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 the NIH Microphysiological Systems (MPS) for Disease Modeling and Efficacy Testing Program is to develop highly reproducible and translatable in vitro models for preclinical efficacy studies through 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. This FOA will provide funding for Investigators to create and test devices that can model the mechanisms or effects of nociception/pain-relevant signaling, addiction, or opioid use disorders (OUDs), using human tissues in in vitro microphysiological systems (MPS). An essential feature of funded projects will be a multidisciplinary approach that brings together experts in pain and opioid use disorder (OUD), bioengineering, microfluidics, material science, "omic" sciences, computational biology, disease biology, pathology, electrophysiology, pharmacology, biostatistics and clinical science.

This program is part 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 UG3/UH3 cooperative agreement award mechanism. The initial UG3 phase will support studies to develop and demonstrate functional validation of tissue chip platforms that can model the mechanisms or effects of nociception/pain-relevant signaling, addiction, or opioid use disorders (OUDs), and/or their respective therapies and treatments, using physiologically-relevant human cells and tissues in in vitro microphysiological systems (MPS). The UH3 phase will support studies to demonstrate the functional utility of the nociception/addiction/OUD tissue chip models for identification of novel therapeutics or treatment mechanisms by identifying aspects of pain circuitry, disease biology or offering new avenues for drug screening and assessment of novel candidate analgesics and therapies against OUD and overdose. A UG3 project that meets its milestones will be administratively considered by NIH Program staff 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

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.

Better understanding of the pathophysiology of chronic pain and the development of nonaddictive therapeutics for the treatment of pain requires the development of novel models for acute and chronic pain. Current in vitro assays and in vivo models to study nociception, OUD and overdose to develop 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.

The Tissue Chips program (https://ncats.nih.gov/tissuechip) supports an innovative approach to preclinical toxicity testing on human tissue: development of in vitro, three-dimensional organ systems from human cells on bioengineered platforms that mimic in vivo tissue architecture and physiological conditions in order to facilitate and accurately monitor key organ-level 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, etc. Tissue chips are useful tools for predictive toxicology and efficacy assessments of candidate therapeutics. An initial MPS program was a five-year partnership among NIH, DARPA and FDA, with NIH investments through (RFA-RM-11-022) and (RFA-RM-12-001) supporting the development and integration of bioengineered multi-organ systems, along with the generation of renewable human cell resources for predictive assessment of drug safety and toxicity. Recent programs to develop disease models on chips (RFA-TR-16-017) have encouraged the application of tissue chips to recreate disease phenotypes and test candidate therapeutics, and to test the technology in independent Tissue Chip Testing Centers (RFA-TR-16-006). This current FOA is building on the success of earlier MPS programs with a focus on developing nociception/addiction/OUD-relevant models that could be used to better understand the mechanisms of pain and opioid use disorders and be used for toxicity, safety and efficacy testing of candidate therapeutics.

Leveraging Existing Research Resources:

Applicants are strongly encouraged to leverage existing research resources for their studies whenever possible. NCATS has led the use of tissue chip technologies to develop microphysiological systems that can be used for safety and efficacy studies of promising therapeutics as well as in modeling human diseases and conditions, and applicants are encouraged to leverage all available internal (e.g. home institutional) and external (e.g. external institutional, NIH, NCATS and/or Tissue Chip Consortium) resources.

The Tissue Chip Consortium (The TC Consortium)

The NIH Tissue Chip for Drug Screening Program is led and managed by NCATS and 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 non-profit organization the IQ Consortium allows for pharmaceutical companies to work with NCATS 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, and the funded investigators, holds an in-person meeting every 6 months and plays a pivotal role in advancing the MPS technology. Awardees from this FOA will become members of the NCATS-led TC Consortium.

Applicants are encouraged 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. Studies are also encouraged that leverage the resources of ongoing clinical trials supported through other Federal or private funds.

Pre-Application Consultation:

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

Research Objectives and Scope

The goal of this FOA is to promote the development of in vitro microphysiological systems to model human nervous and non-nervous tissues that recapitulate the mechanisms or effects of nociception/pain-relevant signaling, addiction, or opioid use disorders (OUDs), and/or their respective therapies and treatments. These systems will mimic the responses and pathology in major human organs and tissues of nociception, addiction and OUDs, with utility of these models to facilitate the assessment of biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents prior to entry into clinical trials.

