Part 1. Overview Information

Key Dates

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

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

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.

IMPORTANT: Per NOT-OD-24-086 updated application forms (FORMS-I) will be used for this opportunity. The updated forms are not yet available and will be posted 30 calendar days or more prior to the first application due date. Once posted, you will be able to access the forms using one of the following submission options:

1. NIH ASSIST
2. An institutional system-to-system (S2S) solution
3. Grants.gov Workspace

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background:

There is a high unmet need for clinical endpoints that can be assessed remotely in clinical trials. As defined in the FDA/NIH’s Biomarkers, EndpointS, and other Tools (BEST) resource, an endpoint is “a precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question”. In clinical trials, endpoints may include one or more clinical outcome assessment and/or biomarkers. Regulatory agencies, industry, and funding organizations recognize the potential of developing endpoints that can be deployed remotely for use in clinical trials to assess efficacy. Remote monitoring assessment tools may include wearable or home monitoring sensor-based digital health technologies (DHTs) or software-based applications that can be used from a web-based application such as a tablet, phone or computer. Remote assessments can improve clinical research by reducing the burden on study participants and caregivers and can be more sensitive to clinically meaningful changes over time due to more frequent assessments that are less susceptible to the variability from differences in an individual’s state at the time of a single clinical visit. However, successful development of meaningful endpoints requires carefully thought-out and rigorous studies in collaboration with study participants and caregivers (“people with lived experience”; PWLE) to help guide what is “meaningful” and feasible.

Although the use of validated digital endpoints is expected to revolutionize clinical trials, successful implementation and regulatory acceptance requires extensive fit-for-purpose validation and must be able to demonstrate that the endpoints reflect clinically meaningful changes in how participants feel, function, or survive. Therefore, studies proposing to develop and validate assessments for future clinical trial endpoints need to understand the regulatory expectations to successfully design and conduct the studies needed to support the evidentiary requirements. While acceptance of web-based applications and DHT derived endpoints by regulatory agencies will require final validation in clinical trials, there is substantial preliminary work that must be done for the initial development and proof of concept clinical validation. Guidance from the Food and Drug Administration (FDA), and Centers for Medicare & Medicaid Services (CMS) among others, highlights several critical questions that need to be clearly addressed, justified, and supported by high quality data.  Many traditional clinical outcome assessments and biomarkers used for monitoring disease progression or response to an intervention are applicable to more than one disease or condition:  they may share common cognitive, motor, or physiological processes, but may manifest and progress at different rates. Developing and validating DHT derived assessments or biomarkers for remote monitoring is a resource intensive process requiring complex analyses of the high-dimensional datasets generated. The goals of this NOFO are to 1) encourage collaboration across disease areas to pool expertise and resources, and 2) support research to generate the data needed for the development, analytical validation, and proof of concept clinical validation of DHT derived assessments and monitoring biomarkers to be used as future endpoints in clinical trials for three or more disease areas.

Research scope and special requirements and considerations:

• Partnerships with patient advocacy organizations and people with lived experience (PWLE) are required to inform study design, endpoint selection, and increase community uptake. 
• Three or more diseases/conditions are required to encourage standardization of remote monitoring assessment and endpoint development and to promote collaboration and pooled resources and successful translation.
• Development and validation of the proposed remote assessments should fill an unmet need as primary or secondary endpoints in clinical trials, which may include, but is not limited to clinical trials for therapeutic development or rehabilitation research, comparative effectiveness research, and/or clinical trials for interventions for preventative medicine approaches.
• As part of defining the contexts of use (COU), consideration should be given to the feasibility of integrating the remote assessments into clinical trials as primary or secondary endpoints.  
• For the purposes of this NOFO, digital health technologies may include sensor based digital health technologies such as wearable devices, in home technologies, or web-based applications.
• A community engagement plan is required that outlines how communities will be engaged throughout the research process. The plan should identify relevant invested parties as collaborators at a level of involvement that is meaningful and feasible for the community partner(s) and appropriate for the project to enhance the impact of the research. No specific community engaged research approach is required but please see the National Academy of Medicine’s Advancing Health Equity and Systems Transformation through Community Engagement strategy for assessing meaningful community engagement as a reference and to identify core principles to follow (see Other Attachments section in Section IV).
• A timeline, annual milestones and UG3/UH3 Transition that describe the project decision points with quantitative metrics for go/no-go decision making throughout the project timeline must be included (see Other Attachments section in Section IV). At the UG3/UH3 Transition the applicant will be required to submit a research performance progress report (RPPR) that includes the list of completed milestones (developed in collaboration with the PI as part of the initial Notice of Award) to progress to the UH3 implementation phase. These UH3 transition requests will undergo administrative review by NIH staff to determine whether the study will be awarded the implementation phase (UH3). Transition decisions will be based on achievement of study milestones, readiness to conduct the UH3 study, feasibility of completing the UH3 study, availability of funds, and program priorities. 

Appropriate activities for each phase of the UG3/UH3 mechanism may include, but are not limited to:

First Phase (UG3; 1-2 years):

• Device selection and analytical validation pilot studies to optimize the algorithms to measure the concept(s) of interest against gold standards in the target patient populations which may include construct and/or content validation. May include head-to-head comparisons of different DHTs to select the best performing or evaluate the generalizability across devices in preparation for use in the second (UH3) phase.
• Evaluate factors that may interfere with the precision and accuracy of the data and measurement(s) made from the DHTs in real world environments.
• Optimize and finalize protocols to ensure standardization across the sites and target populations; take into consideration missing data, amount of wear/use time needed for planned analyses in the prospective longitudinal clinical validation study (UH3 phase)
• Establish the final statistical analysis and data management plans for the UH3 phase.
• Develop user-informed consent and training materials for the UH3 phase with input from individuals with lived experience from diverse backgrounds (investigators are highly encouraged to review the Informed Consent for Research Using Digital Health Technologies: Points to Consider & Sample Language document from NIH:https://osp.od.nih.gov/wp-content/uploads/2024/05/DigitalHealthResource_Final.pdf).
• Conduct outreach activities and establish collaborations with communities that are historically underrepresented in clinical studies including racial and ethnic minorities, individuals in rural populations, and individuals with limited English proficiency, as part of preparation for successful recruitment and retention in the UH3 phase validation study.
• Obtain input from relevant regulatory agencies such as through Critical Path Innovation meetings (CPIM) and/or consultation with the FDA’s Drug Development Tools qualification programs (https://www.fda.gov/drugs/development-approval-process-drugs/drug-development-tool-ddt-qualification-programs) and/or meetings with the Centers for Medicare & Medicaid Services (CMS) (Coverage with Evidence Development: https://www.cms.gov/medicare-coverage-database/view/medicare-coverage-document.aspx?mcdid=38).  

Second Phase (UH3; 3-4 years but no more than 5 years for both the UG3 and UH3 phases combined):

• Conduct a prospective longitudinal study to determine the statistical relationships between the digital monitoring biomarker or performance/functional assessment with established biomarkers, clinical outcome assessments, and consumer/patient informed quality of life metrics.
• Evaluate the digital biomarker or digital functional/behavioral assessment’s response to a therapeutic or behavioral intervention.
• Obtain regulatory input such as through a Critical Path Innovation Meetings (CPIM) and/or submission of a letter of intent to one of the FDA’s Drug Development Tools qualification programs.

