This FOA invites applications that propose the comprehensive functional validation of newly identified therapeutic target candidates for Alzheimer's Disease-Related Dementias (ADRD). This FOA seeks to promote critical target validation approaches to help de-risk subsequent translational research and accelerate the advancement of novel therapies for ADRD. Target(s) or molecular pathway(s) to be considered for validation must have been already identified using tissue expression or genetic data generated in human samples. In its initial phase, this FOA provides support for up to two years (UG3 stage) for the development of customized technologies, models, and protocols to modulate the expression or activity of target candidate(s) in cells and/or tissues and monitor their functional biological consequences in in vitro or in vivo disease models. Upon demonstration of technical feasibilities, a second phase (UH3 stage) will carefully and reproducibly measure and cross-validate the impact of the target modulation in different modalities across collaborating laboratories using the NIH rigor and reproducibility guidelines. Applicants responding to this FOA must address objectives for both the UG3 and UH3 phases and are expected to have a substantial collaborative effort between independent laboratories.
This FOA is not specific for any one or group within the ADRD spectrum of disorders. Disorders covered in these applications are frontotemporal degeneration (FTD), Lewy body dementias (LBD) (including dementia with Lewy bodies (DLB)), Parkinson disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), and mixed dementias including the associated diagnostic challenges of multiple etiology dementias (MED).
March 6, 2019
30 days prior to the application due date
May 6, 2019 by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.
No late applications will be accepted for this Funding Opportunity Announcement.
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.
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.
In 2016, NINDS organized a conference on Alzheimer's Disease Related Dementias (ADRDs) which focused on frontotemporal degeneration (FTD), Lewy body dementias (LBD) (including dementia with Lewy bodies (DLB)), Parkinson disease dementia (PDD), vascular contributions to cognitive impairment and dementia (VCID), mixed dementias including the associated diagnostic challenges of multiple etiology dementias (MED), and issues related to health disparities. The conference complemented the National Institute on Aging's "Alzheimer's Disease Research Summit 2015: Path to Treatment and Prevention." Both conferences responded to the National Alzheimer's Project Act that was signed into law in January 2011. The objective of the ADRD conference was to contribute to the efforts directed at preventing and effectively treating Alzheimer's disease, including Alzheimer's disease-related dementias, by 2025. The Alzheimer's Disease-Related Dementias Summit solicited input from internationally recognized experts to develop prioritized recommendations to guide scientific research. This FOA is responsive to those resulting recommendations.
A major obstacle in the development of promising treatments for ADRD and also other CNS disorders is the need for well-validated targets linked to the disease process. Translating these discoveries to the clinic will depend on the quality of the target validation process plus confidence in a causative link between the modulation of a target(s) and its functional physiological consequence(s) associated with treating or preventing a disease state. In addition, partial and incomplete knowledge about the biology of the selected molecular target(s) often limit their chance to translate into successful future drug screening campaigns and drug discovery projects. This FOA provides the opportunity to address these knowledge gaps.
NIH expects that the end goals of this FOA will provide the translational research community with increased confidence in the efficacy and safety of the novel emerging target(s) to trigger the development of customized therapeutic strategies in ADRD. NIH expects the application to be composed of multi-components and multidisciplinary collaborative teams that have scientific expertise in a specific disorder within the ADRD spectrum, technical proficiency in running CNS functional assays/models plus support in statistical design and analysis. Development of the technological tools to modulate the target expression can be executed within the collaborative team or by a contract research organization.
Research Objectives and Scope
The UG3 phase (year 1- year 2) will support activities for the development of customized technology to specifically modulate the expression or activity of target candidate(s) in cells and/or tissue. Preference will be given to applications that propose target validation strategies using both in vitro human cellular model(s) and in vivo animal models. During this time, applicants will develop, in parallel, protocols to monitor the functional consequences of the target modulation in diseased-relevant in in vitro (e.g. electrophysiology in differentiated human iPSC) or in vivo (e.g., behavior, EEG in knock out/transgenic) models. Target-centric as well as phenotypic target-based validation approaches will be considered. The end of this first UG3 phase will be completed by a proof of concept study showing the feasibility of the chosen technological approach. Progress toward UH3 phase and subsequent year award(s) will be milestone-based.
The UH3 phase (up to two additional years) will carefully and reproducibly measure the positive and negative functional impacts of the target modulation in different proposed modalities across collaborating laboratories. This validation process will follow the NIH rigor and reproducibility guidelines.
Applications should include the following key components.