The nociception/addiction/OUD models to be developed are expected to express critical aspects of human physiology and provide a measurable output for the representative systems. In developing nociception/addiction/OUD models that more accurately represent human physiology and pathology, primary tissues obtained from patients or commercially available cell lines may be used; however, investigators are strongly encouraged to take advantage of recent advances with human stem cells, progenitor cells, induced pluripotent stem cells (iPSC), and gene editing technologies to engineer desired tissues whenever feasible. Essential characteristics of the nociception/addiction/OUD models should include all or some of the following features: 1) multicellular architecture that represents characteristics of the tissues or organs of 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 pathological (i.e. pain-relevant or opioid-addicted/tolerant/withdrawn) phenotypes; and 5) representation of spectrum or heterogeneity of nociception/addiction/OUD phenotypes. 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 to help inform clinical correlates of pain/addiction/OUD. 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 nociception/addiction/OUD models can be for neural or non-neural tissues and for multiple aspects of pain or opioid-related relevant phenotypes. These include models of peripheral and central nervous system tissues, and monogenic or polygenic disorders that affect nociception/addiction/OUDs. Projects should be designed to meet the broader MPS program goals and NIH HEAL initiative goals and should, where appropriate, address multi-organ or multi-systems affectations of nociception/addiction/OUDs. The primary focus of the UG3 phase will be on developing in vitro nociception/addiction/OUD models using tissue chip technologies. The UG3 phase should also be designed for initial validation and testing of critical experimental parameters, which the applicant will identify as quantifiable milestones (see below).

The UG3 phase:

• Develop in vitro nociception/addiction/OUD models using primary tissues, commercially available cells lines, or iPSC-derived patient cell sources on tissues chip platforms. Models should demonstrate a functional representation of normal and pain-relevant/addiction/OUD phenotypes in human tissues.
• Determine pathological and phenotypic relevance of nociception/addiction/OUD models by preliminary testing of key experimental features and outcomes essential to proceed to the UH3 phase of the study. This would involve inclusion of non-invasive endpoints that generate reproducible data under physiological conditions over a long culture period of up to 4 weeks; platform integration to study multiple organ pathology of nociception/addiction/OUD pathology and phenotype; and representation of disease heterogeneity and/or population diversity. The functional validation of the models may be disease model-specific.

The UH3 phase:

The major goals are to demonstrate the functional utility of the nociception/OUD (to include addiction and overdose) models for uncovering new insights into pain/OUD screening and apply them 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 nociception/OUD model end-points with clinical measures in humans.
• Characterization of the parameters of therapy, treatment, intervention or response to exposure.
• Developing translatable pharmacodynamics (i.e., target engagement) biomarkers for validated therapeutic targets.
• Conducting preclinical efficacy testing of candidate therapeutics using innovative approaches, data acquisition and analyses.
• Developing strategies for rapid, open-access dissemination of data and methodology, and for rapid distribution of nociception/OUD 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.

High Priority Areas of Interest

The NIH is interested in supporting the development and initial validation of pain-relevant/nociception/OUD models. It is anticipated that model systems, where appropriate, will address multi-organ or multi-systems affectations of the disease. For this program, MPS may be developed for neural and non-neural tissues, but must be physiologically-relevant and with clear utility to:

• Investigate novel pain-relevant/nociception/OUD mechanism(s)
• Discover, develop and evaluate novel therapeutic targets or pathways for pain/nociception or opioid-related processing and physiological responses to pain/nociception/opioids.

Integrated tissue models of peripheral and central nervous tissue are encouraged, along with platforms that model systemic physiological responses to pain/nociception/addiction/overdose or associated medications and therapies.

Areas of interest for development include, but are not limited to:

