National Institutes of Health (NIH)
U01 Research Project – Cooperative Agreements
The purpose of this funding opportunity announcement (FOA) is to invite pragmatic clinical trial applications to test paradigms designed to address the unmet need to detect cognitive impairment, including dementia, in large and diverse populations seen in primary care across the United States when a patient, relative, or care provider indicates concern. Applications must propose pragmatic clinical trials to test paradigms to detect cognitive impairment, including dementia, with adequate power in up to 3 populations including at least two specified populations that experience health disparities. Clinical paradigms proposed for pragmatic clinical trials should have rigorous supporting preliminary data and utilize tools that are simple to use, standardized, integrated into the electronic medical record (EMR) workflow, and ideally take five minutes or less to administer in a primary care clinical setting. Paradigms must provide standardized and implementable turnkey guidance via the EMR to the care provider for follow-up based on results of either “no objective cognitive impairment detected” or “cognitive impairment possible or detected”.
September 10, 2021
|Application Due Dates||Review and Award Cycles|
|New||Renewal / Resubmission / Revision (as allowed)||AIDS||Scientific Merit Review||Advisory Council Review||Earliest Start Date|
|November 10, 2021||Not Applicable||Not Applicable||March 2022||May 2022||July 2022|
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from NIH Guide for Grants and Contracts).
Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.
Background and Purpose
Early detection of incident cognitive impairment, including dementia, is a recognized healthcare priority in the United States and is a highest level priority among the ADRD Summit 2019 milestones in the National Plan to Address Alzheimer’s Disease. For example, detecting cognitive impairment is a required component of the Medicare Annual Wellness Visit. Assessment tools, as well as signs and symptoms of cognitive impairment and dementia, are made available by the NIA, the Department of Veterans Affairs, the Alzheimer's Association and others. However, and despite the existence of cognitive assessment tools that are widely accessible, cognitive impairment, even when dementia is present, continues to be under-recognized and under-diagnosed in primary care and other everyday clinical settings. The likely result, when cognitive complaints and other warning signs are evident but not pursued in primary care, is increased disease burden due to delayed or obviated treatment including of reversible conditions, delayed recognition of iatrogenic causes such as anti-cholinergic agents and polypharmacy, delayed use of appropriate medical and support services, and forestalled critical planning. The purpose of this FOA is to invite pragmatic clinical trial applications to test paradigms, i.e. clinical methodologies, for detecting incident cognitive impairment, including dementia, when a patient, relative, or care provider indicates concern. The major goal of this program is to address this unmet need, including in populations that experience health disparities, by focusing on pragmatic applied approaches that not only are applicable to but also are appealing for uptake in everyday care settings for large and varied adult populations in the United States. This initiative addresses health equity by mandating that barriers specific to populations that experience heath disparities in the United States be identified and addressed. This is because there is evidence that missed detection of cognitive impairment, including dementia, is even more prevalent among older African Americans, Hispanics and other populations that experience health disparities than among older whites.
One reason for the under-detection of cognitive impairment, including dementia, in primary care is that the existing detection tools have not been tested and standardized into rapid, EMR-compatible, billing-compatible, and user-friendly paradigms that are suitable for primary care and other everyday clinical practice settings. Moreover, a challenge specific for health equity is the need for paradigms, including associated tools, that are appropriate for the population being assessed. For example, few paradigms have been designed around factors that impact health equity of detecting such as low literacy, or stigma associated with cognitive impairment including dementia diagnoses. Taken together, these and other factors represent a barrier to rigorously assessing and addressing the public health importance and impact of cognitive impairment, including dementia, in older adults.
RFA-NS-17-012, the predecessor to this funding announcement, began to address this applied research gap by establishing DetectCID. DetectCID was the first NIH-funded consortium specifically tasked with developing practical paradigms designed to detect cognitive impairment including dementia in primary care and, critically, to provide concrete turnkey guidance for follow-up. During the first funding period of awards under RFA-NS-17-012 funded projects performed this applied research, both individually and in collaboration, to develop and perform the initial validation of paradigms designed to address the unmet need to detect cognitive impairment, including dementia, in large & diverse U.S. populations seen in everyday clinical settings, including in health disparities populations, when a patient, relative, or care provider indicates concern. The clinical paradigms developed and studied utilize tools that are simple to use, standardized, ideally take < 5 minutes to administer in primary care, and provide turnkey follow-up recommendations. Consortium sites at different locations in the United States performed initial development of several paradigms, consistent with the significant challenge at hand, and with the reality of diverse needs across the country that vary across local settings. These paradigms underwent site-specific validation studies as well as cross-site feasibility studies. A critical next step for paradigms supported by sufficient preliminary data, both from DetectCID and also from other research programs, is the opportunity to perform optimally powered pragmatic clinical trials that further and rigorously test their suitability for everyday care settings.
