Is the problem overregulation or one of overinterpretation by IRBs?

New OHRP director brings up issue for discussion

(Editor’s note: IRB Advisor has asked IRB and human subjects protection experts from across the nation to discuss the state of human subjects protection regulations and how IRBs are interpreting federal requirements. In this issue, there is an article on the debate of whether IRBs overinterpret current regulations and an article on how current regulations could be changed to ease the documentation burden carried by IRBs. In future issues, there will be articles on how IRBs and institutions can improve the informed consent process by thinking outside the regulatory box and insisting that sponsors simplify their suggested informed consent documents; on certification and better training of investigators as a way to make the protocol approval process run more efficiently; and on shifting some IRB work to other committees.)

From an IRB member’s perspective, these are trying times. On the one hand, investigators complain that regulations for human subjects research and IRBs are too stringent, making it difficult for them to do their studies. Alternatively, human subjects advocates continually complain that IRBs and institutions are too lax in monitoring clinical studies.

Add to the mix the new privacy regulations and the recent focus on monitoring conflicts of interest — both of which have been shuffled off to IRBs in many cases — and it’s a wonder that anyone volunteers to serve on an IRB.

The biggest question of all might be one that was raised recently by Bernard Schwetz, DVM, PhD, the new director of the Office for Human Research Protections (OHRP) in Rockville, MD.

Schwetz, in speaking to health care attorneys last fall and more recently to IRB Advisor, says that the problem may not be that research is overregulated, but that it is overinterpreted.

"Frequently, I’m at meetings where investigators say, If it weren’t for the regulations, I could do research,’" he notes. "When you look beyond that statement and find out what they’re talking about, very often they’re talking about overinterpretation of the regulations."

Whether it’s the IRB or institutional attorneys, overinterpretation frequently is driven by a fear of litigation, Schwetz says.

Some experts in the field of human subjects research say there is some merit in what Schwetz says, although there are many other factors to consider, such as the role of sponsors in creating more paperwork for investigators and IRBs and the greater media scrutiny paid to institutions that have compliance problems.

"Whether it’s the high-profile shutdowns that took place in the late 1990s to 2001 or the increasing emphasis on compliance, I think IRBs are spending a lot of time shuffling paper without a clear relationship between that effort and the protection of human subjects," says Robert M. Nelson, MD, PhD, associate professor of anesthesia and pediatrics at the Children’s Hospital of Philadelphia.

"The criticism of some of the shutdowns was that they were unrelated to subject protections and more related to whether institutions had dotted i’s and crossed t’s from a regulatory perspective," Nelson says. "The question is, What outcome do you want?’ If that outcome is human subject protection, then should we begin to move toward an outcomes-based approach rather than just a compliance-based approach?"

At the very least, the research and human subjects protection industry need to have a lengthy discussion on this issue, he says.

"When Bernard Schwetz says IRBs are doing too much, then as far as I’m concerned, the next sentence should be, What should they be doing?’" Nelson adds.

The Secretary’s Advisory Committee on Human Research Protection (SACHRP) for the Department of Health and Human Services (HHS) has been looking at the issue of overinterpretation of the regulations, finding problems in some cases, says Ernest Prentice, PhD, chair of SACHRP and associate vice chancellor for academic affairs of the University of Nebraska Medical Center in Omaha.

"We’re actively evaluating 45 CFR 46, subpart D for children, and 46, subpart C for prisoners," Prentice says. "The problem with the regulations is that they have been inconsistently interpreted and sometimes misinterpreted by IRBs across the country."

This inconsistent approach has led some IRBs to approve research that should not have been approved and to turn down research that should have been approved, Prentice says.

"The task force is taking a close look at the regulations to make sure they’re adequate and appropriately interpreted. If they’re not adequate they should be revised," Prentice says.

Basically, SACHRP has concluded that subpart D, involving children, is adequate, but needs to be interpreted appropriately, Prentice says. "But that’s not the case with subpart C, which was written in the 1970s, and, quite frankly, is out of date."

Others say that the blame for the problem rests with investigators, who often lack the necessary training in writing protocols for submission to IRBs.

