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 Institute on Aging (NIA)

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

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

National Center for Complementary and Integrative Health (NCCIH)

National Cancer Institute (NCI)

National Institute of Biomedical Imaging and Bioengineering (NIBIB)

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: Development and validation of remote or patient wearable device derived objective biosignatures or functional assessments to monitor pain for use as endpoints in clinical trials (UG3/UH3 - Clinical Trial Optional)
Activity Code

UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement

Announcement Type
New
Related Notices
  • December 4, 2023 - Notice of Change to Key Dates for RFA-NS-24-023. See Notice NOT-NS-24-029
  • November 22, 2023 - Notice of NIBIB's Participation in RFA-NS-24-023,"HEAL INITIATIVE: Development and validation of remote or patient wearable device derived objective biosignatures or functional assessments to monitor pain for use as endpoints in clinical trials (UG3/UH3)". See Notice NOT-EB-23-020
  • August 31, 2022- Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198.
  • August 5, 2022- Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189.
Notice of Funding Opportunity (NOFO) Number
RFA-NS-24-023
Companion Funding Opportunity
None
Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)
93.853, 93.865, 93.273, 93.866, 93.313, 93.213, 93.393, 93.395, 93.394, 93.286
Funding Opportunity Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to promote the discovery, development, and validation of real-world digital endpoints derived from data generated by existing remote or wearable devices. These endpoints will be used for monitoring the experience of pain, its progression, response to interventions, and impact on quality of life. In this NOFO, endpoints refer to biosignatures obtained from functional and physiological assessments captured by remote or wearable devices. Development of digital endpoints will involve clinical research using existing wearable or remote devices, with a specific focus on selecting and validating novel measurements as appropriate digital endpoints for pain assessment. The proposed digital endpoints may focus on a specific pain condition or encompass multiple pain conditions. Applications aiming to identify digital endpoints across various pain conditions should involve Multiple Principal Investigator (MPI)-led teams that represent each relevant pain condition and associated clinical networks. These teams should collaborate to discover, develop, and validate digital endpoints that accurately measure pain and related outcomes, such as quality of life or appropriate pain-related functional measures. In addition, the applicant should include experts in digital technology, data analysis, and advanced statistical methods to handle real-world data. Applicants must establish centralized resource groups responsible for coordinating clinical trials, standardizing sample or data collection methods, technology development, statistical analysis, and algorithm development across all pain conditions under investigation. For applications focused on developing digital endpoints for a single pain condition, MPI-led teams with cross-functional expertise should be included, along with centralized resource groups responsible for coordinating clinical trials, standardizing sample or data collection methods, technology development, and statistical analysis. Furthermore, the inclusion of people with lived experience in the team is required to incorporate patient perspectives, concerns, and valuable input regarding the relevance and acceptability of digital measurements in the study. The final products of this effort would be algorithms and software designed to analyze data from existing remote or wearable technologies. The goal is to demonstrate that digital biosignatures or digital functional assessments, serving as digital endpoints, are sensitive and objective measures of clinical benefit.

Key Dates

Posted Date
September 01, 2023
Open Date (Earliest Submission Date)
December 30, 2023
Letter of Intent Due Date(s)

December 30, 2023

Application Due Dates

Review and Award Cycles

New

Renewal / Resubmission / Revision (as allowed)

AIDS - New/Renewal/Resubmission/Revision, as allowed

Scientific Merit Review

Advisory Council Review

Earliest Start Date

January 30, 2024

October 4, 2024

Not Applicable

Not Applicable

Not Applicable

Not Applicable

July 2024

March 2025

October 2024

May 2025

December 2024

July 2025

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
  • New Date October 5, 2024 per issuance of NOT-NS-24-029. (Original Expiration Date: January 31, 2024 )
  • Due Dates for E.O. 12372

