Part 1. Overview Information

Key Dates

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

The NIH HEAL Initiative

This funding announcement is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://heal.nih.gov/.

More than 25 million Americans suffer from daily chronic pain, a highly debilitating medical condition that is complex and difficult to manage. In recent decades, there has been an overreliance on the prescription of opioids for chronic pain despite their poor ability to improve function and high addiction liability. This contributed to a significant and alarming epidemic of opioid addictions and overdose deaths. Innovative scientific solutions to develop alternative pain treatment options are thus critically needed.

Through targeted research efforts, the NIH HEAL Initiative aims to accelerate the discovery and preclinical development of new medications to treat pain. This funding opportunity announcement (FOA) is part of a suite of FOAs to support the development of safe and effective therapeutics to treat pain with little or no addiction liability. The following is a list of these coordinated funding announcements:

• RFA-NS-21-029 HEAL Initiative: Planning Studies for Initial Analgesic Development [Small Molecules and Biologics] (R61 Clinical Trial Not Allowed). Because drug discovery and development require diverse expertise, applicants must form multidisciplinary teams. RFA-NS-21-029 will support planning projects that are designed to build a strong research team and conduct studies to establish feasibility, validity, or other technically qualifying results that support, enable, and/or lay the groundwork for a subsequent U19 application to RFA-NS-22-052.

• RFA-NS-22-052 HEAL Initiative: Team Research - for Initial Translational Efforts in Non-addictive Analgesic Development [Small Molecules and Biologics] (U19 Clinical Trial Not Allowed). RFA-NS-22-052 will support team-based research projects that develop assays, screen and propose early optimization work to develop a non-addictive therapeutic to treat pain. Continued work to validate the target and its underlying biology in the context of pain is also within scope. Discovery and/or validation of pharmacodynamic markers as well as pharmacokinetic/pharmacodynamic (PK/PD) studies and efficacy testing will also be supported. The goal of this FOA is to advance a hit or lead asset to the point where it can meet the entry criteria for RFA-NS-21-010 within the five years of the award.

• RFA-NS-21-010 HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional). The purpose of RFA-NS-21-010 is to support preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics to treat pain. Applicants must have a promising biologic or small molecule hit/lead, rigorous biological rationale for the intended approach, and robust, well-validated assays for optimization of the agent. In addition, a strong package of data linking the putative therapeutic target to the proposed disease indication and supporting the hypothesis that altering the target activity will produce desirable outcomes for the pain type is required. The scope of this program includes optimization and early development activities, Investigational New Drug (IND) - enabling studies, development of a pharmacodynamic/target engagement biomarker, assembly and filing of an IND application and Phase I clinical testing.

Research Scope and General Structure of this U19 Funding Opportunity

This FOA will support research programs with up to five research components (listed below) focused on target validation and early development of a new therapeutic asset. An Administrative Core and a Data Management Core are also required components. Applicants may also propose up to three Resource Cores; however, these are optional. All proposed components and cores are expected to be integrated and work together as part of a whole project to develop a single asset. The following research components are necessary for a successful project.

• • Validation of Therapeutic Target and Underlying Biology
  • Development and Validation of Animal Models and/or Outcome Measures
  • Assay Development, Screening, and Early Optimization
  • Discovery and/or Validation of Pharmacodynamic Markers
  • Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies

The individual research components must be part of a cohesive whole where the success or failure of each component is tightly linked to that of all the other components. Additional details on the scope and activities of these research components are described below. At least three of these five components must be proposed within an application. Teams can only propose to omit a component if it can be demonstrated that the necessary activity has already been reasonably completed.

It is anticipated that at the end of the application, successful programs will meet the entry criteria for RFA-NS-21-010 HEAL Initiative FOA: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional), which is a promising hit or lead small molecule or biologic starting point for optimization that has a rigorous biological rationale for the intended approach and scientifically sound assays to test the agent. Applicants must propose to get to the entry point of RFA-NS-21-010 within the five-year grant period. There will be no opportunities for renewal of this award.

Applications should include the following items:

Multidisciplinary Team: Because drug discovery and development require diverse expertise, applicants must form multidisciplinary teams. Teams should include knowledge in both pain biology and all the research activities needed for full target validation and drug development processes. The team may consist of members from multiple institutions. It is critical that these teams work together as a collaborative and integrated unit. The team should include expertise in:

• pain biology (such as pain pathways, relevant disease pathology, relevant pain and reward models)
• project and data management, statistical analysis, experimental design, and scientific/experimental rigor
• assay development and drug discovery (such as assay development, screening, pharmacology, medicinal chemistry)
• early drug development (such as pharmacokinetics, pharmacodynamics, biomarkers, and in vitro ADME (Absorption, Distribution, Metabolism, Excretion)

The team should also include individuals who can help the team plan for future therapy development beyond this RFA (such as later stage drug development experts, regulatory experts, clinicians, etc.). In addition to scientific diversity, applicants should strive to include diversity in team members. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. In spite of tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from groups that are underrepresented in the biomedical, clinical, behavioral and social sciences. Please refer to Notice of NIH's Interest in Diversity NOT-OD-20-031 for more details.

• Input from patients and caregivers on the therapeutic development goals of the project is strongly encouraged.
• National Center for Advancing Translational Sciences (NIH/NCATS) maintains state-of-the-art therapeutic development capabilities and expertise. A detailed description of the capabilities can be found at: https://ncats.nih.gov/heal/intramural-capabilities. Applicants seeking collaborative submission with NCATS Intramural Program are required to consult with NCATS Staff early in the planning of an application. This early contact will provide an opportunity to discuss and clarify NIH policies and guidelines.

Clinical Benefit of Potential Pain Treatment: This FOA supports validation and early therapeutic development for pain targets with little or no abuse liability. No applications targeting the opioid receptors will be accepted for this RFA. Applicants should describe how targets will be discovered and why they have the potential to be better than those of currently available analgesics for patients or in development. Applicants should describe where their potential target(s) fit within the therapeutic development landscape and why their application represents a significant improvement over the current state of the science.

Rationale for the Proposed Approach to Treating Pain: Applications should be supported by a cogent biological rationale for how the proposed approach will result in new and promising non-addictive treatment for pain. Applicants should also discuss how the experimental approach will lead to a novel target and how this novel target should lead to significant improvements over current pain therapies (clinically used and under development by the field). Applications should also have strong supporting rationale for the approach to developing a therapeutic from the identified target. This may be supported by preliminary data or the scientific literature.

Therapeutic Discovery Plan: At the completion of the five-year application, it is expected that applicants have a promising hit or lead asset that can serve as a basis for an application to RFA-NS-21-010, HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional). Entry criteria for RFA-NS-21-010 are: a promising small molecule or biologic starting point for optimization, a rigorous biological rationale for the intended approach, and scientifically sound assays to test the agent . Applicants must propose to get to the entry point of RFA-NS-21-010 within the five-year grant period. Applications should include all steps necessary to get to this point. Within the Research Strategy, it is essential for applicants to include a description of how knowledge gained from this work will support future therapeutic discovery efforts beyond the project period through to early clinical trials. As part of this consideration, attention should be paid to the intended patient population such that appropriate experiments (animal models, biomarkers, end point measures, routes of administration, etc.) are used in the current application. As part of this consideration, applicants should also be aware of intellectual property limitations and how these will be addressed.

Milestones: Annual Go/No-Go milestones must be proposed in the Overall Integrated Development Plan to reflect progress of the overall research program. It should be clearly outlined how the research components are interrelated and which research component activities need to be successfully completed before the initiation of other components. A discussion of the milestones relative to the progress of specific research components and the implications of successful completion of the milestones for the other research components should be included. Milestones must also be included in each research component to reflect progress toward the goals of that component. Milestones should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. Milestones should provide clear indicators of continued success or emergent difficulties. The proposed milestones will be evaluated by scientific peer review. Prior to funding an application, NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the review panel or Program staff. A final set of approved milestones will be specified in the Notice of Award.

Because target and therapeutic discovery and development are inherently high risk, it is expected that there will be significant attrition as programs progress. NIH program staff and leadership will conduct an annual administrative review of progress toward the milestones. Additional meetings with NIH program staff will be arranged on a frequency appropriate for the development stage of the project, as determined by the NIH. If justified, future year milestones may be revised based on data and information obtained during the previous grant period. The administrative reviews will be based on:

• Successful achievement of milestones
• The overall feasibility of program advancement, considering data that may not have been captured in milestones
• Competitive landscape for the disease indication and drug target
• HEAL programmatic priorities
• Availability of funds

U19 Entry Criteria

• Applicants must have a multidisciplinary team (further described below). There should be evidence that this team has the capabilities needed to effectively execute the project as well as plan for the next stages of therapeutic development. There should also be evidence that this team can work together.
• Applicants should have biological rationale with preliminary data or literature-based evidence supporting the feasibility and importance of the approach. Preliminary data should be from well-designed experiments.

Applicants who are lacking these entry criteria should consider the companion RFA-NS-21-029 HEAL Initiative: Planning Studies for Initial Translational Efforts in Non-addictive Analgesic Development [Small Molecules and Biologics] (R61 Clinical Trial Not Allowed).For more extensive work focused on the discovery and validation of novel therapeutic targets to facilitate the development of pain therapeutics, applicants should consider RFA-NS-22-034 HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed).

Research Components

This funding opportunity supports up to five distinct research components. Applicants must propose at least three of these five components and provide justification for those that are omitted to demonstrate that the necessary activity has already been reasonably completed. Component-specific activities should align with the descriptions below; activities should not be moved to or combined with other research components, rather the components should work together as part of a whole project to develop a single asset. It is anticipated that some components will depend on elements (data, models, agents, etc.) developed by other components. As such, some research components will have a delayed start while others will be completed before the end of the five-year project period. Most components will not utilize the full five-year period.

Validation of Therapeutic Target and Underlying Biology: This component should include the discovery and validation of novel therapeutic targets to facilitate the development of pain therapeutics in collaboration with the other proposed research components. Specifically, the focus of this component is on the basic science discovery of targets in the peripheral nervous system, central nervous system, immune system, or other tissues in the body that can be used to develop pain treatments that have minimal side effects and little-to-no abuse/addiction liability. These studies should have the goal of definitively determining the utility of a potential target for therapeutic development. This component must include rigorous validation studies to demonstrate the robustness of the target in the context of pain, preferably for specific pain type(s)/indication(s) and/or disease-associated pain conditions. These validation studies are critical to lower the risk of pursuing the target within the other translational components to develop small molecules, biologics, or natural substances that interact with this target for new pain treatments. Basic science studies of pain and related systems in the body can be proposed in this component and are encouraged in the context of novel pain therapeutic target discovery. The duration of the component may be the full five years of the overall project, where additional validation and rationale to support the asset and target can be produced.

Applicants are strongly encouraged to leverage existing research resources for their studies whenever possible. Such resources may include tissue, cellular, or DNA samples from NINDS BioSEND https://www.biosend.org or other existing biospecimen, imaging and data repositories. The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources from NINDS funded studies that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. Leveraging the resources and support from pain advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program is also encouraged. Studies are also encouraged that leverage the resources of ongoing clinical trials supported through other Federal or private funds.

Development and Validation of Animal Models and/or Outcome Measures: Animal models and ex vivo model systems for analgesic therapeutics discovery and development should represent a significant advance over those that currently exist for defined pain conditions. They can include genetic, chemical, and/or physiological manipulations in animals or ex vivo systems that recapitulate a significant component (clinical manifestations and underlying physiology) of the pain condition in humans. Animal models and endpoints should be compatible with those that are measurable and relevant to the pain types and processes in both preclinical and clinical settings.

