Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Heart, Lung, and Blood Institute (NHLBI)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

National Institute on Drug Abuse (NIDA)

Funding Opportunity Title
HEAL initiative: Pharmacotherapies to Reverse Opioid Overdose Induced Respiratory Depression Without Central Opioid Withdrawal (Target Validation and Candidate Therapeutic Development) (UG3/UH3 Clinical Trials Not Allowed)
Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type
New
Related Notices

None

Funding Opportunity Announcement (FOA) Number
RFA-HL-22-013
Companion Funding Opportunity
None
Assistance Listing Number(s)
93.838, 93.233, 93.273, 93.279
Funding Opportunity Purpose

This FOA invites applications for pre-clinical research to develop novel, mechanism-based pharmacotherapies to selectively reverse respiratory depression induced by opioids or opioid-sedative drug combinations (e.g., opioids plus alcohol, benzodiazepines, gabapentin). Two phases of pre-clinical drug development will be supported. Phase I (UG3): identification and validation of candidate lead ligands for established druggable targets in relevant animal models or human cells/tissues; or characterization of newly-discovered targets with plans for development of druggable ligands; Phase II (UH3): development of hit to lead therapeutic candidate pipelines based on Phase I validation studies, with clearly prioritized assays and quantified go/no go milestones. Anticipated pitfalls and alternative strategies in case of a no go event are expected to be clearly outlined. Applicants who already have lead candidates may propose “critical path” and de-risking studies for the lead and backup molecules during UG3 and Investigational New Drug (IND) enabling studies during UH3. It is expected that applications will include a research plan for both Phases I and II based on systematic and quantifiable metrics delineating key milestones and go/no go decision points pertinent to moving the project closer to FDA approval and / or de-risking potential liabilities. Phase I research will be based on candidate ligands or targets that have been identified and require additional validation and optimization (i.e. not discovery). Phase II extends up to addressing preclinical functional outcomes, toxicology, and pharmacokinetics needed to support an Investigational New Drug (IND) application, and should include a product development plan appropriate to supporting an IND filing. This FOA targets that portion of therapeutic development between ligand or target validation and IND filing. Specific Phase I and II milestones will be formalized pre- and post-award and will serve as a schedule of performance expectations to maximize the output from each phase of study. Milestone performance will be a major, but not the only consideration factor in determining which applications will be selected to transition from Phase I to Phase II. Multi-disciplinary, multiple PI teams combining expertise in respiratory neurobiology, opioid pharmacology and pre-clinical drug development are strongly encouraged. Collaborations between academia, pharma and small businesses may be considered. This FOA is intended for pharmacotherapeutic development. Projects proposing device and model development or validation, elucidation of biological mechanisms, population-based epidemiology, or human subjects research will not be considered responsive to this FOA and will not be reviewed (examples of non-responsive topics are listed below). Reversal of respiratory depression, without inducing generalized opioid withdrawal, or interfering with analgesic effects, addresses a critical medical need for better strategies to couteract the life-threatening respiratory effects of opioids and opioid-sedative combination overdoses.

Key Dates

Posted Date
September 30, 2021
Open Date (Earliest Submission Date)
November 03, 2021
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 Scientific Merit Review Advisory Council Review Earliest Start Date
December 03, 2021 Not Applicable Not Applicable April 2022 May 2022 July 2022

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

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
December 04, 2021
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 SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

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. Funding Opportunity Description

