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 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

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 in 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 overdose deaths and addictions. Innovative scientific solutions to develop alternative pain treatment options are thus critically needed.

Through targeted research efforts, the NIH HEAL Initiative proposes 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-21-016: HEAL Initiative: Planning Studies for Initial Translational Efforts in Non-addictive Analgesic Development [Small Molecules and Biologics] (R34 Clinical Trial Not Allowed)

RFA-NS-21-016 will support planning projects that are designed to support building a strong research team, develop feasibility, validity, or other technically qualifying results that support, enable, and/or lay the groundwork for a subsequent U19 application, RFA-NS-21-015.

• RFA-NS-21-015 HEAL Initiative: Team Research - for Initial Translational Efforts in Non-addictive Analgesic Development [Small Molecules and Biologics] (U19 Clinical Trial Not Allowed)

RFA-NS-21-015 will support team-based research projects that develop assays, screen and propose early optimization work to develop a non-addictive therapeutic to treat pain. Discovery and/or validation of pharmacodynamic markers and efficacy and pharmacokinetic/pharmacodynamic (PK/PD) studies are responsive to RFA-NS-21-015.

• RFA-NS-21-010 HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)

Applications to RFA-NS-21-010 require a promising small molecule or biologic hit or lead for optimization, a rigorous biological rationale for the intended approach, and scientifically sound assays for testing the optimization of the hit or lead. 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 goal of this FOA, RFA-NS-21-015, is to support interdisciplinary and even multi-institutional research teams working on early therapeutics development to advance a hit or lead asset to the point where it 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, there is no opportunity for renewal of this award.

This RFA solicits applications from interdisciplinary research teams that integrate:

• 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
• Efficacy and Pharmacokinetic/Pharmacodynamic (PK/PD) Studies

General U19 Structure for this Funding Opportunity

• Awards within this funding announcement will support research programs with up to 5 research components, and an Administrative Core, a Data Management Core, and optional Resource Core(s) focused on target discovery, validation, and early development of a new therapeutic asset. The components will work together as part of a whole project to develop a single asset.
• The following research components are necessary for a successful project. Teams can only propose to omit a component(s) if it can be demonstrated that the necessary activity has already been reasonably completed.

o Validation of Therapeutic Target and Underlying Biology

o Development and Validation of Animal Models and/or Outcome Measures

o Assay Development, Screening and Optimization

o Discovery and/or Validation of Pharmacodynamic Markers

o Efficacy and PK/PD Studies

• 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 5-year grant period. There will be no opportunities for renewal of the grant.
• Because drug discovery and development require diverse expertise, applicants must form multidisciplinary teams. The team may consist of members from multiple institutions. It is critical that these teams work together as an integrated unit. 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.

Applications should include the following items:

Multidisciplinary Team: The team must be collaborative, integrated and multidisciplinary. They should include knowledge in pain biology and the research activities needed for full target discovery and drug development process.

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. Please refer to Notice of NIH's Interest in Diversity NIH NOT-OD-20-031 for more details.

• Input from patients and caregivers on the therapeutic development goals of the project is strongly encouraged.
• The NIH 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 on 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 RFA 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 currently available analgesics to 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 5-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 . Applications should include all steps necessary to get to this point. It is essential for applicants to include, within the Research Strategy, a description of how knowledge gained from this work will support future therapeutic discovery efforts beyond the program 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. Also, as part of this consideration, applicants should be aware of intellectual property limitations and how these will be addressed.
• Data Management: Data Management is one of the critical core components that will provide a reliable communication to and from the proposed U19 Research Components, as well as to provide a reasonable plan to optimally design a prototype data science framework for facilitating the workflow for data aggregation and analysis between the proposed Research Components.

The Data Management core should include a reasonable plan to follow and co-ordinate with the NIH HEAL Initiative Public Access and Data Sharing. Please visit the HEAL public access and data sharing policy at https://heal.nih.gov/about/public-access-data.

The Data Management Core should provide details on plans to identify best practices, standards, tools, workflows, and computational infrastructures already in use by the research community. The data management team should include appropriate data science staff and software engineering support. Plans to reuse existing best practices, standards, software tools, and computational infrastructures to manage data, algorithms, and workflows should also be included.

The data management plan should describe how the proposed efforts are appropriate and well-justified for providing a prototype data science framework for the specific U19 project.

• Milestones: Annual Go/No-Go milestones must be proposed in the Overall Integrated Development Plan to reflect progress of the overall integrated 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. Clearly indicate what the milestones are for the initiation of any delayed component. Milestones must also be included in each research component to reflect progress toward the goals of the 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. The milestones proposed will be evaluated by scientific peer review and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific 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 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

Entry Criteria

• Applicants must have a multidisciplinary team. There should be evidence that this team has the capabilities needed to effectively execute the project as well as plan for the next stages. There should 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 planning FOA RFA-NS-21-016: HEAL Initiative: Planning Studies for Initial Translational Efforts in Non-addictive Analgesic Development [Small Molecules and Biologics] (R34 Clinical Trial Not Allowed).

Research Components

The components will 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 5-year project. Most components will not utilize the full 5-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 other research component sections. 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 treatments that have minimal side effects and little to no abuse/addiction liability. This component of the program must include rigorous validation studies to demonstrate the robustness of the target as a pain treatment target. This will lower the risk of adopting the target in 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 section and are encouraged in the context of novel pain therapeutic target discovery. The goal of this component to identify novel nonaddictive pain targets that include rigorous target validation studies. These studies should have the goal of definitively determining the utility of a potential target for therapeutic development. The duration of the component may be the full 5 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 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 processes and types 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, ex-vivo systems, or in vitro models. In addition, it is essential that the general experimental design procedures utilized 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 in vitro 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 fMRI or 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 in vitro model system, predictive validity provides the most confidence in the ability of the animal model or model system 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 in vitro model system as it will in the intended clinical population. The evaluation of predictive validity requires a validated molecular tool that has been shown to alter disease progression in humans. Note that experimental therapeutics cannot be used to validate an experimental model. Predictive validation of the model requires a validated tool/therapeutic with a known effect 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 in vitro 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 animal pain model or invitro model system represents a significant advance over existing animal pain models or in vitro model systems.

It is not anticipated that these component activities last the full 5-years of the program since the validated model will need to be available for use in the Efficacy and PK/PD component.

Assay Development, Screening and Early Optimization: This research component section 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 neurological 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 neurological function. 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 5-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 Efficacy and PK/PD 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: The 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 neurological disorder.

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 5-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 Efficacy and PK/PD 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.

Efficacy and Pharmacokinetic/Pharmacodynamic (PK/PD) Studies: This component section should include plans to conduct pharmacodynamic, pharmacokinetic, and in vivo efficacy studies to demonstrate that the proposed asset has sufficient biological activity to warrant further development to treat neurological disorders. In preclinical efficacy studies, a combination of in vivo efficacy, pharmacodynamic (PD) and pharmacokinetic (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.