Development of animal models or model systems that translate to a human pain disorder requires rigorous internal and external validation. In order to demonstrate internal validation, it is important to evaluate and understand the precision, reliability, sensitivity, accuracy, and dynamic range characteristics of the endpoints used to assess the effect of therapeutics or physiological interventions in the animal pain models, in vitro or ex vivo model systems. In addition, it is essential that the experimental design and procedures used in characterizing the model are conducted in a rigorous manner, utilizing randomization, blinding, inclusion/exclusion criteria, and the appropriate sample sizes.

It is also important to address external validation, showing that the animal pain model or model system can recapitulate aspects of the pain pathological phenotype and etiology, where endpoints or biomarkers of disease are similar and measurable in both the model system and in human pain conditions. One component of external validity is face validity - the similarity between the model and the clinical manifestation of the pain condition (as measured by overt clinical symptoms, patterns of activation using functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG), functional or behavioral read-outs, disease progression, etc.). Another component of external validity is construct validity - the similarity between the physiological or biological basis of the model and the actual human pain disorder (i.e., genetic, proteomic, metabolomic markers). Although components of both face and construct external validity are certainly desirable in an animal model or model system, predictive validity provides the most confidence in the ability of the model to translate to human disease. Predictive validity refers to the probability that a clinically validated therapeutic agent (biologic or small molecule) will have the same effects in the animal model or model system as it will in the intended clinical population. Note that experimental therapeutics cannot be used to validate an experimental model. Rather, the evaluation of predictive validity requires a validated molecular tool or therapeutic that has been shown to alter disease progression in humans. Since these tools do not necessarily exist for many pain conditions, it is not always possible to obtain true evidence of predictive validity until the candidate therapeutic is tested in humans. Therefore, it may not always be possible to evaluate the predictive validity of a new animal pain model or model system. However, it is important to include evaluations of internal validity, and face, construct, and predictive validity (to the extent possible), to provide evidence that the proposed model or model system represents a significant advance over existing animal pain models or model systems.

Efficacy testing of the therapeutic asset(s) under development should not be conducted within this component, rather the validated model and/or outcome measure(s) will need to be available for use in the PK/PD and Efficacy component. As such, it is not anticipated that these component activities last the full five years of the program.

Assay Development, Screening and Early Optimization: This research component should include plans for 1) development of new in vitro and/or ex vivo assays, and 2) screening and/or rational design efforts to identify and characterize novel assets for pain conditions/disorders. These activities include (but are not limited to) set up and optimization, standardization, and validation of measures of fundamental cellular/molecular events such as binding, bioactivity at the target, and activity downstream of the target relevant to pain transduction, transmission, or processing. The proposed assays must have sufficient throughput for iterative screening of potential therapeutic agents such as small molecules and biologics. This component should also include design and preparation of a focused set of therapeutic agents based on the hits identified, and characterization thereof. The use of state-of-the art technologies for manipulation, detection, and analysis is encouraged. Applicants are encouraged to consult the NCATS Assay Guidance Manual.

It is not anticipated that these component activities will last the full five years of the program since it may depend on the validation of the target, and since screening hits will need to be available for use in the PK/PD and Efficacy component. Applicants should discuss plans for coordinating with other component teams and should include milestones that need to be successfully met before initiation of this component.

Discovery and/or Validation of Pharmacodynamic Markers: Programs should include a component for the development of pharmacodynamic (PD) markers that indicate the molecular target engagement of the pain assets developed in the application. PD markers typically represent engagement of a molecular component in the pathway mediating the biological effects of therapeutic target modulation. Some examples of PD markers include receptor occupancy, phosphorylation of proteins in the target signaling pathway, changes in substrate or product levels as a result of target enzyme modulation, gene transcription, physiological changes, etc. These PD markers are intended to: 1) represent endpoints that can be measured in both preclinical and clinical settings, and 2) represent a significant advance over PD measurements that may already exist for the therapeutic agent and targeted pain condition.

Since PD markers should represent meaningful and quantitative indices of a therapeutic agent's effects in humans, evidence of robust internal and external validation must be demonstrated. Internal validation includes evaluation of the precision, reliability, sensitivity, accuracy and dynamic range characteristics of the PD measurement. External validation typically verifies that the PD marker represents a component of disease etiology and/or therapeutic target mechanism of action that can be demonstrated in both preclinical and clinical settings. For example, manipulation of the therapeutic target (i.e., knockdown, silencing, activation) should result in a quantitative change in the PD marker that is consistent with knowledge of the target pathway. In addition, manipulation of the target with a therapeutic agent that has been in clinical testing (if any are available) should have the same effects on the PD marker in preclinical and clinical settings.

PD marker development must be in support of the larger program application and reflect target engagement of the asset being developed.

It is not anticipated that these component activities last the full five years of the program since it may depend on the validation of the target, and since the validated PD marker will need to be available for use in the PK/PD and Efficacy component. Applicants should discuss plans for coordinating with other component teams and should include milestones that need to be successfully met before initiation of this component.

Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies: This component should include plans to conduct pharmacokinetic (PK) pharmacodynamic (PD), and in vivo efficacy studies to demonstrate that the proposed asset has sufficient biological activity to warrant further development as a non-addictive analgesic therapeutic. In preclinical efficacy studies, a combination of in vivo efficacy, PD and PK measures are warranted to determine the feasibility of candidate asset to serve as a starting point for further therapy development. Combined measures of PK and PD greatly increase the understanding of the in vivo efficacy of the asset by exploring the relationship between the concentration of the agent at the site of action and the resulting efficacy measures. For the purposes of this FOA, in vivo efficacy measures reflect the effects of the asset on endpoints that are closely tied to the desired clinical endpoints, but do not necessarily reflect target engagement. While PD measures may also reflect the effects of the asset on endpoints closely tied to the desired clinical endpoint, they must also reflect target engagement. Pharmacokinetic measurements reflect the body’s effect on the absorption, metabolism, distribution and excretion of the asset.

Pharmacodynamic studies may include but are not limited to determination of 1) target occupancy (e.g., binding) and 2) proximal target activation (i.e., signal transduction, neurotransmission, protein synthesis, and gene regulation and transcription). Examples of target occupancy studies may include but are not limited to Positron Emission Tomography (PET) and Single-Proton Emission Computed Tomography (SPECT). In addition to the examples of proximal target activation listed above, more remote measures of target activation may also be considered, for example (but not limited to): ex vivo studies of ion channel function, EEG modulation, or changes in cerebral blood flow or metabolism as measured by fMRI.

It is expected that this component utilizes the target, animal model(s), and therapeutic asset(s) generated from the other components within this U19 application. Thus, it is not anticipated that these component activities will take the full 5-years of the program. Applicants should discuss plans for coordinating with other component teams and should include milestones that need to be successfully met before initiation of this component.

Cores

Administrative Core (required): Each application must contain an Administrative Core that is responsible for the overall management, communication, coordination, and oversight of the program.

Data Management Core (required): Each application must contain a Data Management Core as one of the critical core components that will provide reliable data management and communication to and from the proposed U19 Research Components, as well as a reasonable plan to develop a data science framework for facilitating the workflow for data aggregation and analysis between the proposed Research Components. The data management team should include appropriate data science staff and software engineering support. The Data Management Core should provide details on plans to identify best practices, standards, tools, workflows, and computational infrastructures, and to reuse those already in use by the research community, where applicable.

The Data Management core should also include a plan to ensure integration of appropriate data with the HEAL Data Ecosystem in accordance with the NIH HEAL Initiative's Public Access and Data Sharing Policy. More information can be found at https://heal.nih.gov/about/public-access-data.

Resource Core(s) (optional): Applicants may propose up to three Resource Cores to provide specialized services or reagents necessary for the goals of the project. A Resource Core must support at least two research components and should not duplicate resources already available at the institution(s). While the addition of Resource Core(s) is optional, if included in the application, Resource Core(s) should be critical to the success of the U19 project.

Non-Responsive Applications

The following applications will be considered non-responsive to this FOA and withdrawn from consideration without review:

• Applications targeting opioid receptors
• Applications lacking milestones
• Applications lacking either preliminary data or plans for any of the research components: Validation of Therapeutic Target and Underlying Biology; Development and Validation of Animal Models and/or Outcome Measures; Assay Development, Screening and Optimization; Discovery and/or Validation of Pharmacodynamic Markers; PK/PD and Efficacy Studies. Teams can only propose to omit a component if it can be demonstrated that the necessary activity has already been completed.
• Applications that rearrange or combine research components and/or component-specific activities
• Projects in the lead optimization, IND-enabling or clinical stage (such projects should consider applying to RFA-NS-21-010 HEAL Initiative FOA: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain)
• Technical development of neurostimulation or other medical devices for the treatment of pain
• Applications to develop biomarkers other than pharmacodynamic biomarkers (i.e., disease initiation, remission, relapse, prognostic, diagnostic or prediction of progression biomarkers).

See Section VIII. Other Information for award authorities and regulations.

Section II. Award Information

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application.
  • Dun and Bradstreet Universal Numbering System (DUNS) Organization registrations prior to April 2022 require applicants to obtain a DUNS prior to registering in SAM. By April 2022, the federal government will stop using the DUNS number as an entity identifier and will transition to the Unique Entity Identifier (UEI) issued by SAM. Prior to April 2022, after obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.

• eRA Commons - Once the unique organization identifier (DUNS prior to April 2022; UEI after April 2022) is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.

• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support. See, e.g., Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Julia L Bachman, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-7383
Email: [email protected]

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for the Submission of Multi-Component Applications

The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

The above referenced page limits refer to the research strategy section only; a separate "Specific Aims" page for each individual component of the U19 application should be submitted in accordance with the SF424 (R&R) Application Guide Instructions

The application should consist of the following components:

Overall Integrated Development Plan: required - 1
Administrative Core: required - 1
Data Management Core: required - 1
Resource Core: optional; maximum of 3; Each Resource Core needs to support two or more Research Components
Research Components: required; minimum of 3; maximum of 5; Applicants must propose at least three of the following five research components:

• Validation of Therapeutic Target and Underlying Biology
• Development and Validation of Animal Models and/or Outcome Measures
• Assay Development, Screening, and Early Optimization
• Discovery and/or Validation of Pharmacodynamic Markers
• Pharmacokinetic/Pharmacodynamic and Efficacy Studies

Applicants can only propose to omit a component(s) if it can be demonstrated that the necessary activity has already been reasonably completed.

Overall Integrated Development Plan

When preparing your application, use Component Type Overall .

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424(R&R) Cover (Overall Integrated Development Plan)

Complete entire form.

PHS 398 Cover Page Supplement (Overall Integrated Development Plan)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Note: Proposed use (if any) of Human Embryonic Stem Cell lines and Human Fetal Tissue should be described in each relevant research projects and cores, as well as in the overall component.

Research & Related Other Project Information (Overall Integrated Development Plan)

Follow standard instructions.

Facilities and Other Resources
In this section, describe the institutional, commercial, and industrial investments and resources that constitute the environment for this research program. New cost-sharing commitments are not required. Some examples of institutional environment could include recruitment and salary support of new faculty or professional staff positions to support the resource components, startup packages, space renovations for team investigators, new facilities within the research and core components, dedicated equipment for research and resource components, dedicated budget lines or facilities for a team consortium, dedicated use of commercial products and technologies, equipment and technology contributions from commercial collaborators, etc. Summarize how the facilities and resources under each component are complimentary, and critical to the integrated therapeutic development plan of this application. Facilities and resources specific for individual Research Components and Cores should be detailed under the respective component sections.

• In addition to standard items, describe existing facilities and/or other resources (such as existing institutional shared resource cores) available to the proposed U19.
• As applicable and pertinent to the proposed research, describe partnerships (e.g., with industrial entities) that will provide relevant capabilities.

