Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (http://commonfund.nih.gov/) through the NIH Office of the Director, Office of Strategic Coordination (http://dpcpsi.nih.gov/osc/). The FOA will be administered by a trans-NIH team led by the National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) on behalf of the NIH Common Fund Program on Advancing Regulatory Science http://commonfund.nih.gov/regulatoryscience/.

Funding Opportunity Title

Integrated Microphysiological Systems for Drug Efficacy and Toxicity Testing in Human Health and Disease (UH2/UH3)

Activity Code

UH2/UH3 Phase Innovation Awards Cooperative Agreement

Announcement Type

New

Related Notices

U18, RFA-RM-12-001

  • December 5, 2011 - See Notice NOT-RM-12-007. The National Institutes of Health (NIH) Common Fund (CF) Regulatory Science Microsystems Program Team will hold a pre-application teleconference.
Funding Opportunity Announcement (FOA) Number

RFA-RM-11-022

Companion FOA

None

Number of Applications

See Section III. 3. Additional Information on Eligibility.

Catalog of Federal Domestic Assistance (CFDA) Number(s)

93.310

FOA Purpose

This NIH Funding Opportunity Announcement (FOA), supported by funds from the NIH Common Fund (Common Fund) and participating NIH Institute(s) and Center(s), invites applications for projects that will develop accurate cellular and organ microsystems representative of human physiology for the evaluation of drug efficacy and toxicity.  By definition, these cellular and organ microsystems will have a multicellular architecture representing the characteristics and functions of the tissue of origin and will demonstrate a reproducible and viable operation under physiological conditions over a long culture period. It is anticipated that these bio-engineered human tissue models could lead to the development and commercialization of microsystems that will enable rapid and high fidelity evaluation of safety and efficacy for candidate therapeutics.

Applications unresponsive to this FOA are those developing 3D tissues for transplantation, engineering non-human tissue models or developing simple 3D models that do not go significantly beyond those currently available and in use.

Funds from the NIH will be made available through the UH2/UH3 cooperative agreement award mechanism. The initial two-year UH2 phase will support studies to develop modular microsystems from a number of human organ systems that are functionally relevant and also reflect the multicellular, genomic and pathological complexity of the tissues of origin.  During the UH3 phase of the award, it is anticipated that physiologically relevant microsystem modules from the UH2 phase will be integrated at the organ or systems level through synergistic interactions and collaborations among NIH and/or DARPA funded investigators.

The NIH is partnering with the Defense Advanced Research Projects Agency (DARPA) who is conducting a separate but parallel FOA https://www.fbo.gov/index?s=opportunity&mode=form&id=d12e2f420cb12f75d61a8682623c3a79&tab=core&_cview=1. The US Food and Drug Administration (FDA) is also a non-funding partner to both FOAs providing guidance to both programs to help ensure that regulatory challenges of reviewing drug safety and efficacy are considered before and during development of the integrated microsystem.

Key Dates
Posted Date

November 22, 2011

Open Date (Earliest Submission Date)

December 26,2011

Letter of Intent Due Date

December 26, 2011

An informational conference call for prospective applicants will be scheduled after the LOI due date. For details about this call, please visit the NIH Common Fund Regulatory Science website at http://commonfund.nih.gov/regulatoryscience/  

Application Due Date(s)

January 26, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

February - April, 2012

Advisory Council Review

May, 2012

Earliest Start Date(s)

July, 2012

Expiration Date

January 27, 2012

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (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.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Background

The NIH has identified a critical need for improved model systems to predict efficacy, safety, bioavailability, and toxicology outcomes for candidate therapeutics.  Currently, in vivo animal models serve as gold standards for advancement to clinical trials, but the drawbacks associated with such models are major contributors to the costs and uncertainties in therapy development.  Because of interspecies differences, animal models are often poor predictors of human efficacy and toxicology.  In addition, the results of animal studies can be highly variable and difficult to reproduce, making them unreliable as benchmarks for decisions on human clinical trials. In vitro systems that use human tissues could overcome the drawbacks associated with animal studies; however, for these systems to serve as tools that reflect human biology, key physiological features and human health endpoints need to be included in their design for informative and reliable efficacy, pharmacokinetic and toxicity screening.  

