Part 1. Overview Information

Key Dates

Dates in bold and italics reflect changes per NOT-NS-24-082

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.

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

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background and Purpose

The number one goal of the National Alzheimer’s Project Act (NAPA) is to prevent and effectively treat Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias (AD/ADRD) by 2025.  The development of anti-amyloid immunotherapies is perhaps the most notable advance in the ADRD treatment arsenal in recent years, but much remains to be learned about the efficacy and safety of amyloid beta focused immunotherapies. To date two such treatments, aducanumab and lecanemab, have received accelerated approval from the FDA. In April 2022, the Centers for Medicare & Medicaid Services (CMS) announced a National Coverage Determination (NCD) to cover FDA-approved monoclonal antibodies that target amyloid for the treatment of AD through Coverage with Evidence Development (CED), meaning that FDA-approved drugs in this class would only be covered for people with Medicare if they are enrolled in qualifying clinical trials (including NIH sponsored trials).  In July 2023, after lecanemab converted from accelerated to traditional approval, CMS expanded coverage of lecanemab (and, as applicable, other drugs in this class with traditional approval, to include eligible patients whose physician participates in a qualifying registry.More detailed information regarding CMS coverage of monoclonal antibody therapies directed against amyloid, including the NCD CED decision memorandum, may be found on the CMS website.

The NIH now seeks applications proposing placebo-controlled, phase 3 clinical trials to determine the efficacy and safety of FDA approved monoclonal antibody therapies compared to placebo in mixed-etiology dementia (MED) populations with a focus on vascular contributions to cognitive impairment and dementia (VCID). In this NOFO the mixed-etiology dementias (MED) that are of interest and that are in scope are mild cognitive impairment and dementia cases positive for 1) Alzheimer pathology biomarkers, such as amyloid positron emission tomography and/or low cerebrospinal fluid amyloid beta 42 combined with elevated phosphorylated tau; and 2) with evidence of vascular contributions based on imaging (for example, white matter disease and/or subclinical infarction).

Among the U.S. population where high rates of hypertension and diabetes mellitus contribute to vascular risk, MED with evidence of both AD and VCID likely affects a large number of Medicare-eligible individuals presenting with symptoms of cognitive impairment or dementia. However, little is known about the efficacy and safety of amyloid immunotherapy in this population.  Pre-market trials of anti-amyloid agents generally excluded individuals with clinically significant brain lesions that could indicate a dementia diagnosis other than AD. Individuals with low levels of vascular disease burden were eligible for enrollment, but data regarding the number of individuals with concomitant mild vascular disease at the time of enrollment, and the safety and efficacy of therapy in these individuals was not detailed in initial publications.

It is important to study amyloid-beta monoclonal antibody therapies in MED populations that include cerebrovascular disease both to learn whether there is a clinically meaningful benefit of the intervention and to understand the risks associated with these therapies.  Of particular concern is the association of amyloid-beta antibody therapy with amyloid-related imaging abnormalities (ARIA). ARIA may be characterized by focal vasogenic edema (ARIA-E) or microhemorrhage and/or superficial siderosis (ARIA-H).  ARIA may be asymptomatic or associated with fatigue, headache, confusion, dizziness, falls, vision change or nausea. In most patients, symptoms and signs of ARIA-E resolve over time, but recurrence may occur, particularly with dose escalation, and one fatality has been reported.  Microhemorrhage (ARIA-H) is a permanent imaging finding, and in rare cases, more severe bleeds have occurred in individuals receiving amyloid-beta immunotherapy, resulting in at least two deaths.  Risk of ARIA-E appears to be associated with the ApoE4 allele, the presence of > 4 microhemorrhages on baseline MRI, and treatment initiation and dose escalation. Risk of ARIA-H appears to increase with age and cerebrovascular disease burden.

Clinical trials enrolling individuals with known VCID must carefully consider the risks associated with treatment.  More information is needed regarding risk in individuals with evidence of mild-to-moderate cerebrovascular disease, as well as which individuals may be most at risk or most likely to benefit.  Bayesian approaches with response adaptive randomization to examine specific subgroups are encouraged, as are examinations of potential biomarkers.  Successful applications will be powered to determine differences in efficacy among diverse populations representative of the distribution of disease in the United States by sex, race/ethnicity, and geographic area. In addition, particularly given the limited knowledge regarding risks and benefits of anti-amyloid therapies in populations with evidence of VCID as well as AD, input from people who are experiencing mild cognitive impairment or mild dementia of mixed etiology, who can ascribe value to potential benefits and weigh against potential risks is critically important. Applications must include community engagement cores that are incorporated into all stages of program development and at all levels of the organizational structure.

