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 Heart, Lung, and Blood Institute (NHLBI)

National Institute on Aging (NIA)

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 Institute on Drug Abuse (NIDA)

National Institute of Mental Health (NIMH)

National Center for Complementary and Integrative Health (NCCIH)

National Cancer Institute (NCI)

All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.

Office of Research on Women's Health (ORWH)

Funding Opportunity Title
HEAL Initiative: Discovery of Biomarkers and Biomarker Signatures to Facilitate Clinical Trials for Pain Therapeutics (UG3/UH3 Clinical Trial Optional)
Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type
New
Related Notices

None

Funding Opportunity Announcement (FOA) Number
RFA-NS-22-050
Companion Funding Opportunity
None
Assistance Listing Number(s)
93.853, 93.846, 93.279, 93.313, 93.866, 93.837, 93.838, 93.839, 93.840, 93.233, 93.242, 93.393, 93.395, 93.865, 93.121, 93.213, 93.867
Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to promote the discovery of candidate biomarkers or biomarker signatures for pain that can be used to facilitate the testing of non-opioid pain therapeutics in Phase II clinical trials. The biomarkers or biomarker signature will be developed through clinical research specifically focused on the identification of pain biomarkers or biosignatures that predict and/or monitor response to pain therapeutics. The resulting biomarkers or biomarker signatures may be focused on a single pain condition or on several pain conditions with common underlying pathophysiology. Applications to identify biomarkers or biomarker signatures that predict or monitor a therapeutic response across several related pain conditions should feature Multiple Principal Investigator (MPI)-led teams that represent each of the related pain conditions and associated clinical networks. The MPI-led teams are expected to decide upon a single set of measures or biomarker modalities including, but not limited to a combination of omics, Quantitative Sensory Testing (QST), actigraphy, Electroencephalography (EEG), digital measures, etc.as components of the biosignature for all pain conditions represented in the application. Applications should feature centralized resource groups that will coordinate clinical trials and standardize all sample or data collection methods, technology development, statistical analysis and algorithm development across the pain conditions under investigation. Applications seeking to develop biomarkers or biomarker signatures that will be used to predict and/or monitor a therapeutic response for a single pain condition may also feature MPI-led teams that represent the cross functional expertise necessary for biomarker and/or signature development, along with the same types of centralized resource groups that coordinate clinical trials and standardize sample or data collection methods, technology development and statistical analysis. Studies to be supported by this FOA may include those necessary for the identification and initial biological, analytical, and clinical validation of pain biomarkers or biomarker signatures, and must include human samples and data as the source for candidate biomarkers or signatures identification and development if possible. If not, biomarkers or signatures resulting from identification in animal models must be verified in human samples at the end of the UG3 phase or during the UH3 phase. This initiative aims to deliver therapeutic response prediction and/or monitoring candidate pain biomarkers or biomarker signatures that are ready for definitive analytical and clinical validation appropriate for use in clinical trial design or decision-making in clinical practice.

Key Dates

Posted Date
February 08, 2022
Open Date (Earliest Submission Date)
February 11, 2022
Letter of Intent Due Date(s)

30 days prior to 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
March 11, 2022 March 11, 2022 Not Applicable July 2022 October 2022 December 2022
June 23, 2022 June 23, 2022 Not Applicable November 2022 January 2023 April 2023
October 13, 2022 October 13, 2022 Not Applicable March 2023 May 2023 July 2023
February 23, 2023 February 23, 2023 Not Applicable July 2023 October 2023 December 2023

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
February 24, 2023
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

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to promote the discovery of candidate biomarkers or biomarker signatures for pain that can be used to facilitate the testing of non-opioid pain therapeutics in Phase II clinical trials. The biomarkers or biomarker signature will be developed through clinical research specifically focused on the identification of pain biomarkers or biosignatures that predict and/or monitor response to pain therapeutics. The resulting biomarkers or biomarker signatures may be focused on a single pain condition or on several pain conditions with common underlying pathophysiology. Applications to identify biomarkers or biomarker signatures that predict or monitor a therapeutic response across several related pain conditions should feature Multiple Principal Investigator (MPI)-led teams that represent each of the related pain conditions and associated clinical networks. The MPI-led teams are expected to decide upon a single set of measures or biomarker modalities including, but not limited to a combination of omics, Quantitative Sensory Testing (QST), actigraphy, Electroencephalography (EEG), digital measures, etc.as components of the biosignature for all pain conditions represented in the application. Applications should feature centralized resource groups that will coordinate clinical trials and standardize all sample or data collection methods, technology development, statistical analysis and algorithm development across the pain conditions under investigation. Applications seeking to develop biomarkers or biomarker signatures that will be used to predict and/or monitor a therapeutic response for a single pain condition may also feature MPI-led teams that represent the cross functional expertise necessary for biomarker and/or signature development, along with the same types of centralized resource groups that coordinate clinical trials and standardize sample or data collection methods, technology development and statistical analysis. Studies to be supported by this FOA may include those necessary for the identification and initial biological, analytical, and clinical validation of pain biomarkers or biomarker signatures, and must include human samples and data as the source for candidate biomarkers or signatures identification and development if possible. If not, biomarkers or signatures resulting from identification in animal models must be verified in human samples at the end of the UG3 phase or during the UH3 phase. This initiative aims to deliver therapeutic response prediction and/or monitoring candidate pain biomarkers or biomarker signatures that are ready for definitive analytical and clinical validation appropriate for use in clinical trial design or decision-making in clinical practice.

Background

This FOA is part of the NIH HEAL (Helping to End Addiction Long-term) Initiative—an aggressive, trans-agency effort to speed scientific solutions to stem the national opioid public health crisis.