• MPS using human iPSC-derived and/or primary cells that reproduce normal or disease physiology at peripheral, dorsal root ganglion (DRG), trigeminal ganglion (TG), spinal cord, and brain levels, including blood-brain-barrier (BBB).
• Dopaminergic and opioidergic areas of the brain (e.g. rostral ventromedial medulla, prefrontal cortex, basal ganglia) that could inform therapeutic/intervention development, interruption of addictive circuitry.
• Adaptation of existing non-nervous tissues that are involved in nociceptive responses, pain sensation, and/or drug addiction or overdose mechanisms.
• Targets related to mitigating overdose, such as respiratory suppression.
• Development of MPS to model painful disorders of the orofacial region including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental pain, and other conditions. Development of systems that model the interaction of human nervous and non-nervous craniofacial tissues (such as the temporomandibular joint, skeletal, muscle, cartilaginous and ligamentous tissues as well as the circulatory and immune systems) to better understand orofacial pain mechanisms and facilitate the assessment of biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents are of interest.
• Development of in vitro human tissue microphysiological systems that model painful arthritis, musculoskeletal and skin diseases, disorders and conditions, and the interaction of human nervous and non-nervous musculoskeletal and skin organ and tissues such as joints, skeletal muscle, bone, intervertebral disc, cartilage and ligament.

Also of interest are platforms populated with tissues from human donor/patient populations which can predict individuals responses to opioids and other medications, to help drive the personalization of medication-assistance treatment (MAT) approaches. These should be used to identify and evaluate physiological risk factors and vulnerabilities such as genomic variability in response to opioids. Areas of interest for development include, but are not limited to:

• Modeling of mu-opioid receptor variants from healthy and patient subpopulations on tissue chips, and investigation of dopamine release/dopamine receptor (DAR) internalization as a measure of tolerance and addictive-like phenotypes.
• Creation of tissue chips with iPSC-derived cells from patients prescribed opioids/pain therapeutics, and identification of prospective studies that can be carried out in parallel with clinical data collection e.g. to identify biomarkers on chips that can predict OUD/addictive phenotypes in clinical subpopulations and individuals.

Platforms of additional interest would include those developed to study the impact of physiological co-morbidities on clinical trajectory, treatment response, and long-term outcomes for pain/addiction in linked, integrated multi-chip systems. Areas of interest for development include, but are not limited to:

• The linkage of multiple relevant tissue chips to study systemic multi-organ physiological comorbidities of prolonged exposure to opioid/non-opioid pain therapeutics and relevant metabolites.
• The linkage of multiple relevant tissue chips to study physiological comorbidities of opioid-induced constipation or opioid withdrawal.
• Linkage of e.g. brain and GI/cardiovascular/musculoskeletal chips to investigate the multi-organ systemic effects of specific addicted/tolerant/withdrawn brain regions on a chip.
• Use of linked multi-chip systems to investigate repeated overdose treatments to elucidate off-target side effects e.g. levels of nephrotoxicity/hepatotoxicity/cardiotoxicity from repeated naloxone administration.

NIH is supporting the development of tissue chip technology using either primary cells or iPSC-derived cells representative of gender, genetic variations, and demographics to provide insights into differences in pain/OUD in individuals and population-wide. Systems may model individuals, populations, or population/patient subgroups.

Validation of tissue chip technology is required, and all assays and outcomes should be compared to existing 2-dimensional and animal models, with clear advantage of tissue chip technology demonstrated.

In addition, NIH is interested in nociception/OUD models that interrogate the role of the environment in these phenomena. This is in order to elucidate potential environmental risk factors and identify relevant novel biological pathways as the basis for developing safe, effective treatments, as well as for prevention planning and development of public health strategies. TCs promise to be valuable tools in elucidating the toxicological role of chemicals alone or in concert with drug reactions in adult or children s environmental health. Specific areas of interest include, but are not limited to:

• Production and characterization of TC panels using either primary cells or iPSC-derived cells - representative of community, ethnic, or regional demographics to provide insights into individual and population susceptibility to exposures.
• Modeling of environmental disease variation through various population demographics in concert with environmental or endogenous stressors.
• Demonstration of TC utilization that shows superiority over current assays on human tissue for early biomarkers of nociception/addiction/OUD; including genome integrity, DNA damage and repair, receptor activation, metabolism and metabolic competence, and toxicokinetics

Additional Considerations:

Immune incorporation: Inclusion of immune elements (e.g., lymphocytes, macrophages, microglia, neutrophils etc.) should be considered and is strongly encouraged. Innate and adaptive responses modeled on-chip wherever possible. Strong scientific justification will be required for applications lacking immune components.

Genetic manipulation: Where appropriate (e.g. for modeling of monogenic or polygenic pain disorders), genome manipulation strategies, such as CRISPR/Cas9, Talen and Zinc-finger to introduce relevant variants may be considered. Rare genetic disorders may be modeled on-chip if human phenotypes display abnormal pain/opioid responses.