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.

Pharmacokinetic measurements reflect the body’s effect on the absorption, metabolism, distribution and excretion of the asset.

It is expected that this component utilizes the target, animal model(s), and the asset 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.

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; Efficacy and PK/PD Studies. Teams can only propose to omit a component if it can be demonstrated that the necessary activity has already been completed.
• 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 disease initiation, remission, relapse, prognostic, diagnostic or prediction of progression biomarkers

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

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

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:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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)

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)
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Eligible Agencies of the Federal Government - Including the NIH Intramural Program
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

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.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. 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.
• 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.
• o 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.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but 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 DUNS number and 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.

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.

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

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. 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 NOT-OD-11-101).

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.

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.

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: julia.bachman@nih.gov

Available Component Types	Research Strategy/Program Plan Page Limits
Overall Integrated Development Plan	1 for Specific Aims + 12 for Research Plan
Administrative Core	6
Data Management Core	6
Resource Core	6 each
Research Component	6 each

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

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 application should consist of the following components:

Overall Integrated Development Plan: required

Administrative Core: required; maximum of 1

Data Management Core: required; maximum of 1

Resource Core: optional; maximum of 3

Research Components: required; minimum of 3; maximum of 5

- 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

- Efficacy and Pharmacokinetic/Pharmacodynamic Studies

When preparing your application, use Component Type Overall Integrated Development Plan .

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

Complete entire form.

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

Follow standard instructions.

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

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

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 on 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.

Required Other Attachments:

Milestones (maximum 3 pages): Enlist/describe the integrated milestones for the Overall Integrated Development Plan in this section. In addition, annual Go/No-Go milestones must be proposed under each research component in the application, and 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. The milestones proposed will be evaluated by scientific peer review, and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific review panel or NIH Program staff. A final set of approved milestones will be specified in the Notice of Award. 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.

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.

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.

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.

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 section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

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, for an impactful and extended scope of work with a 5-year horizon on 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, Resources Core(s) and Data Management Core 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, multi-institutional (if applicable) application. The overall research strategy should include a description of the goals and strategy for the development and validation of proposed non-addictive pain therapeutic agent and the therapeutic target for specific pain type(s)/indication(s) and/or disease-associated pain conditions. It should also outline on the integration of the research team, the individual research components and resource/core components, and why these components are essential for accomplishing the application’s overall goal of a non-addictive pain therapeutic agent. This section should lay out a compelling argument for why an interdisciplinary team-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, and at an economy of scale. 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 and 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.
• An outline of goals, rationale and a brief research approach/plan for individual research components proposed should be provided.
• Describe the strengths and weaknesses in the rigor of the prior research (both published and preliminary data) that serves as the key support for the proposed project. Also, describe plans to address weaknesses in the rigor of the prior research that serves as the key support for the proposed project.
• An outline of the goals of the core facilities and a brief description summarizing on their role on integrating individual research projects to address the overall goals.
• Integrated research plan for the proposed overall specific aims and goals, integrating the role of, and coordination between individual research components. This should include evidence for feasibility and can include general and background preliminary findings from the multiple research and resource components.
• Applicants should offer well-reasoned justifications for new and innovative approaches, including a discussion of feasibility.
• Describe the experimental design for obtaining robust and unbiased results, consideration of relevant biological variables, and authentication of key biological and/or chemical variables for the integrated application.
• Please refer to https://grants.nih.gov/policy/reproducibility/guidance.htm for guidance on NIH policy on enhancing reproducibility through rigor and transparency.
• Please refer to https://grants.nih.gov/policy/reproducibility/resources.htm for resources on preparing a rigorous application.
• Multidisciplinary team should include knowledge in pain biology and the research activities needed for full target discovery and the drug development process. The team should include expertise in:

o pain biology (such as pain pathways, relevant disease pathology, relevant pain and reward models)

o project and data management, statistical analysis, experimental design, and scientific/experimental rigor

o assay development and drug discovery (such as assay development, screening, pharmacology, medicinal chemistry)

o early drug development (such as pharmacokinetics, pharmacodynamics, biomarkers, and in vitro ADME (Absorption, Disposition, Metabolism, Excretion)

• The team should include those who can help the team plan for future therapy development beyond this RFA (such as later stage drug development experts, regulatory experts, clinicians, etc.).
• We strongly encourage input from patients and caregivers on the therapeutic goals of the project.
• This section should also present very clear evidence that the research team has been or will be able to work together effectively to accomplish the research proposed in the projects. It should define and describe the individual components and 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. 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.
• An overview of the proposed data management plan should be include in this section, summarizing how it will provide a reliable communication to and from the proposed U19 Research Components, as well as provide a reasonable plan to optimally design a prototype data science framework for facilitating the workflow for data aggregation and analysis between the proposed Research Components. Also summarize how it will follow and co-ordinate with the NIH HEAL Initiative PublicAccess and Data Sharing. Please visit the HEAL public access and data sharing policy at https://heal.nih.gov/about/public-access-data
• A descriptive and graphic timeline must be included in the overall research strategy section. 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.

The following sections are not included in the page limit for Research Strategy :

Vertebrate Animals: This should be included under individual research components and cores as applicable. A separate Vertebrate Animals section is not required in the overall integrated development plan component.

Multi PD/PI Leadership Plan: All instructions in the SF424 (R&R) Application Guide must be followed.

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

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, with the following modification:

A Resource Sharing Plan for the entire application must be included in the Overall Integrated Development Plan component. A separate Resource Sharing Plan should 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

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

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.

Note: Proposed use (if any) of Human Embryonic Stem Cell lines and Human Fetal Tissue should be described in each relevant research and core components, as well as in the overall integrated development plan 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 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.

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 or 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 on 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 proposal. Equipment specific for individual Research Components and Cores should be detailed under the respective component sections.

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 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 Administrative 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 (Administrative Core)

Budget forms appropriate for the specific component (Administrative Core) 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 are 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 the Administrative Core.

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 how each Research Component or Resource Core and Data Management Core (as applicable) will draw upon the Administrative Core and how it in turn will respond to Research Component or Resource Core and Data Management Core needs. The description of the Administrative Core should clearly indicate the services and professional skills that the Core will provide. Moreover, information must be provided about how the collective operation of the Core will be affected in a coherent manner.

Additional information required in the Administrative Core Research Strategy:

A Team Director and a Project Manager, along with a governance plan that will organize and direct efforts across the Research Components. When multiple institutional sites are involved, a detailed description of the cooperative administrative arrangements should be included. Documentation of these arrangements should be included in the Letters of Support section. This section should 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.

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 (Administrative Core)

NOTE: NIH-defined clinical trials are not permitted in this RFA.