More than 25 million Americans suffer from chronic pain, a highly debilitating medical condition that is complex and difficult to manage. In recent decades, there has been an overreliance in the prescription of opioids for chronic pain, contributing to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative treatment options are thus critically needed.

Development of non-addictive, novel pain therapeutics continues to present significant challenges, however, as demonstrated by data showing only a 2% probability of drug approval for Phase I candidate pain therapeutics compared to an overall 10% probability in other disease areas.The challenges facing the development of non-opioid alternative pain medications include: a lack of reliable measures of pain biology and perception, a difficult regulatory path with high safety and labeling hurdles, poor predictive power of preclinical models, and a paucity of validated targets. In addition, patient populations are heterogeneous across multiple pain conditions, with high variability in individual responses to intervention. The issue of high variability in individual responses to intervention could be addressed by clinical design tools such as patient selection biomarkers. It has been shown that patient selection biomarkers can improve clinical success by as much as 17.5%.Availability of these biomarkers could facilitate improved clinical trial design and dose selection methods. To date, however, there are no clinical biomarkers for pain approved by the FDA for use in clinical trials of analgesic therapeutics.

Identification of biomarkers or signatures of response to pain therapeutics is complex because pain is a multidimensional phenomenon, with physiological and psychosocial components. Factors influencing patient variability in pain presentation, chronification, resolution, and response to treatment could include clinical, psychosocial, neurophysiological, and pharmacological components.

This FOA calls for integrative study approaches directed toward the development of biomarkers or biomarker signatures to monitor or predict response to pain therapeutics in clinical trials or clinical practice, respectively. By utilizing a variety of innovative analytical tools, such as neural networks, artificial intelligence, and machine learning algorithms, this FOA invites applicants to investigate multi-modal composite pain biomarker signatures to understand and utilize commonalities across related pain conditions for therapy development. This could result in the development of a network of multi-modal signatures of pain pathophysiology that are drawn from empirical clinical research methods that utilize standardized methodologies across different pain conditions, illuminating both common mechanisms and those that distinguish one pain condition from another. In addition, any druggable targets identified in these approaches could be used as the basis for new non-addictive pain therapeutics.

The immediate goal of this FOA is to promote the identification and development of candidate response monitoring or response prediction pain biomarkers or biomarker signatures that can withstand rigorous and definitive validation in clinical trials and clinical practice. Ultimately, these candidate pain biomarkers or biomarker signatures could provide the tools necessary to facilitate both the development of non-opioid therapeutics for the treatment of pain conditions, and treatment decisions in clinical practice.

Definitions

A biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions. A biomarker signature is a combination of multiple variables to yield a patient-specific indicator of normal biological processes or responses to an exposure or intervention including therapeutic interventions. Biomarker modalities are diverse, and can include genetic, protein, cellular, metabolomic, imaging and physiologic measures. As outlined in the Biomarkers, Endpoints and Other Tools (BEST) Resource developed by the FDA-NIH Biomarker Working Group, biomarker use categories include: Susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, and safety. This FOA focuses on therapeutic response monitoring and predictive biomarker categories.

A Response Biomarker is a biomarker used to show that a biological response has occurred in an individual who has been exposed to a medical product or an environmental agent.

A Monitoring Biomarker is measured serially for assessing status of a disease or medical condition or for evidence of exposure to (or effect of) a medical product or an environmental agent.

A Response Biomarker that can be measured serially for the assessment of status for evidence of exposure to (or effect of) a medical product is referred to in this FOA as a Response Monitoring Biomarker.

A Predictive Biomarker is a biomarker used to identify individuals who are more likely than similar individuals without the biomarker to experience a favorable or unfavorable effect from exposure to a medical product or an environmental agent.

Analytical Validation: Establishing that the performance characteristics of a measurement are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include sample collection and standardization procedures). Although the goal of analytical validation is to ensure a rigorous clinical conclusion, the level of analytical rigor that is necessary depends upon the characteristics of the biomarker, the detection technology, the type of clinical question (exploratory/informational) or its intended use as a biomarker (diagnostic, predictive, pharmacodynamic, etc.). Analytical validation establishes the measurement's technical performance,but does not validate the usefulness of the measurement.

Clinical Validation: Establishing that the biomarker acceptably identifies, measures, or predicts the concept of interest.

Use of the BEST (Biomarkers, EndpointS, and Other Tools Resource) standardized biomarker definitions (https://www.ncbi.nlm.nih.gov/books/NBK338448/) is required for all applications.

Research Objectives

Applications to this FOA must propose a research plan designed to develop biomarkers or a biomarker signature that will facilitate Phase II clinical trials for pain therapeutics by serving as a tool to monitor or predict response to a therapeutic. The biomarker should reflect specific pain pathophysiology substrates that are modulated by a therapeutic intervention, reflecting target engagement or overall response to a therapeutic intervention. The biomarker or biosignature may also predict response or lack of response to a therapeutic intervention. The therapeutic itself can either be novel (validated by showing evidence of efficacy in an appropriate animal model that is relevant to human pain condition) or could be well validated in humans, but must have strong, robust evidence of efficacy as demonstrated by statistical significance in repeated studies with clinically meaningful effect size. In the case of non-pharmacological therapeutics, efficacy could be demonstrated as stated above or could be demonstrated by robust evidence that it impacts pain-related pathways. The desired candidate biomarker or biosignature resulting from completion of this research should be sufficiently robust to withstand definitive analytical and clinical validation.

