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
Using Multimodal Biomarkers to Differentially Diagnose ADRDs for Clinical Trials (U19 Clinical Trial Optional)
Activity Code

U19 Research Program Cooperative Agreements

Announcement Type
New
Related Notices

NOT-OD-22-189 - Implementation Details for the NIH Data Management and Sharing Policy

NOT-OD-22-195 - New NIH "FORMS-H" Grant Application Forms and Instructions Coming for Due Dates on or after January 25, 2023

NOT-OD-22-198 - Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023

NOT-OD-23-012 - Reminder: FORMS-H Grant Application Forms & Instructions Must be Used for Due Dates On or After January 25, 2023 - New Grant Application Instructions Now Available

Funding Opportunity Announcement (FOA) Number
RFA-NS-24-001
Companion Funding Opportunity
None
Assistance Listing Number(s)
93.853, 93.866
Funding Opportunity Purpose

The purpose of this funding opportunity is to enable multi-site clinical validation of a multimodal set of neuroimaging and biospecimen biomarkers to use in clinical trials to differentially diagnosis two or more AD/ADRD in individuals presenting similarly clinically. As part of the program deliverables, investigators will be required to work towards qualifying the candidate biomarkers as therapeutic/drug development tools through the FDA’s Biomarker Qualification Program.

Key Dates

Posted Date
February 09, 2023
Open Date (Earliest Submission Date)
May 01, 2023
Letter of Intent Due Date(s)

May 1, 2023

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS Scientific Merit Review Advisory Council Review Earliest Start Date
June 01, 2023 Not Applicable Not Applicable November 2023 January 2024 April 2024

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
June 02, 2023
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the 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.

Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

In 2011, the National Alzheimer's Project Act (NAPA) allocated resources "to prevent and effectively treat Alzheimer's by 2025." Since then, the National Institute on Aging (NIA) and the National Institute of Neurological Disorders and Stroke (NINDS) have held multiple research summits to assess the needs and opportunities relevant to this goal for Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD). In particular, the NINDS has convened expert panels in 2013, 2016, 2019 and 2022, that were tasked with recommending research priorities for advancing the state-of-the-science for the Alzheimer's disease (AD) and Alzheimer’s disease-related dementias (ADRD) by 2025. ADRD are defined as Frontotemporal Degeneration (FTD), Vascular Contributions to Cognitive Impairment and Dementia (VCID), Lewy Body Dementias (LBD) and Multiple Etiology Dementias (MED). The ability to accurately diagnosis the ADRDs to enable better patient selection in clinical trials remains a high priority. ADRDs have overlapping clinical presentation and shared pathological processes with many related neurodegenerative disorders making accurate diagnosis challenging. Thus, postmortem pathology remains the gold-standard for diagnosing most ADRDs.

The difficulty of establishing a definitive clinical diagnosis for the ADRD remains a major obstacle for therapeutic development since targeting the right patient population for a given therapy may not be possible, especially in prodromal or early-stage dementia when therapies are most likely to be beneficial. No individual neuroimaging approach or biospecimen based biomarker has been broadly accepted by the scientific community as capable of differentiating one clinical AD/ADRD diagnosis from another with high sensitivity and specificity. Although distinct anatomical and pathological features have been defined for each condition, Amyloid, Tau, and alpha-Synuclein deposits, as well as markers of cerebrovascular disease and neuroinflammation, are present across patient populations. Significant investments have been made to improve the available biomarkers for AD/ADRD and there have been major advances in developing relevant imaging approaches such as MRI and PET, as well as a wide variety of commercial biospecimen based assays for common neurodegenerative or injury markers. However, each of these approaches alone has limitations and can be ambiguous to interpret in early disease stages. Moreover, given the many differences in the protocols used, and the variation in sensitivity and specificity of the assay or imaging approach under different conditions, comparing results across studies and patient populations remains a challenge. The FDA’s Biomarker Qualification Program (BQP) is designed to formally qualify biomarkers that can be used as therapeutic development tools in clinical trials. In order to be qualified, sufficient evidence must be submitted to the FDA demonstrating that the biomarker can be reliably measured (analytically validated) and clearly interpreted (clinically validated) within a specific Context of Use that describes how the biomarker will be used in drug (or therapeutic) development. Applicants to this RFA must include plans for working with the FDA Biomarker Qualification Program to initiate the qualification process for the biomarkers proposed for differential diagnosis of the ADRDs. ?