When involving human subjects research or clinical research, 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.

When preparing your application, use Component Type Data Management 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.

Note: Proposed use (if any) of Human Embryonic Stem Cell lines and Human Fetal Tissue should be described in each relevant research and core components, as well as in the overall integrated development plan 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.

Facilities and Other Resources:

In this section, describe the institutional, commercial, and industrial investments and resources that constitute the environment for the data management under this integrated therapeutic development proposal. 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 data science and management facilities & resources under each component are complimentary, and critical to the integrated therapeutic development proposal. Facilities and resources specific for individual Research Components or 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 on the availability and accessibility of all necessary equipment towards the data science and management for the entire proposal, and how they are complimentary and critical to the proposed integrated therapeutic development plan.

Other Attachments:

Applications should include a description on the involvement of the Data Management Core on Intellectual property (IP) landscape and strategy (if any) on the proposed therapeutic agent(s) and target(s). Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials.

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 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 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.

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.

Through the NIH HEAL Initiative Public Access and Data Sharing Policy (the Policy), NIH seeks to create an infrastructure that addresses the need for researchers, clinicians, and patients to collaborate on sharing their collective data and knowledge about opioid misuse and pain to provide scientific solutions to the opioid crisis. Under the Policy, applicants for extramural research funding (grants, cooperative agreements, contracts, and other transactions; "Applicants") for NIH HEAL Initiative Research Projects are required to submit a Public Access and Data Sharing Plan that (1) describes their proposed process for making resulting Publications and, to the extent possible, the Underlying Primary Data immediately and broadly available to the public or (2), if applicable, provides a justification to NIH if such sharing is not possible. Underlying Primary Data should be made as widely and freely available as possible while safeguarding the privacy of participants and protecting confidential and proprietary data.

Budgets should include sufficient resources to administer, prepare and disseminate data for the research and core components, and to coordinate all of the data-related activities identified by the NIH HEAL Initiative Public Access and Data Sharing division - https://heal.nih.gov/about/public-access-data).

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. Also, describe how the Data Management Core will interact with and benefit the components of this application.

Innovation: Describe the unique and innovative contributions that will be made by the Data Management Core. Explain how these contributions will be made possible by interactions of the Data Management Core with the research components and resource cores.

Approach: 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. Also, describe the plan to administer, prepare and disseminate data for the research component and resource core(s), and to coordinate data-related activities. Furthermore, it is essential to describe the data sharing activities, in relation to the NIH HEAL Initiative Public Access and Data Sharing requirements (https://heal.nih.gov/about/public-access-data).

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.

As this is a Data Management Core which is expected to disseminate and share data, a Data Management Plan, with a timeline, is a requirement for applications to this FOA, consistent with achieving the goals of the program. A dedicated Data Sharing Plan must be included in this Data Management Core, including a budget justified to support software engineering support and infrastructure as needed. An additional, Data Sharing Plan should not be included in the Resource Sharing Plan in the Overall Integrated Development Plan component. The multi-component therapeutic development plan in the proposed U19 application should drive the Data Management Plan, where the plan's goal is to develop:

1) a service to the proposed U19 research and resource core components

2) a prototype data science framework for facilitating the workflow for data aggregation and analysis between the proposed research and resource core components.

The latter is considered a pilot effort in which high risk-high impact methodologies are employed to validate and optimize the framework for the proposed pain therapeutic agent development plan and produce generalizable approaches for other HEAL Initiative’s analgesic therapeutic development efforts. The plan should be customized to fit the science and the specific data management needs of the research and core components. The prototype framework will be shared with other U19 awardees for further testing, utilization and refinement. The Data Management Plan may 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.
• Define common data formats or create tools to harmonize disparate data formats within the proposed integrated therapeutic development plan.
• Facilitate the comparison of data across species, as appropriate.
• Provide robust and flexible data management and retrieval tools to function within the proposed integrated therapeutic development plan.
• Provide guidance for addressing data provenance.
• Integrate, when appropriate, predictive computational models and analytical tools for driving experiments.
• Incorporate methods of uncertainty quantification to assess the robustness of model predictions and analytical methods.
• Formulate methods to ensure reproducibility and reusability of models and analytical tools developed in the proposed integrated therapeutic development plan (e.g. modular models, useable interfaces, etc.).
• Integrate, when appropriate, formal statistical inference frameworks for causal analyses of the range of data obtained in the proposed integrated therapeutic development plan.
• Help determine the magnitude and type of "missing" data that need to be acquired to improve the causal analyses.
• Provide sufficient documentation, end-user training, and technical support for reuse and refinement of the prototype data science and management framework with other U19 awardees on analgesic therapeutic development programs.
• Participate in the NIH HEAL Initiative Public Access and Data Sharing division/consortium to strategize on harmonizing the Data Management Plan and its implementation with other U19 awardees as appropriate. https://heal.nih.gov/about/public-access-data

The plan must comply with the data science and management qualifications listed below:

1) The data, algorithms, and workflows proposed in the Data Science and Management Plan should consider the FAIR Guiding Principles for scientific data management and stewardship (Wilkinson, M. D. et al. 2016).

2) The Data Science and Management Plan should maximally leverage existing shared data, algorithms, workflows and computational infrastructure resources and capabilities at the institutional, regional, and national levels - in pain therapeutic development programs and other scientific/therapeutic development domains that can be adapted for the purposes of this U19 proposal. The use of these existing resources should be noted in the plan.

3) The data used, collected, and subsequently managed in this application should be well-defined, utilizing reference data where possible. Investigators are encouraged to work toward consensus standards within the appropriate experimental subfield for representation of data in commonly used domains.

4) The analytical methods, models, and tools to visualize and analyze the data should be optimized for the science and therapeutic development plan, consistently annotated, and described for each research and resource core component's own re-use and use by future users. Software services and tools, such as user interfaces and API's, are encouraged.

5) The framework for integrating the data and analysis methods across the proposed research and resource core components should include workflows to expeditiously collect, manage, integrate, archive, and analyze the data. This framework should be developed as a prototype to be shared with other U19 awardees to be further refined and developed with input from within this consortium of investigators and the NIH, as described in the cooperative agreement terms and conditions.

Data scientists and dedicated, software engineering support may be incorporated into the data science plan. Awards made under this FOA must share data using appropriate standards in an appropriate repository. For example, NIH HEAL Initiative Public Access and Data Sharing division (https://heal.nih.gov/about/public-access-data). Project-specific details will be established at the time of award. Budgets should include sufficient resources to prepare and disseminate data, as appropriate and consistent with achieving the goals of the program.

The following sections are not included in the page limit for Specific Aims, Innovation, Approach and Resource Sharing Plan for the Data Management Core :

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

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

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 (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.

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.

Provide descriptions for each proposed Resource Core.

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.