Cells: The use of transformed or immortalized cell lines is discouraged, except for preliminary, proof of concept studies. The use of primary cells, organ explants, or pluripotent stem cells, e.g., iPSC, is encouraged. Multipotent or unipotent stem cells also may be utilized where appropriate. The current NIH guidance on stem cell usage can be found at https://stemcells.nih.gov/policy/2009-guidelines.htm.

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 and the disease experts, clinicians and engagement of patient advocacy groups. Applications should include relevant pain, addiction, or OUD expertise from clinical and/or academic fields.

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

• Development of 2-dimensional cell models.
• Creation of platforms without inclusion of multiple relevant cell types.
• Creation of single-tissue platforms without functional or physical integration with other relevant tissue types.
• Lack of inclusion of immune components, or a lack of strong scientific justification for their exclusion.
• Engineering of non-human tissue models.
• Development of simple organoid models that do not go significantly beyond those currently available and in use.
• Conduct of clinical trials.

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:

Christine Livingston, Ph.D.
Telephone: 301-435-0812
Fax: 301-480-3660
Email: livingsc@mail.nih.gov

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: A separate Milestone plan, to include Gantt chart and UG3/UH3 Go/No-Go milestones, may be included. The filename "Milestone Plan-PI-NAME.pdf" should be used and the document must be limited to 3 pages.

Milestone Plan:

Applications must include a Milestone Plan, describing project milestones and the Go/No-Go milestone for transition from the UG3 phase at the end of Year 2 to the UH3 phase, for 3 years of additional funding. The Milestone plan should:

• Provide detailed quantitative criteria by which milestone achievement will be assessed.
• Provide detailed timelines for the anticipated attainment of each milestone and the overall project goals.
• Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.
• Include a clearly identified Go/No-Go transition milestone for completion of the UG3 and transition to the UH3 phase.
• A timeline (Gantt chart) including milestones is required for all studies. 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.

See https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/Devices-Milestones for example NIH Cooperative Agreement milestones. NOTE: These are suggested formats only and should be adapted as appropriate.

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

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

Cost Matching Requirement for For-profit Applicants

Cost matching or documented in-kind contributions is required for for-profit organizations responding to this FOA. The for-profit awardee is required to match funds or provide at least a 50% matching of funds or documented in-kind contributions at a rate of not less than 50% of the for the total-Federally awarded amount (direct costs, as well as facilities and administrative costs), as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018.
Federal funds may not be used as a source of matching funds. Generally, cost matching requirements may not be met from the following sources:
a) Costs borne by another Federal grant or sub award;
b) Costs or contributions toward cost sharing on another Federal grant, a Federal procurement contract, or any other award of Federal funds;
c) Cost of services or property financed by income earned by contractors under a contract from the recipient (or sub recipient);
(d) Program income; and
(e) Patient incentives.
The for-profit organization 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. Applicants must submit budgets that clearly document the total costs, the source and amount of matching funds, and how valuation was determined in the case of in-kind contributions, as well as the Federal and Institutional (non-Federal) components of the budget. 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.
Budget Justification: All for-profit applicants must document the matching (non-Federal) component and the federal (non-matching) component in the total project budget. That is, the requested budget plus the cost-matching budget must be detailed in tabular format to document the cost-matching (non-Federal) component and the federal (non-cost matching) component. The amount of matching is subject to adjustment based on total allowable costs incurred. All costs and contributions used to satisfy the matching requirement must be documented by the recipient, including how the value for in-kind contributions was determined, and are subject to audit. The cost matching requirement is not negotiable for for-profit organizations.

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.

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:

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:

Provide separate sections that describe both the UG3 and UH3 phases.

Provide a description of the hypothesis to be tested in the UH3 phase of the study.

Letters of Support
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 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.

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 for this FOA: How well will the created nociception/addiction/OUD/overdose model be able to recapitulate pain and opioid-relevant signaling, pathologies and treatment responses? Does the application focus on critical gaps to address important questions or obstacles in the particular systems of interest? Will successful completion of the research aims advance the understanding of pain/OUD pathogenesis and advance the development of diagnostics and interventions?

