Historically, safety and efficacy data on many medicines used in children were surprisingly scarce, and prescribing was often based on extrapolation from trials in adults due to the lack of pediatric data.[1] Now, however, legislation in both the EU and the US requires drug developers to purposefully study medicines marketed in children so that pediatric-specific dosing recommendations can be made. Thus, clinical trials involving children are essential for the development of safe medications, pediatric formulations, age-appropriate interventions, and best practices, but come with unique challenges.
In this article, we discuss the ethical and clinical implications of conducting clinical studies in pediatric patients. We also explore the pediatric trial regulatory landscape in both the EU and the US, with a focus on considerations for sample collection in younger populations.
Ethics in Pediatric Studies: The Imperative
Clinical trials in children have both ethical and clinical implications. From an ethical standpoint, it is important to test medications and treatments on the population for which they are intended. At the same time, children are considered a vulnerable population. As such, it is vital to carefully evaluate whether a clinical trial is in a child’s best interest and, if they do participate, to provide them with additional safeguards to protect them throughout study conduct.
In September 2022, the US Food and Drug Administration (FDA) issued a draft guidance titled Ethical Considerations for Clinical Investigations of Medical Products Involving Children. This document outlines and explains the fundamental concepts for the ethical framework that sponsors, and institutional review boards (IRBs) should consider when reviewing or conducting clinical trials involving children.[2]
Importance of Pediatric Clinical Trials
Children are not simply small adults. From a clinical perspective, there is a significant need for pediatric studies since the physiological, developmental, psychological, and pharmacological characteristics of children vary from those of adults. Children may metabolize medications differently, resulting in sub-optimal therapy, unexpected responses, adverse drug reactions, and toxicity. Importantly, these characteristics also vary among children of different ages and cognitive abilities and may change as they grow from infancy towards adolescence and adulthood.
Pediatric trials provide reliable evidence of treatment effects in children under rigorously controlled testing conditions, creating opportunities to improve outcomes. For example, advances in multicenter oncology trials in children increased 5-year survival rate in childhood cancer from 28% in the late 1960s to 79% by 2005.[1]
Striking a Balance: Safety vs. Research
The vulnerable nature of the pediatric population must be considered when weighing the need for safe and validated therapies against the risks of research. The objective of pediatric clinical trials is to protect each child who participates in a study while serving the pediatric population as a whole. Consequently, any pediatric study must have sufficient scientific merit to justify any risks posed to the subjects. Further, clinical trials involving children should be conducted according to the principles of:[3]
- Respect for persons – individuals should be treated as autonomous agents and those persons with diminished autonomy are entitled to protection
- Beneficence – maximize possible benefits and minimize possible harms
- Justice – fair distribution of the burden and benefits of research
Regulatory Overview: EU & US
The European Pediatric Regulation was adopted in 2006 and entered into force in 2007, codifying rules concerning the development of medicinal products to meet the specific therapeutic needs of children without subjecting the pediatric population to unnecessary clinical or other trials. Any new medicinal product seeking marketing authorization must include a Pediatric Investigation Plan (PIP), unless exempted. In addition, any pediatric trial must be approved by an ethics committee, which specifically assesses the safety and well-being of child participants.
In the US, the Pediatric Research Equity Act (PREA) enacted in 2003 mandates that companies include pediatric studies in their new drug applications (NDAs) for marketing approval if the drugs are expected to be used in children. These studies must undergo review and approval by an IRB. The Best Pharmaceuticals for Children Act (BPCA) provides incentives such as extended exclusivity for companies willing to conduct voluntary pediatric studies. The Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on July 9, 2012, included a provision requiring sponsors planning to submit an NDA for a drug subject to PREA to submit an initial pediatric study plan (iPSP) early in the development process. In 2020, FDA published a guidance document titled Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans.[4]
Consent in Pediatric Studies: Navigating Assent
As with trials involving adults, informed consent must be given before a pediatric patient is enrolled in a clinical study. In most countries, children are unable to provide legally binding consent to participate in a clinical trial.[5] In the EU, a legal representative, typically a parent, must provide informed consent. In the US, by law, children are not able to give informed consent until age 18. Instead, informed consent must be given by at least one parent or legal guardian.
