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

A biomarker is a defined characteristic that is measured as an indicator of a normal biological process, pathogenic process, or responses to an exposure or intervention, including therapeutic interventions. Biomarker modalities are diverse, and can include ‘omics, imaging, behavioral, digital and physiologic endpoints. Because the measurement of the biomarker is integral to defining the biomarker, it is necessary to describe the biomarker in terms of its biological source or matrix, measurable features, and the analytic method used to measure it (“detection method”).

Biomarkers are critical to the discovery and development of therapeutics and can serve a variety of functions such as verifying therapeutic target engagement, improving trial design by patient stratification, and facilitating clinical care decisions. Despite the active pace of discovery of novel biomarker candidates, few biomarkers progress beyond discovery to the robust analytical and clinical validation needed for use in Phase II and Phase III clinical trials. Thus, there is a critical need to advance validation of biomarkers to improve public health, particularly for disorders of the nervous system where advancing therapeutics from discovery to the market are notoriously challenging. Validation of biomarkers for all neurological and neuromuscular disorders within NINDS’ mission are within scope and may include a context of use focused on any part of the age spectrum.

This NOFO is intended to address the gap in biomarker validation by encouraging rigorous clinical validation of the biomarker detection method for one or two specified context(s) of use.

Definitions of terms used in this NOFO:

• Context of Use (COU): A statement that fully and clearly describes the way the biomarker is expected to be used. The COU should include the biomarker category (susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, or safety), the modality, method of detection, and clinical population characteristics. Context of use statements are discussed extensively in the Framework for Defining Evidentiary Criteria for Biomarker Qualification developed by the Biomarkers Consortium: https://fnih.org/sites/default/files/final/pdf/Evidentiary%20Criteria%20Framework%20Final%20Version%20Oct%2020%202016.pdf
• Concept: In a regulatory context, the concept is the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to indicate or reflect.
• Detection method: The method(s) used for measuring the biomarker(s).
• 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 (which may include specimen collection, handling and storage procedures). This is validation of the test’s, tool’s, or instrument’s technical performance to measure the biomarker(s) of interest.
• Clinical Validation: A process to establish that the test, tool, or instrument acceptably identifies, measures or predicts the concept of interest. Clinical validation establishes the data needed to reach conclusions or interpret the results of the biomarker(s) readout, and the level of confidence for these interpretations.
• Composite biomarkers/biomarker signatures: when more than one biomarker is being validated for the same context of use (e.g., a panel of biomarkers, or set of features used as a composite indicator).
• Clinical Outcome Assessment (COA): a measure that describes or reflects how a patient feels, functions, or survives (includes patient-reported outcomes, observer-reported outcomes, clinician-reported outcomes, and performance outcomes).
• 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 assessments (such as measurements derived from accelerometers). Both digital biomarkers and digital performance assessment are within scope of this NOFO, however other patient-reported outcomes, observer-reported outcomes, and clinician reported outcomes are not within scope.

Biomarker categories as defined in the Biomarkers, EndpointS, and Other Tools (BEST) Resources (https://www.ncbi.nlm.nih.gov/books/NBK338448/) include:

• Monitoring biomarkers to track the success of a therapeutic intervention or the disease progression
• Diagnostic biomarkers used to detect or confirm presence of a disease or condition of interest or to identify individuals with a subtype of the disease.
• Prognostic biomarkers for predicting outcomes
• Predictive biomarkers for differentiating individuals based on favorable or unfavorable effect from a therapeutic or other intervention
• Pharmacodynamic/response biomarker that indicates biologic activity of a medical product or environmental agent without necessarily drawing conclusions about efficacy or disease outcome or necessarily linking this activity to an established mechanism of action.
• Safety biomarkers to indicate the likelihood, presence, or extent of an adverse effect
• Susceptibility/risk biomarkers that indicate the potential for developing a disease or medical condition in an individual who does not currently have a clinically apparent disease.

Research Objectives

This NOFO supports research to conduct clinical validation of a biomarker or biomarker signature or composite biomarker for one or two specified context(s) of use. For the purpose of this NOFO, the term “Biomarker(s)” will be used interchangeably with biomarker signature and composite biomarkers.  Premise for the utility of the biomarker(s) should include evidence that the biomarker(s) has undergone preliminary testing in an appropriate clinical population, using either prospective or retrospective data or samples, and shows sufficient clinical sensitivity and specificity to predict or measure the relevant clinical or biological concept of interest to warrant additional investment.  In addition, applications to this NOFO should include evidence that the detection method for the biomarker has already been developed and analytical validated with sufficiently reliable performance for in the proposed context of use. 

