HIV study involving foster children raises questions
HIV study involving foster children raises questions
What was the IRB’s responsibility?
Recent revelations that hundreds of HIV-positive foster children may have been signed up for clinical trials without advocates assigned to ensure their safety have stirred the latest controversy regarding pediatric clinical research.
The practice appears to have been most prevalent in the 1990s, when treatment options for HIV-positive children were limited. Those who conducted the research say special advocates for the children were not necessary because the treatments involved in the clinical trials were therapeutic. But the debate already has led OHRP to issue a letter to Columbia University Medical Center/New York Presbyterian Hospital in New York City, making determinations of noncompliance.
In a statement, Columbia officials stressed their belief that advocates were not required for this research, but acknowledged the need for improvement in documenting its decisions regarding review of pediatric research.
In addition, the New York City Administration for Children’s Services (ACS), whose wards were among the children who participated in the research, has arranged for an outside review of its actions in the matter.
The episode points out the need for IRBs and researchers to become more conversant with all of the relevant regulations regarding research participation of children in foster care, says one investigator who did research with HIV-positive foster children during the 1990s.
"I talked to a number of pediatric HIV clinical investigators around the country after this broke, and I could not find one who had ever heard of an independent advocate," says Mark Kline, MD, professor of pediatrics at Baylor College of Medicine in Houston.
"That includes some who had been HIV clinical investigators for more than 20 years — they had never even heard the term independent advocate.’ This has been a little bit of a painful episode, but I think it has served a useful purpose," Kline says. "Personally, I’m very happy to have a better understanding of what the rules are. I have to say I was amazed at how this could have existed for such a long time and so few of us were really up to speed with what the requirement was."
The Code of Federal Regulations (45 CFR 46.409) does allow for the inclusion of wards of the state in research only if the research is related to their status as wards or conducted in settings where the majority of children involved are not wards.
The regulation goes on to state: "If the research is approved under paragraph (a) of this section, the IRB shall require appointment of an advocate for each child who is a ward, in addition to any other individual acting on behalf of the child as guardian or in loco parentis. One individual may serve as advocate for more than one child. The advocate shall be an individual who has the background and experience to act in, and agrees to act in, the best interests of the child for the duration of the child’s participation in the research and who is not associated in any way (except in the role as advocate or member of the IRB) with the research, the investigator(s), or the guardian organization."
However, Kline, and other researchers and institutions involved in the HIV research say that the advocate requirement does not apply to research that offers the potential for benefit to the subjects.
In testimony before the U.S. House of Representatives, Alan Fleischman, MD, a medical ethicist and professor of pediatrics at Albert Einstein College of Medicine in New York City, stated that his understanding was that research that involved the potential for benefit was governed by a different section of the regulations, 45 CFR 46.405, which requires only the permission of the parent or legal guardian to enroll a foster child.
Kline says Baylor’s attorneys reviewed his research and similarly concluded that advocates weren’t required. "The reason is that all of the studies offered potential benefit," he says. "I was not doing purely academic research, I was doing therapeutic research."
Context of AIDS research
Kline says it’s important to remember the context in which this research was conducted. In the late 1980s and early 1990s, therapeutic treatments for HIV were very limited, particularly for children. Children in foster care also were affected by the disease at a greater rate than the general population — many had parents who had died of AIDS, or who were unable to care for them because of illness or drug abuse.
He says that while there was some debate as to whether to include such a vulnerable population in research at all, the lack of other options led him to believe that it was necessary.
"There were those — and I fell toward this end of the spectrum — who took the position that because of the primitive state of HIV therapeutics at the time, the only way for children to access potentially lifesaving therapy was through clinical trials," Kline says. "And so that it was wrong to exclude foster children as a group from participation because it was, in fact, a death sentence."
He says that his research never targeted foster children and that in fact, they only represented a small percentage of his research subjects. When asking permission for a particular child to participate, he usually contacted the child’s caseworker, and then dealt with a supervisor to whom he described the details of the trial — "the potential benefits, the potential risks, the alternatives to participation in the trial, all the usual basic tenets of informed consent."
