NIH/NIMH – Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3 Clinical Trial Optional)

March 12, 2019 by ssw3an@virginia.edu

The overall goal of this initiative is to identify neurophysiological measures as potential assays for treatment development research. The funding opportunity announcement (FOA) will support efforts to 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 this 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 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. In this way, 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.

Background

The NIMH Strategic Plan for Research outlines research priorities for transforming the understanding and treatment of mental illnesses. The plan includes two cross-cutting themes which are directly relevant to the goals of this FOA, Transforming Diagnostics and Accelerating Therapeutics. A core component of the Transforming Diagnostics theme is the Research Domains Criteria (RDoC) project.  RDoC has grown into a significant effort for the NIMH that frees investigators from the current symptom-based diagnostic categories (i.e., Diagnostic and Statistical Manual, DSM) and encourages clinical researchers to study dimensions of observable behavior and neurobiological measures that may span multiple disorders. Similarly, basic neuroscientists are encouraged to address molecular and neural mechanisms underlying specific domains of mental function, rather than creating animal models of diseases. Relevant to the Accelerating Therapeutics theme, NIMH has shifted its clinical trials portfolio toward studies with defined targets and milestones. In contrast to previous studies that looked only for statistical differences in efficacy, the Institute’s new experimental medicine approach seeks trials that will address the mechanisms of disorders, providing a foundation for building specific treatment strategies.

Implementation of experimental medicine designs in early phase trials of novel treatments for mental disorders requires a demonstration that the proposed intervention engages the target sufficiently to evaluate target-mediated effects on brain processes and clinical outcomes. In this context, ‘target’ refers to the brain signaling system, circuit, or physiological process the therapeutic strategy aims to correct as a means of improving function across mental disorders. The RDoC effort has the potential to identify measures that can be incorporated in experimental medicine trial designs to evaluate links between targets, circuits and key functional domains in relation to clinical improvements. However, the potential success of the emerging clinical efforts is diluted by the lack of reciprocal efforts to develop assays of neural processes in the preclinical species component of a therapeutic development testing funnel. This lack of continuity of functional measures of target engagement between the preclinical species selected for use in treatment development and evaluation of effects in humans contributes uncertainty to an already risky pipeline of treatment development for mental disorders. For example, it is not surprising that commonly used preclinical behavioral assays whose original value was based on their ability to detect certain classes of compounds (e.g., the Porsolt swim test to identify serotonin uptake inhibitors as antidepressants), are poor predictors of the potential clinical efficacy of compounds that engage novel molecular targets.

Research Objectives

The purpose of this FOA is to address the translational divide between preclinical and clinical measures implemented in the treatment development pipeline for mental disorders by supporting the construction of a suite of in vivo functional brain assays and the evaluation of the measures for translational predictive value. Towards this goal, the FOA will support the identification, development, optimization and evaluation of in vivo CNS assays that measure particular brain functions that are evolutionarily conserved between the selected animal species and humans. The FOA will additionally support assessment of the performance (sensitivity) of brain based assays in both the preclinical species and in healthy humans in response to carefully selected pharmacological, physiological, or behavioral manipulations. Assays will aim to identify quantitative, robust and reliable measures that tap into specific neurophysiological systems that are potentially impacted in mental disorders such as neural plasticity, cognitive or affective regulatory processes, or impulsivity. The manipulations will provide a critical first evaluation of how the measure performs in the context of the therapeutic development pipeline spanning from the preclinical species to humans.

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 initiative will support partnerships among basic and translational neuroscientists who are committed to the discovery of translational physiological measures that may be used across preclinical development and that have the highest potential to be advanced into healthy human trials as tools for therapeutic development.

Potential applicants are strongly encouraged to read the Frequently Asked Questions (FAQs) for this FOA and to contact NIMH Scientific/Research Contact(s) prior to preparing an application.

