By Debora Borfitz 

October 11, 2022 | Despite regulatory and congressional efforts to protect human research subjects that date back 75 years, ethical dilemmas concerning the participation of pediatric populations in clinical trials persist with no consensus on several key issues—among them the age at which children are too young to understand what they’re agreeing to, and how to respect nonverbal expressions of dissent. The topic was extensively covered by the New York Academy of Sciences at a recent bioethics symposium, beginning with a discussion about parental permission and privacy when children are unable to assent. 

The event kicked off with a keynote presentation by retired pediatric clinical pharmacologist Stephen P. Spielberg, M.D., Ph.D., whose long list of credentials include establishing the department of pediatric drug development at Johnson & Johnson and leading pharmaceutical industry efforts in Congress on behalf of the Best Pharmaceuticals for Children Act. He frames the discussion as an “ongoing experiment to improve the lives of sick children.” 

Since most medicines are not labeled for pediatric use, children have effectively become “therapeutic orphans,” says Spielberg. The challenge has been generating the safety and efficacy data with limited guidance on how to manage the informed consent process with kids. 

Child labor laws passed in the 1800s were based on animal anti-cruelty laws, and federal human subjects protections that subsequently passed in response to abuses and scandals did little, if anything, to address the needs of children in research, he says. The major milestones in this arena have come only over the past 22 years. 

Highlights include the 2000 International Conference on Harmonization E-11 guidance (Clinical Investigation of Medicinal Products in the Pediatric Population), the 2002 Best Pharmaceuticals for Children Act, the 2003 Pediatric Research Equity Act, the Institute of Medicine’s (IOM’s) 2004 report on Ethical Conduct of Clinical Research Involving Children, the 2006 creation of the National Institutes of Health’s Clinical and Translational Science Awards Program (which covers pediatric studies), and the 2012 Creating Hope Act addressing the development of treatments for rare pediatric diseases.  

One of the key lessons, says Spielberg, is that each milestone required broad input and advances from science and medicine and patient communities together with regulatory agencies and pharmaceutical companies. “Clinical investigation and medical ethics truly are team sports.” 

Rapid Progress 

The task of implementing all the laws and guidelines should be viewed as “an experiment for all of us,” Spielberg says. The partnership with patients is in jeopardy currently because society has done a poor job of educating the masses about the scientific method and why new knowledge leads to a change in approach.  

Change is happening at unprecedented speed, Spielberg saying, noting that the 1739 pharmacopeia was still in use in the late 1800s. In contrast, most of the drugs in the formulary when he started medical school are no longer in use. A huge number of medicines not then imagined have also been found effective, such as therapy involving cloning of the cystic fibrosis gene CFTR. 

Despite rapid progress, trust in science seems to be falling while faith in snake oil is on the rise, he continues. Respectful partnership and better ways to teach about science and medicine are needed, and pediatric trials would be a great platform for moving the agenda forward. 

The terms assent and consent refer to the capacity of children to engage in decision-making based on developmental stages, says Spielberg, adding that his experience in international efforts to harmonize drug development regulations opened his eyes to geographical differences when it comes to age appropriateness and even when adolescence begins.   

During the Q&A that followed with Arthur Caplan, Ph.D., professor of bioethics at NYU Grossman School of Medicine, Spielberg addressed public distrust contributing to the low (5%-6%) rate of COVID vaccinations among children under 5 years of age. It comes back to the need for broad partnerships to counter misunderstandings about how the body responds to disease and immunization and how vaccines are developed, he says. 

Parents, kids, and the public also need to share their insights and work jointly with physicians on an “urgent basis” to ensure good medicines that are developed also get used, he says. It might make sense to place full-time educators in physician offices.  

Undefined Elements 

Assent by children has been under discussion for the past 50 years but “taken for granted to a certain extent,” according to Jeffrey Botkin, M.D., professor of pediatrics and an adjunct professor of human genetics and internal medicine at the University of Utah, who moderated a panel discussion on situations where children are unable to assent. Relatively little empirical research has been done on the topic.  

The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research was charged with developing research guidelines in the 1970s and produced the Belmont Report, says Robert “Skip” Nelson, M.D., Ph.D., senior director of pediatric drug development at Johnson & Johnson. Assent, in this context, means two things: the child says yes, and the need to ask can be waived if that child is not capable of affirmatively agreeing to participate. 

