Development of Objective Measures for Use in Pediatric Drug Trials for Psychiatric and Neurodevelopmental Disorders

Presenter

Meg Grabb, Ph.D.
Division of Translational Research

Goal

This effort aims to stimulate research in a major gap area in pediatric psychopharmacology for psychiatric and neurodevelopmental disorders, by encouraging the development of objective pediatric central nervous system (CNS) measures that can be incorporated into pharmacologic trials. The development of these measures/biomarkers can aid in dose selection for future efficacy trials or enable subgroup stratification to identify which subjects respond better or worse to a particular agent. Overall, this research will improve the safety of prescribed medication in youth populations.

Rationale

Over the last decade, limited drugs have been approved for the treatment of psychiatric and neurodevelopmental disorders in youth. There is a need for more objective measures to be built into early-stage pediatric trials (Phase I/II Proof of Concept studies) to ensure that the dosing used in these and in subsequent registration trials is optimal to test the drug mechanism in question.

Pharmacodynamic (PD) measures are objective measures of drug response that exist in many areas of medicine, yet until recently, CNS imaging and electroencephalogram (EEG) technologies could not provide sufficient evidence in trials for psychiatric indications. Currently, there are no validated pediatric PD measures for assessing optimal drug exposure in psychiatric indications. In drug development, PD measures are typically paired with pharmacokinetic (PK) measures (drug levels in blood) to establish PK/PD models for generating CNS dose-response effects. These models are important in establishing safety in dose selection in clinical trials in children and adolescents through a variety of approaches: 1) bridging studies to move from adult to pediatric populations; 2) direct assessment of drug action in pediatric populations using a candidate drug with extensive adult safety data but not yet approved for any pediatric indication.

In addition to PD measures, stratification measures (including multicomponent biomarkers) are needed to objectively identify patient subgroups that may respond better or worse to drug agents. The development of these measures can help determine patterns in variation to treatment response, identify potential safety issues, and aid in designing later stage trials.

Overall, NIMH emphasizes the need for objective measures to be incorporated into pediatric pharmacologic trials to address issues from past trial failures. NIMH also emphasizes the need for multidisciplinary teams of pediatric psychopharmacologists, CNS imaging/EEG researchers, researchers with digital measure expertise, and clinical pharmacologists to collaborate and to establish the measures/models in different pediatric age groups to support this effort.