Prospective multisite studies in representative patient populations are needed to enable biomarker qualification. Historically, AD/ADRD clinical studies, as with many other conditions, have frequently lacked appropriate demographic representation in the patient populations participating in studies, thereby limiting the translation potential of interventions, and contributing to health inequity. Improving health equity in AD/ADRD research and care is a cross cutting objective of the AD/ADRD research priorities. Biomarker clinical validation studies must include patient populations that reflect real world demographics including but not limited to, racial, ethnic, age, and geographic diversity. One means of increasing appropriate representation is to increase stakeholder engagement in clinical studies including patients, families, their representatives, health professionals, and the clinical research team working in active partnership at various levels across the continuum of clinical research. Community engagement can be used to promote health and health research by reducing barriers and enabling research participation by NIH-designated populations that experience health disparities (HDPs) and populations with limited English proficiency. Therefore, community engagement with a variety of stakeholders representing these groups and patient populations is a key objective of this RFA.

Definitions of key terms:

  • Biomarker: 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 broad array of biomarker modalities are encouraged, and can include omics, imaging, behavioral, digital and physiologic endpoints. As defined by the NIH/FDA Biomarkers, EndpointS and Other Tools (BEST) Resource, biomarkers are categorized as susceptibility/risk, diagnostic, monitoring, prognostic, predictive, pharmacodynamic/response, or safety, depending on how they are used.
  • Biomarker signature/multi-component biomarker: combination of multiple variables/components to yield a patient-specific indicator of normal biological processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions.
  • Concept of interest: the aspect of an individual’s clinical, biological, physical, or functional state, or experience that the assessment is intended to capture or reflect.
  • Detection method: the method used to measure the biomarker or biomarker signature such as the assay, imaging protocol, detection algorithm, etc.
  • Context of Use (COU): The COU is a concise description of the biomarker’s specified use in drug/therapeutic development. The COU includes two components: (1) biomarker category (diagnostic, for this RFA) and (2) the biomarker’s intended use in therapeutic development. Each biomarker qualification effort should identify a single COU which may be refined during the qualification process.
  • Analytical Validation: establishes that the performance characteristics of a test, tool or instrument are acceptable in terms of the sensitivity, specificity, accuracy, precision and other relevant performance characteristics using a specified technical protocol. Analytical validation demonstrates that the biomarker can be reliability and consistently measured.
  • Clinical Validation is defined as establishing that the biomarker acceptably identifies, measures or predicts the concept of interest within a defined context of use. The application should clearly describe how the proposed study plans to ensure broad and reliable clinical use across multiple sites.
  • Biomarker Qualification: Qualification of a biomarker is a determination that within the stated context of use, the biomarker can be relied on to have a specific interpretation and application in or therapeutic development and regulatory review. Qualification through the FDA BQP is a three-stage process that begins with a Letter of Intent, followed by the Qualification Plan, and finally the full qualification package of evidence (https://www.fda.gov/drugs/biomarker-qualification-program/resources-biomarker-requestors).

Research Objectives:

This U19 mechanism is designed to support large multi-site prospective clinical validation of standardized imaging and biospecimen assay batteries to differentially diagnosis two or more ADRDs from related conditions in large prodromal and/or early symptomatic clinical cohorts that reflect real world patient diversity for the context of use and in alignment with the NIH policy for inclusion of women and minorities as participants in research.

Differential Diagnostic Biomarker Qualification: Projects should propose to clinically validate three or more biomarkers (including at least one imaging biomarker and one biospecimen biomarker or biomarker signature) that already have significant evidence of their potential diagnostic utility and have undergone analytical validation of the detection method used to measure each biomarker. Studies must plan to evaluate the diagnostic accuracy, including addressing the positive predictive value and negative predictive value of each of the proposed biomarker modalities alone, and as a combined multi-modal combined biomarker battery for differential diagnosis. Studies must engage with the FDA’s Biomarker Qualification Program and, at minimum, plan to complete both stage 1 (letter of intent) and 2 (qualification plan) of the biomarker qualification process during the project period. Data generated over the course of the project should be submitted as part of the full qualification package to the FDA BQP. Studies must share the final standardized protocols with the research community along with any non-proprietary data and analyses at the end of the project. Projects may also seek to qualify any associated technologies (such as imaging protocols or assays) as assistive diagnostics through the FDA’s Center for Devices and Radiological Health (CDRH); however, this is not a requirement for this RFA.

Community engagement plan: Applications must include a detailed community engagement plan that outlines collaborations with study-relevant organizations, groups representing health disparity populations and populations with limited English proficiency, patients with lived experience, patient or consumer advocacy groups, community champions, community-based organizations, faith-based organizations and/or other relevant stakeholder groups. Projects must provide evidence of relationship development or collaboration, such as through letters of support.

