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Applied Clinical Trials
Regulators and sponsors encourage alternative review models to fit a growing research enterprise.
Continued expansion of human subject research around the world is generating calls for a more efficient and effective oversight system to evaluate research protocols and monitor trial operations. This task largely is the responsibility of Institutional Review Boards (IRBs) at research organizations and in communities where clinical research takes place.
For several years now, research sponsors at government agencies as well as pharma companies have been turning more to central IRBs to provide more timely and coordinated research review of multicenter trials, many involving complex study designs and large numbers of subjects.
This trend has raised an outcry from academic research centers that consider local review critical to understanding the values and attitudes of the local population participating in a study, a particularly important issue for conducting research in foreign countries. At the same time, many local IRBs lack the resources, staff, and expertise needed to evaluate and monitor the growing volume of trials.
The benefits and weaknesses of both local and central IRBs was the subject of debate at a National Conference on Alternative IRB Models in Washington, DC, last November. The conference, which followed the annual meeting of PRIM&R (Public Responsibility in Medicine and Research), attracted 400 participants eager to discuss the changing roles of IRBs in biomedical research. The starting point was a report from a smaller workshop in November 2005 that had been proposed by the Secretary's Advisory Committee on Human Research Protections (SACHRP) to explore alternative models to local IRB review.
Following that workshop, FDA issued a guidance last March (2006) to clarify that reliance on central IRBs to oversee multicenter trials does not violate agency regulations. The guidance explains that FDA regulations permit an IRB at a different location from the actual research site to review the study, so long as the central board understands the local context and is sensitive to community values. Conversely, separate research review at multiple sites can result in "duplication of effort, delays, and increased expenses" says the document, adding that "greater reliance on a centralized IRB review process, in appropriate circumstances, could reduce IRB burdens and delays."
This document and other guidance under development by the Office of Human Research Protections (OHRP) reflect continued tension between the need for IRBs to represent the interests of the local community where research is taking place, and the need for more efficient and coordinated oversight of research at multiple sites.
Conflicts and Confusions
Central IRBs, which may be commercial operations or established by public research organizations such as the National Cancer Institute, often have greater resources, access to experts on cutting-edge science, and large information systems.
Cancer researchers are some of the most vocal proponents of central IRB review, particularly for "smart studies" that test candidate therapies in patients most likely to respond and that need to enroll patients at many sites across the nation and the world, explained Lowell Schnipper, MD, of Harvard Medical School and Beth Israel Deaconess Medical Center. Central IRBs may reduce costs by eliminating duplicative reviews and ensuring consistency in consent forms, protocols, and results across all sites.
Pharma companies have long used central IRBs to obtain efficient review of protocols and research programs, which often involve many study sites, including doctors offices and clinics. Even with the recent increase in industry-sponsored trials at academic institutions, industry sponsors want academic researchers to use a central IRB to oversee the total study, a demand that increasingly dismays many IRB operators.
In fact, officials at research organizations around the country fear that a wholesale shift to central IRBs will undermine the current infrastructure designed to ensure that human subject research fits community standards and values. Richard Bianco, associate vice president for research and regulatory affairs at the University of Minnesota, advised attendees at the IRB conference to "slow down" the rush to outsource research oversight. He maintained that the local system for subject protection "is not significantly flawed," but suffers primarily from a lack of resources and support.
What is really needed is more investment in building the local compliance infrastructure and more help for investigators in developing sound protocols that IRBs can review more efficiently. Bianco blamed delays in local IRB review on poor applications, lengthy intellectual property negotiations, and difficult conflict-of-interest issues. Such problems can be addressed, he proposed, by making the institutional review process more efficient, instead of outsourcing entire categories of research.
Robert Levine of Yale University's Interdisciplinary Center for Bioethics agreed with Bianco's assessment of the situation, but not with his remedy. A key problem is that local IRBs no longer can attract prominent academics as they once did. Leading medical school professors don't want to serve on IRBs, Levine observed, because they're too busy running trials, don't want to discipline colleagues, and don't want to spend hours in meetings and reviewing adverse event reports.
Levine predicted that the shift to central IRBs will accelerate, but acknowledged that "something of immeasurable value will be lost" in the process. There is a need for a local "institutional presence" to remind people of the importance of ethical research, Levine observed, noting that it is hard to transmit a local board's knowledge of a local population and cultural norms to a central IRB.
The leading remedy for this type of town–gown conflict is to clarify responsibilities and articulate which oversight activities are best performed by local and by central organizations under a shared review process. In situations where local context is particularly important for subject protection, a central IRB would collaborate with a local board. But for multicenter trials, most other oversight activities—protocol review, evaluation of study risks, review of safety information—are best achieved centrally, commented Jean-Louis Saillot of Schering-Plough Research Institute.
A key issue is liability for patient harm if there are problems in a clinical trial. Local IRBs are concerned that they are legally responsible for research performed at that institution and thus are obliged to review planned research programs. Any joint oversight model requires written contractual agreements up front, noted Angela Bowen, head of Western IRB. OHRP Director Bernard Schwetz explained that if there is a clear agreement regarding study oversight between a central and local IRB, OHRP will pay attention to this if a problem erupts. But he acknowledged that "the liability issue for IRBs is huge" and that it is difficult to draw the line between central vs. local responsibilities.
The other big issue is the potential loss of resources for local IRBs, Schwetz notes. If research institutes shift more oversight responsibility to outside organizations, local boards stand to lose badly needed funding, making it even more difficult for them to maintain the infrastructure needed to provide efficient and effective oversight. One proposal is that sponsors provide some funding for local board operations out of the savings achieved by shifting review responsibilities to central IRBs.
Whatever model is adopted, Schwetz commented, there is a need to ensure human research protection at every research organization. He objected to suggestions that OHRP has lost confidence in the ability of local IRBs to monitor research or that the agency wants to push researchers to use central IRBs. OHRP's goal is to "match the IRB model to different needs," he said, and to ensure that research sponsors that choose to use alternative oversight models understand the rules and their responsibilities.
OHRP and sponsors of the November conference are preparing a report to clarify the key issues for both research institutions and sponsors to consider in seeking the most appropriate oversight approach.
Jill Wechsler is the Washington editor of Applied Clinical Trials, (301) 656-4634 firstname.lastname@example.org