This Funding Opportunity Announcement will support pragmatic clinical trials for testing paradigms for detecting cognitive impairment, including dementia, in primary care and other everyday care settings. This activity will include both testing in the general population as well as in at least two populations that experience health disparities.
Paradigms should use tools that are simple to implement in large populations, can be standardized and validated, and ideally take five minutes or less (but not longer than 10 minutes) to administer in a primary care clinical setting. Paradigms proposed must be supported by rigorous preliminary data that justifies proceeding to a pragmatic clinical trial.
As the overall goal of this initiative is to support the “real world” assessment of paradigms and tools used to detect cognitive impairment, a strategy for implementation into everyday clinical settings must be included as part of proposed paradigms, with assessment of implementation cost, identification of the areas that are challenging for implementation, and with implementation measures, such as for adoption, fidelity, penetration, and sustainability, considered. Trials may be conducted across single or multiple health care systems. Results from the pragmatic trials supported by this FOA should inform policymakers, payers, doctors and patients in the primary care setting. More information about the approach to and conduct of pragmatic trials conducted within real-life healthcare system settings may be found at, "The NIH Collaboratory: Living Textbook of Pragmatic Clinical Trials." Projects funded under this FOA will participate in Consortium meetings that will ensure and continue collaborative learnings to facilitate successful implementation of these goals.
Research Project Objectives
Applications are to propose pragmatic clinical trials to test paradigms supported by rigorous clinical data for successful implementation in primary care and other everyday clinical settings. Paradigms should allow categorization of patients about whom a concern has been raised (by the patient themselves, a relative, or care provider) regarding cognitive impairment into one of the following two groups, with a rationale and EMR communicated recommendations for follow-up:
1. No objective cognitive impairment detected. This category includes individuals for whom the cause of the concern appears to be a consequence of an identified condition that is not cognitive impairment (e.g. hearing loss). Appropriate recommendations could include measures such as periodic re-assessment, or referral for medical follow-up of the underlying condition that is not cognitive impairment;
2. Detection of or suspicion of cognitive impairment. This category includes both individuals with cognitive impairment due to underlying medical condition(s) that may be managed in primary care, and in some instances may be reversible, as well as individuals with cognitive impairment detected that would benefit from further workup by a specialist. Appropriate recommendations could include treatment in primary care if appropriate, follow-up clinical assessment, and/or referral to one or more specialists.
Paradigms should be simple to implement and ideally take five minutes or less (but not longer than 10 minutes) to administer by the primary care provider in a clinical setting. Paradigms must be integrated into EMR and billing systems. A wide variety of paradigms and tools are in scope, for example: a questionnaire; a paper/pencil test for cognition/memory; a clinical decision support system/phenotypic association tree/principal component analysis of clinical data; report or observation of behavioral symptoms; performance-based instruments of function and instrumental activities of daily living; or other clinical protocols.
Testing in the general population as well as in at least two specified populations that experience health disparities is required. The NIH identifies the following types of health disparities populations in the United States and its territories: race/ethnicity (African Americans, Hispanic/Latinos, Asian Americans, American Indians/Alaska Natives, Native Hawaiians and other Pacific Islanders), low socioeconomic status, rural populations, and sexual and gender minorities (lesbian, gay, bisexual and transgender).
The overall goal of this initiative is to validate in pragmatic clinical trials paradigms (including the cognitive testing tools embedded in these paradigms) for the detection of cognitive impairment that may be successfully integrated into “real world” everyday clinical settings. Applications should address the costs of implementation as well as identify and successfully address challenges and barriers to implementation, as well as for strategies for adoption, fidelity, penetration, and sustainability, considered. Trials may be conducted across single or multiple health care systems.
If successful, this applied program will increase detection of cognitive impairment, including dementia, in the United States, with a rationale and structure for individual medical follow-up that is integrated into electronic medical systems, and will provide information about implementation and use that will be relevant to and ultimately benefit patients, clinicians, health care systems, and other stakeholders.
Other Characteristics of Responsive Applications
Applications must propose pragmatic clinical trial(s).
Applications should identify and evaluate the risks and consequences of over- or under-detection of cognitive impairment using the proposed paradigm(s).