Earlier stage research that still needs to conduct clinical proof of concept studies to establish the relationship between candidate biomarkers with a concept of interest (with or without detection method development) should consider applying to the companion NOFO, PAR-22-089 “Development of Biomarkers or Biomarker Signatures for Neurological and Neuromuscular Disorders”. Alternatively, studies that are seeking to conduct final analytical validation research  should consider the companion NOFO “Clinical Validation of Biomarkers for Neurological and Neuromuscular conditions”.   

This funding opportunity uses a cooperative agreement, milestone driven mechanism that enables significant input from NIH staff to assist investigators with preparing and evaluating their analytical validation strategy through milestone negotiation.

The Analytical Validation NOFOs and companion Clinical Validation NOFOs are designed to help gather the data package needed for clinical trial readiness and may be used to support a submission to the FDA’s Biomarker Qualification Submission or to the FDA’s Center for Devices and Radiological Health, if applicable.

For more information on the Biomarker Qualification program see: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm

Application Characteristics

• One or two clearly defined context(s) of use
• A strong justification for the clinical and/or research need of the biomarker(s) and the detection method for the context(s) of use.
• Justification of feasibility, including potential added clinical burden and cost, of incorporating the biomarker into clinical trials or clinical practice (as appropriate for the context(s) of use).
• A clear and well justified study design and statistical design(s)
• A direct comparison to existing biomarkers or clinical outcome assessments used for the same COU, if applicable.
• A multi-site design to demonstrate reliable results across  sites in a sufficiently representative cohort, or a strong scientific justification why only one site is needed.
• Evidence of scientific rigor in the supporting literature underlying the premise, the preliminary data, as well as in the research strategy, design, execution, and interpretation of the proposed studies.
• A clear and feasible timeline with quantitative annual milestones that demonstrate continued feasibility and progress towards the project’s success (see section IV “Other Project Information”)
• A team management plan (see section IV “Other Project Information”)
• A Plan for Enhancing Diverse Perspectives (PEDP) (see section IV “Other Project Information”)
• If applicable, an Intellectual Property (IP) plan (see section IV “Other Project Information”)

Clinical Validation should include the following metrics with use of FDA guidance standards appropriate for the Context of Use:

• Sensitivity and specificity of the biomarker within the Context of Use, including methods for binary and/or continuous analysis.
• Area Under the Curve (AUC) as determined by Receiver Operator Characteristic (ROC) Analysis
• Estimation of the prevalence of the marker within subjects or patients for the intended clinical context.
• Establishing the appropriate thresholds or reference ranges for the biomarker for decision-making  within the context of use.
• Positive Predictive Value (the probability that a positive screening test result is true, taking into account the prevalence of the disease or condition in the population being measured).
• Negative Predictive Value (the probability that a negative screening test result is true, taking into account the prevalence of the disease or condition in the population being measured).

Collaborations and Consultants

Multidisciplinary collaboration among scientific investigators, clinical scientists, disease/biology matter experts, statisticians, regulatory expertise, and other academic/industry experts relevant to the context of use in the application as well as clinical and laboratory staff are an integral part of the application.

Investigators are also encouraged to form collaborations/obtain consultants with individuals knowledgeable in relevant regulatory processes and/or statisticians knowledgeable in clinical trial design.

Leveraging Existing Resources

Where applicable, applicants are encouraged to leverage existing research resources for their studies. Such resources may include clinical biospecimen samples from the NINDS Human Biospecimen and Data Repository (BioSEND; https://biosend.org/) or other existing biospecimen, imaging and data repositories. Leveraging the resources of ongoing clinical trials or clinical studies supported through other Federal or private funds is also encouraged.

Rigor, Reproducibility, Data Sharing and Intellectual Property

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.

To improve reproducibility and community uptake, investigators are generally expected to share code/scripts, analytic tools/statistical models, protocols/processes and metadata before the end of the project’s period of performance. If there is a plan to commercialize aspects of the project such as analytic software, applicants should consult with their tech transfer office when developing the Data Management and Sharing Plan and intellectual property plan.  Budgets should reflect any costs associated with these efforts. Information on many available NIH supported or frequently used repositories is available at: https://www.nlm.nih.gov/NIHbmic/nih_data_sharing_repositories.html

Applicants collecting biofluid samples from prospectively enrolled study participants are encouraged to share samples through the NINDS biomarker repository, BioSEND (https://biosend.org/ ) to provide the broader scientific community with a data resource for hypothesis generation and test validation. Applicants should contact BioSEND to incorporate sharing plans and cost in their application.