Advances in bioengineering related to materials science, microfabrication, and microfluidics technologies have allowed the manufacture of microsystems representing functional units of an organ that replicate the spatiotemporal, mechanical and biochemical cues that underlie the physiological behavior inherent in those tissues.  These advances have made it possible to initiate the engineering of cellular environments and/or functional units of lung, heart, blood vessels, muscles, bones, liver, nervous system (including eye), gut, and kidney. In general, these microsystems reflect physiologically relevant parameters, including proper cell-to-cell, cell-to-matrix, biochemical and mechanical signaling, but lack the complex architecture of tissues. In parallel with recent developments in bioengineering, advances in stem cell technology now make it possible to obtain tissues from humans with specific genotypes and/or disease phenotypes.  Although, these capabilities present unprecedented opportunities to create biomimetic devices with the potential to capture the dynamics of drug effects in the human body, challenges still remain in differentiating pluripotent cells to span the developmental spectrum.  Once these biomimetics are established, the next challenge is to develop an integrated microsystem platform that can incorporate several different modular biomimetic devices.  These integrated microsystems should recapitulate the complex physiology and biology of the human body, including vascularization and innervation, as well as hormonal, humoral and immunological signaling.  The integrated systems should also be able to mount physiologically relevant responses to metabolic challenges while providing simultaneous evaluation of primary and secondary effects of drugs, toxins, pathogens, particulates and other agents on different tissues.  The anticipated result will be a platform for expedient evaluation of safe and effective pharmaceutical candidates, thus enabling early rejection of ineffective or toxic candidates.  An integrated microphysiological platform will further our understanding of disease etiology and ultimately lead to improvements in the quality and potentially the numbers of novel therapies that move through the drug development pipeline, resulting in better clinical care.

Research Objectives

The goal of this FOA is to promote the development of in vitro microphysiological systems representative of major organs and tissues in the human body, to facilitate the assessment of biomarkers, bioavailability, efficacy, and toxicity of therapeutic agents prior to entry into clinical trials.  During the UH2 phase, support will be provided to develop microsystems that are flexible, robust, and readily integrated into a platform that will express critical aspects of human physiology.  Following administrative review, the UH3 phase will build upon successful UH2 microsystems and a DARPA integrated microphysiological platform http://www.darpa.mil/Our_Work/DSO/Programs/Microphysiological_Systems.aspx or an alternative platform, to model the complexity of the toxic response of an intact organism to drugs and other agents.  It is anticipated that a multidisciplinary team made up of bioengineers, cell biologists, tissue engineers, chemists, toxicologists and other specialized disciplines will be needed to accomplish the goal of this FOA.

A. Research Scope

The in vitro microsystems are expected to express critical aspects of human physiology and provide a measurable output for the representative systems.  In engineering microphysiological systems that more accurately represent human physiology and pathology, established cell lines or primary tissues obtained from patients may be used; however, investigators are also encouraged to take advantage of recent advances with human stem cells, progenitor cells, and iPSC technologies to engineer tissues whenever feasible.  Essential characteristics of an in vitro microsystem should include all or some of the following features:  1) multicellular architecture that represents characteristics of the tissue of origin; 2) functional representation of normal human biology; 3) reproducible and viable operation under physiological conditions maintained up to 4 weeks in culture; 4) representation of normal and disease phenotypes; 5) representation of population diversity; and 6) amenability to high content screening for repeated dose efficacy testing, and for toxicology (absorption, distribution, metabolism, excretion and toxicity (ADMET)) and safety screening.   A critical challenge in engineering an integrated network of microsystems will be the ability to develop and assemble three-dimensional tissue modules that are physiologically relevant, reproducible and compatible with high content screening platforms that include multiple molecular read-outs, such as gene expression, proteomic, metabolomic, or epigenomic analyses. Ideally, in vitro microsystems should 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.  It is anticipated that development of microphysiological systems representative of human tissues and organs will lead to a reduction in the timelines and costs associated with therapeutic development, and will lead to enhancement of efficacy and toxicity information for regulatory decisions.

