Committee looking at 407 review process

Case in point: Pediatric smallpox vaccine

IRBs and research institutions may have some disagreement and confusion over when it’s appropriate to send a pediatric research proposal to the Department of Health and Human Services (HHS) for a 407 review.

While it was extremely rare for IRBs to request 407 reviews in the past, since 2000, these request have become more common, which is one of the reasons the issue is being addressed by the Secret-ary’s Advisory Committee on Human Research Protection (SACHRP), says Ernest Prentice, PhD, chair of SACHRP and the associate vice chancellor for academic affairs at the University of Nebraska Medical Center in Omaha.

In the HHS regulations the Subpart D defines four categories of research involving children, and these fall under 404, 405, 406, and 407. They are based on the level of risk associated with the research and whether there is any direct subject benefit, he explains.

As the risk increases in the absence of direct subject benefit to the child participating in the research, the regulations become more stringent for the approval of the research, Prentice says.

"If the IRB cannot approve an HHS-funded research under 404-406 regulations, then it must be reviewed by an expert panel at HHS," he notes. "This expert panel must review the entire protocol and make a recommendation to the [HHS] secretary of whether or not the protocol should be funded by the federal government."

SACHRP’s pediatric research subcommittee is examining the 407 review process and plans to make recommendations that will help to improve it, says Celia B. Fisher, PhD, a SACHRP co-chair of the pediatric research subcommittee. Fisher also is the Marie Ward Doty university chair and the director of the Center for Ethics Education at Fordham University in Bronx, NY.

"One of the issues right now is that IRBs appear to be unclear about the kind of information and the kind of requirement that they need to go through before they even send a protocol to the Office of Human Research Protections [OHRP] as a 407 review case," she says.

"This is very important because what some of them don’t seem to understand is they need to justify why it’s a 407 review case, and they have to do that through making the argument on paper of why it’s not a 404, not a 405, and not a 406," Fisher explains. "And they need to say why they think it’s ethical to do the study and why they would approve it under 407 if they had the authority."

Instead, what has been happening lately is that IRBs have sent protocols to OHRP for a 407 review if they don’t know what else to do with it, she notes.

"And that’s not really what the requirements are, so one of the things SACHRP wants to do is clarify what the responsibility of the IRB is," Fisher says.

The point is to neither encourage nor discourage 407 reviews, but to use them appropriately, she says.

"If you discourage them, then IRBs may be either disapproving important research or approving research at the 405 or 406 level that should be reviewed as a 407," Fisher explains.

"So if you make the procedure too hard or arduous or unclear, then you’re going to be discouraging IRBs from even attempting to go there," she adds. "And on the other hand, if it’s unclear what a 407 review requires, then the 407 review could become a wastepaper basket for the things an IRB doesn’t want to handle."

A case study

Perhaps one good example of an appropriate 407 review is the one that was held to assess the proposed pediatric smallpox vaccination trials, Fisher says.

The proposed clinical trials involved the Dryvax product and were intended to evaluate the potency, dose, and safety of vaccinia virus vaccine when administered to 40 children, ages 2 to 5 years, at the sites of the University of California-Los Angeles (UCLA) Center for Vaccine Research and the Cincinnati Children’s Hospital Medical Center.

The trials were being considered after the Sept. 11 terrorist attacks in New York City at a time when the nation had heightened concern about bioterrorist attacks as it prepared to go to war with Iraq.

It was very difficult to assess the level of risk that smallpox posed to the general population and to the potential children research subjects, Fisher says.

"If smallpox had a high possibility of being introduced into this country, then one would argue that being tested with the vaccine had the potential for some minimal benefit," she says. "If not, then the risks with the vaccine would outweigh the benefits."

On the other hand, the Dryvax vaccine’s risks were well known, as it had routinely been given to children and adults decades earlier. While it was considered an acceptable risk during the years when smallpox remained a threat on the global stage, by 21st century standards, some 20-plus years after the smallpox virus had been eradicated, the vaccine was considered a high risk because of its potential adverse effects on individuals with autoimmune diseases, emphysema, pregnancy, and other conditions.

While two IRBs found that the proposed pediatric vaccine trial posed an acceptable risk with potential direct benefits, a third IRB reviewing the same protocol disagreed and asked for a 407 review, Prentice says.

A panel of national experts was asked to submit their opinions about the proposed trial as part of the 407 review, and these papers were made public via the Internet, he says.

The resulting public scrutiny resulted in the Dryvax pediatric trials being canceled, Prentice adds.

But the point is that the IRB that called for the 407 review was appropriate in making this decision, Fisher says.

"I think it’s good that there are controversies at the 407 level, which is what the smallpox vaccine proposal was," she says. "In other words, there is permissible research that has small risks to children, and it’s so important to the nation that the secretary of Health and Human Services has the ability to approve it after looking at recommendations from various experts."

From an ethical standpoint, there are certain issues that will always create a dilemma, and these are the sorts of research decisions that perhaps should be requested for a 407 review, Fisher adds.

"I don’t think the purpose of the 407 review is to limit ethical discourse at the IRB level, but the aim is to have greater consistency in what the ethical issues are and what the terms mean," she says. "You do want to make that debate fair and consistent in research across the country, but right now it’s not because the guidelines are not clear, and so they’re open to subjective interpretation, and each IRB tries to do its best."