FAQs for PAR-22-169: Novel Assays to Address Translational Gaps in Treatment Development (UG3/UH3)

1. What is the purpose of this FOA?

The overall goal is to identify, optimize, and evaluate measures of neurophysiological processes that are disrupted within or across mental disorders and which can be assessed in animals and humans. The primary purpose is to improve the efficiency of the therapeutic development process by addressing inconsistencies between the preclinical screening pipeline and clinical evaluation of new treatment candidates, thereby hastening the development of more effective treatments for mental disorders. Expected outcomes include:

• To identify neurophysiological measures as translational assays for testing potential new drug and device therapies and their targets across preclinical development and in early human studies.
• To identify measures where performance between the preclinical species and humans is dissimilar, thus establishing a firm basis for limiting predictions of clinical effects based on preclinical findings.

2. Do all applications require both the UG3 and UH3 phases?

Yes, the UG3 phase is required to optimize the assay for cross species performance evaluation in the UH3 phase. Any assays where there are already sufficient data collected in both species to evaluate the assay would likely not be considered sufficiently innovative.

3. Are there any special considerations in selecting the preclinical species?

The FOA supports assay development around measures that assess the highest level of shared function across species (i.e., the highest common denominator). In most cases, this will limit the selection of the non-human species to mammals.

Applications will be evaluated based on the ability of the proposed experiments to test the involvement of the hypothesized circuit(s) in driving the physiological/behavioral assay measures. For pharmacological manipulations (as might be used in the UH3 phase), dose ranges selected for cross species evaluation of assay performance should be based on pharmacokinetic data for the drug in both species and with the same route of administration. Selection of dose ranges should also be informed by the Cmax and the relationship of drug doses to brain target engagement measures such as receptor occupancy.

4. Can non-human primate models be used as the preclinical species, or are rodents preferred?

Non-human primates (NHPs) can be included. However, in the context of the therapeutic discovery pipeline, rodent assays may be preferable due to ease, throughput, and cost. There would need to be a strong rationale for the use of NHPs, consideration of how and when they could be incorporated into the therapeutic development pipeline, and justification of why NHPs are the best model to support the goals of this FOA.

5. How is the evaluation of applications from foreign investigators different from U.S. investigators?

Non-U.S. institutions are eligible to apply, and collaborations with non-U.S. investigators are allowed. For applications submitted by foreign organizations, reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources. See the Grants and Funding webpage for additional information for foreign applicants and grantees .

6. I would like to test a novel treatment candidate in humans and in animals. Is this research goal aligned with the intent of the FOA?

No. The main purpose of this FOA is to develop and evaluate novel brain based measures as assays for translational purposes, not therapeutic candidates or targets. Applications aimed at therapeutics development or clinical evaluation of new potential therapeutics are directed to the FOAs listed on NIMH Therapeutics Discovery Research webpage.

7. Are industry partners allowed?

Collaborations between academic and industry partners are encouraged as long as the data and protocol sharing plan goals can be maintained.

8. Are new collaborations allowed or do the groups need to have already established working relationships?

Yes, new collaborations are allowed. It is anticipated that new collaborations between groups may need to be developed to address the goals of this FOA.

9. Can studies in patients or preclinical disease models be included?

Only healthy humans may be included. Transgenic preclinical species are allowed, but applications must justify why these are preferable to wild-type animals to address the goal of developing and optimizing assay performance.  Applications proposing inclusion of animal models “of” mental disorders would not be considered responsive to this FOA (for more information, see NOT-MH-19-053 ).

10. Do projects need to include more than one non-human species in addition to healthy humans?

No, one non-human species is sufficient. It is allowable to include more than one non-human species in an assay, with a clear rationale. The goal is to compare assay performance between humans and the other species, and not to evaluate across non-human species.

11. Can the proposal include multiple tasks using different non-human species (e.g., looking at one task across rodent and human and a second task across NHPs and humans)?

Yes, the inclusion of different species for different assays is allowable.

12. The UG3 allows/encourages exploration of multiple assays – do all proposed assays/tasks have to target the same circuit/domain?

No, projects can focus on one circuit function/domain or multiple, based on capability and potential.

13. Should the UG3 and UH3 include all of the same assays?

Not necessarily. Clear go/no-go criteria outlined in the UG3 phase should be sufficiently clear to guide the selection and prioritization of measures and manipulations for full evaluation in both species in the UH3.

14. Can tasks be proposed that are already validated in one species and only require translation to the other species?

Yes, that would be allowable.

15. Are high-risk, high-reward assays allowed/encouraged?

Yes, high risk assays with limited validation data are allowed. It is anticipated that the UH3 phase will be used to conduct initial feasibility and validation work and that many assays will fail at this stage.

16. Is it necessary to have an identified circuit or physiological readout in both species or is a physiological readout in humans and a behavioral readout in animals sufficient?

A physiological readout is required for both species. A solely behavioral measure would not be sufficient to address the goals of the announcement.

17. I am interested in developing and testing a physiological measure. Is it necessary to have the behavioral output as well?

No, a behavioral measure is not required.

18. Is it allowable to propose mechanistic studies for the UH3 phase?

No, mechanistic studies are outside the scope of this announcement.