Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

No late applications will be accepted for this Notice of Funding Opportunity (NOFO).

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of 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

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose:

The purpose of this notice of funding opportunity (NOFO) is to support preclinical optimization and development of safe, effective, and non-addictive analgesic small molecule and biologic therapeutics to treat pain. The goal of the program is to accelerate the optimization and development of promising early therapeutic molecules and to facilitate readiness for the Early Phase Pain Investigation Clinical Network (EPPIC-Net) or other Phase II clinical studies. Applicants must have a promising biologic or small molecule starting point for optimization, robust biological rationale for the intended approach, and identified assays for optimization of the agent. The scope of this program includes optimization and early development activities, IND-enabling studies, pharmacodynamic/target engagement biomarker optimization and use, assembly and filing of an Investigational New Drug (IND) application, and Phase I clinical testing. The expectation is all projects will be entering first in human studies at the end of the project either through NIH contract or the grant. This is a milestone-driven phased cooperative agreement program involving participation of NIH program staff in the development of the project plan and monitoring of research progress.

Background:

This study is part of the NIH 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 the 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://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.

More than 25 million Americans suffer from chronic pain, a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an over reliance on opioids for pain despite their poor ability to improve function. This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative treatment options for pain are thus critically needed. As part of the mission of the HEAL Initiative, NINDS is working with other NIH Institutes and Centers to encourage the translation of basic research into new non-addictive pain treatments. This program announcement is intended to create a foundation to initiate the optimization and development of pain therapeutics and catalyze the development of partnerships between the academic and industrial sectors so that translational research in pain can flourish as a cooperative, iterative process leading to safe, effective, and non-addictive treatments for pain.

Through this Notice of Funding Opportunity (NOFO), the NIH offers researchers funding for drug discovery and development activities that can be conducted in their own laboratories. In addition, researchers have the opportunity to collaborate with NIH-funded consultants and contract research organizations (CROs) that specialize in medicinal chemistry and Good Manufacturing Practices (GMP) manufacturing, pharmacokinetics, biodistribution, protein and virus production, cell line and process development, QC release testing, toxicology, formulations development, and Phase I clinical studies.

The Program Director/Principal Investigator (PD/PI) will be responsible for conducting or leading all studies that involve disease- or target-specific assays, disease models, pharmacodynamic biomarkers and verification of the association between the therapeutic target or pathway and modulation by the therapeutic agent. A PD/PI with, for example, medicinal chemistry expertise and resources, may request funding to conduct structure-activity relationship (SAR) studies in their own lab but collaborate with contractors on in vitro ADMET, in vivo PK, drug manufacturing and IND-enabling toxicology studies. By contrast, a PD/PI with limited experience in drug discovery and development may opt to collaborate with NIH contractors for all activities not related to disease or target biology. Applicants may propose to conduct all drug discovery and development activities themselves or collaborate with NIH contractors on activities of their choice, however, it is expected that all staff be in place at the start of the grant if not utilizing NIH resources for the work.

For each project funded under this NOFO, the NIH will assemble a customized Lead Development Team (LDT). The LDT will be co-chaired by the PD/PI and a NIH consultant and will include members of the PD/PI's team, additional subject matter expert consultants, and NIH staff. The LDT will establish an overall strategy for the project, plan studies to be conducted by NIH contractors, and coordinate activities across different research sites.

Potential applicants are strongly encouraged to contact NIH Scientific/Research staff and participating NIH Institutes/Centers prior to preparing an application to discuss how they may best utilize NIH contract resources and whether their application fits the mission of a particular NIH IC. See also Webinar information under Section IV.7 below ("Other Submission Requirements and Information").

The NIH HEAL Initiative will require a high level of coordination and sharing between HEAL investigators. It is expected that NIH HEAL Initiative recipients will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings, including an annual HEAL Investigators Meeting, as well as other activities.

Scope:

This program announcement is specifically focused on providing the expertise, resources and funding to expedite the preclinical translational development process necessary to advance small molecule and biologic non-addictive therapeutics for pain to Phase I clinical testing. The program supports preclinical optimization and development of small molecules and biologics leading to the assembly and submission of an IND application and the implementation of Phase I clinical testing. The scope of this program excludes basic research, and projects focused on disease mechanism or mechanistic/mechanism of action studies of the intended therapeutic. Further, development of animal models, diagnostics, rehabilitation strategies, or therapeutic devices is nonresponsive as are Phase II and Phase III clinical studies. Finally, this program is intended to provide support of the early therapeutic development process; therefore, requests for support of only a single component of the process, such as a Phase I clinical trial or a GLP toxicology study are nonresponsive.

General Entry Criteria:

This is a two-phased program that is organized into a preparatory UG3 phase and an execution UH3 phase. Projects must enter at the UG3 phase of the program, and this phase must not exceed 2 years. Projects may enter the program at the Discovery or Development stage. All projects must have the ultimate end goal of assembling an IND application and beginning a Phase I study by the end of the project. For entry at the Discovery Stage, projects must have 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 for entry at the Development stage must have identified the candidate therapeutic; no further optimization will be supported, including back-up programs. 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 disease is required. Finally, the proposed therapeutic must have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use.

For the UG3 phase, this NOFO encourages projects proposing the following optimization activities:

Discovery

• Optimization using potency and efficacy screens
• Preliminary efficacy testing in appropriate animal models for pain
• Characterization and testing for ADME (absorption, distribution, metabolism, and excretion)
• Initial development or optimization of pharmacodynamic/target engagement biomarkers associated with the therapeutic target or pathway
• In vivo PK studies

Development

• Activities that fill in efficacy, in vitro non-GLP ADMET and in vivo PK gaps necessary to begin IND-enabling work

It is expected that by the end of the UG3 phase, recipients will have characterized and selected lead candidates that are ready for in vivo efficacy testing, though additional optimization may be necessary.

Progression from the UG3 award to the UH3 award will be based on administrative review. After successful completion of the UG3 phase, a project may proceed to the UH3 phase.