Children who are of an age and cognitive level to understand the research to some extent are involved in the process of making decisions about study enrollment through the process of assent. Assent aims to explain the trial in age-appropriate terms, focusing on what the child can expect from study participation, including procedures, potential discomforts, and the overarching purpose of the study. While assent is not legally binding, it does fulfill an ethical obligation to respect the child’s autonomy to the extent possible. In the EU, assent is generally sought from children considered mature enough to understand the implications, though specific age guidelines vary by member state. Assent must be given freely, and a child’s refusal should be respected unless the trial is potentially lifesaving. In the US, children aged 7 or above are usually required to provide assent, although the age may vary by jurisdiction and IRB. The child must voluntarily agree, and their dissent should be honored unless the research holds the prospect of direct benefit to them.
In general, both consent and assent must be verified by the investigator for the entire period of the trial. If a study participant turns 18, it is important to seek informed consent from them as soon as possible.
Pediatric Sample Collection: Special Considerations
Most clinical trials involve the collection of biospecimens, which requires special consideration in pediatric populations. From an ethical point of view, there is a need to avoid as much as possible, any kind of discomfort or pain to the child and to ensure that the risk is proportional to the benefit. From a clinical perspective, there is a limited volume of blood that can be drawn from a child, and it is important to minimize the risk of iatrogenic anemia.
For clinical research in children, the EU recommends a blood draw limit of 0.8-0.9 mL/kg body weight corresponding to 1% of total blood volume at a single time point and 2.4 mL /kg body weight, or 3% of total blood volume, during a 4-week period. Other IRBs, national health authorities or institutional committees have a larger blood draw allowance. In the US, the National Institutes of Health guideline proposes no more than 5 mL/kg body weight (5% of total blood volume) purposes in a single day and more than 9.5 mL/kg body weight (11% of total blood volume) during any eight-week period.[6]
Both EU and US recommendations point to the need for extra care in managing the pain and reducing the trauma associated with blood draw procedures. EU guidelines also recommend the use of less invasive technologies if available. For example, in hematologic and immunologic diseases or following immunotherapy, it may be necessary to monitor immune cell profiles. Flow cytometry is the most widely applied analytical approach for immune cell profiling but requires significant blood draw volumes, which can be burdensome for pediatric patients. Epigenetic immune monitoring with Epiontis ID® requires less than 100 microliters of blood and can even be performed on dried blood spots (DBS), alleviating ethical, logistical, and technical challenges for immunophenotyping in pediatric populations.
Conclusion: The Critical Role of Pediatric Trials
Pediatric clinical trials serve as a cornerstone for evidence-based medicine tailored specifically to children. These trials allow for fine-tuning of dosages and administration methods for younger populations, but require careful consideration of ethical, clinical, and logistical factors that are unique to conducting research in children. Understanding the landscape and finding a balanced approach that protects the rights and well-being of children while advancing medical knowledge is critical for bringing safe, effective pediatric medicines to market.
Reference:
[1] Joseph PD, Craig JC, Caldwell PHY. Clinical trials in children. Br J Clin Pharmacol 2015;79(3):357-369.
[2] US Food and Drug Administration. New FDA Draft Guidance Aims to Protect Children who Participate in Clinical Trials, September 23, 2022. Available at https://www.fda.gov/news-events/press-announcements/new-fda-draft-guidance-aims-protect-children-who-participate-clinical-trials.
[3] US Department of Health and Human Services. The Belmont Report. Available at https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html#xbasic.
[4] US Food and Drug Administration. Pediatric Study Plans: Content of and Process for Submitting Initial Pediatric Study Plans and Amended Initial Pediatric Study Plans, July 2020. Available at https://www.fda.gov/media/86340/download.
[5] World Health Organization. Clinical trials in children. Available at https://www.who.int/clinical-trials-registry-platform/clinical-trials-in-children.
[6] Peplow, C., Assfalg, R., Beyerlein, A., Hasford, J., Bonifacio, E. and Ziegler, A.-G. (2019), Blood draws up to 3% of blood volume in clinical trials are safe in children. Acta Paediatr, 108: 940-944. https://doi.org/10.1111/apa.14607