Phased Award Mechanism and Transition to UH3

This funding opportunity uses a UG3/UH3 (Exploratory/Developmental Phased Award Cooperative Agreement) Phased Innovation Award mechanism. The UG3 phase will support preparatory studies including activities such as study planning and finalization of team organization, along with initial sample collection, initial identification of the biomarker or biomarker signature, detection method development, preliminary analytical validation of the detection method and correlational studies to define the association between the biomarker or biomarker signature with disease pathology, target engagement or response to an intervention. The UH3 phase will support continued method development, algorithm development and further analytical, biological, and clinical validation as the signature or algorithm is developed. Activities in the UH3 phase must include the use of human samples or measures from human subjects as data sources. If the initial biomarker discovery activities were focused on samples or data from animal models because the therapeutic used to develop the biomarker is novel, it is required that evidence of translation to humans (i.e., ability to reliably detect in humans, other adjunct evidence) is provided in the UH3 phase.

Milestones and Transition from the UG3 to the UH3 Phase

Transition from the UG3 to the UH3 phase is contingent upon the successful completion of Go/No Go milestones proposed for the UG3 phase. These milestones are required as a part of the application,but may be further refined by the PD/PI and NIH program staff at the start of each project and updated as needed. The NIH Program Official will contact the applicant to discuss the proposed milestones prior to the award. The Program Official and Project Scientist will discuss with the Program Director(s)/Principal Investigator(s) any recommended changes to the research plan or suggestions from peer reviewers, and the plan will be revised as appropriate prior to the award.

The milestones must be clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the UG3 phase and the potential for development of a candidate biomarker or signature in the UH3 phase. Milestones could address, for example, 1) Evidence that study planning and team coordination is in place, 2) Evidence that metrics for clinical enrollment have been met, 3) Evidence that quality assurance parameters for sample collection or detection method performance have been met, 4) The desired magnitude and reliability of the association between the biomarker and target engagement or responses to an intervention in preliminary studies, 5) Desired precision, accuracy and dynamic range of the biomarker detection method, and 6) Initial prediction accuracy of the biomarker signature for response to the therapeutic.

Because successful biomarker and biomarker signature development are inherently high risk proposals, it is expected that there will be significant attrition as projects progress. At the end of the UG3 phase, NIH program staff and leadership will determine if the project advances to the UH3 phase. NIH program staff and leadership will also conduct an annual administrative review throughout the grant period. If needed, additional meetings to administratively review progress may take place. If justified, future year milestones may be revised based on data and information obtained during the previous project period. The administrative reviews will be based on:

  • Successful achievement of annual and UG3 transition milestones
  • The overall feasibility of project advancement, considering data that may not have been captured in milestones
  • HEAL Programmatic priorities
  • Availability of funds

Entry Criteria

  • Focus on Pain: The biomarker or biomarker signature must be focused on a pain condition or several pain conditions that may have a common pathophysiology.
  • Strong Biological Rationale: Proposed projects should be supported by a cogent biological rationale for the candidate biomarker or biomarker signature as well as evidence of unmet need and feasibility for its intended use in the development of pain therapeutics or in treatment decisions for pain. The biological rationale should include rigorously obtained evidence that the proposed biomarker or biomarker signature may be an indicator of responses to a therapeutic intervention, or that it could predict response to a therapeutic intervention.
  • Relevance for Therapeutic Development: Proposed projects should be based on a strong argument that the candidate biomarker or biomarker signature is necessary for an efficient and robust clinical trial design or for clear decision-making in clinical practice.
  • Multiple Principle Investigator Organization Plan: Proposed projects focused on multiple pain conditions must include coordinated, multiple principal investigator team organization and should have access (or a feasible plan for access) to standardized samples and data. Proposed projects focused on a single pain condition with a Multiple Principal Investigator approach must also include a Multiple Principal Investigator Organization Plan.
  • Go/No Go Milestones: Projects must be organized in a systematic fashion, including annual decision-making metrics throughoutt the entire period of the project and at the end of the UG3 phase.

Project Characteristics

Examples of pain biomarker or biomarker signature studies and activities that would be appropriate under this FOA include but are not limited to:

  • Identification and optimization of a single biomarker or a biomarker signature (including algorithms) that can accurately monitor, indicate, or predict response to a specific therapeutic agent or therapeutic mechanism for a single pain condition or for several pain conditions that may have the same underlying pathophysiology.
  • Identification and optimization of a single biomarker or a biomarker signature (including algorithms) that can accurately monitor, indicate or predict response to a general therapeutic mechanism, using a well validated or approved pain medication as the biomarker “probe” with all samples from human sources.
  • Identification and optimization of a single biomarker or a biomarker signature (including algorithms) that can accurately monitor, reflect, or predict response to a novel therapeutic agent that has demonstrated robust efficacy, using non-human samples for initial identification followed by translation of the detection method in human samples. An example of evidence for robust efficacy would include statistical significance in repeated studies with clinically meaningful effect size.
  • Identification and optimization of a single biomarker or a biomarker signature (including algorithms) that can accurately monitor, reflect or predict response to a non-pharmacological therapeutic regimen that is generally accepted or widely used in the treatment of pain.
  • If applicable, establishment of a single set of detection method components ( including, but not limited to omics, imaging, QST) across the pain conditions under study in an effort to build a common, multi-modal response monitoring or response prediction pain biosignature/algorithm.
  • Identification and optimization of the biomarker or signature using centralized resources focused on clinical study coordination, detection technology development, standardization of sample and data collection methods and statistical analysis and design methods.
  • If applicable, empirical optimization of the algorithm or signature to finalize the components and component weighting in the signature that results in the most accurate response monitoring or prediction tool for use in clinical trial design or treatment decisions.
  • If applicable, translation of the response monitoring or response prediction biomarker/signature developed in animals to detection methods in humans so that the biomarker/signature is ready for clinical validation in a Phase II clinical trial.