Pragmatic clinical trials involving populations that experience health disparities must identify the major (hypothesized) barriers resulting in delay and/or lack detection of cognitive impairment, including dementia, in the specific population, and clearly indicate which of these barriers are proposed to be overcome by using the paradigm.
Proposed pragmatic clinical trials must be sufficiently powered to definitively test proposed paradigms in at least three U.S. populations for detecting cognitive impairment, including dementia, in aging populations, at least two of which must be populations that experience health disparities.
Attention should be paid to consideration of when the paradigm(s) should and should not be used (e.g. settings, state of the patient).
Applicants should make their paradigm(s) available for others to utilize after the funding period, including how the paradigm(s) will be made available and with minimum cost and burden.
Projects should include a paradigm or paradigms that have preliminary evidence of efficacy and safety in the populations to be included in the trial.
Projects should address potential longer term goals for establishing feasibility and effectiveness, and how the proposed research will facilitate those goals by establishing an essential foundation for future efforts. Specifically, applicants must provide descriptions of: (i) how the research will yield information critical for next steps, including for widespread implementation of developed paradigm(s); (ii) how, including via utilizing paradigm(s) further developed and validated under this FOA, together with other appropriate strategies, it will be possible to fully assess the need and the potential impact in the United States for routinely detecting cognitive impairment, including dementia, in everyday clinical settings, including in primary care.
For applications that propose pragmatic clinical trials that are ancillary studies, the application must provide evidence that data collection on any additional outcome measures proposed in the ancillary study must be completed within the timeline of the parent study (analysis can extend beyond the parent study timeline).
Applications Not-Responsive to this FOA
This FOA is only for studies related to humans; animal or other disease model studies are not responsive to this FOA.
Applications that propose clinical trials to test drug interventions are not-responsive to this FOA.
Applications that do no include at least two populations that experience health disparities.
Applications that are not focused on pragmatic clinical trials for implementing rapid (10 minutes of primary care provider time or less) paradigm(s) for detecting cognitive impairment, including dementia in large human populations in the United States are not responsive.
Applications that do not link the proposed paradigm(s) to the EMR.
Applications that do not link the proposed paradigm(s) to billing.
Applications which do not include paradigms for detecting cognitive impairment, including dementia, which already have evidence of efficacy in the studied populations are not responsive.
Applications that do not indicate how they will make their paradigm(s) available for others to utilize both during the funding period (e.g., at a minimum, to other consortium members), and after, including how and with minimum burden, are not responsive.
Applications that focus on related topics that are not central to the goals of this FOA, such as differentiating among cognitive domains, determining the degree of cognitive impairment and whether the cognitive impairment detected does or does not meet criteria for dementia, and differentiating among different dementia disorders, are not responsive.
Applications that propose mechanistic clinical trials or BESH clinical trials are not responsive.
See Section VIII. Other Information for award authorities and regulations.
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.
Required: Only accepting applications that propose clinical trial(s).
NINDS intends to commit an estimated total of $7,500,000 to fund up to 5 awards.
Application budgets are not limited but need to reflect the actual needs of the proposed project. Up to $1,000,000 direct costs (DC) per year may be budgeted.
The scope of the proposed project should determine the project period. The maximum project period is five years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
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.
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.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
Number of Applications
Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
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:
The letter of intent should be sent to:
Roderick Corriveau, PhD
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.
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.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
Other Attachments: Applicants are required to include the following items in the Other Project Information section of the application: (i) Intellectual Property Strategy; and (ii) Team Management Plan for the proposed research project. These items must be uploaded as separate attachments in pdf format with filenames that correspond to the individual items (e.g. Intellectual Property Strategy.pdf, Team Management Plan.pdf). Applications lacking these required items will be deemed incomplete and will not be reviewed.
Intellectual Property Strategy: Applications must include an Intellectual property (IP) strategy that is no more than two pages in length. Applications that exceed this limit will be withdrawn. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials, as applicable.
The goal of this initiative is to support applied research pragmatic clinical trials that advance research towards the medical implementation of paradigms for detecting cognitive impairment, including dementia that will benefit the public. Accordingly, applicants should describe the copyright and IP landscape surrounding their paradigm(s). This should include any known constraints that could impede development (e.g., copyright considerations, certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar technologies/paradigms that are under copyright, patent and/or are on the market, etc.) and how these issues could be addressed as appropriate and consistent with achieving the goals of the program. If the applicant proposes using a device or technology whose IP or copyright is not owned by the applicant's institution, the applicant should address any questions that may constrain or impede the ability to operate and move the technology forward consistent with achieving the goals of the program. Applicants must include a letter (see Letters of Support) from the entity that owns the IP indicating whether the entity will provide the device or technology, if there are any limits on the studies that can be performed with that device or technology, and agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.