Equipment
Summarize the availability and accessibility of all necessary equipment for the proposed project, and how they are complimentary and critical to the integrated therapeutic development plan of this application. Equipment specific for individual Research Components and Cores should be detailed under the respective component/core sections.

Other Attachments:

1. Milestones (required, maximum 3 pages): This attachment should be entitled "Overall Milestone Plan.pdf . Applications lacking this attachment, as determined by the NIH staff, will be considered incomplete and will not be reviewed. Annual go/no-go milestones for the Overall Integrated Development Plan must be provided in this section. Clearly outline how the research components are interrelated and which research component activities need to be successfully completed before the initiation of other components. Milestones should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. Clearly indicate what the milestones are for the initiation of any delayed component, and provide specific metrics for outputs of research components that will feed into other research components. For example, what physical characteristics and/or in vitro activity does an asset need to exhibit in the Assay Development, Screening and Early Optimization research component in order to be tested in the PK/PD and Efficacy Studies component? The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. Milestones should provide clear indicators of continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the NIH Program Staff. Please see Milestone Examples.

2. Intellectual property (IP) strategy: Applications should include an Intellectual property (IP) strategy. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials.

Applicants should describe the IP landscape surrounding their therapeutic agent. Applicants should describe any known constraints that could impede their therapeutic discovery and development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program. If the applicant proposes using an agent whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should include a letter (see letter of support) from any entities owning the IP indicating there will not be any limitations imposed on the studies or the product which would impede achieving the goals of the funding program.

If patents pertinent to the therapeutic agent being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable.

Applicants should discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved, consistent with achieving the goals of the program. Applications should include a description of the involvement of the Data Management or other Cores on IP landscape and strategy (if any) on the proposed therapeutic agent(s) and target(s) as applicable.

Project/Performance Site Locations (Overall Integrated Development Plan)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research and Related Senior/Key Person Profile (Overall Integrated Development Plan)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall Integrated Development Plan)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A minimum total effort for the overall PD/PI or MPI of the U19 application is 2.4 person months, in aggregate for all functions served on the components the U19. Effort cannot be reduced below this level during the entire project period.

A budget summary in the Overall Integrated Development Plan section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall Integrated Development Plan)

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing (DMS) Plan will be attached in the Other Plan(s) attachment of the Overall Component in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan. The Data Management and Sharing (DMS) Plan must be provided in the Overall component.

Introduction to Application: For Resubmission applications, an Introduction to Application is required in the Overall component.

Specific Aims: Provide a concise description of the goals of the entire application towards the development of a safe, efficacious, and non-addictive therapeutic agent to treat pain. Briefly provide the context for the proposed set of projects/studies with an emphasis on the interdisciplinary research rationale to rigorously design, develop, validate, and deliver appropriate assay(s), model(s), tools, screening, and pharmacodynamic/biomarker (preclinical) with completed proof-of-efficacy for the proposed non-addictive pain therapeutic agent. Briefly describe how the U19 is structured and how the Research Components and Cores alone and together fit into the overall goals. Summarize how the development plan in this application will prepare the proposed non-addictive pain therapeutic agent to meet the entry criteria for the next stage of the NIH HEAL Initiative's lead therapeutic agent optimization RFA-NS-21-010.

Research Strategy: This section should summarize the structure and the overall research strategy for the multi-component application, including a description of the goals and approach for the validation of the therapeutic target as well as the development and validation of proposed non-addictive pain therapeutic agent(s) for specific pain type(s)/indication(s) and/or disease-associated pain conditions. It should also outline the integration of the individual research and core components, and why these components are essential for accomplishing the application’s overall goal(s). This section should also lay out a compelling argument for why an interdisciplinary team-based research approach is needed to address the aims and how the synergy between projects and cores will interact and inform each other in ways not possible as separate research project grants. The Research Strategy should be organized into sections that address the following: Overall Significance; Overall Innovation; Overall Approach; Overall Investigators; and Overall Environment. Specifics of Research Components and Cores should be described separately.

The Overall Integrated Therapeutic Development research plan should include:

• An explanation of how the goals of the program will address a therapeutic gap and challenges in efficacious and non-addictive pain therapeutics development.
• A cogent rationale for the proposed approach to treating pain, including a description of the potential clinical benefit in relation to specific pain type(s)/indication(s) and/or disease-associated pain conditions.
• An outline of goals, rationale, and a brief research approach/plan for the individual research components proposed.
• An outline of the goals of the core facilities and a brief description summarizing their role towards integrating individual research components to address the overall program goals.
• If applicants propose to omit a research component, provide well-reasoned justification and evidence to support that the necessary activities have already been completed.
• Provide an integrated research plan for the proposed overall specific aims and goals, integrating the role of and coordination between individual research components. This section should describe the working scientific and logistical design, as well as the resource support components necessary to implement the research and therapeutic development/validation. Include evidence for feasibility, which can include general and background preliminary findings from the multiple research and resource components.
• Briefly describe plans to demonstrate non-addictive properties and abuse liability of the proposed therapeutic target and agent(s).
• Describe the prior research (both published and preliminary data) that serves as the key support for the proposed project. Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.
• Provide well-reasoned justifications for new and innovative approaches, including a discussion of feasibility.
• Summarize the expertise of the multidisciplinary team, including relevant knowledge and experience in the following areas:
  • pain biology (such as pain pathways, relevant disease pathology, relevant pain and reward models)
  • project and data management, statistical analysis, experimental design, and scientific/experimental rigor
  • assay development and drug discovery (such as assay development, screening, pharmacology, medicinal chemistry)
  • early drug development (such as pharmacokinetics, pharmacodynamics, biomarkers, and in vitro ADME (Absorption, Distribution, Metabolism, Excretion)
• Highlight the expertise of members who can help the team plan for future therapy development beyond this RFA (such as later stage drug development experts, regulatory experts, clinicians, etc.). Input from patients and caregivers on the therapeutic goals of the project is also strongly encouraged.
• Present clear evidence that the research team has been or will be able to work together effectively to accomplish the research proposed in the projects. Define and describe the individual research component teams as well as how the team structure and timeline will allow an interdisciplinary approach necessary to accomplish the goals presented. The necessary expertise of each component should be justified, along with how the value of each component would contribute to the whole.
• Include a broad overview of the proposed administrative and data management plans, summarizing how they will provide reliable communication to and from the proposed U19 Research Components, as well as a plan to develop a data science framework for facilitating the workflow for data aggregation and analysis between the proposed Research Components. Summarize how it will follow and co-ordinate with the NIH HEAL Initiative Public Access and Data Sharing policy.
• A descriptive and graphic timeline must be included in the overall research strategy section, for which applicants should take into account start-up activities, the anticipated rate of validation of therapeutic target, animal models and/or outcome measure of pain, therapeutic design, assay development, screening, early optimization, efficacy and PK/PD studies.. This section should also include specific proof-of-concept test(s) along with any alternative strategies should any component efforts fail to perform as expected.

Letters of Support: Statements of individual and Institutional Commitment, as appropriate to the overall application, should be included in this section.

• Applicants should include letters of support from consultants, contractors, and collaborators.
• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.
• If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.
• If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) will be needed and in place once the project is funded. This letter should come from a high official within the private entity who has authority to speak on these issues.
• If an application plans to utilize the infrastructure or resources of existing projects, whether funded by NIH, other governmental or non-governmental entities, letters of support detailing the terms of collaboration and data sharing must be included.
• If utilization of extant samples is proposed as a component of the study, letters of support or approval for use of those samples should be included.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.

The following modifications also apply:

A Resource Sharing Plan for the entire application must be included in the Overall Integrated Development Plan component. A separate Data Sharing Plan must be included in the Data Management Core section. Separate Resource Sharing Plans for other individual components are not required.

Authentication of Key Biological and/or Chemical Resources: Individuals are required to comply with the instructions for authentication plans for key biological and/or chemical resources as provided in the SF424 (R&R) Application Guide, with the following modification:

Briefly describe methods to ensure the identity and validity of key biological and/or chemical resources used in the proposed studies.

• Key biological and/or chemical resources may or may not have been generated with NIH funds and: 1) may differ from laboratory to laboratory or over time; 2) may have qualities and/or qualifications that could influence the research data; and 3) are integral to the proposed research.
• These include, but are not limited to, animal strains, source, genetic backgrounds & modifications; cell lines, dissociation and/or culture conditions for primary cells, cell lines and primary tissue preparations; specialty chemicals, antibodies, and other biologics.
• Standard laboratory reagents that are not expected to vary do not need to be included in the plan. Examples are buffers and other common biologicals or chemicals.

Information in this section must focus only on authentication of key biological and/or validation of key resources to be used in the study; all other methods and preliminary data must be included within the page limits of the research strategy. See NOT-OD-16-011 and NOT-18-228 for detailed information on authentication of key biological and/or chemical resources. Applications identified as non-compliant with this limitation will be withdrawn from the review process (see NOT-OD-17-105).

Reviewers will assess the information provided in the Authentication of Key Biological and/or Chemical Resources section. Any reviewer questions associated with key biological and/or chemical resource authentication will need to be addressed prior to award.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall Integrated Development Plan)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form (Overall Integrated Development Plan)

All instructions in the SF424 (R&R) Application Guide must be followed.

Administrative Core

When preparing your application, use Component Type Admin Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Administrative Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Administrative Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Administrative Core)

Budget forms appropriate for the specific component will be included in the application package.

The U19 overall PD/PI(s) is/are expected to serve as Core Lead of the Administrative Core with a minimum effort of 0.6 person months. If multiple PD/PIs serve as co-leads for the Administrative Core, each of them is expected to devote at least 0.6 person months.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Administrative Core)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Provide a concise description of the goals of the Administrative Core.

Research Strategy: The Administrative Core is expected to have appropriate and effective administrative and organizational capabilities to support multidisciplinary research, communication, planning and evaluation activities, and to foster synergy.

• Describe the organizational and administrative structure of the proposed multi-component application. Include plans on how the Team Director and a Project Manager (if proposed) will interact and coordinate with Research Component/Core Leaders to organize and direct efforts, identify and resolve problems, and establish a strong collaborative environment for the program.
• Describe how the Administrative Core will ensure that all proposed components and related activities will function in an optimal and synergistic manner. Include details regarding interactions with the Data Management Core to ensure compliance with the NIH HEAL Initiative’s Data Sharing and Public Access requirements.
• Provide an administrative plan that includes a discussion of the structure and roles of administrative staff, including the functions to be performed; services and professional skills to be provided, how fiscal and other resources will be prioritized, allocated and managed; how communications, group meetings, and teleconferences will be facilitated; and how conflict resolution will be attained. Present a leadership succession plan.
• Describe plans for periodic evaluation of project progress related to the milestones, including plans for how decisions to initiate changes will be made and how delays in milestone achievement will be managed with respect to the other research components that may be dependent on the those results and/or reagents.
• When multiple institutional sites are involved, a detailed description of the cooperative administrative arrangements should be included.
• This section should also include acknowledgement of the need for quarterly reporting to NIH program staff of the progress and accomplishments. Additional meetings with NIH program staff will be arranged on a frequency appropriate for the development stage of the project, as determined by NIH.

Letters of Support: If multiple institutional sites are involved, letters documenting the cooperative administrative arrangements should be included.

PHS Human Subjects and Clinical Trials Information (Administrative Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Data Management Core

When preparing your application, use Component Type 'Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Data Management Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Data Management Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Data Management Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Summary/Abstract: All instructions in the SF424 (R&R) Application Guide must be followed.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Data Management Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Data Management Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the Data Management Core component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Data Management Core)

Budget forms appropriate for the specific component (Data Management Core) will be included in the application package.