    Not Applicable

    Required Application Instructions

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

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

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

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

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

    3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


    4. Table of Contents

    Part 2. Full Text of Announcement

    Section I. Notice of Funding Opportunity Description

    Background:
    This NOFO is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://heal.nih.gov/
    More than 25 million Americans suffer from 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 pain therapeutics continues to present significant healthcare challenges, however, only a 2% probability of drug approval for Phase I candidate pain therapeutics compared to an overall 10% probability in other disease areas. 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 response 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.
    The use of remote or wearable device technologies in healthcare is a rapidly expanding market with significant potential for improving clinical trial efficiency and cost. As defined by the FDA, endpoints derived from remote or wearable digital health technologies may include biosignatures that measure or detect common physiological parameters and wirelessly transmit patient information to their health care provider or other monitoring entity. Likewise, digital performance outcomes from a wearable digital health technology may include features from daily activity, movement, or other performance assessments that can be used to monitor how an individual functions over time in a real-world environment.
    The move towards telehealth and wearable device technology-enabled trials has become all the more urgent and accepted due to the pandemic. In pain therapeutic and intervention research, there remains a need for more reliable and sensitive measurements of patient outcomes that represent overall improvements in quality of life. In addition to providing improved measures of patient outcomes, wearable devices can also be used to detect behavioral and physiological information that form multi-parameter, digitally detected endpoints. These digital biosignatures have the potential to reflect characteristics of individual patients with better accuracy and specificity than single parameter endpoints. Therefore, these digital biosignature endpoints could improve clinical trial design by more accurately guiding patient selection. They could also facilitate personalized or targeted interventions in clinical practice. Remote or wearable device technologies have a high potential for assessing pain therapeutic effectiveness and identifying novel clinical endpoints. However, studies are needed to develop and validate wearable device derived objective biosignatures and functional assessments as reliable tools for use in clinical trials and clinical practice.
    This NOFO calls for integrative study approaches aimed at developing validated remote or wearable device-derived objective biosignatures and functional assessments to assess the effectiveness of pain therapeutics and identify novel digital endpoints(Digital Health Technologies for Remote Data Acquisition in Clinical Investigations | FDA). The objective is to create algorithms and software capable of analyzing data from existing remote or wearable technologies, thereby demonstrating that digital biosignatures or digital functional assessments can serve as sensitive and objective measures of clinical benefit. These measures should reflect a meaningful concept of interest (COI) in a regulatory contex within a specified context of use (COU). In this context, a digital biosignature refers to the representation of biological information captured, stored, and transmitted in a digital format, while digital functional assessment pertains to the evaluation and measurement of an individual's functional capabilities and limitations using digital tools and technologies. The COI specifies the aspect of an individual's clinical, biological, physical, or functional state or experience that the assessment aims to capture, and the COU describes the purpose and manner of its use.

    In this phased UG3/UH3 mechanism, the UG3 phase is for proof of concept testing with remote or wearable device(s) to discover and develop the initial digital biosignature or functional assessment. It aims to incorporate user feedback to assess the feasibility of capturing the required data and its relationship to quality of life or appropriate pain-related functional measures. Additionally, the UG3 phase aims to validate the performance of individual components of the digital biosignature, including assessing sensitivity, specificity, and accuracy in capturing the physiological or functional features that make up the biosignature or functional assessment. It also aims to validate the biosignature or composite thereof for its initial sensitivity and specificity. Applicants are expected to consult with the FDA's recently established Digital Health Center of Excellence for software data security standards and seek regulatory guidance early in the UG3 phase. Successful applications that transition to the UH3 phase will conduct longitudinal prospective clinical studies to validate the digital biosignature or functional assessment and evaluate their reliability as digital endpoints representing one or more pain condition. These longitudinal studies should consider diversity of patients and when applicable include participants from minority health and other NIH designated populations experiencing health disparities in clinical research, such as racial and ethnic minorities, individuals living in rural areas, and those with limited English proficiency. As part of the UG3 phase, outreach activities may be conducted to prepare for successful recruitment and retention in the UH3 phase. Including patient representatives or advocacy groups in the team is crucial to incorporate patient perspectives, concerns, and valuable input regarding the relevance and acceptability of digital measurements in the study.

    Diversity:
    In addition to scientific diversity, applicants should strive to incorporate diversity in their team development plan. Research shows that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogenous teams. Scientists and trainees from diverse backgrounds and life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. There are many benefits that flow from a diverse NIH-supported scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved or health disparity populations participate in, and benefit from health research, and enhancing public trust. In spite of tremendous advancements in scientific research, information, educational and research opportunities are not equally available to all. NIH encourages institutions to diversify their student and faculty populations to enhance the participation of individuals from groups that are underrepresented in the biomedical, clinical, behavioral, and social sciences.