Application Requirements:

  • Study design: Projects must propose to conduct prospective multi-site clinical validation of standardized imaging and biospecimen assay batteries to differentially diagnosis two or more ADRDs in large prodromal and/or early symptomatic clinical cohorts. This should describe the diagnostic criteria for the patient populations of interest, current evidence supporting the proposed biomarker as a potential diagnostic tool, plans for harmonizing clinical assessments and biomarker measurement across sites, a stakeholder engagement strategy, planned statistical analyses (including how the decision cut-off points, thresholds, or limits used for decision making will be established), and a timeline for completing all activities (e.g., patient recruitment, letter of intent submitted to the FDA, etc.). Applicants must provide evidence that they have access to the patient populations of interest in sufficient numbers to guarantee that the analyses will be statistically powered.
  • Research projects: At least two research projects must be proposed for validating the biomarkers.
  • Cores: Three cores are required: 1) the Administrative Core, to oversee the overall success of the projects and regulatory interactions, 2) the Clinical Core, to ensure community engagement and patient recruitment, enrollment and retention, and 3) the Data Management and Statistics Core to ensure data quality assurance and quality control (QA/QC) across sites, prepare data submission to the FDA, and oversee rigorous statistical analysis needed for biomarker qualification.
  • Evidence of preliminary clinical validation of the biomarkers: Literature and/or preliminary data demonstrating that the biomarker reflects the intended pathophysiology and/or clinical endpoint appropriate for the diagnostic Context of Use are required. Evidence should include a preliminary estimate of the diagnostic clinical sensitivity and specificity, as defined by Receiver Operator Characteristic Analysis (ROC).
  • Established analytical validation of the detection method: Evidence demonstrating that the detection methods to be used for the imaging and biospecimen biomarkers have undergone analytical validation and are ready to be used for multi-site clinical validation. The performance characteristics of the detection methods should be described in detail as appropriate for each method (include information on precision, dynamic range, analytical sensitivity and specificity, any known sources of error such as from pre-analytical collection method differences, signal to noise, resolution, inter and intra variation across sites/operators/time, and information on any software or algorithms used, as appropriate for each method).

Non-Responsive Applications:

  • Projects that are not primarily focused on AD/ADRD.
  • Projects that do not seek to work with the FDA to ensure that the biomarkers are suitable for use to validate differential diagnosis for ADRD with the intent of qualifying the biomarkers through the FDA Biomarker Qualification Program
  • Projects that do not propose at least one imaging and one biospecimen biomarker.
  • Projects that do not focus on differential diagnosis that will support future clinical trials
  • Projects that do not have a community engagement plan
  • Projects missing any of the 3 required cores or minimum number of projects (at least two)
  • Any project not proposing to do a prospective multi-site study

Leveraging Existing Resources: Whenever possible, applicants should consider leveraging existing clinical patient networks and to use consensus-based and/or standardized assessment approaches (e.g., the National Alzheimer’s Coordinating Center’s LBD or FTLD module, the Parkinson’s Disease Biomarker Program’s LBD protocol, MarkVCID2 protocols, etc). When appropriate, the inclusion of digital/mobile sensor technologies is encouraged, and online assessment or remote- or tele-visits may be incorporated when they can be conducted in a standardized fashion and without compromising data integrity.

Reproducibility and Data Sharing

To improve reproducibility and community uptake, investigators are expected to share protocols/processes code/scripts, analytic tools/statistical models, and metadata (with the exception of any intellectual property for diagnostics that are being commercialized). Investigators should incorporate plans for sharing and dissemination of the data, protocols, and any analytical methods in their research sharing plan and project timeline. Applicants should ensure their consent forms include language that allows sharing data and bio-samples for broad future research goals. Budgets should reflect any costs associated with these efforts. Information on many of the 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 expected 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. If an exemption to sharing biofluid samples is requested, a justification should be included in the research sharing plan.

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

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

Section II. Award Information

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
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).

Funds Available and Anticipated Number of Awards

NINDS intends to fund one award, corresponding to a total of $7,000,000 per year for the RFA, for up to 5 years. Future year amounts will depend on annual appropriations.

Award Budget

Application budgets are limited to up to a total of $4,700,000 in direct costs per year, but must 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
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. The same UEI must be used for all registrations, as well as on the grant application.
  • eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

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 diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the 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 or an institutional system-to-system solution. A button to apply using ASSIST is 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 Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

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

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

  • Descriptive title of proposed activity
  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
  • Names of other key personnel
  • Participating institution(s)
  • Number and title of this funding opportunity

The letter of intent should be sent to:

Carol Taylor-Burds, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
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.

Component Component Type for Submission Page Limit Required/Optional Minimum Maximum
Overall Overall 12 Required 1 1
Administrative Core Admin Core 6 Required 1 1
Data Management and Statistics Core Core 6 Required 1 1
Clinical Core Core 6 Required 1 1
Research Projects Project 12 Required 2 4

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.

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

The application should consist of the following components:

  • Overall: required
  • Administrative Core: required; maximum 1
  • Data Management and Statistics Core: required; maximum 1
  • Clinical Core: required; maximum 1

  • Research Projects: required; minimum 2, maximum 4

Overall Component

When preparing your application, use Component Type Overall .

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

SF424(R&R) Cover (Overall)

Complete entire form.

