Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

National Eye Institute (NEI)

National Institute on Aging (NIA)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Dental and Craniofacial Research (NIDCR)

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

National Center for Complementary and Integrative Health (NCCIH)

National Cancer Institute (NCI)

Funding Opportunity Title
HEAL Initiative: Studies to Enable Analgesic Discovery (R61/R33 - Clinical Trial Not Allowed)
Activity Code

R61/R33 Exploratory/Developmental  Phased Award

Announcement Type
New
Related Notices
  • August 31, 2022- Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198.
  • August 5, 2022- Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189.
Funding Opportunity Number (FON)
RFA-NS-25-012
Companion Funding Opportunity
None
Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)
93.853, 93.121, 93.213, 93.865, 93.846, 93.866, 93.273, 93.847, 93.867, 93.395, 93.393
Funding Opportunity Purpose

This notice of funding opportunity (NOFO) aims to encourage research grant applications for initial translational efforts that will enable a drug discovery program for novel, non-opioid, and non-addictive treatments for pain. The program provides funding to develop and validate assays to support a distinct testing funnel and conduct screening efforts to identify and characterize potential therapeutic agents including small molecules, biologics, and natural products. Preliminary in vivo pharmacokinetic, pharmacodynamic, and efficacy studies may also be supported. The goal of this NOFO is to advance projects to the point where they meet the entry criteria for the Pain Therapeutics Development Program or other later-stage translational programs.

This NOFO is part of the NIH Helping to End Addiction Long Term (HEAL) initiative to accelerate the discovery and preclinical development of safe and effective therapeutics to treat pain with little or no addiction liability.

Key Dates

Posted Date
March 26, 2024
Open Date (Earliest Submission Date)
May 18, 2024
Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed Scientific Merit Review Advisory Council Review Earliest Start Date
June 18, 2024 June 18, 2024 Not Applicable November 2024 January 2025 April 2025
September 17, 2024 September 17, 2024 Not Applicable March 2025 May 2025 July 2025
January 28, 2025 January 28, 2025 Not Applicable July 2025 October 2025 December 2025
May 16, 2025 May 16, 2025 Not Applicable November 2025 January 2026 April 2026
September 17, 2025 September 17, 2025 Not Applicable March 2026 May 2026 July 2026
January 16, 2026 January 16, 2026 Not Applicable July 2026 October 2026 December 2026
May 15, 2026 May 15, 2026 Not Applicable November 2026 January 2027 April 2027
September 17, 2026 September 17, 2026 Not Applicable March 2027 May 2027 July 2027
January 15, 2027 January 15, 2027 Not Applicable July 2027 October 2027 December 2027

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.

Expiration Date
January 16, 2027
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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 How to Apply - Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply - Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply - 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.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

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

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

Through targeted research efforts, the NIH HEAL Initiative aims to accelerate the discovery and preclinical development of new medications to treat pain. The goal of this NOFO is to encourage initial translational efforts that will support and enable a drug discovery program by providing funds for the development and validation of assays and identification and characterization of potential therapeutic agents. It is expected that upon project completion, investigators will have well-validated assay(s) and/or potential therapeutic agent(s)  that meet the entry criteria for the HEAL Initiative’s Pain Therapeutics Development Program (PTDP) or other later-stage translational programs.

This NOFO is not specific for any one or group of pain conditions. Projects focused on acute pain, chronic pain, painful neuropathy, musculoskeletal pain, headache disorders, osteoarthritis, diabetic neuropathy, chemotherapy-induced neuropathy, eye pain, sickle-cell pain, post-surgical pain, cancer pain, visceral pain, obstetric pain, gynecologic pain, post stroke pain, myofascial pain, painful disorders of the orofacial region, pain co-occurring with substance use disorders, pain across the lifespan and in the context of aging, and other conditions will be considered. Projects that seek to identify novel therapeutics for underrepresented patient populations are also responsive for this NOFO. Input from people with lived experience on the therapeutic goals of the project is highly encouraged.

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 Scientific Meeting, as well as other activities.

Scope

This NOFO is intended to support early-stage translational activities including development and validation of assays, screening efforts to identify initial hits or bioactives, and in vitro characterization of potential analgesic agents. Therapeutic agents supported within this NOFO include small molecules, biologics (modalities such as peptides, proteins, oligonucleotides, gene therapies, cell therapies, and novel emerging modalities), and natural products. For the purposes of this NOFO, natural products are defined as extracts, chromatographic fractions, or isolated secondary metabolites derived from herbal, botanical, marine, microbial, or animal sources. Projects funded through this NOFO can include targeted or phenotypic assays (either cell-based or utilizing non-mammalian model organisms (e.g., D. rerio, C. elegans)). Except for limited studies of target deconvolution following phenotypic screening, projects designed for target identification are not covered under this NOFO.

