NEWS

Growing Pains: Central Review Board Project Still Developing

Judith Randal

During the 1970s, when the institutional review board (IRB) process was newly the law of the land, clinical trials done by a single investigator at a single institution were the norm. Today’s trials, however, are more often enterprises in which networks of investigators at hundreds or even thousands of institutions collaborate.

Yet the rule still is, as it was originally, that every institution that plans to have patients on a trial must first have its own IRB review the protocol—the study’s research plan—to be sure that it is ethically sound. Multicenter trials have made clinical trials more widely available and have other advantages as well. It stands to reason, for example, that therapies for adult cancers, in particular, would be more generalizable if the trials cast an even wider net. But there are barriers to trial expansion, and one is the local IRB approval requirement.

Perhaps no one is in a better position to know that than Robert Catalano, Pharm.D., who serves as vice president for regulatory affairs for the Coalition of National Cancer Cooperative Groups, the regulatory officer for the Eastern Cooperative Oncology Group, and the director of scientific affairs for the Clinical Trials Research Center at the Drexel University College of Medicine, all in Philadelphia.

One of the problems, said Catalano, is that IRB review of protocols on an institution-by-institution basis tends to drag out the implementation of trials and thus delay getting them fully up and running. Another is that the duplication of effort by local IRBs does not come cheap. Catalano cited the situation at Drexel, his own institution, as suggestive. "I estimate that we use about 30 to 35 cents of every research dollar on regulatory compliance for human subjects protection," he reported, "and we are surely not unique."

All of this was factored into the National Cancer Institute’s pilot project for the central IRB (CIRB), which was launched in January 2001. Its aim is to enable local IRBs to retain their responsibility for the ethical quality of trial protocols, as the law requires, but to spare them the duplications of effort that Catalano laments.

Local IRBs that sign up for the pilot project (there are now about 100 local IRBs participating) agree to let the CIRB have first crack at assessing the ethical adequacy of all the protocols for cancer-related phase III trials (i.e., randomized controlled trials) that their institutions plan to host.

Once the CIRB—which meets monthly in Maryland near the National Institutes of Health campus—is satisfied that a protocol is ready for implementation, it returns it to its local IRB clients. The local IRB can then simply approve it—a fast-track process known as "facilitated review." But local IRBs that find the CIRB’s work unacceptable still have the option of performing the review themselves. Either way, said Michaele Christian, M.D., associate director of NCI’s Cancer Therapy Evaluation Program, the CIRB and the local IRBs of participating institutions are, in effect, partners.

None of the 16 members of the CIRB are federal employees and, like other IRBs, it consists of physicians, other health professionals, medical ethicists, and patient advocates. Unlike most IRBs, however, it is entirely composed of people with cancer expertise and deals only with cancer trials.

This has made a fan of at least one local IRB chair: Joseph Breault, M.D., of the Ochsner Clinic Foundation in New Orleans. "IRBs are really stressed out all around the country, and ours is no exception," Breault began. "So, just the fact that the CIRB has lightened our administrative load has been wonderful for us. But what matters more, I think, is that it’s the best thing ... to help us protect human subjects in oncology trials. Protecting them can be especially tricky because of the highly toxic drugs the trials typically employ."

A further problem that the Ochsner IRB shares with many others, Breault added, is that its oncologists—the very people most familiar with toxicity issues—usually have to leave the room when a cancer protocol is discussed because they are themselves likely to have patients entered on the trial or to have other ties to it that are possible sources of bias. Thus, the beauty of the CIRB, in his view, is that members rarely need to recuse themselves from the process, so the CIRB is free, unlike many local IRBs, to provide "the kind of knowledgeable scientific review that patients who are candidates for oncology trials deserve."

Much the same point was made by the CIRB’s chair James Wade III, M.D., whose regular job is director of the Cancer Care Institute at the Decatur (Illinois) Memorial Hospital. But beyond that, he offered several examples of issues the panel has dealt with so far.