Research Scope

This FOA will support the phased development of in vivo assays to address translational gaps in treatment development for mental disorders. Support will be provided for assay development efforts that propose quantitative measures to assess alterations in neurophysiology/circuit activity that contribute to or reflect clinically relevant domains of function (e.g., cognitive function, impulsivity, and motivation, etc.).

Proposed projects may include:

  • Development and testing of in vivo neurophysiological measures that tap into fundamental processes that are disrupted within or across mental disorders such as aspects of vigilance, neural plasticity, reward processing, or attentional mechanisms contributing to cognition and/or affect regulation, that can be objectively measured in both live animals and humans using brain imaging or neurophysiological measures such as spectral EEG or MEG to assess brain rhythms with different frequencies. Innovative measures are encouraged.
  • Development and testing of highly tractable behavioral paradigms as assays that may serve as proxies of neural circuit activity linked to a specific functional domain in both humans and animals. For example, the CNTRICS program identified constructs across six cognitive systems relevant to schizophrenia and selected tasks from cognitive neuroscience that measure the constructs http://cntrics.ucdavis.edu/index.shtml. Such studies should combine behavioral and physiological measures (for example, tracking changes in forebrain oscillations during performance). Since the goal is to build innovation and address translational gaps, the inclusion of behavioral paradigms that are already commonly used cross species (e.g., fear conditioning) must incorporate novel measures of underlying neuronal processes.

Projects Out of Scope for this Announcement Include:

  • Development or inclusion of animal models “of” mental disorders. Only healthy wildtype animals should be included
  • Behavioral assays without inclusion of measures of associated brain processes and/or neural circuits
  • Broad batteries of behavioral tests or clinical battery testing
  • Invasive manipulations that cannot feasibly be performed in healthy humans
  • Cell culture, post-mortem, or in vitro assay measures in either species
  • Hypothesis testing (e.g., mechanistic studies of brain systems underlying functional domains, pathophysiology of disease, or treatment response)
  • Studies aimed at clinical testing of therapeutics or therapeutic discovery

Please see the NIH/NIMH Therapeutics Discovery web page for links to other NIMH drug discovery FOAs: Drug Discovery for Nervous System Disorders PAR-16-041 (R01) and PAR-16-042(R21), National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-14-234 (U19) and PAR-14-184 (U01). Please also note the related FOAs titled Temporal Dynamics of Neurophysiological Patterns as Potential Targets for Treating Cognitive Deficits in Brain Disorders PAR-14-153 (R01) and PAR-14-158 (R21).

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 this FOA supports 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.

Expected outcomes include the identification of promising measures for further development as tools for assessing biological effects of novel therapeutic candidates across preclinical and healthy human studies. Data will also identify measures that differ in performance between preclinical species and humans, thus establishing a firm basis for limiting speculations about the potential clinical significance of preclinical assay data. Although only preclinical and healthy human studies would be supported by this FOA, the emphasis is on developing measures that will ultimately be useful for the evaluation of novel therapeutic mechanisms in patients with 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.

Rigor of Data: Translating discoveries into evidence-based treatments is predicated on the existence of strong, well powered, adequately controlled, and replicated preclinical and clinical data. In addition, the value of such research is greatly enhanced when detailed information is made available about study design, execution, analysis and interpretation. Examples of critical elements are outlined in the section IV.2 and detailed in NOT-OD-15-103 as well as NIMH guidelines. As per NOT-OD-15-102, it is expected that animal and human studies will include both males and females.

Milestones

Because novel translational assay development and evaluation in the UG3 phase are likely to be high risk, it is anticipated that there will be attrition of some projects after the assay optimization phase (UG3). Objective milestones of success and go/no-go rules for assay progression will be required and both should have quantitative criteria associated with them (see Section IV.2 for details).

Deadlines:  June 20, 2019, October 18, 2019, February 20, 2020, June 19, 2020, October 20, 2020, February 19,2021, June 21, 2021, October 20, 2021, February 21, 2022 (letters of intent due 30 days prior to the deadline)

URL:  https://grants.nih.gov/grants/guide/pa-files/PAR-19-214.html

Filed Under: Funding Opportunities