Clinical trials play a vital role in developing new treatments and medications. However, when children are involved, the process becomes significantly more complex. Children are considered a vulnerable population, requiring careful ethical, regulatory, and developmental considerations to ensure safety and efficacy. Despite these challenges, including children in clinical research is sometimes unavoidable – particularly for conditions that uniquely affect them or manifest at an early age such as Cystinosis and Vanishing White Matter (VWM). Through projects like Patient One and GuanaRep, Orfenix is committed to making treatments available to children suffering from these conditions. Based on our experience, we have outlined key considerations for designing clinical trials involving children.
1. Ethical and regulatory considerations
Should children be included in the clinical trial?
One of the first questions researchers must address is whether child participation is necessary or if the required data can be obtained through other means. Children, especially infants and young children, may not fully understand the risks and benefits of participating in a clinical study. However, pediatric involvement is ethically justified in situations where:
- The disease specifically affects children.
- Existing adult studies cannot provide sufficient data for child-specific treatment.
Regulations in Europe and the United States
- European Union (EU): The EMA Pediatric Regulation (2007) came into force with the aim to enhance children’s health by facilitating the development and availability of medicines for children aged 0 to 17 years without subjecting children to unnecessary trials or delaying the authorisation of medicines for use in adults. It also led to the creation of the Pediatric Committee (PDCO), which evaluates the studies companies must carry out on children as part of Pediatric Investigation Plans (PIPs).
- United States (U.S.): The FDA mandates that experimental treatments must provide potential clinical benefits to justify risks. Moreover, children participating in the clinical trial must have the disease or condition being studied.
Children are never enrolled in healthy volunteer studies. Regulatory frameworks differ between regions, but the overall emphasis remains on minimizing risk while maximizing benefits for pediatric patients.
2. Age and developmental considerations
Understanding age-related differences
Children are not a homogenous group – age-related physiological differences affect how treatments interact with their bodies. As a result, pediatric clinical trials often segment participants into age groups:
- Neonates (Birth to 1 month)
- Infants (1 month to 2 years)
- Children (2 to 12 years)
- Adolescents (12 to 16/18 years)
Each age category requires tailored approaches to trial design, dosing, monitoring, and symptom assessment.
Challenges in drug development for children
Drug development typically begins with adult studies, and pediatric trials follow later. In cases where both adults and children are affected, such as asthma, researchers must include children at an appropriate stage of the development process. To accelerate pediatric inclusion, some Phase 2/3 clinical trials allow adolescents to participate. However, due to underrepresentation, researchers often struggle to obtain statistical significance, necessitating separate trials for younger participants.
3. Informed consent and assent process
Obtaining consent and assent
Since children are classified as vulnerable subjects, participation requires written consent from parents or guardians. Additionally, children must be informed about the trial at a level they understand and provide assent (age-appropriate agreement).
Sponsors must create different versions of assent documents for different age groups. For young children (under 12), the assent often includes simple explanations with visual aids (e.g., pictures). For adolescents, more detailed information resembling adult consent forms, excluding sections like insurance and data privacy, are generally shared.
Regulatory differences
- EU: The EMA Regulation on Pediatrics applies to children under 18 years, however, each member state sets its own legal requirements. In The Netherlands, for example, children 16+ can consent independently. Adolescents 12-16 years must sign an assent form, and their parents must provide written consent.
- U.S. (FDA): Each state has varying legal ages for consent (16–18 years). Institutional Review Boards (IRBs) determine assent requirements.
For long-term studies, children must reaffirm assent upon transitioning into older age groups.
4. Age-appropriate protocol feasibility
Practical considerations for compliance
A well-structured trial can significantly improve compliance and retention. Considerations include:
- Medication formulation: Can the child swallow tablets, or should a smaller/coated version be created?
- Sample collection: Is urine collection needed for infants?
- Symptom tracking: Are validated questionnaires available for cognitive and quality-of-life assessments?
- Scheduling: Can visits occur after school hours or at home to minimize disruption?
Reducing burdens and enhancing compliance
Pediatric trials often require a significant time commitment from both children and their caregivers. While direct compensation for participation is not allowed, reimbursement for transportation costs, loss of income (parents missing work), childcare support, etc. can make participation more accessible and feasible.
Additionally, engaging patient advocacy groups during the trial design phase can ensure that protocols are realistic and suitable for children.
Advancing pediatric clinical trials
Despite the complexities, pediatric clinical trials remain essential for advancing treatments tailored to children’s unique needs. Conditions such as VWM and cystinosis require clinical research to ensure effective, safe, and accessible treatments.
Through ongoing collaborations with clinicians, regulatory bodies, and advocacy groups, Orfenix continues to drive innovation in pediatric medicine—ensuring that children have access to life-changing therapies.
