Long-Term Neurodevelopmental Safety Evaluation of Medical Products Used in Neonates

What You Need to Know? 👇

What are the key considerations for determining if long-term neurodevelopmental safety studies are needed for neonatal medical products?

Sponsors should assess CNS exposure levels, timing and duration of exposure, patient vulnerability factors like gestational age, disease characteristics affecting blood-brain barrier, nonclinical toxicity data, and clinical experience from other populations to determine study necessity.

How long should neurodevelopmental follow-up studies continue for neonates exposed to investigational medical products?

Follow-up should continue to at least 2 years adjusted age as a minimum. Some outcomes may require longer follow-up into childhood (4-6 years) depending on when specific developmental domains can be reliably assessed.

What neurodevelopmental domains should be evaluated in comprehensive safety assessments for neonatal products?

Comprehensive evaluations should include physical health, sensory function (hearing/vision), motor skills, cognition, emotional/behavioral health, communication/language, social functioning, adaptive functioning, and quality of life measures using validated assessment tools.

When should sponsors engage with FDA regarding neurodevelopmental safety evaluation plans for neonatal studies?

Sponsors should communicate as early as possible with the relevant FDA review division to reach alignment on appropriate approaches for long-term safety evaluations, ideally during early product development planning phases.

What study design considerations are most important for neonatal neurodevelopmental safety studies?

Controlled study designs with concurrent control groups are recommended when feasible. Key considerations include standardization across sites, community engagement, multidisciplinary input, patient retention strategies, minimizing burden, and ensuring data quality.

How do nonclinical studies inform the need for clinical neurodevelopmental safety evaluations in neonates?

Nonclinical studies including pre/postnatal development studies and juvenile animal studies can identify potential risks and inform clinical study design. However, they cannot replace clinical assessments since CNS development complexity makes cross-species extrapolation challenging.

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What You Need to Do 👇

Recommended Actions

1. Assess need for long-term neurodevelopmental safety evaluation early in product development
2. If needed, develop comprehensive evaluation plan considering:
   • Patient population characteristics
   • Product-specific factors
   • Timing and duration of follow-up
   • Appropriate assessment tools and domains
   • Standardization across sites
3. Engage with FDA review division early to align on approach
4. Implement strategies for participant retention and data quality
5. Include plan for clinical referrals if developmental issues identified
6. Consider adjunctive assessments (biomarkers, imaging) when warranted
7. Ensure appropriate collection of covariate data
8. Use validated assessment tools appropriate for population
9. Plan for minimum 2-year follow-up with potential longer duration based on specific concerns
10. Document scientific rationale for evaluation approach

Key Considerations

Clinical testing

• Long-term neurodevelopmental safety evaluations should be conducted up to at least 2 years of age (adjusted for prematurity)
• Controlled study design recommended whenever feasible
• Need to ensure standardization across sites and examiners
• Early consent for long-term follow-up recommended during initial enrollment
• Plan needed for clinical referral if developmental problems identified

Non-clinical testing

• Pre- and postnatal development studies needed
• Embryo-fetal development studies may be warranted
• Juvenile animal studies testing at critical brain development stages
• Alternative non-animal testing methods supported when feasible

Human Factors

• Consider patient/family burden and barriers to participation
• Engage patient families and community leaders early
• Maintain contact strategies to reduce missing data
• Consider integrating data from routine care when appropriate
• Plan for minimizing participant testing burden

Biocompatibility

• For devices with tissue contact, biocompatibility evaluation needed to assess potential adverse responses
• Both active ingredients and excipients should be evaluated for neurodevelopmental toxicity potential

Safety

• Comprehensive assessment of neurologic function needed including:
  • Physical health
  • Sensory function
  • Motor skills
  • Cognition
  • Emotional/behavioral health
  • Communication/language
  • Social functioning
  • Adaptive functioning

Other considerations

• Consider timing of exposure relative to developmental stages
• Account for disease state characteristics
• Evaluate route of administration impacts
• Consider regional differences in healthcare systems
• Collect data on relevant covariates (demographics, socioeconomic factors, etc.)

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Relevant Guidances 🔗

• Use of ISO 10993-1 for Biological Evaluation and Testing of Medical Devices
• Biological Evaluation of Medical Devices Standards in the Accreditation Scheme for Conformity Assessment (ASCA) Pilot Program

Related references and norms 📂

• ISO 10993-1: Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process

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Original guidance

• Long-Term Neurodevelopmental Safety Evaluation of Medical Products Used in Neonates
• HTML / PDF
• Issue date: 2024-10-17
• Last changed date: 2024-10-17
• Status: FINAL
• Official FDA topics: Medical Devices, Pediatric Product Development, Drugs, Biologics, Clinical - Medical
• ReguVirta ID: f7c92b03491a0a29197f8522db83e875