National Institutes of Health (NIH)
U01 Research Project Cooperative Agreements
NOT-OD-22-190 - Adjustments to NIH and AHRQ Grant Application Due Dates Between September 22 and September 30, 2022
The purpose of this funding opportunity announcement (FOA) is to solicit applications for pragmatic clinical trials to decrease or prevent negative clinical outcomes due to vascular contributions to cognitive impairment and dementia (VCID), including locally representative NIH defined populations that experience health disparities in dementia. Examples of responsive projects and interventions that affect VCID outcomes include, but are not limited to, blood pressure control implementation; lifestyle modification using aerobic exercise; and early detection and treatment of VCID risk factors.
August 15, 2022
| Application Due Dates | Review and Award Cycles | ||||
|---|---|---|---|---|---|
| New | Renewal / Resubmission / Revision (as allowed) | AIDS | Scientific Merit Review | Advisory Council Review | Earliest Start Date |
| September 15, 2022 | Not Applicable | Not Applicable | March 2023 | May 2023 | July 2023 |
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.
Not Applicable
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.
Background and Purpose
With the number one goal of the National Alzheimer’s Project Act (NAPA) being to prevent and effectively treat Alzheimer’s Disease and Related Dementias (AD/ADRD) by 2025, more work is needed to identify the best implementation strategies to leverage evidenced-based approaches to prevent, delay, or slow dementia onset and/or progression. This is particularly true in populations experiencing health disparities in the United States and who may also be facing increased socio-economic disadvantages that limit their interactions with health care providers. The NIH-designated populations that experience health disparities (HDPs) include racial and ethnic minority populations, less privileged socioeconomic status (SES) populations, underserved rural populations, and sexual and gender minorities (SGM). More information regarding minority health and health disparities can be found at: Minority Health and Health Disparities: Definitions and Parameters.
Vascular contributions to cognitive impairment and dementia (VCID) are related to modifiable risk factors such as hypertension and diabetes mellitus that require close monitoring and medical management. VCID occurs not only in diagnoses such as vascular cognitive impairment and vascular dementia, but also in clinical Alzheimer’s disease. The scope of this FOA is pragmatic interventions that decrease the burden of VCID in all diagnoses where VCID occurs. These management and monitoring needs are not well met in the general population, and particularly not well met in populations that experience health disparities. Additionally, lifestyle interventions that improve brain health and limit VCID progression may also be more limited or difficult to access in these populations due to socioeconomic factors, including medical insurance coverage. Therefore, there is a clear need for pragmatic clinical trials to decrease or prevent negative clinical outcomes due to vascular risk factors in NIH defined populations that are at high risk for experiencing health disparities in cognitive impairment and dementia.
For this funding announcement, pragmatic clinical trials (PCTs) are defined as studies designed for the primary purpose of informing decision-makers regarding the comparative balance of benefits, burdens, and risks of a biomedical or behavioral health intervention at the individual or population level. (Califf and Sugarman 2015). To achieve generalizable results in an efficient manner, embedded PCTs (ePCTs) commonly take place in the setting where patients already receive their usual clinical care. In contrast to traditional randomized controlled trials, the intention is to avoid the need for a separately constructed infrastructure with specially trained research staff responsible for data collection. For a broader, more representative population, eligibility criteria are minimized and recruitment expanded to potentially all eligible individuals receiving care in the participating setting, with a focus on those most likely to benefit clinically. Intervention delivery, participant follow-up, and adherence protocols are more flexible and closely align with usual care to understand the real-world implications of the intervention. Arguably, many of these pragmatic qualities occur along a spectrum, with some trials being more pragmatic than others (Thorpe et al. 2009). More information about the approach to and conduct of pragmatic trials conducted within real-life healthcare system settings may be found at the NIH Clinical Trial Collaboratory website: https://rethinkingclinicaltrials.org/ and within, "The NIH Collaboratory: Living Textbook of Pragmatic Clinical Trials."