For the UH3 phase, the following are examples of in-scope development activities:

• Any further optimization activities as listed above, if needed
• Non-GLP toxicology studies (e.g. dose range finding toxicology)
• Pharmacokinetics (PK)
• Pharmacodynamic (PD) and related target engagement biomarker studies
• Formulation and stability studies
• Cell bank development and testing
• Gene expression level determination
• Biodistribution, tumorigenicity, and immunogenicity
• Process development
• Manufacturing of candidate therapeutic for IND
• IND-enabling safety pharmacology, genotoxicity, hERG and toxicology studies
• IND assembly and submission
• Phase I Clinical Studies

It is expected that at the end of the UH3 phase, recipients will have advanced their therapeutic to Phase I clinical testing.

Applications Not Responsive to this NOFO

Non-responsive applications will not be reviewed.

Applications will be considered nonresponsive of this announcement if they include:

• Screening to identify initial hit compounds
• Basic research and studies of disease mechanism
• Animal model development
• Development of diagnostics and therapeutic or diagnostic devices
• Studies directed beyond Phase I clinical testing
• Opioid sparing projects and projects targeting the mu-opioid receptor

Applications will be considered incomplete if they are missing any of the following:

• Go/no-go milestones
• A target product profile (TPP) table
• Activities for both the UG3 (preparatory) and UH3 (execution) phases
• A budget for each year of the proposed project, including both UG3 and UH3 phases
• An Intellectual Property (IP) plan attachment

Incomplete applications will be withdrawn. See section IV for instructions for each of these elements.

Additional Resources:

To support these projects, additional existing NIH resources may be made available to the applicant outside of this grant budget and are described below. Applicants are strongly encouraged to contact NIH staff to discuss these options. These resources include, but are not limited to the following:

NINDS

NINDS has established contract support for medicinal chemistry (including synthesis/SAR, computational chemistry and in vitro ADMET), biodistribution, protein and virus production, antisense oligonucleotide production, antibody production, cell line process and development, cell banking, pharmacokinetic studies, toxicology (GLP and non-GLP) and safety testing, drug formulation and GMP manufacturing, QC release testing and Phase I clinical studies. Contractors will provide data and reports in a format suitable for inclusion in an IND application. NIH also provides access to experts in therapeutics development through consulting contracts. Applicants must contact NINDS staff (contacts provided below) in order to utilize these resources and determine how to best leverage these as part of the application. To learn more, visit the HEAL PTDP webpage: https://www.ninds.nih.gov/current-research/trans-agency-activities/ninds-role-heal-initiative/pain-therapeutics-development-program-ptdp. As appropriate, applicants are encouraged to make use of the NINDS Common Data Elements (https://www.commondataelements.ninds.nih.gov/#page=Default).

NIDA

Pursuant to the development of analgesic medications without the liability of producing OUD following chronic use, the National Institute on Drug Abuse (NIDA) offers resources to conduct and support all phases of medications development. These programs include synthesis and preclinical evaluation of potential therapeutics, clinical trial design and execution, and preparing regulatory submissions. More information can be found at: https://nida.nih.gov/about-nida/organization/divisions/division-therapeutics-medical-consequences-dtmc/research-programs#PDP

Complementary Resources:

The NIH HEAL Initiative supports the following resources outside this funding opportunity that are also focused on the development of safe, effective, and non-addictive therapeutics to treat pain. Applicants that are interested in utilizing these complementary resources should contact PSPP or NCATS directly.

NINDS

PSPP: Within the NIH HEAL Initiative, NINDS created the Preclinical Screening Platform for Pain (PSPP) to identify and profile non-opioid, non-addictive therapeutics (small molecules, biologics, natural products, or devices) for pain. NIH staff assess the suitability of assets for acceptance into the PSPP on an ongoing basis. Within PSPP, lead assets are profiled for efficacy in models relevant to human pain conditions. Program staff work with the asset owner to plan the evaluation and direct the studies, which are performed by a contract facility at no cost to the PSPP participants. All evaluation is done under a defined participant agreement that outlines confidentiality and intellectual property protection. More information can be found at: https://heal.nih.gov/research/preclinical-translational/screening-platform

NCATS

Applicants are also encouraged to potentially develop collaborations with NIH National Center for Advancing Translational Sciences (NIH/NCATS) to access the state-of-the-art capabilities at the Center. If selected for a collaboration, NCATS will make available capabilities in support of HEAL initiatives. The capabilities include, screening and scalable production of relevant stem cells and quantitative high-throughput screening to identify promising compounds to be optimized by medicinal chemists. A more detailed description of the capabilities can be found at: https://ncats.nih.gov/heal/intramural-capabilities

Milestones:

Because therapeutics optimization and development are inherently high risk, it is expected that there will be significant attrition as projects progress. Annual go/no-go milestones must outline achievements necessary for the project to progress through the stages of therapeutic development and be tailored to the specific therapeutic and its intended disease indication. Proposed milestones will be used for measuring success in achieving each of the research plan key objectives. One or more milestone(s) must be used for each key objective. More details can be found in Section IV. Application and Submission Information.

Annual go/no-go milestones listed in the application will be finalized by a team consisting of the PD/PI and NIH program staff at the start of each project and updated as needed. If justified, future year milestones may be revised based on data and information obtained during the previous project period.

NIH program staff and leadership will conduct annual administrative reviews. At the end of the UG3 phase, NIH program staff and leadership will determine if the project will advance to the UH3 phase. Annual and UH3 transition administrative reviews will be based on:

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

Intellectual Property:

Since the ultimate goal of this program is to bring new pain therapeutics to the market, the creation and protection of appropriate intellectual property are significant considerations in designing research strategies and prioritizing projects for funding. Each applicant is expected to address intellectual property issues (including permission to utilize proprietary reagents or materials if applicable) related to the proposed therapeutics, with input from the institution's technology transfer officials, if applicable. Peer reviewers will be instructed to comment on the intellectual property landscape for each application. The project milestone plan may include commercialization milestones to protect and leverage intellectual property. Recipients of awards are encouraged to identify potential licensing and commercialization partners early in the therapy development process. The PD(s)/PI(s) is encouraged to work closely with technology transfer officials at their institution, if applicable, to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner. See Section IV.2. Other Project Information for details.

Implementation:

The program provides funding through the UG3/UH3 cooperative agreement mechanism. As a cooperative agreement, implementation will involve participation of NIH program staff in the planning and execution of the therapy-directed projects. The UG3 portion of the award is designed to support optimization research for the first 1-2 years. Based on the progress to milestones, only a limited number of projects will proceed to the UH3 phase for the remainder of the award period which will include final optimization and development leading to assembling an IND application and beginning a Phase I clinical study, either through the grant budget or through NIH contract resources outlined above.