Community engagement (CE) is the process of working collaboratively with groups of people affiliated by geographic proximity, identity, special interest, or similar circumstances to address issues affecting the wellbeing of those people. CE is a strategy that can be used to promote health and health research by addressing barriers to and identifying ways to facilitate research participation across NIH-designated populations that experience health disparities (HDPs). CE should include practices that incorporate genuine bidirectional communication and education about culture, beliefs, motives, health, and clinical research. Continued respectful, equitable, and bidirectional knowledge transfer during community engagement can improve HDP community research participation, retention and adherence to the study protocol, and health empowerment. CE can help build trust in communities that may be fearful of participating in clinical research because of stigmas and medical mistrust. Many core principles (trust, inclusivity, culturally-centered, etc.) are outlined in the National Academy of Medicine’s Advancing Health Equity and Systems Transformation through Community Engagement strategy for assessing meaningful community engagement.  Additionally, domains of assessment include strengthened partnerships & alliances, expanded knowledge, improved health, health care programs and policies, and thriving communities.   

While community engagement is a strategy, Community-Engaged research (CEr) is a research process that broadly implements CE principles and strategies to incorporate perspectives and meaningfully involve patients, caregivers, and other community and healthcare stakeholders throughout the entire research process—from planning the study, to conducting the study, and disseminating study results.  Engaging the community in research contributes to successful health equity study design that is inclusive of diverse participants and perspectives across the research continuum and provides infrastructure to ensure culturally appropriate research strategies, tools, and communication are implemented. Partnering with the community helps with development of sustainable interventions and the translation of study results into practice, potentially improving health outcomes.

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. 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 a placebo-controlled, phase 3 clinical trial to determine the efficacy and safety of FDA approved monoclonal amyloid antibody therapies in diverse mixed etiology dementia (MED) populations with a focus on vascular contributions to cognitive impairment and dementia (VCID).  In this NOFO the mixed-etiology dementias (MED) that are of interest and that are in scope are dementia cases with evidence of 1) Alzheimer brain pathology based on biomarkers such as amyloid positron emission tomography and/or low cerebrospinal fluid amyloid beta 42 combined with elevated phosphorylated tau; and 2) vascular contributions to cognitive impairment and/or dementia based on imaging (for example, white matter disease and/or subclinical infarction).  The inclusion of other emerging blood-based or imaging biomarkers that may be markers of AD or VCID severity or serve as potential indicators of treatment response or risk is encouraged but established brain-based markers should be used to determine the eligible study population.

The proposed study population should be limited to individuals who are eligible to be treated with anti-amyloid therapy under either the CMS National Coverage Determination to cover FDA-approved monoclonal antibodies that target amyloid for the treatment of AD through Coverage with Evidence Development (CED) or under the CMS plan to cover therapies that have received traditional approval when coupled with clinical team participation in a qualifying registry. 

The NINDS is committed to reducing the disproportionate burden of neurological disease borne by underserved groups of society, including racial and ethnic minority, rural, and socioeconomically disadvantaged populations.  In keeping with this commitment, it is expected that successful applications will be powered to determine differences in efficacy among diverse populations representative of the distribution of disease in the United States by sex, race/ethnicity, and geographic distribution.  Bayesian approaches with response adaptive randomization to examine specific subgroups are encouraged.

Applications Not Responsive to this NOFO

This NOFO is only for studies related to humans; animal or other disease model studies are not responsive to this NOFO.

Applications that include patient populations outside of those covered by the CMS registry plan or the CMS National Coverage Determination of CED for FDA-approved anti-amyloid immunotherapies are not responsive to this NOFO.

Applications that include patient populations that do not have evidence of mild cognitive impairment or dementia with evidence of both AD and VCID are not responsive to this NOFO.

Applications that propose the testing of anti-amyloid immunotherapies that do not yet have FDA approval.

Applications that propose mechanistic clinical trials or BESH clinical trials are not responsive to this NOFO.

Delayed-Onset Trials are not responsive to this NOFO.

