Purpose

The purpose of this FOA is to support the development of highly reproducible and translatable in vitro human cell-based ADRD disease models that can be utilized for discovery and validation of translatable biomarkers, development of standardized methods for preclinical efficacy testing and definitive efficacy testing of candidate therapeutics using best practices and rigorous study design. An essential feature will be a multidisciplinary approach that brings together experts in bioengineering, microfluidics, material science, "omic" sciences, computational biology, disease biology, pathology, electrophysiology, pharmacology, biostatistics and clinical science.

Funds from the NIH will be made available through the UG3/UH3 cooperative agreement award mechanism. The initial UG3 phase will support studies to develop and validate in vitro ADRD disease models using tissue chip technologies and iPSC and/or primary tissues derived from patients. The UH3 phase will support studies to demonstrate the functional utility of the disease models for identification of novel treatment mechanisms through better understanding of disease biology, drug screening, assessment of candidate therapies for efficacy and safety assessments, and establishing the pre-clinical foundation that will inform clinical trial design. A UG3 project that meets its milestones will be administratively considered by NINDS and other participating ICs and prioritized for transition to the UH3 award. Applicants responding to this FOA must address objectives for both the UG3 and UH3 phases.

Background

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 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 in the next 5 to 10 years. This FOA addresses the following 2016 ADRD milestones: 1) Multiple etiology Dementias - focus area 2, milestone 5 centered on basic and clinical research in multi-etiology dementias; 2) Lewy Body Dementia - focus area 4, milestone 7 recommends development of in vitro LBD models that recapitulate disease heterogeneity; and 3) Frontotemporal Lobar Degeneration focus area 1 basic science milestone 4 requiring further insight into the pathophysiology related to progranulin, TDP43, FUS, and tau proteinopathies.

The need for next generation human cell models for ADRDs is driven by the failure of new therapeutic candidates in early and late phase clinical trials due to unidentified toxicities and lack of efficacy, respectively. The challenge of accurately predicting drug toxicities and efficacies is in part due to inherent species differences in drug metabolizing enzyme activities and cell-type specific sensitivities to toxicants. To address this challenge in drug development and regulatory science, this FOA supports the development of human three-dimensional cell culture models on bioengineered platforms that mimic in vivo tissue architecture and physiological conditions in order to facilitate and accurately monitor key central nervous system functions. The platforms incorporate complex factors found in vivo, including extracellular scaffolding, three-dimensional structure, cellular interactions (including between different cell types), perfusion, biomechanical stresses (e.g., stretch and shear forces from fluid flow), electrical stimulation of excitable tissue, hormone responses, proteinopathies, etc. Development of 3D human microphysiological systems (MPS) will provide useful tools for predictive toxicology and efficacy assessments of candidate therapeutics.

Research Objectives and Scope

The goal of this FOA is to promote the development of in vitro microphysiological systems that will mimic human ADRD pathophysiologies, to facilitate the assessment of biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents prior to entry into clinical trials.

The ADRD disease models are expected to express critical aspects of human physiology and provide a measurable output for the brain areas affected by disease. Essential characteristics of the disease models should include the following features: 1) multicellular architecture that represents characteristics of brain pathology; 2) functional representation of normal and diseased human biology; 3) reproducible and viable operation under physiological conditions maintained up to 4 weeks in culture; 4) accurate representation of normal and disease phenotypes; and 5) representation of spectrum or heterogeneity of disease presentation. Ideally the platform used should be compatible with high content screening platforms that include multiple molecular read-outs, such as gene expression, proteomic, metabolomic, or epigenomic analyses. The bioengineered platform should also provide spatial and temporal control of the cellular microenvironment, while enabling continuous monitoring (sensing), probing (direct in-cell measurements), and sampling (testing and continuous data collection and analysis) of the system.

The ADRD disease models can be for rare or common diseases, and for monogenic or polygenic diseases. ADRDs include LBD, FTLD, VCI and MED. The primary focus of the UG3 phase will be on developing in vitro disease models using tissue-on-chips technologies. The UG3 phase should also be designed for initial testing of critical experimental parameters, which the applicant will identify as quantifiable milestones (see below). In scope activities for each phase are listed below.

