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Paving the Way for Assessing Novel Pediatric Interventions


Meg Grabb, Ph.D.
Division of Translational Research


Pediatric clinical trials that investigate drug candidates in psychiatry are rare. Yet these trials are critical for evaluating safety, tolerance, efficacy, and optimal dosing in developing children. Molecular targets most relevant to the developing central nervous system (CNS) may be very different from ones appropriate in treating psychiatric disorders in adults. It is important to establish a pediatric trial model where drug candidates can be tested safely, even if the drug candidate has not received formal approval for any psychiatric indication in adults.


The goal of this initiative is to develop and pilot test a clinical trial model to enable early stage, first in pediatric testing of investigational drugs in pediatric populations. Through this model, drug candidates would be identified based on safety/tolerability data in adults and the molecular target’s potential association with pediatric symptoms and drug availability. The adult approval process, that typically happens before pediatric studies are initiated, would be bypassed using a staged pharmacokinetic/pharmacodynamic (PK/PD) bridging design. This model brings together critical multidisciplinary expertise needed for safely testing candidate drugs in children including:  pediatric clinical pharmacologists with expertise in PK modeling and PK bridging studies, pediatric psychiatry trialists, Contract Research Organizations (CROs) or sites within Clinical and Translational Science Awards networks (CTSAs), consultants experienced with the drug agent, and consultants experienced in pediatric regulatory issues.


PK/PD bridging is a key step in testing new mechanisms of action in pediatric populations. This first pilot trial would incorporate a staged PK/PD bridging design to determine in pediatric subjects with a psychiatric disorder, 12-17 years old:  1) if acute drug dosing in pediatric subjects can achieve drug plasma levels that are comparable to adults (PK measure); 2) if adequate acute drug exposure correlates with a CNS functional response (PD measure); 3) if adequate dose exposure is safe and tolerable; 4) if the three milestones above are met in adolescent subjects age 12-17, children age 6-11 years old would be tested; 5) if the three milestones above are met, a sub-chronic study would be performed, 4-6 weeks in length incorporating CNS functional measures and behavioral readouts. Using this staged by age approach, drug dosing in pediatrics can more safely be evaluated. The NIMH together with the Fast Fail NIMH Advisory Council subcommittee have identified a compound to test and the NIMH has received official guidance from the Food and Drug Administration (FDA) on this trial design. Overall, the study is intended to demonstrate a model for moving drug agents into pediatric indications, in a carefully designed, staged approach to minimize safety issues.


This initiative would support a pilot trial with multiple endpoints that may provide important results in terms of age effects on safety, tolerance, and the establishment of dosing for future efficacy trials. Additionally, it would provide a model for researchers to use to test additional candidate drugs. It could also yield information about novel mechanism of action drug candidates in pediatric populations. As well, the registration-quality data generated could be used in a regulatory approval package, if a company was interested in further development for an indicated use.