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

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

Section II. Award Information

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

Section III. Eligibility Information

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

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

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

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

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

2. Cost Sharing

This NOFO 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 NIH Grants Policy Statement Section 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. 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 How to Apply - Application Guide except where instructed in this notice of funding opportunity 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: rebecca.hommer@nih.gov

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 NOFO.

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.

• Applicants must include a Team Management Plan for the proposed research project: Each application submitted in response to this NOFO 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.
• Applicants must include a Community Engagement and Research Inclusivity (CERI) Plan for the proposed research project: Applications must include a detailed community engagement and research inclusivity (CERI) P lan that describes how community engagement strategies and community-engaged research will be incorporated throughout the study. The community(ies) of interest include persons with lived experience (PWLE) of cognitive impairment and/or dementia and their partners or caregivers; efforts should be made to include representation from populations that experience health disparities. Community partner(s) include those who represent communities of interest such as patient or consumer advocacy groups, community champions, community-based organizations, faith-based organizations and/or other relevant groups. The CERI Plan should not exceed two pages.

The CERI Plan should:

• Include PWLE that represent NIH-designated populations at risk for experiencing health disparities and the study population of interest (those with cognitive impairment or dementia with evidence of AD pathology and cerebrovascular disease burden)
• Define expectations of community partners, including the composition and expertise of the community groups, the phase(s) (i.e., design, conduction, analysis, interpretation, and/or dissemination) of research the community partner perspective will be engaged, and a description of how a formal agreement (e.g., memorandum of understanding) will be co-created with or approved by the community partner, if applicable. Community members should be engaged and their input incorporated across at least three touchpoints from the inception to end of a study, with more frequent engagement welcome.
• Outline methods and metrics to monitor community engagement efforts, including a description of how this information will be considered within the framework of the grant activities
• 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 community participants and support and sustain community engagement as well as plans to recognize their efforts.

The Team Management and CERI plans 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.

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

R&R or Modular Budget

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

R&R Subaward 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, with the following additional instructions:

Specific Aims: State the aims and hypotheses to be tested in the proposed clinical trial.

Research Strategy: Organize the Research Strategy by Significance, Innovation, and Approach.

Significance: Applicants must describe the significance of the proposed efficacy clinical trial in the context of the status of therapeutics for MED populations with evidence of both AD and VCID, and the potential risks, costs, and clinically relevant benefits of the proposed study intervention.  Potential adverse effects associated with treatment, including ARIA, should be addressed. Discuss how the trial will test the hypotheses proposed and how the results of the trial (positive or negative) will advance the field. The strength/rigor of prior research supporting the use of the proposed therapeutic(s) should be discussed, and ambiguity, weaknesses or limitations of this prior work should be addressed.

Innovation: Applicants must describe any innovative attributes of the proposed research. Applicants must specify any major (hypothesized) barriers to the proposed research, and clearly indicate how these barriers will be addressed in the application.

Approach: Applicants must describe the rationale for the trial design, population(s) and hypotheses being tested, and control groups. The approach must detail the strengths and appropriateness of the intervention(s) in the targeted MED population(s).  Clinically meaningful endpoints, such as cognitive or functional outcomes, should be included and attention should be paid to the evaluation of safety signals, particularly the development of ARIA-E and ARIA-H, as well as consideration of safety and efficacy across sub-groups of patient populations, such as those with larger vascular disease burden. Plans for engaging diverse patient populations should be detailed 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. A discussion of potential biases and/or challenges in the protocol and how they will be addressed should also be included. 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.

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.

Milestone Plan: This NOFO 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.

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:

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

Other Plan(s):

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

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

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

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Applicants must provide strong evidence of the availability of appropriate institutional resources, and suitable patient populations, providers, clinics, or facilities (depending on unit of randomization). Documentation of availability of eligible participants, clinic sites, or units of randomization, presented in tabular format must be provided. The application must include relevant information that addresses the feasibility of recruiting participants who are eligible for the proposed clinical trial. 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 parties (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 cognitive impairment or dementia 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 diverse 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:

1. Development of data management system and case report forms, incorporating applicable NINDS Common Data Elements
2. Development of tools for data and quality management
3. Coordination of community engagement
4. Development of recruitment and retention strategies, plans to minimize loss to follow-up and projected acceptable attrition rates
5. Finalization of protocol, manual of procedures, consent forms, and data management plan
6. Finalization of planned analyses (including interim analyses, if appropriate)
7. Finalization of the Data Management and Sharing Plan
8. Protocol approval from an IRB & DSMB
9. 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)
10. Initiation of processes for including proposed international clinical sites, if applicable
11. Plans for site activation, execution of contracts and training of additional clinical sites, including any international sites, if applicable