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 for this FOA: Is the Multi-PI leadership plan, if applicable, well-described, including plans for dispute resolution? Have project leadership and other key personnel demonstrated a record of directing research activities related to creating and validating models of pain/addiction/OUD? Are the collaborations, in particular from academic and clinical 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. pain and disease experts, clinicians, patient groups, tissue chip developers?

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 for this FOA: 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 nociception/addiction/overdose that will advance basic and translational science and/or therapy development? Does the project utilize the current advances of genome editing and other cutting-edge technologies? Are the tissue chip platform and cells being proposed suitable to capture the relevant physiological features?

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?

Specific for this FOA: Has the application included an adequate description and justification of the disease, condition, intervention or pathology? Are the technologies or experimental approaches state of the art? Will the expected results lead to advances in technologies used in the treatment of human pain and addiction disorders? Are the proposed approaches, tools and technologies scientifically justified for the particular pain/OUD model? Does the application identify major technical risks, and are the proposed efforts to mitigate or address the risks clearly defined and feasible? Is the proposed transition plan to the UH3 phase complete and in a logical sequence to the elements of the phased UG3/UH3? Does the conceptual framework have testable hypotheses, appropriate design, adequately developed methods and analyses? Are these well integrated, well-reasoned and appropriate to the modality to be modeled? Is the choice of the bioengineered platform, microfluidics, biomechanics and cell sources for the model system well-justified? Are the overall strategies, methodologies and analyses for conducting a translatable study well-reasoned and appropriate?

Milestones:

Are milestones provided for the UG3 and UH3 phases of the overall project? Are milestones appropriate, clearly-defined and quantitative? Are the UG3 and UH3 milestones feasible, well developed and quantitative with regard to the specific aims within each phase? Is the overall timeline feasible for the UG3 and UH3 phases? Are the critical decision points (i.e. go/no-go decision points) and timelines within the UG3 and UH3 phases appropriate? Are adequate criteria provided in the UG3 phase to assess milestone completion in order to make a decision to advance studies 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?

Specific for this FOA: Is there convincing evidence that applicants have infrastructure in place to immediately begin building tissue chip models using appropriate technical and scientific methods? Is there evidence of unique features of institutional support?

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 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?

Part 2, Section VI, Award Administration Information, Award Notices

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. 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 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.
• Submitting monthly/quarterly progress reports during the UG3 phase, in a format as agreed upon by the trans-NIH Microphysiological Systems Working Group. Projects that are selected for continued support through the UH3 mechanism will submit progress reports also on a monthly/quarterly basis.
• Accepting and implementing any other common guidelines and procedures developed for the Tissue Chip Program for Diseases Modeling and Efficacy Testing and approved by the trans-NIH Microphysiological Systems Working Group.
• Accepting and participating in the highly collaborative nature of the NIH Tissue Chips program.
• Attending bi-annual Tissue Chip (TC) Consortium meetings 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 pain/OUD 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.
• Working with the members of TC Consortium to establish agreements that address the following issues: (1) procedures for data sharing among consortium members and data sharing with industry partners, as appropriate; (2) procedures for safeguarding confidential information, including without limitation, any data generated by the consortium as well as information and/or data received from external collaborators; (3) procedures for addressing ownership of intellectual property that result from aggregate multi-party data; (4) procedures for sharing biospecimens under an overarching MTA amongst consortium members that operationalizes material transfer in an efficient and expeditious manner as appropriate and consistent with achieving the goals of the program; (5) procedures for reviewing publications, determining authorship, and industry access to publications.
• 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.

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 expected.

Communication Plans

The Principal Investigator will be responsible for:

• Participating in regular (monthly) conference calls with all NIH TC Project Team members.
• Coordinating efforts with other awardees, especially in circumstances where synergy of efforts and resources is beneficial to the overall goals of the MPS program.
• Participating and presenting findings at the semi-annual workshops convened by the NIH.
• Coordinating or jointly publishing findings in a timely manner, and as to have the broadest impact.
• Making new information and materials known to the research community in a timely manner through publications, web announcements, reports to the NIH Tissue Chip Project Scientist, and other mechanisms.