The UG3 phase:

The major goal of this phase is to develop in vitro disease models using stem cells or iPSC-derived patient cell sources on tissues/organ-on-chips platforms. Models should demonstrate a functional representation of healthy and disease states for the brain regions modeled through:

• Determination of the disease-relevance of MPS by preliminary testing of key experimental features and outcomes essential to proceed to the UH3 phase of the study.
• Inclusion of non-invasive endpoints that generate reproducible data under physiological conditions over a long culture period of up to 4 weeks; and representation of disease heterogeneity and/or population diversity.

The UH3 phase:

The major goals are to demonstrate the functional utility of the disease models for drug screening, assessment of candidate therapies for efficacy and safety assessments, and establishing the pre-clinical foundation that will inform clinical trial design. To achieve this, the applications will focus on outcomes that include:

• Cross-validation of disease model end-points with clinical measures in humans.
• Characterization of the parameters of treatment, intervention or response to exposure.
• Developing translatable pharmacodynamics (i.e., target engagement) biomarkers for well validated therapeutic targets.
• Conducting preclinical efficacy testing of candidate therapeutics using innovative approaches, data acquisition and analyses.
• Extensive characterization and clinical-pathological staging of the disease models with the corresponding stages of clinical disease using translatable biomarkers.
• Developing and implementing methods for formal failure analyses of preclinical efficacy studies.
• Developing strategies for rapid, open-access dissemination of data and methodology, and for rapid distribution of disease models for their use in therapy development.

UG3/UH3 Milestones

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 final 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. Only UG3 projects that meet their milestones will have an opportunity to move to the UH3 phase. UH3 milestones will be the basis for judging progress towards and completion of interim milestones in the UH3 stage.

Additional Considerations

Cells: The use of transformed or immortalized cell lines is discouraged, except for preliminary, proof of concept studies. The use of pluripotent stem cells, e.g., iPSC, multipotent, unipotent stem cells or genetically engineered iPSCs is encouraged. The current NIH guidance on stem cell usage can be found at http://stemcells.nih.gov/policy/pages/2009guidelines.aspx. Human ADRD iPSC resources targeting Frontotemporal Degeneration and Lewy Body Dementia are available through the NINDS Human and Cell Repository (NHCDR).

Biomaterials: Native extracellular matrices (ECM) are dynamic, complex microenvironments that can drive functional and biomechanical development. Applicants should consider the biological properties and potential downstream effects when choosing ECM materials. Biomaterials should be chosen to avoid confounding characteristics, e.g., the plastic polydimethylsiloxane (PDMS) binds hydrophobic drugs or reagents, which decreases the intended concentration, and can leach the endocrine disruptor cyclosilane into the medium.

Collaborations: Collaborative interactions are a critical aspect of this FOA. Model system(s) development will require extensive collaboration among tissue engineering/tissue biology experts, disease experts, and clinicians.

The Tissues-on- Chips Consortium (The TC Consortium): The NIH TC for Drug Screening Program utilizes expertise (organ physiology, regulatory science, stem cells, bioengineering, etc.) from experts representing many Institutes, Centers and Offices at the NIH and the FDA. NIH interaction with the IQ Consortium allows for pharmaceutical companies to work with NIH staff and TC Consortium investigators on context of use, marketability and potential stakeholder feedback, elements crucial to move past the discovery/innovation phase. The TC Consortium, which comprises all these partnerships, plus several new industry collaborators, holds an in-person meeting every 6 months and plays a pivotal role in advancing the MPS technology. Awardees from this FOA will be members of the TC Consortium.

Applications that include the following types of studies will be considered non-responsive for this FOA and will not be reviewed:

• Use of human fetal tissue for tissue chip development
• Development of 3D tissues for transplantation
• Engineering of non-human tissue model
• Development of simple organoid models that do not go significantly beyond those currently available and in use.

1. Eligible Applicants

Higher Education Institutions

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

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

• Eligible Agencies of the Federal Government

• U.S. Territory or Possession

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Applicant organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration , but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101)

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Daniel Miller, PhD
National Institute of Neurological Disorders and Stroke,
Telephone: 301-496-5680
Email: [email protected]

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

PDs/PIs are required to attend an initial kick-off meeting and bi-annual Consortium Meetings in the Washington, D.C. area. Funds to support travel of the PD(s)/PI(s) to attend the kick-off and bi-annual Consortium Meetings should be included in the budget.

Specific Aims: Provide the overall goals or hypotheses for the entire project period and identify separate Specific Aims to be accomplished in the UG3 phase and in the UH3 phase.

