It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). 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.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Purpose

The purpose of this FOA is to leverage the capabilities of the NCATS 3-D Tissue Bioprinting Program through collaborations with academic investigators in the basic and clinical research communities who provide the disease and tissue physiology expertise necessary to develop and validate biofabricated tissues. Through these partnerships, the process of discovery and development of new medicines can be greatly advanced by developing new assay models that better predict the effects of drugs in humans. 3-D tissue models that mimic characteristics of live human tissues are produced on microplates to test effectiveness and toxicity of small molecules or other therapeutics.

This FOA will support development and screening of 3D tissue models of pain, addiction and overdose in multi-well plate format with endpoint assays compatible with the biofabrication and high-throughput screening (HTS) capabilities available at NCATS 3D Bioprinting Laboratory, a component of the NCATS 3D Bioprinting Program. An essential feature of funded projects will be a multidisciplinary approach that brings together experts in pain, opioid use disorders (OUD) and/or overdose with bioengineering, microfluidics, material science, "omic" sciences, computational biology, disease biology, pathology, electrophysiology, pharmacology, biostatistics and clinical science.

This study is part of the of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at: https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.

Public Law 115-141, the Consolidated Appropriations Act of 2018 (signed March 23, 2018) includes a requirement that grantees from for-profit applicant organizations must provide a 50% match and/or in-kind contribution of all federally awarded dollars under the grant award (direct costs, as well as facilities and administrative costs) for research related to opioid addiction, development of opioid alternatives, pain management and addiction treatment.

Matching Requirement: A grantee from a for-profit organization funded under this funding opportunity announcement must match funds or provide documented in-kind contributions at a rate of not less than 50% of the total-Federally awarded amount, as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018.The applicant will be required to demonstrate that matching funds and/or in-kind contributions are committed or available at the time of, and for the duration of, the award. Applications must identify the source and amount of funds proposed to meet the matching requirement and how the value for in-kind contributions was determined. All matching funds and/or in-kind contributions must be used for the portion of allowable project costs not paid by Federal funds under the grant award. NIH will not be the recipient, nor serve as a pass-through entity, of any such matching funds and/or in-kind contributions required under this announcement. See 45 CFR 75.306 for additional details.

As part of the NIH HEAL initiative, funds from the NIH will be made available through the UH2/UH3 bi-phasic cooperative agreement award mechanism. The initial UH2 development phase will support studies to develop and demonstrate functional validation of physiologically relevant human cells and tissues that can model the mechanisms or effects of nociception/pain-relevant signaling, opioid use disorder and overdose, and/or their respective therapies and treatments. The UH3 implementation phase will support studies to develop high density screening platforms on microplates seeded with the tissue constructs developed during the UH2 phase and develop relevant assays for screening novel therapeutics for nociception, opioid use disorder and/or overdose. A UH2 project that meets its milestones will be administratively considered by NIH program staff and prioritized for transition to the UH3 award. Applicants responding to this FOA must address objectives for both the UH2 and UH3 phases.

Background

More than 25 million Americans suffer from daily chronic pain which can result in an overreliance in the use of opioids for relief from chronic pain despite their poor ability to improve function. This has contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative scientific solutions to develop alternative treatment options are thus critically needed.

Recent advances in the fields of engineering, biomaterials science, stem cell biology, physics and medicine have enabled the field of 3-D bioprinting of living tissues. Living cells and scaffolding materials can now be combined into complex 3-D functional tissues produced on microplates (tissue-in-a-well), which are used in pre-clinical drug testing. These tissues are created using either induced pluripotent stem cells (iPSCs) or primary cells taken directly from living tissue. The goal of creating 3-D bioprinted human-like tissues in microplate format for screening is to provide physiological and pharmacological data that predict the effects of drugs better than data from traditional studies using 2-D models. Having access to these 3-D human tissue models could reduce and potentially eliminate animal testing. In addition, these models will have an immediate and long-lasting impact on reducing the cost of drug discovery as well as shortening the time it takes to bring new medicines to more patients.