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

    Definitions:

    • Digital Health Technologies (Wearables/Devices/Technologies): a system that uses computing platforms, connectivity, software, and/or sensors for healthcare and related uses.
    • Clinical Outcome Assessment (COA): a measure that describes or reflects how a patient feels, functions, or survives. Types of COAs include:
    • Patient-reported outcome (PRO): A measurement that comes directly from the patient
    • Observer-reported outcome (ObsRO): An assessment determined by an observer (i.e., a non-clinician such as a parent or caregiver)
    • Clinician-reported outcome (ClinRO): An assessment determined by a trained medical professional
    • Performance outcome (PerfO)/Functional outcome: A measurement based on a standardized task(s) performed by a patient
    • Biomarker: a defined characteristic that can be measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions
    • Digital Biomarker: The term digital biomarker is widely used to mean assessments that include both biological processes (such as changes in heart rate or galvanic skin response) as well as performance/functional/behavioral assessments (such as measurements derived from accelerometers). Both digital biomarkers and digital performance/functional assessment are within scope of this NOFO.
    • Digital endpoint: A Digital Endpoint (a precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question) is derived from or includes a digital measurement. Digital endpoints can be clinical outcome assessments (clinical relevance established de novo) or biomarkers (reliable relationship with existing clinical outcome can be established).
    • Concept of Interest: the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to indicate or reflect.
    • Context of Use (COU): is a statement that fully and clearly describes the way the biomarker is to be used and the biomarker-related purpose of the use. Considerations involved in defining the COU include the biomarker category, modality, method of detection, clinical population characteristics, and unmet need for the new biomarker and type of biomarker

    Research Objectives:

    Applications submitted for this Notice of Funding Opportunity (NOFO) are expected to propose a comprehensive research plan focused on the discovery, development, and validation of novel digital endpoints for pain. The proposals should include research strategies for the selection of outcome assessments, digital health technology, and the patient population during the UG3 phase. Furthermore, the UH3 phase should include the research plans for validating the outcome assessments derived from digital health technology into endpoint(s). This validation process requires conducting longitudinal prospective clinical studies to validate the signature(s) and assess their reliability in monitoring remote digital biosignatures or functional endpoints. These studies need to include minority health and NIH-designated populations that experience health disparities that represent one or more pain conditions. The desired candidate endpoint(s) resulting from the completion of this research should be robust enough for definitive analytical and clinical validation.The desired candidate endpoint(s) resulting from the completion of this research should be robust enough for definitive analytical and clinical validation.
    Phased Award Mechanism and Transition to UH3
    This NOFO uses a UG3/UH3 (Exploratory/Developmental Phased Award Cooperative Agreement) Phased Innovation Award mechanism. Applications must include both the UG3 and UH3 phases. The UG3 phase will support preparatory studies, including activities such as:

    • Selecting candidates of digital endpoint(s) to measure meaningful outcomes of an individual directly, accurately, and reliably or be associated with clinical outcomes,
    • Determining the selection of the candidate wearable(s) or device(s) and the algorithm based on the effect modifiers and tolerability factors for the intended endpoint parameters,
    • Verifying the validity of the analysis of the data from the wearable(s) or remote device(s) for detecting, measuring, and tracking changes in physiological and functional/behavioral aspects of the pain condition(s) against gold standard assessments or technology
    • Determining if the endpoints are related to pain conditions or quality of life or appropriate pain-related functional measures , and identifying and defining the concept of interest that specifies the digital endpoint(s) to seek regulatory guidance.

    The UG3 phase will also support outreach activities in preparation for successful recruitment and retention for longitudinal clinical studies planned in the UH3 phase and activities related to the recruitment of patient representatives or advocacy groups into the team. UH3 phase will support research plans for validating the digital health-technology derived outcome assessment into endpoint(s) in the context of use including conducting longitudinal prospective clinical studies to validate the signature(s) and evaluate their reliability for monitoring remote digital biosignatures or functional endpoints in minority health and NIH-designated populations that experience health disparities representing pain conditions.

