Rising to the Ethical Challenges of Pediatric Drug Development

Recent progress in the understanding of human disease has led to an explosion in the number of medicines available for adults. But children are missing out, with significantly fewer drugs being developed and tested specifically for them. In fact, the vast majority of drugs that are prescribed to children have never actually been studied for safety and efficacy in the pediatric population.

The ethical quandary that underlies this problem—how to provide children with evidence-based treatments while protecting them from inappropriate research—was the focus of a recent symposium held by the New York Academy of Sciences and the NYU Grossman School of Medicine. The program, Ethical Considerations in Research for Pediatric Populations, was sponsored by Johnson & Johnson.

Over two days, September 13 and 14, 2022, leading experts from academia, industry, regulatory institutions, advocacy organizations, and clinical research shared perspectives on ethical dilemmas that surface when designing and conducting research to improve medical care for young people.

Progress and Limitations in Pediatric Research

Pediatric clinical research got a big boost in the early 2000s, when the US Food and Drug Administration (FDA) began to incentivize drug companies to conduct pediatric studies, and also to require such studies for new drugs that could potentially benefit children. These “carrot-and-stick” programs, known as the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) respectively, led to a gradual uptick in pediatric labels—meaning studies and approvals specifically for children.

Over the last two decades, this pair of groundbreaking laws, and updates to them, have had enormous impact. The number of pediatric clinical trials jumped from well below 50 before 1999 to 150 between 1999 and 2004, and to 400 between 2005 and 2009, about the level at which it remains. Importantly, the number of pediatric labels—meaning drugs that are approved specifically for children—has climbed steadily over the last 20 years.

However, certain pediatric groups have benefitted less from BPCA and PREA. It was only in 2018 that PREA started to require drug companies to submit a pediatric study plan (PSP) for new drug applications for orphan diseases.[1] These are rare conditions that affect fewer than 200,000 people in the US.

Nevertheless, pediatric labels for less common diseases are still lagging because there are fewer children to participate in studies. The majority of new pediatric drugs have been for infectious diseases, with far fewer for cancer, heart disease, and neurologic and other conditions.

“The easy drugs have already been studied, that era of easy therapeutic development is already over,” said Lynne Yao, MD, director of the FDA Division of Pediatric and Maternal Health Center for Drug Evaluation and Research (CDER), who gave a keynote lecture at the symposium. Making progress in harder-to-study drugs will require innovations in trial design and exploring the full gamut of data sources, Yao added.

An important group that continues to miss out on the benefits of BPCA and PREA is neonates. These programs rely on adult drug development to drive pediatric drug development, yet certain conditions are specific to neonates. Even for conditions that occur in both newborn babies and adults, the benchmarks for effective therapies in neonates can differ from those in adults.

“We really need to get to a point where we are considering pediatric-specific product development, where [drug company] sponsors are developing products specifically intended to treat a neonatal condition,” said Dionna Green, MD, FCP, director of the FDA’s Office of Pediatric Therapeutics. Green commended the work of the International Neonatal Consortium, launched in 2015, for working to standardize neonatal treatment and disease definitions, which is laying the groundwork for neonatal studies.[2]

As important as it is to expand pediatric drug development, the research raises special ethical considerations. First of all, “children should only be enrolled in a clinical trial if the scientific and/or public health objectives cannot be met through enrolling subjects who can provide informed consent personally, that is adults,” Yao said.

Over the last 20 years, an approach called pediatric extrapolation has been fundamental to planning how to do—or not do—trials in children. The approach, which was originally outlined in 2000 in guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), looks at whether there is a high degree of similarity between a disease course and an expected therapeutic response for a pediatric group and a reference population, such as adults.[3] If so, the design of pediatric studies can be simplified, for example by doing open-label studies and enrolling fewer children.[4] This is the reason that, while the number of pediatric clinical trials has climbed since 2000, the number of children enrolled in trials has dropped. The approach has been used successfully in developing pediatric drugs for heart failure, lupus, and schizophrenia.

The future of pediatric drug development lies, in part, in the innovative use of pediatric extrapolation, Yao noted. A new draft guideline is being developed focusing on the continuum of similarities between adults and children to improve upon the ability to glean drug safety and efficacy in children from adult trial data. Other sources of data are also expected to play an increasingly important role in determining whether pediatric trials are necessary, and if so how to design them. These include nonclinical data sources, such as in silico and animal models, and the large amount of real world data that has been amassed through computational advances, including electronic health records, claims databases, and disease registries.

