By Deborah Borfitz 

October 13, 2022 | Experts recently gathered at a bioethics symposium on ethical considerations in research for pediatric populations, hosted by the New York Academy of Sciences, for a panel discussion focused on parental permission and children capable of assenting to participation. Moderator Christine Grady, Ph.D., chief of the National Institutes of Health (NIH) Clinical Center's department of bioethics, kicked off the conversation by asking what “most matters” in determining if a child can give assent.  

In the rare disease population, it’s children’s understanding of their own disease, says Lauren Gibbs, a site operations associate with the TIME Trial Program of Tempus Labs. Gibbs was diagnosed with spinal muscular atrophy (SMA) type 3 at age 15, when she enrolled in her first clinical trial for nusinersen (Spinraza). Her parents were “very involved” in the consent process for that trial, as is customary in the SMA community, but her neurologist played a big role in initiating the conversation with the family. 

Victoria Miller, Ph.D., a clinical child psychologist at the CHOP, lists a host of factors establishing the ability of children to give assent, among them prior experience with healthcare decision-making, current health status, and their preferences for involvement. The goal is to help kids feel heard and respected. 

Yoram Unguru, M.D., a pediatric hematologist/oncologist at The Herman and Walter Samuelson Children's Hospital at Sinai, says children’s preference for involvement is imperative. Considerations include family dynamics as well as kids’ decision-making experience in the healthcare and research worlds. “What matters is familial position, culture, who makes decisions in the family, and how.” Soliciting assent from a child is just the starting point. 

David Wendler, Ph.D., a philosopher and bioethicist at the NIH Clinical Center, concurs and emphasizes the importance of talking to children in a language they can understand and seeing if they have questions or worries that can be addressed. Further, kids need to know why they are being asked to assent. If a “no” won’t be taken seriously, don’t ask, he says. 

Parent-Child Dynamic 

Wendler shares the story of an 8-year-old boy with a rare condition who, while engaged in the assent process, asked if he could still stay on the floor and play with his friends if he didn’t give blood. “Play versus a needle in the arm... is that really a choice?” 

Figuring out what children truly want is “not always straightforward,” says Unguru. Some kids also want to play a more peripheral role in the decision-making process, while adolescents will often kick parents out of the room. 

One worry is that some children may be ceding control to their parents and say something different if they weren’t in the same room, Wendler says. 

Indeed, meeting with youth alone is one way of dealing with family dynamics, says Miller. This is especially useful when children have a life-threatening illness and there may not have been much conversation at home about it. 

Gibbs is now old enough to consent to trial participation, but for her first study at age 15 her parents were in the room with her during the assent process. She wished they hadn’t been, Gibbs says, noting her twin interests in pleasing her parents and helping the broader SMA community. 

Interestingly, the consent form but not the assent form covered the risks of the required lumbar puncture, she notes. The language in the assent form was easy to comprehend overall, although she didn’t expect to be a study participant for the next 10 years. 

No other SMA treatments were then on the market (three different options are now available) and that was a “driving factor in giving my assent,” says Gibbs. During a barbecue, the particulars of the trial and the drug were explained to her by a family friend and SMA researcher on a napkin. 

By the time of informed consent for a study, the decision has often already been made that a child will participate, and families have traveled to the hospital for that explicit purpose, says Miller. “That adds to the complexity of the child’s role once they get there.”    

Decision Burden 

As for the most challenging aspects of getting assent for a trial, Unguru cites “time urgency” when treatment needs to begin immediately, and the investigator thinks it is in the child’s best interest to enroll. Time is needed, but largely unavailable, to get to know the family and thereby understand issues related to culture and medical decision-making. “The U.S./Western-based approach isn’t always applicable.” 

As an adolescent, Gibbs says, trial participation forced her to miss a lot of school and her parents to take time off from work. The time commitment tends to be unappreciated at the assent stage. 

To the question of whether 7-year-old children should be told about the risk of death, Wendler says it does not make sense not to tell them. Otherwise, he says, what does it mean to get their assent? In general, asking children to decide about a study they can’t understand is a bad idea. 

What matters with kids is not necessarily an understanding of the 12 elements of consent with adults (e.g., risk-benefit ratios) but, more often, what they can expect from a study and how it will impact them in their daily life, says Miller. 

Children and their parents should not be viewed separately, adds Unguru. “Taking the lead from parents is extremely important” since they invariably want to do right by their child. 

At the adolescent stage, the voice of youth becomes more critical, says Miller, but parents still play a vital role. Teens generally want their parents’ support; otherwise, the decision-making responsibility on them can feel burdensome. 