Preclinical in vivo pharmacokinetic (PK), pharmacodynamic (PD), and efficacy studies may also be supported by this NOFO, however applicants will need to provide sufficient evidence demonstrating the proposed agent(s) or tool compound(s) have been sufficiently characterized to support interpretable in vivo studies (see Section IV.2 Research Strategy for details). For the purposes of this NOFO, in vivo efficacy measures reflect the effects of the therapeutic agent on endpoints that are closely tied to the desired clinical endpoints, but do not necessarily reflect target engagement. While PD measures may also reflect the effects of the therapeutic agent on endpoints closely tied to the desired clinical endpoint, they must also reflect in vivo target engagement. Note: Potential agents proposed for in vivo testing must be clearly described in the application. This NOFO is not intended to support projects that include both screening activities and follow-on in vivo testing of newly identified hits. 

This program is intended to support projects with a strong biological rationale for a druggable target, which can be a specific molecule(s), cell type(s), or molecular/cellular pathway(s) or circuits. Rationale for the chosen target should be supported by rigorous experimental evidence from in vitro, in vivo, and potentially clinical studies, confirming its role in the pathophysiology of a particular pain condition and supporting the hypothesis that modulating target activity will produce desirable therapeutic effects. Limited biology studies may be included as a part of applications to this NOFO, but only to fill specific gaps in an otherwise robust data package supporting a validated target. Applicants who are lacking this rationale are encouraged to consider other NIH HEAL Initiative opportunities (https://heal.nih.gov/funding/open) that support discovery and validation of targets that can be used to develop treatments that have minimal side effects and little to no abuse/addiction liability, such as, RFA-NS-22-034 “HEAL Initiative: Discovery and Validation of Novel Targets for Safe and Effective Pain Treatment (R01 Clinical Trial Not Allowed)”.

The goal of this NOFO is to advance projects to the point where they meet the entry criteria for the Pain Therapeutics Development Program (PTDP) or other later stage translational programs. PTDP projects are currently supported through RFA-NS-24-019, “HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain (UG3/UH3 Clinical Trial Optional)”. Entry criteria include the following: applicants must have a promising biologic or small molecule starting point for optimization, robust biological rationale for the intended approach, and scientifically sound assays for optimization of the agent. The scope of PTDP includes preclinical optimization and early development activities, Investigational New Drug (IND)-enabling studies, development of a pharmacodynamic/target engagement biomarker, assembly and filing of an IND application and Phase I clinical testing. While RFA-NS-25-012 (this NOFO) may also support preliminary in vivo studies for sufficiently characterized therapeutic agents, applicants with such agents are strongly encouraged to review the PTDP criteria and to consult with NIH Program staff when determining which funding opportunity is most appropriate.
 

Entry Criteria

  • Novelty: This NOFO seeks to apply new knowledge around targets, mechanisms, pathways, or therapeutic modalities. Projects should aim to develop non-addictive analgesics/therapeutics that are significant improvements over existing pain management strategies.
  • Biological rationale and preliminary data: Projects must have strong biological rationale for the intended approach. Preliminary data should reflect rigorous, well-designed experiments (either from the literature, data from other sources, or, when available, from investigator-generated data). Examples of the most critical elements for a well-designed study are summarized on the NINDS website: https://www.ninds.nih.gov/funding/preparing-your-application/preparing-research-plan/rigorous-study-design-and-transparent-reporting.
  • Relevance for therapy development: Projects should ultimately aim to discover novel therapeutic agents that can be advanced towards development of effective pain management strategies. Applications should be supported by a cogent rationale for how the proposed approach will result in new and promising non-addictive treatment(s) for pain.
     

Research Objectives

This initiative is primarily focused on assay development and validation, screening for identification of initial hits, and in vitro characterization of potential therapeutic agents. Example activities can include, but are not limited to:

  • Development and validation of assay(s) to support a distinct testing funnel, including but not limited to:
    • Assays to evaluate potency, specificity, selectivity, purity, identity, or stability of therapeutic agent(s).
    • Binding assays (e.g., radioligand, yeast-two hybrid, surface plasmon resonance, fluorescent polarization, biopanning, and enzyme-linked immunosorbent assay (ELISA)).
    • Assays for biophysical characterization of secondary or tertiary structure, conformational stability, aggregation, or oligomerization
    • Assays to evaluate cellular uptake, target engagement, transduction/infection, and downstream functional read-outs.
    • Optimization of assays for medium- or high-throughput screening (HTS).

A combination of assays may also be developed to demonstrate relevant biological activity when a single assay may not provide adequate measurement of overall potency due to a complex mechanism of action or multiple activities of a preliminary therapeutic agent.

