Part 1. Overview Information

Key Dates

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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Purpose

The NIH INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) Project seeks to improve health and quality-of-life for individuals with Down syndrome. This NOFO requests research grant applications to support development of clinical trials to treat critical and co-occurring health conditions in individuals with Down syndrome. The overarching emphasis is on the acquisition of knowledge that can be translated into new, enhanced, or tailored therapies for treating Down syndrome and its co-occurring conditions. Applications should focus on delivering better healthcare outcomes and should seek solutions that are effective and deliverable. This NOFO will support clinical trial research to develop or test new and innovative adaptations of current drugs, interventions, and therapies for the treatment and management of co-occurring conditions in Down syndrome. These therapies should be implementable and sustainable in clinical settings beyond the research environment. Research applications may address a particular co-occurring condition at a particular stage of development or across the lifespan in people with Down syndrome. Outcomes research and health services research related to Down syndrome are also responsive to this NOFO. Since some aspects of this research area may be new for the NIH scientific community, there will likely be a need to obtain preliminary data or conduct early-stage clinical trial preparatory activities before moving to a full-scale project. The Exploratory/Developmental Phased Innovation (R61/R33) grant mechanism is appropriate for this purpose. It provides opportunities for creating, developing, and strengthening new and necessary collaborations, as well as acquisition of preliminary data, and allows for milestone-driven research, supporting a phased research project with a stepped approach for implementation of a clinical trial.  Those that are more basic science focused may be more appropriate for RFA-OD-27-004 INCLUDE Project: Transformative Research Awards for Down syndrome (R01 Clinical Trial Not Allowed). Applications not requiring a phased research approach are encouraged to apply under a different funding mechanism (e.g., investigator-initiated R21 or R01).

Background

Down syndrome is the most common genetic cause of intellectual disability, the most common autosomal trisomy, and one of the most visible and universally recognized genetic syndromes. Each year there are approximately 5300 babies born in the United States with Down syndrome. Within the past 25 years, the average lifespan for a person with Down syndrome has doubled, from 30 to 60 years. Despite this increase in lifespan, individuals with Down syndrome and their families face significant and changing health challenges with age, and they have often been excluded from participation in research that could improve their health outcomes and quality of life. While all people with Down syndrome are connected by the common feature of a complete or partial copy of chromosome 21 (trisomy 21), there are significant physical and cognitive differences among them, indicating that inter-individual variability exists.

Down syndrome is associated with an increased prevalence of autism and epilepsy. The lifetime risk of Alzheimer's dementia is over 90% in individuals with Down syndrome with symptom onset a decade or two earlier than typical Alzheimer’s disease. Individuals with Down syndrome also have high rates of hearing loss, eye abnormalities, congenital heart defects, sleep apnea, pulmonary hypertension, gastrointestinal malformations, thyroid disease, leukemia, and other autoimmune or immune dysregulation disorders including celiac disease. However, people with Down syndrome infrequently develop solid tumors such as breast or prostate cancer, and despite multiple risk factors for coronary artery disease and high rates of obesity, sleep apnea, and type 1 diabetes, they rarely develop atherosclerosis or have myocardial infarctions. Understanding this unique combination of risk and resiliencies will inform medical advances for individuals with Down syndrome, and for individuals who do not have Down syndrome but share these co-occurring conditions.

This NOFO is one of several trans-NIH research initiatives created in response to Omnibus Appropriations Reports starting in 2018, which encourage NIH to expand its current efforts on Down syndrome and common co-occurring conditions also seen in the general population, while increasing the pipeline of Down syndrome investigators. Together, the initiatives are called the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE). Information about projects that were funded in prior years, as well as the NIH INCLUDE Down Syndrome Research Plan, are available on the INCLUDE Project website at https://www.nih.gov/include-project. 

The INCLUDE Project has three components:

• Component 1: Conduct targeted, high-risk, high-reward basic science studies on chromosome 21
• Component 2: Assemble a large study population of individuals with Down syndrome
• Component 3: Conduct clinical trials research inclusive of individuals with Down syndrome

Scope

This NOFO addresses Component 3 of the INCLUDE project. Specifically, it is designed to encourage research and increase infrastructure support of clinical trials for co-occurring conditions in individuals with Down syndrome. This includes research on the development of technologies (e.g., wearables to monitor biomarkers of health), screening (e.g., effectiveness in typical primary care settings), access and management through new delivery systems (e.g., telehealth), system barriers (e.g., availability of services) as well as behavioral research at the individual patient level (e.g., patient outcomes). Research is needed to develop or test new and innovative adaptations of current drugs, interventions, and therapies, for the treatment and management of co-occurring conditions in Down syndrome. Solutions should be implementable and sustainable in settings beyond the research environment and should have the potential to address disparities in health care for individuals with Down syndrome.