Another critical ethical issue in deciding whether a pediatric study is appropriate is if children could potentially have direct therapeutic benefit from it. If not, the risk of participating in the trial must be low.

However, regulations around what constitutes minimal risk in non-therapeutic pediatric research “are conceptually flawed and the way they work in the real world is seriously flawed,” said Norman Fost, MD, MPH, professor emeritus of pediatrics at University of Wisconsin School of Medicine and Public Health. Investigators and regulators should clarify the rationale for when to permit non-therapeutic research and the definition of minimal risk, including the time that study participation would require of children and the types of doctors they would see, Fost noted.

An additional complexity in deciding whether to conduct pediatric studies is that the risk-benefit analysis can change over time. For example, in the early days of the COVID-19 pandemic, the virus did not cause severe outcomes in the pediatric population, and thus there seemed to be little direct therapeutic benefit of COVID-19 vaccines and treatments for children. As a result, development of vaccines and treatments in children was not prioritized, a decision that many have criticized. “[But] at different parts of the pandemic, we’ve seen [viral] variants have different levels of risk, for multisystem inflammatory syndrome in children (MIS-C), long COVID, or myocarditis,” said C. Buddy Creech, MD, MPH, FPIDS, professor of pediatrics at Vanderbilt University School of Medicine. “So, we have had a moving target based on what [variant] is circulating.”

Assent and Consent in Trials Involving Children

Getting informed consent from trial participants—a process that involves potential participants talking with research staff about what a study would involve and expressing their willingness to take part—is a critical part of ethical research. However individuals younger than 18 years are not legally able to provide consent in the US.

As pediatric research has increased over the last several decades, there has been more attention to assent and dissent—a minor’s willingness or not to participate in a study. “The difficulty is that there is no definition of the elements of assent as there are for consent,” said Robert (Skip) Nelson, MD, PhD, FAAP, senior director of pediatric drug development at Johnson & Johnson. Without this framework, “it leaves open to people to make their own definitions and there is no requirement to respect dissent.”

The American Academy of Pediatrics and many other groups state that children can generally give assent starting at 7 years. However, the appropriate age can vary a lot depending on the child—and factors such as their developmental stage and health, and the particular elements of assent that a study is using. Some researchers think assent requires a child to be able to assess the benefits and risks of study participation, similar to the consent process, which is a relatively high developmental bar that many children would not meet until 10 to 14 years, Nelson explained. On the other hand, some think children can agree as long as they have a developmentally appropriate understanding of why they are being asked to be in the study and what will happen to them. In that scenario, “arguably there are children, in my view, as young as 4 or 5 years who potentially could be able to give assent,” Nelson said.

Assent can be even more complicated with adolescents and teenagers. Although they often have the ability to understand what the study would entail—particularly if they have already participated in clinical studies—they may decide that they do not want to be part of the decision-making process. For example, they may want to, or feel pressure to, let their parents decide.

“It is important to me in those situations always to understand, what are the motivations for this child’s decision?” said Yoram Unguru, MD, MS, MA, a pediatric hematologist/oncologist at The Herman & Walter Samuelson Children’s Hospital at Sinai and Johns Hopkins Berman Institute of Bioethics. “I think that’s an important bit of information that will help us understand what they truly want and what that preference is,” he added.

To that end, and to help children ask questions and voice concerns, Unguru brings along someone other than a physician, such as a social worker or nurse, to act as a research advocate when meeting with patients and families to discuss clinical study enrollment. This individual can pick up on cues about what children want to talk about and help children understand that it is fine to say “no” to participation. The importance of research advocates, and the possibility of introducing a regulatory requirement for one in pediatric research, was echoed over the two days of the symposium.

Like consent with adults, assent “is not a one-time thing, it is not a form being signed but it’s a discussion,” said Amy Schwarzhoff, MS, MBA, CIP, director of human subjects research at the Children's Hospital of Philadelphia (CHOP). It is important for investigators and all research staff to be educated about the study’s assent process, how to determine children’s willingness, and whether dissent will be respected, she added. There may be a role for institutional review boards (IRBs) to play in assessing not just whether studies will get assent, but the process investigators will take, as IRBs have been increasingly doing for studies with adults.