Pre-Application Consultation

Applicants are strongly encouraged to consult with NINDS Program Staff early on during the planning for an application. This early contact will provide an opportunity to discuss and clarify NINDS policies and guidelines, including the scope of the project relative to the NINDS mission and intent of this NOFO. These discussions can also provide any needed clarification regarding development of an appropriate timeline and milestone plan and guidance for requesting approval of budgets that exceed $500,000 direct cost in any given year.

Funding Considerations

Applications within the top scoring meritorious range will be considered for funding. Within that range, priority may be placed on applications that fill a critical program gap to ensure biomarker development that is reflective of the breadth of disorders and conditions within NINDS’s mission. Additionally, priority will be given to biomarkers that: 1) address an unmet medical need, 2) are supported by a strong biological rationale, 3) include a carefully designed plan for performance evaluation, 4) include a plan for standardization of samples and data collection for use in validation and 5) provide a strong justification for the utility of the biomarker in the clinical setting or for use in clinical trial design.

Applications Not Responsive to this NOFO

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,
• applications where the primary intent is to validate clinical outcome assessments rather than biomarkers,
• applications that do not include a context of use statement
• applications that do not include milestones,
• applications that are not within the NINDS mission

Non-responsive applications will be administratively withdrawn without review.

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

Plan for Enhancing Diverse Perspectives (PEDP)

The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation.  Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex (including gender identify, sexual orientation, or transgender status) of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions.  Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

The PEDP will be submitted as Other Project Information as an attachment (see Section IV).  Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP Guidance materials.

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

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.

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: carol.taylor-burds@nih.gov

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.

Other Attachments:  

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. Annual quantitative milestones are required to provide clear 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 items such as:

• Progress metrics such as enrollment goals, sample and data collection goals, key experiments conducted, etc.
• Performance metrics such as reaching target sensitivity, specificity, precision and accuracy thresholds, achieving target inter and intra rater reliability and achieving other QA/QC thresholds needed for successful analytical validation across sites (if applicable) and operators. 
• If applicable, planned interactions to obtain feedback or submit qualification packages to regulatory agencies such as the FDA or CMS such as, but not limited to, filing for qualification as a medical device development tool, letter of intent for biomarker qualification, CLIA certification, or plans to request a FDA Q-Submission meeting

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

Team management plan (required; 3 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

Associated clinical trial protocols and consent forms (required if applicable; no page limit): Applications that propose to conduct ancillary studies to clinical trials and/or leverage samples/data collected from previous clinical trials must include the clinical trial protocols and consent forms used in the trials.

Intellectual Property Plan (if applicable; 1 page maximum):  

Applicants are encouraged to prepare this section in consultation with their institutions' technology transfer officials.

Applicants should describe any constraints of which they are aware that could impede commercialization (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar biomarkers that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program. If the IP of the detection method device/technology/software is owned by an entity other than the applicant's institution, then a letter of support should be obtained 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 have been filed around the biomarker detection method(s) used in this application, then the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable.

Letters of Support (if applicable; no page limits):

• Applicants should include letters of support from consultants, contractors, and collaborators.
• Include letters of support/agreement for any collaborative/cooperative arrangements, subcontracts, consultants, and / or BioSEND if biospecimens are being collected.
• If applicable, 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 existing biospecimens are to be used, include letters of support or approval for use of those samples, including those banked at BioSEND. For example, if samples include those adjudicated by the Parkinson's Disease Biospecimen Review Access Committee (PD-BRAC), a letter indicating BRAC approval should be included (https://pdbp.ninds.nih.gov/pd-brac)

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity. 
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 2 pages in length and should include:
  • Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
  • Description of how the PEDP will advance the scientific and technical merit of the proposed project;
  • Anticipated timeline of proposed PEDP activities;
  • Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex (including gender identity, sexual orientation, or transgender status).
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex (including gender identity, sexual orientation, or transgender status).

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP Guidance material.

SF424(R&R) Senior/Key Person Profile

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

R&R or Modular Budget

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

PEDP implementation costs

• Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7:https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm).

PEDP implementation costs:

Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7): https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

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:

This NOFO supports the clinical validation of biomarker(s), that are fit for the purpose for one or two contexts of use.

Context of Use and Specific Aims

Context of Use: briefly describe the contexts of use which must include both the BEST biomarker category and the biomarker’s intended use in therapeutic development or clinical practice (no more than two contexts of use should be included).

