Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Neurological Disorders and Stroke (NINDS)

National Institute on Aging (NIA)

Funding Opportunity Title
Development of Biomarkers or Biomarker Signatures for Neurological and Neuromuscular Disorders (R61/R33 Clinical Trial Optional)
Activity Code

R61/R33 Exploratory/Developmental  Phased Award

Announcement Type
Reissue of PAR-19-315
Related Notices

See Notices of Special Interest associated with this funding opportunity

None

Funding Opportunity Announcement (FOA) Number
PAR-22-089
Companion Funding Opportunity
None
Assistance Listing Number(s)
93.853, 93.866
Funding Opportunity Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to promote the development of fit-for-purpose candidate biomarkers and biomarker signatures that enable more efficient clinical trials to advance therapeutic development or be used in clinical practice to help guide clinical care decisions. Specifically, the goal of this phased funding mechanism is to first identify or confirm candidate biomarkers or biomarker signatures using human samples and/or data, followed by an independent retrospective or prospective clinical study to conduct initial clinical validation of the biomarker/signature’s clinical utility for a defined Context of Use(s). In the first phase, applicants are expected to demonstrate that the biomarker acceptably identifies or predicts the concept of interest and may include optimization of the detection method using carefully standardized human samples or datasets. The overarching purpose of this initiative is to deliver candidate biomarkers or biomarker signatures that are ready for definitive analytical and clinical validation studies.

Key Dates

Posted Date
February 23, 2022
Open Date (Earliest Submission Date)
May 22, 2022
Letter of Intent Due Date(s)

30 days prior to the application due date

The following table includes NIH standard due dates marked with an asterisk.
Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
June 22, 2022 June 22, 2022 September 07, 2022 * November 2022 January 2023 April 2023
February 22, 2023 February 22, 2023 May 07, 2023 * July 2023 October 2023 December 2023
June 22, 2023 June 22, 2023 September 07, 2023 * November 2023 January 2024 April 2024
February 22, 2024 February 22, 2024 May 07, 2024 * July 2024 October 2024 December 2024
June 22, 2024 June 22, 2024 September 07, 2024 * November 2024 January 2025 April 2025
February 21, 2025 February 21, 2025 May 07, 2025 * July 2025 October 2025 December 2025

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

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

Expiration Date
May 08, 2025
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).

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

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

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

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

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


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to conduct proof of concept biomarker discovery and development studies followed by preliminary clinical validation to evaluate if the candidate biomarker or biomarker signature may be fit-for-purpose for use in clinical trials or clinical practice. This FOA uses a phased R61/R33 mechanism in which the R61 phase is used to test a hypothesis regarding the candidate biomarker or biomarker signature's relationship to the concept of interest and may also be used to develop or optimize the method for measuring the biomarker or biomarker signature (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 more specified Contexts of Use. Animal studies are not permitted, although data generated from them may be used to support the biological rationale and premise supporting the hypothesis regarding the potential of the candidate biomarker. 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/signature would be an advantage over existing standards. The Context of Use(s) hould be carefully considered and clearly described as studies are expected to directly test the candidate biomarker or biomarker signature for one or more Context of Uses in the R33 phase. The rationale for the proposed studies should be supported by strong biological plausibility linking the candidate biomarker, or potential biomarker signature to be identified, with the pathophysiological process(es) of interest. Applications focused on understanding biological mechanisms, networks, or other fundamental knowledge about the underlying pathophysiology of a disease or condition 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 biomarker signature is a combination of multiple variables to yield a patient-specific indicator of normal biological processes or responses to an exposure or intervention including therapeutic interventions. Biomarker modalities are diverse, and can include 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 from discovery to the market are notorious. 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. The goal of this FOA is to promote a rigorous early evaluation of the candidate biomarkers and biomarker signatures 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/signature. The purpose of the R33 phase is to conduct preliminary clinical validation of the biomarker or biomarker signature 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 the degree of association between the biomarker and the concept of interest needed 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 FOA should result in a candidate biomarker or biomarker signature that meets the entry criteria for the companion FOAs supporting definitive analytical validation of the detection method (PAR-21-056, PAR-21-057) or definitive clinical validation (PAR-21-058, PAR-21-059).

The definitions of terms within this FOA:

  • 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 (or reflect).

  • 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 for predicting outcomes
    • 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.


Entry Criteria

  • 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).
  • Relevance and unmet need for neurotherapeutic development or clinical practice: Projects should address how the candidate biomarker or biomarker signature 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.
  • 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 biomarker signature using the optimized detection method to test the biomarker or biomarker signature's utility on an independent cohort for one or more 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.

Project Characteristics

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

Examples of Biomarker or Biomarker Signature Studies Supported in this FOA 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 a specified Context 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 signature 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 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 FOA 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 Respository 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 grantees utilizing this resource (see NOT-NS-15-046). Applicants planning projects in which biospecimens will be collected are strongly advised to consult the NINDS Biomarkers Repository website for more information about samples banked at the repository (https://www.biosend.org). In addition, applicants are advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email: biosend@iu.edu).


