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)

Funding Opportunity Title
Analytical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U01 Clinical Trial Optional)
Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of PAR-18-550 - Analytical Validation of a Candidate Biomarker for Neurological Disease (U01) (Clinical Trial Optional)

Related Notices

None

Funding Opportunity Announcement (FOA) Number
PAR-21-056
Companion Funding Opportunity

PAR-21-057- Analytical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U44 Clinical Trial Optional)

PAR-21-058 - Clinical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U01 Clinical Trial Optional)

PAR-21-059 - Clinical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U44 Clinical Trial Optional)

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.853

Funding Opportunity Purpose

The purpose of this Program Announcement (PAR) is to enable analytical validation of strong candidate biomarkers for neurological and neuromuscular disorders and conditions. Specifically, the goal of this PAR is to enable the rigorous validation of analytical methods for biomarker measurements, which should include evaluation of the detection method, its performance characteristics, and the optimal conditions that will generate reproducibility and accuracy consistent with FDA guidelines. This PAR assumes that 1) a candidate biomarker has already been identified, 2) detection method technology has already been developed, and 3) the research and/or clinical need and potential context of use has been identified.

Key Dates

Posted Date
November 19, 2020
Open Date (Earliest Submission Date)
January 22, 2021
Letter of Intent Due Date(s)

30 days prior to the application due date.

Application Due Date(s)

February 22, 2021, June 22, 2021, February 22, 2022, June 22, 2022, February 22, 2023, and June 22, 2023.

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

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.

AIDS Application Due Date(s)

May 4, 2021, September 7, 2021, May 7, 2022, September 7, 2022, May 7, 2023, September 7, 2023.

All applications are due by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on the listed date(s).

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.

Scientific Merit Review

June 2021, October 2021, June 2022, October 2022, June 2023, October 2023

Advisory Council Review

October 2021, January 2022, October 2022, January 2023, October 2023, January 2024

Earliest Start Date

November 2021, February 2022, November 2022, February 2023, November 2023, February 2024

Expiration Date
September 08, 2023
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

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. Biomarker modalities are diverse, and can include ‘omics, imaging, behavioral, digital and physiologic endpoints, as well as composite biomarkers or biomarker signatures. Because the measurement of the biomarker is integral to defining the biomarker, it is necessary to describe the biomarker in terms of its biological source or matrix, measurable features, and the analytic method used to measure it.

Biomarkers are critical to the discovery and development of therapeutics and can serve a variety of functions such as verifying therapeutic target engagement, improving trial design by patient stratification, and facilitating clinical care decisions. Despite the active pace of discovery of novel biomarker candidates, few biomarkers progress beyond discovery to analytical validation and clinical practice, and robust, well-validated biomarkers for use in Phase II and Phase III clinical trials remain scant. Thus, there is a critical need to advance validation of biomarkers to improve public health, particularly for disorders of the nervous system where advancing therapeutics from discovery to the market are notoriously challenging.

This PAR is intended to address the gap in biomarker validation by encouraging rigorous analytical validation of the biomarker detection method. Analytical Validation is defined as the process of establishing that the performance characteristics of the measurement(s) are acceptable in terms of the sensitivity, specificity, accuracy, precision, and other relevant performance characteristics using a specified technical protocol (which may include sample collection and standardization procedures). The level of analytical rigor that is necessary depends upon the characteristics of the biomarker, the detection technology, and the intended category(ies) of biomarker (diagnostic, prognostic, predictive, pharmacodynamic/response, monitoring, safety, or susceptibility/risk) within the proposed context of use(s). Analytical validation establishes the measurement's technical performance so that final clinical validation can be established. Applicants with a detection method that has already been analytically validated for its intended Context of Use may apply directly to the companion PAR, Clinical Validation of a Candidate Biomarker for Neurological or Neuromuscular Disorders (U01 - Clinical Trial Optional)" which addresses retrospective and/or prospective clinical validation of candidate biomarkers for use in clinical trials and/or clinical practice.

Research Objectives

Applications to this PAR must propose to conduct analytical validation of a biomarker or biomarker signature that already has a well-defined proof of concept and biological rationale. Premise and proof of concept must include evidence that the biomarker/biomarker signature has been tested in an appropriate clinical population, using either prospective or retrospective data or samples and shows sufficient sensitivity and specificity to warrant additional investment. In addition, applications to this PAR must include evidence that the detection method for the biomarker has been developed and subjected to initial evaluation of precision and analytical sensitivity. The application should clearly describe how the proposed study plans to optimize and standardize the detection method, as well as clearly define and rigorously test the analytic and pre-analytic variables to ensure broad and reliable clinical use across multiple sites.