If copyright or patents pertinent to the paradigms developed under this application have been filed, the applicants should indicate the details such as filing dates, what types of patents are filed, application status, and associated United States Patent Office (USPTO) links, if applicable. Applicants should also discuss future copyright or IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions both within and outside the consortium. Applicants must clarify how IP will be shared or otherwise be managed with other consortium members. All existing and planned copyright that impacts or may impact the proposed paradigm(s) must be disclosed and discussed.
Team Management Plan for the proposed research project: Each application submitted in response to this FOA must have a Team Management Plan for the research proposed within the application's specific aims. The project Team Management Plan must not exceed two pages. Applications that exceed this limit will be withdrawn. NIH strongly encourages applicants to form multidisciplinary teams that consist of non-clinical and clinical scientists, cognitive, statistical, population-based clinical research, and other relevant academic/industry experts and, as applicable, health disparities disease experts. This multi-disciplinary team should have the expertise needed to execute the research strategy, and include representation from the health system(s) involved. The Team Management Plan should describe how team members will collaborate to accomplish the aims as proposed.
All instructions in the SF424 (R&R) Application Guide must be followed.
The range of interdisciplinary expertise of included key personnel that will ensure success and will poise the team for making strong advances should be clearly indicated in the biosketches. Expertise of key personnel should include, but is not limited to, expertise in the design and conduct of pragmatic clinical trials, clinical (including primary care), cognitive, statistical, population-based clinical research, and, as applicable, health disparities. At least one co-investigator from primary care is required as key personnel. The PD(s)/PI(s) of the clinical trial should be experienced in multi-center clinical trial coordination and management, including success in meeting milestones and timelines and the sharing of de-identified clinical data, and have expertise in the content area of the proposed clinical trial. The roles, responsibilities and authority of each PD/PI must be specified. The application must also ensure that a multidisciplinary team of appropriate personnel are proposed at the participating health care systems (HCSs) to facilitate the implementation of all aspects of the clinical trial.
R&R or Modular Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:
Specific Aims: State the aims and hypotheses to be tested in pragmatic clinical trial(s).
Research Strategy: Organize the Research Strategy by Significance, Innovation, and Approach.
Significance: Describe the rationale and rigor of the supporting preliminary data for testing the proposed paradigm(s) in pragmatic clinical trials, including proposed tool(s) and implementation protocol(s); describe the paradigm's potential to detect incident cognitive impairment in adults following a patient complaint (or a family member, caregiver, or health professional on their behalf). Describe the rationale and supporting data demonstrating efficacy of the chosen paradigm(s) and the potential to attain the overall goal of increasing the frequency and improving the quality of detection of incident cognitive impairment, including dementia, in primary care and other everyday clinical settings in large and diverse populations in the United States.
Clearly state why and how the proposed clinical trial is considered a pragmatic clinical trial, and how the trial clearly meets the implementation science goals of this program. For example, how is the paradigm being integrated into health systems in ways that make it attractive for uptake?
Applications must identify the specific disparities in detection of cognitive impairment, including dementia that are addressed by their paradigm(s) during the pragmatic clinical trial(s), and in what population(s). If an application targets more than one disparity (such as minority group, and low socio-economic status), the application must discuss the conceptual framework for each including how they may overlap.
Describe how pragmatic clinical trials to test paradigms to detect cognitive impairment (including dementia) have adequate power for up to three populations, including at least two specified populations that experience health disparities.
Innovation: Describe the leading edge and innovative attributes the application brings to both the specific paradigm(s), including tool(s), proposed, their broad application including via sharing with minimum logistic, legal, and financial burden, as well as the overall technical advances and innovative strengths (including collaborative) that the application has to offer the consortium. For applications investigating health disparities, specify the major (hypothesized) barriers resulting in delay and/or lack of detection of cognitive impairment in the specific health disparities population being addressed, and clearly indicate which of these barriers are addressed in the application.
Approach: The approach must detail the strengths and appropriateness of paradigm(s), including tool(s), for detecting cognitive impairment, including dementia, in large and diverse populations seen in primary care and other everyday clinical settings, plus whether or not the paradigm(s) and measures are quantitative, robust, reproducible, and clearly linked to cognitive impairment. Describe how the paradigm(s) are simple to implement, can be standardized, and ideally take five minutes or less (but not longer than 10 minutes) to administer in primary care clinical settings. Applications must include at least one paradigm that, in its fully developed form, does not require informant participation in the cognitive impairment detection protocol.