Typical of the more truly serious lapses the CIRB has dealt with, Wade said, was an investigational chemotherapy protocol that was expected to predispose patients to certain infections. The protocol, to be sure, specified that such infections be treated with a particular sulfa drug. But it was silent on what to do for trial patients with these infections if they could not tolerate sulfa compounds. To leave that to chance, he noted, could potentially change the trial’s outcome and muddy the meaning of its results.

Nonetheless, the CIRB has its critics, principally in cancer cooperative group circles. Robert Comis, M.D., a professor at the Medical College of Pennsylvania-Hahnemann University, also chairs the Eastern Cooperative Oncology Group. "Many of us believe in the concept of a central IRB because it’s inherently inefficient to have a given protocol reviewed hundreds or thousands of times," he said. "The difficulty is that the pilot project has turned out to be much more complicated than anyone would have imagined."



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Dr. Robert Comis

 
One issue, he and others interviewed for this article said, is that, for whatever reason, many local IRBs that deal with oncology protocols have been reluctant to "buy into" the pilot project. Thus, although some 100 local IRBs have indicated their willingness to at least consider participating in the project, many more have not.

Another issue is that institutions participating in multicenter cooperative group trials used to be able to activate them as soon as they had the green light from their own IRBs, but this piecemeal approach is no longer allowed. Now, a trial cannot open anywhere without the prior approval of the CIRB, and this goes for every phase III randomized controlled trial the cancer cooperative groups initiate. The upshot, Comis said, is that "the entire national program (of cancer cooperative group trials) is being held up by the CIRB process."

For this reason, there are trialists who wish the CIRB would go away or, failing that, that institutions whose IRBs are not in the pilot program could opt out of the wait-for-the-CIRB requirement. But as the NCI’s Jacquelyn Goldberg, J.D., (who directs the pilot project) pointed out, this could result in major protocol inconsistencies between centers that opened a trial before the CIRB acted and those that played by the current rule. "You don’t have to think a lot about it," she said, "to realize that that just wouldn’t work."

Meanwhile, there are those who have other quibbles with the CIRB. Among the most vehement is Hyman Muss, M.D., of the University of Vermont College of Medicine, Burlington. Muss is the protocol chair for a large multicenter cooperative group study (organized by Cancer and Leukemia Group B) in which primary breast cancer patients ages 65 and older who qualify for adjuvant therapy are randomly assigned to a multidrug intravenous regimen—as is standard—or a single drug oral regimen. The hope is that this group of patients would benefit from the simpler regimen if it is shown to be effective.



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Dr. Hyman Muss

 
When it comes to the governance of clinical trials, Muss counts himself more philosophically attuned "to the states’ rights than the federalist position" in any case. He said he also fears that, at a time of high unemployment in much of the country, local IRBs may lose support staff jobs to the CIRB. But he is most aggrieved by the CIRB’s having rejected the breast cancer trial protocol three times, which, he said, delayed the study’s opening by "at least 6 or 8 months."

This trial had already been approved by an NIH study section and the NCI’s Cancer Therapy Evaluation Program when it reached the CIRB. Muss said he was therefore unhappily surprised that the CIRB questioned some aspects of the protocol on what he said were scientific, rather than ethical, grounds.

Rebecca Pentz, Ph.D., who is on the CIRB and is the research ethicist at Emory University’s Winship Cancer Institute, Atlanta, empathized with Muss. "I know how frustrating it can be for investigators to jump through all these hoops only to have another thrown in front of them," she said.

However, she explained that, contrary to Muss’s explanation of the situation, the science of clinical trials and their ethics are not really separable because "the number one ethical test of any (clinical) trial is whether it will answer an important scientific question." As she put it, "science review is part of ethical review" and that makes it critical "not to let a handful of scientists dictate what is ethical." Indeed, that is why IRBs (including the CIRB)—made up as they are of people from a variety of backgrounds—are better arbiters of ethics.

So what does the future hold for the CIRB? There is no sure way to tell, but it is worth noting that the CIRB is still a pilot project and that it may be prudent to cut it some slack. If the $1.9 million program succeeds, as many think it can, in showing that it is possible to expedite ethics reviews, improve the quality of trials, and eliminate redundancy in the process, it will more than pay for itself in the long run and, at the same time, serve future cancer patients well.


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