Objective

This FOA invites applications for pre-clinical research to develop novel, mechanism-based pharmacotherapies to selectively reverse respiratory depression induced by opioids or opioid-sedative drug combinations (e.g., opioids plus alcohol, benzodiazepines, gabapentin). Two phases of pre-clinical drug development will be supported. Phase I (UG3): identification and validation of candidate lead ligands for established druggable targets in relevant animal models or human cells/tissues; or characterization of newly-discovered targets with plans for development of druggable ligands; Phase II (UH3): development of hit to lead therapeutic candidate pipelines based on Phase I validation studies, with clearly prioritized assays and quantified go/no go milestones. Anticipated pitfalls and alternative strategies in case of a no go event are expected to be clearly outlined. Applicants who already have lead candidates may propose “critical path” and de-risking studies for the lead and backup molecules during UG3 and Investigational New Drug (IND) enabling studies during UH3. It is expected that applications will include a research plan for both Phases I and II based on systematic and quantifiable metrics delineating key milestones and go/no go decision points pertinent to moving the project closer to FDA approval and / or de-risking potential liabilities. Phase I research will be based on candidate ligands or targets that have been identified and require additional validation and optimization (i.e. not discovery). Phase II extends up to addressing preclinical functional outcomes, toxicology, and pharmacokinetics needed to support an Investigational New Drug (IND) application, and should include a product development plan appropriate to supporting an IND filing. This FOA targets that portion of therapeutic development between ligand or target validation and IND filing. Specific Phase I and II milestones will be formalized pre- and post-award and will serve as a schedule of performance expectations to maximize the output from each phase of study. Milestone performance will be a major, but not the only consideration factor in determining which applications will be selected to transition from Phase I to Phase II. Multi-disciplinary, multiple PI teams combining expertise in respiratory neurobiology, opioid pharmacology and pre-clinical drug development are strongly encouraged. Collaborations between academia, pharma and small businesses may be considered. This FOA is intended for pharmacotherapeutic development. Projects proposing device and model development or validation, elucidation of biological mechanisms, population-based epidemiology, or human subjects research will not be considered responsive to this FOA and will not be reviewed (examples of non-responsive topics are listed below). Reversal of respiratory depression, without inducing generalized opioid withdrawal, or interfering with analgesic effects, addresses a critical medical need for better strategies to counteract the life-threatening respiratory effects of opioids and opioid-sedative combination overdoses.

Background

The NIH HEAL Initiative:This study 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/.

Novel pharmacotherapies that selectively counteract opioid overdose-induced respiratory depression (OIRD) are urgently needed to address a dramatic increase in opioid related US deaths in recent years. Existing opioid receptor antagonists trigger acute withdrawal, interfere with analgesic properties, and may lead to renarcotization. Opioid antagonists are also insufficient to fully reverse respiratory depression produced by high-affinity, long-acting synthetic opioids, requiring ventilation to be protected for extended periods and until the synthetic opioid is cleared. Opioids are frequently combined with other substances that suppress respiration, including alcohol, benzodiazepines and gabapentin. Pharmacotherapies for OIRD are needed that counteract the effects of opioids, as well as opioid-sedative combinations. Respiratory depression is an unpredictable risk for millions of individuals using prescribed and/or illicit opioids and who are susceptible to overdose from recreational or medical use. Opioid-induced respiratory depression poses significant challenges for the management of patients with both chronic pain and compromised breathing conditions such as COPD, asthma, and sleep apnea. The development of pharmacotherapies, particularly alternatives to opioid receptor antagonists, to counteract opioid overdose and safeguard respiration are urgently needed to prevent opioid overdose deaths, and to enhance opioid-based strategies for pain management. Pharmacotherapies to stimulate respiration, without inducing generalized opioid withdrawal, or interfering with analgesic properties address the ultimate goal of developing better medical countermeasures for management of deleterious consequences of synthetic illicit, as well as prescription opioids.

Investigators interested in submitting applications to this FOA are strongly encouraged to contact NIH scientific staff (see Section VI, Agency Contacts) to discuss proposed aims and FOA requirements well in advance of the application receipt date.

Scientific Direction

Target validation/product development program

This program will be administered as a cooperative agreement with phased (UG3/UH3) and milestone-driven research plans. The cooperative agreement format will allow close interaction between PI/PDs and an NIH Project Scientist to monitor progress, negotiate goals, and address roadblocks which are common in therapeutic development, e.g., making changes to development plans, re-negotiating Phase II milestones based on Phase I results, or closing out non-viable targets, products or programs. This program will support up to 5 Phase I projects, with a maximum of 3 transitioning to Phase II. Therefore, transition to Phase II is not automatic or guaranteed.