Infrastructure support may include the creation of research partnerships among interested organizations (e.g., academia, practice-based research networks, community-based health care organizations, industry, and professional and patient organizations). It may also include support for creating pooled clinical data sets across institutions, agencies, or health care systems to analyze characteristics of patient populations, provider or health care settings and patient outcomes.

Clinical trials researchers may focus on repurposing of existing therapies as well as developing new ones for the unique needs of the Down syndrome population. Approaches could include: (1) obtaining de-identified clinical data, and working with the investigators of prior failed clinical trials to determine “lessons learned,” with a particular focus on inter-individual variation; (2) testing existing therapies for conditions that occur in both the general population and in people with Down syndrome, since their responses to therapy may not be the same as a result of differences in metabolism (for example, standard treatments for leukemia cause exaggerated toxicity in infants with Down syndrome); or (3) testing new therapies that may arise as a result of the basic science studies performed under the auspices of Component 1, building on the biobanked specimens and the participant data from Component 2. Responsive R61/R33 applications must be milestone-driven and may include, but are not limited to, the following questions and research needs:

• Augment inclusion of cohorts of individuals with Down syndrome in clinical trials aimed at common neurological symptoms and syndromes (e.g., infantile spasms, cognitive decline, sleep apnea, cervical spinal cord dysfunction) and stratification of analyses to enable discernment of differences in response to therapy between individuals with and without Down syndrome.
• Use existing clinical trials infrastructure (e.g., NeuroNEXT, NIA’s Alzheimer’s Clinical Trial Consortium, and NCATS-linked institutional networks) to bring agents proposed for use in Alzheimer’s disease that show promise in cognitive improvement in animal models of Down syndrome and related Alzheimer’s dementia to clinical trial in individuals with Down syndrome.
• Use existing networks to explore epilepsy, including dementia-related epilepsy, in aging individuals with Down syndrome, given the peak of epilepsy in adulthood in this group. Studies could range from limited natural history studies in the planning phase to treatment trials in the R33 phase.
• Since more than 50% of individuals with Down syndrome have sleep apnea, a study could provide robust evidence for treatment options, including surgical (e.g., mandibular advancement, tonsillectomy/adenoidectomy), and mechanical (continuous positive airway pressure (CPAP)). Clinical trials could compare individual strategies, or combinations of strategies. In addition to improving hypoxia and sleep, an important question to answer in children is whether effective treatment of obstructive sleep apnea has an influence on future neurocognitive development. Computational modeling of airway flow using data from MRI could help identify optimal trial interventions.
• Exploration of the use of immunosuppression to treat the neuroinflammation and abnormal immune responses in the brains of individuals with Down syndrome or general immune suppression targeted to the dysregulated immune system in those with Down syndrome.

The clinical trial preparatory and/or piloting portion of the research occurs during the R61 phase of the research plan, and implementation and/or clinical trial occurs within the R33 phase. Transition from the R61 phase to the R33 phase is contingent on successful completion of milestones delineated in the application and is subsequently approved by NIH staff (see Section IV.6). At the end of a successful R61/R33, it is expected that there will be measurable and documented advances to address critical health needs related to co-occurring conditions for individuals with Down syndrome.

As an example, in the R61 portion of the application the PD/PI may propose pilot work in which investigators pilot delivery of a hearing intervention to individuals with Down syndrome and hearing loss using a new delivery system. Upon proof of the feasibility of such an approach, the R33 phase would provide funds to perform a clinical trial on a larger population. A second example might be one in which a new technology is developed or refined. Upon completion of the technology development and readiness (R61 phase), the R33 phase would evaluate the utilization of this tool in a larger clinical population. A third example may be one in which in the R61 phase, questionnaires are developed and piloted addressing relevant outcomes for those with Down syndrome and hearing loss. Upon completion, the R33 phase would utilize the questionnaire in a clinical trial.

Studies may include research focused on development or testing new and innovative adaptations of current drugs, interventions, and therapies, for the treatment and management of co-occurring conditions in Down syndrome.

Innovative designs such as platform trials, adaptive, including real-time adaptive methods, seamless Phase I/II designs, and Bayesian designs are encouraged. Decentralized trial elements, including remote informed consent, remote study visits, and wearable or at-home based data collection are also encouraged, as applicable and consistent with the FDA’s Final Guidance on Decentralized Clinicals. 

