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.

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

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



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to conduct proof of concept biomarker discovery and development studies followed by preliminary clinical validation to evaluate if the candidate biomarker or composite biomarker may be fit-for-purpose for use in clinical trials or clinical practice. This NOFO uses a phased R61/R33 mechanism in which the R61 phase is used to test a hypothesis regarding the candidate biomarker or composite biomarker’s relationship to the biological concept of interest and may also be used to develop or optimize the method for measuring the biomarker or composite biomarker (the method of detection). The R33 phase is to conduct the preliminary clinical validation to test the utility of the biomarker or biomarker signature for one or two specified Context(s) of Use. Applications should directly address how the candidate biomarker(s) or biomarker signature would fill an unmet need (i.e. better reliability, more cost-effective, significantly improved sensitivity and specificity, etc.) and how the biomarker/composite would be an advantage over existing standards. The Context(s) of Use should be carefully considered and clearly described as studies are expected to directly test the candidate biomarker or composite biomarker for one or more Context of Uses in the R33 phase. Biomarkers are used to make decisions at the level of the individual patient or person; therefore, the study design and analyses proposed are expected to establish initial decision-making criteria for how the readout of the biomarker result would be used for the proposed context of use. The rationale for the proposed studies should be supported by strong biological plausibility linking the candidate biomarker or composite with the pathophysiological process(es) of interest. Applications focused on understanding biological mechanisms, networks, or other fundamental knowledge rather than focused on developing biomarkers for use as a clinical trial tool or for use in clinical practice to help guide clinical care decisions are not appropriate for this funding opportunity. Projects that successfully complete both the R61 and R33 phases should meet the entry criteria for the later stage Analytical and Clinical Validation PARs.

Background

A biomarker is a defined characteristic that is measured as an indicator of normal biological processes, pathogenic processes or responses to an exposure or intervention, including therapeutic interventions. A composite biomarker is a combination of multiple variables analyzed to yield a patient-specific indicator of normal biological processes or response to an exposure or intervention including therapeutic interventions. Biomarker modalities are diverse, and can include genomic, transcriptomic, proteomic, histologic, metabolomic, imaging, behavioral, physiologic and digital measures.

Biomarkers are critical to the discovery and development of therapeutics. For example, they can serve as indicators of therapeutic target engagement and pharmacodynamic (PD) response and provide an early signal of treatment response in a clinical trial. Biomarkers can also improve the efficiency of clinical trials by stratifying patients to reduce the impact of the variability associated with phenotypic heterogeneity. In addition, biomarkers allow the evaluation and monitoring of therapeutic intervention on disease progression or recurrence, as well as on the clinical manifestation of disease phenotype or severity. Finally, biomarkers are important tools in the evaluation of susceptibility and risk for developing a disease or disorder, thereby improving early diagnosis and therapeutic outcomes in cases where disease or disorder manifestation could be significantly attenuated or prevented with treatment.

Despite the active pace of discovery of novel biomarker candidates, few biomarkers progress into clinical use, and robust, well-validated biomarkers for use in Phase II clinical trials remain scant. Thus, there is a critical need to advance biomarkers to improve clinical research and therapeutic development, particularly for diseases and disorders of the nervous system where failures to advance therapeutics remains a challenge. While many candidate biomarkers may represent pathophysiological processes that be useful in a variety of contexts, studies are needed to evaluate and validate candidate biomarkers within the context they are proposed to be used to establish the evidence needed to inform decision making at the participant or patient level. The goal of this NOFO is to promote a rigorous early evaluation of the candidate biomarkers and composite biomarkers for use as fit-for-purpose tools in clinical trials or in clinical practice.

