Clinical research in pediatric populations is indispensable for developing safe and effective therapies tailored to children.
Children may process drugs differently compared to adults due to differences in physiology and metabolism, organ maturity, body composition, and developmental stage, which may lead to different treatment response. Relying on adult data for pediatric treatments can lead to not optimal dosing, reduced efficacy, and increased risk of adverse effects. Clinical trials that include pediatric patients can determine the appropriate dosing, safety, and efficacy specifically for different pediatric age groups (neonates, infants, children, and adolescents).
However, involving children in clinical trials poses unique ethical challenges due to their status as a vulnerable population. This article explores key ethical principles guiding pediatric clinical research, challenges and practical considerations that arise when applying these principles in real-world studies.
Vulnerability and the Principle of Protection
Children are legally and ethically considered vulnerable because they lack the full capacity for autonomous decision-making. One of the foundational ethical principles in pediatric research is the principle of protection, which asserts that children should only be exposed to research risks when the study offers a prospect of direct benefit or when the risk is minimal and justified by the value of the knowledge to be gained.
The Belmont Report and subsequent ethical frameworks stress that children should not bear more than a minimal risk unless the research holds the potential for significant therapeutic benefit. Importantly, research that does not present the prospect of direct benefit must be justified by its potential to improve the health and well-being of children in general.
Consent and Assent
Informed consent is a cornerstone of ethical research, but in pediatric trials, this process is more complex. Since children, particularly those under the age of legal majority, cannot provide legally valid consent, consent must be obtained from a parent or legal guardian. However, ethical research also requires involving the child in the decision-making process to the extent possible, this process is referred to as Assent.
Assent involves explaining the study in age-appropriate language and seeking the child’s affirmative agreement to participate. The age at which children are capable of assenting varies but is often considered to begin around seven years, depending on cognitive development and maturity. Additionally, studies must be designed to revisit assent over time. In long-term trials or those involving adolescents transitioning to legal adulthood, re-consenting processes must be integrated into the study design to ensure ongoing voluntary participation.
Minimizing Harm, Discomfort and Risk
Another ethical imperative in pediatric trials is the minimization of harm and discomfort, including physical pain, psychological distress, and disruption to a child’s daily life. Clinical trial protocols must consider how to reduce discomfort during procedures such as blood drawing, imaging studies, or drug administration. Researchers may apply many strategies to reduce risk and discomfort in pediatric trials; common approaches include techniques such as topical anesthetics before needle sticks, using an indwelling catheter so that one IV insertion yields multiple samples rather than multiple venipunctures, distraction strategies, and the presence of caregivers can significantly reduce anxiety and distress.
From a clinical perspective, scientific guidelines recommend maximum volume of blood to be drawn from a child, to minimize the risk of iatrogenic anemia. Specific strategies such as micro sampling techniques with microanalytical methods, population PK modeling and sparce sampling, will contribute to reducing the sample blood draw volumes and samples frequency.
Minimization of psychosocial discomfort is important, too. Participation in clinical research can disrupt school routines; therefore, researchers must take steps to reduce the burden on both the child and their family by designing protocols that are flexible and sensitive to these disruptions. Child-friendly settings, trained child-life specialists to help children cope with procedures, allowing caregivers to comfort the child during interventions, or explaining procedures in child-friendly language may reduce anxiety and minimize distress.
Lastly, as ethical guidelines for pediatric research mandate that risks must be minimized and be reasonable in relation to the potential benefits, institutional review boards (IRBs) and ethics committees play a crucial role in evaluating pediatric protocols to ensure they adhere to ethical standards. In addition, safety monitoring during the clinical trial is key to risk reduction and must include close study oversight by independent data safety monitoring boards (DSMBs).
Scientific Necessity and Justification
One of the most important ethical considerations in pediatric research is scientific necessity. Researchers must demonstrate that the trial cannot be conducted with adult participants and that the information sought is essential to improving pediatric care.
Studies should be designed to obtain maximal information with the fewest participants and ensure that each age group is appropriately represented and studied (due to the physiological and developmental differences among children at different ages). Trial design considerations such as age stratification and use of modeling and simulation to reduce sample size will serve to reach these objectives.
Justice and Fair Access
The principle of justice states that individuals within a population should have equitable access to the potential benefits of the intervention and share in the potential risks. The selection of children to be included in a clinical trial should be equitable, and vulnerable subjects should not be exploited for the benefit of the general population. Factors that may disrupt the equitable distribution of participation include demographic differences (e.g., minorities, primary language), mental status, and coercion based on financial incentives.
Researchers must be vigilant to ensure fair and equitable access across different socioeconomic and ethnic backgrounds to the potential benefits of clinical research.
Communication and Transparency
Effective communication with both children and their families is essential for ethical pediatric research. This includes clear disclosure of risks, benefits, alternatives, and the right to withdraw at any time without penalty. Communication should be culturally sensitive and tailored to the child’s developmental level and family’s language and literacy needs.
Transparency also extends to the dissemination of research results. Participants and their families should be informed of study findings in a comprehensible manner, and researchers should ensure that pediatric trial data is published, regardless of the outcome, to contribute to broader scientific understanding.
Transparent communication is key to building trust and engagement with patients and families and helps to address concerns for participating in clinical trials and reassures them that they are under close medical supervision during the trial period and their best interest is a priority, which has a positive impact in a patient´s retention during the study.
Conclusion
Pediatric clinical trials are ethically complex and require a careful balance between advancing medical knowledge and protecting the rights and welfare of children. Core ethical principles—protection from harm, assent and consent, scientific necessity, justice, and transparency—must guide every aspect of study design and conduct. While these principles present practical challenges, adherence to them is critical to ensuring that pediatric research is both scientifically valid and ethical.
Pediatric clinical trials are necessary in modern medicine, to ensure that children will receive evidence-based, safe, and effective therapies.
Author:
Isabel Caballero
Senior Medical Manager
Linical