However, current in vitro assays and in vivo models to study nociception, opioid use disorder and/or overdose and test potential treatments are very limited. Pharmacological probe, lead, and drug development have traditionally utilized canonical cell lines (such as CHO or HEK293) that heterologously express the molecular target of interest, and studies that are performed in animal models often do not fully recapitulate human physiology and may identify candidate compounds that are ineffective in systems that are more relevant to human physiology. While there is a lot of focus on utilizing iPSC-derived models that are amendable to high-throughput screening, such models lack the 3D multicellular structure of native tissue. Therefore, this initiative aims to use 3D biofabrication approaches to develop novel tissue-in-a-well models of nociception, opioid use disorder and/or overdose and facilitate discovery of novel, non-addictive drugs to treat these conditions. 3D biofabricated tissue models supported through this initiative may include but are not limited to normal and diseased human iPSC-derived: sensory/pain neurons (such as peripheral, dorsal root ganglia (DRG), spinal cord, thalamus); neurons relevant to reward pathways; the blood-brain barrier (BBB) and other tissues relevant to pain, opioid use disorder and/or overdose.

As indicated above, this FOA is part of The Helping to End Addiction Long-term (HEAL) Initiative, a trans-NIH effort launched in April 2018 to advance national priorities in addressing the opioid crisis through science. As part of the HEAL Initiative, NCATS goal is to:

• Develop new testing platforms that more closely model human biology of pain, opioid use disorder and/or overdose than currently available cell and animal models, using induced pluripotent stem cells (iPSCs), tissue chips and 3-D tissue biofabrication.
• Identify and de-risk potential drugs that work in novel ways through development of assays (tests), high-throughput screening and optimization of promising compounds.
• Advance promising new drug candidates through rigorous pre-clinical efficacy and safety studies for first-in-human clinical trials as required by the Food and Drug Administration (FDA).

Leveraging Existing Research Resources:

Applicants are strongly encouraged to leverage existing research resources for their studies whenever possible. Applicants are required to utilize the state-of-the-art capabilities at NCATS in support of HEAL initiatives. A detailed description of the capabilities related to HEAL can be found at: https://ncats.nih.gov/heal/intramural-capabilities. In addition, leveraging the resources and support from pain advocacy groups, private research foundations, academic institutions, other government agencies and the NIH Intramural program is also encouraged.

NCATS 3D Bioprinting Laboratory

This FOA requires partnerships between intramural investigators at the NCATS 3D Bioprinting Laboratory, a participant in the HEAL initiative, and extramural researchers. The objective of the 3D Tissue Bioprinting Laboratory at NCATS is to produce 3D tissue models in multi-well plate platforms as disease relevant assays for drug screening. 3D tissue models are biofabricated using tissue engineering and 3D bioprinting technologies with human primary and iPSC derived cells; morphologically and physiologically validated; and relevant disease phenotypic detection endpoints developed that are compatible with HTS capabilities at NCATS for drug screening.

NCATS has unique libraries of pharmacological agents, including approved drugs and mechanistically annotated compounds, which will be used to pharmacologically benchmark the 3D biofabricated tissue models, as well as to repurpose existing drugs and/or understand the pharmacology underlying diseases (https://ncats.nih.gov/preclinical/core/compound).

For projects supported under this FOA, the external research community will provide expertise in developing specific disease models and disease-relevant assays in low-throughput format. The NCATS 3D Bioprinting Laboratory will provide expertise in integrating 3D biofabrication technologies such as engineering, 3D bioprinters and biocompatible polymers and hydrogels, with phenotypic assay models that are compatible with HTS platforms to enable the use of 3D tissue models for drug screening.

Prior Consultation

Applicants are strongly encouraged to consult with NCATS Extramural Program Staff early on during the planning of an application. This early contact will provide an opportunity to discuss and clarify NIH policies and guidelines, including the scope of the project relative to the HEAL initiative mission and intent of this FOA.

Potential applicants are required to obtain a letter of support that documents the collaboration from the Scientific Director of NCATS Division of Preclinical Innovation to be included in their application. For additional information, see the NCATS Bioprinting Laboratory at https://ncats.nih.gov/bioprinting and Letters of Support section below.

