Blind spots: The hidden challenges of conducting multisite intervention research

Abstract

U.S. single-IRB (sIRB) policies require one central IRB to review federally funded multisite research. Although intended to support collaboration, few studies have explored the practical challenges of implementing sIRBs. Drawing on firsthand experience from a multisite project, we present challenges and solutions to inform researchers considering or required to use sIRBs. Challenges include identifying when sIRB review is needed, costs associated with sIRB review, insufficient communication pathways, and complex submission processes. Recommendations include consulting with the IRB early, proactively confirming reliance processes and needed updates, establishing expectations for clear communication across sites, increasing structural support to promote equitable participation, and standardizing local context review requirements to improve consistency and efficiency.

1. Background

Single Institutional Review Board (sIRB), also known as a central IRB, requires one IRB to review all sites participating in a multisite research study [1]. In 2014, the National Institutes of Health (NIH) in the U.S. published a draft that required domestic NIH-funded non-exempt, multisite human subjects research to use a sIRB of record [2]. After public comment and revision, the policy went into effect in January 2018 and was shortly followed by a similar requirement that was incorporated into the revised Common Rule (45 CFR 46.114) [3]. The stated purpose of this mandate is to eliminate redundant review, maintain consistency across different research sites, reduce administrative burdens on investigators and IRBs, and save time and money [4]. Despite positive intentions, implementing the guidance created challenges including the unclear role of the IRB vs. the research institution, limited investigator and institutional experience with the sIRB model, relationships between researchers and the sIRB, and contextual information from the individual research sites that needed consideration in the sIRB review [5]. Given a paucity of literature discussing the impacts and practical challenges of research requiring sIRB review, we present experiences from a research project involving implementation and survey evaluation of a web-based, multilevel behavioral intervention to provide insurance education, promote cost conversations and financial navigation, and connect patients with gynecological, prostate, lung, and colorectal cancer to financial resources to reduce financial toxicity [6]. Because this project required sIRB review, we draw on these experiences to highlight potential “blind spots” and present pragmatic solutions to support the research community. With an increase in collaborative, cooperative research and more funding agencies and organizations requiring this kind of review, there is an urgent need to consider how research teams can proactively prepare for anticipated challenges to avoid lack of harmonization and circuitous processes that contribute to research delays. It is also important to consider how sites can partner to identify and leverage organizational resources and regulatory approaches to streamline oversight and uphold equity, community engagement, and local context in research.

2. Blind spots: potential challenges of sIRB review

2.1. Knowing when a sIRB is needed vs. when it is not

First, research teams may have challenges determining how the project should be designated for IRB purposes, as this decision will guide the entirety of the submission process. Multisite research can either be designated as exempt, which will not require a sIRB, or non-exempt which will require one. When a project is exempt, certain federal regulations such as continuing review do not apply. Examples of exempt research projects include use or focus on established educational practices, educational tests or survey procedures, existing data, public benefit or service program evaluation, or taste and food quality [7]. On the other hand, non-exempt research involves procedures that are either minimal risk or greater than minimal risk that do not meet criteria for exemption [8]. Non-exempt research can be divided into two categories: no more than minimal risk research that can undergo expedited review or greater than minimal risk research that requires full board review [8].

In our project about implementation and survey evaluation of a web-based, multilevel behavioral intervention, our research team initially considered whether the project might qualify as exempt based on exemption category 3. This category details exemption for benign behavioral interventions that are “… brief in duration, harmless, painless, not physically invasive, and not likely to have a significant adverse lasting impact on subjects; further the investigator must have no reason to think the subjects will find the interventions offensive or embarrassing” [9]. We also considered engaging additional sites and collaborators to conduct the research, which raised questions about the extent of their engagement and study procedures at each site. Because there was uncertainty both about the project's exemption status and the level of site engagement, our research team consulted our institution's IRB to determine whether sIRB review would be required. This experience highlights two key challenges. First, research teams must rapidly determine the most appropriate regulatory pathway. This is extremely time sensitive given many research sponsors require IRB approval to release funding to research teams. When an sIRB may be required, extended timelines typically associated with sIRB approval add another layer of complexity and can restrict the release of funds to cover these research related activities. This makes early and accurate classification critical in the initial planning and development phases of the project. Second, interventions may be subject to institutional variability in how IRBs determine whether a project is exempt or requires sIRB review. IRBs occasionally make different decisions about the same study because they interpret and apply key terms in the regulations differently [10].