Examples of applications or studies that are non-responsive for this FOA

  • Applications proposing to develop any biomarker/biomarker signature use categories other than pharmacodynamic/response monitoring or response prediction biomarkers (Target engagement biomarkers, which are also pharmacodynamic/response biomarkers, should utilize measures directly related to the biological substrate for pain pathophysiology targeted by the therapeutic).
  • Natural history studies aimed at understanding disease pathophysiology, genetic, or epigenetic mechanisms in the absence of biomarker identification, development of detection technology and early validation
  • Biomarker identification or validation proposing only animal studies without confirmation using human tissue sources
  • Use of non-standardized sample source collection methods
  • Large, prospective design clinical validation studies
  • Therapeutic target validation and development
  • Determination of efficacy and development of candidate therapeutics as the primary goal
  • Biomarker/biomarker signature development for therapeutics that are not non-addictive therapeutic options for pain conditions
  • Applications that do not include annual and UG3 to UH3 Go-No Go Milestones

Multiple Principal Investigator Team Characteristics

Multidisciplinary teams with Multiple Principal Investigators (MPI) are beneficial for successful development of candidate biomarkers and biomarker signatures. Areas of expertise needed include biomarker development, clinical expertise relevant for the clinical populations of interest, statistical and/or bioinformatics analysis, experience with the use and development of the detection method technology, bio sample, data or tissue source standardization, and biological expertise in the pain condition or conditions under investigation. MPIs should not only coordinate the execution of the project but should also develop the research proposal for the application. Investigators are encouraged to form collaborations and seek additional consultants as needed for the project. In the case of applications seeking to develop a biomarker signature that is focused on one pain condition or that is common to several related pain conditions, MPIs should have access to the clinical networks associated with the relevant pain conditions and/or explore leverage of NIH resources (see “Leveraging Resources”.

Implementation

The program provides funding through the UG3/UH3 cooperative agreement mechanism. As a cooperative agreement, implementation will involve participation of NIH program staff in the planning and execution of the therapy-directed projects. This program is envisioned as a two stage UG3 and UH3 program. The UG3 portion of the award is designed to support preparatory research for the first two years. The goal is to fund a total of ~13 projects from 4 receipt dates during FY22-24, appropriations permitting with projects having a limited budget for the first two years during the UG3 phase. Based on the progress to milestones, only a limited number of projects will proceed to the UH3 phase for the remainder of the award period which will include optimization and initial validation studies for the biomarker or biomarker signature, with the goal of producing a promising candidate biomarker or biomarker signature that will reflect, monitor, or predict a response to a therapeutic agent or therapeutic mechanism at the end of the UH3 phase.

Considerations for clinical trials

This FOA supports the discovery of biomarkers that that predict or monitor a response to a pain therapeutic. Thus, while the studies outlined in an application may be defined as clinical trials, and may make measurements in patients on specific therapies, they should not seek to answer specific questions about safety, tolerability, clinical efficacy, effectiveness, and/or clinical intervention and management.

Prospective applicants are encouraged to discuss project suitability for this FOA with the NINDS Scientific/Research Contact listed in the Agency Contacts section below.

Leveraging Existing Research Resources

In the near future, the HEAL Early Phase Pain Investigation Network (EPPIC-Net) will include a biorepository for samples from EPPIC-Net clinical trials and several other HEAL or Common Fund programs such as BACPAC and the Acute to Chronic Pain Signature program. The biorepository is housed at EPPIC-Net’s Data Coordinating Center at NYU; more information will be provided as the EPPIC-NET biorepository becomes available for use.

Leveraging the resources and support from pain advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged. Studies are also encouraged that leverage the resources of ongoing clinical trials supported through other Federal or private funds.

Additional existing resources that may include tissue, cellular, or DNA samples can be accessed from NINDS BioSEND (https://www.biosend.org/) or other existing biospecimen, imaging and data repositories. The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources from NINDS funded studies that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. Applications proposing to collect biospecimens are strongly encouraged to use the NINDS Biomarkers Repository BioSpecimen Exchange for Neurological Disorders (BioSEND) protocols and procedures; all specimens collected and banked with BioSEND must come from individuals who have consented to banking and sharing broadly with academia and industry. Note that costs for collection are NOT included as a component of the NINDS Biomarkers Repository award. Therefore, most costs for the biospecimen banking are borne by the grantees utilizing this resource (see NOT-NS-15-046). Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NINDS Biomarkers Repository website for more information about samples banked at the repository (https://www.biosend.org). In addition, applicants are advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email: biosend@iu.edu).

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

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
Resubmission

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?

Optional: Accepting applications that either propose or do not propose clinical trial(s).

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

Issuing IC and partner components intend to issue 2-3 awards in 2022, 5-6 awards in 2023 and 3-4 awards in 2024. Awards issued under this FOA are part of funds set aside to support the HEAL (Helping to End Addiction Long-term) initiative.

Award Budget

Application budgets are limited to <$500,000 in direct costs per year for the UG3 phase and up to $1,500,000 in direct costs per year of the UH3 phase.

Award Project Period

Applicants may seek two years of UG3 funding. The UH3 phase cannot exceed three years, since the total period of the UG3/UH3 award cannot be more than 5 years. The actual duration of individual projects will depend on successful achievement of milestones and conditions as described in Milestones Section of the program overview.