Research Objectives

Research Scope

For this FOA, the focus is to develop 3D tissue models for drug discovery and development of new pain, addiction and overdose therapeutics. Extramural investigators will collaborate with the NCATS 3D Bioprinting Laboratory to biofabricate 3D functional tissues using human cells derived from iPS cells in a multi-well plate format together with a relevant HTS-compatible detection endpoints. NCATS integrates 3D biofabrication technologies such as tissue engineering, 3D bioprinters and biocompatible polymers and hydrogels, with phenotypic detection methods that are compatible with HTS platforms such as cell imaging to enable the use of 3D tissue models for drug screening. NCATS capabilities include the biofabrication of functionally and physiologically disease-relevant multi-well plate assay platforms to increase the throughput of drug testing and to create models that are better predictors of human response to new drugs. Specifically, this FOA is looking for collaborations which leverage both the NCATS biofabrication and screening capabilities and the collaborators own internal capabilities for:

• Biofabricating of morphologically and physiologically validated 3D tissues models of pain, addiction and overdose in multi-well plate format
• Scaling up production of iPS cell-derived relevant cells needed to prepare the 3D tissue models for screening
• Developing protocols for fast, high throughput quantitative measurements from the 3D tissues including fluorescence and luminesce cell imaging, and other HTS compatible assay endpoints (e.g. biomolecule measurements from supernatant by ELISA-type or mass spectrometry assays, TEER, Ca2+ flux)
• Screening of drugs libraries in the biofabricated 3D tissue-in-a-well relevant models
• Testing compounds in 3D neurovasculature unit (blood-brain-barrier) models, both for permeability and pharmacological effects on disease phenotypes

3D biofabricated tissue models supported through this initiative may include but are not limited to: normal and diseased human iPSC-derived sensory/pain neurons (such as peripheral, dorsal root ganglia (DRG), spinal cord, and thalamus); neurons relevant to reward pathways; and other tissues important for pain, addiction and overdose.

Phased Innovation Awards

This FOA will use the UH2/UH3 bi-phasic, innovation award mechanism to fund exploratory and developmental research. During the UH2 Phase, support will be provided for the biofabrication of morphologically and physiologically validated 3D tissue models of pain, addiction and overdose.

During the UH2 phase, applicants are expected to:

• Develop a morphologically and physiologically validated tissue in a multi-well platform (at least 6-well plate), including thorough validation of the control and disease tissues using established techniques such as histology, or cell imaging in order to demonstrate appropriate overall architecture, cell composition, tissue markers, disease markers, and utilization of known modulators of relevant pathways or targets to demonstrate correct tissue physiology and appropriate pharmacological responses, in a multi-well platform ( at least 6-well plate).
• Validate the model based on established genetic and protein markers of control normal and disease tissue; appropriate architectural features by histology or cell imaging; appropriate function of relevant cells (e.g. neuronal potential or Ca2+ flux measurements; barrier function assays); and appropriate pharmacological responses based on known modulators of relevant pathways or targets.
• Establish robust and reproducible protocols for the production of primary or iPSC-derived cells needed for the biofabrication of the tissue.
• Develop and establish a robust disease relevant endpoint assay that is HTS compatible
• Establish reproducibility and robustness of the endpoint assays developed with the 3D tissue model

The above activities will be primarily performed in the laboratory of extramural investigator (s). The role of NCATS 3D Bioprinting Laboratory during the UH2 phase will be to provide additional expertise relevant to biofabrication and assay development and drug screening.

UH2 projects that have met the scientific milestones and technical requirements (see below) will be eligible for transition to the UH3 Phase after NIH administrative review (two projects maximum for UH3 phase). The criteria to determine whether a UH2 project will be continued into the UH3 Phase will be negotiated between the NIH and applicant prior to funding, and include the:

• Technical readiness of the assay for adaptation to HTS at NCATS
• Successful achievement of the defined milestones for the UH2 Phase of the project
• Potential for meeting the goals of the Initiative
• The availability of funds
• Program priorities

Organoids are within scope both as a screening platform as well as if included in the context of a biofabricated tissue. Tissue-in-a-chip device in a microtiter plate format can be included if they have open access to 3D bioprinters for tissue bioprinting and are commercially available and amenable to detection endpoints commonly used at NCATS for HTS (https://ncats.nih.gov/bioprinting). These approaches should be discussed with the investigators at NCATS 3D Bioprinting Laboratory before submission.