The elements of assent are undefined, unlike those for consent, he notes, resulting in a “consent light” approach involving a risk-benefit assessment generally limited to those over the age of 10. On the other hand, the assent framework—including being given developmentally appropriate information and understanding what is going to happen to them—could well apply even to 4- and 5-year-olds. 

It is frequently stated that children ages 7 and older should be given an opportunity to provide assent, Nelson says. But that right can be waived, and there is no requirement that they be allowed to dissent to research participation. The problem, as Nelson sees it, is that children’s dissent (perhaps due to a deathly fear of blood tests) is not being respected and yet their need to assent can be shelved. 

This can be a prickly issue in the context of non-therapeutic research, which based on the “minimal risk” standard might be viewed as allowable vis-à-vis ethical regulations, interjects Botkin. 

To breach the “law of battery” (unconsented touching) today can lead to a prison sentence, responds Norman Fost, M.D., professor emeritus in the department of pediatrics at the University of Wisconsin, “yet children are not protected by this basic principle.” 

Corporal punishment remains a widely used “discipline” technique in some states in the absence of severe bruising, for instance, Fost says. Paradoxically, hospitals will also term the “bodily invasion” of children with a needle as “research,” even when kids stand to gain no conceivable benefit and such studied would be frowned upon if the subjects were nonconsenting adults.  

Non-therapeutic research on children is “simple battery,” says Fost. Yet a “substantial” number of people believe that even studies involving a brain stem biopsy meet the definition of minimal risk. The same holds true for genital exams of older children and no-benefit interventional studies where the objective is to see if children can be convinced that they’ve been abused by a parent. 

Parental Quandary 

Regulations do not stipulate the age for assent, although the New York Academy of Sciences and some institutional review boards (IRBs) believe the baseline is once children reach the age of 7, says Botkin. Younger children have no formal role in decision-making about participation. 

In the case of a minimal risk interventional trial looking to enroll participants between the ages of 6 months and 6 years old, IRBs will typically say assent is not needed, only parental permission, Botkin continues. The dilemma for investigators is what to do if a 3-year-old vehemently objects to venipuncture. 

Ideally, every participant assents, says Amy Schwarzhoff, director of human subjects research at the Children’s Hospital of Philadelphia (CHOP). The focus is on research-related procedures, typically blood draws. 

The IRB can waive assent, but the wishes of children need to be respected if they understand what a needle does to them and they object to the procedure, she says. When children vigorously object, the concern is that the study would introduce “additional harms” and they would probably not be enrolled. 

As with informed consent, the assent process is not a single event but ongoing, Schwarzhoff adds. And the setting matters and can cause more anxiety than is necessary. For instance, a child at naptime might be more moody than normal and less likely to understand and be interested in participating in a study. But whether a child is 12 or 3, “we would respect their decision.” 

In the case of a 3-year-old, says Nelson, it can be difficult to distinguish lack of assent and “behavioral dissent.” The question is at what age children are aware of what is happening to them and could stop it by saying no, and the role of parents who might be legitimately torn between the desire to answer a research question and not see their child suffer.  

The quandary is real, according to Pat Furlong, founding president and CEO of the Parent Project Muscular Dystrophy, who has years of firsthand experience with pediatric research. Many clinical trials for Duchenne muscular dystrophy patients ages 3 to 5 require needle biopsies under local anesthesia.  

The procedure causes no obvious pain, she says, but the grinding sensation of the machine can cause parents to change their mind at that point because “they don’t want their child to experience what feels like trauma.” 

This type of trial should not have gone forward in the first place, says Fost, because it is not for the child’s benefit. If 3-year-olds could give a reason for saying no, it would be the same reason as a 7-year-old or 27-year-old—they don’t want to be hurt or annoyed by an experience that is of no benefit to them. “The notion of assent is limited to verbal children, and I don’t understand the reason for that.” 

Most IRBs routinely approve these sorts of studies, says Fost, who is personally opposed. The rationale for allowing the research comes back to the minimal risk concept in the Common Rule (issued by the Department of Health and Human Services in 1991). 

Studies with minimal risk and potential benefit probably would be approved by the IRB at CHOP without requiring assent, says Schwarzhoff. “But if a 3-year-old vigorously dissented, our expectation is that the investigator would not enroll [that child].” Investigators are educated on this point. 