Research Strategy:

• Must provide separate sections that describe both the UG3 and UH3 phases
• Must provide a description of the hypothesis to be tested in the UH3 phase of the study
• Must include the use of cutting edge engineering and cell biology technologies in design of the tissue chip models.

Go/No-Go Transition Milestone for transition from the UG3 Phase to the UH3 Phase

• Must include a clearly identified Go/No-Go transition milestone for completion of the UG3 phase at the end of Year 2 and transition to the UH3 phase for 3 years of additional funding.
• A timeline (Gantt chart) including milestones is required for all studies. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years.

Milestones and the timeline for each stage must be provided in a separate heading at the end of the approach section for each UG3 and UH3 component and include the following.

• Provide detailed quantitative criteria by which milestone achievement will be assessed.
• Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal.
• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, must address a Data Sharing Plan.

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.

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

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

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday , the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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 nonresponsive will not be reviewed.

1. Criteria

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

For this particular announcement, note the following:

The UG3/UH3 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. A UG3/UH3 grant application is not required to have extensive preliminary data, background material or preliminary information, but these may be included if available. Appropriate justification for the proposed work can also be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes the UG3 and UH3 phases.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Is strong justification/rationale provided for potential translational benefit derived from the use of the proposed disease models? How well will the created disease models be able to recapitulate specific alleles and genomic, proteomic, metabolomic and other biological indicators of the disease(s) of interest? Does the application focus on critical gaps to address important questions or obstacles in the particular diseases of interests, as defined by the 2016 ADRD Summit recommendations? Will successful completion of the research aims promote the understanding of disease pathogenesis and advance the development of diagnostics and interventions?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Have project leadership and other key personnel demonstrated a record of directing research activities related to creating and validating models of disease? Are the collaborations, in particular from disease experts and/or patient groups, well-documented, including provision of letters of support ? Does the application provide a feasible strategy for collaboration among the scientific fields relevant to this FOA, i.e. disease experts, clinicians, tissue chip developers?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Are the overall goals of the application conducive to generating significant multidisciplinary investigations that respond to the overall objectives of the FOA, i.e., generating novel models for studies of human diseases that will advance basic and translational science and/or therapy development? Does the project utilize cutting edge technologies, such as recent advances in genome editing? Are the tissue chip platform and cells being proposed suitable to capture the features for the disease?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project ? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

Not Applicable.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

• Will receive a written critique.

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

3. Anticipated Announcement and Award Dates

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

1. Award Notices

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.

2. Administrative and National Policy Requirements

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 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 as a whole, 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:

• Defining the details and goals of the project as a whole within the guidelines of this FOA.
• Determining experimental approaches, designing protocols, setting project milestones and conducting experiments
• Adhering to the NIH policies regarding intellectual property, data release and other policies that might be established during the course of this activity
• Accepting and implementing any other common guidelines and procedures developed by the Tissue Chip Consortium
• Organizing and participating in monthly webinars with NIH program staff
• Accepting and participating in the highly collaborative nature of the NIH Tissue Chips program
• Attending bi-annual workshops organized by the NIH
• Managing all data acquired in a coherent database that will be available to government and private partners.
• Coordinating, cooperating, and participating with NIH staff in the scientific, technical, and administrative management.
• Identifying and maintaining infrastructure and collaborations needed to support the development of the proposed disease model(s).
• When needed, working with private partners to acquire and maintain reference compounds that industry partners will provide.
• Working with NIH Program Officials and industry partners to establish context of use, standardizing and validating approaches.
• Performing established standardization and validation milestones.
• Ensuring that all affiliated staff will maintain the confidentiality of the information developed by the investigations, including, without limitation, informatics tools, protocols, data analysis, conclusions, etc. per policies approved by the consortium as well as any confidential information received by third party collaborators.
• Analyzing, publishing and/or publicly releasing and disseminating results, data and other products of the study in a timely manner, concordant with the approved plan for making quality-assured data and materials available to the scientific community and the NIH, consistent with NIH policies and goals of the FOA.
• Participating in a cooperative and interactive manner with NIH staff, TC investigators and one another.
• Sharing data, materials, informatics tools, methods, information and unique resources that are generated by the project as appropriate and in accordance with NIH policies in order to facilitate progress and consistent with achieving the goals of the MPS program.
• Ensuring that for activities that involve academic and/or industry collaborations within and outside the TC Consortium there are appropriate research collaboration agreements (e.g. CRA, CDA, MTA etc.) with terms that ensure the collaboration is conducted in accordance with the Cooperative Agreement terms of award as well as any additional applicable NIH policies and procedures.
• Ensuring that the research is conducted in accordance with processes and goals as delineated in this Funding Opportunity Announcement.

