Advarra
ingle institutional review board (sIRB) review for multisite or cooperative clinical trials in the United States has had a long, twisty history and is expected to take another turn by the end of the year. Industry sponsors and contract research organizations (CROs) may be aware of the anticipated FDA sIRB mandate, but many don’t fully appreciate its seismic impact.
To comply with the 21st Century Cures Act, the US Food and Drug Administration (FDA) released a Notice of Proposed Rulemaking (NPRM) in September 2022 entitled “Institutional Review Boards; Cooperative Research”. The notice specifically indicates FDA’s intention to require (with few exceptions) any US institution participating in a multicenter clinical trial to rely on the review of an sIRB selected by the sponsor.
The National Institutes of Health (NIH) sIRB policy became effective in 2018 for NIH-funded research. The Federal Policy for the Protection of Human Subjects (or the “Common Rule”) implemented the sIRB mandate in nearly all federally funded human research in 2020. Once the FDA’s sIRB mandate is in effect, it will affect the remainder of non-federally funded research, and then nearly all multisite research conducted in the US will require sIRB review.
Trimming the Fat with Regulatory Alignment
Centralized IRB review will have many downstream effects, but perhaps the greatest impact is the potential for reducing administrative burden on investigators, sites, and sponsors. It also promotes consistent study conduct across all sites, which in turn will produce more reliable data. Collectively, these benefits have the knock-on benefit of significant operational efficiencies when sponsors no longer must navigate multiple IRBs selected by the participating institutions.
For example, in one multisite influenza vaccine trial, the NIH compared the sIRB model to a local IRB approach and found that the mean time to approval was “substantially faster,” 81 versus 121 days. Time to first enrollment was also faster (126 versus 149 days, and faster compared with published averages of 169 days). The financial impact of getting a product approved 40+ days faster given limited patent exclusivity is upwards of millions of dollars.
The FDA has encouraged a centralized IRB review model for multisite trials since publishing its 2006 guidance document, “especially if using centralized review could improve the efficiency of IRB review.” The agency cited the increased number and complexity of clinical trials as a reason to consider an sIRB. Fast-forward 18 years, and indeed not only are there more trials but they are also increasing in complexity: the average number of endpoints, for example, has increased 6% each year since 2003, which adds urgency to transition now.
Given these pressures, Congress has been urging federal agencies to harmonize the many clinical research regulations and making the sIRB model mandatory. When the FDA complies, universities, hospitals, and health systems with their own IRBs (i.e., local IRBs) will be required to cede review to the sponsor’s sIRB of record. The move will likely have a disorienting effect, particularly on academic medical centers (AMCs) that historically prefer to retain the responsibility of overseeing FDA-regulated research at their own institutions.
Even so, the sIRB model is poised to become the standard for multisite FDA-regulated research, marking a sweeping transfer of power—and responsibility—to sponsors. Sponsors will need to take the responsibility for and lead on a smooth transition for all stakeholders, especially with AMCs that are central to most US research.
Three Steps to sIRB Readiness: What Sponsors and CROs Need to do Now
In this new FDA-mandated sIRB paradigm, sponsors will need to work closely with commercial and institutional IRBs to determine the best way to implement the requirements. Here are three important steps forward:
1. Establish clear standards for selecting an sIRB of record.
Sponsors’ first step is to establish clear standard operating procedures (SOPs) on how to choose an sIRB of record. For example:
- identify who will make the final decision or whether there will be a selection committee;
- determine how the process will be documented;
- set up training on the SOPs; and
- create a baseline list of mandatory characteristics for all sIRBs of record that includes the following:
- Accredited by AAHRPP
- Demonstrated substantive (defined by years’ experience, geography) experience overseeing multisite trials
- Proven scientific expertise in the therapeutic area under study
- sIRB has prior experience reviewing trials for the AMCs expected to be involved in the trial
2. Collaborate with AMCs and other Sites to align on new workflows.
Once sponsors have selected their preferred sIRBs, prepare research sites to work most efficiently with sIRBs. Don’t assume all sites are proficient at working with commercial IRBs. Every IRB has different processes, workflows, operations, and preferred contract language, so it is critical to bridge those gaps and ensure that all stakeholders are familiar with one another’s working patterns.
More specifically, take time up front to:
- Introduce sites to the preferred sIRB(s) early so the sIRB and site teams can work together directly to tailor processes. This could be as simple as sending a letter to the study’s selected sites introducing the site’s research team to the study’s sIRB, or as complex as providing a detailed informational package with instructions on how to get started, interactive videos, and other materials.
- Provide the sIRB(s) with the sponsor’s preferred site list so they can see which sites already have sIRB service contracts or other reliance agreements in place and which ones still need to be set up.
- Collaborate with sites on institutionally required informed consent language before a study, so the sponsor and site agree upon what should be included without hampering sIRB processes.
- Establish preferred communication channels and train staff to ease collaboration.
It is important to note that sIRB mandates from NIH or FDA do not eliminate the need for institutions to maintain a local ethics or Human Research Protection Program (HRPP) office. These local research oversight offices have other responsibilities besides administering the IRB review. For instance, verifying researcher and staff training, coordinating other institutional oversight committees, and tracking the status of research overseen by various sIRBs will remain at the institution. Also, a local IRB will still be needed at sites conducting their own investigator-initiated single-site research.
Sponsors will need to recognize that sites retain responsibility for adequate oversight over research conducted on their campuses. Therefore, providing sites with visibility into the sponsor’s sIRB selection criteria and process will improve the partnership and ease the transition.
3. Re-evaluate site performance to drive consistent improvement across the clinical research enterprise.
The proposed mandate offers a great opportunity for sponsors to re-evaluate commonly used trial sites, analyzing their performance based on key and standardized indicators such as study start-up time, enrollment diversity, and participant retention rates. Using consistent metrics, sponsors can make objective comparisons of sites and understand which sites are contributing to efficient and compliant clinical research across the portfolio rather than selecting based solely on institutional reputation or name recognition.
Since the regulations will transfer more leverage to sponsors, the latter have a unique chance to re-evaluate efficiencies and performance, versus deferring to legacy AMC policies. For example, sponsors that blindly select the same cancer center because that’s what they’ve always done could inadvertently cause unnecessary administrative delays. A well-recognized cancer center may still be the right choice, but here is an opportunity to evaluate that choice based on evidence.
Measure Twice, Cut Once
The stakes are high in clinical research, as we sit on the threshold of solving some of medical science’s most intractable mysteries. At the same time, change is constant—especially when it comes to regulations. By taking the time to carefully plan our response to evolving compliance needs, sponsors and CROs can fully reap the efficiency and quality benefits of the sIRB mandate with just one cut to expedite novel medical product development, testing, and regulatory approval for the benefit of patients.