PHS 398 Cover Page Supplement (Overall)

Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

Research & Related Other Project Information (Overall)

Follow standard instructions.

Project/Performance Site Locations (Overall)

Enter primary site only.

A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

Research and Related Senior/Key Person Profile (Overall)

Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

Budget (Overall)

The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.

A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

PHS 398 Research Plan (Overall)

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is required in the Overall component.

Specific Aims:

Provide the overall research objective and specific aims for the entire project; briefly explain how the research projects and cores will work together to achieve the aims

Research Strategy:

Background:

  • Describe the current diagnostic criteria and processes for the conditions selected and describe the limitations and challenges in achieving those diagnoses; directly address how improved differential diagnosis would improve patient selection for future clinical trials.
  • Provide an overview of the current state of the science regarding the underlying pathophysiological similarities and differences involved in each of the diseases/conditions as well as any major gaps in understanding or knowledge.
  • Briefly describe the candidate biomarkers proposed for validation in the research projects and explain how they would be an improvement to the current standards; describe the detection method modality and approach (how each component will be detected/measured).
  • Describe the evidence that the detection methods used for measuring the biomarkers have already undergone analytical validation and include a table or brief summary of the analytical sensitivity, specificity, accuracy, precision and other relevant performance characteristics and references to the specified technical protocol.
  • If validated, describe how and when the biomarkers would be implemented into a diagnostic workflow (it is strongly recommended to include a flow chart or diagram to illustration how the biomarkers could be used within the diagnostic process for a clinical trial).
  • Provide an overview of the approximate time and cost associated with implementing the proposed diagnostic biomarkers and explain why the risk/benefit ratio for improved diagnostic accuracy relative to the additional burden of incorporating the biomarkers into future clinical trials would be justified.

Timeline:

  • Planning Phase (1 year): ?A FDA Critical Path Innovation Meeting (CPIM) and/or Letter of Intent (LOI) to the FDA’s Biomarker Qualification Program for each of the proposed biomarkers to be validated must be scheduled (if a CPIM) or submitted (if LOI) within the first quarter of the first year so that initial feedback from the FDA can be incorporated into the finalization of the protocols and study design, if needed (it is strongly encouraged to reach out to the FDA BQP as part of the application preparation to hold a pre-LOI meeting: https://www.fda.gov/drugs/biomarker-qualification-program/resources-biomarker-requestors). Include an overview of all major activities to be completed during the planning phase which should include, but are not limited to: engagement with the FDA BQP, finalization of study protocols and consent forms, community outreach and engagement activities needed to ensure diverse patient recruitment that includes NIH-designated populations that experience health disparities (HDPs) and populations with limited English proficiency (https://www.nimhd.nih.gov/about/overview/), and setting up data capture and workflow processes (including establishing quality assurance and quality control procedures), finalization of the single IRB, and establishment of an OSMB (if needed).
  • Implementation Phase (remaining years): ?Briefly outline the overall study design for the entire project, including an overview of the proposed clinical protocol and major activities to be completed each year, and final analyzes to be conducted in preparation for biomarker qualification submission.

Letters of Support: A strong commitment to the proposed study by the leadership of the participating clinical sites should be demonstrated by including letters of support from the participating site signed by individuals with financial authority within the systems.

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

It is required that all biospecimens and clinical data collected (including imaging) and/or used for research under funding from this FOA have appropriate informed consent per NIH policy and as mandated by law. Applications must include plans for appropriately collecting, storing, and sharing de-identified clinical data.

When new biospecimens and/or clinical data (including imaging) are collected, consent must allow all enrolled individuals the opportunity to consent to share, including via NINDS repositories, their de-identified samples and data (including post-mortem tissue when possible) with researchers in academics, not-for-profits, and industry (for internal research only, for-profit use is not allowed). Applicants are strongly encouraged to review the Informed Consent of Secondary Research with Data and Biospecimens points to consider document published in 2022: https://sharing.nih.gov/data-management-and-sharing-policy/about-the-data-management-sharing-policies

Applicants collecting biofluid samples from prospectively enrolled study participants are expected 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. If an exemption to sharing biofluid samples is requested, a justification should be included in the research sharing plan.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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


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

Appendix:

Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Overall)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

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 (Overall)

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

Research Projects (minimum of 2, maximum of 4)

When preparing your application, use Component Type Insert Name.

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

SF424 (R&R) Cover (Research Projects)

Complete only the following fields:

  • Applicant Information
  • Type of Applicant (optional)
  • Descriptive Title of Applicant’s Project
  • Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Research Projects)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Research Projects)

  • In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
  • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
  • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
  • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Research Projects)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Research Projects; minimum of 2, maximum of 4)

Introduction to Application: Not Applicable

The most commonly referenced Research Plan attachments are listed below for your convenience. FOA specific instructions are required for the Specific Aims and the Research Strategy in each component. FOA-specific instructions are optional for Letters of Support. Delete Letters of Support if there are no FOA-specific instructions.

