
How Reliance Agreements Make Multi-Site Research Possible
Reliance agreements are one of the many tools that make multi-site and multi-sponsor studies feasible. Reliance agreements are mechanisms by which two or more institutions agree to give authority to the IRB of one of the institutions – sometimes called the IRB of Record – to conduct review of a particular research activity. Before reliance agreements, or deferred review, institutions had to make a decision whether to cede oversight to an external IRB on a case by case basis, adopting a policy that may be inconsistent with their existing practices. Today, the Right of First Review enables institutions to review a study and decide not to approve it for one reason or another, even if the IRB of Record has approved it.
In order to apply for federal funding to conduct a multi-site clinical trial, the NIH requires that applicants specify which single IRB will serve as the IRB of Record. The Common Rule regulation issued on January 19, 2017 (as of January 1, 2019, for federal agencies, and January 20, 2020, for non-federal entities) makes deferred review using a single IRB the default for all non-exempt research subject to Common Rule agencies, with the possibility of exceptions at the enrolling site. There are some statutory IRB review requirements that prohibit reliance on an institution’s own IRB (e.g., The Department of Veterans Affairs, and the Department of Defense).
While reliance agreements can and are used domestically, they also create opportunities to facilitate international research reviewing. The United States, Australia, New Zealand and Canada have presented a work plan that is part of the International Council for Harmonization effort, including a mandate to recognize IRB authorizations across the countries. While there are extremely strong systems in these countries, the humanitarian reasons for cross-border research merit attention.
A growing body of guidance has developed from governmental agencies (in particular, the Office for Human Research Protection), professional organizations (Association for the Accreditation of Human Research Protection Programs, Association of Clinical Research Organizations, Clinical and Translational Science Awards), and independent organizations (e.g., the Public Responsibility in Medicine and Research, the World Health Organization) that serve to identify, and standardize, the types of activities that merit and will occur under reliance agreements.
The Anatomy of a Reliance Agreement
The components of a reliance agreement vary based on the context in which the agreement is created, but there are several common terms present in most agreements. The following components should be expressly addressed: Study information (including a synopsis) should be included in the context of study oversight and needs to be accurate. If sections of the agreement call for approval or modification of the study this information will need to be included as well. For example, in some institution specific language, these changes do not need to be approved by the IRB but the sponsor will have an opportunity to review for compliance. Responsibilities of Each Institution corresponding to study oversight, participant protections, and reporting responsibilities should be clearly defined as well as the responsible contact for each institution (usually a current IRB representative) and an alternate that the other institution can reach out to if needed. Oversight of Research Projects this is where things can get confusing sometimes. A third party IRB can certainly fulfill oversight on those institutions where it is listed as the "IRB of Record." However oversight may include other activities, such as IRB management and data monitoring for clinical studies, that may not be handled by a third party IRB. Therefore, you will need to make sure that the agreement properly accounts for how the IRB of Record will be managing participating sites not requiring oversight by the IRB, or how much of the activities of a local IRB will be handled by the assigned IRB of Record. As mentioned previously, IRB approval in the agreement is not strictly necessary if the allotment of tasks makes it clear that the non-IRB of Record institution will obtain the approval of the local IRB before they begin their participation. Compliance Requirements to all applicable federal regulations (in addition to state and institution specific laws, statutes, and guidelines) would clearly be included. These usually include the Common Rule (at 45CFR 46) and the FDA regulations at 21CFR50 and 21CFR56.
Entering Into a Reliance Agreement
The process of establishing a reliance agreement between institutions seeking to engage in research covered by an FWA is one that should begin early in the protocol development process. Institutional officials with whom relying institutions would be expected to consult pursuant to 45 C.F.R. § 46.103(a) (e.g., the IRB chair or vice chair, the IRB administrator, or the institutional official administering the FWA) should be involved in early discussions about whether it is appropriate for the relying institution to rely on the approving institution’s IRB.
The potential participating institutions should promptly agree upon the mechanism by which a specific IRB will review the proposed research and, if relying, by which it will rely upon the IRB of the other institution. This coordination may occur between their respective institutional officials, one of whom may serve as a central point of communication, to address questions about conflicts of interest for IRB members; trainee involvement in the research; data and safety monitoring arrangements; and any other study matters.
While not required, the mechanism(s) that the participating institutions use to coordinate and communicate with each other may facilitate protocol review and approval while minimizing the duplicative efforts that can delay or hinder timely and consistent decisions by the participating IRBs . Processes for communicating between institutions are important for facilitating efficient processing of the protocol review. Institutions seeking to rely on another institution’s IRB must enter into a written, binding agreement with the IRB of the other institution specifying that the reviewing IRB will be responsible for all required activities under the Common Rule and—when applicable—the FDA regulations (21 CFR parts 50 and 56). Examples of issues that relying institutions may wish to address in the written agreement include the criteria for maintaining a reliance relationship, the sharing of specific study information including the study site location, compensation to subjects, records retention and confidentiality, liability, and review of the agreement.
Institutions that choose to engage in collaborative research may consider the NIH website that serves as a central website for investigators looking for reliable, up-to-date, and comprehensive information on multi-site studies. In addition to general information on study design, NIH has developed several models for "Single IRB Review of Multi-Site Research" (sIRB), which address single IRB review, the roles of participating IRBs, and the responsibilities of the participating institutions involved in multi-site studies.
