Sound studies assured with scientific review
Sound studies assured with scientific review
Process improves protocols
To ensure that a proposed study or clinical trial can fulfill its goals and remain within ethical guidelines, some IRBs have mandated that protocols go through scientific review prior to submission. The purpose of the review is to ensure that studies are built on a solid scientific foundation to achieve the objectives.
"The biggest issue we have that I think holds up approval is the quality of the research design," says Mark Schreiner, MD, chairman of the committee for protection of human subjects at Children's Hospital of Philadelphia (CHOP). "From the IRB's perspective and mine, if a study can't clearly achieve its objective, it's not ethical to start." Scientific review of proposed research has been close to Schreiner's heart, as it was a cause he championed at the IRB of Children's Hospital of Philadelphia. A proposed study that does not have sound science can be a major hindrance to the approval process.
When Schreiner became IRB chairman in 2005 and was running the clinical trials unit, he felt time was being wasted with studies that were not ready for committee. "We can send requests for modifications back, but in resubmissions there were issues still outstanding because the IRB isn't going to give a 20-page list of all the things that should be changed," Schreiner says.
Taking out the frustration
Proposed studies where there were issues with scientific design took longer to approve and were a source of frustration for Schreiner. "Everybody wants the process to be rapid, and it's not when we get things that are not approvable," he says. "It takes away from people who have NIH [National Institutes of Health] approval and funding. The weakest 25% of protocols take up 75% of the time." These submission issues sparked the mandate of scientific review at CHOP.
Before a study can be submitted to the CHOP IRB, it must go through a scientific review process. While the exact steps of that process are left up to individual departments at CHOP, the IRB provides example protocol templates for investigators to follow. With the science of proposed studies reviewed ahead of time, Schreiner has found that studies are approved more quickly, with less time spent on IRB members sending studies back with questions and fewer protocols being deferred. "It actually speeds up the approval time to have that extra polish," Schreiner says.
Studies funded through the National Institute of Health or other large granting agencies, as well as industry-funded studies, are not required to go through the review process, as the science is already considered to be sound.
According to Schreiner, a proposed study can look good in every way and have sound goals, but shaky science and an incomplete analysis plan can lead to rejection. The CHOP IRB recently considered studies that looked good on the surface but had underlying issues. "Our IRB recently saw two studies — one inadequately defined numerous issue, while the other had very ambiguous objectives and the analysis plan did not make sense," Schreiner says. "Both were worth doing, but the provided information was inadequate to support sound scientific design — the IRB deferred those. One was approved at other IRBs."
While it took some time for researchers to get the hang of the process, Schreiner says that many excel. "Over the course of the last five years, people have become more sophisticated. It didn't happen overnight, but it's well worth the effort," he says. "Some of our departments have sophisticated people — for instance, the ED requires fellows to get a master's degree, and most get one in epidemiology. There are plenty of people with strong clinical study design as a result of people with that kind of training."
Even minimal-risk studies are subject to review. "The biggest problems right now are minimal-risk studies that don't involve drugs, and the expedited studies," Schreiner says. "A lot of those are descriptive research — not really a problem because no one's trying to do anything grand. Those are so straightforward that they are relatively easy to approve. It's people who have greater ambitions but don't have the help to design [the studies] to take in all the confounding variables that trouble arises."
Though the studies are considered minimal risk, results can still have a great effect on a population if the results are later proven incorrect. "Some people would say, if there's no harm, then no foul in minimal-risk research," he says. "But there are a lot of instances where real harm has been done. For instance, there was a women's study that said HRT [hormone replacement therapy] reduced the risk of cardiac disease, which was later proven wrong when a randomized trial was done. Things like that can result in negative consequences in a large population."
Departments know best
CHOP isn't the only IRB to embrace the scientific review concept. Boston Children's Hospital has a similar approach, with every department having its own scientific review process and the IRB taking more of a background role. "What we decided to do was really embrace the concept that disciplines know the science the best and each department was to develop their own scientific review process for review of protocols before coming to the IRB," says Susan Kornetsky, MPH, director of clinical research compliance, Boston Children's Hospital. "Each department had to go on record and indicate what the process was — it could be a committee, or a department asks other colleagues to review. It's completely open-ended."
Though each department at Boston Children's can develop its own review process, the IRB developed a central list of questions for each department to follow. The departments expand on the questions as they see fit. After completion, all evidence of the review is to be submitted to the IRB. "The IRB can still consider the science, and if we have questions, we can send them back to the investigator," Kornetsky says.
As with many new things, there was some initial resistance to the scientific review process — mostly due to how much additional time it would take. "Initially, I think there was concern mostly about the timing," she says. "How much time would this take? I think there was resistance at first, but this mandate really came from the president down, and there was no question that they had to do this. The department chairs had to sign on, and it was their responsibility to be responsive to their own faculty and develop a process that wouldn't be cumbersome."
Over the years, the IRB has seen significant improvement in the quality of the protocols submitted. "It's very obvious to the IRB members what departments do this really well — the protocols are much better developed and in better shape," Kornetsky says. "They address issues and are well-prepared and have a meaningful analysis section. Some departments don't do quite as well and protocols are a little less developed."
Over time, Kornetsky found an unexpected benefit of scientific review: a chance for the IRB itself to learn and grow. "Often, we will see the scientific review information, and we have found that the research groups are also pointing out issues they had with other IRBs," she says. "Sometimes, they're actually taking that as a step to help other faculty members from their own experience — they'll point out things that have prompted concern, or they'll make recommendations. It's like getting a little bit of free advice. I think many of the comments that are made are very much on target and helpful. We use it as an opportunity for friendly advice."
All in all, the scientific review process has been a boon to the approval process, particularly for Schreiner. "To me, it takes so much effort to do clinical research well and just as much effort to do it badly," he says. "If we want subjects to go through risks for the benefit of science, we should get something out of it."To ensure that a proposed study or clinical trial can fulfill its goals and remain within ethical guidelines, some IRBs have mandated that protocols go through scientific review prior to submission. The purpose of the review is to ensure that studies are built on a solid scientific foundation to achieve the objectives.
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