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
  • Non-domestic (non-U.S.) Entities (Foreign Institutions)
Foreign Institutions

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

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

Foreign components, as defined in the NIH Grants Policy Statement, are not 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.

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

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

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

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:

Ram Arudchandran, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-402-5257
Email:
ramachandran.arudchandran@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.

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

  • Applicants should describe the IP landscape surrounding their biomarker, biomarker signature or endpoint and its measurement. Applicants should describe any known constraints that could impede biomarker or endpoint development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar biomarkers that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program. If the applicant proposes using an agent(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 project which would impede achieving the goals of the funding program.
  • If patents pertinent to the biomarker being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable.
  • Applicants should discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved.
SF424(R&R) Senior/Key Person Profile

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

Specific to this FOA:

Give details about the investigator's knowledge and experience regarding the biological target and/or disease biology, and the expertise in the target biology, pain condition, clinical phenotype, bioinformatics, detection technology, etc., to design and implement a robust identification/validation plan for the biomarker or biomarker signature.

Give details about the ability of the team to manage the discovery process for the biomarker or biomarker signature, and/or its assay. In addition the roles of each collaborator should be carefully defined in the team management plan. If a multi-disciplinary team is proposed, describe it and provide evidence that it is appropriate for the approach and goals proposed. If the biomarker or biomarker signature will be common across several pain conditions, a Multiple Investigator team appropriate for the proposed approach and goals should be included in the application and should be well described.

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:

All applications must include plans for both the UG3 and the UH3 phases.

Specific Aims:

Within the Specific Aims section, include headers titled UG3 Phase Specific Aims and UH3 Phase Specific Aims. Briefly provide the context for the proposed set of studies, with an emphasis on the biological research rationale for the biomarker or biomarker signature, along with a cogent argument outlining its importance and unmet need. Under each header, state the specific objectives of the efforts. In addition, the major objectives of the proposed study should be stated, including the technical questions to be answered to further develop and validate the biomarker or biomarker signature.

Research Strategy:

The Research Strategy Section should address both the UG3 and UH3 phases and include the following sections:

1. Rationale and Unmet Need

  • Define the pain condition or multiple related pain conditions to be addressed and the unmet need for therapeutics in the specific area.
  • Provide a strong biological rationale that supports the scheme for discovery of the putative biomarker or biomarker signature. If the biomarker or biomarker signature will be investigated across several pain conditions, the basis for choice of these conditions should be specified. The basis for choice of the therapeutic mechanism and “response probe” therapeutic should also be specified.
  • Describe the possible methods of detection and components for the biomarker or biomarker signature and address the feasibility of this method of detection for use in Phase II clinical trials or for decision-making in clinical practice.
  • Specify the intended clinical use (response monitoring, response reflecting or predictive) for the biomarker or biomarker signature and its detection method. Include information on characteristics of the sample (i.e., specimen, image, EEG, behavioral or physiological endpoint) to be used for the measurement and how the measurement result will be used.
  • If applicable, provide a comparison to other biomarker or biomarker signature approaches for the specified pain condition, discussing the advantages of the proposed biomarker approach and addressing the unmet need for a biomarker.
  • Describe the potential for the proposed studies to significantly advance translational medicine in the pain indication area(s) described.
  • Address the probability for the biomarker or biomarker signature and its detection method to be broadly adopted in clinical testing and/or by the health care community for use in treatment.

2. Preliminary Data

  • Provide a clear outline of the preliminary data or literature supporting the biological rationale for the discovery scheme of the new biomarker or biomarker signature. Describe the overall strengths, weaknesses, and rigor of the preliminary data.
  • Provide any existing natural history data that is relevant to the biomarker or biomarker signature discovery scheme.
  • Provide data addressing the feasibility and utility of any existing detection method or biomarker that is related to the proposed discovery scheme.
  • Provide data addressing the efficacy of the novel therapeutic or of the probe therapeutic used to address a general therapeutic mechanism.
  • If the probe therapeutic is non-pharmacological, provide robust evidence that it impacts pain-related pathways.
  • Provide the preliminary rationale for the proposed clinical use.

3. Approach - address each of the items below for both the UG3 and UH3 phases.

The Approach Section should include plans for cross functional coordination and execution of activities such as preclinical or clinical therapeutic intervention, sample and/or data collection across one or several pain conditions, standardization of sample collection methods, harmonization of detection methods, algorithm/signature development and statistical analysis.

Examples of activities comprising the above plans could include but are not limited to:

  • Execution and planning for development and organization of clinical, technology and statistical/modeling resource centers
  • If focus is on development of a signature common to several pain conditions, execution and planning for sample collection from populations representing each pain condition and for selection of core signature components
  • Execution and planning for a clinical or preclinical therapeutic intervention as part of the biomarker/biomarker signature identification process and as part of the initial clinical validation process
  • Plan for ensuring standardization of data/sample collection. If retrospective samples or data are being used, provide details as to how they were collected and plans to address and evaluate differences across sites/sources.
  • Plan for resolution of pre-analytic variables in detection method
  • Biomarker detection methodology development (including algorithm development) and initial validation approach
  • If machine learning will be used to measure or detect the biomarker, or if an algorithm will be used for the biomarker signature, describe the training and testing procedures to be used and the rationale for the approach; address how overfitting will be avoided. Describe how the algorithm stability and reliability will be tested, and the overall rationale for the approach(es)/model(s) selected.
  • Bioinformatics and statistical designs for analysis or deconvolution of sample data and refinement of biomarker or biomarker signature identity
  • Plans to assemble a signature from several, possibly multi-modal, components
  • If biomarker identification and initial proof of concept are based on animal data, outline the approach for translation to human pathophysiology, target engagement or prediction of response to an intervention
  • Plans to obtain proof of concept for the biomarker, biomarker signature and/or signature components using clinical samples or measures

4. Timeline and Proposed Milestones (required)

  • Transition from the UG3 to the UH3 phase is contingent upon the successful completion of one set of proposed milestones. The specific milestone(s) proposed in the application will depend on the goals of the application and the accomplishments necessary in the UG3 phase for advancement into the UH3 phase. Milestones and timelines must be provided under a separate, specific heading at the end of the Research Strategy Section and will be evaluated as part of the scientific and technical merit of the UG3/UH3 application.
  • Milestones should be proposed not only for completion at the end of the UG3 phase, but also for each year of the grant period. Quantitative milestones are required to provide clear indicators of a project's feasibility, continued progress or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of the UH3 phase.