IC-Specific Areas of Interest:

NINDS

NINDS is interested in the discovery and development of non-addictive therapeutics to treat pain disorders. These disorders include, but are not limited to headache, migraine, post-stroke pain, neuropathic pain, pain following traumatic brain injury, pain associated with spinal cord injury, pain associated with Alzheimer’s disease and other dementias, pain associated with Parkinson’s Disease and chronic overlapping pain conditions. NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes and provides supplemental guidance to NIH application instructions related to rigor and transparency ( https://grants.nih.gov/policy/reproducibility/guidance.htm ). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, e.g., by minimizing the risk of bias and transparently reporting methods and results as described at https://www.ninds.nih.gov/Funding/grant_policy . As stated in the NIH application guidelines, if previously published or preliminary studies do not meet these rigor standards to an acceptable degree, applicants should address how the current study design addresses the deficiencies. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity and transparency of experimental results.

NCCIH

NCCIH is interested in supporting neurotherapeutic research aimed at compounds and small molecules from natural products (e.g., cannabinoids, venoms, conotoxins, melatonin, microbial metabolites, etc.) that may be used or developed to modulate CNS-based symptoms with priority given to pain and pain related symptoms including sleep, stress, and mood disorders. Investigators are strongly encouraged to discuss their research plans with the NCCIH Scientific/Research contact prior to submitting their applications.

NIAAA

NIAAA is interested in developing novel non-addictive small molecules/biologicals to treat alcohol-associated pain conditions as well as treatment options for coexisting chronic pain and excessive alcohol use/AUD subjects.

NICHD

The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) is interested in supporting research aimed at developing novel, non-addictive pharmacotherapies for (1) more effective and safer treatment of pain in pediatric or obstetric populations; (2) the treatment of chronic gynecologic pain syndromes, including vulvodynia/vestibulodynia, chronic pelvic pain, dysmenorrhea, dyspareunia, and post-operative gynecologic pain; (3) the management of persistent pain in individuals with physical impairments and/or intellectual or developmental disabilities. Investigators are strongly encouraged to discuss their research plans with NICHD Scientific/Research contact prior to submitting their application.

NIDCR

The National Institute of Dental and Craniofacial Research (NIDCR) is interested in preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics to treat painful disorders of the orofacial region including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain, and other conditions. Investigators are encouraged to contact NIDCR program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.

NIDDK

The NIDDK encourages applications for research to develop therapies and technologies for pain conditions within the mission of NIDDK. Topics of special interest include, but are not limited to the pain associated with diabetic neuropathy; urologic chronic pelvic pain syndromes such as Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) and Chronic Prostatitis/Chronic Pelvic Pain Syndrome; urinary stone disease and post-ureteroscopy stent-associated pain; functional gastrointestinal and motility disorders such as gastroparesis and irritable bowel syndrome; inflammatory bowel disease; hepatobiliary diseases such as primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and biliary dyskinesia; and exocrine pancreatic diseases such chronic pancreatitis.

NCI

NCI is interested in applications for research to develop non-addictive pharmacotherapies for cancer- or cancer-treatment related pain. Pain conditions of interest include, but are not limited to: bone cancer pain, oral cancer pain, metastasis-related pain, post-surgical pain, radiation pain (including skin), aromatase inhibitor-induced arthralgia, chemotherapy-induced peripheral neuropathy, and immunotherapy-related pain.

NEI

NEI is interested in applications that advance the understanding of, and potential therapy for, ocular pain. Ocular surface disease, and dry eye disease, present a currently unmet need despite clear clinical significance. Moreover, photorefractive surgery procedures can result in discomfort and pain in patients who undergo these procedures. While most such patients report an eventual resolution of ocular pain symptoms some patients report longer-term chronic pain. The underlying biology that may account for such individual differences in outcomes is not well understood. NEI encourages applications under this NOFO that may advance non-addictive analgesic therapeutics development in this critical area. Ultimately, the goal is to identify and validate novel or repositioned non-opioid analgesics for corneal pain.

NHLBI

The NHLBI is interested in preclinical optimization and development of safe, effective, and non-addictive small molecule and biologic therapeutics for pain conditions within the mission of NHLBI. Topics of special interest include, but are not limited to the pain associated with blood diseases such as sickle cell disease, hemophilia, and deep venous thrombosis and heart diseases and lung diseases such as chronic obstructive pulmonary disease, cystic fibrosis related arthritis, lung transplantation where opioid dependency can be an issue, chronic pain from tube thoracostomy, severe chronic cough, and pain associated with mechanical ventilation in critical care patients.

NIAMS

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases. In the context of this NOFO, NIAMS is interested in the development of novel non-addictive small molecules/biologicals for more effective and safer treatment of pain in rheumatological, orthopedic, dermatological, bone and cartilage, and muscle diseases.

NIA

The National Institute on Aging (NIA) encourages applications that optimize and develop novel, efficacious, and safe non-addictive small molecule and biologic therapeutics with relevance across a variety of pain conditions in the context of healthy aging as well as diseases and conditions associated with advancing age including multimorbidity and Alzheimer’s Disease and Related Dementias. Important considerations for preclinical translational development include, but are not limited to, age-related changes in physiologic systems (e.g., renal, musculoskeletal, central nervous system) affecting drug metabolism and mechanisms of therapeutic action in the context of aging or aged organisms.

NIDA

Given that the misuse of opioid analgesics can result in OUD, the National Institute on Drug Abuse (NIDA) is interested in evaluating new pain medications, irrespective of pain modality, with low or no risk of abuse in order to prevent the initiation of OUD. Similarly, NIDA is interested in those types of medications with the goal of reducing the progression to more severe forms of OUD.

Other considerations:

Diversity

In addition to scientific diversity, applicants should strive to incorporate diversity in their team development plan. 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 NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. In spite of tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from groups that are underrepresented in the biomedical, clinical, behavioral, and social sciences. Please refer to Notice of NIH's Interest in Diversity NOT-OD-20-031 for more details.