The purpose of this FOA is to invite applications for PCTs designed to decrease or prevent negative clinical outcomes associated with VCID by targeting modifiable risk factors in locally representative NIH defined populations that experience health disparities in dementia. Recent studies have demonstrated that in a controlled research environment, interventions targeting modifiable risk factors have the potential to prevent or slow the development of cognitive impairment including dementia. For example, the NIH-funded SPRINT-MIND trial demonstrated that intensive blood pressure control in a population of adults over age 50 years significantly decreased the risk of mild cognitive impairment and the combined risk of mild cognitive impairment or probable dementia. Despite the large body of evidence to suggest cardiovascular risk factors related to diet, exercise and blood pressure control are associated with VCID and other brain health outcomes, hypertension, obesity, and a sedentary lifestyle are common among the US population and there has not been widespread uptake of interventions to reduce risk. The CDC estimates that nearly half of US adults have hypertension, and only a quarter of those have blood pressure that is well controlled. Black Americans are more likely than Whites Americans to suffer from hypertension and less likely to have blood pressure be well controlled. Rates of dementia have been found to be higher among Black and Hispanic Americans, and data from the NIH-funded REGARDS epidemiologic study suggests that cardiovascular risk may be associated with worse cognitive outcomes among Black as compared to White Americans. Compounding these problems, racial and ethnic minority populations are significantly underrepresented in dementia research.
As described above, implementing medical and lifestyle interventions with proven benefit in the research setting to target risk factors for VCID and studying their clinical impact on larger and more representative segments of the population remains a significant unmet need. The major goal of this program is to address this unmet need 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 strives to achieve a state of health equity by mandating that barriers specific to populations that are at risk for experiencing heath disparities in the United States be identified and addressed. This is because there is evidence that risk factors associated with VCID are even more prevalent among older African Americans, Hispanic Americans and other populations that are at risk for experiencing health disparities than among older White Americans, (and that the strength of these associations may be more significant).
Stakeholder and community engagement are key to achieving health equity in research and clinical care. Stakeholder engagement in clinical studies involves patients, families, their representatives, health professionals, and the clinical research team working in active partnership at various levels across the continuum of clinical research. Continued respectful, equitable, and bidirectional knowledge transfer during stakeholder engagement can improve participant retention and adherence to the study protocol. Engagement can help build trust in communities that may be fearful of participating in clinical research because of stigmas and medical mistrust. 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 and populations with limited English proficiency. Community-engaged research (CEr) is participatory and describes methods to operationalize community engagement within clinical research. Engaging the community in research from study inception to implementation contributes to successful health equity study design that is inclusive and provides infrastructure to ensure culturally appropriate research strategies, tools, bi-directional knowledge transfer, and information dissemination are utilized. Partnering with the community helps with development of sustainable interventions and the translation of study results into practice, potentially improving health outcomes. CEr has the potential to promote wellness by impacting community health literacy and health behavior through community and participant empowerment. When community members participate in their own health promotion by engaging in the research process, they are able to identify their own health needs and develop a sense of belonging within the scientific and medical research community.
In addition, NINDS, as part of NIH, strives for rigor and transparency in all research it funds. For this reason, NINDS explicitly emphasizes and provides supplemental guidance to NIH application instructions related to rigor and transparency (https://grants.nih.gov/policy/reproducibility/guidance.htm). For example, the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, e.g., by minimizing the risk of bias and transparently reporting methods and results as described at https://www.ninds.nih.gov/Funding/grant_policy. As stated in the NIH application guidelines, if previously published or preliminary studies do not meet these rigor standards to an acceptable degree, applicants should address how the current study design addresses the deficiencies. Proposed experiments should likewise be designed in a manner that minimizes the risk of bias and ensures validity and transparency of experimental results. The proposed clinical trial must be based on robust and rigorous supporting data, e.g., from non-clinical in vivo and/or in vitro studies or preliminary clinical studies that demonstrate that there is an adequate scientific foundation to justify the proposed trial. The proposed trial design must likewise demonstrate a rigorous and transparent approach.