‘Pragmatic Compromise’ 

The minimum risk standard was the “pragmatic compromise” of the National Commission in rejecting an argument that the desires of a nonverbal child could be inferred, says Nelson. It was used to set boundaries around decisions that could be made.  

But at the time, minimal risk meant a throat swab and not a brain stem biopsy, says Botkin. 

Minimal risk is tied, definitionally, to risks of ordinary life, adds Fost. A nephrologist can therefore make the case for kidney biopsies they do on a routine basis. Risks of ordinary life can also differ significantly based on where someone lives—say, Madison, Wisconsin, versus anywhere in Ukraine.  

Next up for discussion was a study much like the first but where the intended enrollees are 9-month-old infants with some venipuncture experience (from standard immunizations) who have social anxiety. “I would hope investigators would not proceed with research... if a child was adamantly opposed,” Schwarzhoff says. 

In terms of rare diseases, Furlong says she would want IRBs to consider if the study might elucidate the genetic underpinnings of a disease even if study participants would not personally benefit over the near term. 

But if results of study blood draws aren’t shared with parents, there would be no potential benefit for future care decision-making, points out Schwarzhoff. 

The scientific value of a 9-month-old with a rare condition should have no bearing on the assent process, says Fost. But since clinical management starts with a diagnosis, the babies might see some immediate benefit from study participation. On the other hand, there may be another means to that end that doesn’t involve invading a child’s body in a study, such as use of residual newborn screening samples. 

The stress experienced by infants during a blood draw is inherently hard to articulate, Nelson says, noting that it can be generated just by holding them down during the procedure. The best that can be done is let “pediatric instinct” sort out if the unconsented touching would have untoward consequences. 

Belmont Report For Kids? 

In the rare disease environment, education of physicians and parents is critical, says Furlong. She cautions that referring to children as heroes or warriors might incentivize their participation, which can be disappointing later when the “magic muscle medicine” doesn’t make them function like their peers and they have a breakdown midway through the trial. Her advice is to use an unbiased palliative care specialist to speak honestly with kids. 

“We need a Belmont Report for children,” says Fost, which would define minimum risk and reference routine visits for health surveillance purposes versus with a neurologist or neurosurgeon. Pediatric research also needs someone at the IRB level serving as a research advocate for children to educate institutions and parents. 

Nelson agrees, noting that although the 2004 IOM report proposed that minimal risk be “indexed” to the experiences of healthy children that recommendation was not embraced in regulations. He supports regulatory changes that would both define assent and add an “explicit respect for dissent.” 

“No means no,” adds Fost. “If a child says no in the only way that [he or she knows] how that should be respected.”  

In talking with younger children who are verbal but too young to assent, says Nelson, the goal of engagement should be answering two basic questions: “Why me?” and “What’s going to happen to me?” 

The person discussing the study should be neither the investigator nor the parent, interjects Nelson, but “someone else who doesn’t have an iron in the fire” and can make clear that saying no is an option. 

Furlong says she would add to Nelson’s two questions a third one: “Why does it matter?” Kids usually want to help other kids and to please their parents, she says.  

During the Q&A that followed, Nelson acknowledged that the assent process is culturally challenging not just across international borders but also within the U.S. Views about what is and isn’t appropriate when parents are making decisions for their children vary widely, he says.  

Research at CHOP is reviewed in the context of federal regulations in the U.S. as well as local ethics committees and boards in various countries to ensure studies are meeting a diversity of standards, says Schwarzhoff. Beyond consent, the bigger question is why research is important to conduct in specific communities. 

In cultures where medicine is paternalistic, physicians decide what will or will not happen and children do not even have a role, says Furlong. 

Doing what is ethically right also can’t be abandoned in the name of diversity, adds Fost. 

Stress reduction methods can be useful in minimizing risk, but procedural sedation is not without its controversy, Nelson says. This again highlights the value of having a neutral party in the room who is “not in bed with the investigator and not a parent.”  

One practical suggestion for mitigating harm, adds Nelson, would be to require investigators to do a “mock” MRI with kids prior to their having the imaging procedure at a research visit. Children could crawl in and out of the scanner, to get the feel of it, and then be asked how they would feel about laying still in the machine for an hour.

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