The UH3 Phase involves activities in both intramural and extramural laboratories. NCATS intramural scientists will work towards the adaptation of the 3D tissue models and endpoint assays to a drug screening platform and implementation of screens of up to 1000 compounds. Extramural investigator(s) will work towards validation of any active compounds from the screens in additional in vitro and in vivo assays relevant to pain, opioid use disorder and/or overdose.

Activities supported during the UH3 Phase may include, but are not limited to:

• Adapting biofabrication and detection assay protocols to NCATS screening capabilities at the 3D Bioprinting Laboratory.
• Screening libraries of compounds; cheminformatics analysis of the results at NCATS. Compounds for screening will be selected following close consultations between PD/PIs and NCATS Bioprinting Laboratory and depend on the type of assay, biology and scope of the project.
• NCATS will provide compounds to extramural investigator(s) for additional validation.

The goal of the UH3 phase is to be able to screen up to 1000 compounds at one compound dose per assay to pharmacologically, validate the 3D disease tissue models (establish effect of known modulators), and to identify compounds that modulate the relevant phenotypes for pain, addiction and overdose. The libraries screened will include compounds with annotated target and mechanism of action and approved drugs for drug repurposing screening (https://ncats.nih.gov/preclinical/core/compound). NCATS is also interested in exploring the screening of diversity collections and using artificial intelligence (AI) approaches for lead identification and structure activity relationship (SAR) studies using medicinal chemistry. NCATS has the capability to select and assemble customized library of compounds for screening.

Technical readiness of the 3D disease tissue model assays. It is expected that 3D Tissue disease model assays will have been configured and characterized in a multi-well plate format (at least 6-well plate) by extramural investigator(s) with advice from NCATS scientists and can be rapidly adapted to the biofabrication and screening capabilities at the NCATS. Technical readiness of the 3D tissue models and detection readouts for drug screening will be demonstrated by:

• Morphological and physiological validation of the tissues using established techniques such as histology (to demonstrate appropriate overall architecture, cell composition, tissue markers, disease markers), and other technologies to demonstrate correct tissue physiology depending on the tissue function
• A disease phenotype detection endpoint that is compatible with a multiwell-based (24- or higher, well density) plate format that is amenable for use with HTS liquid handlers and readers; and it is robust for compound screening (meets the doable criteria by established HTS robustness criteria like Z-factor, a calculated parameter that is commonly used to quantify assay performance, and it accounts for both the signal-to-background and the amount of variability in the assay between the control and disease states). Examples of HTS compatible assay readouts include high content imaging with cellular reporters or immunostaining, detection of biomolecules form supernatant using ELISA-like methods or mass spectrometry technologies, cell viability, Ca2+ flux, multi electrode arrays, and transepithelial/transendothelial electrical resistance (TEER) measurements.

Assays that require manual tissue processing and transferring to different platform for assaying (e.g. histology) most likely will not be HTS compatible but should be discussed with the investigators at NCATS 3D Bioprinting Laboratory before submission for alternative options. Clearing protocols for high content screening are acceptable if needed and should also be discussed with the investigators at NCATS 3D Bioprinting Laboratory before submission for advice.

Additional Considerations

Subject Matter Expert. Extramural investigator(s) are advised to recruit at least one expert in pain, opioid use disorder and/or addiction to the team. The expert should be available to provide an advice on pain/addiction pathways, opioid biology, etc., that will assist with the development of in vivo-relevant 3D tissue models.

Cells. The availability and use of human primary cells, or pluripotent stem cells, e.g., iPSC, are strongly encouraged. Multipotent or unipotent stem cells also may be utilized where appropriate. The current NIH guidance on stem cell usage can be found at http://stemcells.nih.gov/policy/pages/2009guidelines.aspx. All normal and pathologically-relevant, as well as any reporter iPS cell lines required for the project must be established and validated prior to submission. For primary cells, the extramural investigators will have to demonstrate availability of the cells in large quantities for subsequent utilization in drug screening platforms.