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

The Analytical Validation PARs and companion Clinical Validation PARs are designed to enable the production of a package of evidence needed for FDA Biomarker Qualification Submission, which is encouraged but not required as part of the application process. For more information on the Biomarker Qualification program see: https://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/BiomarkerQualificationProgram/default.htm

Entry Criteria

Entry Criteria should include the following:

  • Within NINDS mission: The project should focus on detection methods where the biomarker is likely to be used as a tool in the diagnosis, treatment, or prevention of diseases and conditions within the NINDS mission
  • Context of Use: The intended Context of Use (COU) should be identified and applications should include a statement with the heading “Context of Use” that fully and clearly describes the way the biomarker is expected to be used. Considerations involved in defining the context of use should include the biomarker category (susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, or safety), biomarker modality, the method of detection and the clinical population characteristics. The COU is critical for determining the experimental design and level of analytical validation required, therefore it must be carefully considered and clearly defined. Context of use statements are discussed extensively in the Framework for Defining Evidentiary Criteria for Biomarker Qualification developed by the Biomarkers Consortium: https://fnih.org/sites/default/files/final/pdf/Evidentiary%20Criteria%20Framework%20Final%20Version%20Oct%2020%202016.pdf
  • Evidence of preliminary validation of the biomarker: Preliminary data illustrating that the biomarker reflects the intended pathophysiology and/or clinical endpoint appropriate for the Context of Use are required. Evidence should include a preliminary estimate of the clinical sensitivity and specificity and data illustrating the detection method has been developed and subjected to initial evaluation of precision and sensitivity at a minimum.

Application Characteristics

  • A strong justification for use of the proposed detection method and biomarker including clinical and/or research unmet need should be included.
  • Feasibility, including potential added clinical burden and cost should also be directly addressed.
  • The status of the existing detection method and the plan for its optimization in clinical laboratories or point of care settings should be described.
  • The project should include analytical validation in multiple testing sites. If a single site is proposed, a scientific justification should be included.
  • Milestones describing the metrics for evaluating analytical validation to assess success in achieving each of the research plan’s objectives must be included.
  • The Biomarker or biomarker signature should be described using the FDA-NIH Biomarker Working Group BEST (Biomarkers, EndpointS, and other Tools) Resource, available from: https://www.ncbi.nlm.nih.gov/books/NBK326791/. Biomarker categories include:
    • monitoring biomarkers to track the success of a therapeutic intervention or disease progression
    • diagnostic biomarkers for detecting clinical manifestation of disease
    • prognostic biomarkers for predicting outcomes
    • predictive biomarkers for determining responders and non-responders to a therapeutic intervention
    • pharmacodynamic/response biomarkers for demonstrating therapeutic target engagement
    • safety biomarkers to indicate the likelihood, presence, or extent of an adverse effect, and
    • 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.

Although an individual indicator may be useful as more than one category of biomarker (i.e. both diagnostic and monitoring) the type of evidence required to validate it depends on the biomarker category specified; for example, a monitoring biomarker would need to demonstrate robustness in a longitudinal study design whereas a diagnostic may be evaluated at a cross sectional design. Thus, defining the biomarker category(ies) is essential to developing the experimental design and analytical performance necessary to validate it.

  • The research strategy should clearly describe how the application will utilize a rigorous design, execution, and interpretation of the proposed studies. NINDS encourages investigators, whenever possible, to address these elements directly in their applications.

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

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

Responsiveness Criteria

Responsive studies include analytical validation of biomarker detection methods that indicate pharmacodynamic responses to therapeutics, predict efficacy or safety response as well as those for diagnostic, prognostic and disease progression or risk/susceptibility detection.

 Applications Not Responsive to this FOA

Non-responsive studies include those seeking to develop therapeutic agents or devices as the primary intent, as well as those seeking to answer specific questions about clinical efficacy, effectiveness, and/or clinical management as the primary intent. Studies using animal models are non-responsive. Studies that fail to include milestones are also considered non-responsive. Non-responsive applications will be administratively withdrawn without review.

Collaborations

Multi-disciplinary collaboration among scientific investigators, developers, clinicians, statisticians, consultants, and clinical laboratory staff must be an integral part of the application. Projects proposed for this PAR should utilize multi-site design as applicable, with standardized data stewardship to ensure that data are reusable and accessible.

