National Heart, Lung, and Blood Institute (NHLBI)
National Institute on Aging (NIA)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute on Deafness and Other Communication Disorders (NIDCD)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute of Nursing Research (NINR)
National Institute on Minority Health and Health Disparities (NIMHD)
Re-issue of RFA-OD-19-018
July 26, 2019- Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-128
August 23, 2019- Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137
NOT-OD-20-012 Notice of Intent to Publish Funding Opportunity Announcements in Fiscal Year 2020 for the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project
NOT-OD-20-017 Notice of Special Interest to Encourage Development of Animal Models and Related Biological Materials for Research Related to Down Syndrome
NOT-OD-20-020 Notice of Special Interest (NOSI): Ruth L. Kirschstein National Research Service Award (NRSA) Fellowship Awards to Support Training in Research Related to Down Syndrome as Part of the INCLUDE Project
NOT-OD-20-021 Notice of Special Interest (NOSI): Mentored Career Development Awards To Support Training in Research Related to Down Syndrome as Part of the INCLUDE Project
NOT-OD-20-022 Notice of Special Interest: Administrative Supplements for the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project to NIH-funded K12 and KL2 Institutional Career Development Awards
NOT-OD-20-023 Notice of Special Interest: Availability of Competitive Supplements/Revisions for the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndromE) Project (Competitive Supplement/Revision Clinical Trial Optional)
NOT-OD-20-024 Notice of Special Interest: Availability of Administrative Supplements for the INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) Project
NOT-OD-20-025 Notice of Special Interest: NIH Research Project Grants on Down Syndrome (R01)
93.310, 93.213, 93.838, 93.837, 93.839, 93.840, 93.233, 93.866, 93.846, 93.865, 93.173, 93.121, 93.307, 93.853, 93.361
This Funding Opportunity Announcement (FOA) encourages Exploratory/Developmental Phased Innovation (R61/R33) grant applications to support development of clinical trials to treat critical and co-occurring health conditions in individuals with Down syndrome. The proposed research aims should be milestone-driven. The total project period for an application submitted in response to this FOA may not exceed five years. This FOA provides support for up to two years (R61 phase) for preliminary/developmental/planning studies, followed by possible transition to clinical trial support (R33) of up to three years, although the total duration of the award may not exceed five years. This FOA requires measurable R61 milestones.
December 13, 2019
30 days prior to the application due date
February 14, 2020, November 3, 2020, November 3, 2021
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
June 2020, March 2021, March 2022
August 2020, May 2021, May 2022
September 2020, July 2021, July 2022
Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions.
Applications that do not comply with these instructions may be delayed or not accepted for review.
This FOA 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 FOA 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 FOA. Since some aspects of this research area are new for the trans-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. Applications that require a significant investment of resources for development of clinical outcome assessments, biomarkers, or limited natural history data may be submitted under the “Down Syndrome Clinical Trial Readiness FOA (RFA-OD-20-004).” Those that are more basic science focused may be more appropriate for RFA-OD-20-005? "Transformative Research Award for the INCLUDE (Investigation of Co-occurring Conditions across the Lifespan to Understand Down syndrome) Project (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).
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.
Down syndrome is associated with intellectual disability, an increased prevalence of autism and epilepsy, and Hirschsprung’s disease. About 75% of individuals experience cognitive decline in a syndrome that resembles Alzheimer’s disease but has its 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 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. Children with Down syndrome have more severe respiratory infections and acute respiratory distress syndrome, yet the mortality from these conditions is lower in Down syndrome. 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 FOA is one of several trans-NIH research initiatives created in response to Fiscal Year 2018 Omnibus Appropriations Report that provides NIH the opportunity to not only expand its current efforts on Down syndrome and common co-occurring conditions also seen in the general population, but also to build integrated efforts across NIH that will be transformative in these areas. This initiative is known as the INCLUDE Project (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE), and a description of the research plan and its three components is available (https://www.nih.gov/include-project)
This new research initiative expands many of the research objectives and opportunities previously highlighted in the 2014 Down Syndrome Directions: NIH Research Plan on Down Syndrome. More recent discoveries have enhanced our understanding of chromosome segregation and chromosome silencing, identified certain proteins and neurotropic factors involved in brain development using mouse models, and uncovered the role of interferons in immune dysregulation, each of which have the potential to lead to development of novel therapies for individuals with Down syndrome, as well as broader applications. People with Down syndrome are often excluded from clinical research, such as trials of potentially beneficial drugs and therapeutics that are used to treat the same condition in the general population. There is great value in connecting people with Down syndrome to therapies that could improve their overall health and quality of life. And there is great interest in the Down syndrome community in participating in clinical research, based on experience from NICHD’s “DS-Connect®: The Down Syndrome Registry,” (https://DSConnect.nih.gov), an online survey tool that introduces individuals with Down syndrome and their families to research opportunities. A comprehensive clinical cohort study with deep phenotyping and exploration of pan-‘omics' will permit identification of biomarkers and outcomes for the co-occurring conditions in Down syndrome. Coupled with development of a clinical trials readiness program, and informed by basic science discoveries, this combination of resources could have a great impact on addressing health disparities that exist for people with Down syndrome and could also lead to the development of therapies to improve outcomes for those with and without the condition.