Upon completion or termination of the project, ensuring all study materials, tools, 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:

• Coordinate and facilitate the activities of the program, attend and participate in all meetings of the Tissue Chip consortium
• Work with Project Scientists from the trans-NIH TC Project Team, to review the scientific progress and administrative accomplishments of the awardees, and review the project for compliance with operating policies and procedures, including meeting milestones. Based on this review, the Program Officer may recommend to the NIH to continue funding, or to withhold or restrict support for lack of progress or failure to adhere to NIH policies. Review of progress may include regular communications between the Principal Investigator and NIH staff, periodic site visits for discussions with research teams, fiscal review, and other relevant matters. The NIH retains the option of organizing periodic external review of progress.
• Prepare up-to-date summaries of program accomplishments based on manuscripts provided by the awardee within two weeks of acceptance for publication
• Participate in the process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols, project milestones or approaches as warranted.
• Coordinate the efforts of the awardee with others engaged in microphysiological systems research, including other awardees under this FOA and those awardees involved in related NIH programs;
• Attend all NIH Tissue Chips Project Team meetings and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action;
• Work directly with industry and regulatory partners on maintaining or modifying standardized protocols to test MPS devices
• Provide input into the design of research activities and play a key role in coordinating research efforts.
• Monitor milestone progress and help identify recourses if needed
• Ensure that the awarded project(s) adhere to cooperative agreement data-sharing and other resource-sharing policies.
• Facilitate collaborations with and access to other NIH-supported research resources and services.
• Provide advice on project management and technical performance.
• The NIH reserves the right to curtail or phase out the award in the event of (1) a substantial shortfall in accomplishing the management goals and responsibilities as stated in the reviewed application, (2) failure to meet procedures and milestones, and/or (3) substantive changes in the management of award(s) that are not in keeping with the objectives of the FOA.

Publications

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 Scientist within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the 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:

• Collectively awardee(s) and the Project Scientist will determine criteria and processes for quality control of information and data to be posted for the research community, consistent with NIH policies and achieving the goals of the program as described in this Funding Opportunity Announcement.
• Participate in recurring monthly meetings to discuss progress, obstacles and any other TC-related issues and/or activities.

Intellectual Property

The successful development of disease models using microphysiological systems platform and the integration of these microsystems within a common platform may require either substantial investment and support by private sector industries, and/or may involve collaborations with other organizations such as academic, other government agencies, and/or non-profit research institutions not directly involved in the NIH-funded Tissue Chips Program. NIH recognizes that intellectual property rights are likely to play an important role in achieving the goals of this program. To this end, all awardees shall understand and acknowledge the following:

• The awardee is solely responsible for the timely acquisition of all appropriate proprietary rights, including intellectual property rights, and all materials needed for the applicant to perform the project.
• Before, during, and subsequent to the award, the U.S. Government is not required to obtain for the awardee any proprietary rights, including intellectual property rights, or any materials needed by the awardee to perform the project.
• The awardee is required to report to the U.S. Government all inventions made in the performance of the project, as specified by 35 U.S.C. Sect. 202 (Bayh-Dole Act).

Data

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.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel 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.

3. Reporting

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.

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Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
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Daniel Miller, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: [email protected]

Debra Babcock, MD, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
Email: [email protected]

Patrick Bellgowan, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1447
Email:[email protected]

Amelie Gubitz, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email:[email protected]

Danilo Tagle, PhD
?National Center for Advancing Translational Sciences (NCATS)
?Telephone: 301-594-8064
?Email:[email protected]

?Bradley Wise, PhD
?National Institute on Aging (NIA)
?Telephone: 301-496-9350
?Email: [email protected]

Carole Jelsema, PhD
Division of Neuroscience, Development and Aging, DNDA, Molecular, Cellular and Developmental Neuroscience MDCN
Telephone: 301-435-1248
Email: [email protected]

Tijuanna E. DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email:[email protected]

Richard Proper
?National Institute on Aging (NIA)
?Telephone: 301-402-7735
?Email: [email protected]