Definitions used in this NOFO:

• Disease/condition:  A disorder of structure or function, which may have a known cause and a distinctive group of symptoms, signs, or anatomical changes.  How a disease or condition is defined may evolve along with the biological understanding of the etiology or symptomatology. For purposes of this NOFO, applicants should reference the criteria used to define the disease/condition which may include definitions from clinical practice guidelines or consensus papers, or similar standardized definitions.
• Digital Health Technologies and sensor-based digital health technology (DHT) are a system that uses computing platforms, connectivity, software, and/or sensors for healthcare and related uses. For the purpose of this NOFO, DHTs may refer to wearable sensors, mobile/app based cognitive or functional assessments, and in-home monitoring technologies.
• Remote assessment: Collection of data from a participant’s location that is distant from the investigator or trial personnel.
• Concept of interest (COI): the aspect of an individual’s clinical, biological, physical or functional state, or experience that the assessment is intended to indicate or reflect.
• 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)
  • Observer-reported outcome (ObsRO)
  • Clinician-reported outcome (ClinRO)
  • Performance outcome (PerfO)/Functional outcome
• 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
  • Monitoring Biomarker: As defined in the Biomarkers, EndpointS, and Other Tools (BEST) Resource (https://www.ncbi.nlm.nih.gov/books/NBK338448/), a monitoring biomarker is one that is measured repeatedly for assessing status of a disease or medical condition or for evidence of exposure to (or effect of) a medical product or an environmental agent.
• Endpoint:  A precisely defined variable intended to reflect an outcome of interest that is statistically analyzed to address a particular research question. A precise definition of an endpoint typically specifies the type of assessments made, the timing of those assessments, the assessment tools used, and possibly other details, as applicable, such as how multiple assessments within an individual are to be combined (BEST Glossary: https://www.ncbi.nlm.nih.gov/books/NBK338448/#IX-E).  
• 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.
• Validation:  A process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose. This may include:
  • Construct Validation: A process to establish, using quantitative methods, the extent to which the relationships among items, domains, and concepts of a clinical outcome assessment conform to a priori hypotheses concerning logical relationships that should exist with other measures or characteristics of patients and patient groups.
  • Content Validation: A process to establish from qualitative research the extent to which the clinical outcome assessment instrument measures the concept of interest including evidence that the items and domains of an instrument are appropriate and comprehensive relative to its intended measurement concept, population, and use.
• Analytical Validation: A process to establish that the performance characteristics of a test, tool, or instrument are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol. This is validation of the test’s, tool’s, or instrument’s technical performance, but is not validation of the item’s usefulness.
• Clinical Validation:  A process to establish that the test, tool, or instrument acceptably identifies, measures, or predicts the concept of interest.

Non-responsive studies include:

• clinical trials or clinical research where the primary intent is to develop therapeutic agents or devices,
• clinical trials or clinical research to evaluate a therapeutic agent or device’s clinical safety, efficacy, effectiveness, and/or clinical management,
• pre-clinical research using animal models or in vitro models,
• applications where the primary intent is to develop diagnostic or risk assessments or biomarkers rather than for monitoring/endpoint development.
• applications that do not include a statement titled “contexts of use” that specifies how the proposed endpoints will fill an unmet need for the diseases/conditions specified, and clearly defines the three or more diseases/conditions to be included,
• applications that are proposing to develop a device or app rather than using existing devices/platforms,
• applications that do not include milestones,
• applications that do not include diseases/conditions within the participating NIH IC missions.

Non-responsive applications will be administratively withdrawn without review.

Potential applicants are strongly encouraged to contact NIH Scientific/Research staff and participating NIH Institutes/Centers prior to preparing an application to discuss  whether their application fits the mission of a particular NIH IC and seek prior approval for applications expecting to exceed the $500,000 direct costs per year budget cap. See also under Section IV.7 below ("Other Submission Requirements and Information").

Expectations and Requirements for Resource and Data Sharing:

The NIH Policy for Data Management and Sharing (Policy) expects researchers to maximize the sharing of scientific data and data be accessible as soon as possible and no later than the time of an associated publication or the end of the award period, whichever comes first. NIH requires all applications submitted in response to this NOFO to include a Data Management and Sharing Plan (DMS Plan). The DMS Plan is expected to address the Elements as described in Supplemental Information to the NIH Policy for Data Management and Sharing: Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014). The DMS Plan will be reviewed and approved by NIH Program Staff prior to award. Awardees will be required to comply with their approved Plan and any approved updates.