Describe how paradigm(s) proposed for pragmatic clinical trial(s) allow categorization of patients about whom a concern has been raised (by the patient themselves, a relative, or care provider) regarding cognitive impairment, including dementia, into one of the following two groups, with a rationale and recommendations for follow-up provided in the EMR:
1. No objective cognitive impairment detected. This category will include individuals for whom the cause of the concern is unknown or appears to be a consequence of a condition that is not cognitive impairment (e.g. hearing loss). Appropriate recommendations could include measures such as periodic re-assessment, or referral for medical follow-up of the underlying condition that is not cognitive impairment.
2. Detected or suspected cognitive impairment. This category will include both individuals with cognitive impairment due to underlying medical condition(s) that may be managed in primary care, and in some instances may be reversible, as well as individuals with cognitive impairment detected that requires workup by a specialist. Appropriate recommendations could include for treatment in primary care if appropriate, follow-up clinical assessment, and/or referral to one or more specialists.
Describe how the paradigm(s) integrate with medical billing systems.
Detail how the proposed pragmatic clinical trial will implement paradigm(s) in primary care and other everyday clinical settings. Describe the approach to U01 activities, including cohort and population testing, optimization, and validation. Identify the target population(s), methods for ensuring male/female balance, approaches to cohort retention, data collection strategies, and planned clinical outcomes and analysis strategies. Discuss potential biases and challenges with the proposed research and how they will be addressed. Applications should include a plan to identify and evaluate the risks and consequences of over- or under-detection of cognitive impairment using the proposed paradigm.
Describe how the project will establish best practices documents/publications for detection of cognitive impairment and dementia, including in health disparities populations proposed, to meet the goal of making the information gained and paradigm(s) developed accessible to the broader research and clinical community. Specifically address how the paradigm(s) will be made available for others to utilize, including how and with minimum burden. Applicants must provide descriptions of how, including via utilizing paradigm(s) developed under this FOA, together with other appropriate strategies, it will be possible to fully assess the need and the potential impact in the United States of routinely detecting cognitive impairment, including dementia, in everyday clinical settings, including in primary care.
Applications should describe details for the proposed pragmatic trial including projections for recruitment, attrition and the impact of both on power estimations for the proposed trial(s). Investigators are encouraged to describe how the approaches, measures, design, and outcomes proposed are pragmatic or utilize implementation research methods.
The application should describe the HCS partner(s) and the investigative team's experience conducting pragmatic trials within health care systems. The application must provide a rationale for the HCS selected for the Project and provide a description of the infrastructure and expertise
Milestone Plan: The Consortium established by this FOA uses the U01 cooperative agreement mechanism; therefore, include a Milestone Plan under a separate heading in the Approach section. Propose milestones for each year of the project. Milestones must be unambiguous, objective, and scientifically justified. The final Milestone plan is subject to concurrence by the NIH.
Letters of Support: If an application plans to utilize the infrastructure or resources of existing projects, whether funded by the NINDS, other governmental, or nongovernmental entities, letters of support detailing the terms of collaboration and data sharing must be included, and must be from the appropriate authority/ies of the parent activity (e.g. institutional/foundation official, funding sponsor, and lead PI). Any conflicts in sharing with any known entities should be revealed and discussed. If the proposed study is ancillary to an ongoing parent project, the letter of support from the parent study PD/PI and business official must confirm that the proposed research does not interfere with the parent study, does not place undue burden on participants, and follows approved procedures and policies from the parent study. Letters of support from relevant stakeholders may also be included as evidence of necessary expertise (e.g. professional organizations or patient groups). Letters of support from participating HCS are required.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.
The following modifications also apply:
Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:
If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
Section 2 - Study Population Characteristics
2.5 Recruitment and Retention Plan
Applicants must provide strong evidence of the availability of appropriate institutional resources, and suitable patient populations, providers, clinics, or facilities (depending on unit of randomization). Documentation of availability of eligible participants, clinic sites, or units of randomization, presented in tabular format must be provided. The application must include relevant information that addresses the feasibility of recruiting participants who are eligible for the pragmatic trial implementation study. Specifically, applicants must provide evidence that each recruiting center in the study or trial has access to a sufficient number of participants who meet the eligibility criteria as defined in the submitted protocol. For multisite applications, information must be provided for each participating site.