Collaboration Plan and Agreement. Applications for this program will be submitted by the extramural institution with the NCATS intramural scientist(s) integrated into the application as described in the Collaboration Plan. Annual progress reports will be prepared and submitted by the extramural institutions, with the participation and input of the intramural investigator(s) and should include the project findings, publications, data and resource-sharing and impact of the collaborative project. This collaborative translational research between NCATS intramural scientists and extramural investigators will involve either a Cooperative Research and Development Agreement (CRADA) or Research Collaboration Agreement (RCA), which will need to be executed for projects deemed scientifically meritorious by peer review. NCATS will provide CRADA or RCA template documents to help streamline the interaction between NCATS intramural scientists and extramural investigators. These template agreements can be found on https://ncats.nih.gov/alliances/forms. Questions regarding any of these agreements can be referred to the NCATS Office of Strategic Alliances at [email protected]. Applicants should review this document and consult with their institutes about their willingness to agree to the conditions well in advance of submitting an application to this FOA. The CRADA or RCA will need to be executed after the application has been identified for funding. While the CRADA or RCA may not be in place before the award is made, it will be useful to have a statement from the applicant’s Sponsored Research Office that they agree, in principle, to the conditions of the CRADA/RCA.

Applications that are submitted to this FOA that are an identical application to RFA-TR-19-003 Tissue Chips to Model Nociception, Addiction, and Overdose (UG3/UH3 Clinical Trial Not Allowed) will not be accepted.

IMPORTANT: Applicants are required to consult with Director of the 3D Bioprinting Laboratory at NCATS https://ncats.nih.gov/bioprinting. Early contact provides an opportunity for IC staff to discuss the program scope and goals, and to provide information and guidance.

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

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

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH 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 and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. 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.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

For grantees from a for-profit organization, this FOA does require cost sharing, as defined in the NIH Grants Policy Statement. More information on cost matching requirements is in Section IV.2 R&R or Modular Budget

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. 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).

Buttons to access the online ASSIST system or to download application forms 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.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

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:

• 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:

Carol Lambert, Ph.D.
Telephone: 301-435-0814
Fax: 301-480-3660
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

Other Attachments: The following attachments are required.

Collaboration Plan:

Applications must include a Collaboration Plan, describing how the proposed collaboration will be maintained throughout the duration of the award.

The following areas should be addressed:

• Organizational structure
• Management plan detailing how existing resources, including 3-D Bioprinting Laboratory at NCATS will be utilized
• Planned interaction and responsibilities of key personnel
• Clear and well described advantage to bringing the intramural and extramural investigators together in a collaborative partnership
• Description of how research teams will communicate (e.g., videocast, web meeting, etc.)
• Description of any pre-existing Intellectual property
• While the CRADA may not be in place before the award is made a statement from the Sponsored Research Office agreeing in principle to the terms of the template must be included.

The filename "Collaboration Plan-PI-NAME.pdf" should be used and will be reflected in the final image bookmarking for easy access by reviewers. The Collaboration Plan is limited to 5 pages.

Milestone Plan

Applications must include a Milestone Plan, describing the Go/No-Go transition milestone for transition from the UH2 phase to the UH3 phase. The Milestone plan should:

• Include a clearly identified Go/No-Go transition milestone for completion of the UH2 phase at the end of Year 2 and transition to the UH3 phase for 3 years of additional funding.
• 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.
• 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.

The filename "Milestone Plan-PI-NAME.pdf" should be used and will be reflected in the final image bookmarking for easy access by reviewers. The Milestone Plan is limited to 3 pages.

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

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

Because of the anticipated complexity of the budget information and the need to clearly delineate costs for the extramural awardee, applicants must submit a detailed R&R budget. Submission of a Modular Budget is NOT allowed for this FOA.

The budget request for this FOA must distinguish between extramural costs, and the NIH intramural investigator costs. Extramural costs are associated with the extramural investigator and the applicant organization. NIH intramural investigator costs are those required by the intramural investigator for carrying out the proposed work and which are specifically identified with the project.