Specific Aims: Provide a concise description of each of the biomarkers to be validated and the specific aims of the project needed to achieve their validation. Each research project should focus on qualifying one or more biomarkers for differential diagnoses of the AD/ADRD within the specified context of use. The final aim should include the analysis plans for evaluating the biomarkers as a multi-modal composite biomarker.

Research Strategy:

  • Studies must plan to evaluate the diagnostic accuracy, including assessing or modeling the potential positive predictive value and negative predictive value of each of the proposed biomarkers within the research projects, describe the plans for inclusion into a combined multi-modal composite biomarker assessment for differential diagnosis.
  • Summarize the literature and/or data justifying the rationale for the selection of the biomarker as a candidate differential diagnostic biomarker and address any limitations or controversies around the interpretation of the supporting evidence (literature and preliminary data).
  • Describe the current clinical diagnostic standards/approaches available and the diagnostic accuracy needed for these biomarkers to enable an earlier clinical diagnosis. Directly address the unmet need these biomarkers would fill and the estimated impact (both positive and negative) if they were to be validated and used for patient selection in future clinical trials.
  • Studies must engage with the FDA’s Biomarker Qualification Program (BQP) and may wish to first set up an initial Critical Path Innovation Meeting. Projects must plan to complete both stage 1 (letter of intent) and 2 (qualification plan) of the biomarker qualification process during the 5 year project period.
  • Data generated over the course of the project should be used as part of the full qualification package to the FDA BQP. For each biomarker or set of biomarkers to be validated in the research projects, include the following information:
    • Describe how the biomarker (imaging, biospecimen, or other) would be used both alone and in combination with the other biomarkers for differential diagnosis of AD/ADRD (include a specific Context of Use).
    • Describe the overall study design including the clinical protocol and statistical analysis plan. This section should provide a detailed description of the assumptions used in determining the power calculations and provide evidence supporting these assumptions. Applicants are strongly encouraged to ensure the study is powered to incorporate subgroup analyses of understudied patient populations, such as NIH-designated populations that experience health disparities (HDPs) and populations with limited English proficiency as well as comorbidities that are often underrepresented or excluded in clinical trials.
    • Describe what methods of detection are to be used (as appropriate, specify which assays, platforms, devices, imaging protocols, software, etc are to be used). If multiple assays/devices/etc are to be used, describe the analysis plan for ensuring results can be interpreted across them (this may also be directly tested during the first year planning phase, if appropriate).
  • Include a Gantt chart or similar, outlining the individual timeline, deliverables and other milestones to be achieved (this may be a project specific version of one included in the overall research plan, with additional project specific deliverables and milestones outlined in more detail).

Letters of Support:

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, with the following modification:

Appendix:

Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Administrative Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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..

Administrative Core

When preparing your application, use Component Type Insert Name.

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

SF424 (R&R) Cover (Administrative Core)

Complete only the following fields:

  • Applicant Information
  • Type of Applicant (optional)
  • Descriptive Title of Applicant’s Project
  • Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Administrative Core)

Enter Human Embryonic Stem Cells in each relevant component.

Research & Related Other Project Information (Administrative Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Administrative Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Administrative Core)

  • In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
  • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
  • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
  • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Administrative Core)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Administrative Core)

The most commonly referenced Research Plan attachments are listed below for your convenience. FOA specific instructions are required for the Specific Aims and the Research Strategy in each component. FOA-specific instructions are optional for Letters of Support. Delete Letters of Support if there are no FOA-specific instructions.

Specific Aims: Aims for this core should define key aspects of administration and management of the study.

Research Strategy:

  • The Administrative Core is responsible for implementing the overall governance and project management strategy.
  • Describe the organizational structure that will facilitate coordination and integration of progress across research projects, cores, and committees and coordinate interactions with the FDA for biomarker qualification.
  • The application should describe both a Project Governance and Project Management Plan:
    • The Project Governance Plan should describe how each of the cores and research projects will interact to make decisions and oversee the overall objectives of the projects including interactions with the FDA and any outside/independent Advisory Committees (if applicable).
    • The Project Management Plan should describe the operational processes to facilitate interactions among research projects, cores, scientific leadership, and, if applicable, the observational study monitoring board, as well as any other support processes, as needed.
    • Include a detailed description of the proposed staffing for completing activities during the first-year planning phase as well as the overall plans for the implementation phase, including a detailed timeline.

Letters of Support:

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, with the following modification:

Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA.

Appendix:

Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Administrative Core) format

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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.

Clinical Core

When preparing your application, use Component Type Insert Name.