Specific Aims Briefly describe the project aims, including the questions to be answered and the performance outcomes and characteristics needed in order to be used and interpretable for the stated Context of Use(s). A scientific hypothesis is not required for this type of application.

Research Strategy

The Research Strategy Section should include the following sections and address the following topics:

Clinical Context and Unmet Need:

• Provide a paragraph under the heading “Context of Use” that expands on the Context of Use described in the aims page, and explains how the biomarker/biomarker signature/composite is intended to be used to advance therapeutic development or in clinical practice, including the specific clinical population(s) where the biomarker is intended to be used.
• Describe the unmet need for the candidate biomarker(s); if applicable, justify how the candidate biomarker and detection method will be a meaningful advancement to any existing biomarkers, outcome assessments, or other tools that are currently being used for the same context of use.
• Describe the feasibility of broadly implementing the biomarker(s) for the proposed context of use, including limiting factors such technical expertise required, amount of time or cost, or burden for patients and clinicians. 
• Explain how the evidence generated in the application will enable clinical trial readiness and advance translational medicine for the context of use specified.

Premise, Biological Rationale and Technical Readiness:

• Provide rigorous supporting literature and/or preliminary data supporting the biological premise for the candidate biomarker(s) as an indicator(s) of a normal biological process, pathogenic process, or biological responses to an exposure or intervention, including therapeutic interventions, as appropriate for the specified context of use.
• Describe the overall strengths, weaknesses, and rigor of the supporting literature and preliminary data.
• Describe the evidence that the biomarker has undergone initial testing in the relevant clinical population using retrospective or prospective data, including the initial sensitivity(ies) and specificity(ies) that has/have been found.
• Describe the method of detection and cite any protocols, patents for prototypes demonstrating it has been analytically validated and has the necessary dynamic range, sensitivity, specificity, accuracy and precision  for the contexts of use.

Approach and Statistical Analysis Plans

• NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications. These recommended research practices include, where applicable, expressing clear rationale for the chosen model(s) and primary/secondary endpoint(s), describing tools and parameters clearly, blinding, randomizing, ensuring adequate sample size, pre-specifying inclusion/exclusion criteria, appropriately handling missing data and outliers, implementing appropriate controls, preplanning analyses, and using appropriate quantitative techniques. It is also strongly recommended to indicate clearly the exploratory vs. confirmatory components of the study, consider study limitations, and plan for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.
• Describe and justify the overall research strategy, experimental design, including clinical outcomes or endpoints chosen for validating the biomarker(s) for the proposed Context of Use. Include the clinical outcomes or endpoints chosen, how they will be measured (a graphic of the clinical validation study design is encouraged).
• Justify the statistical analysis plans (SAP) and how they will provide the information needed to interpret results of measuring the biomarker(s) for decision-making at the individual patient or participant level within the Context of Use and how its interpretation will be established to represent a clinically meaningful effect, impact, or outcome as well as the level of confidence for these interpretations.
  • If applicable, the SAP should include sufficient details about any computer simulations used to investigate the operating characteristics or to determine sample size, accounting for the impact of noncompliance, missing data, subject eligibility criteria, etc. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.
  • If an algorithm, or machine learning is used to measure the biomarker(s), provide detailed descriptions of the validation of the algorithm(s) and the training and testing procedures used to develop it; address how overfitting was avoided. Describe how the algorithm stability and reliability of the algorithm(s) was established and how it will be validated, and the overall rationale for the approaches(es)/model(s) selected.
• Describe the approaches for monitoring data quality including plans to audit data completeness or variations from protocol. If retrospective samples or data are being used, provide details as to how they were collected and plans to address and evaluate differences across sites/sources.
• If applicable, describe the plans for engaging with the FDA or other regulatory agencies such as a submitting a letter of intent to the FDA's Biomarker Qualification Program or requesting a Critical Path Innovation Meeting. 
• If an application proposes to use only a single site for analytical validation, then a short paragraph with the heading “justification for single site clinical validation” must be included to justify why a multisite setting is unnecessary or impossible (such as for rare diseases/conditions that can only be diagnosed or treated in a few specialized settings).

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. 

Applicants planning to collect biofluid samples from prospectively enrolled study participants should also provide the broader scientific community with a biofluid sample resource for hypothesis generation, test validation, and discovery related through the NINDS biomarker repository, BioSEND (https://biosend.org/). Applicants should contact BioSEND to incorporate sharing plans and cost in their application. Note that costs for collection are NOT included as a component of the NINDS Biomarkers Repository award. 