The Data Management Core Lead(s) must commit to a minimum of 0.6 person months of effort.

Budgets should include sufficient resources to administer, prepare, and disseminate data for the research and core components, and to coordinateall thedata-related activities in accordance with the NIH HEAL Initiative Public Access and Data Sharing Policy. More information can be found at:https://heal.nih.gov/about/public-access-data. Software and engineering support as well as infrastructure should be included as needed with appropriate justification.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

Research & Related Subaward Budget (Data Management Core)

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Research Plan (Data Management Core)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for the Data Management Core.

Specific Aims: Describe the contribution of the Data Management Core to the overall goals of the application and provide an overview of the data management and analysis practices that will be utilized for this program. Highlight how the Data Management Core will interact with and benefit each of the other components of this application.

Research Strategy: The Data Management Core should be customized to fit the science and the specific data management needs of the research and core components, thus the Overall Integrated Therapeutic Development plan of the proposed U19 application should drive the Data Management Core’s approach to develop 1) a service to the proposed U19 research and resource core components, and 2) a data science framework for facilitating the workflow for data aggregation, integration, and analysis between the proposed research and resource core components.

• Describe the Data Management infrastructure that will support the proposed activities and how the services of this Core will support and advance the outcomes from the proposed research program.
• Describe and offer evidence for the type and magnitude of data to be collected, analyzed, and managed from multiple research components and resource core(s) in the entire application.
• Describe and offer evidence for the feasibility of the proposed data management plan, the advantages of any new data management methodologies, the potential pitfalls and alternative approaches for data management, and how these might impact the overall progress.
• Highlight any unique and innovative contributions that will be made by the Data Management Core.
• Describe how the Data Management Core will provide bioinformatics expertise, data integration and analysis support, and study design and statistical support/services to project investigators as appropriate for the goals of the U19 program.
• Include a description of the staffing plan that will support the functions associated with this Core, including any professional staff or staff with specialized skills to fully address the extent of the Core needs, including submission of data, meta-data and related data analyses according to the NIH HEAL Initiative’s Public Access and Data Sharing requirements (https://heal.nih.gov/about/public-access-data)
• Provide an overview of the plan to administer, prepare, and disseminate data from the research components and core(s) and to coordinate data-related activities, including those in relation to the NIH HEAL Initiative Public Access and Data Sharing requirements. Specific details of this plan should be included in the required Data Sharing Plan (described below).
• The Data Management plan may also include efforts to:
  • Identify best practices, standards, tools, workflows, and computational infrastructures already in use by the research and therapeutic development community.
  • Adopt existing resources for use by the research and core components of the proposed integrated therapeutic development plan.
  • Provide robust and flexible data management and retrieval tools to function within the proposed integrated therapeutic development plan.
  • Integrate, when appropriate, predictive computational models and analytical tools for driving experiments.

Data Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modifications:

As this is a Data Management Core which is expected to disseminate and share data, a dedicated Data Sharing Plan must be included in this Data Management Core. An additional Data Sharing Plan should not be included in the Resource Sharing Plan in the Overall Integrated Development Plan component.

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing. Consistent with the HEAL Initiative Public Access and Data Sharing Policy (https://heal.nih.gov/about/public-access-data), all applications, regardless of the amount of direct costs requested for any one year, are required to include a Data Management and Sharing Plan outlining how scientific data and any accompanying metadata will be managed and shared. The plan should describe data types, file formats, submission timelines, and standards used in collecting or processing the data. It is expected that data generated by HEAL Initiative-funded projects will be submitted to study-appropriate domain-specific or generalist repositories in consultation with the HEAL Data Stewardship Group to ensure the data is accessible via the HEAL Initiative Data Ecosystem. Additional guidance on data related activities can be found at https://www.healdatafair.org/.

To maximize discoverability and value of HEAL datasets and studies, and facilitate data integration and collaboration, applications submitted in response to this FOA are strongly encouraged to incorporate standards and resources where applicable:

• Applicants are encouraged to ensure that data collected by the study conform to Findable, Accessible, Interoperable, and Reusable (FAIR) principles.
• Applicants are specifically encouraged to incorporate into their planning, an alignment with the guidelines, principles and recommendations developed by the HEAL Data Ecosystem, including but not limited to preparing data to store in selected specified repositories, applying minimal metadata standards, use of core HEAL Clinical Data Elements (CDEs, https://heal.nih.gov/data/common-data-elements), and other necessary requirements to prepare data to connect to the HEAL Data Ecosystem.
• All new HEAL clinical pain studies are required to submit their case-report forms/questionnaires to the HEAL Clinical Data Elements (CDE) Program. The program will create the CDE files containing standardized variable names, responses, coding, and other information. The program will also format the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C 794 (d)), which require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities. HEAL Initiative clinical studies that are using copyrighted questionaries are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program.

The NIH notices referenced below provide additional NIH guidance that should be considered in developing a strong data management and sharing plan. The list is instructive but not comprehensive.

• Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014)
• NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016).
• NIH encourages the use of data standards including the PhenX Toolkit (www.phenxtoolkit.org) (for example, see NOT-DA-12-008, NOT-MH-15-009)
• NIH encourages researchers to explore the use of the HL7 FHIR (Fast Healthcare Interoperability Resources) standard to capture, integrate, and exchange clinical data for research purposes and to enhance capabilities to share research data (NOT-OD-19-122). The FHIR standard may be particularly useful in facilitating the flow of data with EHR-based datasets, tools, and applications.
• NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards, as they are applicable (NOT-OD-20-146). Use of the USCDI can complement the FHIR standard and enable researchers to leverage structured EHR data for research and enable discovery.

Recipients conducting research that includes collection of genomic data should incorporate requirements under the NIH Genomic Data Sharing Policy (NOT-OD-14-124, NOT-OD-15-086).

PHS Human Subjects and Clinical Trials Information (Data Management Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Resource Core

When preparing your application, use Component Type Resource Core.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

SF424 (R&R) Cover (Resource Core)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Resource Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Resource Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Resource Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Resource Core)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Core Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Resource Core)

Budget forms appropriate for the specific component will be included in the application package.

Resource Core Lead(s) must commit to a minimum of 0.6 person months of effort. Budgets are also required for each consortium (subcontract), if they are part of any core.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Resource Core)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Provide a concise description of the goals of the Resource Core and state their relationship to the goals of the U19 project. List in priority order, the broad activities and services of the proposed Resource Core and explain how the Resource Core will contribute to the research activities of two or more Research Components of the U19 application.

Research Strategy:

• Describe the contribution of the Resource Core to the overall goals of the program and how this Core will interact with and benefit from other components.
• Describe the facilities and/or services that will be provided and how the facilities and/or services will meet the specific needs of each Research Component.
• State the rationale for centralizing activities in a Resource Core rather than including them in individual Research Component(s). Note: Resource Cores should not duplicate resources already available at the institution, nor should they duplicate the activities proposed within individual Research Components or other Cores.
• Indicate why the Resources Core is an essential part of the U19 application and how the proposed services will facilitate accomplishment of the proposed goals of the pain therapeutic development program and milestones.
• Describe the unique and innovative contributions that will be made by this Resource Core. Explain how these contributions will be made possible by team synergy beyond the otherwise independent Research Components.
• Describe and offer evidence for the type of resources to be managed for and disseminated to (and/or from) multiple Research Components and Resource Core(s) of the U19 application. Offer evidence for the feasibility of the proposed resource management plan, the advantages of any new resource types and methodologies, the potential pitfalls and alternative approaches, and how these might impact the overall progress.
• Include a prioritization plan for providing the services and plans for quality control.
• If the Resource Core is at a different geographic location than the Research Component(s) it serves, describe plans for data/sample transfer and communication.
• Describe the role(s) of the Resource Core Lead and key personnel without duplicating information provided in the Biosketches or Budget Justification.
• Describe any plans for collaborations or contracting for specific services to outside facilities (academia and/or industry), with justification and letters of support/service.
• Where appropriate, describe how the Resource Core will be a point of contact for dissemination of technology, expertise, materials, animal models, and potential collaborations with other research investigative teams.

Authentication of Key Biological and/or Chemical Resources: Individuals are required to comply with the instructions for authentication plans for key biological and/or chemical resources as provided in the SF424 (R&R) Application Guide, with the following modification:

Briefly describe methods to ensure the identity and validity of key biological and/or chemical resources used in the proposed studies.

Information in this section must focus only on authentication of key biological and/or validation of key resources to be used in the study; all other methods and preliminary data must be included within the page limits of the research strategy. See NOT-OD-16-011 and NOT-18-228 for detailed information on authentication of key biological and/or chemical resources. Applications identified as non-compliant with this limitation will be withdrawn from the review process (see NOT-OD-17-105).

Reviewers will assess the information provided in the Authentication of Key Biological and/or Chemical Resources section. Any reviewer questions associated with key biological and/or chemical resource authentication will need to be addressed prior to award.

• Key biological and/or chemical resources may or may not have been generated with NIH funds and: 1) may differ from laboratory to laboratory or over time; 2) may have qualities and/or qualifications that could influence the research data; and 3) are integral to the proposed research.
• These include, but are not limited to, biological and chemical reagents / tools, source, species backgrounds & modifications; positive or negative comparator cell lines, dissociation and/or culture conditions for primary cells, cell lines and primary tissue preparations; specialty chemicals, antibodies, and other biologics.
• Standard laboratory reagents that are not expected to vary do not need to be included in the plan. Examples are buffers and other common biologicals or chemicals.

Appendix:
Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Resource Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Research Components

When preparing your application, use Component Type Research Component.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions, as noted.

Out of the following five research components, a minimum of three are required. Proposed research components should be included in the application in the order listed below. Component-specific activities as described in Section I should not be moved to or combined with other research components. Applications that rearrange or combine research components and/or component-specific activities will be deemed non-responsive and withdrawn without review

SF424 (R&R) Cover (Research Component: Validation of Therapeutic Target and Underlying Biology)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Research Component: Validation of Therapeutic Target and Underlying Biology)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Component: Validation of Therapeutic Target and Underlying Biology)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Other Attachments: Milestones (maximum 2 pages) - required: This attachment should be entitled "Target Validation Milestone Plan.pdf . Applications that propose to conduct this research component but are lacking this attachment, as determined by the NIH staff, will be considered incomplete and will not be reviewed. Annual Go/No-Go milestones must be proposed under each research component, and should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress. Milestones should be realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. Milestones should provide clear indicators of continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the NIH Program staff. Please see here (link) for examples of milestones.

Project /Performance Site Location(s) (Research Component: Validation of Therapeutic Target and Underlying Biology)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Component: Validation of Therapeutic Target and Underlying Biology)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Research Component: Validation of Therapeutic Target and Underlying Biology)

Budget forms appropriate for the specific component will be included in the application package.

The PD/PI is expected to devote a minimum effort of 1.8 person months for each Research Component they are leading. If multiple PD/PIs serve as co-leads for this Research Component, they are expected to devote a combined minimum effort of 1.8 person months.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Component: Validation of Therapeutic Target and Underlying Biology)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Briefly provide the biological rationale for the discovery and validation of the proposed pain therapeutic target(s) in the context of specific pain type(s)/indication(s) and/or disease-associated pain conditions with unmet challenges in effective non-addictive pain management. Outline the major objectives and/or aims of the proposed study, research approach and technical questions to be answered to validate the proposed non-addictive pain therapeutic target(s).

Research Strategy: Investigators are urged to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.