The UG3 Phase I will support rigorous validation of candidate lead ligands or targets, with pre-established quantifiable metrics (i.e., milestones) for evaluating and selecting candidates to transition to product development. The UH3 Phase II will support pre-clinical development of therapeutic candidates validated in Phase I. Quantifiable milestones for each selected ligand or target are exptected to include, but are not limited to specific benchmarks for moving product development from candidate selection to IND application enabling status, and critical go/no go decision points (i.e., decision tree) to determining when to continue or discontinue development of a particular target or product. Specific Phase I and II milestones will be formalized pre and post-award and will serve as a schedule of performance expectations to maximize the output from each phase of study. Milestone performance will be a major consideration in evaluating scientific progress, but will not guarantee approval to transition from Phase I to Phase II. In addition to performance metrics, the evaluation of progress will take into consideration the quality and strength of data included in progress reports, the feasibility of proposed Phase I ligands or targets for therapeutic development, and the potential of the selected products and product development plan to be IND application enabling. All proposed studies will be expected to lead toward US regulatory approval of a specific therapeutic product(s).

This FOA is intended to support applications that provide a description and timeline of the specific studies proposed, noting that the cumulative data collected by the conclusion of the project may not be sufficient for an IND without additional research. However, the application is expected to include a clear rationale for how the proposed research to be conducted will be IND enabling.

PI/PD(s) will be required to submit annual progress reports and make a formal presentation to NIH staff of their UG3 results and plans for Phase II transition. A committee of NIH staff with appropriate expertise will be convened to evaluate progress and viability as projects seek to transition from the UG3 to UH3 phase. PI/PD(s) should plan for a (1) monthly virtual meeting to discuss their individual project with the NIH PO and PS, (2) bi-annual meeting involving all funded PI/PD(s)of this RFA (one of which may be in person in the Washington DC Metro area), and (3) annual two-day HEAL PD/PI meeting (virtual or in-person in the Washington DC Metro area).

Landmark advances in understanding the development, organization, and homeostasis of ventilatory control mechanisms present immediate opportunities to move candidate targets (e.g., neurotransmitters and modulators, signaling pathways, receptors/ion channels, and molecular/genomic markers) and ligands (e.g., small molecules, biologics, natural products) into early pre-clinical testing for validation (Phase I of this FOA) and therapeutic development (Phase II of this FOA). Selected examples of potential targets include, but are not limited to the following:

  • The central respiratory pattern generator (RPG) in the ventral and rostral medulla triggers the fundamental drive to breathe (i.e., inhale and exhale). A network of RPG excitatory and inhibitory neurons, glial cells, receptors and signaling mechanisms (e.g., amino acids, serotonin, purines, cytokines, growth factors) has been delineated, providing candidate targets for validation and therapeutic development of countermeasures for opioid-induced respiratory suppression.
  • Chemoreceptors located in the brainstem and peripheral carotid bodies rapidly detect changes in O2, CO2, and pH, and trigger RPG compensatory breathing responses via an array of modifiable cation channels (BK, TASK, TRP), gasotransmitters (e.g., CO, H2S), and intracellular signaling pathways (e.g., hypoxia inducible factor [HIF]). Targets to enhance or maintain chemoreceptor sensitivity and efferent responses offer a therapeutic entry point to protect breathing during opioid-induced suppression.
  • Defined respiratory networks in the brainstem pontine region (e.g., apneustic and pneumotaxic centers) drive the breathing rhythm by relaying chemosensory and lung mechanoreceptor input to the RPG, and represent potential targets for protection of breathing in response to opioids.
  • Molecular signatures (e.g., expression of phox2b, dbx1 and other genes) identified in brainstem rhythm generating neurons reveal specific cell types to prioritize as potential targets to sustain respiratory rhythm in the presence of opioids.
  • Peripheral/autonomic mechanisms controlling muscle activity and sensory processes underling respiratory effort and gas exchange serve as potential targets to improve respiratory drive, upper airway patency and oxygenation to counteract opioid effects on breathing.