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

SF424 (R&R) Cover (Clinical Core)

Complete only the following fields:

  • Applicant Information
  • Type of Applicant (optional)
  • Descriptive Title of Applicant’s Project
  • Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Clinical Core)

Research & Related Other Project Information (Recruitment and Retention Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Clinical Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile (Clinical Core)

  • In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
  • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
  • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
  • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Clinical Core)

Budget forms appropriate for the specific component will be included in the application package.

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Clinical Core)

The most commonly referenced Research Plan attachments are listed below for your convenience. FOA specific instructions are required for the Specific Aims and the Research Strategy in each component. FOA-specific instructions are optional for Letters of Support. Delete Letters of Support if there are no FOA-specific instructions.

Specific Aims: Aims for this core should define the key aspects of the study's recruitment and retention plans which must include community engagement plans to increase recruitment and retention of understudied populations including NIH-designated populations that experience health disparities (HDPs) and populations with limited English proficiency.

Research Strategy:

  • Include discussion of the approach to managing clinical sites and criteria defining performance of the sites, as well as a plan describing how performance will be monitored and measured, and what corrective actions may be taken.
  • Describe the plans for outreach and community engagement efforts and how recruitment and retention strategies will be implemented.
  • Include stakeholders that represent NIH-designated Health disparity populations as well as the patient/caregiver representatives for the diseases/conditions being studied.
  • Describe patient engagement activities and methods to monitor and evaluate outcomes related to engagement
  • Include linguistic and cultural competence strategies to enable recruitment and retention of populations that experience health disparities (e.g., cultural competence training; translation of study materials, services, etc.)
  • Identify and propose solutions to known barriers (e.g., social determinants of health) to recruitment, participation, and/or retention of health disparity populations with limited English proficiency (i.e., limited internet access, caregiving, work, transportation, etc.)
  • Include resources to compensate stakeholders and patients and support and sustain community engagement

Letters of Support: Include any letters of support from community leaders, partners with established community networks including patient advocacy organizations, that will provide guidance or be leveraged to help with recruitment and consent processes.

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, with the following modification:

Appendix:

Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Recruitment and Retention Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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.

Data Management and Statistics Core

When preparing your application, use Component Type Insert Name.

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

SF424 (R&R) Cover (Data Management and Statistics Core)

Complete only the following fields:

  • Applicant Information
  • Type of Applicant (optional)
  • Descriptive Title of Applicant’s Project
  • Proposed Project Start/Ending Dates

PHS 398 Cover Page Supplement (Data Management and Statistics Core)

Research & Related Other Project Information (Data Management and Statistics Core)

Human Subjects: Answer only the Are Human Subjects Involved? and 'Is the Project Exempt from Federal regulations? questions.

Vertebrate Animals: Answer only the Are Vertebrate Animals Used? question.

Project Narrative: Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

Project /Performance Site Location(s) (Data Management and Statistics Core)

List all performance sites that apply to the specific component.

Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

Research & Related Senior/Key Person Profile Data Management and Statistics Core)

  • In the Project Director/Principal Investigator section of the form, use Project Role of Other with Category of Project Lead and provide a valid eRA Commons ID in the Credential field.
  • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
  • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
  • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.

Budget (Data Management and Statistics Core)

Budget forms appropriate for the specific component will be included in the application package.

The cost for running software and services in the cloud environment (if appropriate) may be included in the budget. Applicants may wish to enroll in the NIH STRIDES Initiative to take advantage of discounts and other resources. For more information see: https://cloud.nih.gov/

Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

PHS 398 Research Plan (Data Management and Statistics Core)

Introduction to Application: For Resubmission and Revision applications, an Introduction to Application is allowed for each component.

The most commonly referenced Research Plan attachments are listed below for your convenience. FOA specific instructions are required for the Specific Aims and the Research Strategy in each component. FOA-specific instructions are optional for Letters of Support. Delete Letters of Support if there are no FOA-specific instructions.

Specific Aims: Aims for this core should define the key aspects of the study's data management plans and statistical support.

Research Strategy:

  • Describe how the Data and Statistics Core will facilitate the harmonization of data collection, management, curation and analysis between the proposed Research Components including:
    • Development of harmonized protocols, including selection and use of common data elements, CDISC standards, and any modality or other methodological specific standards to be used.
    • Ensuring rigorous and unbiased collection and analyses practices (https://www.ninds.nih.gov/Funding/grant_policy) including, but not limited to describing methods of blinding, strategy for randomization, defined criteria for inclusion/exclusion of individuals or samples and documentation of data collection practices, quality control checks and version control.
    • The analytic tools, workflows, and platforms to be used.
    • Any training and start up activities to be conducted during the planning phase.
  • Provide the Statistical Analysis Plans and rationale for the study design for each of the study protocols, including the selection of the primary and any additional secondary endpoints that the biomarkers will be validated against; include how the sample size was determined; how the biomarker cutoffs will be determined and how missing data will be handled. Potential biases and/or challenges in the study design and protocol should be identified and addressed.
  • The plan for integrating and modeling the multi-modal composite biomarker should be described and justified with considerations of the thresholds for sensitivity, specificity, and variance allowed within the model to reach the diagnostic accuracy needed.