Investigators are encouraged to form collaborations with individuals knowledgeable in the FDA qualification process as well as those familiar with the process of analytical validation, including statistical design and analysis experts.

Leveraging Existing Resources

Applicants should leverage existing research resources for their studies. Such resources may include clinical biospecimen samples from the NINDS Human Biospecimen and Data Repository (BioSEND; https://biosend.org/) or other existing biospecimen, imaging and data repositories. Leveraging the resources from advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program are also encouraged. Studies are also encouraged to leverage the resources of ongoing clinical trials supported through other Federal or private funds.

Project Milestones

A project timeline with annual milestones must be included in the application (see Section IV). Milestones should describe project decision points with results-driven, quantitative metrics for go/no-go decision making throughout the funding period.

The NIH Program Official will contact the applicant to discuss the proposed milestones prior to the award. The Program Officer and Scientific Officer will discuss with the Program Director(s)/Principal Investigator(s) any recommended changes to the research plan or suggestions from peer review, and the plan will be revised as appropriate prior to the award.

Reproducibility and Data Sharing

To improve reproducibility and community uptake, investigators are expected to share code/scripts, analytic tools/statistical models, protocols/processes and metadata before the end of the project’s period of performance. The resource sharing plan should describe where information and data will be shared, including where the original controlled datasets exist and how to request access to them. Investigators should incorporate plans for sharing and dissemination of the data, protocols, and any analytical methods in their research sharing plan and project timeline. Budgets should reflect any costs associated with these efforts. Information on many available NIH supported or frequently used repositories is available at: https://www.nlm.nih.gov/NIHbmic/nih_data_sharing_repositories.html

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

Pre-Application Consultation

Under this Cooperative Agreement mechanism, NINDS Program Staff will have substantial communication and involvement with researchers in decision making prior to award and during the conduct of the study to provide oversight of data and safety monitoring, ensure the timely completion of the proposed studies and to maximize the positive impact of the studies on upcoming clinical trials.

Applicants are strongly encouraged to consult with NINDS Program Staff early on during the planning for an application. This early contact will provide an opportunity to discuss and clarify NINDS policies and guidelines, including the scope of the project relative to the NINDS mission and intent of this PAR. These discussions can also provide any needed clarification regarding development of an appropriate timeline and milestone plan.

Funding Considerations

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

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

Section II. Award Information

Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

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 should to reflect the actual needs of the proposed project.

Award Project Period

The scope of the proposed project should determine the project period. The maximum project period is 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 Governments

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

Other

  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
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 not 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.

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. 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.
  • 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.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but 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 DUNS number and 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.  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 NOT-OD-11-101)

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.

Letter of Intent

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

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

  • Descriptive title of proposed activity

  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)

  • Names of other key personnel

  • Participating institution(s)

  • Number and title of this funding opportunity

The letter of intent should be sent to:

Carol Taylor-Burds, PhD

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

Page Limitations

All page limitations described in the 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.

Other Attachments: Applications should include an Intellectual property (IP) strategy. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials.

Applicants should describe the IP landscape surrounding their biomarker and its measurement. Applicants should describe any known constraints that could impede biomarker 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 product 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 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 or Modular Budget

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

Not Applicable

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:

This PAR supports the validation of analytical methods for biomarker measurements, including evaluation of the detection method, its performance characteristics, and the optimal conditions that will generate reproducibility and accuracy consistent with FDA guidelines that are fit for the purpose of the detection method.

Specific Aims

Briefly provide the Context of Use(s) for the biomarker, the biological research rationale for the identified biomarker, and a cogent argument outlining its importance and unmet need. Briefly describe the project aims, including the technical questions to be answered and the performance outcomes and characteristics needed in order to be used for the stated Context of Use(s). A scientific hypothesis is not required for this type of application.

Research Strategy

The Research Strategy Section should include the following sections

Rationale and Unmet Need

  • Define the disease or condition and the clinical population focus of the biomarker/biomarker signature.
  • Define the intended clinical Context of Use for the biomarker and its measurement. Include information on characteristics of the sample (i.e., specimen, image, EEG, behavioral endpoint, algorithm) to be used.
  • Describe the unmet need for the candidate biomarker and why the biomarker and its detection method will be feasible to conduct in the intended future clinical setting.
  • If applicable, provide a comparison to existing detection methods available for the biomarker and disease or condition of interest.
  • Describe the potential for the proposed studies to significantly advance translational medicine in the disease or condition area described.
  • Depending on the type of biomarker, address the probability for the biomarker and its detection method to be broadly adopted by the health care community for use in treatment or prevention.