Cost of NCATS Intramural work

Please note that the NCATS Intramural Research program (IRP, in this case NCATS 3D Bioprinting Laboratory) costs and participation will not be included in the award paid to the grantee. However, cost of IRP reagents and consumables should be submitted as a separate budget page in the application. IRP budgets may not include any salary and related fringe benefits for career, career conditional or other federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project. The IRP budget may also include consultant costs, equipment, supplies, travel, and other items typically listed under other expenses. Funds can be requested for services by an external investigator or contractor as a subcontract/consortium including the applicable indirect (F&A) costs of the contractor/collaborating institution. Justification must be provided for all requested support. In addition, justification for federal employees who will be committed to the project (although no funds may be requested in the application) must also be included. Applicants should indicate the number of person-months devoted to the project even if no funds are requested for salary and fringe benefits. Scientific Review Groups will evaluate the appropriateness of the IRP staff and budget request for the work proposed and will therefore need to know the level of effort being proposed to conduct the work.

Intramural costs will include such items as laboratory supplies for tissue biofabrication, cell production, compound acquisition, as well as costs associated with data analysis (e.g. software licenses). No funds will be included to support salaries. The Extramural Applicant is encouraged to consult with the Director of the NCATS 3D Bioprinting Laboratory (https://ncats.nih.gov/bioprinting) and include in their budget submission a detailed description of the support that will be provided by NCATS.

Extramural Grantee Costs

Extramural costs may include such items as salary support for the extramural PD/PI and staff at the applicant organization, supplies, laboratory animals, data analysis, and other allowable costs for work performed at the (extramural) applicant organization, as well as travel costs for the extramural investigator(s).

• The PD/PI and up to one other key personnel with complementary expertise are required to attend semi-annual program meetings. Funds to attend these workshops should be budgeted in the application.
• Extramural costs should also include travel costs for in-person meetings with NCATS collaborators.

F&A (Indirect) Costs: Applicant organizations are reminded that Facilities and Administrative (F&A) or indirect costs are allowable for only the allowable extramural costs of the project.

Budget Justification: Detailed information should be included in the narrative "Budget Justification" section.

Additional Guidance on Budget Preparation

Initial cooperative agreement awards for up to 2 years will be granted for developing of tissue constructs and appropriate assays that are deemed to be compatible for high-throughput screening. This is referred as UH2 phase. If the project meets the metrics described for the UH2 phase, then the project will proceed to the UH3 phase pending review and availability of funds. The UH2 phase will focus on development and demonstration of physiologically relevant human cells and tissues that can model the mechanisms or effects of nociception/pain-relevant signaling, addiction, or OUDs, and/or their respective therapies and treatments. It is anticipated that during the UH2 phase majority of the funds will be dedicated to the work in extramural laboratory. Intramural NCATS 3D Bioprinting Laboratory will provide consultation with regard to biofabrication of tissue constructs and assay development. During the UH3 phase, high density screening platforms on microplates seeded with the tissue constructs developed during the UH2 phase will be developed and coupled to relevant assays for screening novel therapeutics for nociception, OUD and overdose. This work will be primarily performed at the NCATS intramural 3D Bioprinting Laboratory. Once screen is performed and hits are identified, extramural investigators will be provided with compounds and perform validation of hits identified in screen in their laboratories. The application budget should reflect actual needs of the proposed project and align with the distribution of the work during the two-phase project.

The budget requests for this FOA are more complex and will require more coordination than those of other programs. Therefore, extramural investigators are encouraged to begin discussions about logistics and budget issues with their intramural collaborators and with NIH staff in the early phases of application preparation.

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

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

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

Letters of Support: Applications submitted in response to this FOA must include a current (i.e. within 2 months of application due date) letter from the Scientific Director of the NCATS Division of Preclinical Innovation to confirm that the NCATS 3D Bioprinting Laboratory will be able to accommodate the proposed research and that the NCATS intramural scientist will be able to collaborate on the project. APPLICATIONS SUBMITTED WITHOUT THIS LETTER OF SUPPORT WILL BE CONSIDERED INCOMPLETE AND WILL NOT BE REVIEWED.