Significance (Rationale and Supporting Data)

• Provide a clear outline of the preliminary data supporting the rationale for the proposed scheme to validate the novel pain therapeutic target(s).
• Provide any preliminary data supporting the rationale for the pain type(s) or pain condition(s) or disease-associated pain to be studied and utilized towards the validation of the proposed pain therapeutic target(s).
• Provide any preliminary data and/or rationale supporting the non-addictive nature of the proposed pain therapeutic target(s).
• This section should also explain the contribution of this research component to the overall goals of the U19 program and how this research component will interact with and benefit from other components.

Innovation

• Describe the unique and innovative contributions that will be made by this component with regards to the proposed therapeutic target(s) and rigorous validation approach in the context of type(s) of pain or pain condition(s) or pain-associated with specific disease(s).
• Explain how these contributions will be made possible by team synergy beyond the otherwise independent research projects.

Approach

• Outline the proposed approach towards identification and validation for the proposed pain therapeutic target(s).
• Describe and offer evidence for the feasibility of the proposed experiments, the advantages of any new methodologies, assays, outcome measures, preclinical models, and the potential pitfalls and alternative approaches for the project.
• Include plans to ensure appropriate standardization of assays, samples, data and controls that are used in the process of target validation.
• The approach must include experimental verification and analyses to demonstrate a lack of abuse liability and non-addictiveness of the proposed target(s).
• Plan to obtain proof-of-concept validation for the proposed target(s) using clinical samples and measures. Carefully relate and justify any proposed studies on human tissue or fluids for the understanding on the proposed pain type(s) or pain condition(s) or disease-associated pain in the overall project/program.
• Highlight the proposed interdisciplinary nature and collaborative team-based approach for rigorous validation of therapeutic target(s), including any plans for independent replication and reproduction of methodologies, assays, models, and outcome measures in multiple laboratories in the project/program.
• Discuss plans (if any) for collaborations with outside resources (academic facilities, contractors, or industry), other than the Resource Cores in this U19 application.

Letters of Support: Statements of individual and Institutional Commitment, as appropriate to the research components, should be included in this section.

• Applicants should include letters of support from consultants, contractors, and collaborators.
• If utilization of extant samples is proposed as a component of the study, letters of approval for use of those samples should be included.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Note: Do not submit Data Sharing Plans here. The Data Sharing Plan should be submitted only in the Data Management Core component.

Authentication of Key Biological and/or Chemical Resources:

Individuals are required to comply with the instructions for authentication plans for key biological and/or chemical resources as provided in the SF424 (R&R) Application Guide, with the following modification:

Briefly describe methods to ensure the identity and validity of key biological and/or chemical resources used in the proposed studies.

• Key biological and/or chemical resources may or may not have been generated with NIH funds and: 1) may differ from laboratory to laboratory or over time; 2) may have qualities and/or qualifications that could influence the research data; and 3) are integral to the proposed research.
• These include, but are not limited to, animal strains, source, genetic backgrounds & modifications; cell lines, dissociation and/or culture conditions for primary cells, cell lines and primary tissue preparations; specialty chemicals, antibodies, and other biologics.
• Standard laboratory reagents that are not expected to vary do not need to be included in the plan. Examples are buffers and other common biologicals or chemicals.

Information in this section must focus only on authentication of key biological and/or validation of key resources to be used in the study; all other methods and preliminary data must be included within the page limits of the research strategy. See NOT-OD-16-011 and NOT-18-228 for detailed information on authentication of key biological and/or chemical resources. Applications identified as non-compliant with this limitation will be withdrawn from the review process (see NOT-OD-17-105).

Reviewers will assess the information provided in the Authentication of Key Biological and/or Chemical Resources section. Any reviewer questions associated with key biological and/or chemical resource authentication will need to be addressed prior to award.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Research Component: Validation of Therapeutic Target and Underlying Biology)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Research Component: Development and Validation of Animal Models and/or Outcome Measures

SF424 (R&R) Cover (Research Component: Development and Validation of Animal Models and/or Outcome Measures)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Research Component: Development and Validation of Animal Models and/or Outcome Measures)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Component: Development and Validation of Animal Models and/or Outcome Measures)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Other Attachments: Milestones (maximum 2 pages) - required: This attachment should be entitled "Animal Models and Measures Milestone Plan.pdf . Applications that propose to conduct this research component but are lacking this attachment, as determined by the NIH staff, will be considered incomplete and will not be reviewed. Annual Go/No-Go milestones must be proposed under each research component, and should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress. Milestones should be realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. Milestones should provide clear indicators of continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the NIH Program staff. Please see here (link) for examples of milestones.

Project /Performance Site Location(s) (Research Component: Development and Validation of Animal Models and/or Outcome Measures)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Component: Development and Validation of Animal Models and/or Outcome Measures)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Research Component: Development and Validation of Animal Models and/or Outcome Measures)

Budget forms appropriate for the specific component will be included in the application package.

The PD/PI is expected to devote a minimum effort of 1.8 person months for each Research Component they are leading. If multiple PD/PIs serve as co-leads for this Research Component, they are expected to devote a combined minimum effort of 1.8 person months.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Component: Development and Validation of Animal Models and/or Outcome Measures)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Describe overall goals and the impact of developing animal model(s) and/or outcome measures in relation to the specific pain type(s)/indication(s) and/or disease-associated pain conditions. Outline the major objectives and/or aims of the proposed approach and technical questions to be answered, highlighting those which are critical to enhance the translatability of the proposed project/program.

Research Strategy: Investigators are urged to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.

Significance (Rationale and Supporting Data)

• Provide the rationale for developing animal models and/or outcome measures in relation to the specific type(s) of pain or pain condition(s) or pain-associated with specific disease(s) in humans.
• Summarize the current gaps and challenges and provide a comparative view of other/existing animal models and/or outcome measures in relation to specific pain type(s)/indication(s) and/or disease-associated pain conditions. Discuss the advantages of the proposed animal models and/or outcome measures.
• Summarize how the proposed animal model(s) and/or outcome measures would enhance the translational relevance and accelerate the validation and development of non-addictive pain therapeutic target(s) and agent(s) that are the focus of other research components of the application.
• Provide a clear outline of the preliminary data supporting the rationale for the scheme to develop and rigorously validate animal model and/or outcome measure(s) for specific type(s) of pain, pain condition(s), or disease-associated pain in humans.
• This section should also explain the contribution of this research component to the overall goals of the U19 program and how this research component will interact with and benefit from other components.

Innovation

• Describe the unique and innovative contributions that will be made by this research component with regards to translational validity of the proposed therapeutic target and non-addictive pain therapeutic.
• Explain how these contributions will be made possible by team synergy beyond the otherwise independent research projects.
• Describe the unique contribution of experts in the specific type(s) of pain or pain condition(s) in humans and in the specific human pathologies/disease(s).

Approach

• Outline the experimental design, approach, and validation of the proposed development of animal model and/or outcome measures for pain. Include specific details regarding plans for both internal and external validation studies (including face, construct, and predictive validity (to the extent possible)).
• Describe and offer evidence for the feasibility of the proposed approach, the advantages of any new methodologies, and potential pitfalls and alternative approaches for the project.
• Carefully relate and justify any proposed studies on human tissue or fluids for the cross-validation of the proposed animal model and/or outcome measures of pain.
• Highlight the proposed interdisciplinary nature and collaborative team-based approach for rigorous validation of animal model and/or outcome measures, including any plans for independent replication and reproduction of methodologies in multiple laboratories in the project/program.
• Discuss plans (if any) for collaborations with outside resources (academic facilities, contractors, or industry), other than the Resource Cores in this U19 application.

Letters of Support: Statements of individual and Institutional Commitment, as appropriate to the research components, should be included in this section.

• Applicants should include letters of support from consultants, contractors, and collaborators.
• If utilization of extant samples is proposed as a component of the study, letters of approval for use of those samples should be included.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Note: Do not submit Data Sharing Plans here. Data Sharing Plans should be submitted only for the Data Management Core component.

Authentication of Key Biological and/or Chemical Resources:

Individuals are required to comply with the instructions for authentication plans for key biological and/or chemical resources as provided in the SF424 (R&R) Application Guide, with the following modification:

Briefly describe methods to ensure the identity and validity of key biological and/or chemical resources used in the proposed studies.

• Key biological and/or chemical resources may or may not have been generated with NIH funds and: 1) may differ from laboratory to laboratory or over time; 2) may have qualities and/or qualifications that could influence the research data; and 3) are integral to the proposed research.
• These include, but are not limited to, animal strains, source, genetic backgrounds & modifications; cell lines, dissociation and/or culture conditions for primary cells, cell lines and primary tissue preparations; specialty chemicals, antibodies, and other biologics.
• Standard laboratory reagents that are not expected to vary do not need to be included in the plan. Examples are buffers and other common biologicals or chemicals.

Information in this section must focus only on authentication of key biological and/or validation of key resources to be used in the study; all other methods and preliminary data must be included within the page limits of the research strategy. See NOT-OD-16-011 and NOT-18-228 for detailed information on authentication of key biological and/or chemical resources. Applications identified as non-compliant with this limitation will be withdrawn from the review process (see NOT-OD-17-105).

Reviewers will assess the information provided in the Authentication of Key Biological and/or Chemical Resources section. Any reviewer questions associated with key biological and/or chemical resource authentication will need to be addressed prior to award.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Research Component: Development and Validation of Animal Models and/or Outcome Measures)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Research Component: Assay Development, Screening, and Early Optimization

SF424 (R&R) Cover (Research Component: Assay Development, Screening, and Early Optimization)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Research Component: Assay Development, Screening, and Early Optimization)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Component: Assay Development, Screening, and Early Optimization)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Other Attachments: Milestones (maximum 2 pages) - required: This attachment should be entitled "Assay, Screening, and Optimization Milestone Plan.pdf . Applications that propose to conduct this research component but are lacking this attachment, as determined by the NIH staff, will be considered incomplete and will not be reviewed. Annual Go/No-Go milestones must be proposed under each research component, and should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress. Milestones should be realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. Milestones should provide clear indicators of continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the NIH Program staff. Please see here (link) for examples of milestones.

Project /Performance Site Location(s) (Research Component: Assay Development, Screening, and Early Optimization)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Component: Assay Development, Screening, and Early Optimization)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Research Component: Assay Development, Screening, and Early Optimization)

Budget forms appropriate for the specific component will be included in the application package.

The PD/PI is expected to devote a minimum effort of 1.8 person months for each Research Component they are leading. If multiple PD/PIs serve as co-leads for this Research Component, they are expected to devote a combined minimum effort of 1.8 person months.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Component: Assay Development, Screening, and Early Optimization)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Briefly provide the rationale for the design of the specific pain therapeutic agent(s) proposed, development and validation of assays, as well as therapeutic agent screening plans. Provide succinct justification on the assays and therapeutic agent screening in relation to the specific pain type(s)/indication(s) and/or disease-associated pain conditions with unmet challenges in effective non-addictive pain management. Outline the major objectives and/or aims of the proposed study, research approach, and technical questions to be answered.

Research Strategy: Investigators are urged to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.

Significance (Rationale and Supporting Data)

• Describe the overall goals and impact of the proposed therapeutic agent, validated assays and screening approach in the context of the specific pain type(s)/indication(s) and/or disease-associated pain conditions.
• Provide a strong rationale for the specific therapeutic type and design proposed for the identified/validated target.
• Provide rationale for the development and/or validation of in vitro and/or ex vivo assays for the identification and/or characterization of therapeutic agent(s).
• Provide strong justification for the proposed screening and/or rational therapeutic design efforts for the validated therapeutic target in relation to the pain type(s), condition(s), or pain-associated with specific disease(s).
• Discuss the advantages of the proposed therapeutic agent type and design, assays, and screening approach over comparable/existing approaches.
• Provide preliminary data and/or evidence supporting the rationale for 1) the proposed therapeutic type and design as a new/novel non-addictive pain therapeutic agent, and 2) the proposed development and/or validation of in vitro and/or ex vivo assays for screening and/or characterization of the therapeutic agent
• This section should also explain the contribution of this research component to the overall goals of the U19 program and how this research component will interact with and benefit from other components.