Preliminary Data

Describe the evidence that the biomarker and detection method have met the Entry Criteria (see Section 1):

  • Describe the evidence that the biomarker has undergone initial testing in the relevant clinical population using retrospective or prospective data, including the initial sensitivity(ies) and specificity(ies) that has/have been found.
  • Describe what the detection method is, publications demonstrating its utility and feasibility, and cite any patents for prototypes (if applicable).
  • Provide any additional preliminary data supporting an argument that the biomarker is ready for analytical validation.
  • Describe the development status of the assay or method of detection and its potential use in a clinical setting.
  • Provide a clear outline of the method of detection, including the current key reagents, technologies and types of specimens or signals that will be used (e.g., fresh frozen or formalin-fixed tissue, serum or plasma, neuroimaging signals, behavioral or physiological measures, or composite biomarker signatures).
  • Discuss whether any of the analytical validation metrics listed in Section I above have been analyzed or completed; if so, provide the metrics,

Approach - address each of the items below

Describe the plans to perform analytical validation of the method of detection and its biomarker within its proposed Context of Use, including any plans for refinement of the Context of Use. The approach should include:

  • Plan to obtain appropriate samples (i.e., specimens, imaging data, physiology, or behavioral data) for further development and optimization of the assay or method of detection
  • Power analysis/justification for sample sizes
  • Plan to initiate and complete validation of the assay or method of detection
  • Plan to ensure appropriate standardization of samples and data that are used to validate the assay or method of detection
  • Plan to address pre-analytic variables of the assay, such as sample collection and preparation, interference, as well as relevant demographic variables such as race, gender, age etc. (See (iv) Analytical specificity below)
  • Plan for evaluation of (i) Accuracy, (ii) Precision, (iii) Analytical sensitivity, (iv) Analytical specificity including interfering substances/signals, (v) Reportable range of test results for the test system, (vi) Reference intervals (normal values) with controls and calibrators, (vii) Harmonization of analytical performance characteristics if the detection method is to be performed in multiple laboratories, (viii) quality control and improvement procedures, (ix) Any other performance characteristic required for test performance with determination of calibration and control procedures
  • Plan to address a revised Context of Use based on results of the analytical validation, such as establishing an alternate threshold or cut-off.
  • If applicable, provide detailed plans for validation of algorithm(s) for multi-modal biomarkers.

If an application proposes to use only a single site for analytical validation, then a short paragraph with the heading “justification for single site analytical validation” must be included clearly explaining why a multisite setting is unnecessary or impossible, such as for rare diseases/conditions that can only be diagnosed or treated in a few specialized settings

Timeline and Proposed Milestones (required)

Milestones and timelines must be provided under a separate, specific heading at the end of the Research Strategy Section. Milestones should describe project decision points with quantitative metrics for go/no-go decision making throughout the funding period. Annual quantitative milestones are required to provide clear indicators of a project's continued progress or emergent difficulties. Milestones will be used to monitor project progress as part of the evaluation for continued funding by the Program Director(s)/Principal Investigator(s), Program Official and Project Scientists. A timeline for the anticipated attainment of each milestone must be included.

Quantitative milestones are dependent on the project but should include items such as:

  • Progress metrics (i.e. enrollment goals, sample and data collection goals, key experiments conducted)
  • Performance metrics (i.e. level of consistency across replicates, reaching target sensitivity and specificity thresholds, demonstration of standardization across sites, data quality standards)
  • If applicable, qualification metrics (letter of intent submission for FDA qualification and/or consultations)
  • For each milestone, provide a brief description of the success criteria along with a brief justification for those criteria.
  • Provide a timeline for the anticipated attainment of each milestone.

Team Management Plan:

  • Applicants are strongly encouraged to form multidisciplinary teams that consist of clinical scientists, clinicians with drug development experience, regulatory experts, statisticians, and other academic/industry experts relevant to the therapeutic modality. Describe the team's ability to design the details of the plans and experiments, and to execute the research strategy.
  • Describe how the team will work together (e.g., data generation, reporting of data and integrated review across teams with various disciplines, decision-making, etc.) over the course of the project (and include letters of support below). This description should include an outline of roles and responsibilities for each team member

Letters of Support:

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

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.