In addition, letter(s) from other collaborators/consultants should also be included.
For-profit applicants must include a letter(s) of support confirming that the required secured cost matching (cash; in-kind commitments such as salary, consultant costs, equipment) is available and confirm that the essential personnel have the authority within the organization to allocate resources.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

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

Appendix:

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

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

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

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

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 Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. 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.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

The UH2/UH3 phased innovation grant supports investigation of novel scientific ideas that have the potential for significant impact on advancement of development of novel non-addictive treatments for pain, OUD and/or overdose. A UH2/UH3 grant application need not have substantial preliminary data, extensive background material or preliminary information; however, if such data is available, inclusion of it in the application is strongly encouraged. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding in the field. Reviewers will assign a single impact score for the entire application, which includes both the UH2 and UH3 Phases..

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

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 FOA: Are the proposed model and associated assay of high physiological and pharmacological relevance to the problem that is proposed to be addressed? What is the likelihood that the proposed approaches will have relevance for and/or inform development of novel 3D biofabricated models and drug screening?

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 FOA: Has the PD/PI assembled a team of collaborators that includes experts on pain, OUD and/or overdose, as relevant to the project? Has the PD/PI or investigative team previously shown the ability to successfully participate in, or lead one or more complex projects? Does the PD/PI have experience in working collaboratively with multi-disciplinary teams?

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 FOA: Will the proposed strategy/strategies improve the ability to adequately model nociception, OUD and/or overdose in vitro and utilize the model to advance discovery and development on novel treatments?

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

Specific to this FOA: Is the Collaboration Plan well defined with identifiable responsibilities for the NIH intramural investigator and the extramural applicant? Is a plan for management of the collaboration clearly presented, with well-defined descriptions of what each participant proposes to provide to the collaborative partnership? Is there a clear and well described advantage to bringing the intramural and extramural investigators together in a collaborative partnership?

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?

Specific to this FOA: Are the proposed approaches state of the art and scientifically justified? Are all the cell lines that will be utilized established and well-characterized? If differentiated iPSC will be used, are all the differentiation protocols already established and tested for robustness and reproducibility? Can the protocols be readily scaled up to produce larger amounts of cells for HTS?

Is the proposed assay physiologically relevant and HTS-compatible? Is there a secondary assay that will facilitate validation of hits following HTS? Does the application identify major technical risks, and are the proposed efforts to mitigate or address the risk clearly defined and feasible? Are appropriate, quantitative milestones provided for the UH2 and UH3 stages and clearly defined? Are the UH2 and UH3 milestones feasible, well developed, and quantifiable with regard to the specific aims of each phase? Is the timeline feasible for the UH2 and UH3 stages? Are the critical decision points (i.e. go/no go decision points) and timelines appropriate for the UH2 and UH3 stages? Are adequate criteria provided in the UH2 stage to assess milestone completion in order to make a decision to advance studies to the UH3 stage? Is the proposed transition plan to the UH3 phase complete and in a logical sequence to the elements of the phased UH2/UH3? Do the milestones and timelines proposed clearly identify successful completion of the UH2 and the appropriateness of advancement to the UH3 phase?

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?

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

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

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

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

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

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

Not Applicable.

Not Applicable.

Not Applicable.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Not Applicable.

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.

Specific to this FOA:
How likely is it that the plans for cost matching will be adequate?

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

As part of the scientific peer review, all applications:

• 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.

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the NCATS Advisory Council or Board. The following will be considered in making funding decisions:

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

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

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

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

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

Special award condition specific to this FOA: A grantee from a for-profit organization funded under this announcement must match funds or provide documented in-kind contributions at a rate of not less than 50% of the total-Federally awarded amount, as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018. See 45 CFR 75.306 for additional details. Matching funds must be non-Federal funds set aside for this project and are available from the source(s) identified in the application, as committed to by the recipient. Cost matching will be evaluated by the awarding office to ensure that this requirement is being met. Compliance with the matching requirement must be verified on an annual basis and must be documented in the annual and final FFR.

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.

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.

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.

