Component analysis is latest model for IRB review process, particularly with kids
Component analysis is latest model for IRB review process, particularly with kids
Model places greater demand on balancing risks and benefits
A movement slowly gaining ground in North America suggests an alternative way to assess the risks and benefits of human subjects research, particularly when studies involve children.
Called component analysis, the method is different from the more commonly used collective analysis. It sets the IRB review bar a little higher by requiring a more stringent look at various pieces of a proposed study's protocol.
Investigators and clinical trial sites could find the IRB review process more rigorous than it is currently if greater numbers of IRBs begin to use component analysis.
The idea of component analysis was formed in the early 1990's in the Clinical Trials Research Group (CTRG) of McGill University's Biomedical Ethics Unit of Montreal, Quebec, Canada, says Charles Weijer, MD, PhD, an associate professor of philosophy and medicine and the Canada research chair in bioethics at the University of Western Ontario in London, Ontario, Canada.
"Some of the earliest parts of component analysis were formed in that group led by Benjamin Freedman, a well-known philosopher and thinker on ethics," Weijer says.
Freedman was the co-founder and director of the CTRG. He died in 1997.
Other groups have struggled with finding a way to conceptualize research benefits and harms, Weijer notes.
"The National Commission, which wrote the Belmont Report, and their view in the end, and report on IRBs, is quite close to component analysis," Weijer says. "So it's an idea that has strong historical roots in the U.S."
The question germane to the whole issue of component analysis is this one: Can anticipated direct benefit that is associated with one intervention in a protocol be used to justify the risks of another intervention? says Ernest Prentice, PhD, an associate vice chancellor for academic affairs at the University of Nebraska Medical Center in Omaha, NE, and chair of the Secretary's Advisory Committee on Human Research Protection (SACHRP) for the U.S. Department of Health and Human Services.
Under collective analysis, an IRB will assess the composite of all of the interventions detailed in a study and assess whether the use of interventions that do not provide a prospect of direct benefit is justified by the sum of anticipated benefits associated with those interventions that do have the prospect of direct benefit, Prentice explains.
"Collective analysis allows you to look at all of the risks in total, and if the potential risks are at least balanced by some of the potential benefits then you say the risk-benefit relationship of the research is acceptable," Prentice says.
Under component analysis, IRBs assess the potential harms and benefits of each intervention or procedure, he adds.
"The potential benefits of one component of the research should not be held to offset or justify the risks presented by another," Prentice says.
In the United States, component analysis is something that has been highly recommended for application to pediatric research, but not generally to research applied to adults, Prentice says.
Ideally, it would be applied to all human subjects research, Weijer says.
"It provides a comprehensive approach for competent adults, incompetent adults, and children," Weijer says. "It's such an important idea because until now IRBs have not had a structured approach to thinking through whether benefits or harms in a particular research study are acceptable."
Component analysis provides a clear, structured approach that can be applied to any protocol reviewed by an IRB, he adds.
"IRBs struggle with how to think through whether there are acceptable benefits or harms in studies," Weijer says. "A major challenge in IRBs has been in achieving consistency in review across IRBs."
Component analysis provides precisely the structure IRBs need, he adds.
Weijer's component analysis framework is discussed in an August, 2001, report by the National Bioethics Advisory Commission (NBAC), titled, "Ethical and Policy Issues in Research Involving Human Participants."
NBAC recommended in this report that an analysis of the risks and potential benefits of study components should be applied to all types of covered research and that each component of a study should be evaluated separately, and the risks should be both reasonable and justified by the potential benefits to society or the participants.1
Prentice says that SACHRP looked at component analysis and made this recommendation: "Each research procedure in a study must be evaluated independently in terms of potential benefits and risks to subjects. Different procedures in a single trial may be approved or disapproved under different subpart D categories."
Subpart D is the additional protections for children involved in research, Prentice says.
"If we go back in history to the National Commission's work in 1978, in their report of recommendations for additional protections for children involved in research, they also recommended that we utilize component analysis when assessing the risk-benefit analysis of research involving children," Prentice explains.
"It's because of the vulnerability of children," Prentice says. "Why should we ask children to accept a certain element of risk when there's absolutely no benefit associated with that procedure?"
For example, a randomized clinical trial evaluating drug A versus drug B in pediatric subjects, ages four through 12, has a non-therapeutic component of pharmacokinetic (PK) testing, Prentice says.
The PK testing is not going to be used to alter dosing, and it's done purely for scientific purposes with no associated direct benefit to the child, he adds.
The protocol could be divided into two main elements: one is the administration of drug A or drug B, both of which have the prospect of therapeutic benefit; the second part is the PK testing, which has no prospective benefit.
The PK test will involve an indwelling, intravenous catheter, serial blood sampling, and an overnight hospitalization of the children, Prentice adds.
Under collective analysis, an IRB might find that the risk posed by the PK testing is justified by the anticipated direct therapeutic benefits of the drugs studied in the trial, he says.
"It's only that element of the research that has any prospect of direct subject benefit," Prentice notes. "You add up the risks of the drugs and risks of the PK testing and ask whether they are outweighed or at least balanced by the anticipated benefits of the drugs."
If an IRB uses collective analysis and says that the risks in total are outweighed or balanced by the potential benefits of the drugs, then the IRB can approve the study under a category of subpart B involving research with greater than minimal risk but offering the prospect of direct subject benefit, Prentice explains.
On the other hand, if an IRB uses component analysis and breaks the study down into each intervention, then the review might find that the risks of drug A and drug B are justified by the anticipated direct benefits of the drugs, Prentice says.
But the anticipated benefits of the drugs cannot be used to justify or balance the PK testing.
"You have to look at the PK testing separately," he says. "So the first thing you have to say is, 'What are the risks of PK testing?'"
Risks involve the indwelling intravenous catheter, periodic blood sampling, and the overnight hospitalization.
Since the pediatric subjects in this theoretical case are sick enough to need drugs, one could argue that the indwelling IV catheter and serial blood sampling are a minor increase over minimal risk, Prentice says.
"One would have to then judge whether or not whatever data they get from PK testing is of significant importance — how important is it to do this on kids?" Prentice says. "It's an add-on, and in research we have a lot of add-ons, and you're taking advantage of the availability of the subject population, which is undergoing certain procedures."
IRBs typically review a study's add-on with the "sniff" test, Prentice notes.
"They probably are not applying component analysis, but are asking, 'Why does the investigator want to do this, and is it justified?'" he says. "A lot of IRB members have never heard about component analysis."
However, it's increasingly being used in pediatric research, Prentice says.
One of the reasons why component analysis is catching on is because of a fundamental aspect of clinical research: it often contains a mixture of procedures and some of those procedures hold out the possibility of direct benefit for research subjects, and others are done solely for scientific purposes, Weijer says.
"Allowing therapeutic benefit in a study to compensate for large amounts of nontherapeutic risk would be a very significant problem in a study where the possibility of excellent treatment allows you to do a lot of things to people for nontherapeutic purposes," Weijer says. "By separating these components out, it allows the IRB to separate their analysis of these two kinds of procedures."
Component analysis allows IRBs to focus on the incremental risk associated with study participation, Weijer adds.
Reference:
- Ethical and Policy Issues in Research Involving Human Participants. National Bioethics Advisory Commission. Vol. 1 Report and Recommendations by NBAC. August, 2001:77.
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