Gibbs agrees, with the proviso that more of the risks of participation be included on the assent form. It may well have made a difference in her willingness to participate in her first trial.  

How the assent conversation is framed matters, says Unguru, noting that investigators should assume the posture of a “car salesman... in a good way” rather than inadvertently “disrupt the hope.” Unguru always brings a social worker or nurse to the dialogue to pick up on cues from the family. Parents also tend to better understand what is said by a nonphysician, he adds, which might also be the patient’s primary nurse or a child life specialist.  

Going in, Unguru says he has an idea of what children need to know based on their disease process and wellbeing. The conversation often happens within 24 hours of their initial meeting.  

Surveys of adolescents reveal that they commonly welcome the opportunity to be in studies and like to feel they are helping others, says Wendler. “It’s not often that a 10-year-old has the chance to do something truly important and valuable.” 

Exploring Perspectives 

The assent process will vary a great deal child to child, continues Wendler, including some who feel fully in control and others so overwhelmed by their disease that they want their parents to make decisions on their behalf. It’s best not to enter the room with too many preconceptions, he warns.  

With adolescents, it is also best not to have too many adults in the room with the child, says Miller. Teens prefer to have doctors speak directly to them. 

There are occasions where parents should not be involved at all, says Wendler, by virtue of family dysfunction as well as the nature of the illness (e.g., sexually transmitted disease). In some respects, federal regulations defer to state rules. 

More than a decade ago, shares Unguru, an 8-year-old leukemia patient essentially consented to a clinical trial by convincing her reluctant mother to allow her to enroll. 

Contrarily, when children are reluctant, but their parents are not, CHOP investigators will explore their perspective, says Miller. The approach respects children’s hesitancy and encourages them to talk about it more. In minimal risk research, Miller would not want to enroll such children. 

“It depends on the situation,” Unguru says, drawing a distinction between children upset because their hair is falling out in a therapeutic trial versus ones in a relapse setting who have “been through the ringer.”  Children with prior trial experiences are savvier and Unguru is thus more inclined to honor their dissent, although steps might be taken to meet in the middle and avoid potentially fracturing familial relationships. 

Grady then shares a story of a 16-year-old initially reluctant to enroll in a study involving genetic analysis. After talking with him for over an hour, saying it was his choice and he would not directly benefit from participating, he announces “I’ll do it,” primarily because of the imagined repercussions from his parents if he did not concede to their wishes, she notes. 

In some cases, adolescents may initially say no just to feel in control, says Wendler. “I don’t think an initial no is a formal no... [and] at times, we need to take the burden off of kids and say we’ll decide for you.” 

To enroll reluctant adolescents might in any case trip up trials with missed study visits and uncompleted questionnaires, Miller says. At CHOP, unless teens say, “I’ll do it,” they are generally not enrolled. 

Daily Impacts 

Unguru admits to using “persuasion” if a trial will better risk-stratify children, so they get less chemotherapy. “It makes me feel better. But we’ve all been [involved with] studies where it has not panned out better and there were real side effects. We have to be honest about that.” 

Wendler cautions that bias can influence investigators’ judgment, even when they are feeling confident that a trial is the best therapeutic option for a particular child.   

Gibbs recalls that her parents used persuasion by offering to take her skiing during the monthly, study-related treks to Salt Lake City. Several participants dropped out of that trial, as she recalls. The study compensated for food and stays at a hospital-sponsored hotel, which improved her overall experience. 

A reluctant parent can be handled in much the same manner as a reluctant child, says Unguru, by helping them understand the trial and its rationale. He has also had parents pivot from a no to a yes for the wrong reason—i.e., perceived access to a drug in short supply—and he became the one saying no. 

As for the many potential day-to-day impacts of trial participation for children and their parents, Miller suggests a visual for parents separate from the consent form. Beyond the time commitment of accompanying their child to study visits, barriers might include the necessity of working two jobs and paying for childcare. 

For Gibbs, the transition from being a minor to an adult in the same study was unremarkable, she says. The biggest change was in having to travel to three different sites. Her dad also wasn’t in the room for the consenting process, and she voiced more questions. 

The assent and consent processes have positively impacted the diversity of pediatric trials, says Miller. The relational process and interactions certainly help establish trust better than a yes/no checkbox. 

Since people in different parts of the same city make decisions differently, says Unguru, decisional aids are not truly boilerplate but relatable to a variety of cultures, races, and ethnicities. 

Importantly, adds Wendler, increasing diversity in trials means addressing the participation burdens on families. Parents might need help with transportation, finding parking, and paying for childcare, and it’s likely they won’t always be able to leave their job in the middle of the day.

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