Awardees are expected to share data and/or biospecimens through broad-sharing data and/or biospecimen repositories. For applications that aim to analyze existing data, DMS plans should describe where and how other researchers can access that data to enable reproducibility and reuse.

IC Interest Areas:

National Institute of Neurological  Disease and Stroke (NINDS)

NINDS is interested in applications that propose to develop assessments that meet an unmet need for neurological diseases and conditions across the lifespan. NINDS recognizes that DHT derived measurements needed for use in pediatric or elderly populations may be substantially different than adult populations and require distinct efforts.  This NOFO is aligned with the NINDS 2021-2026 Strategic Plan’s priority areas of supporting the development and validation of biomarkers and outcome measures, as well as aiding in the efforts to promote health equity by supporting representative validation efforts and by developing remote assessments that can reduce the barriers to participate in clinical trials. Research activities outside of the NINDS mission or traditionally supported by another NIH Institute or Center that is not signed onto this NOFO will not be considered. 

National Cancer Institute (NCI)

NCI is interested in applications aligned with the NCI mission and scientific priorities and focused on the development and validation of cancer-specific digital monitoring biomarkers, clinical outcome assessments, and endpoints. As cancer is a group of diseases, applicants may define each cancer type or subtype (including molecular subtypes) as separate diseases if scientifically justified. NCI is particularly interested in applications that:

• Address unmet needs of high-risk, understudied, and/or underserved cancer populations including but not limited to individuals with early-onset cancers, rare cancers, pediatric cancer survivors, older cancer patients with comorbities, and rural patient communities,
• Develop and validate digital biomarkers to monitor cancer treatment related symptoms, sequelae, and/or outcomes (e.g., pain, cognitive impairment, adverse events, late effects toxicity),
• Develop and validate cancer-specific biomarkers using analyte data derived from electrochemical DHTs,
• Use DHTs to monitor physiological status and/or clinical outcomes associated with physical function, nutritional or dietary status, aerobic capacity, body composition, sleep/circadian disruption, and/or mobility, and
• Use DHT-measured physiological and analyte data to monitor treatment response and inform treatment selection, optimized dosing, and adaptive designs.

National Institute of Aging (NIA)

NIA is interested in applications that focus on development, verification and validation of digital biomarkers and digital clinical outcome assessments in age-related neurological disorders, such as Alzheimer’s Disease (AD) and related dementias (ADRD).  AD/ADRD are a spectrum of conditions that cause a decline in cognition, function, and behavior. In addition to AD, examples of ADRD are Lewy body dementia (LBD), frontotemporal disorders (FTD), limbic-predominant age-related TDP-43 encephalopathy (LATE), Vascular contributions to cognitive impairment and dementia (VCID) as well as mixed dementias. Through this NOFO, NIA supports research based on systematic collection, scientifically sound analysis, and interpretation of clinically meaningful health information to improve age-related outcomes, decrease health disparities and improve care delivery of older adults. This NOFO is aligned with NIA/NAPA AD+ADRD Research Implementation Milestone for Diagnosis, Assessment, and Disease Monitoring, as well as joining the efforts to promote health equity by developing remote assessments that can reduce the barriers to participate in clinical trials. NIA welcomes applications aligned with NIA’s strategic mission. Applications addressing topics related to AD and ADRD are strongly encouraged.