    The milestones should be robust and associated with clear, quantitative criteria for success that allow go/no-go decisions at the UG3/UH3 transition point and during each year of the grant period. For example, the milestones can address items such as evidence that study planning and team coordination is in place, evidence that metrics for clinical enrollment have been met, or evidence that quality assurance parameters for sample collection or detection method performance have been met. Milestones can also address the desired magnitude and reliability of the association between the biomarker and target engagement or responses to an intervention in preliminary studies. Additional examples of quantitaive milestones include the desired precision, accuracy and dynamic range of the biomarker detection method, and initial prediction accuracy of the biomarker signature for response to the therapeutic. The set of milestones should allow the evaluation of progress in the UG3 phase, and the successful completion of these milestones should provide confidence that the investigator will be able to successfully implement the UH3 phase and achieve its end goals within the timeline of this grant mechanism. Quantitative criteria should be justifiable, and the timelines proposed for achieving the milestones should be realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps.

    When applicable, milestone reports should adhere to rigorous principles, including statistically adequate sample sizes with biologically relevant effect sizes, randomization, blinding, control of bias, independent replication, and adequate reporting of experimental details and results as described at https://www.ninds.nih.gov/Funding/grant_policy.
  • Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal. Indicate when it is anticipated that essential components of the project will be completed. The proposed timeline with specific milestones should be clearly delineated and should appear as the last element of the Research Strategy section.
  • Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

5. Team Management Plan (required):

  • Applicants planning to develop biomarkers or biomarker signatures common to several pain conditions are required to form Multiple Principal Investigator (MPI)-led multidisciplinary teams that may consist of clinical and possibly preclinical scientists, bioinformatics, artificial intelligence and statistical experts, technical experts with experience relevant for the detection method, clinicians with drug development experience, regulatory experts, and other academic/industry experts relevant to the therapeutic modality. Describe the team's ability to design the details of the plans and experiments, and to execute the research strategy. Applicants planning to develop biomarkers or biomarker signatures for single pain conditions are also strongly encouraged to form an MPI multi-disciplinary team with expertise described above.
  • Describe the plans for establishing and utilizing multiple principal investigators (MPI)Team-Initiated centralized research groups (Research/Clinical Coordination, Technology/Statistical Analysis) where all signature components are standardized across a specific pain condition or pain conditions. Describe how the team will work together (e.g., data generation, reporting of data and integrated review across teams with various disciplines, decision-making, etc.) over the course of the project (and include letters of support below). This description should include an outline of roles and responsibilities for each team member.

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) will be needed and in place once the project is funded. This letter should come from a high official within the private entity who has authority to speak on these issues.
  • If an application plans to utilize the infrastructure or resources of existing projects, whether funded by the NINDS, other governmental or non-governmental entities, letters of support detailing the terms of collaboration and data sharing must be included.
  • If utilization of extant samples is proposed as a component of the study, letters of support or approval for use of those samples should be included.

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

The following modifications also apply:

  • All applications, regardless of the amount of direct costs requested for any one year, must address a Data Sharing Plan.
  • Many NIH ICs encourage the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human participants research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Investigators are encouraged to consult the NIH CDE Repository and describe in their applications any use they will make of NIH-supported CDEs in their projects, when applicable. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological diseases), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a “Common Data Element (CDE) Repository Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research.

  • The following modifications also apply:

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

    • Applicants are encouraged to ensure that data collected by the study conform to Findable, Accessible, Interoperable, and Reusable (FAIR) principles.

    • Applicants are specifically encouraged to incorporate into their planning, an alignment with the guidelines, principles and recommendations developed by the HEAL Data Ecosystem, including but not limited to preparing data to store in selected specified repositories, applying minimal metadata standards, use of core HEAL Clinical Data Elements (CDEs, https://heal.nih.gov/data/common-data-elements), and other necessary requirements to prepare data to connect to the HEAL Data Ecosystem.

    • All new HEAL clinical pain studies are required to submit their case-report forms/questionnaires to the HEAL Clinical Data Elements (CDE) Program. The program will create the CDE files containing standardized variable names, responses, coding, and other information. The program will also format the case-report forms in a standardized way that is compliant with accessibility standards under Section 508 of the Rehabilitation Act of 1973 (29 U.S.C § 794 (d)), which “require[s] Federal agencies to make their electronic and information technology accessible to people with disabilities.” HEAL Initiative clinical studies that are using copyrighted questionaries are required to obtain licenses for use prior to initiating data collection. Licenses must be shared with the HEAL CDE team and the program officer prior to use of copyrighted materials. For additional information, visit the HEAL CDE Program.

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

    • Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014)

    • NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016)

    • NIH encourages the use of data standards including the PhenX Toolkit (https://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.

    • Recipientsconducting 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.

Foreign Institutions

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

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

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

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). 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 fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review 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.