Engaging People with Lived Experience and Other Collaborators:

People with lived experience (e.g., patients, patient advocates, caregivers, families, community leaders) have important insights that can improve meaningful outcomes, uptake of research findings, and health equity across the continuum of research from basic through implementation studies. The perspectives of other relevant collaborators (e.g., health service providers, payors, public health agencies, community-based organizations, biotech, pharma) can further improve research impact. The NIH HEAL initiative strongly encourages applicants to specify their plan for meaningful engagement of people with lived experience and other collaborators in the research process. Meaningful engagement will vary with the focus of the research but should at minimum ensure that researchers are connecting with relevant collaborators and incorporating their perspectives throughout the conception, implementation, and dissemination of the research. Meaningful engagement should address what the researchers will learn and how the people with lived experience and/or collaborators will benefit from the partnership. To promote health equity, as is relevant for the research proposed, it is recommended that at least two people with lived experience from populations who experience health disparities should be meaningfully engaged in these efforts (see this resource for more information in engaging people with lived experience: https://aspe.hhs.gov/lived-experience).

Clinical Trial Accrual:

This NOFO will support applications that include a series of milestones for completion of the clinical trial and provide contingency plans to proactively confront potential delays or disturbances in attaining the milestones. Continuation of the award is conditional upon satisfactory progress, availability of funds, and scientific priorities of the HEAL Initiative. If, at any time, recruitment falls significantly below the projected milestones for recruitment, NIH will consider ending support and negotiating an orderly phase-out of the award. NIH retains the option of periodic external peer review of progress. NIH program staff will closely monitor progress at all stages for milestones, accrual, and safety.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

All organizations administering an eligible parent award may apply for a supplement under this NOFO.

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

• Eligible Agencies of the Federal Government
• 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

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

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

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

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Mary Ann Pelleymounter, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

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

The following section supplements the instructions found in the How to Apply Application Guide and should be used for preparing an application to this NOFO.

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

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

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

The following additional instructions apply:

Facilities & Other Resources

All applicants must describe their institutions existing or planned infrastructure for bringing the compound or biologic to practical application (e.g., licensing for further drug development, managing IP, commercializing discoveries) consistent with achieving the program goals. 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 intellectual property) among institutions consistent with achieving the goals of the program. Applicants must clarify how IP will be shared or otherwise managed if there are multiple PD/PIs and institutions involved in the UG3/UH3-supported work, to ensure that IP remains unencumbered.

Other Attachments:

Intellectual Property (IP) Strategy

In an Other Attachment entitled IP Strategy , all applicants must include an Intellectual property (IP) strategy (2 pages maximum). Applicants are encouraged to prepare this section in consultation with their institutions' technology transfer officials.

For Discovery stage projects, applicants should describe any constraints of which they are aware that could impede their use of compounds, biologics, assays, or models for research purposes and/or commercial development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, similar compounds or therapies that are under patent and/or on the market, etc.) and how these issues would be addressed. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

For Development stage projects, applicants should describe their efforts to confirm that there are unlikely to be IP or other legal constraints that could block or impede development or commercialization of the proposed therapeutic. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

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

R&R Budget

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

A budget for each year of the proposed project, including both UG3 and UH3 phases, must be included. The UG3/UH3 award is intended to support studies to be conducted by the PD/PIs and associated personnel. The UG3/UH3 budget may not support drug development activities that the applicant proposes to conduct through NIH contracts. Equipment requests are allowed but not encouraged. Equipment requests should be considered only if the equipment is absolutely necessary to the success of the project and cannot be supported by any other means. This is likely to be a subject of negotiation before an award is made. Some budget requests may be made for the PD/PI's Institution to assemble and file the IND.

It is expected that the PD/PI will dedicate at least 20% level of effort (2.4 calendar months) to managing the proposed project. It is strongly recommended that potential applicants consult NIH staff about their anticipated budget in the early stages of preparing an application.

R&R Subaward Budget

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

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

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

Specific Aims:

The Specific Aims section must include Aims delineated for both the UG3 and UH3 phases.

Research Strategy:

The Research Strategy section must include the following subsections:

• Clinical Impact (Significance subsection)
• Biological Rationale (Significance subsection)
• Testing strategy (Approach subsection)
• Team management (Approach subsection)
• Innovation
• Table of proposed activities that provides the following information: Activity (optimization effort, assays, PK, etc.), throughput (e.g., samples per month), source (PD/PI lab, sub recipient , NIH Contractor, etc.), and advancement criteria. (Approach subsection) Clearly indicate which activities will be conducted by the PD/PI and associated personnel (i.e., funded by the UG3/UH3 award) and which activities will be conducted by NIH contract research organizations and/or consultants. Include experimental designs and justification for all studies that will be conducted by the PD/PI and associated personnel. Activities that will be conducted by NIH contractors need not be described in detail in the application since these will be planned after the award by the lead development team (LDT), but the overall goal of the activities must be provided.

Clinical Impact (Significance):

Each application generally must focus on one or more specific pain condition(s). The target patient population and intended use guide the design of the drug and of the preclinical studies, such as toxicology and formulation.

For the specific pain condition(s) proposed, briefly describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed condition indication.

• Briefly discuss available treatments, including all treatment modalities, and their limitations.
• Discuss how the proposed project relates to therapeutics development efforts underway in academia and industry.
• Provide a Target Product Profile (TPP), a table based on an FDA template that summarizes the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy (see guidance and example at http://neuroscienceblueprint.nih.gov/resources/target-product-profile.htm). Explain why the minimally acceptable and ideal parameters offer advantages over currently available treatments and how they relate to other therapeutics under development. Applications that fail to include a TPP will be considered incomplete.
• Briefly comment on the feasibility of conducting clinical trials toward the goals in the TPP (e.g., availability of patients for clinical trials).
• Describe the clinical expertise used to determine the goals of the drug development program and the clinical trial.

Biological Rationale (Significance):

• Describe the intended biological target/pathway and pathophysiology. Indicate whether evidence from multiple groups supports this is a compelling target for the condition.
• Provide the evidence that links this target to the particular pain condition proposed.
• Provide the evidence that altering target activity as proposed will give desirable outcomes for the proposed pain condition.
• Describe what is known about your agent(s) i.e., structure, function, identity, selectivity, bioactivity, potency, stability, production, etc.
• Define desired characteristics of an optimized candidate including but limited to quantitative characteristics for structure/identity, in vitro testing activities and in vivo pharmacology, specificity, selectivity, stability, etc. Explain how the desired quantitative characteristics are consistent with the desired TPP. Introduce what parameters of the agent(s) will be modified during the funding period.
• NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm). These recommended research practices include, where applicable, expressing clear rationale for the chosen model(s) and primary/secondary endpoint(s), describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. Investigators must indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as described above.