Research Project Objectives
Applicants are to propose PCTs designed to intervene on modifiable vascular risk factors to decrease or prevent negative clinical outcomes in locally representative NIH defined populations that experience health disparities in dementia.
Interventions targeting factors associated with VCID should be supported by rigorous clinical data in controlled clinical trials and have the potential for successful implementation in primary care or other everyday clinical settings. Interventions should be integrated into the clinical care workflow and electronic health record (EHR) and billing systems. Examples of responsive projects and interventions with the potential to improve vascular contributions to cognitive outcomes include but are not limited to blood pressure control implementation; lifestyle modification using aerobic exercise; early detection of cognitive impairment including dementia (as, for example, in the NIH funded DetectCID program) and detection and treatment of other VCID risk factors.
Testing in at least one HDP is required. The NIH defines HDPs as racial and ethnic minority populations, less privileged socioeconomic status (SES) populations, underserved rural populations, sexual and gender minorities (SGM), and any subpopulations that can be characterized by two or more of these descriptions.
As the overall goal of this initiative is to support the real world assessment of interventions to decrease or prevent negative clinical outcomes, a strategy for implementation into everyday clinical settings must be included as part of proposed paradigms, and a community engagement plan is also required. Applications should be multi-level in approach to address such factors as the costs of implementation as well as identifying and successfully addressing challenges and barriers to implementation, including factors such as structural, systemic, individual, and patient level factors. Strategies for adoption, fidelity, penetration, and sustainability should be considered. Trials may be conducted across single or multiple health care systems. If successful, results from the pragmatic trials supported by this FOA will provide information about implementation and use of interventions to decrease, slow or prevent the development of negative clinical outcomes associated with VCID that will be relevant to and ultimately benefit patients, clinicians, health care systems, and other stakeholders.
Characteristics of Responsive Applications
Applications must propose pragmatic clinical trial(s).
Pragmatic clinical trials involving populations that experience health disparities must identify the major (hypothesized) barriers to care in the specific population and clearly indicate how these barriers will be addressed.
Proposed pragmatic clinical trials must be sufficiently powered to test the proposed intervention(s) in at least one population defined by the NIH as experiencing or at risk for experiencing health disparities.
Attention should be paid to when the intervention(s) should and should not be used (e.g. settings, state of the patient).
Projects should include an intervention or interventions 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.
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).
Applicants are expected to publish their results. While there is particular interest in successful interventions that can be made available to others with minimum cost and burden, study results, even if negative, should be published.
NIH and NINDS encourage data sharing. . An agreed upon subset of clinical data and samples (if applicable) should be made available to the scientific community within 2 years of collection. As applicable, informed consent procedures should thus consider the sharing of de-identified data and samples.
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.
Delayed-Onset Trials.
Applications that do not include at least one population that is at risk for experiencing health disparities.
Applications that do not have a main focus on clinical outcomes associated with VCID.
Applications with neuroimaging outcomes as a primary endpoint.
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.
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.
Required: Only accepting applications that propose clinical trial(s).
NINDS intends to commit an estimated total of $6,000,000 to fund up to 3 awards.
Application budgets must reflect the actual needs of the proposed project.
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.
1. Eligible Applicants
Higher Education Institutions
- Public/State Controlled Institutions of Higher Education
- Private Institutions of Higher Education
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
- Hispanic-serving Institutions
- Historically Black Colleges and Universities (HBCUs)
- Tribally Controlled Colleges and Universities (TCCUs)
- Alaska Native and Native Hawaiian Serving Institutions
- Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)
Nonprofits Other Than Institutions of Higher Education
- Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
- Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
For-Profit Organizations
- Small Businesses
- For-Profit Organizations (Other than Small Businesses)
Local Governments
- State Governments
- County Governments
- City or Township Governments
- Special District Governments
- Indian/Native American Tribal Governments (Federally Recognized)
- Indian/Native American Tribal Governments (Other than Federally Recognized)
Federal Government
- Eligible Agencies of the Federal Government
- U.S. Territory or Possession
Other
- Independent School Districts
- Public Housing Authorities/Indian Housing Authorities
- Native American Tribal Organizations (other than Federally recognized tribal governments)
- Faith-based or Community-based Organizations
- Regional Organizations
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.