  • Screening to identify initial hits, including application of biophysical and computational methods (e.g., virtual screening based on target structure, siRNA scanning).
  • Synthesis and in vitro characterization of a focused set of therapeutic agents. This could include for example, in vitro potency, selectivity, degradation products, or in vitro absorption, distribution, metabolism, and excretion (ADME).
  • Assessment of therapeutic agent properties using computational analysis and early physicochemical measurements, polar surface area, solubility, cell permeability and efflux.
  • Preparation of therapeutic agent(s) and confirmation of structure, sequence, purity, stability, or biological characteristics.
  • Development and selection of cell lines/vectors to produce bioactive agents (non-GMP/GLP).
  • Development of bioanalytical assays or detection methods to accurately quantify therapeutic agents (and potential metabolites).
  • Limited in vitro or ex vivo biology studies for validation of an agent’s mechanism of action or to fill specific scientific gaps that directly inform critical path activities in a drug discovery program.

Applicants should consider the role the assay(s) will play in the therapeutic discovery and decision-making process for the intended target and its relevance for treatments of specific human pain conditions/disorders. The proposed assays should also have sufficient throughput for iterative screening of potential therapeutic agents. Applications proposing screening activities should clearly identify the source and the size of the library to be screened. There is no minimum required size, but the library should be suitable for screening and sufficient to identify promising analgesic hits. Projects conducting computational work must include follow up in vitro characterization to at least confirm hit activity and potentially other key characteristics. Projects may also include preparation of a focused set of therapeutic agents based on the hits identified, and in vitro characterization thereof. Follow-on studies for phenotypic screening and/or screening of natural product libraries may include medicinal chemistry efforts, but these must be limited to efforts designed explicitly to elucidate mechanism of action of the compound (e.g., target pull down, click chemistry, etc.). For use and development of iPSC lines, please see NOT-NS-24-019. 

For projects with potential therapeutic agents or tool compounds: Applications including in vivo studies must have a potential therapeutic agent or tool compound in hand with sufficient evidence to support its use for the proposed studies (see Section IV.2 Research Strategy for details). Example activities can include, but are not limited to:

  • Pharmacokinetic studies to determine direct or indirect therapeutic agent levels. For some biologic modalities, traditional PK might not apply; such applicants should still aim to measure the kinetics and distribution as needed for therapeutic development. For gene and cell therapy, these can include characterization of gene copy numbers or tropism in tissues or cell engraftment.
  • Studies to confirm that therapeutic agent(s) reach and engage the target site (directly or indirectly) at a concentration that exceeds in vitro pharmacological potency over the desired period.
  • Studies to confirm selectivity of the therapeutic agent(s) or mechanism of action.
  • Pharmacodynamic and/or in vivo efficacy studies in suitable animal models including positive and negative controls, as appropriate.
  • Assessment of potential off target activities, addictive potential, or other liabilities (e.g., preliminary safety).
  • Limited biology studies for validation of an agent’s mechanism of action.
  • Validation and replication studies to confirm observed results.

Applicants proposing in vivo efficacy studies will be expected to provide strong rationale for the chosen model(s), outcome measures, and endpoints, and should consider the extent to which these have been rigorously validated. As pain is a multidimensional experience, applicants are highly encouraged to consider the sensory/discriminative, affective/motivational, and cognitive aspects of pain in the context of the chosen model(s). Preferred measures of pain in animals are those that are non-invasive, non-evoked, objective, and that permit a behavioral or functional assessment of pain and pain treatment outcomes.

Phased Award Mechanism and Transition to the R33 Phase

This NOFO uses the R61/R33 Phased Innovation Award mechanism in which the R61 phase is generally utilized to support preparatory or prerequisite activities that establish feasibility for execution of the R33 phase. The R61 and R33 phases cannot overlap in time. Applicants should propose R61 and R33 phase activities based on the stage of the project relative to identification of potential therapeutic agents and what is needed to inform downstream activities and/or further de-risk the project. Examples can include, but are not limited to:

  • Initial development, refinement, and validation of in vitro/ex vivo assays in the R61 phase with screening and hit confirmation/characterization in the R33 phase.
  • Assay optimization for increased throughput and a pilot screen in the R61 phase with a full-scale HTS in the R33 phase.
  • Small scale screening, synthesis, and/or bio- and physicochemical characterization of potential therapeutic agents in the R61 phase followed by cell-based functional and electrophysiology-based assays in the R33 phase.
  • For applications with predefined and well-characterized therapeutic agents, PK should be conducted in the R61 phase to inform dosage and timing of any in vivo studies in the R33 phase.