    In the first UG3 phase of the project, activities may include, but are not limited to:

    • Verification and Validation of Pilot Studies to compare the digital measurements obtained from the algorithms developed to measure the concept of interest against established gold standards. These studies could include testing, optimizing, and refining the algorithms and ensuring their accuracy and reliability in the target patient populations
    • Studies to identify and evaluate factors that may interfere with the precision and accuracy of the proposed DHT measurement(s)
    • Evaluation and Comparison of various Digital Health Technology (DHT) factors such as usability, reliability, cost, scalability, and compatibility to determine the most suitable DHT(s) with optimized options with the measurement algorithms for the subsequent validation study

    In the UH3 phase.In preparation for the UH3 phase, developing user-informed consent and training materials with input from individuals with lived experience and representatives from minority health and NIH-designated populations that experience health disparities to ensure successful recruitment and retention in the validation study (UH3 phase), initiation of outreach activities and collaborations with minority health and NIH-designated populations that experience health disparities and these communities may include racial and ethnic minorities, individuals in rural populations, and individuals with limited English proficiency.

    In the second UH3 phase of the project, activities may include, but are not limited to:

    • Conducting a prospective longitudinal study to investigate the statistical relationships between the digital monitoring biomarker or performance/functional assessment and established biomarkers, clinical outcome assessments, and quality of life metrics and validate and demonstrate the value of the digital assessment(s) as an endpoint(s) compared to existing standards.
    • Assessing how the digital endpoint or functional/behavioral assessment responds to therapeutic or behavioral interventions by determining whether the digital assessment can accurately measure changes in the targeted health outcomes or behaviors in response to specific interventions
    • Submitting a letter of intent to the FDA Biomarker or COA Qualification Program

    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 the development of a candidate biomarker or signature as a digital endpoint 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/data collection or detection method performance have been met, and 4) Evidence that the minimum acceptable sensitivity, specificity, accuracy, and precision of the detection and measurement of digital performance/functional assessments or endpoints are met 5) Evidence for the successful completion of other activities that demonstrate feasibility and readiness for the UH3 phase, in particular, activities for successful recruitment and retention for the longitudinal clinical studies.
    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

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

    Intellectual Property (IP):
    The program strongly encourages the recipients and/or their collaborators to establish an IP agreement with the digital health technology manufacturers for the algorithms and/or related software used to detect, measure, and monitor digital biosignatures or digital functional assessments (see instructions on attachment or letters to address IP issues in Section IV). Recipients of awards are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the development process. Investigators are expected to work closely with technology transfer officials at their institution to ensure that patent filings, and all other necessary intellectual property arrangements are completed in a timely manner.

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

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

    Non-Responsive (Out of Scope) Studies:

    • Studies focused solely on device development with the primary goal being to develop devices rather than validating data analysis and interpretation from those devices.
    • Studies only focused on patient-reported outcomes, observer-reported outcomes, or clinician-reported outcomes rather utilizing those data for developing digital endpoints or functional assessments.
    • Natural history studies that aim to understand disease pathophysiology, genetic mechanisms, or epigenetic mechanisms but do not include the verification and validation of digital endpoints or functional assessments.
    • Studies focused on therapeutic or behavioral interventions that aim to develop or test therapeutic or behavioral interventions for assessing safety or efficacy.
    • Incomplete applications: Applications missing the required components, such as applications with only the UG3 or the UH3 phase or applications missing the Go/No Milestones.

    Non-responsive applications will be administratively withdrawn prior to review.

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

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

    Section II. Award Information

    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 NOFO.

    Application Types Allowed
    New

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

    Clinical Trial?

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

    Funds Available and Anticipated Number of Awards

    The NIH HEAL (Helping to End Addiction Long-term) Initiative intends to commit an estimated total of $5.1 million to fund 4-6 awards in FY 2024. Awards pursuant to this funding opportunity are contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

    Award Budget

    Application budgets are limited to $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 NOFO.

    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 Governments

    • 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 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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted 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. The same UEI must be used for all registrations, as well as on the grant application.
    • eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov 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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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

    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 NOFO 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 NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

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

    Section IV. Application and Submission Information

    1. Requesting an Application Package

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

    2. Content and Form of Application Submission

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

    Letter of Intent

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

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

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

    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.