Investigators are strongly encouraged to contact NIH program staff to ensure that their applications are responsive.

Applications are assigned to participating Institutes and Centers (ICs) based on receipt and referral guidelines, and applications may be assigned to multiple participating ICs with related research interests. Applicants are encouraged to identify a participating IC that supports their area of research and to contact Scientific/Research staff from relevant ICs to inquire about their interest in supporting the proposed research project. IC-specific funding priorities are listed on the INCLUDE website. Questions about the suitability of applications can also be addressed to the scientific/research (program) contact listed in the "Agency Contacts" section of this NOFO.

Projects that propose to recruit subjects with Down syndrome are encouraged to promote enrollment of research subjects in the Down syndrome patient registry supported by NIH, DS-Connect®. For biospecimens collected from human genetic or non-genetic studies, awardees are encouraged to use biorepositories designated by INCLUDE staff that meet requirements for broad sharing. An NIH resource describing Common Data Elements may be helpful during the planning phases of a project when considering ways to optimize data collection in order to facilitate broad data sharing. For those applications that generate clinical data, it is expected that the data sharing plan will include the INCLUDE Data Coordinating Center (DCC).

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

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

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 - Includes all types

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized).

Federal Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Organizations)

Foreign Organizations/International Collaborations

Non-domestic (non-U.S.) Entities (Foreign Organizations) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

NIH will no longer issue awards (i.e., new, renewal, or non-competing continuation) to domestic or foreign entities that involve foreign subawards/subcontracts. All NIH-funded research involving foreign subawards/subcontracts must be submitted in response to a NOFO that is specifically designated for funded international collaborations. See NIH Grants Policy Statement 16.8 Collaborative International Research Awards.

Applications involving foreign subawards/subcontracts submitted in response to this NOFO will be deemed noncompliant and will not be considered for funding. This policy applies to all monetary international collaborations resulting in foreign subawards/subcontracts, however, it does not preclude unfunded international collaborations or foreign components, funding for foreign consultants, or procurement of unique equipment or supplies from foreign vendors.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply- 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications for additional information.

• 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. Foreign organizations must obtain a NATO Commercial and Government Entity (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 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.

All PD(s)/PI(s) must be registered with ORCID. The personal profile associated with the PD(s)/PI(s) eRA Commons account must be linked to a valid ORCID ID. For more information on linking an ORCID ID to an eRA Commons personal profile see the ORCID topic in our eRA Commons online help.

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.

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 How to Apply-Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

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 (in this NOFO, in a policy notice, or other notice from NIH Guide for Grants and Contracts). 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.

Page Limitations

All page limitations described in the How to Apply- Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply- Application Guide and should be used for preparing an application to this NOFO.

SF424(R&R) Cover

All instructions in the How to Apply - Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the How to Apply- Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the How to Apply- Application Guide must be followed.

R&R Budget

All instructions in the How to Apply- Application Guide must be followed.

Budgets should include all costs associated with Data Safety and Monitoring Board (DSMB) activities, including preparing reports for the DSMB, assessing DSMB member conflict of interest, meeting reimbursement for DSMB members, and support for at least one DSMB meeting per year.

R&R Subaward Budget

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the How to Apply - Application Guide must be followed.

PHS 398 Research Plan

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

Research Strategy

The Research Strategy should contain separate subsections that describe the R61 and the R33 phases:

The clinical trial preparatory and/or piloting portion of the research occurs during the R61 phase. This subsection should describe the need for conducting the trial preparatory and/or piloting study activities. Applicants should describe the clinical trial needs (e.g., biomarker or clinical outcomes validation or qualification, feasibility studies, cohort development, etc.) that will be addressed by the R61 phase.

The implementation and/or clinical trial occurs within the R33 phase. This subsection should describe the clinical trial that will be initiated following successful completion of the milestones delineated in the R61 phase.

Milestones and R61/R33 Transition

The application must include milestones the researchers expect to achieve by the end of the R61 phase, as well as milestones for the R33 phase. Milestones should be specific, quantifiable, and scientifically justified; they should not be a restatement of the specific aims for the R61 phase. It is recommended that PD(s)/PI(s) include a section labeled "milestones" describing milestones to be achieved during the R61 phase to qualify for the transition to the R33. It is understood that the proposed milestones for the R33 phase may be revised based on activities during the R61 phase. In the event of an award, the PD(s)/PI(s) and NIH staff will negotiate the list of milestones for each award phase.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply - Application Guide.