Note: Proposed use (if any) of Human Embryonic Stem Cell lines and Human Fetal Tissue should be described in each relevant research and core components, as well as in the overall integrated development plan 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 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.

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 proposal. Facilities and resources specific for individual Resource Core(s) should be detailed in this section.

• 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 on 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 Resource Cores should be detailed in this section.

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 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 (Resource Core)

Budget forms appropriate for the specific component (Resource Core) 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.

Research & Related Subaward Budget (Resource Core)

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

PHS 398 Research Plan (Resource Core)

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

Specific Aims: Provide a concise description of the goals of the Resource Core. List in priority order, the broad activities and services of the proposed Resource Core. In addition, state the Core's relationship to the U19's goals and how the Core relates to one or more of the Research Components in the application.

Research Strategy: Explain how the Resource Core will contribute to the research activities for one or more Research Components of the U19 application.

• Describe the facilities and/or services that will be provided, how the facilities and/services will meet the specific needs of each Research Component, a prioritization plan for providing the services, and plans for quality control. State the rationale for centralizing activities in a Resource Core rather than including them in individual Research Components.
• Where appropriate, describe how Resource Cores will be a point of contact for dissemination of technology, expertise, materials, animal models, and potential collaborations with other research investigative teams in research and administrative components. 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 on pain therapeutic development program and milestones.
• 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 participants, and do not duplicate information provided in the Biosketches or the Budget Justification.
• Resource Cores should not duplicate resources already available at the institution. Also, the activities of Resource Cores must not overlap with each other or with the activities of a Research Component.
• Describe any plans on collaborations or contracting for specific services to outside facilities (academia and/or industry), with justification and letters of support/service.

Significance: Describe the contribution of the Resource Core to the overall goals of the 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 Resource Core. Explain how these contributions will be made possible by team synergy beyond the otherwise independent Research Components.

Approach: Describe and offer evidence for the type of resources to be managed and disseminated for (and/or from) multiple Research Components and Resource Core(s) in the entire application. Describe and 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.

The following sections are not included in the page limit for Specific Aims, Research Strategy, Significance, Innovation and Approach for each Resource Core :

Vertebrate Animals: This should be included under each research component (if applicable).

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

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

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

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.

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.

Provide descriptions for each proposed research component. Out of the following five research type/activity components, a minimum of three are required.

Complete only the following fields:

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

Enter Human Embryonic Stem Cells in each relevant component.

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.

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 should be detailed in this section (under respective research components).

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

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.

• 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 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. 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.

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

Specific Aims: Briefly provide the biological rationale for the discovery and validation of the proposed novel 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 and target(s) proposed.

Research Strategy:

Innovation

• Describe the unique and innovative contributions that will be made by this project, 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 on therapeutic target discovery/validation.

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 and 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).
• Describe the overall strengths, weaknesses, and rigor of the preliminary data, including the data in published studies that are used to support the rationale for the proposed studies.
• Address potential shortcomings of the research plans, and strategies for dealing with them.
• Provide preliminary data and/or evidence in support of the proposed interdisciplinary nature and collaborative team-based approach for rigorous validation of therapeutic target(s).

Approach

• Provide details of plans to assure a rigorous experimental design for data and sample collection, analytical methods, statistical analysis or deconvolution of data leading to identification and validation of the proposed pain therapeutic target(s).
• The approach must include experimental verification and analyses to demonstrate a lack of abuse liability and on-addictiveness of the proposed 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. Also, describe how these might impact overall progress.
• Plan to ensure appropriate standardization of assays, samples, data and controls that are used in the process of identification and validation for the proposed target(s).
• Plans for experimental blinding, independent replication & reproduction of methodologies, assays, models and outcome measures in multiple laboratories in the project/program.
• 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.
• Discuss plans (if any) for collaborations with outside resources (academic facilities, contractors and/or industry), other than the Resource Cores in this U19 application.
• Discuss plans for addressing NIH rigor guidelines (https://grants.nih.gov/policy/reproducibility/guidance.htm; NOT-18-288) including blinding, randomization, authentication of key biological variables, etc.

The following sections are not included in the page limit for Specific Aims and Research Strategy for this Research Component :

Vertebrate Animals:

This should be included under each research component (if applicable).

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

References Cited:

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

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 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 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.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Separate Resource Sharing Plans for each research component are not required for this FOA.

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.

Required Other Attachments: Milestones (maximum 2 pages):

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. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. A discussion of the milestones relative to the progress of the specific research component, and the implications of successful completion of the milestones for the other research components should be included. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. The milestones proposed will be evaluated by scientific peer review, and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific review panel or NIH Program staff. A final set of approved milestones will be specified in the Notice of Award. 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.

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

NOTE: NIH-defined clinical trials are not permitted in this RFA.

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

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 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.

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 or 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 on 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 proposal. Equipment specific for individual Research Components and Cores should be detailed under the respective component sections.

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

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

The PD/PI is expected to devote a minimum effort of 1.8 person months. 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 this component.

Specific Aims: Briefly summarize the current gaps and challenges in animal models and/or outcome measures in the context of specific pain type(s)/indication(s) and/or disease-associated pain conditions with unmet needs for effective non-addictive pain management. Outline the major objectives and/or aims of the proposed animal model and/or outcome measure development and validation, research approach to achieve those, and technical questions to be answered, which would be critical to enhance the translatability of the proposed pain therapeutic target(s) and pain therapeutic(s) in the overall project/program.

Research Strategy:

1. Rationale

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.

Provide a comparative view on other/existing animal models and/or outcome measures for the specified pain types or pain conditions or disease-associated pain, discussing the advantages of the proposed animal models and/or outcome measures.

Provide the contribution of the proposed animal models and/or outcome measures towards enhancing the development of the proposed non-addictive pain therapeutic target and pain therapeutic in the entire project application.

2. Significance

Describe overall goals and the impact of developing animal model(s) 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 how the proposed animal model(s) and outcome measures would accelerate the validation and enhance the translatability of therapeutic target and non-addictive pain therapeutic.

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.

3. 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 in the context of type(s) of pain or pain condition(s) or pain-associated with specific disease(s) in humans.

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) to the development and validation of the proposed animal model and/or outcome measures of pain.

4. Supporting Data

Provide a clear outline of the preliminary data supporting the rationale for the scheme to develop animal model and/or outcome measure(s) for specific type(s) of pain or pain condition(s) or disease-associated pain in humans, as well as the rigorous validation of those.

Provide any preliminary data and rationale on the critical use of the proposed animal model(s) and/or outcome measure(s) for the validation and enhanced translatability of the proposed analgesic target(s) and non-addictive pain therapeutic agent.

Describe the overall strengths, weaknesses, and rigor of the preliminary data, including the data in published studies that are used to support the rationale for the proposed studies.

Address potential shortcomings of the research plans and strategies for dealing with them.