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

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

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

Other

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

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

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply-Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of  a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019 and Notice of NIH's Interest in Diversity, NOT-OD-20-031.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the 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:

Carol Taylor-Burds, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Page Limitations

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

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Timeline and Proposed Milestones (required; 3 pages maximum):

Milestones should describe project decision points with quantitative metrics for go/no-go decision making throughout the funding period. Clear deliverables with corresponding Go/No-Go milestones should be included at the end of the UG3 phase and annual quantitative milestones are required for each year of the UG3 and UH3 phases as indicators of a project's continued progress or emergent difficulties. Milestones will be used to monitor project progress as part of the evaluation for continued funding by the Program Official and Project Scientists.

For each milestone, provide a brief description of the success criteria and justification for those criteria.

• Quantitative milestones are dependent on the project but should include but are not limited to:
• Progress metrics such as evidence of community engagement, obtaining user feedback, reaching enrollment and data collection goals, etc.
• Performance metrics such as demonstrating data quality and completeness, reaching target analytical sensitivity, specificity, precision and accuracy thresholds, etc.

A Gannt chart for the timeline of attaching each milestone is strongly encouraged.

Team Management plan (required; 2 pages maximum)

All applicants must include a team management plan that describes the workflow of the team/key personnel. Applicants are strongly encouraged to form multidisciplinary teams that consist of clinical scientists, disease/biology matter expertise, statisticians, particularly those with clinical trial design expertise, regulatory expertise, and other academic/industry experts relevant to the modalities used in the application. 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 section should be complementary to the “Multiple PD/PI Leadership Plan” leadership plan by focusing on how the project will be managed across sites, PIs, co-Is and consultants. Effective project management is a critical component of achieving the program goals, especially as the team size increases. Elements to consider include:

• Organizational structure, team composition, and roles
• Shared vision, contributions, and distributed responsibility for decision-making
• Resource sharing and allocation
• Credit assignment
• Knowledge transfer
• Coordination and communication
• Intra-team data sharing, archiving, and preservation

Community engagement plan (required; 2 pages maximum):

Community engagement plan: In an Other Attachment entitled “Community Engagement Plan.pdf”, all applicants must include a summary that describes how community engagement strategies, community input, and community-engaged research will be incorporated throughout the study. The attachment should describe the community partners (e.g, who they consist of – community advisory boards, community organization, families from diverse linguistic and cultural backgrounds), their role, and how they will be collaboratively engaged in the research project (e.g., activities, frequency and duration of involvement). The community engagement plan should justify how the planned partners and level of involvement will enhance the research project and relevance of the project to the communities the research is meant to impact. The plan also should demonstrate the feasibility of engaging the community partners in the research at the planned level of involvement. Demonstration of feasibility should include (but is not limited to) letters of support and/or formal roles on the application (e.g., co-investigator, consultant).Serving as a research participant is not considered a collaboration, nor is solely informing recruitment and retention strategies.

Intellectual property (IP) Strategy

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

Applicants should describe the IP landscape surrounding any software development or analysis algorithms if commercialization is intended and any known constraints that could impede development and how they will be addressed. If the applicant proposes using a DHT whose IP is not owned by the applicant's institution, the applicant should include a letter addressing their freedom to operate (see letter of support) from any entities owning the IP, and indicating there will not be any limitations imposed on the studies or the product which would impede achieving the goals of the funding program.

If patents pertinent to the DHT derived biomarker or COA being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable.

Applicants should discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved.

Other Attachments:

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Context of Use and Specific Aims

Contexts of Use: briefly describe the contexts of use as to how the proposed DHT derived remote assessments (biomarkers and/or COAs) will be used as primary or secondary endpoints, what type(s) of clinical trials they are currently most needed for, and how they would be used to complement or replace existing standards.

Specific Aims; Briefly describe the project aims for both the UG3 and UH3 phases, including the questions to be answered and general approach taken. 

Research Strategy

The Research Strategy Section should include the following sections and address (but is not limited to) the following topics:

Clinical Contexts and Unmet Needs:

• Describe what kinds of clinical trials the potential DHT derived endpoints would be used for, and how they would fill an unmet endpoint need and/or be a significant improvement over existing assessment.
• Describe what the current standard assessments are for the same use cases and what the limitations are that the remote assessments are designed to overcome.