    Intellectual Property (IP) Strategy (Required, 3 pages maximum):

    Applications exceeding three pages or without the attachment "IP Strategy.pdf" will be withdrawn. If applicable, the IP strategy section should be prepared in consultation with the institution's technology transfer office.
    This NOFO calls for projects that aim to advance research toward developing products that benefit the public. Therefore, applicants will be required to describe the IP landscape of measurements derived from digital health technology (DHT) device(s) that includes any known constraints that could limit the development of the algorithms and associated software (i.e., certain restrictions under transfer or sharing agreements, applicants' past or present IP filings and publications, similar technologies under patent and/or available on the market, etc.) and address them accordingly.

    • If the applicant proposes using a digital health technology (DHT) device(s) or the algorithms and associated software whose IP is not owned by the applicant's institution, 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. The letter of support from the owner of the IP should indicate whether the owner provides the device or technology without restrictions or if there are any restrictions on using the device or technology in the proposed project. The applicant should address how to resolve constraints or impediments if the device or technology does not belong to the applicant's institution. In addition, the applicant should address whether there is an agreement or plan for public disclosure of the results.
    • The applicant must provide information on the filing dates, types of patents, and status, as well as links to the United States Patent Office (USPTO) if patents are being developed related to measurement algorithms and/or associated software under this application.
    • Applicants should also discuss future IP filing plans, including multiple PD/PI and multiple institution filings. 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 NOFO:

    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 digital endpoints or digital biosignatures or digital functional assessments.
    Give details about the ability of the Multiple Principal Investigator (MPI)-led multidisciplinary teams that may consist of clinical and possibly preclinical scientists, bioinformatics, artificial intelligence and statistical experts, data scientists, technical experts with experience relevant for understanding software development tools and expertise to understand digital tools and interfaces , clinicians with drug development experience, regulatory experts, and other academic/industry experts relevant to the therapeutic modality.

    R&R Budget

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

    R&R Subaward Budget

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

    PHS 398 Cover Page Supplement

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

    PHS 398 Research Plan

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

    Specific to this NOFO:

    Research Strategy:


    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 studies, emphasizing the biological research rationale for the digital endpoints or digital performance/functional assessments with a cogent argument outlining its importance and unmet need. Under each header, state the specific objectives of the efforts. In addition, describe the main aims of the proposed study, including the technical questions that will be addressed to develop and validate the digital endpoints or digital performance/functional assessments.
    Significance and clinical Impact:
    Describe why it is necessary to develop and validate digital endpoints or digital performance/functional assessments for future clinical trials for the pain conditions of interest; describe why they may be useful secondary or primary endpoints in clinical trials to advance therapeutic development, behavior/lifestyle interventions, and/or comparative effectiveness studies. Explain how verification and validation studies supported by this RFA will contribute to obtaining regulatory approval for commercialization of associated software or dissemination of open-source analysis packages for use in future clinical trials.
    Approach:
    The approach should describe and justify research plans for both UG3 and UH3, which should include but are not limited to:
    In the first UG3 phase of the project,