UG3 Phase I (2 years): Target validation and lead development

The aim of Phase I is to rigorously validate the best potential pharmacotherapeutic candidate lead ligand(s) or target(s) to improve central or peripheral control of breathing and gas exchange in the presence of opioids or opioid-sedative combinations (e.g., opioids plus alcohol, benzodiazepines, gabapentin). Potential ligands or targets include orthosteric and allosteric modulators of neurotransmitter release and function, as well as modulators of receptors, ion channels, signaling pathways, genes, or other biological mechanisms. Targets might include central or peripheral control mechanisms (e.g. respiratory rhythmogenesis, hypercapnic or hypoxic control), control of thoracic and / or laryngeal musculature, or mechanisms that interfere with pulmonary gas exchange such as impacts on endothelial function and induction of arterial-alveoli oxygen gradients by pulmonary edema. An array of in vivo, in vitro, and computational approaches may be considered to validate candidate ligands and targets. Potential strategies include, but are not limited to cell lines (animal and/or human), in vivo assays or ex vivo tissue preparations of respiratory circuits, genomic technology (e.g. knockouts/mutants, siRNA), electrophysiology, optogenetic models, imaging, and chemical probes/pharmacology). For applicants with previously-established lead molecules, studies may focus on de-risking programs such as establishing efficacy and appropriate pharmacokinetics (PK) and metabolite profiles in animal models, and / or target selectivity, geno- and cardiotoxicology, and backup molecule development. Phase I research applications are expected to include a screening tree that prioritizes the importance of various assays and contains defined, quantifiable milestones and go/no go values for each point in the tree. Such a hierarchical structure is essential to evaluate progress toward validation and selection of the most promising OIRD countermeasure target(s) / lead candidates for progressing into Phase II.

Examples of target validation research include, but are not limited to:

  • in vivo or ex vivo assays that provide a comprehensive understanding of target function, bioactivity, and which are specifically related to respiratory rhythmogenesis and chemoreception in animal models and human cells/tissues
  • Assessment of target distribution and localization in situ
  • Use of animal models for demonstration of direct respiratory and chemosensory effects of target activity, and level of manipulation needed to affect breathing and/or chemoreception
  • Assessment of target activity in appropriate cellular system(s)
  • Development of in vitro systems to determine target activity, ideally with potential for conversion to high throughput format

 Examples of hit to lead ligand validation research include, but are not limited to:

  • Characterization of the affinity, efficacy and selectivity of hit ligand at the confirmed relevant target
  • Establishment of the physical and chemical characteristics that limit the hit ligand’s value (such as solubility, chemical and metabolic stability) and other “druggability” issues such as barrier permeability and survival in the digestive system
  • Rational or combinatorial chemistry program to seek analogues which may improve one or more of the identified weaknesses that may limit development potential of the original hit ligand
  • Identified analogues that could be subject to similar suitability assays as the original hit molecule in an iterative manner, in order to select a lead candidate for Phase II development

Examples of research that would not be responsive for this program include:

  • Research which does not state a previously identified target(s), biological pathway, or system with relevance to reversing opioid-induced respiratory depression
  • Research which does not achieve the programmatic goals of reversing OIRD
  • Research which does not state appropriate milestones to monitor progress of the project
  • Hypothesis-driven initial mechanistic discovery research that lacks medication development
  • Research on opioid receptor antagonists or targets that interfere with analgesia or induce/exacerbate opioid withdrawal
  • Research focused on targets for device development


