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Considerations for Long-Term Clinical Neurodevelopmental Safety Studies in Neonatal Product Development: Guidance for Industry

FinalCenter for Biologics Evaluation and Research Center for Devices and Radiological Health Center for Drug Evaluation and Research Office of the Commissioner,Office of the Chief Medical Officer,Office of Pediatric Therapeutics10/17/2024
Clinical PharmacologyData quality

Description

The purpose of this guidance is to provide a framework for considering whether and what type of long-term neurologic, sensory and developmental evaluations could be useful to support a determination of safety of a drug, biological product, or device (referred to as ‘medical product’ in this guidance) for use in neonates, and if so, which domains of neurodevelopment may be most applicable.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

4
Drug

Defined in section 201(g) of the FD&C Act; Articles intended for use in diagnosis, cure, mitigation, treatment, or prevention of disease; Product classification based on chemical action or specific intended uses like altering pH

Biological Product

Regulated under section 351(i) of the PHS Act; Virus, therapeutic serum, toxin, vaccine, or protein applicable to prevention or treatment; Alternative regulation category for products meeting device definition

Device

Defined in section 201(h) of the FD&C Act; Instrument or apparatus which does not achieve primary purpose through chemical action; Product classification based on primary intended purpose and chemical action

Gene Therapy

A type of ATMP involving recombinant nucleic acids or viral vectors.

Stakeholders

2
Sponsor

Entity responsible for submitting applications under section 524B

Clinical investigators

Source of safety information in clinical trials

Regulatory Context

Regulatory Activities

6
Neonatal Product Development

The overall process of developing medical products for neonates

Observational Studies

Alternate strategy for data collection

Patient Registries

Alternate strategy if long-term follow-up studies are not feasible

Best Pharmaceuticals for Children Act

Legislation made permanent under FDASIA

Pediatric Research Equity Act

Legislation made permanent under FDASIA

Food and Drug Administration Safety and Innovation Act

FDASIA Title V made BPCA and PREA permanent

Document Types

1
Protocol

Defines the standard of veterinary practice and limits for anesthetic regimens

Attributes

4
Gestational age

Factor related to neurodevelopmental vulnerability

2 years of age

Minimum duration for evaluating neurodevelopmental safety outcomes

Adjusted Age

Chronological age reduced by the number of weeks born before 40 weeks of gestation

Birth weight

Information to be recorded in the Comments element in case of prematurity.

Technical Details

Substances

2
Ethyl alcohol

Excipient to be considered for toxicity

Benzyl alcohol

Excipient to be considered for toxicity

Testing Methods

8
Auditory brainstem-evoked response

Neurophysiologic testing method

Biomarkers of Neurodevelopmental Outcome

Adjunctive assessments used in safety evaluations

Neuroimaging

Adjunctive neurological assessment

Electroencephalography

Adjunctive neurological assessment; Neurophysiologic testing for safety signals

Pharmacokinetic studies

Used to quantify systemic exposure

Juvenile animal studies

Nonclinical toxicity testing in young animals

Clinical Outcome Assessment

Tools used to measure neurologic function and daily life functioning

Brain MRI

Neuroimaging study used to assess anatomical evidence of toxicity

Processes

1
Biocompatibility evaluation

Assessment for devices contacting human tissues

Clinical Concepts

10
Neonates

Target population for long-term neurodevelopmental safety studies

Neurodevelopmental Safety

Primary focus of the long-term clinical evaluations; Primary outcome being evaluated in neonatal product development

Preterm newborn infants

Sub-population within the neonatal period definition

Neonatal population

Target population for long-term safety evaluations

Bronchopulmonary dysplasia

Condition treated with high-dose corticosteroids

Necrotizing enterocolitis

Condition unique to neonates

Retinopathy of prematurity

Condition unique to neonates

Prematurity

Comorbidity factor affecting neurodevelopmental outcomes

Congenital Heart Disease

Comorbidity factor to be considered as a covariate

Seizure Disorder

Physical health domain assessment

Identified Hazards

Hazards

1
Neurodevelopmental toxicity

Potential risk from active ingredients or excipients

ICH References (3)

ICH E11(R1)

Addendum: Clinical Investigation of Medicinal Products in the Pediatric Population

ICH S11

Nonclinical Safety Testing in Support of Development of Pediatric Pharmaceuticals.

ICH E11

Clinical Investigation of Medicinal Products in the Pediatric Population.

Related MFDS Guidelines

Korean regulatory guidelines covering similar topics