Phased Award Mechanism Research Objectives and Transition to R33 Phase

This funding opportunity uses a R61/R33 Phased Innovation Award mechanism. The R61 phase will support biomarker and biomarker signature proof of concept studies to test a hypothesis that a candidate biomarker or biomarker signature is an indicator of a particular concept (a biological process or response to an intervention). Studies must use clinical samples, tissues, and/or data to evaluate the candidate biomarker or biomarker signature (animal studies are not allowed). Studies may also include optimization or additional development of the detection method including preliminary analytical validation needed to measure the biomarker/composite. The purpose of the R33 phase is to conduct preliminary clinical validation of the biomarker or composite biomarker for a specified Context of Use. Context of Use should include defining the category of biomarkers defined in the Biomarkers, EndpointS, and other Tools (Biomarkers, EndpointS, and other Tools (BEST) Resource and how it will be measured and used in clinical trials or clinical practice. Transition from the R61 to the R33 phase is contingent upon the successful completion of Go/No-Go milestones. The milestones should include pre-specified quantitative metrics that demonstrate the construct validity of the biomarker(s) and the concept of interest to demonstrate potential clinical utility, as well as the sensitivity, specificity, and internal validity of the detection method to measure the biomarker or signature. Milestones must be clearly defined, quantifiable, and scientifically justified to allow the investigator and program staff to assess progress in the R61 phase (Please refer to Project Milestones, end of Section I). Completion of a research project resulting from successful application to this NOFO should result in a candidate biomarker or biomarker signature that meets the entry criteria for the companion NOFOs supporting definitive analytical validation of the detection method (PAR-24-095, PAR-24-098)) or definitive clinical validation (PAR-24-097, PAR-24-096).

The definitions of terms within this NOFO:

• Proof of Concept: Establishing that the biomarker acceptably identifies, measures or predicts the concept of interest.
• Internal Validation of the detection method: Establishing that the performance characteristics of a measurement are acceptable in terms of its sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include sample collection and standardization procedures).
• 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.
• 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.
• Validation:  A process to establish that the performance of a test, tool, or instrument is acceptable for its intended purpose.
  • 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, 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.
• 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 for detecting clinical manifestation of disease or differentiating between diseases and conditions.
  • Prognostic biomarkers used to identify likelihood of a clinical event, disease recurrence or progression in patients who have the disease or medical condition of interest.
  • Predictive biomarkers for differentiating individuals based on favorable or unfavorable effect from a therapeutic or other intervention.
  • Pharmacodynamic/response biomarkers for demonstrating therapeutic target engagement and response to an intervention.
  • 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.

Project Characteristics

The biomarker or biomarker signature must be focused on a neurological or neuromuscular disease or disorder within the NINDS mission.

Applications are expect to provide:

• A strong biological rationale: Projects should include a cogent biological rationale supporting the concept and plausibility of the candidate biomarker or biomarker signature. The biological rationale should include rigorously obtained evidence that the proposed biomarker or biomarker signature concept may be an indicator of normal biological processes, potential susceptibility or risk, pathogenic processes, or response to an exposure or intervention, including therapeutic interventions (as appropriate for the Context of Use).
• Clear clinical unmet need and justification for use as a tool in neurotherapeutic development or clinical practice: Projects should address how the candidate biomarker or composite biomarker will fill an unmet need for neurotherapeutic development or clinical practice and address how, if successful, the biomarker would be an improvement on current available tools for the Context of Use(s) proposed.
• A rigorous and clearly described study design: In the R61 phase the study should be designed to establish/confirm the candidate biomarker’s ability to be used as an indicator for the biological process or response to an intervention and the relationship to the clinical concept(s) of interest, as well as establish the performance of the detection method; in the R33 phase the study should conduct preliminary clinical validation of the biomarker or composite biomarker using the optimized detection method to test the utility on an independent cohort for one or two Contexts of Use. The end of the R61 must include milestones defining the performance criteria that need to be met for the biomarker and method of detection in order to be useful for the Context of Use proposed in the R33 phase.