Beyond Assent, to Engagement in Research and Trial Design

Progress in pediatric research over the years could not have taken place without the involvement of patients and their families, and the path that lies ahead for the field will be significantly shaped by the engagement of these groups and their partnerships with researchers, regulators, and other stakeholders.

In many ways, families play a part in supporting children as they decide whether they assent to participate in a study. Families can help reduce a child’s anxiety by bringing them to the study site with a trusted relative and using neutral language when talking about the study, said Pat Furlong, founding president and CEO of Parent Project Muscular Dystrophy (PPMD). Families can sometimes overstate the benefits of being in a study to their child because they “want or need change in terms of the predicted outcome,” she said. In addition, families can help children who do assent by paying attention to their behavior while they are in the study to pick up on signs that their willingness might have waned, Furlong noted.

Patients and families should also be encouraged to get involved well before the stage of enrolling in a clinical trial, from helping to bring awareness to the need for research to advising about appropriate designs of clinical trials. Organizations made up of pediatric patients and their families, particularly The International Children’s Advisory Network (ICAN) and European Young Persons Advisory Group Network (eYPAGnet), are focused on doing just that.

“We need families at the table…because professionals…can sometimes forget to step back and look at something from a more ethical perspective,” said Nancy Goodman, JD, founder and executive director of Kids v Cancer. For example, pediatric trials of cancer therapies sometimes test a new drug by giving it to one group of kids and comparing them with a control group that did not get the drug. But the drugs have often already shown efficacy in adult trials, so it is inappropriate if some children in the study do not receive it. “Parents should be at the table to fight against those control arms,” Goodman said.

Overcoming Bias and Structural Racism in Study Design

A key tenet of clinical research is that trials should include groups that are most likely to benefit from the drug. Yet, certain groups that could potentially benefit from new treatments continue to be underrepresented in studies, which can also damage their trust in science.

Racism and discrimination, which can lead to less access to healthcare and other poor health outcomes, can also create barriers for participating in studies. “In terms of…how we structure our research, we have to factor that in, to not only how we look at their outcomes, but also how we design studies so that everyone can participate in new knowledge,” said Maria Eva Trent, MD, MPH, professor of pediatrics at Johns Hopkins University, in a keynote lecture.

Trent and her colleagues have used a number of strategies to reach and retain vulnerable members of the Baltimore community, such as those with few public transportation options, in both healthcare delivery and adolescent research. These strategies include training investigators and study staff that are diverse and trusted in the community, providing car share rides to wellness visits for individuals in public transportation deserts, and using telemedicine for easier access to testing and treatment.

Similar strategies could help increase racial and socioeconomic diversity in clinical trials, as several experts discussed during the symposium. These include allowing participants to visit study sites at nights and on weekends, providing childcare, and decentralizing studies so that participants can complete study activities at nearby sites without having to travel to the investigator locations.

The FDA issued guidance in 2020 for how drug companies can increase the enrollment of underrepresented groups in clinical trials, such as by expanding eligibility criteria. The agency followed up in 2022 with draft recommendations for companies to submit a diversity plan to the agency early in clinical drug development that includes strategies for enrolling underrepresented racial and ethnic groups.

Approaches to reduce barriers to clinical trial participation, such as extending study site hours, can be effective in not just urban communities but also rural and suburban areas. In rural areas, there is the added complication of needing to train local research staff. “[But] if you build it, they will come…the biggest barrier is convincing ourselves in academia, in industry to [do] those trials, even if they are more expensive,” said Barbara Pahud, MD, PhD, of Pfizer. Pahud previously worked in the IDeA States Pediatric Clinical Trials Network (ISPCTN) to set up pediatric clinical trials in Rural Kansas City.

During the COVID-19 pandemic, the need to include children from underrepresented groups in vaccine and therapeutic trials was especially stark. Researchers quickly learned that Black and Hispanic children were more likely than White children to have severe outcomes from infection, and to develop MIS-C in the weeks after. To help recruit children from these groups, Pahud established a local registry for families in the Kansas City area interested in COVID-19 trial participation, similar to the national COVID-19 Prevention Network. As soon as trials opened in the area, Pahud and her colleagues focused their calls on Black and Hispanic families in the registry, to help enroll a representative number of children from these racial groups.