Selection of the target candidate, potential druggability and knowledge gaps
Comprehensive applications will initially include a target identification package that will cover the rationale and supporting experimental data in human for the target selection and its association to the ADRD disease state. Such target identification approaches include, but are not limited to, genetics, genomic, proteomic, metabolomics or other omics-based approaches, system biology, analysis of public literature-big data mining and the bioinformatic tools used to analyze large data sets. A summary of the results should include a description of the experimental protocols and statistical analyses used to assess the rigor and quality of the data linking the target candidate to the pathology of ADRD. A target identification package must be included in the Appendix (see section IV).
Drug screening and discovery efforts are out of scope for this application. Nevertheless, applicatons should address the current knowledge about the biology and potential “druggability” of the selected target and the hypothesized nature of the modulatory interaction that would either mimic or restore to normalcy the physiological abnormality observed in a disease state. Such modulatory interaction(s) could include small molecules, biologics or natural products.
Novel target candidates include, but are not limited to, proteins, lipids, sugar, or nucleic acids. Those targets can commonly be used for a target-centric drug discovery approach but could also be proposed to develop future phenotypic assay(s) and drug discovery strategies. Target(s) for future phenotypic assay(s) and drug screening could include, but are not limited to, indirect read out of the target activity via an engineered reporting system, molecular and metabolic pathways, or cellular and physiological tissue functions. The validation strategy of the “phenotypic target(s)” should demonstrate that its modulation leads to the normalization or impairment of the functional read outs selected to represent respectively the disease or control states in in vitro or in vivo models.
The expected direction and efficacy of the target modulation leading to a therapeutic effect or mimicking a disease state should be discussed to justify the choice of the target validation approaches. In the absence of a strong hypothesis, the application could propose a comprehensive and un-biased target validation strategy that would test both the inhibition and activation of the target in a dose dependent manner.
The application should address and discuss the knowledge gap(s) about the biological function of the target(s) related to the pathophysiology of the ADRD disease state and its therapeutic application. The following describes some examples of questions related to the expected effectiveness of the translational ability of the validation approach. Are the target’s mechanism of action and physiological consequences well understood at different system organizational levels (molecular, metabolic, cellular, tissue, neuronal network and behavior)? How is the target selected and expressed when multiple uncharacterized isoforms or genetic variants are present? Which degree of modulation is expected to reach target-related maximal therapeutic effect(s) while minimizing negative safety side-effect(s)? Does the prevention or mimicking of a disease state require the co-influence of environmental insults and aging process?
Target validation approaches
Comprehensive target validation is a low-throughput process that involves more than a single method or assay. It depends on convergent evidence collected from a variety of studies. Therefore, preference will be given to applications proposing a comprehensive target validation strategy with different but complementary tools and multi-disciplinary in vitro assays and in vivo models. The functional validation strategy should include the technical approaches to be used to modulate the target expression or activity under different modalities and the functional assays/models to monitor their physiological impacts.
First, the selection and description of the target validation tool(s) should be outlined. Examples of tools to modulate the expression of the target or pathway include, but are not limited to, the state-of-the-art gene manipulation methods for genome editing, silencing, knocking out, or knocking in. Examples of tools used to modulate the activity of the target or pathway are antibodies, chemical genomics or pharmacology if specific small molecules or peptides have been previously identified and characterized.
Second, the application should include a description of the models and functional read out(s) selected to monitor the physiological consequences of the modulation of the target expression or activity on cellular, ex vivo or in vivo systems. For in vitro, proposed cellular models should include highly differentiated and organized CNS 2D or 3D cultures in order to replicate some of the relevant disease physiological processes. The use of transformed, immature, immortalized or cancerous cell lines is out of scope. Examples of acceptable cellular models with relevance to the disease mechanism(s) are highly differentiated CNS cultures derived from human induced pluripotent stem cells (iPSCs) or from animals generated with engineered genetic modifications (transgenic, knockout/in, viral infection…). This later example could also represent the main sources for the in vivo animal models. Other animal models using pharmacological and surgical modifications can be also proposed as long as a solid case can be made for their relevance to certain aspects of the disease mechanism(s) or phenotypic exhibition. Examples of physiological read outs include, but are not limited to, measurements of activity of molecular pathway(s), organelle and cellular functions, synaptic and channel electrophysiology, structural and functional imaging, neuronal network activity and animal behaviors, anatomy and safety profiles.
Third, the application should include a description of the different experimental modalities that should be tested in the UH3 phase. Those should include parameters that can achieve comprehensive validation and inform future therapeutic approaches on the optimal level of target tuning or engagement to obtain maximal therapeutic efficacy and minimal adverse effects. Examples of modalities include, but are not limited to, testing a different range of expression levels of the target, time window of modulation, age of onset, various isoforms or genetic variants, or environmental conditions.