Transition from the R61 to the R33 phase is contingent upon the successful completion of proposed project milestones. For the purposes of this NOFO, milestones are quantitative goals used for measuring success that support go/no-go decision-making. Milestones should have timelines and quantitative criteria associated with them, and all milestones should be useful as a measure of progress toward the overall goal of the project. NINDS emphasizes the importance of the robustness and reproducibility of experimental results in evaluating progress. Specific Aims or a list of activities planned for each year are not considered milestones because they do not provide decision-making goals. Section IV includes additional information regarding project milestones. For frequently asked questions and milestone examples, please see https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/Funding-Programs-Researchers/IGNITE.

Prior to funding an application, NIH Program staff may contact the applicant to discuss the proposed milestones and any changes suggested by the review panel or Program staff. A final set of approved milestones will be specified in the Notice of Award.

Leveraging Existing Resources 

Additional information on guidance for assay development may be found in the online comprehensive Assay Guidance Manual (http://www.ncbi.nlm.nih.gov/books/NBK53196/), HTS assay protocols deposited in the PubChem BioAssay Database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pcassay) as well as the published literature. Applicants are also encouraged to take advantage of the resources provided by the NIH Molecular Libraries and Imaging Program (https://commonfund.nih.gov/molecularlibraries/index). One notable publicly available natural products library is managed by the National Cancer Institute (https://dtp.cancer.gov/organization/npb/introduction.htm).


Applications Not Responsive to this NOFO

Applications that include the following activities will be considered non-responsive and will be withdrawn and not reviewed:

  • Projects focused on target identification and validation, basic research, or studies of disease mechanism.
  • Animal model development.
  • Opioid sparing projects and projects targeting the mu-opioid receptor.
  • Projects consisting entirely of computational studies (i.e., virtual or in silico screening and/or characterization without any follow-on in vitro or in chemico testing).
  • Projects in the optimization or IND-enabling stage(s) or projects that include the following activities:
    • Hit-to-lead or structure-activity relationship (SAR)-driven chemistry to improve activity of agents against a target of interest or other drug-like properties.
    • Lead optimization to improve efficacy and/or pharmacokinetics.
    • Investigational New Drug (IND) enabling studies.

Such projects should consider applying to RFA-NS-24-019 HEAL Initiative: Non-addictive Analgesic Therapeutics Development [Small Molecules and Biologics] to Treat Pain.

  • GMP manufacturing or manufacture of therapeutic agents for clinical use.
  • Discovery and development of risk, detection, diagnostic, prognostic, predictive, or prevention biomarkers, although use of existing biomarkers is appropriate.
  • Discovery or development of devices, device/drug combinations, surgical procedures, or rehabilitation strategies.
  • Clinical research (see NIH definition: https://grants.nih.gov/grants/glossary.htm#ClinicalResearch)

Applications that are missing the following are deemed to be incomplete and will be withdrawn and not reviewed:

  • Activities for both the R61 and R33 phases with a clear demarcation of which activities are in the R61 phase and which are in the R33 phase, as described in Section IV.2.
  • Quantitative Go/no-go Project Milestones in the Research Strategy, as described in Section IV.2.
  • An Intellectual Property (IP) Strategy as an attachment, as described in Section IV.2.


Additional Considerations

Collaborations
Developing therapeutics requires a multidisciplinary approach. Investigators should form collaborations with those familiar with successful drug/biologic development (such as those from industry) as well as those familiar with what the desired end-product should look like (such as biostatisticians, technical experts, and clinicians). Applicants should consider how they will identify and foster relationships with potential licensing and commercialization partners early in the therapy development process once an award is made. PDs/PIs are expected to work closely with their institutional technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project.

In addition to scientific diversity, applicants should strive to incorporate diversity in their teams. 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).

Rigor and Transparency
NIH strives for rigor and transparency in all research it funds. For this reason, the NIH HEAL Initiative explicitly emphasizes and provides supplemental guidance to NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm) and provides additional guidance to the scientific community (https://www.ninds.nih.gov/funding/preparing-your-application/preparing-research-plan/rigorous-study-design-and-transparent-reporting). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, applicants should address how the current study design addresses the deficiencies in rigor and transparency. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity of experimental results.


IC-Specific Areas of Interest

National Institute of Neurological Disorders and Stroke (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-related dementias, pain associated with Parkinson’s Disease and chronic overlapping pain conditions. 

National Center for Complementary and Integrative Health (NCCIH)
NCCIH is interested in supporting research aimed at natural product-derived small molecules and biologics that may be used or developed as analgesics. The small molecules may include a secondary metabolite (i.e., natural products) inclusive of the array of chemical space derived from botanicals, microorganisms (e.g., commensal microbes), marine invertebrates, and venomous species. The biologics may include marcromolecular natural products such as peptides and toxins from marine and terrestrial plants, animals, and microbes, and microbial-based interventions such as probiotics. Investigators are strongly encouraged to discuss their research plans with the NCCIH Scientific/Research contact prior to submitting their applications. 