Testing Strategy (Approach):

In this section, applicants must elaborate on their research plans to achieve the ultimate goal of assembling an IND application and beginning a Phase I Clinical Trial by the end of the project. This can include a table indicating acceptable and ideal characteristics of the eventual lead therapeutic and a diagram of in vitro and in vivo screening funnels. Applications that fail to include activities for both the UG3 (preparatory) and UH3 (execution) phases will be considered incomplete.

Include details on efforts to ensure the experimental design is rigorous. This includes, but is not limited to justification for model systems, endpoints, minimal requirements for agent purity, route and timing of delivery, adequacy of controls and sample sizes, description of statistical analyses, inclusions of measures to reduce bias, and plans for replication, if applicable.

Milestones

Annual milestones to be used for measuring success in achieving each of the research plan key objectives must be provided. One or more milestone(s) must be used for each key objective. Applications that fail to include milestones will be considered incomplete.

• For each milestone, provide details on methods, assumptions, experimental designs, and data analysis plans.
• Specify the quantitative criteria for measuring success and related rationale. The quantitative criteria must be robust and be consistent with the state-of-the-art in the field. The quantitative criteria for success in the milestones will also be used for making go/no-go decisions.
• Specify the timeline for each milestone. There must be at least one milestone each year.
• NIH recognizes time sensitivity in developing therapeutics for patients who urgently need new or better treatment. If the research contains parallel activities from an independently funded, ongoing study prior or during the funding period, it must be noted with appropriate milestones.
• Specify and provide details on what other NIH resources may be utilized in the project.

Team management (Approach):

Team building is an essential step in the development of the overall plan for therapeutics development. Because translational research is intrinsically interdisciplinary, the plan will often involve cooperation among basic researchers, experts in preclinical development, and clinicians, and may include the participation of private-sector companies and voluntary organizations.

• Any collaborators, consultants, or subcontractors outside of NIH resources must be identified, no matter when during the conduct of the research activity the proposed interaction occurs.
• Describe how the team, including consultants, has already been engaged and a plan as to how they will continue working together over the course of the project (e.g., recurring team meetings, review and report of data across disciplines, decision-making, participate in meetings with NIH, communication, etc.).
• Explain how other NIH resources are or are not applicable to the project as appropriate.
• Explain the plan for collaboration to develop pharmacodynamic or target engagement biomarkers.
• Letters of support must be included and must not be generic, but instead indicate what has been contributed so far and what they expect to provide during the project to allow an evaluation of team engagement (see below).
• Indicate the willingness of the PD/PI(s) and key personnel to operate under the cooperative agreement terms and conditions outlined in section VI.2. of the NOFO.

Innovation:

Applications must explain how the project offers a novel approach to treating the proposed disease indication:

• If therapeutics that target the same molecule, pathway, or cellular process have been tested in clinical trials for the proposed disease indication, explain why the proposed approach would be expected to provide a benefit over those therapeutics.
• If similar drugs have been tested in clinical trials for the proposed disease indication, explain why the proposed drug would be expected to give significantly better clinical outcomes.
• Comment on the novelty of proposed approach, target, pathway, assays or models.

Letters of Support:

Applicants must include letters of support from consultants, contractors, and collaborators not provided through NIH.

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 must come from a high official within the private entity who has authority to speak on these issues.

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.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

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

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

• Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014)
• NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016).
• NIH encourages the use of data standards including the PhenX Toolkit (www.phenxtoolkit.org) (for example, see NOT-DA-12-008, NOT-MH-15-009)
• Data should be organized according to a standard model that is widely accepted within the field. An example for the clinical research studies would be the OMOP Common Data Model, which has also been successfully adapted for use with observational (including survey) studies more generally. In addition, the HL7 FHIR (Fast Healthcare Interoperability Resources) standard (NOT-OD-19-122) may facilitate the flow of data with EHR-based datasets, tools, and applications.
• NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards, as they are applicable (NOT-OD-20-146). Use of the USCDI can complement the FHIR standard and enable researchers to leverage structured EHR data for research and enable discovery. In addition to USCDI, OMOP, and FHIR standards for enhanced interoperability, investigators and data centers should align their data collection and management practices with recommended guidance emerging from the HEAL CDE and Data Ecosystem programs.

HEAL Public Access and Data Sharing Policy:

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing and immediate access to publications (https://heal.nih.gov/about/public-access-data). Guidelines for complying with the HEAL Public Access and Data Sharing Policy can be found at https://heal.nih.gov/data/complying-heal-data-sharing-policy. Resources and tools to assist with data related activities can be found at https://www.healdatafair.org/.

Publications resulting from NIH HEAL Initiative funded studies must be immediately publicly available upon publication.

• For manuscripts published in journals that are not immediately open access, authors should arrange with journals in advance to pay for immediate open access.
• Costs to ensure manuscripts are immediately publicly available upon publication should be included in budget requests.

The HEAL Initiative has additional requirements that must be addressed in the Data management and Sharing plan. All HEAL-generated data must be shared through the HEAL Initiative Data Ecosystem following HEAL’s compliance guidance (https://heal.nih.gov/data/complying-heal-data-sharing-policy). Specifically, HEAL applicants must include:

• Plans to submit data and metadata (and code, if applicable) to a HEAL-Compliant data repository (https://www.healdatafair.org/resources/guidance/selection) and follow requirements of the selected repository.
• Plans to register your study with the HEAL platform within one year of award (https://heal.github.io/platform-documentation/study-registration/).
• Plans to submit HEAL-defined study-level metadata within one year of award (https://github.com/HEAL/heal-metadata-schemas/blob/main/for-investigators-how-to/study-level-metadata-fields/study-metadata-schema-for-humans.pdf) and https://heal.github.io/platform-documentation/slmd_submission/).
• HEAL pain clinical studies must include plan to use HEAL core Common Data Elements (https://heal.nih.gov/data/common-data-elements). HEAL Initiative clinical studies that are using copyrighted questionaries are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials.
• To the extent possible, all other (non-pain) HEAL studies conducting clinical trials or research involving human subjects are expected to use questionnaires by the HEAL Clinical Data Elements (CDE) Program (https://heal.nih.gov/data/common-data-elements) if applicable and relevant to their research.
• Studies using CDEs, regardless of whether they are part of the HEAL repository, will be required to report which questionnaires are being used.
• To the extent possible, HEAL recipients are expected to integrate broad data sharing consent language into their informed consent forms.