All projects will be milestone-driven with clear go/no-go criteria that are quantifiable. Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UG3 and UH3 milestones and any changes suggested by NIH staff or the NIH review panel. The Program Official and the applicant will negotiate and agree on a set of approved UG3 milestones which will be specified in the Notice of Award. These milestones will be the basis for judging the successful completion of the work proposed in the UG3 stage and progress towards interim milestones in the UH3 stage. An administrative review will be conducted by NIH program staff to decide which projects will advance from the UG3 phase to the UH3 phase. Only UG3 projects that meet their milestones will have an opportunity to move to the UH3 phase.
UG3 milestones guidelines:
1. The implementation of the modulatory tools in the in vitro and/or in vivo models should show that the expression or activity levels of the target(s) are measurable and significantly different between the “control” and the “disease” biological samples. The degree and the direction of the target modulation should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.2. Modulation of the target(s) expression or activity in in vitro and/or in vivo models should translate into measurable functional or physiological differences between the “control” and the “disease” biological samples. The degree and the direction of the functional read out modulations should be consistent with the proposed validation and disease hypothesis. Power analysis should address reproducibility and significance of the results.
Before moving to the next UH3 phase, the Program Official and the applicant will negotiate and agree on a final set of UG3 specific-milestones which will be specified in the Notice of Award. UH3 milestones will be the basis for judging progress towards and completion of interim milestones in the UH3 stage.
UH3 milestones guidelines:
Collaborative interactions between interdisciplinary teams are a critical aspect of this FOA. Successful target validation applications will require extensive collaboration among experts. The later would include, but are not limited to, specialists in assay biology and development, CNS cellular models, tissue engineering, ADRD pathophysiology, animal models and behaviors, histopathology, electrophysiology, drug discovery and translational research, bioinformatics and biostatistics. Development of the technological tools to modulate the target expression can be executed within the collaborative team or via a contract research organization. The application should describe how the collaboration between this interdisciplinary team would work in the UG3 and UH3 phases of the grant.
Applicants are encouraged to leverage existing NINDS resources for disorders within the ADRD spectrum. Such resources may include cellular or DNA samples from NINDS BioSEND or other existing biospecimen and data repositories. Human ADRD iPSC resources targeting Frontotemporal Degeneration and Lewy Body Dementia are available through the NINDS Human and Cell Repository (NHCDR). Studies are also encouraged that leverage the resources of cell banks supported through other Federal or private funds.
The following types of studies are non-responsive and will not be reviewed:
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
NINDS intends to fund 2-3 awards up to $2,400,000 in DC in the UG3 phase and $4,000,000 in DC in the UH3 phase.
The UG3 phase is limited to two years. The UH3 phase is limited to two years. The combined phases are limited to 4 years
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
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.
For information on Application Submission and Receipt, visit Frequently Asked Questions – Application Guide, Electronic Submission of Grant Applications.
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:
Pascal Laeng, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
All instructions in the SF424 (R&R) Application Guide must be followed.
PDs/PIs are required to organize an initial face-to-face kick-off meeting at the PI/PD's host institution. Additional virtual project meetings should be scheduled via conference calls to report and discuss the overall progress and challenges of the target validation project. Funds to support travel of the PD(s)/PI(s) and key collaborating team members to attend the kick-off meeting and organize the administrative logistics of the virtual project meetings should be included in the budget.
Define the type of disease within the ADRD spectrum that is considered for this target validation application. Describe a brief history of the target identification main result, the hypothesized biological function of the target in the pathophysiology of the ADRD disease, and the target validation approach. Provide a description of the overall goals or hypotheses for the entire project. Identify the Specific Aims to be accomplished in the UG3 phase and UH3 phase.
Under this FOA, the research strategy should include the following components relevant to the technical tools and protocols to modulate the expression/activity of the target and to monitor their physiological consequences in in vitro assays and/or in vivo models.
Milestones Plan and Progression Metrics
Letters of support
The following modifications also apply:
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.
Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?
Specific to this announcement:
How strong is the target identification package to convincingly link the proposed target to the pathophysiology or symptoms of the disease within the ADRD spectrum? Are the quality and number of human samples, big data search, methods and statistical analysis supportive of the applicant’s conclusions?
Is the proposed target validation approach answering the knowledge gap(s) about the biological function of the target(s) in relation to the pathophysiology of the ADRD disease state and its translational applicability toward a successful therapeutic application?
Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?
Specific to this announcement:
Do the investigators and their key collaborators have the required expertise in the different multi-disciplinary technical and scientific domains, as well as data and analysis, to complete this functional target validation approach successfully?
Are the roles of each investigator clearly defined in the research plan?
Are the investigators knowledgeable and experienced about the biological target and the ADRD disease biology?Are any key letters of support missing?
Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?