 Other Plan(s): 

All instructions in the How to Apply - Application Guide must be followed, with the following additional instructions:

• A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data. Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format should not exceed two (2) pages. Where the DMS Plan Format Page requires a “Yes or No” response, no additional narrative is allowed. 

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply- 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 How to Apply - Application Guide must be followed.

Delayed Onset Study

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

PHS Assignment Request Form

All instructions in the How to Apply- Application Guide must be followed.

Foreign Organizations

Foreign (non-U.S.) organizations must follow policies described in the NIH Grants Policy Statement, and procedures for foreign organizations described throughout the How to Apply- Application Guide.

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

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. 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 How to Apply-Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

Applications must be submitted electronically following the instructions described in the  How to Apply – 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  How to Apply – 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. 

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov.

Post Submission Materials

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

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 scored review criteria and additional review criteria (as applicable for the project proposed). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

As applicable for the project proposed, reviewers will consider the following additional items while determining scientific and technical merit, but will not give criterion scores for these items, and should consider them in providing an overall impact score.

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by Center for Scientific Review, 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.

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

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 NOFO. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov. NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 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.

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

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

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.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

By applying for or accepting federal funds from HHS, recipients certify compliance with all federal antidiscrimination laws and these requirements and that complying with those laws is a material condition of receiving federal funding streams. Recipients are responsible for ensuring subrecipients, contractors, and partners also comply.

Applicants and recipients are strongly encouraged to refer to the NIH Director’s Statement of Priorities, entitled “Advancing NIH’s Mission Through a Unified Strategy.” 

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations. Pursuant to 2 CFR 200.340, by accepting an NIH award, the recipient agrees that continued funding for the award is contingent upon the availability of appropriated funds, recipient satisfactory performance, compliance with the Terms and Conditions of the award, and may also otherwise be terminated, to the extent authorized by law, if the agency determines that the award no longer effectuates the program goals or agency priorities, in line with 2 CFR 200.340(a)(4).

Pursuant to the Cybersecurity Act of 2015, Div. N, § 405, Pub. Law 114-113, 6 USC § 1533(d), the HHS Secretary has established a common set of voluntary, consensus-based, and industry-led guidelines, best practices, methodologies, procedures, and processes.

Successful recipients under this NOFO agree that:

When recipients, subrecipients, or third-party entities have:

• ongoing and consistent access to HHS owned or operated information or operational technology systems; and
• receive, maintain, transmit, store, access, exchange, process, or utilize personal identifiable information (PII) or personal health information (PHI) obtained from the awarding HHS agency for the purposes of executing the award.

Cybersecurity plans and procedures must at minimum include the following:

• Develop cybersecurity plans and procedures, modeled after the NIST Cybersecurity framework, to protect HHS systems and data:
  • Identify:
    • Develop an inventory of all assets and accounts with access to HHS owned and operated information or operational technology systems or which obtain PII or PHI for the purposes of the award.
  • Protect:
    • Limit access to HHS owned and operated systems to only those in need of access to complete reward activities.
    • Require all staff to complete annual cybersecurity and privacy awareness training. Visit 405(d): Knowledge on Demand (hhs.gov) to obtain free trainings, if needed.
    • Enable multifactor authentication for all employees, subrecipients, and third-party entities to access HHS owned and operated information or operational technology systems.
    • Regularly backup sensitive data and test backups.
  • Detect:
    • Install anti-virus or anti-malware software on all devices, servers, and accounts used to connect to HHS owned and operated systems.
  • Respond:
    • Develop an incident response plan. See Incident-Response-Plan-Basics_508c.pdf (cisa.gov) to learn about developing incident response plans.
    • Have cybersecurity incident reporting procedures that ensure the relevant HHS awarding agencies are notified of a cybersecurity incident within 48 hours of discovery. A cybersecurity incident is defined as an unplanned interruption to a technology service or reduction in the quality of a technology service, or an occurrence that actually or potentially jeopardizes the confidentiality, integrity, or availability of an information system or the information the system processes, stores, or transmits.
  • Recover:
    • Investigate incidents and plug any security gaps identified. 

All activities proposed in your application and budget narrative must align with applicable law, including but not limited to statutes, executive orders, federal regulations and applicable judicial holdings.  Accordingly, discretionary awards shall not be used to fund, promote, encourage, subsidize, or facilitate; racial preferences or other forms of racial discrimination by the recipient, including activities where race or intentional proxies for race will be used as a selection criterion for employment or program participation; denial by the recipient of the sex binary in humans, or the belief that sex is a chosen or mutable characteristic; illegal immigration; or any other initiatives that compromise public safety.  If an application does not align, the application will not receive funding to the extent permitted by law and applicable court orders.

