Consent or assent — when and how do you obtain it from children?
Here are some ideas for writing guidelines
Special Report: Children and the IRB
When approving clinical research projects involving children, IRBs naturally want to be sensitive to issues specific to younger participants. However, there have been few concrete guidelines for how researchers should broach the subject of obtaining consent or assent from their minor participants. Now, with the U.S. Food and Drug Administration’s (FDA’s) recent interim rule covering children in clinical investigations of FDA-regulated products, IRBs may need to write or revise policies regarding research involving minors.
A first step is to recognize that there is a difference between the terms "consent," "permission," and "assent." The federal government defines consent as what is obtained from research subjects who are legally adults, whereas assent is an agreement from a minor who is to be a subject in a study. Permission is what is obtained from parents or guardians of subjects who are legally minors.
"Some people think a minor approaching the age of majority can consent for themselves, and if we’re talking about regulated studies, they cannot," says Paul W. Goebel Jr., vice president of Chesapeake Research Review Inc. in Columbia, MD.
The Code of Federal Regulations (45 CFR 46.116) states that investigators must obtain legally effective informed consent of the subject or permission from the subject’s legally authorized representative. Since the code further states that children have not attained the legal age for consent to treatments or procedures involved in research (45 CFR 46.402[a]).
This effectively means that children are incapable of exercising their right to informed consent under national and international law, so they are at a disadvantage and must rely on others to protect them from harm, says Vera Hassner Sharav, MLS, president and co-founder of the Alliance for Human Research Protection (AHRP) in New York City.
Since children cannot give legal consent to their participation in clinical trials, some researchers and IRB directors use the term "assent" to indicate that a child has been notified of a research trial’s purpose and possible benefits and side effects. Obtaining assent from a child is an ethical accommodation demonstrating respect for the child whose cooperation is being sought, Sharav says. "Assent is not, however, a substitute for informed consent," Sharav adds. "I have my doubts about the assent of children who had to endure painful procedures, such as lumbar punctures for experimental purposes."
Nonetheless, an IRB may choose to have a guideline that addresses when obtaining assent from children is necessary and how it is documented, says Janet Donnelly, director of the Chesapeake Research Review. "It’s a good idea to have age guidelines, but I don’t think you can have a strict policy on age groups," Donnelly says. "It’s going to depend on a case-by-case basis of the type of study and the psychological age of the child."
Here are some suggestions for how to establish a policy regarding research that involves minors:
• Include an age classification of pediatric patients.
The U.S. Department of Health and Human Services (HHS), FDA, and other federal agencies have published guidance for the industry on the clinical investigation of medicinal products in the pediatric population. Calling its guidance a possible categorization, HHS suggests dividing pediatric patients in this way:
- preterm newborn infants;
- term newborn infants (0 to 27 days);
- infants and toddlers (28 days to 23 months);
- children (2 to 11 years);
- adolescents (12 to 16-18 years depending on region).
"On a state-by-state basis, there is also some confusion about what an emancipated minor might be, especially as a child gets closer to the age of major," says Felix Gyi, PharmD, and chief executive officer of the Chesapeake Research Review. "One of our recommendations is to have an investigator consider whether an individual is an emancipated minor or not," Gyi says.
For the purposes of nonpharmaceutical clinical studies, IRBs may further divide children into a category of 7 to 11 or 12. "The general rule of thumb is that children under the age of 7 are usually not capable of understanding the ramifications of a study," Goebel says.
• Outline ethical guidelines for conducting research with a pediatric population.
"IRBs must first ascertain whether the proposed research is intended to be potentially therapeutic to the child subjects," Sharav says. "This means the child must have a medical condition that may benefit from the child’s participation in the research." The research should follow the pre-eminent ethical principle of "First, do no harm," and should have benefits that outweigh possible risks, Sharav adds. "Unfortunately, lacking guidance or specificity in current federal regulations, there are widely varying standards being applied when IRBs make this assessment of risks," Sharav says. (See "AAP’s guidelines for pediatric-based research" in this issue.)
IRBs also would be wise to research state regulations and legal cases regarding children used as subjects in clinical research. For example, on Aug. 16, 2001, the Maryland Court of Appeals, responding to the case of Grimes v. Kennedy Krieger, issued a 6-1 decision that said a child may not be subjected to risks in a nontherapeutic study that promises no medical benefit to the child whatsoever, Sharav says.
The court also said that parents do not have the authority to give permission for their child to be exposed to risks without benefit, Sharav adds. "The court was asked to reconsider or partially modify its strongly-worded August opinion, and that request was denied," Sharav says. "The court clarified its intended meaning of the phrase any risk’ by saying, By any risk, we mean any calculable risk beyond the minimal kind of risk that is inherent in any endeavor.’"
At the very least, an IRB’s policies and procedures should be written straight from regulations, including an IRB’s responsibility to make a risk assessment of the study. "This needs to be in the guidelines, and it should be documented in the minutes of the meeting of what level of risk the study is," Goebel says. It’s also a good idea for an IRB to have a written checklist for researchers to complete to make certain everything is covered when they do research involving children, Goebel says. "And they should always return to the IRB if they have any questions."