    • Selecting the specific digital measurement, identification of the aspect of pain specifying the meaningful health aspect to be studied, and identifying the scope of assessment/ concept of interest (COI)
    • Verification and Validation of Pilot Studies to compare the digital measurements obtained from the algorithms developed to measure the concept of interest against established gold standards. These studies could include testing, optimizing, and refining the algorithms and ensuring their accuracy and reliability in the target patient populations
    • Studies to identify and evaluate factors that may interfere with the precision and accuracy of the proposed DHT measurement(s)
    • Evaluation and Comparison of various Digital Health Technology (DHT) factors such as usability, reliability, cost, scalability, and compatibility to determine the most suitable DHT(s) with optimized options with the measurement algorithms for the subsequent validation study in the UH3 phase
    • Description of the study population for which the endpoint is developed
    • Developing user-informed consent and training materials with input from individuals with lived experience and representatives from minority health and NIH-designated populations that experience health disparities
    • Initiation of outreach activities and collaborations with minority health and NIH-designated populations that experience health disparities and these communities may include racial and ethnic minorities, individuals in rural populations, and individuals with limited English proficiency to ensure successful recruitment and retention in the validation study (UH3 phase)
      In the second UH3 phase of the project, the approach should include a research plan to validate the measurement in the Context of Use (COU), which should include but are not limited to:
    • Defining a measurable improvement or outcome that has practical significance and is beneficial to patients, evaluating relevance, sensitivity, and content validity to which the measure reflects the intended scope of assessment (i.e., COI) for the specified patient population, selecting appropriate measurement approaches and defining endpoints is crucial to effectively capture treatment benefits, and evaluating responsiveness, test-retest reliability, validity and sensitivity to demonstrate that the measure effectively detects the change
    • Conducting a prospective longitudinal study to investigate the statistical relationships between the digital monitoring biomarker or performance/functional assessment and established biomarkers, clinical outcome assessments, and quality of life metrics and validate and demonstrate the value of the digital assessment(s) as an endpoint(s) compared to existing standards
    • Assessing how the digital endpoint or functional/behavioral assessment responds to therapeutic or behavioral interventions by determining whether the digital assessment can accurately measure changes in the targeted health outcomes or behaviors in response to specific interventions
    • Submitting a letter of intent to the FDA Biomarker or COA Qualification Program


    Go/No-Go Milestones:
    Clear quantitative Go/No-Go milestones must be included in the research plan to assess progress in the UG3 phase and the potential for the development of a candidate biomarker or signature as a digital endpoint 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/data collection or detection method performance have been met, and 4) Evidence that the minimum acceptable sensitivity, specificity, accuracy, and precision of the detection and measurement of digital performance/functional assessments or endpoints are met 5) Evidence for the successful completion of other activities that demonstrate feasibility and readiness for the UH3 phase, in particular, activities for successful recruitment and retention for the longitudinal clinical studies.

    Team Management Plan:

    • Applicants 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, data scientists, technical experts with experience relevant for understanding software development tools and expertise to understand digital tools and interfaces , 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.Describe how patient representatives or advocacy groups will be included in the team to incorporate patient perspectives, concerns, and valuable input regarding the relevance and acceptability of digital measurements in the study.
      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.

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

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


    All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.
    The HEAL Initiative has additional requirements that must be addressed in the Data management and Sharing plan. All HEAL-generated data must be shared through the HEAL Initiative Data Ecosystem following HEAL’s compliance guidance (https://heal.nih.gov/data/complying-heal-data-sharing-policy). Specifically, HEAL applicants must include:

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

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

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

    • No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

    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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

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

    5. Intergovernmental Review (E.O. 12372)

    This initiative is not subject to intergovernmental review.

    6. Funding Restrictions

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

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

    7. Other Submission Requirements and Information

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

    Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

    For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

    Important reminders:

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

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

    See more tips for avoiding common errors.

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

    Post Submission Materials

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

    Section V. Application Review Information

    1. Criteria

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

    For this particular announcement, note the following:

    This NOFO supports integrative study approaches directed toward the development of validated remote wearable device-derived digital biosignatures or functional assessments to assess pain therapeutic effectiveness and to identify new digital endpoints. Ultimately the final products would be the algorithms and software used to analyze data from existing wearable technologies demonstrating that the digital biosignatures or functional assessments are sensitive and objective measures of clinical benefit that will withstand rigorous validation and ultimately provide the tools necessary for use in clinical trials and clinical practice.

    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.


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

    In addition, for applications involving clinical trials

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

    Specific to this NOFO:

    How effectively does the project address the need to develop and validate digital endpoints or digital biosignatures, as well as functional assessments for future clinical trials targeting pain conditions of interest? Furthermore, does the project demonstrate the potential value of these endpoints in advancing therapeutic development, behavior/lifestyle interventions, and comparative effectiveness assessments in clinical trials?
    How effectively do the proposed verification and validation studies support the acquisition of regulatory approval for the commercialization of associated software or the dissemination of open-source analysis packages for use in future clinical trials?