2.2. Costs

Another challenge research teams may encounter are recurring costs associated with sIRB management, including submission, modifications, and continuing reviews, which are embedded throughout the lifecycle of the study. Research projects may not include sIRB fees in the initial grant budget, creating funding constraints later in the research project. At a structural level, current funding and regulatory frameworks often do not provide clear guidance or standardized expectations for budgeting sIRB review, which could potentially lead to exclusion in the research budget or recurrent underestimation of these costs [11,12]. sIRB activities generally fall into two categories: primary and secondary. Primary activities include the initial review, continuing review, and study-wide modifications involving the ethical review of the research protocol and informed consent document(s) [13,14]. Secondary activities include completing site-specific documentation, reviewing reportable events from participating sites, and submitting protocol deviations [13,14]. Although IRB costs are often counted as indirect costs under institutions’ Facilities and Administration (F&A) rate, industry sponsored studies and studies using independent IRBs such as Western Copernicus Group (WCG) or Advarra are typically not paid by the institution and are considered direct costs [15]. When these fees are not anticipated, the IRB of record may charge for each primary and secondary activity. Not only is this costly from a financial perspective, but it is also costly from a time perspective.

Preparation for sIRB submission and approval for our research project took approximately 4 months (October 2025 - February 2026). Even with a research coordinator experienced in sIRB submissions, this timeline was lengthy because it required drafting consent forms, finalizing questionnaires, and completing all necessary information security reviews and web-risk assessments before submission. When these activities are unplanned, extended sIRB timelines require additional, unfunded effort to prepare submissions and satisfy regulatory requirements, which can unintentionally divert effort from other projects and delay research progress. Collectively, these financial and time burdens may restrict research teams from applying for funding mechanisms with strict submission timelines or short funding periods, threaten the feasibility and sustainability of multisite research, and disproportionately disadvantage investigators and institutions with fewer resources.

2.3. Communication

2.3.1. Communication across sites and IRBs

Research teams may also experience communication challenges as coordinating, aligning, and sharing information across multiple institutions and teams require streamlined processes. A study of 34 IRB, industry, and research team representatives identified insufficient communication as a common barrier to implementing the sIRB review process [16]. Specific challenges include limited correspondence between reviewing IRBs and relying sites, irregular feedback and updates, lack of an established point of contact or changes to points of contact due to IRB staff turnover, and a lack of clarity about how determinations are made by the reviewing IRB [16]. These challenges are exacerbated when IRBs have strict policies about engagement with external sites in multisite research. Some IRBs prefer to communicate directly with the research team at their own institution (e.g., lead principal investigator or designated delegate), whereas others prefer to communicate directly with relying sites on an as-needed basis.

In our experience, when a participating site had questions about consent form modifications and workflow adaptations (e.g., using MyChart messaging for recruitment) to fit their site's needs, a member of the research team at the reviewing IRB site needed to contact the IRB for guidance. Without direct channels for relying sites to ask the reviewing IRB questions to properly execute submissions, prolonged cycles of clarification and responses between groups may occur [3]. Overall, lack of streamlined processes, designated points of contact, and direct communication can lead to confusion and project delays.

2.3.2. Insufficient communication pathways

Other challenges include lack of real-time guidance for completing forms, complex electronic document management, and limited transparency regarding review delays [17]. This is compounded by the absence of a shared electronic platform across sites. In our project, one participating site had questions about the submission process, and our research team was unable to see or offer support unless we were added as a delegate in their system. Although delegates are required for anyone accessing or editing study materials, this may not be appropriate in cases where relying sites need support but would like to manage submissions and study-related documents on their own because of legal responsibility. Thus, lack of shared access to specific platforms and information may hinder the hands-on support that research teams, especially those with limited sIRB experience, often need throughout the submission process to ensure timely submission and response to the reviewing IRB (or IRB of record).

2.4. Complex submission process

2.4.1. SMART IRB agreements

Multisite collaborative research is often supported through the Streamlined, Multisite, Accelerated Resources for Trials IRB (SMART IRB) Reliance Platform. This platform, funded by the NIH to support national adoption of sIRB review, provides a master reliance agreement, a method for institutions to join as participating sites, supporting resources and education, and a web-based process to request, track, and document study-specific reliance agreements [3]. Although more than 1,400 participating institutions have joined the SMART IRB, sites must maintain compliance; as of March 2025, all participating institutions must join version 3.0 to initiate new reliance agreements [18].