The following modifications also apply:

All applications, regardless of the amount of direct costs requested for any given year, should include a Data Sharing Plan. 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.

  • Plans should describe how, where, and when the data, analytical code/scripts, metadata and protocols/standard operating procedures will be shared.
  • Applicants planning to collect biofluid samples from prospectively enrolled study participants should also provide the broader scientific community with a data resource for hypothesis generation, test validation, and discovery related through the NINDS biomarker repository, BioSEND (https://biosend.org/). Applicants should contact BioSEND to incorporate sharing plans and cost in their application. Note that costs for collection are NOT included as a component of the NINDS Biomarkers Repository award.
Appendix:

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

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

  • Standardized protocols for measuring the biomarkers proposed
  • For proposed ancillary studies, provide the protocol for the parent clinical trial or longitudinal study and the consent form for the parent study
  • For clinical trials, provide the consent forms to be used
  • If applicable, guidance documents provided by the FDA regarding qualification of the proposed biomarker(s)
PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

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

PHS Assignment Request Form

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

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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

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

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH 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 field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. 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 DUNS number it provides 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 components of participating organizations, 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.

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.

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:

  • Will the proposed studies significantly advance translational medicine in the disease or condition area described?
  • Are the biomarker and its detection method likely to be broadly adopted by the health care and/or research community for use in treatment or prevention decisions or studies?

In addition, for applications involving clinical trials

  • Is the need for a clinical trial to test the proposed biomarker well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms?
  • For trials with clinical or public health endpoints, is this clinical trial necessary for testing the validity of the biomarker that can lead to a change in 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:

  • Are the investigators knowledgeable and experienced about the biological target and/or disease biology?
  • Do the investigators have sufficient expertise in the areas of development and analytical validation of the detection method within the specified clinical context of use, statistical analysis, experimental design as appropriate for the project?
  • Will the team be able to manage the further development of the detection method should the detection method be successful so that it is distributed and ultimately available to the healthcare and/or research community?
  • Are the roles of each collaborator carefully defined in the research plan?

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:

  • Is there innovation in the detection method, study design or clinical context? Does the detection method offer a significant improvement over existing methods of detection for the proposed type of biomarker?

In addition, for applications involving clinical trials:

  • Does the design/research plan include innovative elements, as appropriate, that enhance the biomarker’s 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?

Further criteria specific to this opportunity:

  • Are the outcomes and performance criteria clearly stated and scientifically justified?
  • Are pre-analytic variables adequately addressed and are there plans to include control of these variables?
  • Are the plans for optimization and validation appropriate for the biomarker detection method being used?
  • Is there an adequate plan to ensure that samples and data are collected in a standardized and representative way?
  • Are there plans to ensure that the study is scientifically rigorous with appropriate use of blinding, randomization, replicates, and controls in place to minimize bias?
  • Is the statistical analysis plan clearly described and appropriate for the experimental design with adequate statistical power to test the performance of the detection method?
  • If a single site design is proposed, is it scientifically justifiable and sufficiently representative to meet the goals of the study?
  • Are there appropriate plans to refine the context of use if results of the analytical validation warrant it?

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

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable:

Study Design

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

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

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

Data Management and Statistical Analysis

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

 

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 and Timeline

Do the milestones describe appropriate project decision points with quantitative metrics for go/no-go decision making throughout the funding period? Do the annual quantitative milestones provide clear indicators of the project's continued progress? Is the timeline appropriate for the anticipated attainment of each milestone? Are the progress metrics (i.e. enrollment goals, sample and data collection goals, key experiments conducted) appropriate for the project's successful and timely completion? Are the performance metrics (i.e. level of consistency across replicates, reaching target sensitivity and specificity thresholds, demonstration of standardization across sites, data quality standards, etc) satisfactory for the context of use proposed? If applicable for the application, is the timeline for the qualification metrics (letter of intent submission for FDA qualification and/or consultations) appropriate? Are the quantitative success criteria for each milestone clear, appropriate and sufficiently justified?

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

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

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.

Intellectual Property

1) Does the application outline any known constraints that could impede biomarker 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 while achieving the goals of this program? 2) Does the applicant outline the IP landscape of their biomarker assay or method of detection? 3) If applicable, how strong is the applicant's IP portfolio/position (pertinent to the proposed project), and to what extent does the applicant have a reasonable strategy to protect its IP going forward? 4) If the applicant has filed patents pertinent to the biomarker detection method, do they provide details about those patents? 5) If IP will be shared among co-investigators, does the applicant provide details about the plans for IP sharing?

