The FDA released final guidance for industry on conducting long-term clinical neurodevelopmental safety studies in neonatal product development in October 2024. The document provided a framework for evaluating whether and what type of long-term neurologic, sensory, and developmental assessments may be necessary to determine the safety of drugs, biological products, and devices intended for use in newborns.

The guidance addressed the unique challenges of evaluating medical product safety in neonates, acknowledging that short-term safety evaluations typical for adults may fail to identify important adverse effects in this vulnerable population. It noted latent effects may follow early-life exposures, and historically, most medical products used to treat neonates were not approved for use in this population, leading to a lack of systematic evaluation of long-term effects.

The document outlined several factors for sponsors to consider when determining the need for long-term neurodevelopmental safety evaluations:

1. General considerations included central nervous system exposure, timing of exposure relative to vulnerable stages of organ development, and duration of exposure.
2. Patient and population-specific considerations encompassed neurodevelopmental vulnerability and disease state characteristics.
3. Product-specific considerations included nonclinical toxicity data, clinical pharmacology, clinical experience in other populations, route of administration, and product components.

When long-term evaluations were deemed necessary, the FDA recommended a controlled study design whenever feasible. The guidance emphasized the importance of standardization across study sites, community acceptance and inclusivity, multidisciplinary input, and strategies to address patient recruitment and retention challenges.

The document provided detailed recommendations on what to measure, when, and for how long. It suggested that outcomes should be evaluated at a minimum of 2 years adjusted age, with earlier and/or later evaluations potentially warranted depending on the specific domains of concern. The FDA emphasized the use of well-defined and reliable clinical outcome assessments (COAs) that measure how a subject is functioning in daily life.

Key characteristics of measurement tools highlighted in the guidance included:

1. Minimizing participant burden and avoiding duplication to increase compliance and reduce behavioral interference.
2. Identifying and accounting for potential confounding factors that may compromise assessment validity.
3. Carefully considering the type of scores to utilize within neurodevelopmental assessments.
4. Selecting COAs with well-established psychometric properties and demonstrated reliability across demographic groups.

The guidance recommended that comprehensive neurodevelopmental evaluations should assess multiple domains, including physical health, quality of life, sensory function, motor skills, cognition, emotional and behavioral health, communication/language, social functioning, and adaptive functioning. It also suggested collection of relevant covariates and consideration of adjunctive assessments, such as neuroimaging or neurophysiologic testing, when appropriate.

The FDA's guidance did not specifically address effectiveness, safety, or benefit/risk assessments for products primarily intended to improve neurologic outcomes. It also did not focus on nonclinical safety studies, clinical study design in neonatology, or neonatal safety assessments following studies conducted during pregnancy.

This guidance provided a structured approach to assessing and evaluating long-term neurodevelopmental safety in neonates for sponsors developing medical products for this population.