UH3 Phase II (3 years): Therapeutic product development

The purpose of Phase II is to accelerate pre-clinical development of novel therapeutic products to reverse OIRD and hypoxia. Phase II will support research designed to advance the Phase I project towards preparation of an IND application. Studies include IND-enabling studies such as identifying appropriate species for toxicology studies, establishing and validating bioanalytical methods, formulation development, and pharmaceutical chemistry and manufacturing development. This FOA seeks applications that include a product development plan describing how the research will enable IND filing. Phase II research protocols are expected to include specific and quantifiable milestones and go/no go decision points with alternative strategies in case of a no go event. Research activities for therapeutic development include, but are not limited to:

  • Identifcation of compounds that modulate a validated target for respiratory rhythmogenesis or chemosensory function and assessment of their pre-clinical proof of principle and efficacy, via the desired route of administration
  • Evaluation of the selectivity, functionality, and "drugability" of compounds that modulate a validated respiratory/chemosensory target to select a lead candidate
  • Determination of the disposition and bioavailability (i.e., absorption, metabolism, distribution, and elimination) of a lead candidate therapeutic
  • Evaluation of safety by performing in vitro toxicology studies and/or in animal model(s)
  • Evaluation of the chemical properties and manufacturing specifications of the candidate drug substance (e.g., purity/stability, polymorph screening)
  • Formulation development
  • Manufacture and scale up process development of lead candidate
  • Pharmacokinetic studies of drug product and metabolic profiling in proposed species for toxicology

Examples of research that would not be responsive for this program include:

  • Product development not based on validated pharmacotherapeutic targets identified in Phase I of the application
  • Research involving human subjects
  • Research which does not state appropriate milestones to evaluate progress and include go/no go decision points and alternative strategies to determine feasibility of developing the pharmacotherapeutic
  • Projects that do not propose a product development plan that will lead to an IND filing
  • Research on products with existing INDs for reversal of opioid-induced respiratory depression

In addition to scientific diversity, applicants should strive to incorporate diversity in their team development plan. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. Please refer to Notice of NIH's Interest in Diversity NOT-OD-20-031 for more details.

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

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

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed
New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?

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

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. NIH intends to commit total costs of up to $3,850,000 to fund up to 5 phase I awards in FY2022. NIH intends to commit up to $4,620,000 to fund up to 3 phase II awards in FY24. Future year amounts will depend on annual appropriations.

Award Budget

Application budgets may request up to $500,000 direct costs to support Phase I activities per year and up to $1,000,000 direct costs per year in Phase II. Investigators are encouraged to request what is well-justified for their research program.

Award Project Period

The maximum project period of the combined UG3 and UH3 phases is five years, with up to 2 years for the UG3 phase and up to 3 years for the UH3 phase. The UG3 and the UH3 cannot be awarded in the same fiscal year. The scope of the proposed project should determine the requested project award period.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

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

Other

  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
Foreign Institutions

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

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

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

Required Registrations

Applicant organizations

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

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov – Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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 his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, 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 FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Page Limitations

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

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

If proposed, provide justification for the need of third party (e.g. pharma, small business) involvement.

SF424(R&R) Senior/Key Person Profile

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

Desscribe the team's expertise in respiratory neurobiology, opioid mechanisms, and pre-clinical drug development. Describe the team's track record of pharmacotherapeutic development research.

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Describe the goals of IND-enabling pharmacotherapeutic validation and development research for pharmacotherapeutics to selectively counteract opiate induced breathing depression.

Research Strategy: Provide a research plan for both Phase I (UG3, ligand or target validation) and Phase II (UH3, product development) of the proposed project. The research strategy must include a justification for the selection of ligand or target mechanism(s) and must describe how the ligand(s) or target(s) are mechanism-based and clinically relevant to counteracting opioid induced respiratory depression. Discuss the desired (i.e., reversing OIRD) and non-desired (i.e., blocking analgesia, triggering withdrawal) effects of the candidate ligand or target and product.