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 should include specific comments on whether the Resource and Data Sharing plan includes adequate information on the following questions:

  • Is the plan for sharing the protocols, related tools, software and/or code used for evaluating the biomarker appropriate? Are the repositories specified and appropriate?
  • Will the final curated datasets be made available? If not, is there a justifiable reason? If so, is there a clear description of where the data will be held and how to request access?
  • Is the timeline for disseminating information appropriate?

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

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. 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 grantee’s business official.

Awardees 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: Grantee 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 awardee 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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

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. This includes ensuring programs are accessible to persons with limited English proficiency. 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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/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 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

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

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

  • Defining the overall research objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
  • Determining experimental approaches, designing protocols, and overseeing the conduct of experiments.
  • Developing and proposing rigorous milestones that will be achieved during the project period;
  • Overseeing and coordinating the effort of the multi-disciplinary team and participating institutions and ensuring their optimal integration.
  • Overseeing the conduct of research projects and ensuring their scientific rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not. In cases when NINDS Program staff request raw data, awardees agree to provide the data.
  • Ensuring compliance with the applicable mandatory regulations (including protection of human subjects).
  • Adhering to the NIH policies regarding intellectual property, data release, and other policies that might be established during the course of this activity.
  • Submitting updates on progress and problems in a brief format as agreed upon with the NIH;
  • Submitting annual updates on human subject and accrual reports upon initiation of validation studies when appropriate.
  • Participating in progress meetings (teleconferences) that are organized by NIH staff once or twice a year.
  • Inviting NIH Program Staff to participate in interactions with regulatory agencies, include providing meeting dates and agenda.
  • Provide study reports from CROs, meeting minutes (and associated data packages if applicable), letters and other forms of communications with FDA, and other authorities, and to provide IND# and registration numbers in ClinicalTrial.gov, if applicable.
  • Awardees will retain custody of and have primary rights to the data, technologies, and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

NIH staff will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards (as appropriate regarding clinical trials):

  • Each project will have the support of one or more Project Scientists from NIH Program staff who are assigned an administrative role for the neurological or neuromuscular disorder being studied and have expertise in the implementation of the NINDS Biomarker Program in Translational Research.
  • The Project Scientists will have substantial scientific/programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants.
  • Providing input on the milestones and makes decisions regarding their finalization.
  • Providing input on experimental and clinical approaches, assisting in designing protocols, and consulting on updates to project milestones;.
  • Assessing the progress of the project towards the specified milestones, and for recommending if further funds should be released to the project.
  • In consultation with the PDs/PIs, may add critical experiments that need to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds.
  • Participates in meetings together with PDs/PIs with regulatory agencies related to the funded project when appropriate.
  • Providing advice to the awardees on specific scientific, analytical, and clinical issues as appropriate.
  • Assisting and advising awardees with regard to various regulatory and compliance issues as appropriate.
  • Participating in quarterly or biannual teleconferences with PDs/PIs to monitor progress and facilitate cooperation as appropriate.
  • Tracking monthly accrual of participants for clinical testing to ensure proper completion of this essential step as appropriate.
  • Contributing to publications and presentations resulting from the project if appropriate.
  • An important part of the NINDS Biomarker program is the coordination of research efforts across different funding mechanisms and research capabilities, and the coordination among efforts aimed at different neurological and neuromuscular disorders. NINDS Project Scientists will have the primary responsibility for this overall coordination.
  • Additionally, an NINDS Program Official will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. Some Program Officials may also have substantial programmatic involvement (as Project Scientists/Coordinators). In that case, the individual involved will not attend peer review meetings of renewal (competing continuation) and/or supplemental applications or will seek NINDS waiver as stated above.
  • NIH leadership will make decisions on project continuation based on Program staff recommendations, programmatic prioritizations and budget considerations. NINDS Program staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones)

Areas of Joint Responsibility include:

Dispute Resolution:

Any disagreements that may arise in scientific and/or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting; one NIH designee; and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

  • overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.
  • Clarifying, negotiating and finalizing the milestones and timelines.

3. Reporting

When multiple years are involved, awardees 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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All awardees 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, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: carol.taylor-burds@nih.gov

Mary Ann Pelleymounter, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email:mary.pelleymounter@nih.gov

Peer Review Contact(s)

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

Financial/Grants Management Contact(s)

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

Section VIII. Other Information

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

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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