Examples of Biomarker or Biomarker Signature Studies Supported in this NOFO Include, but Are Not Limited to:

• Characterization of a candidate biomarker in clinical samples or data relative to the biological process and clinical outcomes of interest, as well as optimization of the detection method, followed by retrospective or prospective testing in an independent clinical cohort in the R33 phase to determine the sensitivity and specificity of the biomarker or biomarker signature for a specified Context of Use
• Development and evaluation of a candidate biomarker signature algorithm from a set of known biological markers associated with neurological or neuromuscular disorders to optimize the algorithm including establishing sample/data curation or collection procedures for one or more Context of Uses, followed by testing the optimized algorithm in an independent cohort in the R33 phase for one or two specified Context(s) of Use
• Unbiased discovery approaches from one or more large multisite datasets or sample repositories to identify new biomarkers and characterize their relationship to relevant biological processes and outcomes within a disease or condition, followed by prospective validation in the R33 phase for a specified Context of Use
• Retrospective analyses of longitudinal studies (such as natural history studies) data to evaluate one or more candidate biomarkers' ability to monitor changes in disease state or predict progression followed by independent validation with an optimized protocol in the R33 phase for a specified Context of Use
• First in human identification or evaluation of a candidate pharmacodynamic/response biomarker to determine the candidate biomarker's ability to be used to demonstrate target engagement or establish dosing decisions in response to a therapeutic intervention and to develop or optimize the detection method using samples and/or data from one or more clinical trials, followed by independent validation using the optimized method in the R33 phase.

The R61 phase may include preliminary Analytical Validation of the detection method including metrics such as:

• Precision
• Accuracy
• Analytical sensitivity
• Analytical specificity including interfering substances or signals
• Reportable range of test results for the test system
• Reference intervals (range of normal values) with controls and calibrators
• Harmonization of analytical performance if the method of detection is to be performed in multiple laboratories
• Establishment of appropriate quality control and improvement procedures
• Any other performance characteristic required to test performance with determination of calibration and control procedures

The R33 phase may include preliminary Clinical Validation of the biomarker or signature including metrics such as:

• Demonstration that the result of the biomarker detection method is associated with a clinical endpoint (e.g., response to a therapeutic, target engagement, neuro-pathophysiology or clinical manifestation) in samples or data from patients that have been exposed to an intervention or confirmation that they have or will develop a disease or disorder.
• Demonstration of clinical sensitivity and specificity for the intended use of the biomarker or biomarker signature as evaluated through an area under the AUROC and/or continuous outcome measures, as appropriate.

Non-Responsive Studies

• Biomarker or biomarker signature studies for diseases or disorders outside the mission of NINDS and NIA
• Studies using animal models.
• Studies where the primary focus is to develop a diagnostic device or detection method without evaluating the utility of the biomarker or composite biomarker for one or more specified Context of Uses
• Studies where the primary intent is to understand the mechanisms and pathophysiology of a disease or condition
• Natural history studies aimed at understanding disease pathophysiology, genetic, or epigenetic mechanisms
• Studies that only propose to do phenotyping or classification studies without also proposing analyses to establish preliminary criteria for interpreting the results of the biomarkers to make decisions at the level of the individual participant (group level comparisons rather than individual level
• Studies where the primary intent is to develop or test a therapeutic intervention for safety or efficacy endpoints

Investigator Team Characteristics

Multidisciplinary teams are necessary for successful development of candidate biomarkers and biomarker signatures. Areas of expertise needed include biomarker development, clinical expertise relevant for the clinical populations of interest, statistical and/or bioinformatics analysis, experience with the use and development of the detection method technology, biosample, data or tissue source standardization, and biological expertise in the disorder/disease pathophysiology. Investigators are encouraged to form collaborations and seek additional consultants as needed for the project.

Considerations for clinical trials

Studies meeting the NIH definition of a clinical trial are allowed when the primary intent is to evaluate the biomarker relative to the intervention of interest, however clinical trials are not supported if the primary intent is to evaluate the intervention's safety, tolerability, clinical efficacy, effectiveness, and/or clinical intervention and management. For the reasons outlined above, this NOFO typically supports only mechanistic types of clinical trials (Basic Experimental Studies Involving Humans (BESH)).