Provide preliminary data and/or evidence in support of the proposed multidisciplinary nature and collaborative team-based approach.

5. Approach

Provide details on the experimental design, approach and validation of the proposed development of animal model and/or outcome measures for pain.

Provide details on experimental validation of animal model and outcome measures in the context of condition/disease parameters, outcome measures and endpoints, in relation to specific type(s) of pain or pain condition(s) or disease-associated pain in humans.

Detail the plans to assure a rigorous experimental design for data and sample collection, analytical methods, statistical analysis or deconvolution of data leading to the validation of proposed animal model and/or outcome measures.

Describe and offer evidence for the feasibility of the proposed design, experiments, the advantages of any new methodologies, assays, outcome measures, potential pitfalls and alternative approaches for the project. Also, describe how these might impact overall progress.

Plan to ensure appropriate standardization of assays, samples and data that are used in the process of validation of the proposed development of animal model and/or outcome measures for pain, in the context of specific type(s) of pain or pain condition(s) or disease-associated pain in humans.

Plans for experimental blinding, independent replication & reproduction of methodologies, assays, models and outcome measures in multiple laboratories in the proposed 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.

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.

Discuss plans for addressing NIH rigor guidelines (https://grants.nih.gov/policy/reproducibility/resources.htm; NOT-18-288) including blinding, randomization, authentication of key biological variables, etc.

The following sections are not included in the page limit for Specific Aims and Research Strategy for this Research Component :

Vertebrate Animals:

This should be included under each research component (if applicable).

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

References Cited:

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

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 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 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.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Separate Resource Sharing Plans for each research component are not required for this FOA.

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.

Required Other Attachments: Milestones (maximum 2 pages):

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. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. A discussion of the milestones relative to the progress of the specific research component, and the implications of successful completion of the milestones for the other research components should be included. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. The milestones proposed will be evaluated by scientific peer review, and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific review panel or NIH Program staff. A final set of approved milestones will be specified in the Notice of Award. 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.

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

NOTE: NIH-defined clinical trials are not permitted in this RFA.

When involving human subjects research or clinical research, 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.

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 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.

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 or 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 on 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 proposal. Equipment specific for individual Research Components and Cores should be detailed under the respective component sections.

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

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

The PD/PI is expected to devote a minimum effort of 1.8 person months. 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 this 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:

1. Rationale

• 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 validation of specific therapeutic target and therapeutic agent(s), in relation to the type(s) of pain or pain condition(s) or pain-associated with specific disease(s).
• Provide strong justification for the proposed screening and/or rational therapeutic design for the validated therapeutic target, in relation to the type(s) of pain or pain 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.

2. Significance

• Describe overall goals and the impact of the proposed therapeutic agent, validation assays and screening approach, on specific pain type(s)/indication(s) and/or disease-associated pain conditions with unmet challenges in effective non-addictive pain management.
• 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.

3. 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.

4. Supporting Data

• Provide a clear outline of the preliminary data supporting the rationale for the proposed therapeutic type and design as a new/novel non-addictive pain therapeutic agent.
• Provide any preliminary data supporting the rationale for the proposed development and/or validation of in vitro and/or ex vivo assays for the validation and screening of the therapeutic agent.
• Describe the overall strengths, weaknesses, and rigor of the preliminary data, including the data in published studies that are used to support the rationale for the proposed studies.
• Address potential shortcomings of the research plans and strategies for dealing with them.
• Provide preliminary data and/or evidence in support of the proposed multidisciplinary nature and collaborative team-based approach.

5. 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 encouraged.
• 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.
• Discuss plans (if any) for collaborations with outside resources (academic facilities or contractors or industry), other than the Resource Cores in this U19 application.
• Discuss plans for addressing NIH rigor guidelines (https://grants.nih.gov/policy/reproducibility/resources.htm; NOT-18-288) including blinding, randomization, authentication of key biological variables, etc.

The following sections are not included in the page limit for Specific Aims and Research Strategy for this Research Component :

Vertebrate Animals:

This should be included under each research component (if applicable).

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

References Cited:

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

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 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 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.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Separate Resource Sharing Plans for each research component are not required for this FOA.

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.

Required Other Attachments: Milestones (maximum 2 pages):

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. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. A discussion of the milestones relative to the progress of the specific research component, and the implications of successful completion of the milestones for the other research components should be included. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. The milestones proposed will be evaluated by scientific peer review, and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific review panel or NIH Program staff. A final set of approved milestones will be specified in the Notice of Award. 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.

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

NOTE: NIH-defined clinical trials are not permitted in this RFA.

When involving human subjects research or clinical research, 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.

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 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.

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 or 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 on 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 proposal. Equipment specific for individual Research Components and Cores should be detailed under the respective component sections.

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

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

The PD/PI is expected to devote a minimum effort of 1.8 person months. 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 this 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:

1. Rationale

• Define and provide the rationale for the association of the pharmacodynamic markers to the type(s) of pain or 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.

2. Significance

• Describe overall goals and the impact of pharmacodynamic marker(s) and development approach proposed in relation to the current state and challenges in the field.
• This section should also 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.

3. Innovation

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

4. Supporting Data

• 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.
• Provide any preliminary data supporting the feasibility of the proposed studies.
• Describe the overall strengths, weaknesses, and rigor of the preliminary data, including the data in published studies that are used to support the rationale for the proposed studies.
• Address potential shortcomings of the research plans and strategies for dealing with them.
• Provide preliminary data and/or evidence in support of the proposed multidisciplinary nature and collaborative team-based approach.

5. Approach

• Describe plans for initial development of the pharmacodynamic markers. In that case, describe how decisions and plans will be made. Describe potential pitfalls and alternative strategies.
• Discuss optimization and validation related to feasibility, endpoint range, sensitivity, identification of confounding variables, etc.
• Discuss plans (if any) for collaborations with outside resources (academic facilities or contractors or industry), other than the Resource Cores in this U19 application..
• Discuss plans for addressing NIH rigor guidelines (https://grants.nih.gov/policy/reproducibility/resources.htm; NOT-18-288) including blinding, randomization, authentication of key biological variables, etc.

The following sections are not included in the page limit for Specific Aims and Research Strategy for this Research Component :

Vertebrate Animals:

This should be included under each research component (if applicable).

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

References Cited:

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

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 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 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.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Separate Resource Sharing Plans for each research component are not required for this FOA.

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). Separate plans for authentication of key biological and/or validation of key resources for other individual components are not required.

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.

Required Other Attachments: Milestones (maximum 2 pages):

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. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. A discussion of the milestones relative to the progress of the specific research component, and the implications of successful completion of the milestones for the other research components should be included. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. The milestones proposed will be evaluated by scientific peer review, and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific review panel or NIH Program staff. A final set of approved milestones will be specified in the Notice of Award. 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.

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

NOTE: NIH-defined clinical trials are not permitted in this RFA.