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

    In addition, for applications involving clinical trials

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

    Specific to this NOFO:

    How effectively does the application address the investigators' expertise in the target biology, pain condition, clinical phenotype, bioinformatics, detection technology, etc., in order to design and implement a robust identification/validation plan for the digital endpoints or digital biosignatures or digital functional assessments ? How well-versed and experienced are the investigators in pain management and understanding pain conditions, as well as in the analysis and interpretation of large datasets, and the design and development of innovative digital tools and devices for pain assessment? How thoroughly does the application describe the role of statistical analysts in validating the endpoints? How well does the application explain the involvement of patient representatives or patient advocacy groups? How clearly are the roles and responsibilities of collaborators defined in the team management plan?
    How does the application describe the proposed multidisciplinary team, and how effectively does it convey whether the team is suitable for the approach and goals outlined?


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

    In addition, for applications involving clinical trials

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

    Specific to this NOFO:

    How effectively does the application describe an innovative approach to developing and validating digital endpoints, digital biosignatures, or digital functional assessments for pain conditions? Additionally, how well does this approach help improve the objectivity, reliability, and validity of pain research, enhance patient engagement, and achieve cost efficiency, ultimately leading to more effective and personalized pain management strategies?


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

    If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

    In addition, for applications involving clinical trials

    Does the application adequately address the following, if applicable

    Study Design

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

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

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

    Data Management and Statistical Analysis

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

    Specific to this NOFO:

    In the first UG3 phase of the project, how well does the study design/approach describe:

    • The selection of the specific digital measurement, identification of the aspect of pain specifying the meaningful health aspect to be studied, and identifying the scope of assessment/ concept of interest (COI)
    • The verification and validation of Pilot Studies to compare the digital measurements obtained from the algorithms developed to measure the concept of interest against established gold standards. These studies could include testing, optimizing, and refining the algorithms and ensuring their accuracy and reliability in the target patient populations
    • The identification and evaluation of factors that may interfere with the precision and accuracy of the proposed DHT measurement(s)
    • The evaluation and comparison of various Digital Health Technology (DHT) factors such as usability, reliability, cost, scalability, and compatibility to determine the most suitable DHT(s) with optimized options with the measurement algorithms for the subsequent validation study in the UH3 phase
    • The description of the study population for whom the endpoint is developed
    • The development of user-informed consent and training materials with input from individuals with lived experience and representatives from diverse communities
    • The initiation of outreach activities and collaborations with historically underrepresented communities that may include racial and ethnic minorities, individuals in rural populations, and individuals with limited English proficiency to ensure successful recruitment and retention in the validation study (UH3 phase)


    In the second UH3 phase of the project, how well does the approach/research plan describe the validation of the measurement in the Context of Use (COU) in terms of the following:

    • Defining measurable improvement or outcome that has practical significance and is beneficial to patients, evaluating relevance, sensitivity, and content validity to which the measure reflects the intended scope of assessment (i.e., COI) for the specified patient population, selecting appropriate measurement approaches and defining endpoints is crucial to effectively capture treatment benefits, and evaluating responsiveness, test-retest reliability, validity and sensitivity to demonstrate that the measure effectively detects the change
    • Conducting a prospective longitudinal study to investigate the statistical relationships between the digital endpoints or digital biosignatures or digital functional assessments and established biomarkers, clinical outcome assessments, and quality of life metrics and validate and demonstrate the value of the digital assessment(s) as an endpoint(s) compared to existing standards
    • Assessing how the digital endpoint or functional/behavioral assessment responds to therapeutic or behavioral interventions by determining whether the digital assessment can accurately measure changes in the targeted health outcomes or behaviors in response to specific interventions
    • Submitting a letter of intent to the FDA Biomarker or COA Qualification Program

    Milestones:
    Do the proposed milestones sufficiently address the following to assess and determine the progression of the project from the UG3 phase to the UH3 phase:

    • Evidence that study planning and team coordination is in place
    • Evidence that clinical enrollment metrics have been met
    • Evidence that quality assurance parameters for sample/data collection or detection method performance have been met
    • Evidence that the minimum acceptable sensitivity, specificity, accuracy, and precision of the detection and measurement of digital performance/functional assessments or endpoints are met
    • Evidence for the successful completion of other activities that demonstrate feasibility and readiness for the UH3

    Team Management Plan:

    • Does the proposed Multiple Principal Investigator (MPI)-led multidisciplinary team management plan cover in sufficient detail about the inclusion of preclinical scientists, bioinformatics, artificial intelligence and statistical experts, data scientists, technical experts with experience relevant for understanding software development tools and expertise to understand digital tools and interfaces , clinicians with drug development experience, regulatory experts, and other academic/industry experts relevant to the therapeutic modality, and describe the team's ability to design the details of the plans and experiments, and to execute the research strategy
    • Does the team management plan 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, and how well 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
    • Does the application effectively outline the inclusion of patient representatives or advocacy groups in the team to incorporate patient perspectives, concerns, and valuable input regarding the relevance and acceptability of digital measurements in the study

    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.