The participant recruitment and retention plans must include a discussion of the availability of participants for the proposed study and the ability of enrollment sites to recruit and retain the proposed number of participants meeting the eligibility criteria, including women and minority participants as applicable. Data supporting recruitment and retention estimates must be provided. Evidence should be provided that relevant stakeholders (e.g., potential participants, referring and treating physicians, patient groups) have sufficient equipoise, consider the question to be important and the study acceptable.
For a multicenter trial, applicants should survey the potential clinical sites to ensure that recruitment targets can be met. Present the survey results using a table where the rows represent potential clinical sites and the columns include responses to questions from the survey. The survey questions will depend on the nature of the trial and the protocol-specified screening procedures but might include these:
2.7 Study Timeline
Applicants should provide detailed project performance and timeline objectives. The proposed milestones must include achievable goals for each stage of the project as follows:
For preparatory activities:
Proposed milestones should be included for the entire trial, including any time beyond the five-year award. This information will be used for planning purposes and to support the rationale for the full trial but does not guarantee continued funding beyond the initial funding cycle.
Milestones and timelines will be refined and finalized in consultation with Program staff at the time of award.
Section 3 - Protection and Monitoring Plans
3.3 Data and Safety Monitoring Plan
Applicants should refer to the NINDS Guidelines for Data and Safety Monitoring in Clinical Trials (https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/NINDS-Guidelines-Data-and-Safety-Monitoring) when developing their DSMP.
3.5 Overall Structure of the Study Team
Describe a Clinical Site Monitoring Plan including how site adherence to the protocol will be ensured, who is responsible for site monitoring, the frequency of planned monitoring activities, and the plan for handling deficiencies. Also describe plans for training and, if needed, certifying site personnel to complete study procedures.
Describe a Data Management Plan including the methods and systems for data collection and quality control, and for ensuring data confidentiality and privacy, and the process for locking the final dataset and providing for data sharing. Describe the plans, if any, to use non-traditional data collection approaches (e.g., digital/mobile/sensor technologies and web-based systems) and why these are appropriate.
Describe the composition and role of any advisory committees.
Discuss the responsibilities, oversight and coordination of any centers or cores.
Describe any subcontracts or service agreements for personnel or facilities."
Section 4 - Protocol Synopsis
4.1 Study Design
4.1.a Detailed Description
The following information must be included:
As applicable, state how the following resources for clinical research will be utilized to the degree possible:
• NINDS Common Data Elements (https://www.commondataelements.ninds.nih.gov/#page=Default);
• NIH Toolbox (http://www.healthmeasures.net/explore-measurement-systems/nih-toolbox); and
4.3 Statistical Design and Power
Applicants must provide a description of statistical methods including sample size and power calculations, study outcome measures, plans for interim and final analyses, methods of bias control, and methods for handling missing data. Examples of the critical elements of a well-designed study are summarized on the NINDS website.
Design, Analysis, and Sample Size for Studies to Evaluate Group-Based Interventions: applicants may propose a study in which groups or clusters are assigned to study arms and individual observations are analyzed to evaluate the effect of the intervention. Such studies may propose a parallel group- or cluster-randomized trial, a stepped-wedge design, or a quasi-experimental version of one of these designs. In these studies, special methods may be warranted for analysis and sample size estimation. Applicants should show that their methods are appropriate given their plans for assignment of participants and delivery of interventions. Additional information is available at https://researchmethodsresources.nih.gov/.
Applicants should provide a Statistical Analysis Plan (SAP) including details on the analyses specified in the study protocol, including a description of how the statistical analysis of the primary, secondary and other endpoints will be performed, how the sample size was determined, how missing data will be handled, plans for interim analyses for safety, efficacy and futility, plans for recalculation of the sample size midway through the trial (if applicable), etc. If computer simulations were used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs), to choose between alternative outcome measures, or to determine sample size, accounting for the impact of noncompliance, missing data, subject eligibility criteria, etc., sufficient details about the simulations should be provided if the SAP. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.
4.5 Will the study use an FDA-regulated intervention?
4.5.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status: If the study intervention is a drug, biologic, or device, applicants must provide documentation from the FDA providing information on one of the following scenarios:
(a) The protocol has been submitted under an open IND and the IND is not under full or partial hold. Under this scenario, applicants must provide documentation such as a "may proceed" email or letter from the FDA.
(b) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has fully approved the IDE or IDE supplement. Under this scenario, applicants must provide documentation of an IDE or IDE supplement full approval letter from the FDA.
(c) The protocol has been submitted under an IND and is on full or partial hold. Under this scenario applicants must provide full documentation from the FDA on the reasons for hold and the FDA recommendations. Applicants should discuss how they intend to address the hold issues and when they believe they will have FDA approval to proceed with trial implementation.
