Key Dates

Reissue of PAR-19-214 - Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3 Clinical Trial Optional)

NOT-MH-22-211 - Notice of Intent to Publish a Funding Opportunity Announcement for Building in vivo Preclinical Assays of Circuit Engagement for Application in Therapeutic Development (R01 Clinical Trial Not Allowed)

National Institute of Mental Health (NIMH)

The National Institute of Mental Health (NIMH) intends to publish a Funding Opportunity Announcement (FOA) to solicit applications to identify neurophysiological measures as potential assays for treatment development research. This FOA will be a reissue of PAR-19-214.

This Notice is being provided to allow potential applicants sufficient time to develop meaningful collaborations and responsive projects.

The FOA is expected to be published in Spring 2022 with an expected first application due date of October 21, 2022.

The FOA will utilize the UG3/UH3 activity code. Details of the planned FOA are provided below.

Consistent with the objectives of PAR-19-214, studies appropriate for the FOA will optimize and evaluate measures of neurophysiological processes that are disrupted within or across mental disorders in both healthy humans and in another species relevant to the therapeutic development pipeline. The initiative will support initial proof of concept studies aimed at identifying measures for potential development as preclinical assays for evaluating potential new drug and device therapies and their targets. Data will also reveal assay measures where the performance between preclinical animal species and humans is dissimilar, thus establishing a firm basis for limiting speculative extrapolations of preclinical animal findings to humans. The ultimate practical goal of the FOA is to improve the efficiency of the therapeutic development process by identifying coherence of measures and inconsistencies between the preclinical screening pipeline and clinical evaluation of new treatment candidates and thereby hasten the development of more effective treatments for mental disorders.

The overall goal is to transform experimental protocols in both animals and humans into assays for use in the therapeutic development pipeline. Ideally, the most promising in vivo assays have potential to be standardized and adapted for broader use across laboratories. This effort will build towards a critical understanding of the predictive value of assays as applied across preclinical species and humans. The effort will also begin to build critical measures of analytical performance (sensitivity, specificity, precision, stability, and reproducibility) that may be used to set standards for replication and verification of assay findings and to advance promising biomarkers and targets to clinical applications in subsequent projects

The objectives of the FOA will be accomplished by supporting partnerships among basic and translational neuroscientists who are committed to advancing the discovery of in vivo physiological measures as tools for target validation and therapeutic development. Groups will be tasked with developing and optimizing in vivo assays of brain processes in both animals and in healthy humans. Groups will evaluate assay performance across both species in response to specific chemical, physiological, or behavioral manipulations. Projects will reveal the potential of specific assays to translate from animals to humans, suggesting assays for further development as tools in the treatment development pipeline.

Proposed assay measures are expected to have reasonable likelihood of shared conservation of physiology and brain circuitry across healthy human controls and a preclinical species. While there is a risk that measures of some brain processes may be difficult to optimize for cross-species evaluation or may not show coherence between species, this risk is managed by the UG3/UH3 mechanism, a two stage phased innovation cooperative agreement award. The UG3 phase supports the planning and preliminary studies needed to conduct an evaluation of the performance of assays in both species in the UH3 phase. Projects will be milestone driven with an administrative review by internal NIMH staff to identify UG3 projects attaining milestones and demonstrating feasibility of assays in both species for advancement to the assay testing (UH3) phase. The cooperative agreement component allows for greater involvement of NIMH staff in the conduct of the projects, including suggesting external advisors, and providing opportunities for multiple FOA awardee groups to interact and share data. Should multiple UG3/UH3 awards be issued, it is expected that the groups will meet annually as a consortium to share updates on progress, to troubleshoot, and to outline strategies for disseminating data.

While it is understood that many protocols and the data generated will be at an early proof-of-concept stage, a central goal of this FOA is to contribute to building a more robust, experimentally based therapeutic development pipeline for mental disorders. Regardless of study outcomes, it is expected that experimental protocols and data generated through both the UG3 and UH3 phases of this FOA will be made available to the research community as a valuable source of information regarding relationships between animal assay results and human data no later than within one year of completion of the studies.

The UG3/UH3 is a two phased mechanism. Each phase is milestone driven and only those projects attaining the UG3 milestones have potential to progress to the UH3 phase. The UG3 phase supports feasibility testing and optimization of measures in animals and humans. The UH3 phase supports parallel testing of the measures in both animals and humans in response to variations of a manipulation as a way to evaluate the performance, sensitivity, and coherence of measures across species.

1. The UG3 Preparatory Testing and Prioritization Phase (Stage 1) for the FOA will support milestone-driven optimization of testing and prioritization of measures that tap into mental health relevant brain processes (e.g., neural plasticity, cognitive or affect regulatory processes, impulsivity) and neural circuit activity as assays in both animals and humans. For example, some assay measures that are already developed in the animal species selected will need to be adapted for humans while other assays may need to be back-translated from humans to the preclinical species. Other measures in this phase may need to be optimized in both species. Studies are expected to be performed in live animals and humans and not in cell culture, post mortem, or in vitro preparations. The only exception would be the allowance of a small number of limited studies in the UG3 phase aimed at identifying levels (e.g., doses) of the manipulations to be used in the UH3 phase for equivalent target engagement across species.

UG3 projects are milestone driven and include go-no-go criteria for each assay that will be used to determine whether assays are sufficiently optimized and methodologically equated across species. UG3 assays that meet the scientific milestones and feasibility requirements may be eligible for transition to the second UH3 stage pending NIH administrative review, availability of funds, and programmatic balance.

2. The UH3 Measure Evaluation Phase (Stage 2) will support milestone-driven evaluation of measures optimized in the UG3 phase by examining the effects of manipulations in both humans and the preclinical species in parallel. By employing the same manipulation at more than one level (dose, intensity, duration, etc.), where levels are chosen for comparable potency across species, data collected in this phase will assess the degree of cross species coherence of performance of the measures as assays. Examples of the types of manipulations appropriate for this phase include, but are not limited to:

• An FDA approved medication that targets a circuit critical to the measure
• A chemical challenge such as lactate or CO2 to engage hypervigilance
• Transcranial magnetic stimulation (TMS) to modify cortical circuits underlying specific learning processes
• Alterations in reward contingencies to modify striatal circuits
• A noise distractor manipulation to assess the impact of different brain rhythms on plasticity

The purpose of the manipulations is solely to evaluate the performance of the assays, not to address mechanistic hypotheses or test novel therapeutic targets.

A companion R01 FOA will also be released (see NOT-MH-22-211, reissue of PAR-19-289).

TBD

Applications are not being solicited at this time.

Please direct all inquiries to:

Jamie Driscoll

National Institute of Mental Health (NIMH)

301-443-5288

[email protected]