Ethical Considerations for Clinical Investigations of Medical Products in Children (DRAFT)
This guidance outlines FDA's current thinking on ethical considerations for clinical investigations of medical products (drugs, biological products, and medical devices) in children. It focuses on protecting children as a vulnerable population who cannot consent for themselves and require additional safeguards when participating in clinical research.
This is a draft guidance. Not for implementation.
What You Need to Know? 👇
What are the key ethical requirements for conducting clinical trials in children under FDA regulations?
FDA requires additional safeguards under 21 CFR Part 50 Subpart D, including risk-benefit assessment, parental permission, child assent when appropriate, and IRB approval under specific criteria (50.51, 50.52, or 50.53) based on risk level and prospect of direct benefit.
How does FDA define “minimal risk” versus “minor increase over minimal risk” in pediatric studies?
Minimal risk means probability and magnitude of harm are not greater than those in daily life of healthy children. Minor increase over minimal risk is a slight increase posing no significant threat to overall health, with transient, reversible harms.
When can children participate in research without prospect of direct benefit?
Children can participate in non-beneficial research only if risk is minimal (21 CFR 50.51) or minor increase over minimal risk with experiences commensurate to their medical/social situations and likely to yield vital generalizable knowledge about their condition (21 CFR 50.53).
What evidence is needed to establish “prospect of direct benefit” in pediatric clinical trials?
Evidence may include adult efficacy data for the same condition, animal studies, device modeling, biomarker effects, or nonclinical data. The evidence must support potential clinical benefit from the specific research intervention, not ancillary procedures.
How should placebo-controlled trials in children be ethically evaluated?
Component analysis is required - active arm may offer prospect of direct benefit, but placebo arm must meet minimal risk or minor increase criteria. Consider placebo intervention, administration route, frequency, withholding effective therapy risks, and rescue therapy availability.
What are the requirements for parental permission and child assent in pediatric research?
Parental/guardian permission is required with informed consent elements. Children ≥7 years often capable of assent unless capability limited or intervention offers important direct benefit only available through research. IRBs may waive assent under specific minimal risk criteria.
What You Need to Do 👇
Recommended Actions
- Conduct thorough scientific necessity assessment before initiating pediatric studies
- Document comprehensive risk/benefit analysis for each study component
- Implement appropriate risk mitigation strategies, especially for procedures requiring sedation
- Establish clear processes for obtaining parental permission and child assent
- Design studies to maximize information while minimizing number of subjects
- Consider adaptive trial designs when additional dose finding is required
- Ensure studies are conducted at facilities with appropriate pediatric expertise
- Develop clear communication materials for subjects and parents regarding non-therapeutic procedures
- Consult with FDA early in development program regarding pediatric study plans
- Consider potential for 21 CFR 50.54 review if procedures exceed minor increase over minimal risk
Key Considerations
Clinical testing
- Clinical investigations must be scientifically necessary to answer important questions relevant to children’s health
- Studies should be well-designed to collect interpretable data
- Early inclusion of children may be appropriate in some cases without prior adult data
- Study duration should be sufficient to offer potential clinical benefit
- Multiple sources of information can inform pediatric trial design
Non-clinical testing
- Nonclinical studies in disease-specific animal models can support initial pediatric dosing
- Juvenile animal studies may be needed to support pediatric age groups
- Bench testing and modeling/simulation data can inform device trials
Safety
- Risk assessment requires adequate safety data from clinical or non-clinical studies
- Procedures solely for research must be minimal risk or minor increase over minimal risk
- Sedation risks must be carefully evaluated and minimized
- Risk mitigation strategies should be included in study protocols
Other considerations
- Parental/guardian permission required
- Child assent needed for children 7 years and older if capable
- Component analysis required to evaluate risk/benefit of each study procedure
- Prospect of direct benefit must be supported by scientific evidence
- Placebo use requires careful risk assessment
Relevant Guidances 🔗
- Process for Research Involving Children that Requires FDA and OHRP Review under 21 CFR 50.54 and 45 CFR 46.407 (Draft)
- Process for Clinical Investigations Involving Children Requiring Additional Safeguards
- Pediatric X-Ray Imaging Device Premarket Submissions: Design, Testing, and Labeling Considerations
- Premarket Assessment of Medical Devices for Pediatric Use
- Providing Pediatric Use Information for Medical Device Premarket Submissions Under Section 515A
- Leveraging Existing Clinical Data for Pediatric Medical Device Indications
Related references and norms 📂
- 21 CFR 50: Protection of Human Subjects
- 21 CFR 56: Institutional Review Boards
- 45 CFR 46 Subpart D: Additional Protections for Children
Original guidance
- Ethical Considerations for Clinical Investigations of Medical Products in Children
- HTML / PDF
- Issue date: 2022-09-26
- Last changed date: 2024-04-12
- Status: DRAFT
- Official FDA topics: Medical Devices, Pediatric Product Development, Drugs, Biologics, Clinical - Medical
- ReguVirta ID: 4cde5fa9af749edc99481a9b8dd3c967