National Institute on Alcohol Abuse and Alcoholism (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.

National Institute of Dental and Craniofacial Research (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.

National Cancer Institute (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.

National Institute on Aging (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.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (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.

National Institute Arthritis and Musculoskeletal and Skin Diseases (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 identification and characterization 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.

National Eye Institute (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.

National Institute of Diabetes and Digestive and Kidney Diseases (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.

Pre-Application Consultation
Applicants are strongly encouraged to consult with HEAL Scientific/Research Staff early on during the planning for an application. This early contact will provide an opportunity to discuss and clarify NIH policies and guidelines, including the scope of project relative to the HEAL initiative mission and intent of this NOFO.

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

Section II. Award Information

Funding Instrument

Grant: A financial assistance mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
New
Resubmission

The OER Glossary and the How to Apply - Application Guide provides details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials.

Funds Available and Anticipated Number of Awards

The NIH HEAL (Helping to End Addiction Long-term) Initiative intends to commit an estimated total of $2,500,000 to fund 4-5 awards in FY 2025. Awards pursuant to this funding opportunity are contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget

Application budgets are limited to direct costs of $350,000 per year and need to reflect the actual needs of the proposed project.

Award Project Period

The total project period for a combined R61/R33 application submitted in response to this NOFO may not exceed three years, with no more than two years for the R61 phase and no more than two years for the R33 phase.

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

Eligible Organizations

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 including the NIH Intramural Program
  • 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
Foreign 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. 

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply - 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.

Eligible Individuals (Program Director/Principal Investigator)

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 How to Apply - 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 How to Apply - Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Julia L. Bachman
National Institute of Neurological Disorders and Stroke
Email: julia.bachman@mail.nih.gov

Page Limitations

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

Instructions for Application Submission

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.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply - Application Guide must be followed.

Other Attachments:

Intellectual Property (IP) Strategy (Required – 2 pages maximum):
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 of the application in consultation with their institution's technology transfer officials.

Applicants should describe the IP landscape and any known constraints 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.

If the applicant proposes using an agent(s) whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should include a letter (see letter of support) from any entities owning the IP indicating there will not be any limitations imposed on the studies or the product which would impede achieving the goals of the funding program.

Applicants should discuss future IP filing plans and should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved, consistent with achieving the goals of the program.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply - Application Guide must be followed.

R&R Budget

All instructions in the How to Apply - Application Guide must be followed.

A budget for each year of the proposed project, including both R61 and R33 phases, must be included.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Specific Aims: Within the Specific Aims section, include headers titled “R61 Phase Specific Aims” and “R33 Phase Specific Aims”. Under each header, state the specific objectives of the efforts, including the technical questions to be answered. Since the goal is therapy development, hypothesis testing, per se, may not be the driving force in developing such an application.

Research Strategy: The Research Strategy must include the following sections:

A. Significance
B. Approach
C. Innovation
D. Therapeutic Discovery Plan
E. Milestones and Timeline

Note: The HEAL Initiative strongly encourages applicants to form multidisciplinary teams that consist of academic/industry experts relevant to the research plan (i.e., biostatisticians, clinicians, drug development experts, technical experts). This multidisciplinary team should be able to define the goals of the research, outline specific gaps that need to be addressed during this funding period, and execute the research strategy. HEAL also strongly encourages applications from diverse teams of investigators, including PI/PDs and team members that are underrepresented in the biomedical workforce (defined in NOT-OD-20-031) as well as meaningful engagement of people with lived experience (see Section I of the funding opportunity for more information). Applicants should highlight elements of such collaborations within the research strategy.

A. Significance:
Applications must include a section that clearly outlines the biological and therapeutic rationale for the project, including: 1) a description of the biological rationale linking the proposed therapeutic target and the specific human pain condition(s) and/or disease of interest, 2) evidence for unmet medical need relevant to the targeted pain indication, 3) a brief description of the therapeutic landscape, including any pertinent history for therapeutic development in the disease area or for the proposed therapeutic target, 4) a description of why the target, therapeutic modality, and/or proposed plan are likely to have an impact on the unmet medical need, and 5) rationale supporting limited potential for addiction liability of the proposed therapeutic approach.