Applicant organizations
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
- System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
- NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
- Unique Entity Identifier (UEI)- A UEI is issued as part of the SAM.gov registration process. SAM registrations prior to fall 2021 were updated to include a UEI. For applications due on or after January 25, 2022, the UEI must be provided on the application forms (e.g., FORMS-G); the same UEI must be used for all registrations, as well as on the grant application.
- eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their full SAM and Grants.gov registrations; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
- Grants.gov Applicants must have an active SAM registration in order to complete the Grants.gov registration.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
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. See, e.g., 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)
1. Requesting an Application Package
The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
2. Content and Form of Application Submission
It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.Letter of Intent
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
- Descriptive title of proposed activity
- Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
- Names of other key personnel
- Participating institution(s)
- Number and title of this funding opportunity
The letter of intent should be sent to:
Rebecca Hommer, M.D.
Telephone: 301-827-2257
Email: [email protected]
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: a Team Management Plan for the proposed research project and a Community Engagement Plan. These items must be uploaded as separate attachments in pdf format with filenames that correspond to the individual items (e.g., Team Management Plan.pdf). Applications lacking these required items will be deemed incomplete and will not be reviewed.
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 physicians with appropriate disease expertise, non-clinical and clinical scientists, community engagement experts, health disparities experts, community members, patients or patient advocates, cognitive, statistical, population-based clinical research, and other relevant academic/industry 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.
Community Engagement Plan for the proposed research project: Applications must include a detailed community engagement plan that outlines collaborations with study-relevant organizations, groups representing populations that experience health disparities 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 proposing CEr are encouraged to provide evidence of relationship development or collaboration, such as through letters of support.
The Community Engagement Plan should:
- Include stakeholders that represent NIH-designated populations at risk for experiencing health disparities and the study population of interest
- Describe patient engagement activities and methods to monitor and evaluate outcomes related to engagement
- Describe the roles of community partners from the inception to implementation of the study
- Include linguistic and cultural competence strategies to enable recruitment and retention of populations that are at risk for experiencing 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 populations that experience health disparities and 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
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 health equity. At least one co-investigator from primary care (or the health care setting that is central to the proposed intervention) is suggested 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 PD(s)/PI(s) or key personnel should also have experience in the design and implementation of large-scale clinical studies within an HCS; for example, expertise in using electronic health records for recruitment and outcomes assessment. 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 the pragmatic clinical trial(s).
Research Strategy: Organize the Research Strategy by Significance, Innovation, and Approach.
Significance: Describe the rationale and supporting data demonstrating efficacy of the chosen intervention(s) and the intervention's potential to attain the overall goal of preventing, decreasing or slowing the progression of cognitive impairment including dementia in primary care and other everyday clinical settings in HDPs in the United States by addressing modifiable risk factors that impact clinical outcomes. The strength/rigor of prior research supporting the use of the proposed intervention should be addressed, and ambiguity, weaknesses or limitations of this prior work should be addressed.
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? Explain how the completion of the proposed pragmatic trial may change the management of patients at risk for or with VCID, and how study outcomes will provide clinically meaningful information to stakeholders.
Applications must identify the specific disparities in the modification of risk factors associated with VCID that are addressed by their proposed pragmatic clinical trial, and in what population(s). If an application targets populations experiencing multiple health disparities the application must discuss the conceptual framework for each including how they may overlap.
Innovation: Describe the innovative attributes the application brings via both the specific intervention(s), proposed and their integration into the health care system. Specify the major (hypothesized) barriers to care, and clearly indicate which barriers will be addressed and how these barriers will be addressed in the application.