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.

The Appendix should include the following, as appropriate for the proposed study:

• Standardized protocols for measuring the biomarkers proposed
• If applicable, guidance documents provided by the FDA regarding qualification of the proposed biomarker(s)

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

Part I. 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.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

Applications must include annual milestones. Applications that fail to include annual milestones will be considered incomplete and will be withdrawn. Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be withdrawn before review.

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 SF424 (R&R) 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 grantdisclosures@oig.hhs.gov.

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 scored 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. As part of the overall impact score, reviewers should consider and indicate how the plan to enhance diverse perspectives affects the scientific merit of the project.

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: 

• If successful, assess how likely the proposed biomarker(s) are to be used in future clinical trials or decision-making in clinical practice for the proposed context(s) of use.
• If successful, assess if the benefits of implementing the biomarker(s) for the proposed context(s) of use significantly outweigh the potential implementation costs such as, but not limited to, technical requirements/feasibility, time, cost, or any added burden on patients/participants and clinicians. 

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/gender categories.
• For clinical trial applications, evaluate whether the study timeline and milestones are feasible.

Specific to this NOFO: 

• Milestones and Timeline:
  • Assess how well do the milestones describe critical quantitative go/no-go decision points necessary to demonstrate progress success.
  • Assess how appropriate are the performance metrics (i.e. level of consistency across replicates, reaching target sensitivity and specificity thresholds, demonstration of standardization across sites, data quality standards, etc) for the context of use proposed.
  • Evaluate how appropriate is the proposed timeline is for completing the research goals in an efficient but feasible manor.
  • If the study is leveraging an ongoing clinical trial, assess if the aims of the biomarker validation study proposed will add significant additional burden to the participants in the ongoing trial.?  If the study is leveraging an ongoing clinical trial assess if there is sufficient time left in the ongoing trial for the current study to be able to collect the requisite samples or data needed.
• Team management plan:
  • Assess how well does the team management plan describes the team/key personnel workflow over the course of the project including things such as organizational structure, team composition, roles, contributions, resource sharing and allocation, credit assignment, etc.

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 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 for this NOFO: 

• Associated clinical trial protocols and consent forms (if applicable):
  • Assess if the consent forms used in the original trial(s) include consent for the proposed biomarker studies. If the consent form is inadequate and do not extend to the proposed studies, evaluate if the concerns are likely to be addressable by re-consenting the participants (should that be feasible) or will the lack of appropriate consent impede the feasibility of the overall study. 
• Intellectual Property (IP) Plan (if applicable):
  • If the applicants intend to commercialize a product from the results generated in this application, assess if the IP plan is appropriate and sufficient with consideration of elements such as the IP landscape of the biomarker(s) and/or detection method, and assessany constraints if applicable, and provide any patents filed, if applicable.
  • If applicable, assess how well the plan addresses how the IP will be handled among the institutions and investigators involved.

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

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

Renewals

Not Applicable

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

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

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this 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, consistent with applicable law.

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

Please note that reviewers will not consider race, ethnicity, age, or gender of a researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors in making its funding decisions.

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. 

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) 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
• Provide updates at least annually on progress in PEDP implementation

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

• 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.
• Each project will also have 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.
• NIH program staff provide input on the milestones and make recommendations regarding their finalization.
• NIH Program Officer 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 NIH Subject Matter Expert(s) may advise the Program Officer on aspects of the research as needed.
• NIH Program Officer, in consultation with the PIs, may in rare occasions add critical experiments that need to be conducted prior to or during the award as an additional milestone(s). In some cases, these studies will be supported by additional funds from NIH. The NIH Subject Matter Expert(s) may advise the Program Officer on these critical elements and milestones.
• NIH Program Officer and Subject Matter Expert(s) may participate in meetings together with PIs with regulatory agencies related to the funded project.
• NIH Program Officer and Subject Matter Expert(s) may consult as necessary with independent consultants or specialists with relevant expertise, assuming confidentiality agreements are in place to mitigate conflicts and protect intellectual property.
• The continuation of funding recommendation is made by the Program Official after input from the Subject Matter Expert(s),and is 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.

Areas of Joint Responsibility include:

None; all responsibilities are divided between recipients and NIH staff as described above.

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.

• Awardees will provide updates at least annually on implementation of the PEDP.

Recipients  will provide updates at least annually on implementation of the PEDP.

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: GrantsInfo@nih.gov (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: support@grants.gov

Carol Taylor-Burds, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: carol.taylor-burds@nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: nindsreview@nih.gov

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

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.