For applications proposing to conduct in vivo studies to assess initial PK, PD, preliminary efficacy, or safety: applicants MUST identify and clearly describe the therapeutic agent(s) to be tested and provide sufficient evidence such that reviewers can evaluate whether 1) the agent has been sufficiently characterized in vitro and 2) the physicochemical and/or biological properties of the agent are suitable and appropriate to justify in vivo efficacy testing. Evidence should include demonstration of the following, as appropriate for the therapeutic modality and intended target: confirmation of chemical identify, purity, stability, and biological activity (i.e., potency, selectivity, and specificity). Provide any additional evidence that demonstrates knowledge of the agent’s mechanism of action or intended impact on cell signaling pathways. Note: therapeutic agents should be characterized enough for meaningful initial preclinical proof of concept in an animal model. It is not required that compounds be at a lead stage. Hit-to-lead and lead-optimization work is supported in PDTP. Please see RFA-NS-24-019 for details.

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

B. Approach:

Describe the overall strategy, methodology and other considerations that will be used to accomplish the Specific Aims of the R61 and R33 phases. Applicants must describe both the R61 and the R33 phases. Clear demarcation of which activities are in each phase is required. The phases must not overlap in time.

Applicants must include detailed descriptions of their actual and proposed assays, including a definition of their intended purpose and data or plans to obtain data indicating the robustness, reliability, and throughput of the assay(s) (e.g., acceptable Z-factor or variability, and sufficient sensitivity, specificity, and dynamic range). Specify any reference standards, positive, and negative controls that will be used to assess assay behavior. Assays must be presented within the context of a screening and follow-up assay flow diagram or a distinct testing funnel for bioactive agent characterization. This can include, for example, a primary screening assay and downstream assays that are intended to verify specific activity of identified actives (e.g., counterscreens, orthogonal assays, selectivity assays, mode of action assays). Within the flow diagram or testing funnel, applicants must clearly indicate the process or criteria for selecting compounds/biologics at each stage or iteration.

Applications conducting a screen must include rationale for selection of the proposed library as well as provide sufficient characteristics of the library to justify its use against the proposed assay, such as composition, internal controls, storage conditions, and availability of compounds for follow-up testing. Applications must also outline the schema that will be used to follow up on hits to confirm activity, selectivity, and specificity as well as appropriate criteria for defining a useful active hit. Incorporating a pilot screen to verify suitability of the assay for future screening efforts is strongly encouraged, where appropriate (i.e., prior to initiating a large HTS).

Applications conducting in vitro characterization of a focused set of preliminary therapeutic agents must include a carefully designed plan for characterizing the agent(s) from a physicochemical, biophysical, and biological perspective, as appropriate for the therapeutic modality, intended target, and pain indication. Plans for establishment of a dose-response relationship to understand the concentration-dependent effects of the proposed therapeutic agent(s) are strongly encouraged.

For applications proposing to conduct in vivo studies to assess initial PK, PD, preliminary efficacy, or safety: Describe how the PK studies and/or PD studies will be used to inform subsequent efficacy testing and provide rationale for the proposed route and timing of therapeutic dosing. Where appropriate, include data or plans to obtain data indicating the sensitivity and specificity of any proposed analytical methods for quantitative analysis of the therapeutic agent. Applicants must also provide strong rationale for the chosen model(s) as well as evidence to support the robustness of any proposed PD measure(s), behavioral outcome measure(s) or pathophysiological endpoints used therein. This includes rationale for what would be considered a clinically meaningful effect size along with justification of sample size and statistical methods. 

An R61/R33 Phased Innovation Award application in translational research should have a strong biological rationale for the intended approach, supporting data from rigorously designed experiments, and proposed studies that exhibit methodological rigor. Furthermore, sufficient information should be available about study design, execution, analysis, and interpretation in order to assess the predictive value of the research. NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm  and additionally recommends the research practices described https://www.ninds.nih.gov/Funding/grant_policy. This will ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, 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, pre-planning analyses, and using appropriate quantitative techniques. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.

C. Innovation: 
Applicants must include a section addressing how the project offers a novel approach to treating the proposed disease indication. Novelty of the therapeutic strategy over what is currently available in the clinic or under therapeutic development by the field should be emphasized. Comment on the novelty of proposed approach, target, pathway, assays, or models.

D. Therapeutic Discovery Plan: 
At the completion of this project, it is expected that applicants will have made significant progress towards advancing projects to the point where they meet the entry criteria for the Pain Therapeutics Development Program (PTDP), or other later-stage NIH program or private investment.  Within this section, applicants must include a description of how knowledge gained from this work will support future therapeutic discovery efforts beyond the project period through to early clinical trials. As part of this consideration, attention should be paid to the intended patient population such that appropriate experiments (assays, targets, animal models, end point measures, routes of administration, etc.) are used in the current application. Applicants are strongly encouraged to review the PTDP entry criteria and associated funding opportunity RFA-NS-24-019 when preparing this section. More details can be found at https://www.ninds.nih.gov/current-research/trans-agency-activities/ninds-role-heal-initiative/pain-therapeutics-development-program-ptdp

E. Milestones and Timeline
Provide a timeline with specific project milestones for progression from the R61 phase to the R33 phase. Within the timeline, indicate when it is anticipated that essential components of the project (e.g., validation of assays, identification of screening hits, generation and in vitro characterization of therapeutic agents, pharmacokinetics studies (if applicable)) will be completed.