HEAL has developed additional details and resources to fulfill these requirements (https://www.healdatafair.org/resources/road-map).

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) 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 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.

Note that if human subject work in the application is proposed to be conducted by NIH contracts (i.e. not part of the grant budget), you should answer No to the question Are Human Subjects Involved? , and you do not need to describe the clinical trial research plan in your application.

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.

For this NOFO, if you are proposing to perform a Phase I clinical study and are not proposing to utilize NIH contracts to conduct the study please code your application as Delayed Onset .

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

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

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

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). 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply Application Guide.

5. Intergovernmental Review (E.O. 12372)

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 Section 7.9.1 Selected Items of Cost.

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

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) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

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

See more tips for avoiding common errors.

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

Webinar

In order to learn more about this NOFO, visit our website to access past webinars: https://www.ninds.nih.gov/current-research/trans-agency-activities/ninds-role-heal-initiative/pain-therapeutics-development-program-ptdp

Applicants are required to follow the instructions for post-submission materials, as described in the policy

Section V. Application Review Information

1. Criteria

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 particular announcement, note the following:

The NIH is encouraging applications for translational research that may involve standard methodologies applied toward novel therapeutic approaches. Therefore, a project that does not necessarily employ novel methodologies may still be essential to advance the field.

Projects should not be penalized if the mechanism of action of the compound is unknown. While this may add to the risk, the increased risk may be counterbalanced by increased novelty.

Evaluation of the approach should emphasize the biological rationale, the potential for identifying a candidate with suitable properties, potential patient benefit, competitive landscape (novelty), and strengths/weaknesses of studies to be conducted by the PD/PI. Any additional resources (e.g., contracts or consultants) provided by NIH should be presumed to be industry standard.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project 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 project proposed).

Scored Review Criteria

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

Significance

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

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this NOFO:

• If the project is successful in meeting its proposed Target Product Profile, will it result in the development of safe, effective, and non-addictive small molecule and biologic therapies to treat pain as proposed in the application? What significant hurdles might the applicants not be considering?
• Scientific Premise: what is the robustness of the preliminary data provided in support of the target/intervention (can be molecular, cellular or system) for the intended pain condition? Were the unpublished and published data used in support of the application from rigorously designed experiments and are they relevant? For key experiments, did the application explain assumptions for power analysis, describe statistical analysis methods and criteria for data inclusion or exclusion, and detail the procedures of how blinding and randomization were conducted? Have key data been replicated? If not, evaluate plans under Approach section.
• What plans are needed for optimization to achieve the desired candidate profile specified if the starting agent(s) are not sufficiently robust? How will the parameters proposed for optimization result in a candidate consistent with the requirements stated in the TPP? What is the evidence of clinical feasibility?
• How suitable (e.g., the dynamic range, variability) and accessible are the essential assays (in vitro and in vivo) that will be used to optimize the agent(s) for the proposed use?

Investigator(s)

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

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific to this NOFO:

Based on the team management plan and letters of support, does the team seem capable of successfully completing the activities needed to obtain an optimized therapeutic candidate (taking into account how the members have already contributed to the design and proposed implementation of the project and how they will continue working together over the course of the project)? Has an appropriate multidisciplinary team been engaged? Is any expertise lacking? Are they appropriately leveraging NIH resources in a complementary fashion? Note that the work performed by the NIH contractors is assumed to be industry standard and not subject to review.

Innovation

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

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Specific to this NOFO:

How would the proposed drug be expected to give significantly better clinical outcomes than have been observed in previous efforts focused on the same target? How will it offer a safer, effective, and non-addictive small molecule or biologic therapy to treat pain?

Approach

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

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?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this NOFO:

How appropriate are the testing strategy and annual milestones for facilitating go/no-go decision-making and the eventual development of a lead therapeutic? How do the activities for the UG3 and UH3 phases of the grant contribute to the success of the project? What activities or milestones are lacking or could be further elucidated?

How rigorous is the experimental design proposed (including justification for model systems, endpoints, minimal requirements for agent purity, route and timing of delivery, adequacy of controls and sample sizes, description of statistical analyses, inclusions of measures to reduce bias)?

To what extent will the Team Management plan (e.g., collaborative arrangements, expertise, team engagement) contribute to the success of the project?

Environment

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

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Specific to this NOFO:

To what extent will features of the environment described in the Team Management Plan (e.g., collaborative arrangements, geographic diversity, institutional support) contribute to the success of the project?

Additional Review Criteria

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.

Specific to this NOFO:

Are there any intellectual property constraints that could potentially impede the development of the therapeutic and/or commercialization and achievement of the goals of the program? How does the Intellectual Property Strategy address potential legal constraints that could block or impede development or commercialization of the proposed therapeutic?

Study Timeline

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

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

Resubmissions

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

Renewals

Not Applicable.

Revisions

Not Applicable.

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

Specific to this NOFO:

Does the project appropriately leverage any existing NIH resources? Note that the work performed by the NIH contractors is assumed to be industry standard and not subject to review.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

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

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 NOFO. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke Council. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

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

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

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

Any application awarded in response to this NOFO 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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

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

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

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, including of note, but not limited to:

• Federal-wide Standard Terms and Conditions for Research Grants
• Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
• Acknowledgment of Federal Funding

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

If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the HHS Office for Civil Rights website.

HHS recognizes that NIH 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 NOFO.

