Special committee looks at subject protections

Research with children a focus

The newly formed Secretary’s Advisory Committee on Human Research Protection has its work cut out — committee members already have three subcommittees establishing work plans, and there many more top priorities to be chosen from the federal regulations.

The committee, established by the Department of Health and Human Services (HHS), has been charged by HHS Secretary Tommy Thompson to advise him on human subjects, placing particular emphasis on special populations, including children. 

Committee members also will identify research issues involving the use of tissue samples, investigate conflicts of interest, and monitor activities by the Office of Human Research Protections, says Ernest Prentice, PhD, chair of the Secretary’s Advisory Committee and an associate vice chancellor for academic affairs at the University of Nebraska Medical Center in Omaha.

Here are some of the issues that the committee will address:

• Adverse event reports: "Although it’s not specifically included in our charter, we’re looking at adverse event reviews by IRBs," Prentice says. "IRBs are being inundated with IND [investigational new drug] safety reports from all over the world in multicenter clinical trials, and they often do not have sufficient data to allow anybody to make an assessment of an adverse event."

Some institutions receive more than 11,000 adverse event reports a year, Prentice says. "Even smaller institutions feel this is a significant problem," Prentice adds. "So our committee is going to be looking at the adverse event problem and at ways to help IRBs resolve this tremendous workload."

One issue the committee will address is whether and how IRBs should review external adverse events, since the regulations don’t require such reviews, he says.

"IRBs are not prepared to review adverse events that occur thousands of miles away and that involve patients about whom they know nothing," Prentice says. "This has been a phenomenon that has developed over the last 20 years, and we see every year more and more of these IND reports come across our desks."

One solution might be having a data safety monitoring board serve as a gatekeeper to the reports, deciding which need to be sent to IRBs, he suggests.

• HHS regulations, subpart D: A subcommittee is looking at the subpart D regulation that provides additional protection for children. The HHS regulation is 20 years old, and the Food and Drug Administration (FDA) issued an equivalent regulation in 2001, Prentice says.

"It’s been my experience over the last 20 years that many IRBs do not understand subpart D," he says. "We want to examine subpart D in detail and advise the secretary on appropriate interpretation of subpart D, so that we neither underprotect children or overprotect children."

Pediatric research serves the greater public good, benefiting children everywhere; however, sometimes trials are not conducted because IRBs do not approve or understand the regulations," Prentice says. "And there are other trials that shouldn’t be approved but are."

Another aspect of subpart D that the subcommittee will address involves the 407 panel review process in which a pediatric research project is reviewed by a HHS expert panel if the research doesn’t fit into one of four categories of research, he says.

"These categories are based upon the level of risk associated with the research and whether or not there are any direct subject benefits," Prentice says. "As the risk increases in the absence of direct benefit to the child participating in the research, the requirements are more stringent."

When an IRB sends a protocol to HHS for a 407 review, the expert panel must review the entire protocol and make a recommendation to the secretary of whether the protocol should be funded by the federal government, he explains.

"Now it’s interesting to note that between 1983 when the regulations first came out and somewhere around the latter part of 2000, there might have been no more than seven expert panel reviews," Prentice says. "Then since 2000, we’ve maybe a half-dozen of 407 reviews."

407 case study

• HHS and FDA reviews: One proposed pediatric clinical trial recently became the first proposal to be subject to both a HHS 407 review and an FDA review, and the controversy that surrounded this trial is another reason why the 407 review requirements need to be addressed by the secretary’s committee, he says.

The study proposed to evaluate the potency, dose, and safety of vaccinia virus vaccine (Dryvax) when administered to 40 children, ages 2 to 5 years, at two sites, including the University of California — Los Angeles (UCLA) Center for Vaccine Research and the Cincinnati Children’s Hospital Medical Center.

At the time the trials were being considered, the country was preparing to go to war with Iraq following the Sept. 11, 2001, terrorist attacks in New York City, and the public mood could be described as fearful, Prentice notes.

There were fears at the top levels of government that terrorists could obtain the few remaining samples of smallpox and create a virus that quickly would decimate populations.

Alternatively, the Dryvax vaccine, which routinely had been given to children and adults decades earlier, is considered by 21st century standards to be high risk because it may produce dangerous side effects among individuals with autoimmune diseases, emphysema, and other conditions, and it may pose serious health problems for pregnant women and infants.

"It’s hard to identify exactly what is the bioterrorist threat associated with utilizing smallpox as a bioweapon," Prentice says.

The public’s fear of Iraq and terrorism during the pre-war period may have created a mindset that thought of smallpox as a greater risk than it was, he suggests.

But there were no hard data showing that smallpox had ever been used as a bioterrorist weapon or that it was indeed a part of Iraq’s biological weapons arsenal, as was suggested by some bioterrorism experts, or that Iraq or anyone else would use it on an unvaccinated nation.

Both the public and individual subject interests were being considered by the IRBs that reviewed the pediatric Dryvax protocols, and the IRBs came to different conclusions. The Kaiser Permanente Southern California IRB decided in favor of the protocol, while the Harbor-UCLA Medical Center IRB voted 6-to-5 against it.

Also, the Cincinnati Children’s Hospital Medical Center IRB voted to approve the protocol after deciding that it would fall under subpart D, 405, meaning that there was indeed a prospect of direct subject benefit, Prentice says.

"Whereas the UCLA IRB didn’t find the protocol approvable and referred it to a 407 review," he explains, "two institutions utilizing the same set of regulations came to different conclusions because they interpreted it differently."

Had both IRBs approved the protocol, then the trial would have been conducted, but because one of them referred it for a 407 review, the trials were never begun. In fact, the trials also were called for an FDA equivalent review, and eventually after some public scrutiny, the pediatric Dryvax trials were canceled, Prentice says.

The HHS expert review itself was controversial because it lacked public transparency, he notes.

"It was not conducted in an open forum, although the materials were posted on web sites," Prentice says. "Many of us would contend that [the review] was an inappropriate mechanism for performing a review of pediatric research."

The panel had asked a group of experts, including Prentice, who declined to participate, to write a review with their conclusion of whether the pediatric Dryvax trials should be conducted. Then the reports were posted on the Internet, but they were never discussed between the participants at a meeting where a consensus might be reached, he says.

"It was like having an IRB review meeting and having people send in reviews that are never discussed," Prentice says.

So the secretary’s committee is going to look at how the 407 review system could be changed and improved, he reports.

"We’re looking at whether or not it might be appropriate for the 407 review to take place under the auspices of a subcommittee," Prentice says. "The subcommittee would meet three times a year and make recommendations to the Secretary’s Advisory Committee on Human Research Protection."

What the committee agrees upon is that it’s not appropriate for the 407 panel reviews to be held behind closed doors, he adds.

"One of the benefits to having a face-to-face meeting is so you can listen to the opinions of others, which might serve to modify what you think," Prentice says. "But there was no opportunity for dialogue in how the smallpox vaccine protocol was reviewed."