(d) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has conditionally approved the IDE or IDE supplement. Under this scenario applicants must provide full documentation from the FDA on the conditions of approval. Applicants should discuss how they intend to address these conditions and when they believe they will have FDA approval to proceed with trial implementation.
(e) The protocol is exempt from an IND. Under this scenario applicants must provide a copy of the exemption letter from the FDA.
(f) The protocol is either exempt from the IDE regulations or does not require IDE approval because it is determined to be nonsignificant risk. Under this scenario applicants must provide either an IDE exemption letter or a copy of the risk determination letter from the FDA. Applications that do not include this information at the time of submission must indicate i) that it will be submitted subsequently and ii) when the regulatory documentation from the FDA is likely to be available. After the assignment of the application to a review group is visible in the eRA Commons, the applicant should contact the Scientific Review Officer (SRO) for that review group to discuss logistics for submission of the regulatory information. Applications that are not able to provide this information will be withdrawn and not reviewed. Prior to grant award, awardees who do not have an exemption from the FDA must provide any additional FDA correspondence regarding the status of the protocol to the NINDS, especially if the trial has been placed under full or partial hold.
Delayed Onset Study
Delayed Onset Studies are not responsive to this FOA.
All instructions in the SF424 (R&R) Application Guide must be followed.
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.
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
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.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.
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.
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.
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).
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.
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?
To what extent do the proposed paradigm(s), including tool(s) and approaches for detecting cognitive impairment, including dementia, have strong potential to address the unmet need to detect cognitive impairment and dementia in large and diverse populations seen in primary care practice and other everyday clinical settings across the United States, when a patient, relative, care provider, or health professional voices concern? For health equity research proposed, how does the application identify the major (hypothesized) barriers resulting in delay and/or lack of detection of cognitive impairment, including dementia, in the specific population being addressed, and clearly indicate which of these barriers are addressed in the application? How strong is the evidence of efficacy or effectiveness for the paradigm that will be integrated into the health delivery system? How will the completion of the proposed pragmatic trial change the management of patients with concern for cognitive impairment in health care systems? How will potential outcomes provide clinically meaningful information to stakeholders?
To what extent is there rigourous supporting preliminary data for the proposed pragmatic clinical trial(s)?
To what extent are there clear rationale and substantial supporting preliminary data for testing the proposed paradigm(s) in pragmatic clinical trials, including proposed tool(s) and implementation protocol(s)? In what way does the paradigm have strong potential to detect incident cognitive impairment in adults in primary care following a patient complaint (or a family member, caregiver, or health professional on their behalf) in large and diverse populations in the United States?
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?
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?
To what extent does the expertise of key personnel include clinical (including primary care), cognitive, statistical, population-based clinical research, and health equity? To what extent do key personnel have a history of collaborations within clinical research consortia, as well as experience sharing of de-identified clinical data and biospecimens for a broad range of biomedical research? Are appropriate collaborators from the participating health care system (HCS) identified? To what extent do the PD(s)/PI(s) and key personnel have the necessary expertise in design and implementation of large-scale clinical studies within an HCS? For example, do they have expertise in using electronic health records for recruitment and outcomes assessment? Do the PD(s)/PI(s) have extensive experience in performing pragmatic clinical trials, and to what extent do they have a track record of successful recruitment and retention in prior studies, investigative collaborations or partnerships with (within) health delivery organizations in conducting clinical studies within an HCS?
To what extent is the proposed Team Management Plan appropriate to support the research proposed within this application?
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?
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?
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?
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?
To what extent is the proposed paradigm(s) feasible and suitable for detecting cognitive impairment and dementia in a real world setting of large and diverse populations seen in primary care and other everyday clinical settings in the United States? How are the paradigm(s) and measures quantitative, robust, reproducible, and clearly linked to cognitive impairment?
How effectively do the proposed paradigms allow categorization of patients about whom a concern has been raised (by the patient themselves, a relative, or care provider) regarding cognitive impairment into one of the following two groups, with a rationale and recommendations for follow-up?
1. No objective cognitive impairment detected. This category includes individuals for whom the cause of the concern is unknown or appears to be a consequence of a condition that is not cognitive impairment (e.g. hearing loss). Appropriate recommendations could include measures such as periodic re-assessment, or referral for medical follow-up of the underlying condition that is not cognitive impairment
2. Detection of cognitive impairment. This category includes both individuals with cognitive impairment due to underlying medical condition(s) that may be managed in primary care, and in some instances may be reversible, as well as individuals with cognitive impairment detected that requires workup by a specialist. Appropriate recommendations could include for treatment in primary care if appropriate, follow-up clinical assessment, and/or referral to one or more specialists.