Premise and Rationale for the Proposed DHT Derived Biomarkers or COAs:

• Define the diseases/conditions being included and the similarities and differences in how the proposed DHT derived biomarkers or COAs would be used for the different populations.       
• For DHT derived biomarkers and COAs describe the relationship between the proposed biomarkers with the biological/physiological processes and/or symptoms/features of the diseases/conditions, respectively.
• Applicants are STRONGLY encouraged to include a table that specifies each of the biomarkers and/or COAs being measured and the “concept of interest” it is intended to reflect.
• Describe why these measurements are expected to reflect clinically meaningful changes and how “meaningfulness” was or will be established
• Address the rigor of any preliminary data and/or supporting literature used to support the premise and rationale.

Approach and Statistical Analysis Plans:

Describe the overall study designs and statistical approaches for the UG3 and UH3 phases and describe how the studies are designed to establish:

• what is/are the best DHT(s) to use to measure the candidate endpoints and what criteria were/will be used for the selection process (applicants may propose to do head-to-head comparison of these DHTs in the first phase of the application, or they may describe the criteria and/or processes that were used to select the DHT(s) proposed in the application)
• how the technical validity (analytical validation) will be established to demonstrate that the DHT(s) are sufficiently reliable and accurate for measuring the concepts of interest that the proposed endpoints will measure in real world environments
• if applicable, what and how other established outcome assessments and/or biomarkers will be used to demonstrate construct validity
• what control group(s) will be recruited in the prospective longitudinal study (UH3 phase) and how the normative reference dataset generated will be used to statistically inform interpretation of the biomarkers/COAs such as defining rate of disease progression/change and identifying and controlling for biological or environmental confounds
• how the minimum clinically important difference (MCID) at the individual participant or patient level will be quantified and statistically established to inform clinical trial design decision making
• how the study will be designed to assess if the DHT derived measure(s) is/are an improvement over existing measures.

Scientific Rigor:

• This NOFO explicitly emphasizes the NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm). For example, the 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. These recommended research practices include describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply- Application Guide. 

Other Plan(s): 

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

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

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply- 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-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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

Information on the submission process and a definition of on-time submission are provided in the How to Apply- Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

Applications must be submitted electronically following the instructions described in the How to Apply-Application Guide.  Paper applications will not be accepted.

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

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

Important reminders:

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

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply-Application Guide.

See more tips for avoiding common errors.

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

Webinar

In order to learn more about this NOFO and to have the opportunity to ask questions, a pre-application informational webinar will be held once a year in December, and the recording will be posted online at: https://www.ninds.nih.gov/current-research/focus-tools-topics/focus-biomarkers-research  under the News & Events section.

Information on how to register for the webinar is posted on the NINDS Events page: https://www.ninds.nih.gov/news-events/events?page=1 under “PAR Webinar: Digital Health Technology Derived Biomarkers and Outcome Assessments for Remote Monitoring and Endpoint Development (UG3/UH3 - Clinical Trial Optional)”

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the How to Apply-Application Guide.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113  and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

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.

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). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Review Criteria

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

Factor 1: Importance of the Research

Significance

• Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance.
• Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g. prior literature and/or preliminary data) and whether the scientific background justifies the proposed study.

Innovation

• Evaluate the extent to which innovation influences the importance of undertaking the proposed research. Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field.
• Evaluate whether the proposed work applies novel concepts, methods or technologies, or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

Specific to this NOFO: 

• Assess how likely the proposed sDHT derived biomarker(s) and/or clinical outcome assessments would be used in future clinical trials for the contexts of use proposed.
• Evaluate the added value of these candidate endpoints to reduce burden to study participants/caregivers and/or improve clinical trial efficiency by reducing endpoint variability if the study achieves its goals.
• Assess  if the benefits of implementing the sDHT derived biomarker(s) and/or clinical outcome assessments for the proposed contexts outweigh any foreseen implementation issues.  