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 2 CFR Part 200.206 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

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

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

The PD(s)/PI(s) will have the primary responsibility for:

• Determining experimental approaches, designing protocols, conducting experiments, and analyzing and interpreting research data for studies funded through this UG3/UH3.
• Serving as co-chair of the project Lead Development Team (LDT).
• With the LDT, assisting in the finalization of a project milestone plan at the outset of the project.
• Hosting a virtual or face-to-face meeting at the outset of the project and working with NIH staff to assist in the finalization of a project milestone plan.
• Presenting project updates (including raw data, when requested) in regular conference calls or other intermittent face-to-face meetings.
• Coordinating and participating with NIH staff in all aspects of scientific and technical management of the project, including the development of meeting agendas and minutes.
• Collaborating and communicating effectively with NIH service contractors to achieve project goals
• Implementing all scientific and policy decisions approved by NIH staff or an oversight committee.
• Submitting periodic milestone progress reports in a standard format, as agreed upon at the initiation.
• Preparing for administrative site visits as necessary, by NIH Program staff.
• Ensuring that all data, including primary and secondary screening data and assay protocols developed as a part of this project are deposited in a centralized relational database (NIH provided access) according to the timeline agreed upon by the LDT and the NIH Program Official and according to program policies.
• Recipients agree to participate in the overall coordination of NIH research efforts in translational research in pain. This participation may include collaboration and consultation with other translational research recipients , and the sharing of information, data, and research materials.
• Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• Working closely with their institution's technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner. Recipients are responsible for pursuing patent protection.
• Submission of the IND application and scheduling meetings with the FDA.
• Ensuring NIH staff and consultants on the LDT are included in all meetings with the FDA.
• Providing protocol, supporting clinical documents and regulatory documents required for administrative review prior to clinical trial.

NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

• Each project will have the support of one or more Project Scientists from NIH program staff who are assigned an administrative role for the target or pain condition being studied and have expertise in the implementation of NINDS cooperative agreement programs.
• The NIH Project Scientists will have substantial scientific/programmatic involvement during conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants.
• Providing the LDT with NIH consultants who can provide strategic and technical guidance.
• NIH Project Scientists will coordinate and participate in LDT meetings to discuss project status, planning, and implementation.
• NIH Project Scientists will facilitate collaboration and data exchange among the recipient , NIH-contracted consultants, and service providers.
• NIH Project Scientists will enhance the project progress by providing access to various NIH resources when appropriate.
• NIH Project Scientists will assist in the development of a finalized project milestone plan at the outset of the project and approve the final milestone language for incorporation into the award notice.
• NIH Project Scientists will be responsible for assessing the progress of the projects toward the accomplishment of specified milestones, and for recommending if further funds should be released to the project.
• The NIH Project scientists will serve as scientific liaisons among the recipient and other NIH program staff and report periodically on the progress of the project to NIH leadership.
• NIH Project Scientists will facilitate the establishment of contacts and collaborations between recipients and other persons or organizations whose participation will assist with the accomplishment of project goals. These persons or organizations may include the FDA, disease voluntary organizations, pharmaceutical companies, or research organizations that can provide essential services on contract.
• An important part of the NIH HEAL Initiative is the coordination of research efforts across different funding mechanisms and research structures, and coordination among efforts aimed at different pain conditions. NIH Project Scientists will have the primary responsibility for this overall coordination and provide a perspective on the priorities of the HEAL Initiative and other NIH translational programs.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. The assigned program director may also serve as an NIH Project Scientist.

Leadership of the Institute/Center funding the project will make decisions on project continuation with input from NIH staff and/or any established oversight committee, based on:

• Successful achievement of milestones
• The overall feasibility of project advancement, considering data that may not have been captured in milestones
• Based on emerging and published literature on competition for the disease indication and drug target
• Program priorities
• Availability of funds

Areas of Joint Responsibility include:

Project Lead Development Team (LDT): The LDT typically will be co-chaired by the PD/PI and an NIH-contracted drug development consultant and will include additional members from the PI's group, consultants and NIH staff. This team will collaboratively set strategic direction and guide the workflow for the project on an ongoing basis. The LDT will meet approximately every two weeks via teleconference to analyze and interpret data from the PD/PI and contracted laboratories and to formulate the subsequent experimental plan. The LDT will propose milestones and produce progress reports for evaluation by an External Oversight Committee and program staff as needed.

The members of this collaborative effort are all made aware of the requirement for confidentiality due to the intent of the recipient to pursue commercialization of any qualified outcomes. Contractors and consultants of NIH will be made aware of the confidential nature of work done under this collaborative effort. The handling and disposition of this confidential data and business privileged information may be covered by the Trade Secrets Act, 18 U.S.C. Section 1905.

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 Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient . This special dispute resolution procedure does not alter the recipient'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.

3. Data Management and Sharing

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

HEAL Data Sharing Requirements

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing (https://heal.nih.gov/about/heal-data-ecosystem). All HEAL Initiative award recipients, regardless of the amount of direct costs requested for any one year, are required to comply with the HEAL Public Access and Data Sharing Policy (https://heal.nih.gov/data/public-access-data) and NIH data sharing requirements. This includes complying with their approved data management and sharing plan, which must align with the HEAL-specific requirements outlined below and as described in HEAL’s compliance guidance (See Already Funded section: https://heal.nih.gov/data/complying-heal-data-sharing-policy):

1. Select a HEAL Compliant data repository (https://www.healdatafair.org/resources/guidance/selection)

• Data generated by HEAL Initiative-funded projects must be submitted to study-appropriate, HEAL-compliant, data repositories to ensure the data is accessible via the HEAL Initiative Data Ecosystem.
• Some repositories require use of specific data dictionaries or structured data elements, so knowing your repository’s requirements up front can help reduce the burden of preparing data for submission.
• HEAL-funded recipients must follow requirements for selected repository

2. Within one year of award, register your study with the HEAL platform (https://heal.github.io/platform-documentation/study-registration/)

• This process will connect the Platform to information about your study and data, including metadata, and identify the selected repository.
• HEAL requests initial registration within one year of award, with annual updates, and to be updated in accordance with any release of study data.

3. Within one year of award, submit HEAL-specific study-level metadata.

• Some of the required study-level metadata (https://github.com/HEAL/heal-metadata-schemas/blob/main/for-investigators-how-to/study-level-metadata-fields/study-metadata-schema-for-humans.pdf) will be auto-populated as part of the registration process.

4. Submit data and metadata (and code, if applicable) to HEAL-Compliant repository

• At the completion of the study and/or when prepared to make the final data deposits in the repositor ies) of choice, ensure your study registration (https://heal.github.io/platform-documentation/study-registration/) is complete.
• The NIH HEAL Initiative expects data sharing timelines to align with the NIH data management and sharing policy.

5. Additional Requirements for HEAL Initiative studies conducting clinical research or research involving human subjects.