Innovation

• Describe the unique and innovative features of the proposed therapeutic type and design, validation assays and screening plans.
• Explain how these contributions will be made possible by team synergy beyond the otherwise independent research projects.

Approach:

• As this component builds on the earlier components, it is possible that complete plans cannot be formulated until after the project is underway. In that case, describe how decisions will be made. Describe potential pitfalls and alternative strategies.
• Provide details of plans to validate the assays proposed (such as primary, secondary, selectivity, orthostatic assays etc.), including plans to ensure assay reproducibility, robustness, and throughput necessary for therapy development.
• For screening efforts, describe the library used. For rational therapeutic design, describe the strategy used to identify potential therapeutic agents.
• Provide detailed plans for how the assays will be used for decision making. A table or figure with the testing funnel is highly encouraged.
• As appropriate to the stage of development of a given therapeutic agent, describe plans to assess the agent’s chemical, biophysical, and biological characteristics.
• Discuss how hits will be optimized, including what features will be important and how triage decisions will be made. This optimization may include a consideration for potency, physicochemical properties and/or in vitro ADME.
• Highlight the proposed interdisciplinary nature and collaborative team-based approach for this component, including any plans for independent replication and reproduction of methodologies in multiple laboratories in the project/program.
• Discuss plans (if any) for collaborations with outside resources (academic facilities or contractors or industry), other than the Resource Cores in this U19 application.

Letters of Support: Statements of individual and Institutional Commitment, as appropriate to the research components, should be included in this section.

• Applicants should include letters of support from consultants, contractors, and collaborators.
• If an application plans to utilize the infrastructure or resources of existing projects, whether funded by NIH, other governmental or non-governmental entities, letters of support detailing the terms of collaboration and data sharing must be included.
• If utilization of extant samples is proposed as a component of the study, letters of approval for use of those samples should be included.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Note: Do not submit Data Sharing Plans here. The Data Sharing Plan should be submitted only in the Data Management Core component.

Authentication of Key Biological and/or Chemical Resources:

Individuals are required to comply with the instructions for authentication plans for key biological and/or chemical resources as provided in the SF424 (R&R) Application Guide, with the following modification:

Briefly describe methods to ensure the identity and validity of key biological and/or chemical resources used in the proposed studies.

• Key biological and/or chemical resources may or may not have been generated with NIH funds and: 1) may differ from laboratory to laboratory or over time; 2) may have qualities and/or qualifications that could influence the research data; and 3) are integral to the proposed research.
• These include, but are not limited to, animal strains, source, genetic backgrounds & modifications; cell lines, dissociation and/or culture conditions for primary cells, cell lines and primary tissue preparations; specialty chemicals, antibodies, and other biologics.
• Standard laboratory reagents that are not expected to vary do not need to be included in the plan. Examples are buffers and other common biologicals or chemicals.

Information in this section must focus only on authentication of key biological and/or validation of key resources to be used in the study; all other methods and preliminary data must be included within the page limits of the research strategy. See NOT-OD-16-011 and NOT-18-228 for detailed information on authentication of key biological and/or chemical resources. Applications identified as non-compliant with this limitation will be withdrawn from the review process (see NOT-OD-17-105).

Reviewers will assess the information provided in the Authentication of Key Biological and/or Chemical Resources section. Any reviewer questions associated with key biological and/or chemical resource authentication will need to be addressed prior to award.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Research Component: Assay Development, Screening, and Early Optimization)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Research Component: Research Component: Discovery and/or Validation of Pharmacodynamic Markers

SF424 (R&R) Cover (Research Component: Discovery and/or Validation of Pharmacodynamic Markers)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Research Component: Discovery and/or Validation of Pharmacodynamic Markers)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Component: Discovery and/or Validation of Pharmacodynamic Markers)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Other Attachments: Milestones (maximum 2 pages) - required: This attachment should be entitled "PD Marker Milestone Plan.pdf . Applications that propose to conduct this research component but are lacking this attachment, as determined by the NIH staff, will be considered incomplete and will not be reviewed. Annual Go/No-Go milestones must be proposed under each research component, and should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress. Milestones should be realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. Milestones should provide clear indicators of continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the NIH Program staff. Please see here (link) for examples of milestones.

Project /Performance Site Location(s) (Research Component: Discovery and/or Validation of Pharmacodynamic Markers)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Component: Discovery and/or Validation of Pharmacodynamic Markers)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Research Component: Discovery and/or Validation of Pharmacodynamic Markers)

Budget forms appropriate for the specific component will be included in the application package.

The PD/PI is expected to devote a minimum effort of 1.8 person months for each Research Component they are leading. If multiple PD/PIs serve as co-leads for this Research Component, they are expected to devote a combined minimum effort of 1.8 person months.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Component: Discovery and/or Validation of Pharmacodynamic Markers)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Briefly describe the biological rationale for this research component and how it fits within the goals of the overall application. Outline the major objectives and/or aims of the proposed approach and technical questions to be answered.

Research Strategy: Investigators are urged to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.

Significance (Rationale and Supporting Data)

• Describe the overall goals and impact of the pharmacodynamic marker(s) and development approach proposed in relation to the current state and challenges in the field.
• Define and provide the rationale for the association of the pharmacodynamic markers to the type(s) of pain, pain condition(s) or pain-associated with specific disease(s).
• Describe why the proposed pharmacodynamic marker has the potential to inform the development of the proposed therapeutic for pain.
• As this component builds on other components, it is anticipated that the preliminary data supporting this section might not be complete. In this case, data supporting the validity of the target should be reflected in the project milestones to be completed before initiation of this component.
• Explain the contribution of this research component to the overall goals of the U19 program and how the component will interact with and benefit from other components.

Innovation

• Describe the unique and innovative contributions that will be made by this component.
• Explain how these contributions will be made possible by team synergy beyond the otherwise independent research projects.

Approach

• Describe plans for initial development of the pharmacodynamic marker(s). It is possible that complete plans cannot be formulated until after the project is underway. In that case, describe how decisions and plans will be made. Describe potential pitfalls and alternative strategies.
• Highlight aspects of the approach that ensure the identified pharmacodynamic marker(s) will be meaningful and quantitative indices of the therapeutic agent's effects in vivo.
• Discuss optimization and validation related to feasibility, endpoint range, sensitivity, identification of confounding variables, etc.
• Highlight the proposed interdisciplinary nature and collaborative team-based approach for this component, including any plans for independent replication and reproduction of methodologies in multiple laboratories in the project/program.
• Discuss plans (if any) for collaborations with outside resources (academic facilities or contractors or industry), other than the Resource Cores in this U19 application.

Letters of Support: Statements of individual and Institutional Commitment, as appropriate to the research components, should be included in this section.

• Applicants should include letters of support from consultants, contractors, and collaborators.
• If utilization of extant samples is proposed as a component of the study, letters of approval for use of those samples should be included.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Note: Do not submit Data Sharing Plans here. The Data Sharing Plan should be submitted only in the Data Management Core component.

Authentication of Key Biological and/or Chemical Resources:

Individuals are required to comply with the instructions for authentication plans for key biological and/or chemical resources as provided in the SF424 (R&R) Application Guide, with the following modification:

Briefly describe methods to ensure the identity and validity of key biological and/or chemical resources used in the proposed studies.

• Key biological and/or chemical resources may or may not have been generated with NIH funds and: 1) may differ from laboratory to laboratory or over time; 2) may have qualities and/or qualifications that could influence the research data; and 3) are integral to the proposed research.
• These include, but are not limited to, animal strains, source, genetic backgrounds & modifications; cell lines, dissociation and/or culture conditions for primary cells, cell lines and primary tissue preparations; specialty chemicals, antibodies, and other biologics.
• Standard laboratory reagents that are not expected to vary do not need to be included in the plan. Examples are buffers and other common biologicals or chemicals.

Information in this section must focus only on authentication of key biological and/or validation of key resources to be used in the study; all other methods and preliminary data must be included within the page limits of the research strategy. See NOT-OD-16-011 and NOT-18-228 for detailed information on authentication of key biological and/or chemical resources. Applications identified as non-compliant with this limitation will be withdrawn from the review process (see NOT-OD-17-105).

Reviewers will assess the information provided in the Authentication of Key Biological and/or Chemical Resources section. Any reviewer questions associated with key biological and/or chemical resource authentication will need to be addressed prior to award.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Research Component: Discovery and/or Validation of Pharmacodynamic Markers)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies

SF424 (R&R) Cover (Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies)

Complete only the following fields:

• Applicant Information
• Type of Applicant (optional)
• Descriptive Title of Applicant’s Project
• Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Other Attachments: Milestones (maximum 2 pages) - required: This attachment should be entitled "PK/PD and Efficacy Milestone Plan.pdf . Applications that propose to conduct this research component but are lacking this attachment, as determined by the NIH staff, will be considered incomplete and will not be reviewed. Annual Go/No-Go milestones must be proposed under each research component, and should be well-described, quantifiable, and scientifically justified to allow program staff to assess progress. Milestones should be realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. Milestones should provide clear indicators of continued success or emergent difficulties and will be used to evaluate the application as part of the consideration of the awarded project for further funding of non-competing award years by the NIH Program staff. Please see here (link) for examples of milestones.

Project /Performance Site Location(s) (Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies)

• In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
• In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
• Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
• If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies)

Budget forms appropriate for the specific component will be included in the application package.

The PD/PI is expected to devote a minimum effort of 1.8 person months for each Research Component they are leading. If multiple PD/PIs serve as co-leads for this Research Component, they are expected to devote a combined minimum effort of 1.8 person months.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for each component.

Specific Aims: Briefly describe the biological rationale for this research component and how it fits within the goals of the overall application. Outline the major objectives and/or aims of the proposed study, research approach and technical questions to be answered to validate the proposed analgesic therapeutic agent and target proposed.

Research Strategy: Investigators are urged to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.

Significance (Rationale and Supporting Data)

• For the pharmacokinetic studies, describe what features are important to measure in the context of the proposed pain indication.
• Describe how the pharmacodynamic measures being used will provide added confidence that the potential therapeutic is working as intended.
• Describe how the efficacy studies, if successful, will reflect the potential of the proposed therapeutic to be a starting point for further development. Describe how these studies will prepare the asset for RFA-NS-21-010.
• Provide any preliminary data supporting the feasibility of the proposed studies. As this component builds on other components, it is anticipated that the preliminary data supporting this section might not be complete. In this case, data supporting the validity of the target, the potential of the therapeutic agent, the relevance and validity of the model, etc. should be reflected in the overall milestones to be completed before initiation of this component.
• If using existing animal models and/or outcome measures, discuss their clinical relevance in relation to the type(s) of pain, pain condition(s) or pain-associated with specific disease(s).

Innovation

• Describe the unique and innovative contributions that will be made by this component.
• Explain how these contributions will be made possible by team synergy beyond the otherwise independent research projects.

Approach

• As this component builds on other components, it is possible that complete plans cannot be formulated until after the project is underway. In that case, describe how decisions and plans will be made. Describe potential pitfalls and alternative strategies.
• Propose plans for measuring target engagement, if possible, and evaluating PK/PD.
• Discuss how the pharmacokinetic studies will inform the efficacy studies.
• Discuss how the efficacy studies will be done and to what extent the results will be clinically relevant/meaningful and support decisions regarding further development. Where plans cannot be described in full detail, applications should discuss how results from other components will inform the approach.
• As appropriate, describe plans to demonstrate a lack of abuse liability and non-addictiveness of the proposed therapeutic agent(s).
• As needed, describe plans for early selectivity and safety studies.
• Highlight the proposed interdisciplinary nature and collaborative team-based approach for this component, including any plans for independent replication and reproduction of methodologies in multiple laboratories in the project/program.
• Discuss plans (if any) for collaborations with outside resources (academic facilities, contractors, or industry), other than the Resource Cores in this U19 application.