Approach:The approach must detail the strengths and appropriateness of the intervention(s) in the targeted population(s), seen in primary care and other everyday clinical settings, as well as describe how the intervention will be implemented. Evidence should be provided to support the extent to which the proposed intervention is feasible and suitable for implementation in a real world setting. Particular attention should be paid to engaging the patient population defined by the NIH as experiencing or at risk for experiencing health disparities, and the proposed intervention(s) should be culturally appropriate and sensitive to the target population(s) and the known disparities for cognitive impairment and dementia.
Identify the target population(s) and describe the approach to U01 activities, including partnerships with health care systems, community groups or providers, approaches to cohort engagement, recruitment, retention, data collection strategies, and planned clinical outcomes and analysis strategies. Detail how the proposed pragmatic clinical trial will engage the target population(s), implement intervention(s) in primary care and other everyday clinical settings. Discuss potential biases and challenges with the proposed research and how they will be addressed.
Describe how the paradigm(s) integrate with the EHR and medical billing systems.
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 experience of the investigators in engaging the target NIH population that is at risk for experiencing health disparities should also be clearly described, including a description of members of the research team with a history of active engagement with the stated community. The application must provide a rationale for the HCS selected for the Project and provide a description of the infrastructure and expertise
Applications should include multi-level interventions and address the costs of implementation as well as identify and successfully address challenges and barriers to implementation, including structural, systemic, individual, and patient-related factors. Strategies for adoption, fidelity, penetration, and sustainability should be considered and evidence provided for acceptable fidelity in a real-world setting
Describe how, if successful, this applied program will prevent, delay or slow the development of negative clinical outcomes associated with VCID, including in populations who experience health disparities in dementia, and how it will provide information about implementation and use that will be relevant to and ultimately benefit patients, clinicians, health care systems, and other stakeholders. The targeted modifiable risk factors should be clearly identified and linked to VCID clinical outcomes.
NINDS urges investigators to follow the NIH guidance for rigor and transparency in grant applications (https://grants.nih.gov/policy/reproducibility/guidance.htm) and additionally recommends the research practices described at https://www.ninds.nih.gov/Funding/grant_policy to ensure that robust experiments are designed, potential experimenter biases are minimized, results and analyses are transparently reported, and results are interpreted carefully. These recommended research practices include, where applicable, rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, ensuring adequate sample size, pre-specified inclusion/exclusion criteria, handling of missing data and outliers, appropriate controls, preplanned analyses, appropriate quantitative techniques, clear indication of exploratory vs. confirmatory components of the study, consideration of limitations, and plans for transparent reporting of all methods, analyses, and results so that other investigators can evaluate the quality of the work and potentially perform replications.
Investigators should indicate whether data presented or cited in the application as key support for the proposed work were collected, analyzed, and reported in a rigorous and transparent manner as indicated above. A plan to address any ambiguity, weaknesses, or limitations in the prior research should be included in the application. Proposed experiments should similarly adhere to these high standards of rigor and transparency.
For all clinical trials, describe the rationale for the trial design, population(s) and hypotheses being tested, and control groups. The proposed study design should additionally describe potential biases and/or challenges in the protocol and how they will be addressed. For efficacy or effectiveness (typically Phase III or later) clinical trials, the proposed study design should account for clinical relevance of the expected effect size and include measures to reduce the risk of systematic biases, such as blinding and randomization.
Milestone Plan: 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. When applicable, milestone reports should adhere to rigorous principles, including statistically adequate sample sizes with biologically relevant effect sizes, randomization, blinding, control of potential bias, independent replication, and adequate reporting of experimental details and results as described at https://www.ninds.nih.gov/Funding/grant_policy. 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: A resource sharing plan is required. Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide.
The following modifications also apply:
- All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
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 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 racial and ethnic 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:
- Has the PD/PI previously recruited patients with this disease into a clinical trial?
- Does this site have all necessary equipment to complete eligibility evaluations?
- If not, how far (in miles) will patients need to travel to complete eligibility evaluations?
- What is the total number of patients seen at this site in the past 12 months?
- How many of these appear to meet the pre-screening eligibility criteria?
- How many of these are likely to be found fully eligible and consent to be enrolled?