The application must include specific and quantifiable milestones the researchers expect to achieve by the end of the UG3 phase (labeled as UG3 Milestones), as well as milestones for the UH3 phase (labeled as UH3 Milestones). Milestones should be specific, measurable, results-focused, and time-bound metrics, and must identify critical go/no go decision points (i.e., decision tree and timeline) identifying critical stages of ligand or target validation and product development. Alternative strategies must be described to address no go events. Applications must include a Product Development Plan describing how the project will lead to an IND filing/application. It is understood that the proposed milestones for the UH3 phase may be revised based on results from the UG3 phase.

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

NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing.Consistent with the HEAL Initiative Public Access and Data Sharing Policy (https://heal.nih.gov/about/public-access-data), and in line with the new NIH Policy for Data Management and Sharing (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-21-013.html), all applications, regardless of the amount of direct costs requested for any one year, are required to include a Data Management and Sharing Plan outlining how scientific data and any accompanying metadata will be managed and shared. The plan should describe data types, file formats, submission timelines, and standards used in collecting or processing the data. It is expected that data generated by HEAL Initiative-funded projects will be submitted to study-appropriate domain-specific or generalist repositories in consultation with the HEAL Data Stewardship Group to ensure the data is accessible via the HEAL Initiative Data Ecosystem.

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

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

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

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

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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 Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

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

Post Submission Materials

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

Section V. Application Review Information

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.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

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

Significance

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

Specific to this FOA:

To what extent are the proposed pharmacotherapeutic ligand(s) or target(s) mechanism-based, and clinically relevant to reverse OIRD? To what extent is the proposed UG3 Phase likely to produce validated and viable ligand(s) or target(s) to move into UH3 Phase product development? How likely are the proposed Phase I validation and Phase II product development research plans to be IND enabling? To what extent are the proposed milestones and go/no go decision points measurable, and aligned with IND enabling validation and product development requirements?

Investigator(s)

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

Specific to this FOA:

To what extent is the goal of bringing together respiratory neurobiology, opioid mechanisms, and pre-clinical drug development expertise achieved, and is the combined expertise of study personnel well aligned for pre-clinical pharmacotherapeutic validation and IND enabling product development science? How strong is the research team’s track record of success in conducting pharmacotherapeutic development research? If third party (e.g., pharma, small business) involvement is proposed, is the collaboration clearly described and the need justified?

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?

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 FOA:

How well does the research plan address the desired (i.e., reversing OIRD) and non-desired (i.e. blocking analgesia, triggering withdrawal) effects of the candidate ligand/target and product? How specific, measurable, and viable are the proposed milestones for evaluating scientific progress, determining viability of transitioning targets from Phase I to Phase II, and making go/no go decisions at critical points of therapeutic development? How well are alternative strategies described in the case that no go events occur? How strong is the research and product development plan to enable development of an IND application? How adequate is the proposed Data Management and Sharing plan?

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.

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

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.

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 following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Sharing Model Organisms; and (2)  Genomic Data Sharing Plan (GDS), and whether they address HEAL Initiative Public Access and Data Sharing Policy requirements.

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 NHLBI, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

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

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

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

3. Anticipated Announcement and Award Dates

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

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

Section VI. Award Administration Information

1. Award Notices

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

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

Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the 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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

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

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

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

Providing effective leadership and management of research projects, i.e., science, personnel, budget, progress reporting.