Factor 2. Rigor and Feasibility

Approach

• Evaluate the scientific quality of the proposed work. Evaluate the likelihood that compelling, reproducible findings will result (rigor) and assess whether the proposed studies can be done well and within the timeframes proposed (feasibility).

Rigor:

• Evaluate the potential to produce unbiased, reproducible, robust data.
• Evaluate the rigor of experimental design and whether appropriate controls are in place.
• Evaluate whether the sample size is sufficient and well-justified.
• Assess the quality of the plans for analysis, interpretation, and reporting of results.
• Evaluate whether the investigators presented adequate plans to address relevant biological variables, such as sex or age, in the design, analysis, and reporting.
• For applications involving human subjects or vertebrate animals, also evaluate:
  • the rigor of the intervention or study manipulation (if applicable to the study design).
  • whether outcome variables are justified.
  • whether the results will be generalizable or, in the case of a rare disease/special group, relevant to the particular subgroup.
  • whether the sample is appropriate and sufficiently diverse to address the proposed question(s).
• For applications involving human subjects, including clinical trials, assess the adequacy of inclusion plans as appropriate for the scientific goals of the research. Considerations of appropriateness may include disease/condition/behavior incidence, prevalence, or population burden, population representation, and/or current state of the science.

Feasibility:

• Evaluate whether the proposed approach is sound and achievable, including plans to address problems or new challenges that emerge in the work. For proposed studies in which feasibility may be less certain, evaluate whether the uncertainty is balanced by the potential for major advances.
• For applications involving human subjects, including clinical trials, evaluate the adequacy and feasibility of the plan to recruit and retain an appropriately diverse population of participants. Additionally, evaluate the likelihood of successfully achieving the proposed enrollment based on age, racial, ethnic, and sex or gender categories.
• For clinical trial applications, evaluate whether the study timeline and milestones are feasible.

Specific to this NOFO;  

• Evaluate whether the milestones are appropriate with quantitative Go/No-Go milestones and success criteria that must be achieved by the end of the UG3 phase in order to transition to the UH3 phase.
• Evaluate how well the milestones are clear indicators of feasibility and include appropriate performance metrics of the DHT biomarker and detection method(s) for measuring the COA endpoint of interest
• Assess how well the Community Engagement plan: 1) Describes the roles of the community partners and provide sufficient resources to support their engagement, 2) describes the potential research benefits to the community partners, 3) describe how information from the study will be disseminated back to the community, 4) describes the feasibility of success in ensuring the research is relevant to the communities it is meant to impact. 
• Evaluate how well the experimental design proposed will test if the DHT can be used as proposed for the  Contexts of Use described

Factor 3. Expertise and Resources

Investigator(s)

• Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.

Environment

• Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.

.

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

Specific to this NOFO:

• Assess if there are any significant concerns with the Intellectual Property (IP) strategy or known landscape that could be a barrier to translational success and adoption into future clinical trials.  

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, 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, 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.

Vertebrate Animals

When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals 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. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.

Resubmissions

As applicable, evaluate the full application as now presented.

Renewals

Not Applicable

Revisions

Not Applicable

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the ICs which applications are assigned in accordance with NIH peer review policies and practices, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

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.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 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.

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

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk. For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances.  See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

Successful recipients under this NOFO agree that:

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by any funded entity, recipients and subrecipient(s) are required to: Use health IT that meets standards and implementation specifications adopted in 45 CFR part 170, Subpart B, if such standards and implementation specifications can support the activity.  Visit https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-D/part-170/subpart-B to learn more.

Where the award funding involves implementing, acquiring, or upgrading health IT for activities by eligible clinicians in ambulatory settings, or hospitals, eligible under Sections 4101, 4102, and 4201 of the HITECH Act, use health IT certified under the ONC Health IT Certification Program if certified technology can support the activity. Visit https://www.healthit.gov/topic/certification-ehrs/certification-health-it to learn more.