- Do the sites have appropriate demographics to comply with the Inclusion of women and minorities NIH Policy?
- Is there a clear plan for recruitment of patients from populations that experience health disparities , based on the patient population seen at that facility or in the local community?
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:
- Development of data management system and case report forms, incorporating applicable NINDS Common Data Elements
- Integration of the intervention paradigm into the HCS EHR pathway.
- Development of tools for data and quality management
- Coordination of community engagement
- Development of recruitment and retention strategies, plans to minimize loss to follow-up and projected acceptable attrition rates
- Finalization of protocol, manual of procedures, consent forms, and data management plan
- Finalization of planned analyses (including interim analyses, if appropriate)
- Finalization of the study data sharing plan
- Protocol approval from a Medical Monitor and/or Study Monitoring Committee
- Initiation of contracts and training of clinical site personnel (NINDS expects the initiation of all study sites to occur in the start-up stage; if a large number of sites is needed, a plan that describes how additional sites will be added after the initiation of the study should be included)
- Initiation of processes for including proposed international clinical sites, if applicable
- Plans for site activation, execution of contracts and training of additional clinical sites, including any international sites, if applicable
For enrollment:
- Completion of start-up activities (finalization of protocol, contracting of sites, registration in ClinicalTrials.gov, completion of any final regulatory approvals, etc.)
- Earliest possible enrollment date
- Enrollment of 25%, 50%, 75% and 100% of the targeted sample size
- Completion of all study data collection
- Completion of primary endpoint and secondary endpoint data analyses
- Completion of final study report
- Publication of primary study results
- Reporting of results in ClinicalTrials.gov
- Submission of final public use dataset to NINDS
- If an adaptive design is to be used, indicate when adaptions will be considered.
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. A data sharing plan is required for this RFA. 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:
- A summary of participant eligibility criteriaincluding the demographic characteristics of the people to be tested (such as age, sex, ethnicity), and how it will be determined whether or not a given individual or groups of individuals will be enrolled (may refer to details in Section 2.2).
- A brief description of all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the research paradigm. Do not include copies of the assessment tools.
- Overview of efficient data management and methods for monitoring quality, methods for monitoring the quality and consistency of the intervention delivered, and methods for ensuring participant confidentiality. Applicants are expected to incorporate data elements from the NINDS Common Data Elements (CDE) Project when appropriate in their data collection forms.
- Overview of informed consent process, and example consent language that describes sharing (may refer to Section 3.1 to avoid duplication). Consent should allow sharing of de-identified clinical data and, if applicable, biospecimens, for broad biomedical research.
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);
NeuroQOL (http://www.healthmeasures.net/explore-measurement-systems/neuro-qol);
NIH Toolbox (http://www.healthmeasures.net/explore-measurement-systems/nih-toolbox); and
PROMIS (http://www.healthmeasures.net/explore-measurement-systems/promis).
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/ and may also be found in the NIH Pragmatic Clinical Trial Collaboratory’s Living Textbook chapters on study design https://rethinkingclinicaltrials.org/chapters/design/experimental-designs-randomization-schemes-top/experimental-designs-and-randomization-schemes-introduction/ .
Applicants should provide a Statistical Analysis Plan (SAP) for 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. Sufficient details should be provided in the SAP about any computer simulations 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. 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
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.
Delayed Onset Studies are not responsive to this FOA.
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
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
5. Intergovernmental Review (E.O. 12372)
This initiative is not subject to intergovernmental review.
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.
Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential fieldof the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the unique entity identifier provided on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by 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.
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.
For this particular announcement, note the following:
All applications under this announcement are to be assigned to the NINDS as the administrative institute.
A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.
Overall Impact
Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).
Scored Review Criteria
Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.
Significance
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Specific to this FOA:
To what extent and in what way do the proposed intervention(s) have strong potential to address the unmet need to decrease, slow or prevent negative clinical outcomes associated withVCID by targeting and adequately addressing modifiable risk factors?