Cooperative Agreement Terms and Conditions of Award

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 as follows:

• The PD(s)/PI(s) will have the primary responsibility to define objectives and approaches, and to plan, conduct, analyze, and publish results, interpretations, and conclusions of their studies.
• Awardees are responsible for identifying specific milestones that will be achieved during the project period.
• Awardees agree to participate in the overall coordination of research efforts. This participation includes collaboration and consultation with NIH investigators, and the sharing of information, data, and research materials.
• Awardees accept and agree to participate in the cooperative nature of the program.
• Awardees agree to participate in monthly calls by the NIH during the award period.
• Awardees agree to participate in semi-annual meetings. The PI and up to one other key personnel with complementary expertise are required to attend these meetings. Funds to attend these workshops should be budgeted in the application.

Publications

The Program Director/Principal Investigator (PD/PI) 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 PD/PI 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 expected.

Intellectual Property

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). 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.

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

The NIH Program Officer will have substantial involvement in the study and will be responsible for the normal scientific and programmatic stewardship of the award. The Program Officer will have decision-making authority on matters of budgetary and funding actions, and management of intellectual property issues. The responsibility for final decision making may reside with Senior Institute management, separate organizational components and/or oversight committees.

The NIH reserves the right to phase out or curtail the study (or an individual award) in the event of (a) failure to develop or implement a mutually agreeable protocol, (b) substantial shortfall in subject recruitment, consortium participation and collaboration with other awardees, (c) substantive changes in the agreed-upon methodologies and tools with which NIH cannot concur, (d) human subject ethical issues that may dictate a premature termination, or (e) results that substantially diminish the scientific value of study continuation.

The NIH intramural scientist is expected to have primary responsibility for a substantial portion of the proposed research and provide advice and technical assistance as needed. The NIH intramural scientist will also participate in the analysis, interpretation, and reporting of findings in the scientific literature, to the community at large and to the public policy community within the Federal government through various media, as appropriate. The NIH intramural scientist is subject to the same publication/authorship policies as the official NIH publication policy.

Areas of Joint Responsibility include:

Since the purpose of this FOA is to establish and/or further develop collaborative arrangements between extramural and intramural investigators, many responsibilities are shared between awardees and NIH staff and will require close coordination. Responsibilities will be divided between awardees and NIH staff, as described above. Awardees will participate in monthly calls with the NIH and semi-annual meetings. Annual progress reports will be prepared and submitted by the extramural institutions, with the participation and input of the intramural investigator(s) and should include the project findings, publications, impact of the project, a description of what NCATS 3D BioPrinting Laboratory unique resources were utilized and the new intramural-extramural partnerships that developed. This will be evaluated by the program official/IC program director.

Performance Requirements:

• Meeting yearly milestones as defined by extramural and intramural investigators and NIH program at the time of award.
• Working with, cooperatively interacting with, and actively seeking input from NIH.
• Sharing data and biological specimens with the broader scientific community, using established data sharing guidelines.
• Attending semi-annual in-person meetings.

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 of the awardee, and NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two. 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.

T&C Inclusions and Modifications

The Terms and Conditions of Award will include references to the currently approved versions of the Collaboration Plan and the Multiple PD(s)/PI(s) Leadership Plan, if applicable, and the Sharing Plans for Resources and Data. Before the initial award is made, NIH and the awardees may negotiate changes or additions to the versions of these plans in the application. Future changes or additions to these plans may be developed by the NIH and the PD(s)/PI(s). Changes will be documented by an exchange of correspondence and the updated plans will become part of the Terms and Conditions of a revised Notice of Award.

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

A final Research Performance Progress Report (F-RPPR), invention statement, and the expenditure data portion of the Federal Financial Report, including Federal and non-Federal share for cost matching, are required for closeout of an award, as described in the NIH Grants Policy Statement

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.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten on-time submission, and post-submission issues)
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: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Dobrila D. Rudnicki, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-2080
Email: [email protected]

Danilo A. Tagle, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-8064
Email: [email protected]

Anton Simeonov, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-217-5721
Email: [email protected]

Marc Ferrer, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-217-5722
Email: [email protected]

Michael Oshinsky, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9964
E-mail: [email protected]

Carol Lambert, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0814
Email: [email protected]

Kristin Wegner
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0848
Email: [email protected]

Tijuanna Decoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
E-mail: [email protected]

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