Our research team experienced delays when we learned the reviewing institution (or IRB of record) was on version 3.0, but the relying site was on version 2.0. Despite the relying site being sent an initial notification to join version 3.0, uncertainty in the process around the required activation steps after execution of the agreement resulted in a discrepancy between the relying sites' records, which showed they were on version 3.0, and the IRB of record, which indicated they were not. We initially anticipated a quick update, but we learned that the relying site's contracts office needed to be re-engaged to review the new version. Reviewing reliance agreements for compliance is an important but often lengthy process, particularly when legal review raises concerns about specific provisions in the reliance agreement [19]. Even when research teams anticipate and carefully plan timelines to account for the reliance review process, unanticipated delays are common. These delays further impact project timelines and milestones because reviewing institutions generally will not review submissions or agree to assume oversight responsibilities until reliance agreements are fully executed.

2.4.2. Local context review

Local context review is the most frequently cited challenge of implementing sIRB review [20]. The NIH sIRB policy and updates to the Common Rule not only increase the prevalence of multicenter research but also increase the number of research projects reviewed by an IRB external to the research site. In addition to executing reliance agreements when there is an external IRB, sites must often complete local context review, a supplementary process in which relying sites review study documents to ensure that the research complies with state laws, institutional policies, and overall community standards. Local context review is outlined in Common Rule stipulations that require IRBs to “be able to ascertain the acceptability of proposed research in terms of institutional commitments (including policies and resources) and regulations, applicable law, and standards of professional conduct and practice,” and to be sensitive to such issues as “community attitudes” [21]. This policy does not offer explicit criteria or concrete examples of what constitutes “community attitudes.” It also provides very limited guidance on how local IRBs or sIRBs should attend to local contextual considerations in review and oversight [22]. As a result, there is confusion and a lack of consensus about what this process should entail [23]. Stakeholders frequently report a wide range of what is considered local context among different IRBs. This has very important implications for justice if disparities arise in protections for human subjects across sites, and for social value if institutional policies restrict the generation of scientific knowledge by introducing unnecessary administrative burdens that significantly delay research [21].

Although adapting protocols and consent documents to best fit the research site and the populations it serves (e.g., translating documents to Spanish based on the demographic makeup of the area) is extremely important, local context review can often be duplicative. For example, one partnering site in our study needed to submit two applications before the start of the research project: one to our sIRB as expected, but their local IRB also required full submission. This process adds significant time and can delay the study launch as each institution has unique review timelines and requirements for submissions. Further complicating local context review, especially for cancer-related trials, some institutions require approval from additional governing bodies, such as Protocol Review and Monitoring Committees (PRMCs) before IRB applications can be submitted. Secondly, in cases where consent forms needed to be translated, some partnering sites’ IRBs required certified translations or additional review by an IRB member or person fluent in that language. Many study teams would agree that these procedures promote beneficence by helping ensure that all participants understand study procedures and can make informed decisions. The challenge is that they can substantially extend research timelines by adding significant administrative burden. Thus, while the Common Rule clearly requires attention to local context, its lack of operational detail leaves institutions to interpret local context considerations on their own, resulting in inconsistent and duplicative processes that do not align with the intended goal of making collaborative research more streamlined and efficient.

3. Corrective lenses: solutions to streamline the process

3.1. Consult with your IRB early

Partnering with the IRB throughout the entire lifecycle of the single IRB project is hugely important, but especially in the initial planning and development phases to prevent delays and clarify regulatory expectations. First, consulting with the IRB during the grant writing phase can minimize unexpected costs by developing a budget justification that appropriately reflects sIRB fees, staff time required for submission, and funding to cover the time needed for regulatory review. Secondly, when researchers engage their IRB early in the process, these conversations help guide protocol development, recruitment plans, and help clarify each site's roles and responsibilities in the project. Moreover, researchers gain critical guidance on risk classification, consent procedures, and the appropriate designation of the project (i.e., exempt, expedited review, or full board).

In our behavioral research example, there was a possibility the project could be designated as exempt, which would not require sIRB review. Early consultations with the IRB helped to determine the most efficient and appropriate submission pathway for the research project. This early alignment helped us design our study in a compliant way from the start rather than needing to make major changes later, which can also significantly contribute to sIRB implementation bottlenecks. Not only does early IRB consultation serve as a strategy to support smoother submission, but it also helps research teams better understand fee schedules and potential charges associated with conducting the research. Unexpected fees can cause major budgetary burdens, so understanding how/when regulatory tasks such as modifications, unanticipated problem reporting, or continuing reviews incur costs can help support project planning. Early guidance also reduces the likelihood of multiple protocol revisions which can incur extra charges at some institutions. Overall, early IRB engagement helps research teams budget accurately, avoid preventable fees, and submit the protocol for review without unexpected costs.