For health equity research proposed, to what extent does the application identify the major (hypothesized) barriers to implementing treatment that may decrease, slow, or prevent the progression of VCID in the specific population, and clearly indicate which of these barriers are addressed in the application and how they will be addressed?
What is the strength or rigor of the evidence of efficacy/effectiveness for the intervention that will be integrated into the health delivery system? To what extent does the application adequately describe whether prior research that serves as the key support for the proposed project employed rigorous practices?
How well does the application address ambiguity, weaknesses, or limitations in rigor of the prior research, if applicable?
To what extentwill the completion of the proposed pragmatic trial change the management of patients at risk for or with VCID in health care systems? To what extent will potential outcomes provide clinically meaningful information to stakeholders?
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?
Specific to this FOA:
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?
To what extent are appropriate collaborators from the participating health care system (HCS) identified and included?
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?
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?
Specific to this FOA:
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?
Specific to this FOA:
To what extent are the targeted modifiable risk factors identified and linked to VCID clinical outcomes?
To what extent is the proposed intervention(s) culturally appropriate and sensitive for the target population(s) and the known disparities for cognitive impairment and dementia?
How well does the proposed intervention address and adequately provide a solution to overcome barriers to care in the target populations?
To what extent have relevant HCS stakeholders have been included in the study planning process and expressed commitment to remain engaged during study implementation?
To what degree will the results provide relevant information and adequate data for other 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?
How much potential do the proposed intervention(s) have for future implementation?
How well-developed is the proposed strategy for broad and harmonized implementation into everyday clinical settings? How well does the application include assessment of implementation cost, identification of the areas that are challenging for implementation, and address implementation measures such as for adoption, fidelity, penetration, and sustainability?
To what extent are the proposed milestones appropriate?
If an FDA-regulated intervention will be studied:
- Does the application document FDA approval to proceed with implementing this trial? Otherwise, if the trial is on full or partial hold, does the application make clear that the hold issues are readily addressable?
- How well does the application show evidence of involvement of patient groups in study design and recruitment plans?
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?
If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?
If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?
If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?
Additional Review Criteria
As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.
Team Management Plan:
To what extent is the proposed Team Management Plan appropriate to support the research proposed within this application?
Community Engagement Plan:
To what extent does the community engagement plan (1) Include study appropriate representation of populations that experience health disparities and the study population? (2) Include patient engagement activities and methods to monitor and evaluate outcomes related to engagement? (3) Include roles of community partners from the inception to implementation of the study? (4) Include linguistic and cultural competence strategies to enable recruitment and retention of populations that experience health disparities? (5) Identify and propose solutions to known barriers to recruitment, participation, and/or retention of HDPs? (6) Include resources to compensate stakeholders and patients and support and sustain community engagement?
Study Timeline
Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
Protections for Human Subjects
For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.
For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.
Inclusion of Women, Minorities, and Individuals Across the Lifespan
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
Vertebrate Animals
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Biohazards
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
Resubmissions
Not Applicable.
Renewals
Not Applicable.
Revisions
Not Applicable.
As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.
Applications from Foreign Organizations
Not Applicable.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; and (2) Genomic Data Sharing Plan (GDS).
Authentication of Key Biological and/or Chemical Resources:
For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.
Budget and Period of Support
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
2. Review and Selection Process
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) 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 NINDS Advisory Council. 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.
- Compliance with resource sharing policies.
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.
1. Award Notices
If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.
A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.
Recipients must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the recipient must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).
Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).
2. Administrative and National Policy Requirements
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities, including of note, but not limited to:
- Federalwide Research Terms and Conditions
- Prohibition on Certain Telecommunications and Video Surveillance Services or Equipment
- Acknowledgment of Federal Funding
If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.
Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex (including gender identity , sexual orientation, and pregnancy). This includes ensuring programs are accessible to persons with limited English proficiency and persons with disabilities. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html
HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.
- Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. For guidance on meeting the legal obligation to take reasonable steps to ensure meaningful access to programs or activities by limited English proficient individuals see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.htmlandhttps://www.lep.gov.