In addition, the Scientific Review Officer (SRO) will accept regulatory meeting minutes and transcripts, and patents, and not later than 30 calendar days prior to the peer review meeting.

Section V. Application Review Information

1. Criteria

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

For this particular announcement, note the following:

This FOA supports studies focused on the discovery of promising candidate response monitoring or prediction biomarkers or biomarker signature for one or more related pain indications that will withstand rigorous validation and ultimately provide the tools necessary for the development of non-opioid therapeutics for the treatment of pain conditions.

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

Overall Impact

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

Scored Review Criteria

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

Significance

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

Specific to this FOA:

What is the potential of the candidate biomarker or biomarker signature to address an unmet medical need in the specified pain condition or conditions? What is the strength of the biological rationale for the biomarker or biomarker signature and for the choice of the therapeutic “probe” used to develop the biomarker or biomarker signature? Has the investigator carefully considered plans to translate preclinical data to clinical data? What is the overall potential for the proposed studies to significantly advance biomarkers, and translational medicine in the field of pain indication described? How likely are the biomarker or biomarker signature to be utilized in Phase II clinical trials or broadly adopted by the health care community for use in treatment?

In addition, for applications involving clinical trials

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

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:

Are the investigators knowledgeable and experienced about the biological target and/or disease biology? Do the investigators have sufficient expertise in the target biology, pain condition, clinical phenotype, bioinformatics, detection technology, etc. to design and implement a robust identification/validation plan for the biomarker or biomarker signature? Will the team be able to manage the discovery process for the biomarker or biomarker signature, and/or its assay? Are the roles of each collaborator carefully defined in the team management plan? Is a multi-disciplinary team proposed and is it well described and appropriate for the approach and goals proposed? If the biomarker or biomarker signature will be common across several pain conditions, has a Multiple Investigator team been included in the application and is it well described and appropriate for the approach and goals proposed?

In addition, for applications involving clinical trials

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

Innovation

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

In addition, for applications involving clinical trials

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

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?

Does the proposed research incorporate adequate methodological rigor including, but not limited to, rationale for the chosen model(s) and primary/secondary endpoints, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications?

Specific to this FOA:

Does the application outline a clear and realistic organization and execution plan for the identification and early validation of a response monitoring or prediction biomarker/signature that could consist of multiple modalities and have commonalities across more than one pain condition? What are the strengths and rigor of the data supporting the rationale, including the choice of therapeutic probe? What is the feasibility of measurement of the biomarker or biomarker signature from a clinical perspective? How well considered are the plans for the execution and planning for the therapeutic intervention, including the choice of the therapeutic “probe”? How well considered are the plans for ensuring standardization of data/sample collection? How feasible and carefully considered are the plans for the biomarker detection technology development? If machine learning will be used to measure or detect the biomarker, or if an algorithm will be used for the biomarker signature, how appropriate and rigorous are the training and testing procedures, how will overfitting be avoided and how rigorous are the plans to assure algorithm reliability and stability? Are the plans for bioinformatic and statistical analysis or deconvolution of data leading to initial biomarker or biomarker signature identification sufficiently rigorous and feasible? How carefully considered are the plans to assemble a signature from several, possibly multi-modal components? Are the plans for initial proof of concept and validation logical and based on a clear understanding of the pain condition phenotype and biological basis? If the biomarker/signature will be identified using preclinical species, is there a reasonable plan for translation in the UH3 phase? Do the plans for development and validation of the detection technology show evidence of adequate knowledge of analytical design and requirements?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Environment

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

In addition, for applications involving clinical trials

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

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

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

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

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 milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions at the UG3/UH3 transition point and during each year of the grant period? For example, do the milestones address items such as: Evidence that study planning and team coordination is in place, Evidence that metrics for clinical enrollment have been met, Evidence that quality assurance parameters for sample collection or detection method performance have been met, The desired magnitude and reliability of the association between the biomarker and target engagement or responses to an intervention in preliminary studies, Desired precision, accuracy and dynamic range of the biomarker detection method, and Initial prediction accuracy of the biomarker signature for response to the therapeutic? Does the set of milestones allow the evaluation of progress in the UG3 phase and will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the UH3 phase and achieve its end goals within the timeline of this grant mechanism? If a criterion is not to be used for go/no-go decisions, is it justifiable? Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?

Do the proposed milestones, where applicable, adhere to rigorous principles, including statistically adequate sample sizes with biologically relevant effect sizes, randomization, blinding, control of bias, independent replication, and adequate reporting of experimental details and results?

Study Timeline

Specific to applications involving clinical trials

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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

Not Applicable

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

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

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

Resource Sharing Plans

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

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 appropriate national Advisory Council or Board. 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.

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

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

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

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

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

2. Administrative and National Policy Requirements

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

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

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

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

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 at 45 CFR Part 75, 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for the HEAL Biomarker 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 recipients and the NIH as defined below. Recipient will retain custody of and have primary rights to the data and software developed under this award, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

Establishing, and utilizing multiple principal investigators (MPI)Team-Initiated Resource Cores (Research/Clinical Coordination, Technology/Statistical Analysis)

Determining research approaches, setting project milestones, designing protocols with the PD/PIs of the multidisciplinary teams, executing the research strategy, conducting research, data generation, reporting of data and integrated review across teams with various disciplines, and decision-making .The recipient agrees to accept close coordination, cooperation, and participation of NIH staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.

Implementation of the protocol, each study, whether a single pain condition or multiple pain conditions, and following the procedures required by the protocol regarding study conduct and monitoring, participant management, data collection, and quality control.