Specific to this announcement:
Does the application describe convincing supporting data and evidence for the novelty of the target and its preliminary association to the pathophysiology of ADRD? How innovative are the proposed target and the validation approach?
What is the likelihood that the completion of the target validation research objectives will provide the field with sufficient new technologies (methods, assays, models, functional read outs), knowledge (e.g., optimal degree of target modulation) and confidence to prime the target for translational screening research projects and the discovery of novel therapeutics in ADRD?
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 announcement:
Is each component of the target validation approach (selection of the modulatory tools, physiological read outs, protocols, in vitro and in vivo models, testing of different experimental modalities) well discussed and does each component fit the hypothesized druggability of the target and the proposed mechanisms for the disease and therapeutic intervention? Will the proposed proof of concept experiment (UG3 phase) and the key final target validation results (UH3 phase) be generated with a sufficient number of independent replicates and statistical power? Do the proposed experimental modalities to be tested in the UH3 phase, i) complement the knowledge gap(s) about the target and ii) aim to find optimal conditions for the target modulation to optimize therapeutic and limit negative effects? Is the monitoring of potential negative functional (side effects) read outs included in the application? In case the modulation of the target expression or activity shows positive and potential negative effects on the functional read outs is there a plan to propose an acceptable therapeutic index and path forward toward the development of novel therapeutics?
Is there a plan to address blinding of the samples and scientific rigor to provide high quality data? Are the functional or physiological read outs in the different models fitting the known or hypothesized biological role of the target(s)? Is the approach addressing the target validation in more than one biological system level (molecular and metabolic pathways, cellular, tissue, neuronal circuitry, behavior…)?
For in vitro assay(s) and in vivo model(s):
If models are used for exhibiting mechanistic or phenotypic aspects of the ADRD disease, does the application describe the expected benchmark criteria for the disease and reference control states? If human iPSC lines are generated in the application, are the sources of the biosamples and engineered methods well identified and described? Does the approach to identify functional phenotypic difference(s) between control and disease states address genetic mosaicism and other potential pitfalls from expanding cell lines in vitro? Are feasible alternatives proposed (e.g. multiple lines, isogenic cell lines from genetic isoforms of the target…)?
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?
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?
Are the proposed Go/No Go milestones and the design of the proof of concept experiment(s) for the UG3 phase and the final project deliverables for the UH3 phase clearly outlined, customized and well-timed to the technical challenges of the research approach?
If multiple institutions are proposed, is it clear how intellectual property will be shared or otherwise managed to avoid encumbering the IP, consistent with achieving the goals of the program?
Does the application include a sufficient number of external collaborators with complementary expertise to address the scope and objectives of the research? If this is not the case, do the internal resources (team or institution) of the applicant provide sufficient multi-disciplinary expertise to fulfil all the components (modulatory tools, models, functional read outs) of the research objectives without limiting the overall scope and mission of this FOA?
Does the project management plan communicate and coordinate the logistics effectively between each collaborating members of the team, address progress toward the milestones and potential issues, and incorporate regular meetings (one kick off on site meeting and bi-annual virtual conferences)?
Is the PI proposing to cross-validate some of the key results with a collaborating team in the UH3 phase?
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.
Individuals Across the Lifespan
When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.
The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.
Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.
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), 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.
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights 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.html; and https://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 following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.
The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project, although specific tasks and activities may be shared among the awardees and the NIH as defined below.
The PD(s)/PI(s) will have the primary responsibility for:
Upon completion or termination of the project, ensuring all study materials, tools, models, databases and procedures developed from the project are broadly available (e.g., putting into the public domain) or made accessible to the research community according to the NIH-approved plan submitted for each project, for making data and materials available to the scientific community and the NIH for the conduct of research. The data sharing plan should include a plan to accomplish this within 90 days of the end of the study.
NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
The NIH staff will review the scientific progress and administrative accomplishments of the awardees and review the project for compliance with operating policies and procedures, including meeting and milestones.. Review of progress may include communications between the Principal Investigator and NIH staff, site visits for discussions with research teams, fiscal review, and other relevant matters. The NIH retains the option of organizing external review of progress.
The Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to the NIH Project Officer and Program Officer within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the Principal Investigator and appropriate Project Leaders and will require appropriate acknowledgement of NIH support. Timely publication of major findings is encouraged.
Areas of Joint Responsibility include:
NIH recognizes that intellectual property rights may likely play a role in in this program. To this end, all awardees shall understand and acknowledge the following:
Awardees will retain custody of and have primary rights to the data and resources developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee from the Cures Acceleration Network Review Board chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.
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 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
Pascal Laeng, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
National Institute on Aging (NIA)
Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: (301) 496-9223
National Institute on Aging (NIA)
Tijuanna E. DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
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