- For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including reasonable accommodations and making services accessible to them, see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.
- HHS funded health and education programs must be administered in an environment free of sexual harassment, see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.
- For guidance on administering programs in compliance with applicable federal conscience protection and associated anti-discrimination laws see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.
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 75.205and 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.
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:
- Adherence to all applicable NIH/NINDS policies including for data sharing and human subjects as appropriate and consistent with achieving the goals of the program
- Determining experimental approaches, designing protocols, and conducting experiments
- Submitting annual progress reports, other required reports, and meeting milestones during the funding period, in a format as agreed upon by NINDS program staff
- Make new information and materials known to the research community in a timely manner through publications, web announcements, reports to NINDS program staff, and other mechanisms
- Timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement
- The PD(s)/PI(s) and Project Leaders are requested to submit manuscripts to the NIH Project Scientist within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained
- Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the PD(s)/PI(s) and appropriate Project Leaders and will require appropriate acknowledgement of NINDS support. Timely publication of major findings is required
- These awards will be co-funded by the National Institute on Aging and the National Institute of Neurological Disorders and Stroke. All publications, posters, oral presentations at scientific meetings, seminars, and any other forum in which results of this co-funded research are presented must include a formal acknowledgement of the NINDS/NIA support, citing the NINDS grant number as identified on this award document
- Establishment of informed consent such that when new clinical data (and biospecimens, if applicable) are collected, consent allow all enrolled individuals the opportunity to share via NINDS Repositories their de-identified data (and samples, if applicable) to researchers in academic, not for profit, and industry (for internal research use only, for profit use is not allowed). Assurance that the de-identified clinical data and samples, if applicable, will be securely stored and can be distributed to scientists for use in research and teaching only. Assurance that the de-identified data and samples, if applicable, will be available for use in any type of biomedical research, not only for research on the detection of cognitive impairment and dementia
NINDS will identify two different program staff members to be involved with the cooperative agreement - one will be the Project Scientist and the other will be the Program Officer. The following describes the roles and responsibility of each:
The Project Scientist will provide technical assistance, advice, coordination, and other program actions to support the recipients of the cooperative agreements during the conduct of an activity. Specifically, the Project Scientist will contribute to developing final milestones for the study, serve on committees related to the conduct of the approved trials as appropriate, assist in promoting the availability of data and resources developed during this project to the scientific community, and assist in the development, if needed, of policies for dealing with situations that require coordinated action. The Project Scientist will refrain from activities that rise to a level of involvement that results in conflicts of interest, and will be recused from all funding decisions, RPPR and milestone reviews, and go/no-go project decisions. Should the extent and nature of staff involvement evolve to the level where conflicts of interest arise, NINDS will carefully re-evaluate the alignment of duties among staff and implement specific strategies to manage the conflicts of interest.
The Program Officer will be responsible for normal programmatic stewardship of awards and will sign off on the funding documents. The Program Officer will be responsible for stewardship of the award, including review of milestones and progress reports and monitoring implementation of the data and research resource sharing plans. The Program Officer retains the option to recommend the withholding or reduction of support from any cooperative agreement that either substantially fails to achieve the goals agreed to at the time or the 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.
Selection of the Project Scientist and Program Officer will be made at the time of award, and the Program Officer will be named in the award notice.
Areas of Joint Responsibilities include:
None
Dispute Resolution:
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.
3. Reporting
When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement. NIH FOAs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All recipients of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.
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: [email protected] (preferred method of contact)
Telephone: 301-480-7075
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]
Richard Benson, MD, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9135
Email:[email protected]
Rebecca Hommer, MD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-2257
Email:[email protected]
Partha Bhattacharyya, Ph.D.
National Institute on Aging (NIA)
Phone: (301) 496-3131
E-mail: [email protected]
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email:[email protected]
Replace this text with Staff Contact Name
Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email:[email protected]
Ryan Blakeney
National Institute on Aging (NIA)
Phone: 301-451-9802
E-mail: [email protected]
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.
and Human Services (HHS)