Leveraging Existing Research Resources

Applicants are strongly encouraged to leverage existing NINDS and NIA research resources for their studies whenever possible (https://www.nlm.nih.gov/NIHbmic/nih_data_sharing_repositories.html). Such resources may include tissue, cellular, or DNA samples from NINDS BioSEND (https://www.biosend.org/) or other existing biospecimen, imaging and data repositories, such as the NINDS Human Cell and Data Repository (https://nindsgenetics.org/), The Federal Interagency Traumatic Brain Injury Research (FITBIR) informatics system, the National Centralized Repository for Alzheimer's Disease and Related Dementias (NCRAD; https://ncrad.iu.edu/) and the Accelerating Medicines Partnership for Alzheimer's Disease (https://adknowledgeportal.synapse.org/) and Accelerating Medicines Partnership for Parkinson's Disease (https://amp-pd.org/). The NINDS BioSEND repository receives, processes, stores, and distributes biospecimen resources from NINDS funded studies that can be shared by the neuroscience research community, and currently banks a variety of biospecimens including DNA, plasma, serum, RNA, CSF, and saliva. The NINDS Human Cell and Data Repository provides 1) disease-relevant stem cell lines for biomarker discovery, and/or 2) the capacity to bank blood for the creation of new cell lines relevant to their disease of interest. Leveraging the resources and support from neurological disorder advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged. Finally, applicants are encouraged to leverage the resources of ongoing clinical trials supported through other Federal or private funds.

Applications proposing to collect biospecimens are strongly recommended to use the NINDS Biomarkers Repository BioSpecimen Exchange for Neurological Disorders (BioSEND) protocols and procedures, and all specimens collected and banked with BioSEND must come from individuals who have consented to banking and sharing broadly with academia and industry.

Note that costs for collection are NOT included as a component of the NINDS Biomarkers Repository award. Therefore, most costs for the biospecimen banking are borne by the recipients utilizing this resource (see NOT-NS-15-046). Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NINDS Biomarkers Repository website for more information about samples banked at the repository (https://www.biosend.org). In addition, applicants are advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email: [email protected]).

Pre-Application Consultation

Applicants are strongly encouraged to consult with NIH Scientific/Research 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 or NIA mission and intent of this NOFO. In order to learn more about this NOFO and to have the opportunity to ask questions, a pre-application informational webinar is held at least once a year (usually in December and/or April) and the recordings are posted online at: https://www.ninds.nih.gov/current-research/focus-tools-topics/focus-biomarkers-research  under the News & Events section.See also Applicant Webinar information under Section IV.7 below ("Other Submission Requirements and Information").

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 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, Ph.D

National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-451-4551
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, 1-2 pages maximum):

• Timeline and Milestones must be provided under a separate, specific heading at the end of the Research Strategy Section and will be evaluated as part of the scientific and technical merit of the R61/R33 application.
• Provide an overview and/or Gantt chart of the major activities and timeline of the project for both the R61 and R33 phase.
• Provide quantitative Go/No-Go milestones and success criteria that must be achieved by the end of the R61 phase in order to transition to the R33 phase; milestones should provide clear indicators of feasibility and should include performance metrics of the biomarker or biomarker signature and detection method(s) for measuring the biomarker or biomarker signature
• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

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

Applications should include an Intellectual property (IP) strategy unless the products are intended to be provided as open source tools. Applicants are encouraged to consult their institution's technology transfer officials when preparing this section of the application.