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

        1) ongoing and consistent access to HHS owned or operated information or operational technology systems; and 

        2) receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Recipients shall develop plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data. Please refer to NIH Post-Award Monitoring and Reporting for additional information. 

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.
• Defining objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
• Developing and proposing rigorous milestones that will be achieved during the project period.
• Pursuing patent protection, as appropriate and consistent with the terms and conditions of the award and goals of the program.
• Providing progress reports with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not. In cases when NIH program staff request raw data, recipients agree to provide the data.
• Participate in progress meetings (virtual) at once or twice a year that are organized with NIH staff.
• Communicating any regulatory meeting dates and agenda to the NIH program staff and invite their participation.
• Communicating study reports from CROs, meeting minutes (and associated data packages if applicable), letters and other forms of communications with FDA, and other authorities, if applicable.
• Providing regulatory and clinical documents that are required for administrative review.
• Verifying that the clinical study is performed in accordance with Good Clinical Practices (GCP) and all IC specific guidelines for data and safety monitoring in clinical trials (e.g. NINDS Guidelines for Data and Safety Monitoring in Clinical Trials: http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm, and must provide data and regular updates to NIH

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

• Each project will have the support of one or more Subject Matter Expert(s) from NIH program staff who are consulted based on their expertise in the disorder(s) being studied and / or the implementation of the proposed translational research. The responsibility of the SME is to advise the Program Official on project approvals such as questions related to the landscape of the disease or condition(s) being studied.
• One or more NIH Program Officer(s) will be assigned to this award. The Program Officer(s) will be responsible for scientific and programmatic stewardship and guidance and will be named in the Notice of Award.     
• Prior to award, the Program Officer(s) will develop and negotiate final milestones with the PD/PIs that will be incorporated into the Notice of Award.
• The Program Officer(s) will be responsible for assessing the progress of the project towards the specified milestones, and for recommending if further funds should be released to the project.
• The Program Officer(s) may require the PIs seek regulatory input and share the results of those meetings to demonstrate the project’s continued translational relevance. In rare cases, additional supplementary funding to complete additional work required by regulatory agencies to meet translational objectives, may be considered (if funds are available).     
• The Program Officer(s) may consult as necessary with other NIH Program Officer(s) with relevant expertise, assuming confidentiality agreements are in place to mitigate conflicts and protect intellectual property.
• The continuation of funding recommendation is made by Program Officer(s) reviewed by the Associate Division Director overseeing this program. Funding decisions take into consideration progress towards milestones and overall progress towards meeting the project goals as well as programmatic prioritization, and budget considerations.
  • In rare, well-justified occasions, future-year milestones may be renegotiated based on data and information obtained during the previous year.
  • If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued.
  • In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NIH portfolio balance and program priorities, competitive landscape, and availability of funds.
  • Milestone negotiation and finalization will be done collaboratively with the Program Officer(s) and PD/PIs.
  • Virtual meetings will be held once or twice a year for the PDs/PIs to provide updates on the research and discuss progress with the NIH Program Officer(s).

Areas of Joint Responsibility include: 

• Milestone negotiation and finalization will be done collaboratively with the Program Officer(s) and PD/PIs. 
• Virtual meetings will be held once or twice a year for the PDs/PIs to provide updates on the research and discuss progress with the NIH Program Officer(s). 

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.

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

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 Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR Part 200.301.

Section VII. Agency Contacts

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

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

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

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

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

Carol Taylor-Burds, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Dana L. Wolff-Hughes, Ph.D.

National Cancer Institute (NCI)
Telephone: 240-620-0673
Email: [email protected]

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

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

Crystal Wolfrey
National Cancer Institute (NCI)
Telephone: 240-276-6277
Email:[email protected]

Section VIII. Other Information

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

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