3.2. Proactively confirm reliance processes and needed updates

Establishing reliance processes early is also important during the planning and development phase of a sIRB. Reliance processes are the operational backbone for multisite projects, so this allows time to confirm whether an institution has signed on as a SMART IRB member and if so, which version of the agreement it operates under. In our experience, institutions can sign older SMART IRB agreements and still be using these reliance templates and internal documents that require updates before new protocols can be approved. By addressing this early, sites can proactively update reliance documents, secure signatures, meet with institutional governing bodies, and transition to newer, correct versions. When initiated later than the planning and development phases, these steps can often take longer than expected. Early coordination also ensures that each site clearly understands their roles and responsibilities, clarifies expectations for reporting and documentation, and clearly outlines project workflow before protocols are submitted and implemented. Finally, confirming reliance processes early allows sites time to identify local context requirements and adjustments, ancillary reviews, and data sharing standards. Strategic, proactive planning of reliance agreements can allow for smooth multisite coordination rather than prolonged, reactive processes.

3.3. Establish clear communication

Multisite research requires clear, effective communication across sites to ensure the research is truly collaborative as intended. To increase engagement across sites, our research team met at least once a month during the planning and development phase to discuss unanticipated barriers, establish timelines (e.g., start or launch dates), conduct training, review the manual of procedures (MOP), and answer project-related questions. First, transparent communication helps ensure compliance by preventing protocol deviations, missed reporting requirements, or misunderstandings about local context [24]. Although the study described in this paper is a minimal risk behavioral study, this is especially important for multisite, high-risk investigational trials that may have unanticipated problems that often need to be reported within a specified time period. Not only do the principal investigator and the IRB of record serve as a point of contact for the conduct of the research to ensure compliance, but they also serve as a source of support throughout the submission process for the relying sites. Strong communication allows research team members at the reviewing institution, who are often more familiar with the protocol, to guide relying sites through application preparation and submission. Identifying these internal points of contact and providing regular opportunities for communication can significantly reduce errors, incomplete submissions, and back-and-forth revisions. Moreover, points of contact offer a continuous resource throughout the project; when issues arise, knowing who to contact can minimize project disruptions and increase overall engagement.

3.4. Increase structural support to promote equitable participation

Structural challenges such as differences in research infrastructure across sites, lack of dedicated regulatory staff, and limited training could be addressed if structural support for relying sites was strengthened. First, providing both principal investigators and staff with training in sIRB processes could fill critical gaps. The Trial Innovation Network (TIN) provides a robust example of how sites can increase engagement and provide researchers with support. In addition to having consultations with research teams, TIN provides tailored training for study personnel via webinar, phone, or in-person to help sites navigate the onboarding process and prepare materials for submission [5]. Individualizing support rather than providing one-size-fits-all recommendations is important because not all sites start with the same organizational resources or knowledge of the IRB's expectations, forms, and workflows. Thus, educating and training study teams empowers them to lead and support their sites effectively.

Secondly, structural support for navigating electronic systems required throughout the project is key. Implementing simplified submission portals that increase shared access and increase relying sites’ ability to submit documents, track revisions, and receive updates could systematically support one of the main goals of the sIRB framework: to increase collaborative research. These structural solutions ensure that all institutions, especially those newer to research or with fewer resources than large academic centers, can contribute fully to the conduct of the research. Increased engagement and partnership with diverse institution types (e.g., institutions of different sizes and experience) reduces disparities in which institutions can contribute to the generation of scientific knowledge and creates a more equitable and efficient sIRB ecosystem.