Performance Requirements

The Principal Investigator will be responsible for:

• Meeting yearly milestones as defined by investigators and NIH Program Officer at the time of award.
• Working with, cooperatively interacting with, and actively seeking input from NIH.
• Sharing broadly data and biological specimens with academic, industry and government researchers is a critical feature of this program that is consistent with applicable laws, regulations, and policies. All subjects must be properly consented to allow appropriate sample and data distribution to researchers in academics and industry.
• Attending one in person "kickoff meeting" at the beginning of the award period; this meeting will serve as an organizing workshop together with NIH staff, including representatives from the trans-NIH Microphysiological Systems Working Group. The workshop will go over Terms and Conditions of Awards for the UG3/UH3 phases, TC Consortium responsibilities and duties, and provide an opportunity for awardees to describe their project to the consortium.
• Attending semi-annual consortium meetings to be held in the Washington/Maryland region.

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 Chip 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.

NIH staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards.

NCATS will designate program staff, including a Program Officer, to provide stewardship and administrative oversight of the cooperative agreement. The Program Officer will be named in the Notice of Award (NoA).

NIH Tissue Chip Project Scientists are members of the trans-NIH Microphysiological Systems Working Group that will have substantial scientific/programmatic involvement in the technical assistance, advice and coordination of this team; the NIH Tissue Chip Project Scientists will facilitate and not direct the activities of the team.

Specifically, the NIH Tissue Chip Project Scientist will be substantially involved in this project as follows:

• Coordinate and facilitate the activities of the program, attend and participate in all meetings of the TC Consortium.
• Work with Project Scientists from the trans-NIH Microphysiological Systems Working Group 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 (with the other trans-NIH Microphysiological Systems Working Group members) in the group 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.
• Serve as a liaison between the awardees, the Advisory Councils for those Institutes that plan to administer elements of the NIH Tissue Chips program, and the larger scientific community.
• 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 trans-NIH Microphysiological Systems Working Group meetings and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action.
• Periodically report progress to the Directors of NIH institutes involved in the NIH Tissue Chip program.
• Lend relevant expertise and overall knowledge of NIH-sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve as External Scientific Consultants, as needed.
• Maintain public-private partnerships established under the NIH Tissue Chip program.
• 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.
• Facilitate negotiations with companies interested in working with the awardees.
• Provide advice on project management and technical performance.
• Coordinate and manage trans-NIH Microphysiological Systems Working Group efforts.
• Provide guidance to the awardees on private-public partnerships and regulatory agency policies.
• Invite experts with relevant scientific expertise to provide feedback on TC program activities.
• 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.
• The NIH will enlist additional scientific consultants as necessary from within the NIH, other government agencies, and from industry partners whose function will be to assist the Program Director in carrying out the goals and aims of the approved studies.

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.

The NIH will enlist additional scientific experts as necessary from within the NIH, other government agencies, such as the FDA, and from industry partners whose function will be to assist the Program Director in carrying out the goals and aims of the approved studies.

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 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.

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: GrantsInfo@nih.gov (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: support@grants.gov

Lucie Low, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-7609
Email: lucie.low@nih.gov

Danilo Tagle, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-8064
Email: Danilo.Tagle@nih.gov

Fei Wang, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5055
Email: wangf@mail.nih.gov

Seila Selimovic, PhD
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301-451-4577
Email: seila.selimovic@nih.gov

Katerina Tsilou, MD
National Institute of Child Health and Human Development (NICHD)
Telephone: 301-496-6287
Email: tsiloue@mail.nih.gov

Nathan M. Appel, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-5918
Email: nathan.appel@nih.gov

Yolanda F. Vallejo, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-827-4655
Email: yolanda.vallejo@nih.gov

Margaret Sutherland, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-5680
Email: sutherlandm@mail.nih.gov

Martha S. Lundberg, PhD
National Heart, Lung and Blood Institute (NHLBI)
Telephone: 301-435-0513
Email: lundberm@nhlbi.nih.gov

Carol Lambert, Ph.D.
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0814
Email: lambert@mail.nih.gov

Ki-Cha Flash
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0846
Email: flashk@mail.nih.gov

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Tel: 301-594-7760
Email: edgertont@mail.nih.gov

Katie Ellis
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301-451-4791
Email: kellis@mail.nih.gov

Bryan Clark
National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clarkb1@mail.nih.gov

Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-1159
Email: pfleming@mail.nih.gov

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: rutbergd@mail.nih.gov

Tijuanna Decoster
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@mail.nih.gov

Anthony Agresti
National Heart, Lung, and Blood Institute (NHLBI)
Telephone: 301-827-8014
Email: agrestia@nhlbi.nih.gov

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.