When involving human subjects research or clinical research, 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.

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

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Research Component: Efficacy and PK/PD 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 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.

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 or 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 on 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 proposal. Equipment specific for individual Research Components and Cores should be detailed under the respective component sections.

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

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

The PD/PI is expected to devote a minimum effort of 1.8 person months. 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: Efficacy and PK/PD Studies)

Introduction to Application: For Resubmission applications, an Introduction to Application is allowed for this 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:

1. Rationale

• Discuss how the pharmacokinetic studies will inform the efficacy studies.
• 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, HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional).
• Describe how the pharmacodynamic measures being used will provide added confidence that the potential therapeutic is working as intended.

2. Significance

• This section should also explain the contribution of this research component to the overall goals of the U19 program and how it will interact with and benefit from other components.

3. Innovation

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

4. Supporting Data

• 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 project milestones to be completed before initiation of this component.
• Provide any preliminary data supporting the feasibility of the proposed studies.
• Describe the overall strengths, weaknesses, and rigor of the preliminary data, including the data in published studies that are used to support the rationale for the proposed studies.
• Address potential shortcomings of the research plans and strategies for dealing with them.
• Provide preliminary data and/or evidence in support of the proposed multidisciplinary nature and collaborative team-based approach.

5. 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.
• Describe what features are important to measure in pharmacokinetic studies in the context of the pain indication.
• Propose plans for measuring target engagement, if possible, and evaluating PD/PK.
• Discuss how the efficacy studies will be done and how they are clinically meaningful. Where plans cannot be described in full detail, applications should discuss how results from other components will inform the approach.
• As needed, describe plans for early selectivity and safety studies.
• Discuss plans (if any) for collaborations with outside resources (academic facilities or contractors or industry), other than the Resource Cores in this U19 application. By the end of this research component, it is expected that applicants have a promising asset for RFA-NS-21-010, HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional).
• Discuss plans for addressing NIH rigor guidelines (https://grants.nih.gov/policy/reproducibility/resources.htm; NOT-18-288) including blinding, randomization, authentication of key biological variables, etc.

The following sections are not included in the page limit for Specific Aims and Research Strategy for this Research Component :

Vertebrate Animals:

This should be included under each research component (if applicable).

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

References Cited:

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

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 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 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.

All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

Separate Resource Sharing Plans for each research component are not required for this FOA.

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). Separate plans for authentication of key biological and/or validation of key resources for other individual components are not required.

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:

If there are modifications to Appendix instructions, (see https://grants.nih.gov/grants/guide/notice-files/NOT-OD-16-129.html), add the following text:

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.

Required Other Attachments: Milestones (maximum 2 pages):

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. Specific aims or a list of activities are not considered milestones because they would not provide decision-making goals. A discussion of the milestones relative to the progress of the specific research component, and the implications of successful completion of the milestones for the other research components should be included. The clarity and completeness of the outlined milestones with regard to specific goals and feasibility are critical. The milestones proposed will be evaluated by scientific peer review, and NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the scientific review panel or NIH Program staff. A final set of approved milestones will be specified in the Notice of Award. 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.

PHS Human Subjects and Clinical Trials Information (Research Components)

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 (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.

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.

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.

This initiative is not subject to intergovernmental review.

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.

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 field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. 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 DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management (SAM). 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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

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.

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.

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.

For this FOA, note the following review criteria:

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 & 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 will produce new and effective pain management strategies.

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), Cores (one numerical score), and Overall Milestones (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.

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. Furthermore, the reviewers will evaluate if the proposed integrated therapeutic development plan will be likely to generate a pain therapeutic asset 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. 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. 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. Is there synergy between the components that could not be achieved through individual NIH award mechanisms? Are there clear advantages of conducting the proposed therapeutic development plan as a collective team-based program rather than through separate efforts? Individual Components will be assessed for relevant strengths and weaknesses in the context of the entire integrated pain therapeutic development plan. The Final Impact Score need not reflect a cumulative enumeration of minor weaknesses but should reflect a balance of the quality of the individual components as well as the potential impact of the research on the treatment of pain.

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 and thereby to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the pain therapeutic development project proposed).

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.

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? Does the project address a critical barrier to progress in the development of safe and effective therapeutics to treat pain, with little or no addiction liability? If the goals of the project are successfully completed then how it will significantly impact pain management?

Further criteria 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 pain type(s)/indication(s) and/or disease-associated pain conditions?

Is there strong biological rationale for the rigorous plan for target discovery and validation justified? What are the strength and rigor of the target validation plan?

Are the rationale and appropriateness for the proposed development and validation of animal models and/or outcome measures justified in the context of pain type(s)/indication(s) and/or disease-associated pain conditions?

Are the rationales for the proposed therapeutic agent design, assay development and screening appropriate, rigorous and justified?

Are there rigorous demonstration of non-addictive properties and abuse liability of the proposed therapeutic target and agent?

Are the proposed efficacy and PK/PD studies of the therapeutic agent appropriate and rigorous?

Is there a plan to monitor the direct effects of potential therapeutic agents on the intended biological target using pharmacodynamic markers?

How likely is the proposed therapeutic development plan to advance the therapeutic asset to 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 proposed timeline?

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, and at an economy or scale?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the proposed 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?

Further criteria 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?

Does the team have extensive knowledge in pain biology and research activities needed for full target discovery, validation and drug development process? Does the team include 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 (Absorption, Disposition, Metabolism, Excretion).

In addition, the team should include those who can help the team plan for future therapy development beyond this RFA (such as later stage drug development experts, regulatory experts, clinicians).

Are the team management plans clear and appropriate?

Team Director: Has the proposed Team Director 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 Team Director demonstrated her/his ability to organize, direct, and administer a complex research and therapeutic development program?

Individual Team/Group Leaders: Have the leaders on the individual team/group demonstrated knowledge, experience and leadership in the proposed research component? Are there prior demonstrations of collaborative teamwork?

Is there evidence that the research team has been/will be able to work together effectively to accomplish the research proposed in the projects?

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?

Further criteria 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 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?

Does the project offer significant improvement over existing pain therapeutic approaches?

What is the innovativeness of the proposed pain therapeutic target and therapeutic agent identified & validated, in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project to develop non-addictive therapeutics to treat pain? Have 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?

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?

Further criteria specific to this FOA:

Is there a sufficiently developed interdisciplinary plan for the discovery and rigorous validation of the proposed pain therapeutic target and therapeutic agent 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? What is the strong likelihood that the proposed approach will demonstrate strong internal and external validity (face validity, constructive validity and predictive validity) of animal models and/or outcome measures in the context of related 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, in relation to the validated therapeutic target and related pain type(s)/indication(s) and/or disease-associated pain conditions? 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 efficacy and PK/PD characteristics robust? Will the PD and in vivo efficacy plan support future therapeutic development? Will it produce therapeutic agents that 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?