Obstacles to Reliance Agreements
One of the major challenges with managing IRB reliance agreements is ensuring that the participating IRBs are performing the same the number and types of review activities as the IRB of record. There are a few institutions that have adopted policies to ensure that reliance partner IRB(s) perform reviews but that information must be properly reviewed by the program compliance staff. The reliance agreement should be specific about which institution/adult or children populations will be enrolled in the research, and which institution will be obtaining consent (if relevant). If the IRBs have multiple roles, it is important to ensure the study team understands the multiple IRB role description and what each IRB requires in order to fulfill their requirements.
There are also potential concerns with one-site major protocol changes and/or unanticipated problems that may not be reported to each reliance partner IRB in a timely manner. There seems to be different interpretations of what "immediate reporting" means within the IU and external research community. If an adverse event occurs at one site and an IRB authorized investigator identifies an immediate reporting timeline should be developed in order to prevent duplication of reporting and IRB action. The potentially differing expectations of reliance partner IRBs can spark conflict if not properly communicated to the study teams and understood. The IRB staff can provide the study team with template language to include in continuing review reports that will help the IRB of record better inform each relying IRB. A potential concern is the level of detail described in individual site submissions submitted to the IRB of record versus one site. If one site provides detailed information about adverse events occurring at its’ site and the IRB of record approves the report, the relying sites will receive more information than if the IRB of record received a group report from the study team.
The IRB could potentially face compliance challenges if a relying site does not follow the approved protocol. If a relying IRB was unaware that a relying site/organization has modified the approved study design, and the modification is later identified to be a significant deviation or violation that could negatively affect the protocol, the relying IRB could be cited for noncompliance. Sites should keep in mind that the IRB is the IRB of record for all sites combined, therefore there may be conflicts between the common practice and how the protocols and consent forms were presented to the IRB of record. A communication plan should be developed that makes it clear to investigators and study teams that they can submit a group submission or individual submission.
Reliance Agreement Best Practices
To ensure continued compliance with IRB policies, procedures, and applicable regulations, institutions should monitor and audit the activities occurring under reliance agreements. Conducting internal audits of ongoing research protocols can alert institutions to compliance vulnerabilities and provide the opportunity to explain and correct these vulnerabilities to ensuring compliance moving forward. IRBs may consider including a Monitoring Protocol that is customized to each protocol relying on its services. As mechanisms to distinguish commonplace violations from those requiring more immediate attention, monitoring protocols should include a review of the following: Once an issue is identified, IRBs should report and resolve issues expeditiously. In order to address compliance matters internally, institutions should develop and implement SOPs or QA Plans detailing which department or personnel is responsible for investigating protocol noncompliance and how corrective action will be evaluated and implemented. The institution may also choose to implement a plan detailing when and how corrective actions will be reported to, and subsequently tracked by, the IRB. The actions taken by the IRB, including corrective actions that are mandated or voluntary, and the rationale behind such actions should all be documented in the IRB’s minutes. A Compliance Plan, which may be an appendix to the institution IRB’s SOPs, should accompany the institution’s assurance and provide additional details. For serious or continuing noncompliance, the IRB is required to promptly send the institution and the IRB with oversight responsibility, if different, a report of the noncompliance (see 45 CFR 46.113; 21 CFR 56.108(f)). In addition to a description of the noncompliance, the report should describe what corrective actions were, or should be, taken to prevent the recurrence of the noncompliance. The IRB must also file an Office for Human Research Protections ("OHRP") report. While OHRP has issued the Guidance, it is essential to note that IRBs and institutions, and researchers and research staff-regardless of whether employed at or affiliated with institutions holding an OHRP FWA-must comply with the revised Common Rule, which takes effect January 20, 2018. Institutions with single IRB review plans that will rely on external IRBs should, therefore, familiarize themselves with the revised rules and develop corresponding SOPs to address the actions required, limiting the external IRB’s responsibility to only those requirements applicable to the relying institution.
The Future of Reliance Agreements and IRBs
It is becoming increasingly clear that the past several years have brought a metamorphosis in human subjects research protections as we knew them. As institutions. IRBs, and sponsors adapt to modernization, so must reliance agreements.
The growing phenomenon of single IRB review for multi-center trials is becoming more and more established as the National Institutes of Health (NIH) and industry trial sponsors continue to move toward streamlining review on multi-site studies. With the NIH, in particular, mandating single IRB review for most of its supported research, other funding agencies are likely to follow suit. Large multi-center networks like the Clinical and Translational Science Awards (CTSA) program at NIH already have transitioned to single IRB review. These changes are in line with a large push toward efficiency and reduction of duplicative activities in human research protection programs.
The number of institutions relying on one another for review through reliance agreements is also increasing. To support this, the federal-wide system of federal regulations , the Common Rule, has established a framework for such arrangements. That framework is further defined in the Draft NIH Policy for the Use of a Single Institutional Review Board of Record for Multi-Site Research, which streamlines the process for studies funded or conducted by the NIH. Healthcare institutions across the nation have already implemented local practices consistent with the Common Rule, including policies on how to enter into a reliance agreement.
Institutional Reliance Decision Trees are also emerging and provide a critical tool to guide decisions about how to proceed when a study requires multi-site implementation or a single site must rely on another IRB. These resources can help sponsors, institutions, and IRB members navigate the complexities of single IRB review and make informed decisions.
As protocols become more complex, expanding the number of institutions involved in study implementation, and the Regulatory Framework continues to be updated, the relevance and applicability of Reliance Agreements will only increase.