FDA outlines criteria for conducting long-term neurodevelopmental safety studies in neonates

The US Food and Drug Administration (FDA) issued a draft guidance to assist sponsors in determining the need to conduct long-term neurodevelopmental studies to support the safety of drugs, biologics and devices used in neonatal populations in mid-February 2023.  Such studies, said FDA “will help ensure a safer product.”

The guidance addresses factors for determining when it is necessary to conduct a long-term safety study, how to develop a safety study and what to measure in these evaluations.  The guidance does not address efficacy of products intended to improve neurologic outcomes.  The guidance was developed by the FDA’s Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), as well as the Office of Pediatric Therapeutics (OPT).

FDA notes that Congress has enshrined incentives for pediatric drug development under the Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act PREA), which were made permanent under Title V of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA).

FDA states that “although short-term safety evaluations may be acceptable for adults or other populations, such short-term evaluations may not identify important adverse events in the neonatal population, as latent effects may follow early-life exposures and drug treatment during the neonatal period coincides with a time of critical growth and physiologic development.”

In defining the age of neonates, FDA defers to the International Council of Harmonisation’s (ICH) E11(R1) guideline on the clinical investigation of medicinal products in the pediatric population, which defines the neonatal period as the day of birth plus 27 days.  The Agency said that “the degree of systemic exposure, which should be quantified in early pharmacokinetic or animal studies, if possible, may inform the need for long-term safety assessments. In general, higher levels of systemic exposure may be associated with higher central nervous system (CNS) exposure and potential risk for long-term sequelae.”

Also, drugs and biological products thought to penetrate the CNS are likely to warrant long-term safety assessment in neonates.

In developing neurodevelopmental safety evaluations, sponsors should use “sound scientific rationale,” and the agency recommends a controlled study design “whenever feasible.” FDA states that “although a single-arm study may be useful for collecting some types of safety information, the absence of a concurrent control arm (placebo or active comparator) will generally make clear interpretation of the results difficult, if not impossible.”

In terms of what, when and how to measure the drug’s effect on safety, FDA specifies that safety evaluations can be performed during the first two years of age and “longitudinal monitoring” should include measurements of head growth, hearing and vision testing, neurologic exams, and other “developmental milestones.”

The public has 60 days to comment.

REFERENCE:  Regulatory Focus (Regulatory News); 10 FEB 2023; Joanne S. Eglovitch