Transition from the R61 to the R33 phase is contingent upon the successful completion of one set of proposed project milestones. The application MUST include milestones that are clearly specified, well-defined, measurable, and include quantitative criteria for success to allow objective assessment of progress and support go/no-go decision making. Project milestones must be scientifically justified and appropriate for the proposed objectives of the application, therapeutic approach, and indication. Discuss the suitability of the milestones for assessing progress in the R61 phase and the implications of successful completion of these milestones for the proposed R33 phase. Milestones will be used to evaluate the application in peer review as well as in consideration of the awarded project for funding of non-competing award years. 

Letters of Support: Applicants should include letters of support from consultants, contractors, and collaborators.

  • If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.
  • If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.
  • If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) is in place. This letter should 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 How to Apply - 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 How to Apply - 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.

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:

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

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

PHS Human Subjects and Clinical Trials Information

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 How to Apply - 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 How to Apply - Application Guide must be followed.

Delayed Onset Study

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

PHS Assignment Request Form

All instructions in the How to Apply - Application Guide must be followed.

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. 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.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the How to Apply - 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 How to Apply - 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.

Applications Involving the NIH Intramural Research Program

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

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this NOFO. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

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

Intramural scientist cannot be a PI or MPI on an extramural award. 

Post Submission Materials

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 NOFO, note the following:

The HEAL Initiative 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.

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). The overall impact score should also reflect reviewers’ assessment of the likelihood for the research to advance projects to the point where they can meet the entry criteria for RFA-NS-24-019 under the Pain Therapeutics Development Program (PTDP), or other later stage translational programs. 

Key entry criteria for PTDP include having the following: 

  • a promising biologic or small molecule starting point for optimization, 
  • robust biological rationale for the intended approach, and 
  • scientifically sound assays for optimization of the agent.

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?

Specific to this NOFO: 

  • How strong is the biological rationale supporting the target and proposed therapeutic approach?
  • Does the application adequately describe the therapeutic landscape and unmet need relevant to the targeted pain condition(s)/indication(s)?
  • Will the project, if successful, produce results that can support future therapeutic discovery efforts? 
  • To what extent will the project, if successful, bring the investigators closer to a non-addictive analgesic/therapeutic that will be a substantial improvement over existing pain management strategies?
  • For applications proposing to conduct in vivo studies (i.e., initial PK, preliminary PD and/or efficacy studies): Has the proposed therapeutic agent(s) been clearly defined, well-described, and sufficiently characterized in vitro? Are the physicochemical and/or biological properties of the agent suitable and appropriate to justify in vivo testing?
  • Does the application adequately describe whether prior research that serves as the key support for the proposed project employed rigorous practices such as minimization of potential experimenter biases, robust experimental designs, transparent reporting of results and analyses, and careful interpretation? Does the application adequately describe ambiguity, weaknesses, or limitations in rigor of the prior research, if applicable?

Investigator(s)

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

Specific to this NOFO: 

  • Does the investigative team have sufficient pain biology expertise, and are they knowledgeable and experienced with the proposed biological target? 
  • Do the researchers have sufficient preclinical and drug discovery expertise relevant to the proposed therapeutic modality? 

Innovation

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

Specific to this NOFO: 

  • Does the project pursue novel but validated targets, mechanisms, pathways, and/or treatment approaches? 
  • Does the application make a compelling case that the strategy proposed is distinct from other therapeutic approaches and has a reasonable chance of success considering the landscape?

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?

Specific to this NOFO: 

  • Will the approach provide sufficient evidence that the assays developed are robust, reliable, and have sufficient throughput for their intended use? Will the assay(s) be able to support a distinct testing funnel for future analgesic discovery and development?
  • Is the process for selecting compounds/biologics at each stage or iteration of the testing funnel clear and appropriate?
  • If screening activities are proposed, is the library suitable? Is there a sufficiently developed and appropriate plan to follow up on hits to confirm activity, selectivity, and specificity?
  • If proposed, is there a sufficiently developed plan for the assessment of the therapeutic agent’s physicochemical, biophysical, and biological characterization?
  • If proposed, are the in vivo models, outcome measures, and endpoints appropriate for the proposed pain indication? To what extent are the efficacy studies appropriately informed by the PK and/or PD studies? What is the likelihood the approach will provide sufficient evidence to support a decision regarding further development of the therapeutic agent(s)?
  • Are the proposed experiments part of a well-thought-out and clearly defined therapeutic discovery plan? 
  • Does the proposed research incorporate adequate methodological rigor where applicable, including, but not limited to, clear rationale for the chosen model(s) and primary/secondary endpoint(s), clear descriptions of tools and parameters, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, preplanned analyses, and appropriate quantitative techniques? Do the applicants clearly indicate the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications?

