NEWS

Reports Bring Several Changes To IRBs

Robert Finn

A series of new reports, regulations, and recommendations on the conduct of human-subjects research will lead to substantial changes in the inner workings of institutional review boards, which supervise human-subjects research.

This spring, the Department of Health and Human Services’ Office of Inspector General issued one report on the status of its 2-year-old recommendations on protecting human research subjects, another on the U.S. Food and Drug Administration’s oversight of clinical trials, and two others on recruiting subjects for clinical trials. In late May, DHHS Secretary Donna E. Shalala announced several related initiatives. One requires formal training of IRB members and investigators working with human subjects. Another requires increased monitoring of clinical trials. A third is a legislative proposal to allow the FDA to fine investigators and institutions for violations of informed consent rules.

This increased attention to human-subjects protections is no accident, says Paul Root Wolpe, Ph.D., a faculty associate at the University of Pennsylvania’s Center for Bioethics.



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Dr. Paul Root Wolpe

 
"A couple of good scandals is always good for the ethics business," he said. "We’ve had a few of those recently, not the least of which happened at our own institution: the death of Jesse Gelsinger in gene therapy. I also think there’s a recognition that the nature of clinical research is fundamentally changing. In that change are a number of challenges to human-subjects protection, and that’s just now filtering down to the agencies responsible for overseeing this, although people involved in this have seen it for quite a while."

Protecting Human Subjects

Issued in April, the first Inspector General’s report notes that the National Institutes of Health and FDA made little progress on reforms involving IRB flexibility, accountability, oversight, education, conflicts of interest, and workload. Several of these have since been addressed by Shalala’s announcement late in May.

The April report suggests that the most important barrier to reform involves difficulty in changing the so-called Common Rule—the core regulations involving human subjects—issued in 1991. The difficulty arises because 17 separate Federal agencies adhere to the Common Rule, and any changes to the Rule would require the concurrence of all of them. "Legislation will be necessary, or else changes in these agencies will be glacially slow," noted Wolpe.

While some federal agencies may be moving slowly, IRBs are apparently running as fast as they can just to stay in the same place. Sharon K. Friend, director for Research Subjects Protection Committees at the University of California at San Francisco, maintains a chart in her office showing that at UCSF the number of protocols reviewed annually grew from under 100 in 1966 to almost 4000 in 1999.

Although she provides staffing for two IRBs, each with about 16 members meeting weekly, Friend noted that the committees can spend only a few minutes discussing each protocol. On the other hand, staffers and individual committee members certainly spend a good deal of additional time studying the protocols and preparing for the discussion.

"Clearly the IRBs in average academic institutions are severely overworked," said Emil C. Gotschlich, M.D., vice president for medical sciences at Rockefeller University, New York. "There is no particular reward structure for people who serve on IRBs. It really is a labor of love, and it is an intense one. More support is needed both for staff and for members. Probably the IRBs will have to proliferate. More IRBs will have to be set up in institutions in order to make the load on members be somewhat more reasonable."



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Dr. Emil C. Gotschlich

 
Help may be on the way. The IG report states that NIH is considering the provision of an extra increment of grant funds to be used for additional investment in IRBs.

Training and Education

According to the IG report, "The most important continuing protection for human subjects is the presence of well-trained and sensitized investigators and IRB members." Friend agreed, saying, "You know, people working with animals have to be trained in animal handling. But historically there hasn’t been training for people doing human research."

Wolpe pointed out that "Most IRB members come and sit on an IRB never having taken a course or particularly read anything in the research-subjects-protection literature at all, and they learn on the job over time. And so IRBs become little subcultures with very different standards about what is acceptable and what is in their purview and what isn’t."

This situation will soon change as a result of Shalala’s announcement in May. She directed that all clinical investigators, research administrators, IRB members, and IRB staffers receive training in research bioethics and human-subjects protection. NIH does not endorse any specific training courses, but in a June 5 announcement enforcing Shalala’s initiative, it notes that some institutions, such as the University of Rochester, have developed online educational programs.

Gotschlich said that at Rockefeller University, "We actually anticipated that recommendation proactively, and in late April we set up guidelines to require all our investigators and IRB members to use the Rochester module for a self-education program. In addition to that we have set aside a half hour in each IRB meeting itself for one of the members—who happens to be the head of our sponsored research program and is in the nexus of all the regulations—to bring all members up to date on what is happening."

Oversight and Sanctions

The IG report pointed out that because of the burden of reviewing new and renewing protocols, IRBs have generally failed to provide continuing oversight of ongoing trials to determine, for example, if subjects are being treated appropriately during the research process. Wolpe explained, "As far as I’m concerned, the single biggest problem in the IRB structure is continuing oversight. Once the IRB approves a study and makes any changes it wants to make in the study process and in the informed consent form, that study is then in the hands of the investigator.

"Nobody from the IRB or the Office of Research Administration staff ever goes to the site to look and see whether the investigator is carrying out appropriately what the IRB has suggested. They don’t sit in on informed consent sessions and see if people are being properly briefed."

To address this issue, Friend said, UCSF is considering the establishment of a compliance unit that would be associated with, but not part of, the IRB. Such a unit might interview research subjects to determine, for example, whether the informed-consent rules were being followed.

But Gotschlich is concerned about a possible unintended consequence of such regulatory bodies. "The difficulty with this is that as soon as you devise a set of standards, you also make it a target for lawsuits. IRBs up to this time have not attracted the attention of tort law. And if this process of dealing with oversight of IRBs has as an unfortunate consequence that it is used as a mechanism for attack by tort law, IRBs will be in real trouble."

If Shalala has her way, Congress will give the FDA the power to sanction institutions and individual clinical investigators for violations of informed consent and other research practices. And these sanctions will be no mere slaps on the wrist. If the proposals are enacted, the FDA will be allowed to fine individual investigators up to $250,000 and institutions up to $1 million for failures to obey federal guidelines.

FDA Oversight

The IG’s report on FDA oversight stems from a perception that the FDA seems more concerned with data integrity than with human-subjects protection. The report found that in fiscal year 1999 the FDA inspected only 468 of 14,000 clinical investigators potentially involved in clinical trials. Because such inspections take place after the conclusion of clinical trials, any violations are uncovered too late to protect the human subjects involved.

"I think the FDA is suffering from the same fundamental problems that the IRBs themselves are," suggested Wolpe, "which is, nobody has come up with a good way to create a continuing review process that’s both meaningful and affordable, and affords subjects the kind of protections they deserve."

On the other hand, not everyone agrees that the FDA should be required to provide ongoing oversight of clinical trials in progress. "It does seem to me to be putting a very large load on the FDA, above and beyond the scope of what it should be doing," maintained Gotschlich. "I think the FDA is fundamentally an organization that should assure the American public that drugs and devices are safe and effective. Clearly if somebody is proposing a glaringly unethical experiment in an IND application I would expect the FDA to recognize that and act upon it. But I would not think that it really should be charged with oversight in this area."

While all four recent reports shine an occasionally embarrassing spotlight on deficiencies in the IRB system, Friend believes that this increased attention will have beneficial effects overall. "There are a lot of people competing for resources," he said. "We [the IRBs] are just one voice crying in the wilderness to the budget office. Finally it seems like we’ve reached some critical mass of reports, some critical mass of attention, so that now people other than those in the IRB world are actually listening.

"Now I think that we do need to reexamine ourselves. I think these [reports] are good tools to do it. I don’t know if they’re perfect, I don’t know if they’re enough, but I think they’re a step in the direction of keeping us focused on our real work, which is not just handling the paper. The real work is to protect subjects in research and to help the institution follow the ethical principles of research."



             
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