  • Developing and defining study approach, conduct of the study, data analysis and interpretation, quality control, preparation of publications, dissemination of data, and resource sharing
  • Meeting goals, timelines, and milestones of approved studies.
  • Submitting progress reports at required intervals and proposing a formal plan for the UG3/UH3 transition.
  • Collaborating with NHLBI Program Officer (PO) and NIDA Project Scientist (PS) in all aspects of scientific and technical research needed for the management of the study.
  • Attending all required PI meetings and teleconferences. Note: The PI/PD(s) should plan for a monthly virtual meeting to discuss their individual project with the NIH PO and PS, and a bi-annual virtual meeting involving all funded PI/PD(s) (one of which may be in person in the Washington DC Metro area).
  • Attendance in all required HEAL PI/PD meetings. Note: The PI/PD(s) should plan for an annual HEAL meeting (virtual or in-person in the Washington DC Metro area).
  • It is expected that public dissemination of results, tools, protocols, resources and other products will be accomplished in a timely manner, in accordance with NIH and HEAL data and resource sharing policies.
  • Support or other involvement of industry or any other third party in the study - e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIH support; or special access to project results, data, findings, or resources - may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur with the concurrence by NIH PO to ensure objectivity of research.
  • Award recipients will own the rights in any tangible work products created under the terms of the cooperative agreement. Work products may include such things as research reports, papers, research, findings, data sets, and other materials. All such products shall be made accessible to the public and are subject to Government rights of access, as appropriate, in accordance with NIH's legal directives and authorities.

Support or other involvement of any other third party in the study,--e.g. participation by the third party may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NHLBI.

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

NHLBI staff will interact with the PI/PD(s) on a regular basis to monitor progress and negotiate goals. Monitoring may include: regular communication with the PI and their staff, site visits for discussion with recipients’ research team, evaluation of progress toward pre-established milestones, evaluation of plans based on go/no go decision points, fiscal reviews, and other relevant stewardship matters.

For each award there will be an NHLBI PO responsible for the normal scientific and programmatic stewardship of the award. The PO will be named in the award notice. The NHLBI will also retain its typical stewardship role.

In addition, a NIDA Project Scientist will be named in the Notice of Award. The Project Scientist will have substantial scientific involvement during the conduct of this activity. The PS will have primary responsibility for:

  • Serving as a resource to provide scientific/programmatic support throughout the project, and implementation of the study by participating in the design of the activities, advising in the selection of sources or resources, advising in management and technical performance, and participating in the preparation of publications.
  • Assisting post-award in the development of milestones and on decision points against which scientific progress will be evaluated. The PS will collaborate to identify iterative changes to research plans, as needed.
  • Evaluating scientific progress throughout the project timeline, and make recommendations to NHLBI PO regarding the achievement of milestones, the feasibility of UG3/UH3 transition, or early close-out of projects not meeting goals.
  • Providing assistance, coordination, and facilitating interactions and collaborations between the individual projects funded under this program.

The NIH reserves the right to phase out or curtail the award (or an individual component of the award) in the event of inadequate progress, data reporting, or resources to carry out the required studies.

Areas of Joint Responsibility include:

Conference calls between the PI/PD(s)s and the NIH PS will take place on a regular basis. These reports will discuss project development, progress toward milestones, go/no go decisions, and obstacles and steps taken to all relevant sub-projects including pre-clinical testing, and compound synthesis/manufacture, as well as project progress, and obstacles taken to remedy them.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the recipient, an NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. 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.

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

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

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

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

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Scientific/Research Contact(s)

Aaron D. Laposky, PhD
National Heart, Lung and Blood Institute (NHLBI)
Telephone: 301-827-7837
Email: laposkya@nhlbi.nih.gov

Aidan Hampson
National Institute On Drug Abuse (NIDA)
Phone: 301-827-5925
E-mail: aidan.hampson@nih.gov

Jenica Dawn Patterson
National Institute On Alcohol Abuse And Alcoholism (NIAAA)
Phone: 301-827-6166
E-mail: jenica.patterson@nih.gov

Peer Review Contact(s)

Director, Office of Scientific Review
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-435-0270
Email: NHLBIChiefReviewBranch@nhlbi.nih.gov

Financial/Grants Management Contact(s)

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

Pamela G Fleming
National Institute On Drug Abuse (NIDA)
Phone: 301-480-1159
E-mail: pfleming@mail.nih.gov

Judy Fox
National Institute On Alcohol Abuse And Alcoholism (NIAAA)
Phone: (301) 443-4704
E-mail: jfox@mail.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, 2 CFR Part 200, and 45 CFR Part 75.


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