Letters of Support:

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, with the following modification:

Appendix:

Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

PHS Human Subjects and Clinical Trials Information (Data Management and Statistics Core)

When involving human subjects research, clinical research, and/or NIH-defined clinical trials 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 a 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.

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) using ASSIST or other electronic submission systems. 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.

For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

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) and component Project Leads must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the 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, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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.

Post Submission Materials

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

Letters of Intent outcomes submitted to the FDA Biomarker Qualification Program and any associated meeting minutes may added after application submission.

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.

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

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 - Overall

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 - Overall

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?

Additional criteria specific to this opportunity:

  • Does the proposal describe the current diagnostic criteria for the proposed conditions and how the proposed studies will address limitations with those criteria?
  • Is it current state of the science regarding the underlying pathophysiological similarities and differences clearly described?
  • Is the cost/benefit ratio of implementing the proposed diagnostic biomarkers for use in clinical trials described in the application?
  • If validated, are the proposed biomarkers likely to fill an unmet need for use in clinical trials?

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?

Additional criteria specific to this opportunity:

  • Does the research team include sufficient expertise in each of the neurological conditions, diagnostic modalities, and statistical and data science expertise needed for the project's objectives?

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?

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?

Additional criteria specific to this opportunity:

  • Is it clear how and when the biomarkers will be used for differential diagnosis and is it appropriate for the context of use described?
  • Are the endpoints and outcomes clearly defined and relevant for validating the biomarkers for the context of use described?
  • Is there sufficient evidence that the candidate biomarkers selected for validation are ready for multi-site clinical validation?
  • Is there evidence that the detection methods for measuring the biomarkers have been analytically validated and can be reliably used across sites?
  • Are the patient populations described with clear diagnostic criteria? Do the PIs provide evidence of access to these populations in numbers sufficient for statistical power?
  • Are the statistical analysis plans clearly described and justified? Are the proposed subgroup analyses appropriate for the clinical patient populations? Are the power calculations reasonable and scientifically justified?
  • Are there appropriate methods of blinding, strategy for randomization and defined criteria for inclusion/exclusion of individuals and/or samples?
  • Are the overall planning and implementation activities clearly described and appropriate for the study objectives?

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?

Scored Review Criteria - Project and Cores

Research Projects

  • If successful, will the candidate biomarkers provide a significant improvement over the current clinical diagnostic standards/approaches available that can enable earlier clinical diagnosis to improve patient selection in clinical trials?
  • Is the plan for evaluating the diagnostic accuracy of the candidate biomarkers rigorous and well designed? Is the plan for combining the composite biomarkers clearly described and justified?
  • Is there rigorous supporting literature and/or preliminary data supporting the rationale for the selection of the biomarkers as a candidate differential diagnostic biomarker for the Context of Use described?
  • Is there a reasonable timeline to engage with the FDA’s Biomarker Qualification Program (BQP) and any Critical Path Innovation Meetings appropriate?
  • Is it clear how each candidate biomarker (including imaging, biospecimen, or other) would be used both alone and in combination with the other biomarkers for improved differential diagnosis of the ADRD?
  • Are the methods used to detect the biomarkers clearly described? Is there evidence that these have undergone sufficient analytical validation that they can be reliably used in a multi-site clinical study, including information on the performance characteristics of the detection methods (such as precision, dynamic range, analytical sensitivity and specificity, and any known sources of error such as from pre-analytical collection method differences, signal to noise, resolution, inter and intra variation across sites/operators/time, and information on any software or algorithms used, as appropriate for each method)? Is there any additional analytical validation needed and if so, are the plans appropriate within the first planning phase/year 1 of the study?
  • Are the power calculations used clearly justified and appropriate for goals of the study, including addressing questions related to utility in understudied patient populations?
  • Is the overall timeline and milestones appropriate for the success of the study? If not, are there other critical milestones that may increase the probability of success and/or minimize risk?

Administrative Core

  • Is the overall organizational structure clearly described and appropriate to facilitate coordination and integration of progress across research projects, cores, and committees and coordinate interactions with the FDA towards obtaining biomarker qualification?
  • Are the project Governance and Management plans well thought out and appropriate for the success of the project?
  • Are the activities and plans for the first year planning phase appropriate and feasible within the time permitted?