• Applicants should describe the IP landscape surrounding their biomarker or biomarker signature and its measurement. Applicants should describe any known constraints that could impede biomarker or biomarker signature development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar biomarkers that are under patent protection and/or on the market, etc.) and how these issues could be addressed with achieving the goals of this program. If the applicant proposes using an agent(s) whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should include a letter (see letter of support) from any entities owning the IP indicating there will not be any limitations imposed on the studies or the project which would impede achieving the goals of the funding program.
• If patents pertinent to the biomarker being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, and application status, and associated USPTO links, if applicable. Applicants should also provide information regarding foreign interests and patents.
• 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.

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 materials.

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.

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:

Specific Aims:

Briefly provide the context for the proposed candidate biomarker or biomarker signature along with a cogent argument outlining its importance and unmet need. Briefly describe the hypothesis and biological rationale that the candidate biomarker or biomarker signature to be measured reflects the relevant biological, physiological, or pathological pathway(s) relevant to the clinical concept(s) of interest.  Within the Specific Aims section, include headers titled “R61 Phase Specific Aims” and “R33 Phase Specific Aims”. Under each header, state the specific aims of the efforts for each phase of the study. State the major objectives of the aims including the technical questions to be answered to further develop and evaluate the biomarker or biomarker signature.

Research Strategy:

The Research Strategy Section should include:

1. Clinical Context and Unmet Need:

• Describe the unmet need for the candidate biomarker or biomarker signature within the neurological or neuromuscular disease or condition(s) of interest including how it would be used and why it would be an advance over existing standards.
• Include a heading "Proposed Context of Use(s)" for the biomarker or biomarker signature: define the Context of Use including the type or types of biomarker(s) using the BEST glossary terminology and describe how the biomarker/biomarker signature would be used by clinical trialists and/or health care professionals to make decisions.
• Describe the feasibility and practicality of using the proposed detection method to be used, developed or optimized relative to how the biomarker is expected to be used (proposed Context of Use(s)); discuss any potential burden, risks and costs of the proposed method of detection relative to existing approaches or standards current standards.

2. Premise and Biological Rationale:

• Provide rigorous supporting evidence for the hypothesis that the candidate biomarker or biomarker signature to be measured reflects the relevant biological, physiological, or pathological pathways relevant to the clinical concept(s) of interest. If unbiased screening approaches are proposed, describe what biological, physiological, or pathological pathways are expected to be detected and the hypothesis to be tested regarding their relationship to the clinical concepts of interest.
• Include rigorously conducted supporting literature and any relevant preliminary data, if applicable
• Describe the overall strengths, weaknesses, and rigor of the supporting literature and preliminary data supporting the biological rationale

3. Approach and Experimental Design:

• Describe the overall experimental design to test if the biomarker or biomarker signature can be used as an indicator for the outcomes of interest within the Context of Use(s) proposed.
• Describe any development or optimization of the detection method to be conducted as part of the study to accurately detect the biomarker or biomarker signature, including validation plans for inter and intra reliability, precision, accuracy, and dynamic range; provide evidence of the feasibility including preliminary data and/or supporting literature from the investigative team.
• Describe the approaches for ensuring standardization of data/sample collection. If retrospective samples or data are being used, provide details as to how they were collected and plans to address and evaluate differences across sites/sources.
• Include descriptions of the statistical analysis plans for both the R61 and R33 phases including statistical assumptions being made. If the R33 phase analysis plan is dependent on unknowns to be determined in the R61 phase, describe the overall rationale for the statistical analysis plan and describe the decision process and criteria to be used to finalize the R33 statistical analysis plan
• If machine learning will be used to measure or detect the biomarker, or if an algorithm will be used for the biomarker signature, describe the training and testing procedures to be used and the rationale for the approach; address how overfitting will be avoided. Describe how the algorithm stability and reliability will be tested, and the overall rationale for the approach(es)/model(s) selected.
• If more than one possible Context of Use is proposed, describe how the Context of Use will be refined based on the results from the R61 phase.
• Describe the approach for the preliminary clinical validation of the biomarker or biomarker signature for the proposed Context of Use(s) in the R33 phase.

