What is covered in this guidance?

This draft guidance provides a framework for considering neurodevelopmental 

evaluations that could be useful to assess long-term safety of a medical product intended 

for use in neonates.

Why is this guidance important?

Treatment with medical products during the neonatal period coincides with a time of critical 

growth and physiologic development. Short-term safety evaluations typical for adults or other 

populations may fail to identify important adverse effects in the neonatal population, as latent 

effects may follow early-life exposures.

Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about the considerations for long-term clinical neurodevelopmental safety studies in 

neonatal product development, read the guidance.

www.fda.gov 1

Domains for evaluating neurodevelopmental clinical outcomes for safety

General Neurodevelopmental

Physical health Sensory

 Health conditions Motor

 Feeding problems Cognition

 Somatic growth Emotional and behavioral health

 Sleep Communication

Quality of life and global function Social functioning

Receipt of developmental interventions and 

educational services Adaptive functioning

Considerations for Long-Term Clinical 

Neurodevelopmental Safety Studies in 

Neonatal Product Development

DRAFT GUIDANCE FOR INDUSTRY
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about the considerations for long-term clinical neurodevelopmental safety studies in 

neonatal product development, read the guidance.

www.fda.gov 2

Examples of considerations when determining the need for long-term 

neurodevelopmental safety evaluations

Increasing likelihood that long-term neurodevelopmental safety evaluations will be needed

Systemic (and CNS) Exposure 

Timing of Exposure

Duration of Exposure

Population Characteristics

Product Information

low

HOURS DAYS WEEKS MONTHS

high

Less vulnerable 

stage of organ/tissue 

development

Older gestational age

Higher birth weight

Underlying disease does not 

increase neurologic risk

Younger gestational age

Lower birth weight

Underlying disease 

increases neurologic risk

Vulnerable stage 

of organ/tissue 

development 

Product components (e.g., active ingredient, excipients, impurities) and 

nonclinical toxicity, clinical pharmacology, and clinical experience data

Data do not suggest 

potential adverse 

neurological effects

Data suggest 

potential adverse 

neurological effects
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about the considerations for long-term clinical neurodevelopmental safety studies in 

neonatal product development, read the guidance.

www.fda.gov 3

Key points when developing a plan to evaluate long-term 

neurodevelopmental safety and considering what to measure, 

when, and for how long

A controlled study design is 

recommended to allow for 

more reliable discrimination 

of drug or device-related 

patient outcomes from 

outcomes caused by other 

factors

Neurodevelopmental safety 

evaluations should be 

well-defined, reliable, and 

relevant; clinical outcome 

assessments should include 

validated tools, when 

available

Certain objective developmental measures 

with established reference standards (e.g., 

growth, vision, and hearing screening) captured 

during routine care may be used when 

collected reliably, but general developmental 

screening and formalized assessments of 

neurodevelopment are not interchangeable

Neurodevelopmental 

outcomes should be 

evaluated up to at least 

2 years adjusted age; 

evaluation of some outcomes 

may also require assessment 

later in childhood

Sponsors should ensure 

reliable and consistent 

evaluations across study 

sites and examiners

Long-term functional assessments provide 

the most meaningful outcome information; 

in general, adjunctive assessments and 

biomarker measures (e.g., neuroimaging and 

neurophysiologic studies) may be useful to 

support the evaluation of neurodevelopmental 

safety in certain circumstances, but may not 

substitute for functional evaluations

A general evaluation of all 

key neurodevelopmental 

domains is recommended, 

with additional evaluations 

based on domains of concern; 

physical, mental, and social 

health should also be included

Data should be collected 

on co-variates that may 

affect neurodevelopmental 

outcomes (e.g., perinatal 

factors, comorbidities, 

socioeconomic factors, etc.)
www.fda.gov 4

Guidance Snapshots are a communication tool and are not a substitute for the guidance document.

To learn more about the considerations for long-term clinical neurodevelopmental safety studies in 

neonatal product development, read the guidance. 

To see additional Guidance Snapshots, check out the pilot program.

Continue the Conversation

Share your thoughts on the draft 

guidance

Guidance Recap Podcast

Hear highlights from FDA staff

Speakers: Gerri Baer, MD | An Massaro, MD

Click here to listen

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read transcript

Click here to provide 

official comments to 

the FDA Docket

Medical Product Development Timeline

* When to Apply the Draft Guidance Recommendations

BASIC 

RESEARCH

PROTOTYPE 

DESIGN OR 

DISCOVERY

FDA 

FILING & 

PRECLINICAL APPROVAL

DEVELOPMENT*

Consider initiating any 

nonclinical studies 

needed to evaluate 

the product’s potential 

adverse effects on 

the neonate or young 

infant’s developing 

central nervous 

system

POSTMARKET OR 

POSTAPPROVAL 

STUDIES*

In select circumstances, 

long-term neurodevelopmental 

safety studies may be completed 

after initial approval

CLINICAL DEVELOPMENT*

Communicate early with the relevant 

FDA review division to design clinical 

trials that adequately evaluate long-term 

neurodevelopmental safety

4

Community acceptance, inclusivity, and engagement

✔ Collaborate with families and additional stakeholders

○ Stakeholders such as caregivers, healthcare providers, educators, and developmental specialists can help identify

clinically meaningful outcomes and assess study feasibility

✔ Understand patient family perceptions on clinical trial participation

○ Engage with patient families and community leaders to get input on the clinical trial protocol and help promote

participation of historically underrepresented communities

✔ Minimize the burden of study participation for patients and families

○ Streamline evaluations to avoid duplication and help ensure pediatric patients will be willing to complete the tests

○ Integrate data from community-level services and providers (e.g., early intervention programs), when appropriate

○ Use mobile technologies or other streamlined methods for information collection

✔ Connect early and keep in contact with families

○ Include long-term follow-up plans as a component of the initial study enrollment and stay in touch with patient

families to help reinforce the importance of long-term follow-up