Letters of Support: Statements of individual and Institutional Commitment, as appropriate to the research components, should be included in this section.

• Applicants should include letters of support from consultants, contractors, and collaborators.
• If utilization of extant samples is proposed as a component of the study, letters of approval for use of those samples should be included.

Resource Sharing Plan:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Note: Do not submit Data Sharing Plans here. The Data Sharing Plan should be submitted only in the Data Management Core component.

Authentication of Key Biological and/or Chemical Resources:

Individuals are required to comply with the instructions for authentication plans for key biological and/or chemical resources as provided in the SF424 (R&R) Application Guide, with the following modification:

Briefly describe methods to ensure the identity and validity of key biological and/or chemical resources used in the proposed studies.

• Key biological and/or chemical resources may or may not have been generated with NIH funds and: 1) may differ from laboratory to laboratory or over time; 2) may have qualities and/or qualifications that could influence the research data; and 3) are integral to the proposed research.
• These include, but are not limited to, animal strains, source, genetic backgrounds & modifications; cell lines, dissociation and/or culture conditions for primary cells, cell lines and primary tissue preparations; specialty chemicals, antibodies, and other biologics.
• Standard laboratory reagents that are not expected to vary do not need to be included in the plan. Examples are buffers and other common biologicals or chemicals.

Information in this section must focus only on authentication of key biological and/or validation of key resources to be used in the study; all other methods and preliminary data must be included within the page limits of the research strategy. See NOT-OD-16-011 and NOT-18-228 for detailed information on authentication of key biological and/or chemical resources. Applications identified as non-compliant with this limitation will be withdrawn from the review process (see NOT-OD-17-105).

Reviewers will assess the information provided in the Authentication of Key Biological and/or Chemical Resources section. Any reviewer questions associated with key biological and/or chemical resource authentication will need to be addressed prior to award.

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Research Component: Pharmacokinetic/Pharmacodynamic (PK/PD) and Efficacy Studies)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov.

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies) using ASSIST or other electronic submission systems. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) and component Project Leads must include their eRA Commons ID in the Credential fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the unique entity identifier (DUNS number or UEI as required) provided on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

In order to expedite review, applicants are requested to notify the NINDS Referral Office by email at [email protected] when the application has been submitted. Please include the FOA number and title, PD/PI name, and title of the application.

Applications Involving NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided to the NIH Intramural Program, not through the extramural awardee's institution. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this FOA. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

A meritorious Team Research for Initial Efforts in Non-addictive Analgesic Therapeutics Development U19 application is expected to be well-balanced in interdisciplinary science that spans expertise in analgesic target discovery and validation, preclinical models and measures of pain, therapeutic design, assay development, early optimization, efficacy and pharmacokinetic/pharmacodynamic studies. The overarching goal of this funding program is to increase pain treatment options for patients. Exemplary applications should articulate how the proposed analgesic therapeutic development plan will produce new and effective pain management strategies.

This FOA is a part of a suite of NIH HEAL initiative FOAs with a goal of development of safe, effective and non-addictive therapeutics to treat pain. Reviewers should evaluate whether a strong rationale, supporting experimental data and research team, rigorous research plan and interdisciplinary team-based approach have been provided to validate non-addictive pain therapeutic targets and therapeutic agents.

The entire research application will receive one Impact Score based on critical consideration of all the components of the entire application. To guide the final scoring, reviewers will make interim assessment scores of the Overall Integrated Development Plan, as well as each Research component (scores 1-9) and Core (exceptional, adequate, or inadequate). The final Impact Score will reflect assessment of aggregate impact and synergies of the entire application that will balance the collective strengths and weaknesses of the overall goals and the individual components, and not necessarily the arithmetic average of the interim assessment scores. Reviewers should also provide their evaluation on the research application with regards to feasibility and meeting milestone requirements, since there is no opportunity for renewal of grant awards under this FOA.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the research and therapeutic development program to develop and validate non-addictive therapeutic agents (and their targets) to treat pain, as well as advance pain therapeutic assets to the point where they can meet the entry criteria for RFA-NS-21-010 HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional) within the 5 years of the award, in consideration of the following review criteria and additional review criteria (as applicable for the pain therapeutic development project proposed). The U19 team application will be evaluated on its cohesiveness and synergy as an integrated research and therapeutic development effort. The relationship and contributions of the Research Components and Resource Cores to the overall objectives will be discussed and evaluated. Reviewers should evaluate whether there is synergy between the components that could not be achieved through individual NIH award mechanisms and whether there are clear advantages of conducting the proposed therapeutic development plan as a collective team-based program rather than through separate efforts.

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA:

• What is the strength of the proposed research and development plan to validate pain therapeutic targets and therapeutic agents, in the context of specific pain type(s)/indication(s) and/or disease-associated pain conditions?
• Have the applicants provided a strong and cogent rationale for the proposed approach to treating pain in relation to specific pain type(s)/indication(s) and/or disease-associated pain conditions??
• Is the rationale for the proposed development and validation of animal models and/or outcome measures appropriate and well-justified in the context of the specific pain type(s)/indication(s) and/or disease-associated pain conditions?
• Does the application adequately describe whether prior research that serves as the key support for the proposed project employed rigorous practices such as minimization of potential experimenter biases, robust experimental designs, transparent reporting of results and analyses, and careful interpretation? Does the application adequately describe ambiguity, weaknesses, or limitations in rigor of the prior research, if applicable?
• Are the Research Components and Cores synergistic, such that they will interact and inform each other in ways not possible as separate research projects grants?
• If proposing to omit one or two of the research components, have the applicants provided sufficient justification?
• How likely is the proposed therapeutic development plan to advance a therapeutic asset to meet the entry criteria for RFA-NS-21-010 within the proposed timeline?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA:

• Is the team diverse, collaborative, and multidisciplinary, such that it is comprised of appropriate content experts recognizable as leaders in their field(s)?
• Does the team have extensive knowledge in pain biology and research activities needed for full target discovery, validation, and drug development processes? Does the team include adequate expertise in:
  • Pain biology (such as pain pathways and circuits, relevant disease pathology, relevant pain and reward models)
  • Data management, statistical analysis, experimental design, and scientific/experimental rigor
  • Assay development and drug discovery (such as assay development, screening, pharmacology, medicinal chemistry)
  • Early drug development (such as pharmacokinetics, pharmacodynamics, biomarkers, and in vitro ADME)
• Does the team include individuals with appropriate expertise who can help the team plan for future therapy development beyond this RFA (such as later stage drug development experts, regulatory experts, clinicians)?
• Has the proposed PD(s)/PI(s) demonstrated extensive knowledge, experience, and leadership in the area of pain therapeutic discovery and development, with a strong record of scientific achievements? Has the proposed PD(s)/PI(s)demonstrated her/his ability to organize, direct, and administer a complex research and therapeutic development program?
• Have the leaders on the individual Research Components or Cores demonstrated adequate knowledge, experience, and leadership in their respective component(s)?
• Is there evidence that the research team has been/will be able to work together effectively to accomplish the research proposed in the projects? Are there prior demonstrations of collaborative teamwork?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this FOA:

• Does the applicant explain how the pain target and pain therapeutic agent both innovative and feasible for advancing the pain therapeutic assets to the point where they can meet the entry criteria for RFA-NS-21-010 within the 5 years of the award?
• Does the project offer significant improvement over existing pain therapeutic approaches?
• What is the innovativeness of the proposed pain therapeutic target and/or therapeutic agent identified and validated, in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this FOA:

• Is there a sufficiently developed interdisciplinary plan for the discovery and rigorous validation of the proposed therapeutic target in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?
• Is the proposed approach for the development and validation of animal models and/or outcome measures appropriate, rigorous, and relevant to the pain type(s)/indication(s) and/or disease-associated pain conditions?
• Is there a sufficiently developed plan for the design and assessment of the therapeutic agent’s chemical, biophysical, and biological characterization?
• Are the development and standardization of in vitro, ex vivo and in vivo assays for the proposed therapeutic agent scientifically sound and rigorous? What is the likelihood that these assays will provide rigorous specificity testing and screening of the proposed therapeutic agents?
• Are the proposed plans for testing the PK/PD characteristics and efficacy robust? Will the PD and in vivo efficacy plan support future therapeutic development?
• Will the proposed approach to identify pharmacodynamic markers produce meaningful and quantitative indices of the therapeutic agent's effects in vivo?
• Is synergy between individual research components and cores interdisciplinary and adequate to accomplish the individual and overall goals of the proposed program?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Overall Milestones

Reviewers should evaluate the integrated nature of the overall milestones in relation to the key outputs of the individual research components and cores

• Are the milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions?
• Are the milestones proposed scientifically justified and appropriate to address the key objectives of the overall program?
• Will successful completion of these milestones demonstrate feasibility and/or provide confidence in the outputs of the research component?
• Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps?

Timeline

• Is the timeline described in detail, taking into account start-up activities, the anticipated rate of validation of therapeutic target, animal models and/or outcome measure of pain, therapeutic design, assay development, screening, early optimization, efficacy and PK/PD studies?
• Is the projected timeline feasible and well justified?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Intellectual Property (IP) Strategy:

Are the following addressed as appropriate and consistent with achieving the goals of the program:

• Does the application outline any known constraints that could impede the therapeutic from being developed and how these issues could be addressed?
• If applicable, how strong is the applicant's IP portfolio/position (pertinent to the proposed project), and to what extent does the applicant have a reasonable strategy to protect its IP going forward?
• If the applicant has filed patents pertinent to the project, do they provide details about those patents?
• If multiple investigators and/or institutions are involved, is IP sharing adequately addressed?

Applications from 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.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Sharing Model Organisms; and (2) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

Scored Review Criteria: Research Components

Reviewers will consider each of the review criteria below in the determination of scientific merit and give separate numeric scores for the following five criteria under each research component to judge the likelihood of the impact of each research component on the development and validation of safe, and effective non-addictive therapeutics to treat pain with little or no addiction liability. For example, a project that by its nature is not innovative may be essential to advance the validated pain therapeutic agents for further optimization and accelerating subsequent translational and clinical trial processes.

Significance

• What is the strength of the proposed research and development plan in the context of validating effective targets and therapeutic agents for the treatment of pain with little or no abuse-liability?
• Have the applicants adequately considered the context of specific pain type(s)/indication(s) and/or disease-associated pain conditions when developing plans for this research component?
• Is there strong biological rationale to support the plans proposed within this research component?
• Does the application adequately describe whether prior research that serves as the key support for the proposed research component employed rigorous practices such as minimization of potential experimenter biases, robust experimental designs, transparent reporting of results and analyses, and careful interpretation? Does the application adequately describe ambiguity, weaknesses, or limitations in rigor of the prior research, if applicable? If the aims of the research component are achieved, how it will co-ordinate and contribute to other research components to address the goals of the overall project?

Specific to the Validation of Target and Underlying Biology Component:

• What is the potential of the candidate target to demonstrate little to no abuse liability?

Specific to the Validation of Animal Models and Outcome Measures Component:

• Is there strong clinical rationale for the development of animal models and/or pain outcome measures in relation to human pain type(s) or pain condition(s) or pain associated with disease(s)?

Specific to the Assay Development, Screening, and Early Optimization Component:

• What is the likelihood that these assays will provide rigorous specificity testing and screening of the proposed therapeutic agents?