For applications involving substance abuse, the application must not support harm reduction. Please see Updated Funding Guidance for Recipients on Supplies and Services.

As of October 1, 2025, HHS has adopted 2 CFR Part 200, with some modifications included in 2 CFR Part 300. These regulations replace those in 45 CFR Part 75. However, for NIH, under the Consolidated Appropriations Act for FY 2026, (P.L. 119-75, Division B, Title II, Sec. 224), the provisions relating to indirect costs in 45 CFR 75 continue to apply to NIH awards. Consistent with the statute, NIH will not apply updated thresholds outlined within 2 CFR Part 200, at this time.

Not Applicable

A Data Management and Sharing Plan (DMS Plan) is required for any NIH-funded or conducted research that will generate scientific data. Applicants must submit the DMS Plan at the time of application using the NIH DMS Plan Format Page. The DMS Plan must address the elements in the structured format should not exceed two (2) pages. Where the DMS Plan Format Page requires a “Yes or No” response, no additional narrative is allowed. 

• 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.
• NIH intends to maximize the impact of INCLUDE-supported projects through broad and rapid data sharing. Consistent with the priorities of the INCLUDE Project, all applications, regardless of the amount of direct costs requested for any one year, are required to include a Data Management and Sharing Plan outlining how scientific data and any accompanying metadata will be managed and shared, regardless of whether the data are used to support scholarly publication. The plan should describe data types, file formats, submission timelines, and standards used in collecting or processing the data. It is expected that all de-identified human data generated by INCLUDE-funded projects will be submitted to NIH-designated repositories in coordination with the INCLUDE Data Coordinating Center (DCC). All applications generating human genomic data should include, as an attachment, an Institutional Certification (https://grants.nih.gov/policy-and-compliance/policy-topics/sharing-policies/gds/institutional-certifications) which indicates the data use limitations and/or modifiers stating how individual level sequence data can be shared with and used by secondary users, under the guidance of the NIH Genomic Data Sharing Policy: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-14-124.html. For more information regarding INCLUDE data sharing, visit https://www.nih.gov/include-project/frequently-asked-questions.

Considerations

To maximize comparisons across datasets or studies, and facilitate data integration and collaboration, applications submitted in response to this RFA are strongly encouraged to incorporate the following standards and resources (where applicable):

• Projects that propose to recruit subjects with DS are encouraged to promote enrollment of research subjects in the DS patient registry supported by NIH, DS-Connect®.
• For biospecimens collected from human genetic or non-genetic studies, researchers are encouraged to use biorepositories designated by INCLUDE staff that meet requirements for broad sharing.
• Applicants are encouraged to ensure that data collected by the study conform to Findable, Accessible, Interoperable, and Reusable (FAIR) principles.
• NIH encourages researchers to explore the use of the HL7 FHIR® (Fast Healthcare Interoperability Resources) standard to capture, integrate, and exchange clinical data for research purposes and to enhance capabilities to share research data (NOT-OD-19-122). The FHIR® standard may be particularly useful in facilitating the flow of data with EHR-based datasets, tools, and applications.
• NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards (NOT-OD-20-146), as they are applicable. Use of the USCDI can complement the FHIR® standard and enable researchers to leverage structured EHR data for research and enable discovery.
• NIH encourages the use of data standards including common data elements, such as those available through the PhenX Toolkit (www.phenxtoolkit.org) and the NIH CDE repository (cde.nlm.nih.gov), terminologies and ontologies such as Mondo Disease Ontology (mondo.monarchinitiative.org), Human Phenotype Ontology (hpo.jax.org), and common data models such as the Observational Medical Outcomes Partnership (OMOP;ohdsi.org).

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 Section 8.4.1 Reporting. To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting.

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 Section 8.6 Closeout. 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 2 CFR Part 200.301.

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.

Grants.gov Support Center - Questions regarding Grants.gov registration and services (e.g., Workspace, subscriptions).

The INCLUDE Project
Email: DownSyndromeINCLUDE@mail.nih.gov

Center for Scientific Review (CSR)
Email: NOFOReviewContact@csr.nih.gov

The INCLUDE Project
Email: DownSyndromeINCLUDE@mail.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 2 CFR Part 200.