Participating in group activities, including meetings of (MPI)Team-Initiated Resource Cores, the HEAL Biomarker Program initiated project team meetings which will meet once a year either in-person or virtually, and additional times if needed by teleconference during the planning year and other meetings as needed. The HEAL Biomarker Program will recommend the frequency of other in-person and teleconference meetings as needed.

Providing reports and data in a timely fashion as agreed upon by the HEAL Biomarker Program

Preparing abstracts, presentations, and publications and collaborating Consortium-wide in making the public and professionals aware of the program.

Adhering to policies regarding data sharing and publication established by the NIH and the HEAL Program.

Abiding by common definitions, protocols, and procedures, as determined in collaboration with the HEAL Program.

Submitting periodic progress reports in a standard format, as agreed upon by the HEAL Program

Attending and participating in the HEAL Biomarker Program initiated project team meetings and accepting and implementing decisions by these groups, as appropriate.

The PD(s)/PI(s) will manage the involvement of industry or any other third party in the study. Except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by the NIH.

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

The NIH Project Scientist(s) will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. The Project Scientist(s) will participate as members of the HEAL Biomarker Program. The Project Scientist(s) will have the following substantial involvement:

Participating through the HEAL Biomarker Program in addressing issues that arise with planning, operation, assessment, and data analysis. The Project Scientist(s) will assist and facilitate the group process and not direct it.

Serving as a liaison, helping to coordinate activities, including acting as a liaison to other NIH Institutes/Centers, and as an information resource for the recipients. The Project Scientist(s) will also help coordinate the efforts of the HEAL Biomarker Program with other groups conducting similar efforts.

The Project Scientist(s) will be responsible for working with the recipients as needed to manage the logistic aspects of the HEAL Biomarker Program.

Reporting periodically on progress to the NIH Leadership.

Assisting recipients in the development, if needed, of policies for dealing with situations that require coordinated action.

Providing advice in the management and technical performance of the award.

Assisting in promoting the availability of the data and related resources developed during this program to the scientific community at large.

In addition, an agency Program Official or IC Program Director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and Project Scientist will negotiate with the applicant and agree on a final set of approved milestones which will be specified in the Notice of Award. The NIH Program Official, in consultation with the Project Scientist and NIH Leadership, will determine if the recipient has met the milestones required for each year of funding.

NIH reserves the right to withhold funding or curtail an award in the event of:

Substantive changes in the project, or failure to make sufficient progress toward the work scope with which NIH concurred, or

Ethical or conflict of interest issues.

Areas of Joint Responsibility include:

Close interaction among the participating investigators will be required, as well as significant involvement from the NIH, to manage, assess, and implement the HEAL Biomarker Program. The recipients and the Project Scientist(s) will meet through the HEAL Biomarker Program, a minimum of twice a year during the planning year, and on conference calls as needed to share information on methodologies, analytical tools, and preliminary results. PDs/PIs, key co-investigators, and pre- and post-doctoral trainees, especially those who are members of under-represented minority groups or those from different but related disciplines, are eligible to attend these meetings. The HEAL Biomarker Program may add additional members, and other government staff may attend the meetings as desired.

The recipient agrees to work collaboratively to:

Provide for secure, accurate, and timely data submission.

Participate in presenting and publishing new processes and substantive findings.

Assess and disseminate HEAL data and resources.

Interact with other relevant NIH activities, as needed, to promote synergy and consistency among similar projects.

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. The three members will be: a designee of the HEAL Biomarker Program chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D, and DHHS regulation 45 CFR Part 16.If this FOA is not a cooperative agreement, make no changes to this section.

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)

Ram Arudchandran, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-402-5257
Email: ramachandran.arudchandran@nih.gov

Xincheng Zheng (Ted), M.D, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phone: (301) 594-4953
E-mail: zhengx4@mail.nih.gov

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

Alexis Bakos, Ph.D., M.P.H., R.N.
National Cancer Institute (NCI)
Telephone: 301-921-5970
Email: alexis.bakos@nih.gov

Karen C. Lee, MD MPH
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-827-3973
Email: Karen.Lee2@nih.gov

Shelley Su
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-402-3869
E-mail: shelley.su@nih.gov

Wen G. Chen, M.MSc, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-451-3989
Email: chenw@mail.nih.gov

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

David A. Thomas, Ph.D.
Office of Research on Women’s Health (ORWH)
Telephone: 301-435-1313
Email: david.thomas@nih.gov

Dena Fischer, DDS, MSD, MS
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: (301) 594-4876
Email: dena.fischer@nih.gov

Dana K. Andersen, M.D.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Phone: 410-868-0638
E-mail: dana.andersen@nih.gov

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

Alexander M. Talkovsky, Ph.D.
National Institute of Mental Health (NIMH
Telephone: 301-827-7614
Email: alexander.talkovsky@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

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Phone: 301-594-7760
E-mail: erik.edgerton@nih.gov

Jeni Smits
National Institute on Aging (NIA)
Phone: (301) 827-4020
E-mail: jeni.smits@nih.gov

Sean Hine
National Cancer Institute (NCI)
Phone: 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

Pamela G Fleming
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: 301-480-1159
E-mail: pfleming@mail.nih.gov

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

Karen Robinsonsmith
NEI - NATIONAL EYE INSTITUTE
Phone: (301) 451-2020
E-mail: kyr@nei.nih.gov

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: rutbergd@mail.nih.gov

Elizabeth Gutierrez
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Phone: 301-594-8844
E-mail: gutierrezel@mail.nih.gov

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

Tamara Kees
National Institute of Mental Health (NIMH)
Telephone: 301-443-8811
Email: tamara.kees@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 45 CFR Part 75.

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