For enrollment:

1. Completion of start-up activities (finalization of protocol, contracting of sites, registration in ClinicalTrials.gov, completion of any final regulatory approvals, etc.)
2. Earliest possible enrollment date
3. Enrollment of 25%, 50%, 75% and 100% of the targeted sample size
4. Completion of all study data collection
5. Completion of primary endpoint and secondary endpoint data analyses
6. Completion of final study report
7. Publication of primary study results
8. Reporting of results in ClinicalTrials.gov
9. Submission of final public use dataset to NINDS
10. 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 to seven 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 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 criteria, including the anticipated demographic characteristics of the people to be enrolled (such as age, sex, ethnicity), and how it will be determined whether or not a given individual 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).
•   NINDS Biorepository BioSEND (biosend.org) for prospective biospecimen collection and banking. Please note: costs for biospecimen collection are not included as a component of the NINDS BioSEND repository award. Therefore, most costs for the biospecimen banking are borne by the grantees utilizing this resource (see NOT-NS-15-046). Applicants planning projects in which biospecimens will be collected are strongly advised to consult with NINDS Biomarkers Repository staff to obtain a quote for biospecimen banking costs (email:biosend@iu.edu).

4.3 Statistical Design and Power

Applicants should provide a Statistical Analysis Plan (SAP) including details on the analyses specified in the study protocol, including a description of how the statistical analysis of the primary, secondary and other endpoints will be performed, how the sample size was determined, how missing data will be handled, plans for interim analyses for safety, efficacy and futility, plans for recalculation of the sample size midway through the trial (if applicable), etc. If computer simulations were used to investigate the operating characteristics of complex clinical trial designs (such as adaptive designs), to choose between alternative outcome measures, or to determine sample size, accounting for the impact of noncompliance, missing data, subject eligibility criteria, etc., sufficient details about the simulations should be provided if the SAP. It is particularly important to discuss the range of conditions that were considered in the simulation and why this range was considered appropriate, how robust the findings were across the range of conditions considered, and how the study will adjust for any design deficiencies (e.g., bias, loss of power) the simulations revealed.

4.5 Will the study use an FDA-regulated intervention?

4.5.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status:

If the study intervention is a drug, biologic, or device, applicants must provide documentation from the FDA providing information on one of the following scenarios:

(a) The protocol has been submitted under an open IND and the IND is not under full or partial hold. Under this scenario, applicants must provide documentation such as a "may proceed" email or letter from the FDA.

(b) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has fully approved the IDE or IDE supplement. Under this scenario, applicants must provide documentation of an IDE or IDE supplement full approval letter from the FDA.

(c) The protocol has been submitted under an IND and is on full or partial hold. Under this scenario applicants must provide full documentation from the FDA on the reasons for hold and the FDA recommendations. Applicants should discuss how they intend to address the hold issues and when they believe they will have FDA approval to proceed with trial implementation.

 (d) The protocol has been submitted as an original IDE or as a new study under an open IDE, and FDA has conditionally approved the IDE or IDE supplement. Under this scenario applicants must provide full documentation from the FDA on the conditions of approval. Applicants should discuss how they intend to address these conditions and when they believe they will have FDA approval to proceed with trial implementation.

(e) The protocol is exempt from an IND. Under this scenario applicants must provide a copy of the exemption letter from the FDA.

(f) The protocol is either exempt from the IDE regulations or does not require IDE approval because it is determined to be nonsignificant risk. Under this scenario applicants must provide either an IDE exemption letter or a copy of the risk determination letter from the FDA.

Applications that do not include this information at the time of submission must indicate i) that it will be submitted subsequently and ii) when the regulatory documentation from the FDA is likely to be available. After the assignment of the application to a review group is visible in the eRA Commons, the applicant should contact the Scientific Review Officer (SRO) for that review group to discuss logistics for submission of the regulatory information. Applications that are not able to provide this information will be withdrawn and not reviewed. Prior to grant award, awardees who do not have an exemption from the FDA must provide any additional FDA correspondence regarding the status of the protocol to the NINDS, especially if the trial has been placed under full or partial hold. 

Delayed Onset Study

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.

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 field of the Senior/Key Person Profile form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this NOFO for information on registration requirements.