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?

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.

Milestones and Timelines:

  • Are the project milestones clearly specified, well-defined, and associated with measurable, quantitative criteria for success that allow go/no-go decision-making?
  • Do the milestones allow the evaluation of progress in the R61 phase, and will successful completion of these milestones provide confidence that the investigator(s) will be able to successfully implement the R33 phase?
  • Are the milestones scientifically justified and appropriate to address the objectives of the application and therapeutic approach?
  • Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps? 

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

Additional Review Considerations

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

Intellectual Property (IP) Strategy
Are the following addressed as appropriate and consistent with achieving the goals of the program: Does the application outline any known constraints that could impede the therapeutic from being developed (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar therapies that are under patent protection and/or on the market, etc.) and how these issues could be addressed while achieving the goals of the program? If applicable, how strong is the applicant's IP portfolio/position (pertinent to the proposed project), and to what extent does the applicant have a reasonable strategy to protect its IP going forward? If IP will be shared among co-investigators, is a clear plan in place for sharing of the IP that will set the project up for success beyond this NOFO? 

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 policies and practices, 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 (NANDSC). The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 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. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

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.

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

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:

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 Laws and Regulations Enforced by 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 System for Award Management (SAM.gov) requirements. SAM.gov requires Federal agencies to review and consider information about an applicant in the designated integrity and performance system (currently SAM.gov) prior to making an award. An applicant can review and comment on any information in the responsibility/qualification records available in SAM.gov. NIH will consider any comments by the applicant, in addition to the information available in the responsibility/qualification records in SAM.gov, 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.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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. 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. HEAL award recipients must following all requirements and timelines developed through the HEAL Initiative Data Ecosystem (https://heal.nih.gov/about/heal-data-ecosystem), 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 submission 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.

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

6. 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.
  • 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.

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 Scientific Meeting, as well as other activities.

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.

  • Recipients will be required to submit a Non-Competing Continuation Progress Report at the time of transition to the R33 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 (Responsibility/Qualification in SAM.gov, formerly 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.

Application Submission Contacts

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: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-637-3015

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

Scientific/Research Contact(s)

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

Mark Egli, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: 301-594-6382
E-mail: megli@mail.nih.gov

Devon Oskvig, Ph.D.
National Institute on Aging (NIA)
Phone: (301) 496-9350
E-mail: devon.oskvig@nih.gov

Rachel Altshuler, Ph.D.
National Cancer Institute (NCI)
Telephone: 240-276-5873
Email: rachel.altshuler@nih.gov

Helena H. Ahn, PhD
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-3207
Email: helena.ahn@nih.gov

Charles H. Washabaugh, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5050
Email: Charles.Washabaugh@nih.gov

Patrick C. Still, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-682-1895
Email: patrick.still@nih.gov  

Dana K Andersen, MD
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: 410-868-0638
E-mail: andersendk@mail.nih.gov

Melissa M Ghim, PhD
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: none
E-mail: ghimm@mail.nih.gov

Houmam H Araj
NEI - NATIONAL EYE INSTITUTE
Phone: (301) 435-8166
E-mail: ha50c@nih.gov

Peer Review Contact(s)

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: (301) 496-9223
Email: nindsreview.nih.gov@mail.nih.gov

Financial/Grants Management Contact(s)

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

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: judy.fox@nih.gov

Kathleen Moy 
National Institute on Aging (NIA) 
Phone: 301.827.2856
E-mail: kathleen.moy@nih.gov

Sean Hine
National Cancer Institute (NCI)
Telephone: 240-276-6291
Email: hines@mail.nih.gov

Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: margaret.young@nih.gov

Erik Edgerton
NIAMS - NATIONAL INSTITUTE OF ARTHRITIS AND MUSCULOSKELETAL AND SKIN DISEASES
Phone: 301-594-7760
E-mail: erik.edgerton@nih.gov

Debbie Chen
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-594-3788
Email: debbie.chen@nih.gov

Elizabeth Gutierrez
NIDDK - NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
Phone: 301-594-8844
E-mail: gutierrezel@mail.nih.gov

Gabriel Hidalgo, MBA
NIDCR - NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
Phone: 301-827-4630
E-mail: hidalgoge@mail.nih.gov

Karen Robinson Smith
NEI - NATIONAL EYE INSTITUTE
Phone: 301-435-8178
E-mail: kyr@nei.nih.gov

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.

Authority and Regulations

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.

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