These studies must meet the following additional requirements:

• HEAL Initiative trials that are required to register in clinicaltrials.gov should reference support from and inclusion in the HEAL Initiative by including the standardized terms the HEAL Initiative (https://heal.nih.gov/) in the Study Description Section.
• All new HEAL clinical pain studies are required to use core questionnaires required by the HEAL Clinical Data Elements (CDE) Program (https://heal.nih.gov/data/common-data-elements). Outside of the core questionnaires, studies should select questionnaires from among the repository of supplemental questionnaires that are already being used by other HEAL clinical pain studies. The program has created the CDE files containing standardized variable names, responses, coding, and other information for all of these questionnaires The program has also formatted the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C 794 (d); https://www.govinfo.gov/content/pkg/USCODE-2011-title29/html/USCODE-2011-title29-chap16-subchapV-sec794d.htm) which require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities.
  • Studies that wish to use questionnaires not already included in the HEAL CDE repository should consult with their program official and the HEAL CDE team. New questionnaires will be considered for inclusion in the repository on a case-by-case basis and only when appropriate justification is provided.
  • HEAL Initiative clinical studies that are using copyrighted questionaries are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program (https://heal.nih.gov/data/common-data-elements).
• To the extent possible, all other (non-pain) HEAL studies conducting clinical trials or research involving human subject are expected to use questionnaires by the HEAL Clinical Data Elements (CDE) Program (https://heal.nih.gov/data/common-data-elements) if applicable and relevant to their research.
• Studies using CDEs, regardless of whether they are part of the HEAL repository, will be required to report which questionnaires are being used.
• To the extent possible, HEAL recipients are expected to integrate broad data sharing consent language into their informed consent forms.

Additional details, resources, and tools to assist with data related activities can be found at https://www.healdatafair.org/.

All data collected as part of the NIH HEAL Initiative are so collected under a Certificate of Confidentiality and entitled to the protections thereof. Institutions who receive Data and/or Materials from this award for performance of activities under this award are required to use the Data and/or Materials only as outlined by the NIH HEAL Initiative, in a manner that is consistent with applicable state and federal laws and regulations, including any informed consent requirements and the terms of the institution’s NIH funding, including NOT-OD-17-109 and 42 U.S.C. 241(d). Failure to adhere to this criterion may result in enforcement actions.

This award is funded through the NIH HEAL Initiative (https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative). The requirements here include, but are not limited to, reporting requirements and data sharing are incorporated due to the need to respond to the national opioid public health crisis. As part of the response to this crisis, the NIH intends to maximize the availability of publications and the sharing of underlying data for NIH HEAL Initiative supported research projects. Award recipients are expected to cooperate and comply with all NIH data sharing including the complying with their approved data management and sharing plan, which must include the HEAL-specific requirements developed for this public health emergency during the project period.

Participation in Annual Investigator Meetings

The NIH HEAL Initiative will require a high level of coordination and sharing between investigators. It is expected that NIH HEAL Initiative recipients will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings, including an annual HEAL Investigators Meeting, as well as other activities.

Report and ensure immediate public access to HEAL-funded publications

As stated in the HEAL Public Access and Data Sharing Policy (https://heal.nih.gov/data/public-access-data), publications resulting from NIH HEAL Initiative funded studies must be immediately publicly available upon publication.

• For manuscripts published in journals that are not immediately open access, authors should arrange with journals in advance to pay for immediate open access
• Costs to ensure manuscripts are immediately publicly available upon publication should be included in budget requests

Prior to publication, HEAL expects investigators to alert their program officers of upcoming manuscripts to ensure coordination of communication and outreach efforts.

Award recipients and their collaborators are required to acknowledge HEAL Initiative support by referencing in the acknowledgement sections of any relevant publication:

This research was supported by the National Institutes of Health through the NIH HEAL Initiative (https://heal.nih.gov/) under award number [include specific grant/contract/award number; with NIH grant number(s) in this format: R01GM987654].

4. Reporting

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

• When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
• Recipients will be required to submit a Non-Competing Continuation Progress Report at the time of transition to the UH3 phase.
• Report and ensure immediate public access to HEAL-funded publications:
  • Publications resulting from NIH HEAL Initiative funded studies must be immediately publicly available upon publication.
    • For manuscripts published in journals that are not immediately open access, authors should arrange with journals in advance to pay for immediate open access
    • Costs to ensure manuscripts are immediately publicly available upon publication should be included in budget requests
  • Prior to publication, HEAL expects investigators to alert their program officers of upcoming manuscripts to ensure coordination of communication and outreach efforts.
  • Award recipients and their collaborators are required to acknowledge HEAL Initiative support by referencing in the acknowledgment sections of any relevant publication:
    • This research was supported by the National Institutes of Health through the NIH HEAL Initiative (https://heal.nih.gov/) under award number [include specific grant/contract/award number; with NIH grant number(s) in this format: R01GM987654].

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

The Federal Funding Accountability and Transparency Act of 2006 as amended (FFATA), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

Section VII. Agency Contacts

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

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

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

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

Mary Ann Pelleymounter, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Michael Oshinsky, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
Email: [email protected]

Charles Cywin, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Mark Egli, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: 301-594-6382
E-mail: [email protected]

Hye-Sook Kim, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-827-6910
Email: [email protected]

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

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

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

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

Melissa M Ghim, PhD
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: none
E-mail: [email protected]

Dana K Andersen, M.D
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: 410-868-0638
E-mail: [email protected]

Devon Oskvig, Ph.D.
National Institute On Aging (NIA)
Phone: (301) 496-9350
E-mail: [email protected]

Charles H Washabaugh, PhD
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-496-9568
E-mail: [email protected]

Edward Andrew Townsend
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: none
E-mail: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: (301) 496-9223
Email: [email protected]

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

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: [email protected]

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

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

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

Karen Robinson Smith
NEI - NATIONAL EYE INSTITUTE
Phone: 301-435-8178
E-mail: [email protected]

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

Diana Rutberg, MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: (301) 594-4798
E-mail: [email protected]

Christina Coriz
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: 301-594-8848
E-mail: [email protected]

Jeni Smits
National Institute On Aging (NIA)
Phone: (301) 827-4020
E-mail: [email protected]

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

Pamela G Fleming
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-480-1159
E-mail: [email protected]

Section VIII. Other Information

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

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