Are the plans for bioinformatic and statistical deconvolution of data sufficiently rigorous and feasible?

Will the proposed approach/plan on 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, in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

Is the timeline reasonable for the work proposed?

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?

For the Overall Milestone document, reviewers will provide their evaluation as exceptional, adequate, or inadequate (without any numeric scores). Reviewers will evaluate the integrated nature of overall milestones, in relation to the milestones of individual research and core 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. Note: For the milestone document under each research component, reviewers will provide their evaluation as exceptional, adequate, or inadequate (without any numeric scores). For all research components included in the application the following general review criteria should be followed:

Significance

What is the strength of the proposed research and development plan to validate effective targets and therapeutic agents for the treatment of pain with little or no abuse-liability, in the context of pain type(s)/indication(s) and/or disease-associated pain conditions?

Did the applicant address the rigor of the prior research that served as the key support for the proposed project?

If the aims of the research component are achieved, how it will co-ordinate and contribute to other research components, and to address the goals of the overall project, as well as in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers of the research component well suited to accomplish the goals of the proposed project?

Did the PD(s)/PI(s) propose plans for data management, statistical analysis, experimental design, and rigor for the specific research component.

Are there prior demonstrations of collaborative teamwork? Are the team management plans clear and appropriate?

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, as well as for the overall project?

Innovation

How is the proposed pain therapeutic target and therapeutic agent(s) innovative in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

What is the innovativeness 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?

Did the applicant address the rigor of the prior research that served as the key support for the proposed therapeutic?

Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed research component?

Have the investigators presented strategies to ensure a robust and unbiased experimental design, methodology, analysis, interpretation and reporting of results, as appropriate for the work proposed?

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 managed? And, how this would impact the other research components of the overall project?

Are adequate plans provided to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

How will the specific research component coordinate with other research components and cores to accomplish the individual and overall goals of the proposed program, in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

Is the timeline reasonable for the work proposed?

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 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 for specific research components:

Research Component - Validation of Therapeutic Target and Underlying Biology

Reviewers will evaluate the impact of this specific research component, validation of therapeutic target and underlying biology, on the likelihood of advancing the proposed pain therapeutic agents in this proposal for further optimization and accelerating subsequent translational and clinical trial processes.

Significance

Is there a strong biological rationale for the target discovery and validation plan? What are the strengths and rigor of the target validation plan?

Investigator(s)

Are the investigators knowledgeable and experienced in pain biology (such as pain pathways and circuits, relevant disease pathology, relevant pain and reward models)?

Have the PD/PI(s) and/or team demonstrated an ongoing record of accomplishments that have advanced the discovery and validation of pain therapeutic targets, underlying biological mechanisms, pathways and circuits, pain conditions and disease types?

Innovation

What is the innovativeness of the proposed target validation approach, and does it offer significant improvement over existing therapeutic target validation approaches?

Approach

If the proposed pain therapeutic target discovery and validation are in the early stages of development, will the proposed strategy establish feasibility, and will particularly risky aspects be managed? And, how this would impact the other research components of the overall project?

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

Reviewers will evaluate the impact of this specific research component, development and validation of animal models and/or outcome measures, on the likelihood of advancing the proposed pain therapeutic agents in this application for further optimization and accelerating subsequent translational and clinical trial processes.

Significance

What is the strength of the proposed development and validation plan for animal models of pain and/or pain outcome measures, in the context of pain type(s)/indication(s) and/or disease-associated pain conditions? What are the strength and rigor of the proposed plan?

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)?

Investigator(s)

Are the investigators knowledgeable and experienced in animal models of pain and/or pain and associated outcome measures in animal models?

Do the PD/PI(s) and/or team have experience and track record demonstrating human disease/pathology-relevant animal model development and validation, and/or validation of pain and associated outcome measures in animal models?

Innovation

How is the proposed animal model development & validation and/or outcome measure development & validation plan innovative, in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

What is the innovativeness of the proposed validation approach, and how such approach offers significant improvement over existing animal models and/or outcome measures for pain?

Approach

Is there a sufficiently developed interdisciplinary plan for the development and validation of the proposed animal model and/or outcome measures, in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

If the proposed animal model and/or outcome measures are in the early stages of development, will the proposed strategy establish feasibility and will particularly risky aspects be managed? And, how this would impact the other Research Components and Cores of the overall proposal?

Research Component - Assay Development, Screening and Early Optimization

Reviewers will evaluate the impact of this specific research component, assay development, screening and early optimization, on the likelihood of advancing the proposed pain therapeutic agents in this application for further optimization and accelerating subsequent translational and clinical trial processes.

Significance

What is the strength of the proposed therapeutic type and design, assay development, screening and early optimization work, in the context of pain type(s)/indication(s) and/or disease-associated pain conditions? What are the strength and rigor of the proposed plan?

Is there strong rationale for the therapeutic type, design, assay and screening proposed in relation to human pain type(s) or pain condition(s) or pain associated with disease(s)?

Investigator(s)

Are the investigators knowledgeable, experienced and do they have track record in assay development (in vitro, ex vivo and in vivo) and other critical aspects of drug discovery (such as screening, pharmacology, medicinal chemistry)?

Innovation

How are the proposed therapeutic type and design, validation assays, screening and early optimization plans innovative?

How do the proposed therapeutic type and assay & screening approach offer significant improvement over existing therapeutic types and validation/screening, in the context of related pain type(s)/indication(s) and/or disease-associated pain conditions?

Approach

Is there a sufficiently developed interdisciplinary approach for the proposed therapeutic type and design, validation assays, screening and early optimization plans?

If the proposed therapeutic type and design, validation assays, screening and early optimization plans are in the early stages of development, will the proposed strategy establish feasibility, and will particularly risky aspects be managed? And, how this would impact the other Research Components and Cores of the overall proposal?

Research Component - Discovery and Validation of Pharmacodynamic Markers

Reviewers will evaluate the impact of this specific research component, discovery and validation of pharmacodynamic markers, on the likelihood of advancing the proposed pain therapeutic agents in this proposal for further optimization and accelerating subsequent translational and clinical trial processes.

Significance

What is the strength of the proposed pharmacodynamic marker(s) discovery and validation towards informing the development of the proposed pain therapeutic?

Is there strong rationale for the association of the pharmacodynamic markers to the type(s) of pain or pain condition(s) or pain-associated with specific disease(s)?

Investigator(s)

Are the investigators knowledgeable, experienced and have track record in discovery and validation of pharmacodynamic markers and/or biomarker studies?

Innovation

How are the proposed pharmacodynamic marker discovery and validation research plan innovative?

How does the proposed pharmacodynamic marker discovery and validation approaches offer significant improvement over existing pharmacodynamic markers (if any)?