    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)?


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

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


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


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


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


    Not Applicable.


    Not Applicable.


    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.


    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.

    Intellectual Property (IP) Strategy:
    How well does the intellectual property (IP) strategy address whether the applicant institution owns the IP for the proposed digital health technology (DHT) devices and the algorithms and associated software? If the applicant's institution is not the owner, does the application include a letter of support from the entities? How well does the letter of support describe scenarios where there are no limitations imposed on the studies or the project, allowing the use of the device or technology without restrictions? If there are any restrictions on using the device or technology, how does the letter of support outline the resolution of constraints or impediments?
    How effectively does the application discuss future plans for filing intellectual property (IP), including filing with multiple principal investigators (PD/PI) and institutions? Does the application clearly explain how the IP will be shared or managed if multiple PD/PIs and institutions are involved?


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


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


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


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

    2. Review and Selection Process

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

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

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

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

    Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this NOFO. Following initial peer review, recommended applications will receive a second level of review by the 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 2.4.4 Disposition of Applications.

    Section VI. Award Administration Information

    1. Award Notices

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

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

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

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

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

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

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

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

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

    2. Administrative and National Policy Requirements

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

    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 will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. 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 NOFO.

    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 (HHS) grant administration regulations at 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

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

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

    • Recipients will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.
    • 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 have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

    • Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
    • The 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 recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

    3. Data Management and Sharing

    Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

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

    HEAL Data Sharing Requirements
    NIH intends to maximize the impact of HEAL Initiative-supported projects through broad and rapid data sharing. All HEAL Initiative award recipients, regardless of the amount of direct costs requested for any one year, are required to comply with the HEAL Public Access and Data Sharing Policy. HEAL award recipients must following all requirements and timelines developed through the HEAL Initiative Data Ecosystem (https://heal.nih.gov/about/heal-data-ecosystem), as described in HEAL’s compliance guidance (See Already Funded section: https://heal.nih.gov/data/complying-heal-data-sharing-policy):

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

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

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

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

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

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

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

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

    5. Additional Requirements for HEAL Initiative studies conducting clinical research or research involving human subjects.
    These studies must meet the following additional requirements:

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

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

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

    4. Reporting

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

    Report and ensure immediate public access to HEAL-funded publications:

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

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

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

    Award recipients and their collaborators are required to acknowledge HEAL Initiative support by referencing in the acknowledgment sections of any relevant publication:
    This research was supported by the National Institutes of Health through the NIH HEAL Initiative (https://heal.nih.gov/) under award number [include specific grant/contract/award number; with NIH grant number(s) in this format: R01GM987654].

    A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 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 the threshold. 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 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200 Award Term and Condition for Recipient Integrity and Performance Matters.

    5. Evaluation

    Section VII. Agency Contacts

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

    Application Submission Contacts

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

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

    General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
    Email: GrantsInfo@nih.gov (preferred method of contact)
    Telephone: 301-637-3015

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

    Scientific/Research Contact(s)

    Tiffany Lash, Ph.D.
    National Institute of Biomedical Imaging and Bioengineering (NIBIB)
    Telephone: 301-451-4778
    Email: baileyti@mail.nih.gov

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

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


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


    Emrin Horgusluoglu, Ph.D.
    National Center for Complementary & Integrative Health (NCCIH)
    Phone: 240-383-5302
    Email: emrin.horgusluoglu-moloch@nih.gov


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


    Susan Marden, PhD, RN
    Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
    Telephone: 301-435-6838
    Email: mardens@mail.nih.gov


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

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

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


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


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


    Section VIII. Other Information

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

    Authority and Regulations

    Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.

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