Notice Number: NOT-MH-17-044

Key Dates
Release Date: August 17, 2017

NOT-MH-17-039
PAR-17-327

Issued by
National Institute of Mental Health (NIMH)

Purpose

NIMH is issuing this Notice to highlight its interest in supporting early stage pediatric clinical trials to investigate selective GABAergic agonists in first-in-pediatric studies for autism spectrum disorder (ASD).

Specifically, the NIMH is interested in supporting staged-by-age pharmacokinetic/pharmacodynamic (PK/PD) bridging studies to test a GABA-A a2/a3 subtype selective positive modulator (AZD7325; available through the NCATS repurposing program (https://ncats.nih.gov/ntu/assets/2017#Pediatric_Indications) in pediatric subjects with autism spectrum disorder (ASD), ages 6-17 years old, with social deficits. A benzodiazepine comparator should also be included. This GABA receptor target was selected based on the hypothesis that glutamate/GABA imbalance is part of the pathology in ASD and there are currently no treatments approved for the indication of social deficits in ASD (a core symptom). This candidate drug (AZD7325) was selected based on its lack of sedation (compared to benzodiazepines), good safety profile in human volunteers, and adult patients with Generalized Anxiety Disorder and ASD, and data on target engagement through PET receptor occupancy and human and preclinical pharmacodynamic (PD) data using EEG. The NIMH previously funded a contract and obtained the acute and repeated dosing (6 week) safety data on AZD7325 in adult ASD subjects with social deficits; the data are available for research access in the NIMH Data Archive.

NIMH is interested in investigator-initiated studies that include multiple endpoints that address the following questions: 1) is AZD7325 safe/tolerable, is there adequate drug exposure and observed CNS effects in pediatric ASD subjects at 12-17 years old; 2) is AZD7325 safe/tolerable, is there adequate drug exposure and observed CNS effects in pediatric ASD subjects at 6-11 years old; 3) does AZD7325 subchronic exposure impact social dysfunction in the younger or older pediatric ASD subjects age ranges? 4) how do CNS effects and side effects differ between the two GABAergic drugs? An additional goal of the studies is to obtain registration quality data in support of proceeding for a pediatric efficacy trial with AZD7325 and for use in a regulatory approval package if a pharma/biotech company chose to pursue further pediatric development of the drug candidate.

The NIMH requires the following expertise in applications focused on the design and conduct of first-in-pediatric drug candidate trials, including: a pediatric clinical pharmacologist with expertise in regulatory, PK modeling, PK/PD studies, a pediatric ASD pharmacologic trialist, and an EEG expert. Additionally, the site(s) which are proposed to conduct the studies are required to have regulatory infrastructure expertise to conduct first-in-pediatric drug trials. It is expected that investigators will partner with the National Center for Advancing Translational Sciences’ Clinical and Translational Science Award (CTSA) Trial Innovation Network by submitting a proposal to the Trial Innovation Network. If you have any questions, please contact [email protected]. The Trial Innovation Network has the capability to provide the pediatric regulatory and pharmacologic expertise for study design consultation and implementation. Alternatively, or in addition to partnering with the Trial Innovation Network, applicants may propose the use of Contract Research Organizations (CROs) that have a proven track record of requisite experience for first-in-pediatric trials for psychiatric disorders. The use of either the CRO or the CTSA Trial Innovation Network is a requirement.

Investigators interested in the research specified by this Notice should apply to the NIMH U01 Funding Opportunity Announcement (FOA) entitled, “First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders” (PAR-17-327). Interested investigators must use the multiple Principle Investigator (MPI) mechanism in which the ASD clinical expert and the pediatric clinical pharmacologist will be the MPIs, to provide the appropriate level of expertise and involvement in the design, implementation and management of the studies, with respect to their distinct expertise. As such, the pediatric pharmacologist, ASD clinical expert and a leading investigator of the CRO or Trial Innovation Network would participate on steering committee calls with NIMH staff. Under the U01 cooperative agreement funding mechanism (PAR-17-327), the NIMH will have a substantial programmatic involvement that is above and beyond the normal stewardship role in awards. For more information, please review the Administrative and National Policy Requirements section of the U01 (PAR-17-327).

It is expected that these PK/PD studies will enable testing of investigational drugs in pediatric populations with unmet medical need. Additionally, the study design expedites safety assessment in order to enable testing of novel mechanism of action drug candidates in pediatric subjects in psychiatry. This effort provides another path beyond the traditional process where pediatric trials are not initiated until the adult approval process is completed.

For further information about the submission process, please consult the U01 FOA.

Inquiries

Please direct all inquiries to:

Margaret C. Grabb, Ph.D.
Division of Translational Research
Telephone: 301-443-3563 
Email: [email protected]