For a list of projects funded in FY2018 and 2019, see https://www.nih.gov/include-project/funding.
The purpose of this FOA is to encourage research and increase infrastructure support to address component 3 of the INCLUDE project, namely to promote 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 to work 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); and (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:
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.
Questions about the suitability of applications should be addressed to the research/scientific (program) contact listed in the "Agency Contacts" section. Investigators are strongly encouraged to contact NIH program staff to ensure that their applications are responsive.
Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.
The NIH intends to commit total costs of at least $4,000,000 in FY2020 to fund up to 4 awards.
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications. Future year amounts will depend on annual appropriations.
Application budgets for the R61 phase and the R33 phase are not limited but need to reflect the actual needs of the proposed project.
The scope of the proposed project should determine the project period. The maximum period of the combined R61 and R33 phases is 5 years, with up to 2 years for the R61 phase and up to 3 years for the R33 phase. Applications with a project period less than 5 years are encouraged where feasible.
Higher Education Institutions
The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:
Nonprofits Other Than Institutions of Higher Education
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
The letter of intent should be sent to:
All instructions in the SF424 (R&R) 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.
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.
Letters of Support
Provide letters of collaboration from individuals who will contribute in a substantive, meaningful way to the scientific development or execution of the project, whether or not salaries are requested. As appropriate, letters should document access to expertise, equipment and/or patients .
For ancillary studies, provide a letter of support from the PD/PI of the parent study that includes:
The following modifications also apply:
All applications, regardless of the amount of direct costs requested for any one year, should include a Data Sharing Plan. The Data Sharing Plan will be considered during peer review and by program staff as award decisions are being made as appropriate and consistent with achieving the goals of the program. It is expected that the results of INCLUDE-funded research will be shared with the wider scientific community in a timely manner.
NIH intends to maximize the availability of publications and the sharing of underlying data and biospecimens for Investigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE)-supported supplements and projects. Under the goals of INCLUDE, recipients are required to develop a Public Access and Data Sharing and Management Plan that (1) describes their proposed process for making resulting publications and biospecimens, and to the extent possible, the underlying primary data immediately and broadly available to the public; (2) if applicable, provides a justification to NIH if such sharing is not possible. Underlying primary data should be made as widely and freely available as possible while safeguarding the privacy of participants and protecting confidential and proprietary data.
All applications involving human subjects should address a Data Sharing Plan and include an Institutional Certification which indicates the data use limitations and/or modifiers stating how individual level 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. Applicants are expected to agree that all sequence data generated by INCLUDE studies and related phenotype data will be deposited in repositories designated by the INCLUDE staff, in a manner consistent with NIH policy http://grants.nih.gov/grants/policy/data_sharing/ and achieving the goals of the INCLUDE Project. For autism-related data, awardees are required to deposit their data in the NIMH Data Archive (https://ndar.nih.gov/). 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® (https://DSConnect.nih.gov/). For other data and biospecimens from human genetic or non-genetic studies, awardees are encouraged to use the NICHD Data and Specimen Hub “DASH” (https://dash.nichd.nih.gov) or other equivalent broad-sharing data and/or biospecimen repositories.
The following 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: https://www.nlm.nih.gov/cde/.
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.
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.
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov
Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or non-responsive will not be reviewed.
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.
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?
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?
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?
How strong is the design/research plan regarding innovative elements, as appropriate, that enhance its sensitivity, potential for information, or potential to advance scientific knowledge or clinical practice?
Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?
Specific to this FOA:
To what extent are the listed milestones for each phase appropriate for the goals of the project? To what extent are the milestones specific, quantifiable, and scientifically justified?
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:
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?
Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?
Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?
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?
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)?
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.
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
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).
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).
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.
Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the 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.
Information regarding the disposition of applications is available 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 grantee’s business official.
Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.
Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.
Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.
ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov ). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm
Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.
Data and Safety Monitoring Requirements: A data and safety monitoring board is required for applications responding to this FOA. 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. A data and safety monitoring board is required 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).
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. 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.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.
In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 – Award Term and Conditions for Recipient Integrity and Performance Matters.
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Please direct inquiries related to specific interests of the participating NIH Institutes and Centers to the IC contacts listed on the INCLUDE Project website.
Grants Management Branch
Eunice Kennedy Shriver National Institute of Child Health and Human Development
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