Eliminating time wasters

Another example of how institutions over-interpret regulations involves the recording of IRB minutes, says Erica Heath, MBA, CIP, president of the Independent Review Consulting Inc. of San Anselmo, CA.

"The regulations say the minutes are a summary of controverted issues," she explains. "But with every warning letter or guidance, there is more to include."

IRBs have to include all issues discussed, reference the regulatory elements, people present during a vote, and show when each member came and went during meeting, Heath says.

"It’s my opinion that the minutes protect the institution more than the subject," she says. "If you put that same amount of time into communicating with investigators about the issues and problems, that education would be a part of human subject protection."

On the other hand, having detailed IRB meeting minutes reduces an institution’s risk of being found deficient, which leads to newspaper headlines and could result in a loss of reputation, she notes.

"When I look at complaints over the years, it’s not that IRBs have overinterpreted the regulations, but that investigators have not provided enough information for the IRB to make a good decision," says Dale Hammerschmidt, MD, FACP, associate professor of medicine at the University of Minnesota Medical School in Minneapolis.

"Having said that, I also think that institutions and IRBs have been running a little scared for the last several years, because of institutional shutdowns," Hammerschmidt says. "Ours was the first one. They just excluded the offending department from the assurance, so the headlines were smaller 10 years ago."

Fear of litigation a driving force

The prospect of a shutdown and newspaper headlines has made IRBs and institutions nervous about whether IRBs are stringent enough, he adds.

Perhaps it’s not so much an issue of IRBs’ over-interpreting regulations as it is a matter of institutions expecting more from their IRBs, says Felix A. Khin-Maung-Gyi, PharmD, MBA, CIP, chief executive officer of Chesapeake Research Review Inc. of Columbia, MD. He also is the senior policy fellow with the Center for Drugs and Public Policy at the University of Maryland in Baltimore.

"Not only are IRBs interpreting regulations in a way that may or may not be appropriate, the institutions are applying the interpretation of the regulations in a way that may or may not be appropriate as well," he says.

An example is adverse event reporting, which is a huge issue for many IRBs, Khin-Maung-Gyi notes.

"The interpretation of the regulations has led the research enterprise to behave in a way that has [made] the IRB the gatekeeper of all adverse event information," he reports. "So sponsors submit it to the investigators with the expectation that the investigator will report it to the IRB, but the regulations don’t give guidance on what the IRB should do once it reports them."

Schwetz says an example of overinterpretation involves how some local IRBs are failing to take advantage of a central IRB’s time and effort.

The National Cancer Institute, for instance, has created a central IRB model for use with oncology studies nationwide, he notes.

"These studies are reviewed by the NCI’s central IRB, and an investigator at University X agrees to be part of this study," Schwetz explains. "The investigator takes the protocol to a local IRB and has the approval of the central IRB, and asks the local IRB, Are you going to review this locally or accept the authority of the central IRB where the review has already been done?’"

Often, when a local IRB is given this choice, it will choose to do a full review of the protocol rather than accepting the central IRB’s decision or doing a simplified review of just the consent form, he says.

"The institution’s attorney says, You have to review the protocol in detail,’ so there’s duplication of effort and a concern over litigation," Schwetz explains.

"We see a lot of interpretation of the regulations that account for the workload that investigators and IRBs have to deal with," he says. "So there are quite a few sources of additional burden that in some cases have little or nothing to do with human subjects."

Institutions may decide to conduct full local IRB reviews in these cases because it’s the job of the local IRB to reflect the interests of the community in protecting human subjects, says Steven Peckman, associate director for human subjects research at the Office for Protection of Research Subjects at the University of California-Los Angeles.

"I think there are a lot of issues here, but I don’t know if any of it has to do with overinterpretation of regulations," he says. "It seems to me that lawyers are concerned about institutional responsibility, and if an investigator does research at an institution, does the institution have responsibility to oversee or review the work?"

Alternatively, if an institution decides to let the central IRB review the work and the local IRB only provides a review of part of the project, such as the informed consent document, does this make the institution responsible for all of the project if anything goes wrong, Peckman asks.

"Or do we wash our hands of all of it and make the central IRB responsible?" he says. "I don’t think that has to do with overinterpretation so much as it has to do with lawyers doing their jobs."