Approach

Is there a sufficiently developed interdisciplinary approach for the proposed plans on the discovery and validation of pharmacodynamic marker(s), in relation to the proposed therapeutic target, therapeutic agent and pain type(s)/indication(s) and/or disease-associated pain conditions?

If the proposed pharmacodynamic marker discovery and validation plans are in the early stages of development, will the proposed strategy establish feasibility, and will particularly risky aspects be managed?

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

Reviewers will evaluate the impact of this specific research component, efficacy and PK/PD studies, on the likelihood of advancing the proposed pain therapeutic agents in this application for further optimization and accelerating subsequent translational and clinical trial processes.

Significance

What is the strength of the proposed PK studies on the proposed therapeutic agent, and how does it will inform efficacy studies?

Is there strong rationale for the proposed efficacy studies in relation to the type(s) of pain or pain condition(s) or pain-associated with specific disease(s)?

What is the strength of the proposed PD measures on building the 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 investigators knowledgeable, experienced and do they have a track record in early drug development work (such as pharmacokinetics, pharmacodynamics, biomarkers, and in vitro ADME)?

Innovation

Is the proposed PK/PD study plan innovative?

Does the proposed PK/PD study approach offer a significant improvement over existing pharmacodynamic markers (if any)?

Approach

Is there a sufficiently developed interdisciplinary approach for the proposed PK/PD studies, in relation to the therapeutic agent and pain type(s)/indication(s) and/or disease-associated pain conditions?

Reviewers will assign one numerical score based on the following criteria (these criteria do not receive separate scores):

Leadership

Are the scientific qualifications, involvement, leadership and time commitment of the Leader(s) sufficient for the requirements of the proposed U19?

Administrative Management

Does the plan for the Administrative Core adequately address administrative management including fiscal and data operations?

Is the administrative and organizational structure clearly defined, and is it appropriate?

Is there evidence that clerical and administrative personnel and quality controls are in place for the smooth running and total integration of the U19?

Is there an adequate succession plan for U19 leadership?

Is there a sufficient plan for conflict management?

Planning and Evaluation

Are there clear descriptions of the functions and intended areas of required expertise? Does the Administrative Core clearly indicate how the collective operation of the whole program will be managed in a coherent manner?

Are there suitable descriptions of how the U19 will be evaluated during the project period, how milestones will be assessed, and how decisions to initiate changes will be made?

Does the Administrative Core section include plans for how the U19 team will handle potential problems and provide alternative

Integration of U19 Components

Does this Core adequately facilitate communication and integration across all Projects and Shared Resources Cores?

Communication with Data Management Core

Is there a a specific plan to collaborate with the designated Data Management Core, and NIH HEAL Initiative’s Data Sharing and Public Access requirements?

Reviewers will assign one numerical score based on the following criteria (these criteria do not receive separate scores):

Investigators

Are the qualifications, experience, and commitment of the Resources Core Director(s) and other key personnel adequate and appropriate for providing the proposed facilities or services?

Approach

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 plan for 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 like dissemination of resources, products and expertise to the greater research community?

What is the overall quality of the proposed Core services and are adequate quality control processes proposed for the facilities or services provided by the Resource Core (including procedures, techniques, and quality control)?

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?

Are the institutional support, equipment and other physical resources available adequate for the Core proposed?

Environment

Is the environment for the Resources Core appropriate to support the program as proposed?

Reviewers will assign one numerical score based on the following criteria (these criteria do not receive separate scores):

Investigators

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 & sharing facilities or services?

Approach

Does the Data Management Core provide a reliable service to the proposed U19 research components?

Does the Data Management Core provide a reasonable plan to optimally design a prototype data science framework for facilitating the workflow for data aggregation and analysis between the proposed Research Components? To what extent is the proposed data science framework development process incorporating risk to test new models, methodologies and assays to produce generalizable approaches for the development of safe and effective therapeutics to treat pain, with little or no abuse liability?

Does the Data Management Core proposal include a reasonable plan to follow and co-ordinate with the NIH HEAL Initiative Public Access and Data Sharing? Please visit the HEAL public access and data sharing policy at https://heal.nih.gov/about/public-access-data

Does the application offer a Data Management Core that will identify best practices, standards, tools, workflows, and computational infrastructures already in use by the research community?

Does the application provide robust and flexible data management and retrieval tools to function within the U19 project? Does the core integrate, where appropriate, predictive computational models and analytical tools for driving experiments?

Does the plan incorporate appropriate data science staff and software engineering support?

Have the investigators appropriately included plans to reuse existing best practices, standards, software tools, and computational infrastructures to manage their data, algorithms, and workflows?

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 prototype data science framework for this U19 project?

Environment

Is the environment for the Resources Core appropriate to support the program as proposed?

Are the institutional support, equipment and other physical resources available to the establishment and functioning of the proposed Resource Core and its investigators adequate?

Are there unique features of the Resource Core s institutional environment, infrastructure, or personnel that will contribute to the probability of success?

Are resources available within the scientific environment to support electronic information handling and data management?

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.

Study Timeline

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

Is the projected timeline feasible and well justified?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of milestones not met)?

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.

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.

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.

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.

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.

Not Applicable

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.

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.

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).

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .

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.

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

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:

• 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.
• Will receive a written critique.

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.

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.

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.

Awardees must comply with any funding restrictions described in Section IV.5. 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: Recipient 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 awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Awardee-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 awardee institution will comply with the NIH Guidance on Changes That Involve Human Subjects in Active Awards and That Will Require Prior NIH Approval.
• The awardee 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: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

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. This includes ensuring programs are accessible to persons with limited English proficiency. 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 and http://www.hhs.gov/ocr/civilrights/understanding/section1557/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. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please 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 further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please 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. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. 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.
• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please 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 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

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) 2 CFR Part 200 Administrative Regulations, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, NIH Grants Policy Statement (which implements the aforementioned HHS Regulations (45 CFR Part 75), 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 awardees is 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 awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and 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 efficacy and PK/PD 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 Publica Access and Data Sharing center. 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.

Awardees 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 & milestone meeting;
• Participating in the development and evaluation of trans-U19 activities under this program; and 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. The Program Official may also have substantial programmatic involvement as a Project Scientist.

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, awardees 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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees 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 $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, 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 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: support@grants.gov

Michael L. Oshinsky, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
Email: michael.oshinsky@nih.gov

Julia L. Bachman, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-7383
Email: julia.bachman@nih.gov

D.P. Mohapatra, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
Email: dp.mohapatra@nih.gov

Asif Rizwan, PhD
National Heart, Lung and Blood Institute (NHLBI)
Telephone: 301-435-0070
E-mail: asif.rizwan@nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: nindsreview@nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.nih.gov

Nina Hall
National Heart, Lung and Blood Institute (NHLBI)
Telephone: 301-827-2393
E-mail: nina.hall@nih.gov

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.