3.5. Standardize local context to improve consistency and efficiency

Because local context review is often the most cited challenge of sIRB implementation, there is a clear need to develop operationalized definitions of local context review so that institutions and regulatory bodies interpret NIH and federal guidelines consistently. A scoping review identified five potential goals of local context review: (1) protect the rights and welfare of local participants; (2) ensure compliance with applicable laws and policies; (3) assess feasibility; (4) promote the quality of research; and (5) promote procedural justice [21]. The review also identified four categories of information that might be considered part of local context review: (1) population/participant-level characteristics; (2) investigator and research team characteristics; (3) institution-level characteristics; (4) state and local laws; and (5) characteristics for study exclusion from sIRB requirements [21]. Widespread adoption of these priority areas can reduce variability, create more predictable workflows for oversight and review, strengthen compliance, and overall provide smoother collaboration experiences for sites. To give attention to these priority areas and further implement standardized processes, SMART IRB recently published Recommendations for the Harmonization of Local Considerations [25]. The recommendations highlight three key areas: (1) definition of local considerations; (2) the type and detail of information collected to address local considerations; and (3) assessing local considerations throughout the life of a study to improve consistency and efficiency [25]. With more clearly defined local review processes, more sites could begin to submit abbreviated local forms with defined criteria to confirm all local requirements have been addressed prior to sIRB submission, which would reduce the need to submit a full local IRB submission in addition to a separate sIRB submission.

4. Conclusions

The intended purpose of the sIRB mandate is to eliminate redundancies, improve consistency, reduce administrative burden, and streamline processes. While the National Cancer Institutes' Central IRB has become the archetype of demonstrated sIRB efficiencies (e.g., saving effort and time, rapid reviews, and cost savings) [26], other entities are awaiting similar results. Innovative approaches to solve these challenges include the SMART IRB and information technology platforms to facilitate multisite review [27]. Such innovations have improved the administrative feasibility of sIRBs and matured the reliance infrastructure, but day-to-day implementation challenges remain for research teams due to persistent bottlenecks and inefficiencies. These practical challenges are timely to address given the NIH and Food and Drug Administration (FDA) requirements, which will likely continue to increase use of sIRBs. Although there is literature predicting how these policies would impact research teams, there is a paucity of literature exploring the practical challenges of implementing these requirements, especially for specific project types. Because grant-funded projects must operate within strict timelines, addressing potential bottlenecks in the sIRB pathway is critical to avoiding unintended delays, unexpected costs, and non-compliance. In this paper we identify “blind spots” and offer practical solutions, or “corrective lenses,” research teams should consider as they prepare grants and IRB submissions. Reducing implementation barriers has important implications for the research ecosystem. For external sites less connected to the main site's research environment, a streamlined sIRB can support greater engagement and provide valuable exposure to a wider range of research opportunities. When barriers disproportionately impact research teams without robust sIRB knowledge, as well as non-academic sites and institutions with limited research infrastructures, steep learning curves and differential access to resources needed to overcome these barriers undermine the collaborative nature of multisite research. While research teams can mitigate some of these barriers, system-level changes are still needed. Communication pathways and submission processes surrounding sIRBs should be restructured to reduce administrative burden and redundancy. Although these recommendations are based on the U.S. sIRB context, they may offer useful insights for a broader community of researchers conducting collaborative, multisite research. Future work should further examine how these issues may differ across study types and regulatory environments.

Funding

The research project described was funded by the National Cancer Institute (U19CA291430-5631). The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or other funding agencies.

CRediT authorship contribution statement

Krista E. Cooksey: Writing – review & editing, Writing – original draft, Conceptualization. Rachelle Roy: Writing – review & editing, Conceptualization. Carissa Minder: Writing – review & editing. Mary C. Politi: Writing – review & editing, Supervision, Funding acquisition. Ashley J. Housten: Writing – review & editing, Supervision, Conceptualization, Funding acquisition.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Krista E. Cooksey reports financial support was provided by National Institutes of Health National Cancer Institute. Rachelle Roy reports financial support was provided by National Institutes of Health National Cancer Institute. Mary C. Politi reports financial support was provided by National Institutes of Health National Cancer Institute. Ashley J. Housten reports financial support was provided by National Institutes of Health National Cancer Institute. Carissa Minder reports a relationship with SMART IRB Ambassador that includes: employment. Mary C. Politi reports a relationship with EPI-Q Inc that includes: consulting or advisory. Mary C. Politi reports a relationship with UCB Biopharma that includes: consulting or advisory. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

List of abbreviations

sIRB

Single Institutional Review Board

NIH

National Institutes of Health

F&A

Facilities and Administration

WCG

Western Copernicus Group

SMART IRB

Streamlined, Multisite, Accelerated Resources for Trials IRB

PRMCs

Protocol Review and Monitoring Committees

TIN

Trial Innovation Network

FDA

Food and Drug Administration

Data availability

No data was used for the research described in the article.