Usually, Kline says, a supervisor for the Texas Division of Child Protective Services would approve the child’s participation. Occasionally, he says, a judge would sign the consent form.
As far as Kline can remember, no one ever raised the question of appointing special advocates at any point in the process, including IRB review.
"Thinking back, it was something I would have been happy to do then," he says. "I didn’t not appoint special advocates because I thought it was onerous or unnecessary or unimportant or anything. I would have been happy to do it at the time, if it had been a requirement."
In New York, ACS officials have estimated that about 465 foster children participated in clinical trials between 1988 and 2001. The Associated Press reported that New York City could find records showing that only 142 were assigned independent monitors.
The city has asked the Vera Institute of Justice, a nonprofit research institution, to look at ACS policies and determine whether necessary consents and monitoring were conducted. The agency also has proposed a new policy for enrolling foster children in clinical trials. It would require an individualized, independent medical review concluding that enrollment offered a child a "significant potential treatment benefit not available outside of the clinical trial, while posing a concomitant minimal risk of harm." The proposed new policy is currently awaiting state review.
In May, OHRP issued a compliance oversight determination letter to Columbia/Presbyterian, laying out the following determinations of non-compliance regarding pediatric HIV studies:
- Columbia’s IRB records demonstrated "a failure of the IRB to obtain sufficient information" regarding the selection of wards of the state and foster children as research subjects.
- The documents showed the IRB failed to obtain sufficient information regarding the process for obtaining permission of parents or guardians for those children.
- The documents showed the IRB failed to obtain sufficient information regarding additional safeguards for enrollment of those children as required by federal regulations.
OHRP noted that Columbia planned to take several corrective actions, including reviewing IRB procedures and appointing a task force to develop a training program on the participation of children in research.
Patricia El-Hinnawy, a spokeswoman for OHRP, says the Columbia/Presbyterian case is the only one open at this time in connection with the HIV trials.
Columbia spokeswoman Marilyn Castaldi says the institution is in the process of responding to the OHRP letter.
In a statement issued in response to a query about the matter, she says Columbia "has acknowledged to ORHP the need for improvement in how information is collected and decisions documented in its review of research involving children. Standard practice in this regard at leading research institutions has changed significantly since the early 1990s. The University is committed to meeting current and evolving standards for protection of all research subjects, including children."
New York Presbyterian referred questions to Columbia, saying they fell under the university’s jurisdiction.
Document discussions
How should IRBs deal with proposals for this type of research involving wards of the state?
Kline contends that they won’t see many such proposals in the future regarding HIV and AIDS research, thanks to the evolution of medical care for the disease.
"We have such a large menu of treatment options right now that I think it would be an extraordinary circumstance where I would enroll a foster child in an HIV clinical trial, because we have prescription drugs that do a very good job of suppressing the virus and maintaining the child’s health," he says.
There are few other diseases Kline can think of to which foster children might be particularly vulnerable, but he says the controversy related to the HIV trials represents an opportunity for IRBs to better understand the regulations regarding care of children in vulnerable situations.
For one thing, IRBs may not even realize they have foster children involved in the clinical trials they approve.
"On the IRB applications, we don’t tell whether we’re enrolling foster children," he says. "When we file our annual reports and tell them how many patients were enrolled, they don’t ask whether they were foster children. There’s no line in the informed consent document that says anything about foster children. There’s nothing in any of the materials I’ve ever seen that says, If you plan to enroll foster children, check the box here.’"
He says IRBs should familiarize themselves with the pertinent federal regulations, as well as any restrictions that individual state governments place on the inclusion of foster children in research. International research would require dealing with those governments involved as well.
When an IRB is dealing with a study that does require an independent advocate, Kline says it should alert the investigators about the requirements. And follow that up with diligent documentation, Fleischman says.
"It appears that the most important issue for IRBs is to document their discussions and assure that the children are adequately protected, regardless of the section of the regs under which the proposal is approved," he says.
Recent revelations that hundreds of HIV-positive foster children may have been signed up for clinical trials without advocates assigned to ensure their safety have stirred the latest controversy regarding pediatric clinical research.Subscribe Now for Access
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