Specific to the Discovery and/or Validation of Pharmacodynamic Markers Component:

• What is the likelihood that the identified marker will be clinically relevant and/or useful for therapeutic development?

Specific to the PK/PD and Efficacy Studies Component:

• To what extent will the proposed PD measures build confidence that the therapeutic agent is working as intended?
• If the proposed efficacy studies are successful, what is the potential of the proposed therapeutic agent for entering into the HEAL Initiative’s Non-addictive Analgesic Therapeutics Development Program to Treat Pain (RFA-NS-21-010)?

Investigator(s)

• Are the PD(s)/PI(s), collaborators, and other researchers of this research component well suited to accomplish the goals of the proposed project? Do they have sufficient knowledge and experience in areas relevant to the scientific focus of this research component?
• Are there prior demonstrations of collaborative teamwork? Is there evidence that investigators for this research component have been/will be able to effectively work together with investigators in other research components and cores to accomplish the goals of the overall application?
• If the research component project has multiple PIs, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the research component?

Innovation

• How novel is the proposed therapeutic target, therapeutic agent(s), assays and/or models in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?
• What is the novelty of the proposed approach for the specific research component, and does it offer significant improvement over existing approaches?

Approach

• Is there a sufficiently developed interdisciplinary approach, in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?
• Does the proposed research incorporate adequate methodological rigor where applicable, including, but not limited to, rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications?
• Are potential problems, alternative strategies, and benchmarks for success presented?
• If the proposed approach and experimental plans are in the early stages of development, will the proposed strategy establish feasibility, and will particularly risky aspects be effectively managed? How would this impact the other research components of the overall project?
• Is the timeline reasonable for the work proposed?
• Are adequate plans provided to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
• If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults) justified in terms of the scientific goals and research strategy proposed?

Specific to the Validation of Target and Underlying Biology Component:

• Are there adequate plans to address addiction potential of the proposed target?

Specific to the Development and Validation of Animal Models and/or Outcome Measures Component:

• Does the proposed approach adequately incorporate studies that would demonstrate rigorous internal and external validity (face validity, constructive validity and predictive validity, as appropriate) of the models and/or measures in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

Specific to the Assay Development, Screening, and Early Optimization Component:

• Will the proposed approach, if successful, provide sufficient evidence that the assays developed are robust and well-validated?
• Will the proposed assays provide sufficient throughput for their intended use within the proposed timeframe?
• Is there a sufficiently developed plan for the design and assessment of the therapeutic agent’s chemical, biophysical, and biological characterization?

Specific to the Discovery and/or Validation of Pharmacodynamic Markers Component:

• Will the proposed approach identify markers with potential to produce meaningful and quantitative indices of the therapeutic agent's effects in vivo?

Specific to the PK/PD and Efficacy Studies Component:

• If utilizing pre-existing animal models and/or outcome measures, are they appropriate for the relevant pain type(s)/indication(s) and/or disease-associated pain conditions?
• To what extent is the approach of the efficacy studies informed by the PK and PD studies?
• What is the likelihood the approach will provide sufficient evidence to support a decision regarding further development of the therapeutic agent(s)?
• If needed, are there adequate plans to address addiction potential of the proposed therapeutic agent(s)?

Environment

• Will the scientific environment in which the work will be done for the proposed research component contribute to the probability of success?
• Are the institutional support, equipment and other physical resources available to the investigators adequate for the proposed research component?
• Will the research component benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
  

Additional Review Criteria: Research Components

Milestones

• Are the milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions?
• Are the milestones proposed scientifically justified and appropriate to address the key objectives of the research component?
• Do the milestones allow for the evaluation of progress each year, and will successful completion of these milestones demonstrate feasibility and/or provide confidence in the outputs of the research component?
• Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?

Scored Review Criteria: Administrative Core

Reviewers will assess this Core as exceptional, adequate, or inadequate, based on the following criteria:

• Is the administrative and organizational structure clearly defined and is it appropriate and adequate to accomplish the objectives of the program?
• Is administrative plan appropriate and will it facilitate attainment of the program’s goals?
• Are the experience, level of commitment, and availability of the Administrative Core Leader and Program Manager (if proposed) adequate to manage the overall program?
• Are the plans for coordination, problem identification and resolution, and the establishment of a strong collaborative environment for the program appropriate?
• Will this Core adequately facilitate communication and integration across all Research Components and Cores?
• Are there suitable descriptions of how progress will be evaluated during the project period, how milestones will be assessed, how delays will be managed, and how decisions to initiate changes will be made?
• Are there adequate plans to coordinate with the Data Management Core to ensure compliance with the NIH HEAL Initiative’s Data Sharing and Public Access requirements?

Scored Review Criteria: Data Management Core

Reviewers will assess this Core as exceptional, adequate, or inadequate, based on the following criteria:

• Are the qualifications, experience, and commitment of the Data Management Core Director(s) and other key personnel adequate and appropriate for providing the proposed data management and sharing facilities or services?
• Will the Data Management Core provide a reliable service to the proposed U19 Research Components and Core(s)?
• Does the Data Management Core provide a reasonable plan to develop a data science framework for facilitating the workflow for data aggregation and analysis between the proposed Research Components and Core(s)?
• Is the proposed Data Management plan feasible and appropriate to achieve the goals of the project?
• Is there a reasonable plan to follow and co-ordinate with the NIH HEAL Initiative’s Public Access and Data Sharing (https://heal.nih.gov/about/public-access-data)?
• Are there efforts to identify best practices, standards, software tools, and/or computational infrastructures to manage their data, algorithms, and workflows? Are there efforts to reuse those that already exist in the research community?
• Does the application provide robust and flexible data management and retrieval tools to function within the U19 project?
• To what extent have the investigators proposed to develop new data standards, software tools for reusability, and computational infrastructures? Is this effort appropriate and well-justified for providing a data science framework for this U19 project?
• Is the environment for the Data Management Core appropriate to support the program as proposed? Are the institutional support, equipment, and other physical resources and infrastructure available adequate for the proposed Core?
  

Scored Review Criteria: Resource Core

Reviewers will assess this Core as exceptional, adequate, or inadequate, based on the following criteria:

• Are the qualifications, experience, and commitment of the Resource Core Director(s) and other key personnel adequate and appropriate for providing the proposed facilities or services?
• Does the proposed plan demonstrate that the activities of the Core are well-integrated with those of the Research Components and that the investigators therein are working closely with those of the Core to meet the objectives?
• Does the proposed Resource Core address a critical need or technical barrier to progress in the Research Components? Does the application describe how each Resource Core will respond to Research Component needs and other Overall Program needs?
• What is the overall quality of the proposed Core services and are adequate quality control processes proposed?
• Evaluate the criteria for prioritization and usage of Resources Core products and/or services.
• If the Core is at a different geographic location than the site(s) of Research Component(s) it serves, are the cooperative administrative arrangements and plan for data and/or sample transfer and communication adequate?
• Is the environment for the Resource Core appropriate to support the program as proposed?
• Are the institutional support, equipment and other physical resources available adequate for the Core proposed?

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke Council (NANDSC). The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Prior Approval of Pilot Projects

Recipient-selected projects that involve {clinical trials or studies involving greater than minimal risk to human subjects} require prior approval by NIH prior to initiation.

• The recipient institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval.
• The recipient institution will provide NIH with specific plans for data and safety monitoring, and will notify the IRB and NIH of serious adverse events and unanticipated problems, consistent with NIH DSMP policies.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: Generaland Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:

• Federalwide Research Terms and Conditions
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identity, sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov.

• For information on an institution's specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75 and 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipientsis anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the recipientsfor the project as a whole, although specific tasks and activities may be shared among the recipientsand the NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:
The PD(s)/PI(s) will have primary authority and responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of studies conducted under this program. The PD(s)/PI(s) assume responsibility and accountability to the applicant organization officials and to the NINDS for the performance and proper conduct of the research supported by the U19 award. Specific responsibilities and rights include:

• Validating targets for non-addictive pain therapeutics
• Developing and validating animal models and/or pain outcome measures relevant to specific pain type(s)/indication(s) and/or disease-associated pain conditions in humans;
• Developing novel analgesic therapeutic agents
• Developing and validating appropriate assays for testing, screening and early optimization of novel analgesic therapeutic agents
• Discovery and validation of pharmacodynamic markers
• Conducting PK/PD and Efficacy studies on novel analgesic therapeutic agents
• Working with the Administrative, Resource and Data Management Cores to collaborate with other U19 teams to conduct the above-mentioned drug discovery and development research work; and to share data, models, specimens, and agents
• Coordinating with the NIH HEAL Initiative Data Ecosystem and HEAL Data Platform. Please visit the HEAL public access and data sharing policy at https://heal.nih.gov/about/public-access-data
• Participation in quarterly and annual progress and milestone meetings, working groups, and/or teleconferences as needed
• Implementation of the data sharing plan; Institutions/organizations participating in the NIH HEAL Initiative's Team Research for Initial Translational Efforts in Non-addictive Analgesic Therapeutics Development programs will be expected to share knowledge, data, research materials, and any other resources necessary and relevant to this program;
• Adhering to the NIH HEAL Initiative and NIH Programmatic staff recommendations and policies (to the extent consistent with applicable grants regulation) to ensure that the goals of the funded project and the NIH HEAL Initiative's Team Research for Initial Translational Efforts in Non-addictive Analgesic Therapeutics Development program are accomplished.

Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, NIH, and the NIH HEAL Initiative policies.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
Designated NINDS Program Staff member(s), acting as Program Director(s) and Project Scientist(s), will participate in the following activities:

• Assisting in avoiding unwarranted duplications of effort across the NIH HEAL Initiative's Team Research for Initial Translational Efforts in Non-addictive Analgesic Therapeutics Development program;
• Helping to coordinate collaborative research efforts that may involve multiple U19 awardees;
• Aiding in directing U19 awardees to NIH resources which may be helpful to the goals of the U19;
• Monitoring the operations of the U19s and making recommendations on overall project directions;
• Reviewing the progress of individual U19s and making recommendations on overall project directions;
• Participating in quarterly and annual progress and milestone meetings;
• Assisting the U19 awardees as a liaison in stimulating their broader interactions with other HEAL Initiative and NIH programs to disseminate results and outcomes and effectively leverage existing NIH/HEAL resources and infrastructures (e.g., databases).

In addition, an NIH Program Director acting as the Program Official will be responsible for the normal scientific and programmatic stewardship of the awards and will be named in the award notice.

Dispute Resolution:
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the awarded U19 grant without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM)about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Julia L. Bachman, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-7383
Email: [email protected]

Marie Mancini, Ph.D.
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-5032
E-mail: [email protected]

Rachel Altshuler, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5873
Email: [email protected]

Asif M Rizwan
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-435-0070
E-mail: [email protected]

Helena H. Ahn, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-3207
Email: [email protected]

Devon Oskvig, Ph.D.
National Institute on Aging (NIA)
Phone: 301-827-5899
Email: [email protected]

Houmam H Araj
NEI - NATIONAL EYE INSTITUTE
Phone: (301) 435-8166
E-mail: [email protected]

Melissa Ghim, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-529-6570
Email: [email protected]

Inna Belfer, MD, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-435-1573
Email: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Erik Edgerton
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-7760
E-mail: [email protected]

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: [email protected]

Nina Hall
NHLBI - NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
Phone: 301-435-0710
E-mail: [email protected]

Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: [email protected]

Jeni Smits
National Institute on Aging (NIA)
Phone: 301-827-4020
Email: [email protected]

Karen Robinsonsmith
NEI - NATIONAL EYE INSTITUTE
Phone: (301) 451-2020
E-mail: [email protected]

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-594-3788
Email: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.