Fitting Rare Diseases into the Pediatric Drug Development Framework

While a disease is considered rare if it affects fewer than 200,000 people in the US, very rare diseases may affect only a single person or several dozen people worldwide. Because of the low prevalence, clinical trials of therapies for very rare diseases are impossible. Overall there is scant research and regulatory guidance and ethical framework for developing drugs for rare diseases, half of which affect children and most of which are debilitating or life-threatening.[5]

In recent years researchers and organizations have started to use whole genome sequencing to identify the genetic cause of a patient’s disease—most rare diseases are genetic—and formulate customized therapies.[6] In 2017, Tim Yu, MD, PhD, of Boston Children’s Hospital, Harvard Medical School, treated a young girl with a rare form of Batten disease by designing a snippet of artificial genetic material known as an antisense oligonucleotide (ASO) to target the underlying abnormality. A center developing these therapeutics has opened in the Netherlands, and interest is cropping up in Europe, Australia, and Japan.

The n-Lorem Foundation, based in California, has recently been developing treatments based on ASO technology for several patients with very rare diseases each year. It hopes to increase that number to a few thousand annually. It is able to provide the therapies to patients at no cost, in part because it built an industrialized process for making ASOs, said Stanley Crooke, MD, PhD, founder and chief executive officer of the Foundation, during the symposium. n-Lorem is supported by investments from pharmaceutical companies and individuals, including Crooke.

This therapeutic area got a boost in 2021 when the FDA issued draft guidance for investigators doing “N of 1” studies, which focus on developing therapies for individual patients. It includes considerations for submitting investigational new drug applications (IND), which must be done for each therapy and thus each patient, and dosing and monitoring patients.

Despite the growth in drug development for extremely rare diseases, these cases raise unique ethical questions. One of the most important is whether providing these treatments constitutes practicing medicine or conducting clinical research. Whereas medicine is intended to help an individual, “the ultimate driving aim [of research] is to come up with generalizable data that can be extrapolated from that individual to others,” said Alison Bateman-House, MA, MPH, PhD, assistant professor of population health at NYU Grossman School of Medicine. Because of the potential of medical research to have broad impact, it is subject to rules and oversight bodies, such as IRBs, that do not exist in medicine.

Bateman-House explained that personalized rare disease therapies are in a gray zone between medicine and research, and as such it is unclear which rules apply. “Are we going to stay in this ‘research light’ realm, where we are primarily trying to help individual people, and if we learn a little bit on the side, fantastic? Or can we build some sort of super structure where we intervene for each of these individuals…[and] also prospectively gather information that really is intended to create generalizable data?” she said.

Even if treatments are for only a single patient, “we are obligated to learn, it’s just that simple. And then the only question is, how do we learn?” Crooke said. n-Lorem has developed approaches for N of 1 research such as setting endpoints for the ASO and collecting natural history data for patients to allow comparisons before and after receiving treatment. Its scientific review committee assesses these data to determine whether a patient is responding to the treatment. The Foundation is publishing case reports in peer-reviewed journals and is devising analytical approaches to aggregate data from different patients.

Although pediatric drug development, especially for rare diseases, has long been neglected, “we have finally realized that we can’t go on like this,” said Ronald Cohn, MD, FACMG, president and CEO of The Hospital for Sick Children (SickKids). There are opportunities now to rewrite history, he added. By embracing innovation in trial design and updating regulations, partnering with patients and families, and including underrepresented groups in research, the future looks promising for expanding treatments for children through ethically appropriate research.

Arthur Caplan, PhD, professor of bioethics at NYU Grossman School of Medicine, was the Chair of the Scientific Organizing Committee for the symposium. The additional members of the Scientific Organizing Committee were Christine Grady, MSN, PhD, of the NIH Clinical Center; Sam Maldonado, MD, and Sandra Morris, PhD, of Johnson & Johnson; Perdita Taylor-Zapata, PhD, of the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) at NIH; Brit Trogen, MD, of Icahn School of Medicine at Mt Sinai; and Melanie Brickman Borchard, PhD, MSc, of the New York Academy of Sciences.

[1] https://premier-research.com/blog-understanding-regulatory-changes-pediatric-oncology-trials/
[2] https://journals.lww.com/advancesinneonatalcare/fulltext/2016/02000/noteworthy_professional_news.2.asp
[3] https://www.pmda.go.jp/files/000244623.pdf
[4] https://www.centerwatch.com/articles/26076-pediatric-extrapolation-ok-to-evaluate-safety-ich-draft-guideline-says
[5] doi: 10.4161/rdis.23579
[6] doi: 10.4161/rdis.23579