Letters of Support:

• Applicants should include letters of support from consultants, contractors, and collaborators.
• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.
• If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.
• If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), any limitations on sharing of data (including negative results), and whether a licensing agreement(s) will be needed and in place once the project is funded. This letter should come from a high official within the private entity who has authority to speak on these issues.
• If an application plans to utilize the infrastructure or resources of existing projects, whether funded by the NINDS, other governmental or non-governmental entities, letters of support detailing the terms of collaboration and data sharing must be included
• If existing  biospecimens will be used as a component of the study, letters of support or approval for use of those samples should be included

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the 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.

Applicants proposing to collect samples from subjects are encouraged to provide the following information in the Appendix: 

Study Protocol, Consent Forms

For Ancillary studies:

• The protocol for the parent study
• Investigator’s Brochure, if applicable, for the parent clinical study
• Consent forms (for both the parent clinical study and the ancillary studies, if different)
• Written agreement to conduct the ancillary study from parent clinical study sponsors.

IRB approval of the informed consent forms is not required at the time of submission of the application. However, drafts of informed consent forms must be included.

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.

Technical Assistance Webinars: 

In order to learn more about this NOFO and to have the opportunity to ask questions, a pre-application informational webinar is held at least once a year (usually in December and/or April) and the recordings are 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 “Technical Assistance Webinar: NINDS Translational Biomarker Funding Opportunities” 

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.

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.

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 [email protected].

Post Submission Materials

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

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

Section V. Application Review Information

1. Criteria

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

This NOFO supports studies focused on the identification and development of promising candidate biomarkers or biomarker signatures for neurological and neuromuscular disorders/diseases that will withstand rigorous validation to become tools necessary for the development of neurotherapeutics or for use in treatment decisions within clinical practice.

Priority will be given to biomarkers or biomarker signatures and associated detection methods that: 1) address an unmet medical need for the neurological or neuromuscular disorder/disease specified, 2) are supported by a strong biological rationale for the biomarker and the technology concept, 3) include a carefully designed plan for data and sample collection that is supported by a strong biological and statistical rationale, 4) include a well thought-out plan for development and evaluation of detection technology that carefully considers the feasibility of the detection method for use in a clinical trial setting or clinical practice, 5) include a rigorous plan for biological proof of concept and 6) have the potential to produce a candidate biomarker that can withstand rigorous prospective analytical and clinical validation studies.

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:

• Evaluate the likelihood that the proposed biomarker(s) to be used in future clinical trials or decision making in clinical practice for the proposed context(s) of use.
• Evaluate whether 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:

• Evaluate whether the milestones are appropriate with quantitative Go/No-Go milestones and success criteria that must be achieved by the end of the R61 phase in order to transition to the R33 phase.
• Evaluate how well the milestones are clear indicators of feasibility and include appropriate performance metrics of the biomarker or biomarker signature and detection method(s) for measuring the biomarker or composite biomarker. 

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:

• Intellectual property (IP) Plan (if applicable):
  • If the applicants intend to commercialize a product from the results generated in this application, evaluate if the IP plan appropriate and sufficient with consideration of elements such as the IP landscape of the biomarker(s) and/or detection method, or known constraints if applicable.
  • If applicable, evaluate if the plan addresses how 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

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), 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.

The review will be convened by the National Institute for Neurological Disorders and Stroke (NINDS).

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. 

Not Applicable

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.

At the end of the R61 Phase applicants must include a detailed report including rigorous data on how the milestones have or have not been met. Additional information including protocols may be requested. 

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.

At the end of the R61 Phase, PIs may be asked to participate in a R61/R33 Transition Review call where they will be asked to present the progress towards meeting the Go/No-Go milestones and overall progress of the project to NINDS Program Staff including the Program Officer and one or more subject matter experts. This meeting will be used to help clarify and questions from the progress report and may be used to help contextualize the funding recommendation for the R33 phase to NINDS leadership. 

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 Ph.D
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS))
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.