• Make certain parents have full information about potential risks and alternative treatments.
IRBs should include in its policy a requirement that a parent or guardian give written permission prior to the minor’s participation in a research study. Information about known and potential risks and alternative treatments must be clearly spelled out in the informed consent form that parents sign, Sharav says.
When an IRB has no separate policy regarding informed consent for minors, the general informed consent policy would apply, says Carla Alamia, BS, CCRC, IRB coordinator at the John T. Mather Memorial Hospital in Port Jefferson, NY. "Our IRB encourages researchers to ask potential subjects short questions, after the research has been described and the consent form read, in order to assess that the potential subject has at least a basic understanding of what the research involves," Alamia says.
These questions include:
- Tell me in your own words what this study is all about?
- What do you think will happen to you in this study?
- What do you expect to gain by being in this study?
- What risks might you experience?
- What options do you have if you decide you don’t want to be in this study?
IRBs also need to consider the unusual situation of a parent or guardian who also is a minor, in the cases of teen-age mothers, Goebel suggests. "In many states, those parents can make decisions for their children, but may not be able to make decisions for themselves," Goebel says.
Another tricky situation is when a minor has gone to court and asked to be emancipated and this was mandated by the state. "So IRBs should know what their state law is and clinical investigators should too," Goebel says.
Another detail to add in a permission/assent/ consent policy might be to note when the IRB will require researchers to obtain a single parent/ guardian’s permission and when the IRB requires documented permission from two parents/ guardians, Goebel says. For example, when the research does not involve greater than minimal risk or when the research provides direct benefit to the individual child, it might be necessary to obtain only one parent/guardian’s written permission. In other cases, two signatures might be required unless one parent is deceased, unknown, incompetent, or not reasonably available, Goebel adds.
• Decide when to require an assent/consent from a minor.
Some IRBs may have a general policy of requiring investigators to provide minors, depending on age and maturity, with an assent form to review and sign, Alamia says.
Any policy on assent forms should at least follow the FDA’s interim rule with regard to FDA-regulated products about how a researcher will determine whether an assent is necessary and how it will be documented, Donnelly says. (See "FDA issues in-effect interim rule" in this issue.)
In fact, it might be a good policy for IRBs to ask researchers to be open with children and involve them in the information and consent/ assent process as much as they are able to participate, suggests Dale E. Hammerschmidt, MD, FACP, associate professor of medicine and director of Education in Human Subjects’ Protection for the University of Minnesota Medical School in Minneapolis. "Just as in consent from adults, don’t forget that assent and information are ongoing processes," Hammerschmidt says. "The dialogue doesn’t end just because the child has initialed a piece of paper."
IRBs should have the assent form professionally written by someone who knows language and comprehension skills of children, Hammerschmidt says. (See "Writing an assent form for minors to sign" in this issue.)
"If a child is immature and is not capable of understanding or discussing the situation and not capable of reading a consent form, then researchers should just document it in the study record," Goebel says. "If the child is capable of reading a simplified assent form then they can sign the assent form, and older children or teen-agers can read the consent form," Goebel adds.
While an IRB may have a general policy of having minor subjects excluded from an investigation if they do not provide their own assent, this could backfire if investigators are not careful about how they obtain this assent. "The greater the risk or discomfort and the greater the likelihood that a child would actually dissent, the more useful it is to have some documentation of an assent process," Hammerschmidt says. "A signed form is a pretty standard tool for such documentation."
For example, children may be more concerned about being stuck with a needle than they are about the potential risks of a particular drug. This is why it’s important for investigators to let children subjects know exactly what to expect in the trial, including details that might not seem as important when disclosing the same information to adults, Gyi says. "If there are seven needlesticks in one visit, they should know that because what you don’t want is for the child to panic after the third needlestick and say, No more,’" Gyi adds. "Not only is that stressful for the child, but you don’t get any useful data."
A vulnerable group
• Watch out for hidden agendas.
By paying extra attention to the ethical considerations, an IRB may better ensure that a child will not be harmed during an investigation. "Children are vulnerable to exploitation," Sharav says. "Even parents may not always act in their children’s best interest — especially if there is a financial incentive for parents."
Sharav suggests that IRBs include in a policy a requirement that approved pediatric research not involve a monetary incentive beyond travel expenses. "And when a guardian’ is involved, questions about whether the child’s best interests are served must be even more carefully ascertained," Sharav says.
History has shown that children have long been exposed to harmful and even abusive experiments, Sharav notes. "In its 1994 report, The Advisory Commission on Human Radiation Experiments lists a string of such unethical experiments involving children," Sharav says. "In AHRP’s amicus brief to the Maryland Court of Appeals, we provided recent cases in which children were harmed — not helped — all of them conducted at prestigious academic research centers."