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 FOA.

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

Section II. Award Information

Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
New
Resubmission
Revision

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

Clinical Trial?

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

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.

Award Budget
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Award Project Period

The R61 phase can be from 1-3 years and the R33 phase can be 1-3 years, with a total project duration of no more than 5 years

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

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

Other

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

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

Required Registrations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

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

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

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

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

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

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

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

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

 

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: carol.taylor-burds@nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Applications should include an Intellectual property (IP) strategy. Applicants are encouraged to 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.
SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific 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.

4. Timeline and Proposed Milestones

  • 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.

Letters of Support:

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

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

  • All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. Applicants should review the “Supplemental Information to the NIH Policy for Data Management and Sharing: Elements of an NIH Data Management and Sharing Plan” when developing their plan: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-21-014.html
  • If patent protection is being sought, investigators should explain how data will be shared after filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.
  • Applicants utilizing NINDS data and resource sharing repositories should address fulfillment of compliance requirements for the resource they have chosen to utilize in the Resource/Data Sharing Plan and include any associated sharing costs in the budget and described in the budget justification.
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

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 SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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

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

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

4. Submission Dates and Times

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

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

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

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

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

In addition, the Scientific Review Officer (SRO) will accept regulatory meeting minutes and transcripts, and patents, 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 FOA 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, 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 validation studies.

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

Overall Impact

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

Scored Review Criteria

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

Significance

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

Further criteria specific to this opportunity: 1) Will the biomarker or biomarker signature address an unmet medical need for the Context of Use or Uses proposed? 2) Is there sufficient biological rationale to support the biomarker or biomarker signature concept? 3) Is there sufficient potential for the proposed studies to significantly advance biomarkers and translational medicine for the neurological or neuromuscular disorder/disease(s) described? 4) Will the detection method be appropriate, practical and feasible for the Context of Use(s) proposed?

In addition, for applications involving clinical trials

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

Investigator(s)

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

Further criteria specific to this opportunity: Does the team include sufficient multidisciplinary expertise, including but not limited to, expertise in the underlying biology of the disease or condition, development or optimization of the detection method(s) or technologies, clinical expertise for the disease or condition, statistical/bioinformatic expertise, and regulatory consultants (if appropriate for the project's goals)? Will the team be able to manage both the development phase and preliminary clinical validation phase?

In addition, for applications involving clinical trials

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

Innovation

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

Further criteria specific to this opportunity: Are there innovative aspects of the project such as in the study design or detection method? Will a validated biomarker provide an important improvement over existing biomarkers or other available tools for the proposed Context of Use(s)? Although not required, is there innovation in the biological/pathophysiological concept being tested?

In addition, for applications involving clinical trials

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

Approach

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

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

Further criteria specific to this opportunity: Is the approach for identification and early verification of the biomarker clearly described ? Are there appropriate plans for standardization of samples and/or data? Is the detection method for the biomarker modality(ies) appropriate for the Context of Use and are the development or optimization plans feasible? Are the plans for validating the detection method(s) appropriate, rigorous and well thought out? Are the statistical analysis plans, including underlying assumptions clearly described and justified? Are the statistical analysis plans appropriate for both the R61 and R33 phases? If machine learning is to be used to identify and select the biomarker(s), or if an algorithm will be used for the biomarker signature, are the training and testing procedures clearly described and justified including addressing potential overfitting, and are there plans to evaluate and address stability and reliability issues? If retrospective samples and/or data are being used is there evidence they were obtained from appropriate sources with sufficient quality control and standardization procedures in place? If more than one possible Context of Use is proposed, are the criteria for refining the Context of Use described and appropriate? Will the approach for preliminary clinical validation in the R33 provide evidence of the biomarker's utility for the Context of Use(s) proposed?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

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

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

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

Data Management and Statistical Analysis

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

Environment

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

In addition, for applications involving clinical trials

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

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

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

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

Additional Review Criteria

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

Milestones
Are the milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions at the R61/R33 transition point? Does the set of milestones allow the evaluation of progress in the R61 phase and will successful completion of these milestones provide confidence that the investigator will be able to successfully implement the R33 phase and achieve its end goals within the timeline of this grant mechanism? Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?

Study Timeline

Specific to applications involving clinical trials

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

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

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

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

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

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

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3)  Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), 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. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

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

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

Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

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

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

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

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

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

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

2. Administrative and National Policy Requirements

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

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

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

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

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 and 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

Not Applicable

3. Reporting

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

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000.  See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

Application Submission Contacts

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

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-945-7573

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

Scientific/Research Contact(s)

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

Yuan Luo, Ph.D.
National Institute on Aging (NIA)
Phone: 301-496-9350
Email: yuan.luo@nih.gov

Peer Review Contact(s)

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: nindsreview@mail.nih.gov

Financial/Grants Management Contact(s)

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

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

 

Section VIII. Other Information

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

Authority and Regulations

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

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