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

See more tips for avoiding common errors.

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

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process.  Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

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?

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?

To what extent does this application address the significance of the study of the use of monoclonal amyloid-beta antibody therapeutics in the MED population with evidence of both AD and VCID, as well as the potential risks, costs, and benefits?  To what extent is consideration given to potential adverse effects of treatment, including ARIA?

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?

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?

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?

To what extent does the application indicate how hypothesized barriers to the proposed research will be addressed?

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?

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?

To what extent does the proposed research incorporate adequate methodological rigor where applicable, including, but not limited to, rationale for the chosen model(s) and primary/secondary endpoints, clear descriptions of tools and parameters, blinding, randomization, adequate sample size, pre-specified inclusion/exclusion criteria, appropriate 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? 

For clinical trials, to what extent is the scientific rationale of the proposed study based on well-designed, rigorous, and transparent previous preclinical and/or clinical research? How well does the proposed study design describe potential biases and/or challenges in the protocol and how they will be addressed? To what extent is the proposed study design justified and appropriate, adequately controlled, and powered to address primary and secondary outcome variable(s)/endpoints, if applicable, that will be clear, informative, and relevant to the population and hypothesis being tested? To what extent are the study population(s) (i.e., gender, age, demographic group), proposed intervention arms and/or dosage, and duration of the trial appropriate and well justified? How compelling is the provided rationale for the chosen subjects, endpoints, and statistical methods?

How well does the proposed study design account for clinically meaning outcomes focused on cognition and safety, including risk for and sequelae of ARIA? How well does the proposed study design account for clinical relevance of the expected effect size, and to what extent do the methods used to assign participants and deliver interventions properly apply blinding, randomization, controls, and approaches for handling missing data and outliers?To what extent does the application address clinically meaningful endpoints that assess cognitive or functional outcomes? To what extent does the application address the evaluation of safety signals, particularly the development of ARIA-E and ARIA-H, as well as consideration of safety and efficacy across sub-groups of patient populations?  How well are plans for engaging diverse patient populations that experience MED detailed?  To what extent are the proposed intervention(s) culturally appropriate and sensitive to the target population(s) and the known disparities for cognitive impairment and dementia?  

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 and Research Inclusivity (CERI) Plan:

To what extent does the CERI plan (1) Include study appropriate representation of populations with or affected by cognitive impairment or dementia with evidence of AD pathology and cerebrovascular disease burden, including those from populations that experience health disparities? (2) Include roles for community partners from the inception to implementation of the study, including at least three touchpoints? (3) Include a description of the methods and metrics that will be used to monitor community engagement efforts and their impact on 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 Animals Section.

Biohazards

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

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

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

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

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

Applications will be assigned to NINDS.  Applications will compete for available funds with all other recommended applications submitted in response to this NOFO.  Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke 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.

3. Anticipated Announcement and Award Dates

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

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

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

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

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this NOFO 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:

• Federal-wide Standard Terms and Conditions for Research Grants
• 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 will be required to complete an HHS Assurance of Compliance form (HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a condition of receiving the grant, to administer programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity, The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. 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 NOFO.

• 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.html and https://www.lep.gov.

• For information on an institution’s specific legal obligations for serving qualified individuals with disabilities, including providing program access, reasonable modifications, and to provide effective communication, see https://www.hhs.gov/civil-rights/for-individuals/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 religious nondiscrimination laws and 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 75.205 and 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.”

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  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
• Recipients(s) will retain custody of and have primary rights to the data and software developed under these awards, subject to Government policies regarding rights of access consistent with current DHHS, PHS, and NIH policies.

NIH staff have substantial involvement that is above and beyond the normal stewardship role in awards, as described below. 

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 the normal scientific and programmatic stewardship of the award, including review of milestones and progress reports and monitoring implementation of the data and research resource sharing plans,and will be named in the notice of award.  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. Data Management and Sharing

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

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

4. Reporting

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

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 NOFOs 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 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period.  The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS).  This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313).  As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available.  Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 and 2 CFR Part 200– Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

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

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

Finding Help Online: https://www.era.nih.gov/need-help (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

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

Rebecca Hommer, MD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-2257
Email:rebecca.hommer@nih.gov

Laurie Ryan, Ph.D
NATIONAL INSTITUTE ON AGING (NIA)
Phone: 301.496.9350
E-mail: ryanl@mail.nih.gov

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

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

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

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 and 2 CFR Part 200.