Clinical Core

  • Is the approach to managing clinical sites including the performance criteria clearly described and reasonable?
  • Are the plans for monitoring site performance clearly described with appropriate plans to incorporate corrective strategies, if needed? If not, are there additional strategies that should be added?
  • Are the plans for outreach and community engagement efforts and how recruitment and retention strategies will be implemented clearly described and well thought out?I Is there appropriate representation of stakeholders that represent NIH-designated Health Disparity populations as well as the patient/caregiver representatives for the diseases/conditions being studied?
  • Are the patient engagement activities and methods described to monitor and evaluate outcomes related to engagement appropriate?
  • Are the plans to incorporate linguistic and cultural competence strategies to enable recruitment and retention of populations that experience health disparities (e.g., cultural competence training, translation of study materials, services, etc.) clearly described and sufficient for the success of the project? If not, are there additional activities or approaches that could or should be included?
  • Is there evidence that the team understands and can address known barriers contributing to challenges in recruitment, participation, and/or retention of health disparity populations with limited English proficiency (i.e., limited internet access, care-giving, work, transportation, etc.)?
  • Are there appropriate resources budgeted to compensate stakeholders and patients and support and sustain community engagement?

Data Management and Statistics Core

  • Is the role of the Data and Statistics Core clearly described including addressing how the Core will facilitate 1) the development of harmonized protocols, including selection and use of common data elements, CDISC standards, and any modality or other methodological specific standards to be used, 2) Ensuring rigorous and unbiased collection and analyses practices (https://www.ninds.nih.gov/Funding/grant_policy) including, but not limited to describing methods of blinding, strategy for randomization, defined criteria for inclusion/exclusion of individuals or samples and documentation of data collection practices, quality control checks and version control, 3) the analytic tools, workflows, and platforms to be used, and 4) any training and start up activities to be conducted during the planning phase?
  • Is the overall study design to evaluate each individual biomarker and the final composite biomarker composite or battery across projects described?
  • Is there an overall plan for incorporating the biomarkers into a final composite biomarker or diagnostic battery, with adequate consideration of the statistical criteria that must be met?
  • Are the Statistical Analysis Plans described including the rationale for the study design for each of the study protocols, including the selection of the primary and any additional secondary endpoints that will be used to validate the biomarker against?
  • Is the rationale for the sample sizes used for each biomarker and research question clearly described and justified?
  • Is the approach to establishing the biomarker cutoffs described and reasonable?
  • Is there an appropriate plan to handle missing data?
  • Are potential biases and/or challenges in the study design and protocol identified with plans to address them?
  • Is the plan for integrating and modeling the composite biomarker (across research projects) described and justified with considerations of the thresholds for sensitivity, specificity, and variance allowed to reach the diagnostic accuracy goals needed?
Additional Review Criteria - Overall

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:

  • Is the timeline clear, feasible, and appropriate for the validation of the proposed biomarkers and interactions with the FDA?
  • Are there additional milestones or deliverables that should be included that are critical to the success of the project or to demonstrate sufficient diagnostic value of the candidate biomarkers?

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 Animals 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

Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations - Overall

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

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) will not be evaluated at time of review.

Reviewers will comment on whether the Resource Sharing Plan(s) (i.e., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

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.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. 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.6. 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 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).

Prior Approval of Pilot Projects

Recipient-selected projects that involve clinical trials or studies involving greater than minimal risk to human subjects require prior approval by NIH prior to initiation.

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 will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. 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

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 2 CFR Part 200, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the recipients is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients 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, recipients 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, including 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.
  • Recipients 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 may 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 such as:
    • 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 recipients on specific scientific, analytical, and clinical issues as appropriate.
    • Assisting and advising recipients with regard to various regulatory and compliance issues as appropriate.
    • Participating in quarterly, biannual, or annual video-conferences with PDs/PIs to monitor progress and facilitate cooperation as appropriate.
    • Tracking 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.
  • A 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 prioritization 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), overall progress, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.

Areas of Joint Responsibility include:

  • Clarifying, negotiating and finalizing the milestones and timelines.

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 recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

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

Applicants collecting biofluid samples from prospectively enrolled study participants are expected 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. If an exemption to sharing biofluid samples is requested, a justification should be included in the research sharing plan.

4. Reporting

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

Progress reports should briefly describe status of pilot projects, including data and safety monitoring, and should notify NIH of serious adverse events and unanticipated problems.

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 the threshold. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113and 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 75and 2 CFR Part 200 Award Term and Condition 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: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-480-7075

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

Scientific/Research Contact(s)

Yuan Luo, Ph.D.
NATIONAL INSTITUTE ON AGING (NIA)
Division of Neuroscience (DN)
Phone: 301-496-9350
E-mail: luoy2@mail.nih.gov

Carol Taylor-Burds, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-301-478-2522
Email: carol.taylor-burds@nih.gov

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

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

Financial/Grants Management Contact(s)

Philip Smith
NATIONAL INSTITUTE ON AGING (NIA)
Phone: 301-555-1212
E-mail: philip.smith2@nih.gov

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

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

Section VIII. Other Information

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

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 and 2 CFR Part 200.

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