Do proposed paradigm(s) use and validate in large populations tools that are simple to implement, can be standardized and validated, and ideally take five minutes or less (but not longer than 10 minutes) for a care provider to administer in a primary care clinical setting? For health disparities applications, is the proposed paradigm(s) culturally appropriate and sensitive for the target health disparities population and the known disparities for cognitive impairment and dementia? Does the proposed paradigm, including tool(s), address or adequately provide a solution to the disparity?
How much evidence is there that relevant HCS stakeholders have been included in the study planning process andw will remain engaged during study implementation?
Will the proposed paradigm be integrated into the HCS’s EMR and billing systems?
To what degree will the results provide relevant information and adequate data for others potentially adopting HCS settings to determine applicability?
To what extent are the projections for recruitment, ongoing engagement, attrition and effect size estimation based on data in the proposed HCS or similar settings?
Does the proposed pragmatic clinical trial(s) have adequate power for up to three populations?
Is the degree of pragmatic aspects of the approaches, measures, design and outcomes well justified for the design elements of the proposed study?
How will broad but adequate eligibility criteria be used, as proposed?
How much potential do the proposed paradigm(s) have for easy implementation in the future?
How will rigorous controls be included in the design?
How will the approaches proposed overcome barriers to research in the HCS setting?
How well-developed is the proposed strategy for broad and harmonized implementation into everyday clinical settings proposed and developed, including with assessment of implementation cost, identification of the areas that are challenging for implementation, and with implementation measures such as for adoption, fidelity, penetration, and sustainability?
To what extent does the application include a safety plan for the proposed pragmatic clinical trial(s), including a plan to identify and evaluate the risks and consequences of over- or under-detection of cognitive impairment using the proposed paradigm(s)?
Does the application include at least one paradigm that, in its fully developed form, does not require informant participation in the cognitive impairment detection protocol?
How well does the application adequately describe how the applicants will establish best practices documents/publications for detection of cognitive impairment and dementia, including in health disparities populations if proposed, to meet the goal of making the information gained and paradigm(s) developed accessible to the broader research and clinical community?
To what extent are the proposed plans for making the paradigm(s) available for others, reasonable and practical?
To what extent are the proposed milestones appropriate?
Does the application adequately address the following, if applicable:
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?
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?
To what extent does the application provide sufficient rationale for the HCS (s) selected for the Project? Is commitment from the HCS to the project evident? Has/have the HCS (s) successfully conducted clinical studies, such that there are sufficient infrastructure and expertise (e.g. clinical investigators, informaticists) to implement the proposed pragmatic trial within all proposed HCSs?
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?
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.
Team Management Plan
Is the proposed Team Management Plan appropriate to support the research proposed within this application?
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.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
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.
For Renewals, the committee will consider the progress made in the last funding period.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
Intellectual Property Strategy
Is the Intellectual Property Strategy clear, viable for broad sharing of paradigm(s) without undue burden of logistics or cost, and consistent with achieving the goals of the project and of the program supported by this FOA?
Applications from Foreign Organizations
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
Authentication of Key Biological and/or Chemical Resources:
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the 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 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:
Information regarding the disposition of applications is available in the NIH Grants Policy Statement.
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.
Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
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. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.
HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.
Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
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 Parts 75, 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 for:
The NINDS Project Scientist will:
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below. NINDS program staff will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NINDS Project Scientist will be to facilitate and not to direct the activities. An NINDS Administrative Project Officer will be responsible for the normal programmatic stewardship of the award and will be named in the award notice. The NINDS Administrative Project Officer retains the option to recommend the withholding or reduction of support from any cooperative agreement that either substantially fails to achieve its goals agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award including biospecimen and data sharing requirements as appropriate and consistent with achieving the goals of the program.
Additionally, the NINDS Scientific Project Officer will:
Areas of Joint Responsibilities include:
Any disagreements that may arise in scientific 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 will be convened, and will vote to resolve the dispute. The Dispute Resolution Panel will have three members (with one vote each): a designee of the award governing body chosen without NIH staff input, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two Panel members. 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 DHHS regulation 45 CFR Part 16.
When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Roderick A. Corriveau, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Rebecca Hommer, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Laurie Ryan, Ph. D.
National Institute on Aging (NIA)
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute on Aging (NIA)
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 2 CFR Part 200, 42 CFR Part 52 and 45 CFR Part 75.
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