The focus of this FOA is the development of physiologically and pathologically accurate human models of any of the systems below, using tissue engineering platforms that either already exist or that are being developed simultaneously through the initiative just released by DARPA (https://www.fbo.gov/spg/ODA/DARPA/CMO/DARPA-BAA-11-73/listing.html ). The NIH efforts will focus on the development of microsystems which are physiologically accurate, genetically diverse, and pathologically representative. While the NIH emphasis is not specifically directed towards platform development, it is expected that NIH awardees will have synergistic interactions with DARPA’s efforts. Ideally, the integrated platform should support a network of microsystems that can monitor in real-time and at high resolution inflammatory responses, epithelial and endothelial barrier functions, exposure to environmental and infectious agents and absorption and metabolism of drugs. 

In bioengineering microphysiological systems that more accurately represent human physiology and pathology, established cell lines or primary tissues obtained from patients may be used; however, investigators are also encouraged to take advantage of recent advances with stem cells, progenitor cells, and iPSC technologies to engineer tissues whenever feasible. The latter approach allows for an integrated microsystem to be made from tissues with a uniform genomic background rather than a mosaic. In addition, genetically diverse microphysiological systems may be able to differentiate drug responsiveness in sub-populations for whom a drug may be either beneficial or toxic.

A. UH2 Phase

During the UH2 phase, the NIH is interested in developing and validating microsystems from the following organ systems: circulatory, endocrine, gastrointestinal, immune, integumentary, musculoskeletal, nervous (including the eye), reproductive, respiratory and urinary.  Examples of microsystems and potential disease modeling for the organ systems listed above may include, but are not limited to:

Circulatory:

Endocrine:

Gastrointestinal:

Immune:

Integumentary:

Musculoskeletal:

Nervous:

Reproductive:

Respiratory:

Urinary

The UH2 phase of the grant application should address the following critical areas: 1) multicellular architecture that represents characteristics of the tissue of origin; 2) functional representation of normal human biology; 3) reproducible and viable operation under physiological conditions over a long culture period of up to 4 weeks; 4) representation of disease phenotypes, including multisystem disorders such as malignancies and metastases; 5) representation of population diversity; and 6) amenability to high content screening for repeated dose efficacy testing, toxicology {absorption, distribution, metabolism, excretion and toxicity (ADMET)} and safety screening including readouts for genomic, epigenomic, metabolomic, or proteomic measures.  It is anticipated that for certain complex organ systems, a single microsystem will not be able to fully capture the functional complexity of the human organ.  To accommodate this challenge, applicants may propose to develop several modular microsystems during the UH2 phase that model different cellular architecture and/or physiological functions of a given organ.  When integrated the function of these modular microsystems should be more representative of the physiological complexity of a given organ system, than any single module on its own.  The investigator should indicate how the microsystem(s) will be integrated with other microsystems during the UH3 phase and demonstrate during the UH2 phase, the feasibility of creating an integrated system(s).

B. UH3 Phase

The UH3 phase will be awarded, after an administrative review, to investigators whose UH2 projects have successfully met their milestones, demonstrated functionality of their microsystems, and have a well conceived plan to scale up to a fully integrated model during the 3-year Phase II period.  To meet the goal of an integrated multisystem platform, the UH3 phase may involve the development of consortia through the integration of UH2 projects that best represent multiple tissue or organ microsystems. During the UH3 phase, funding will be provided towards integration of the modular microsystems into organoids or into multi-organoid systems using either an integrated microphysiological platform developed under the DARPA initiative or an alternative platform that supports multisystem function and analysis. These integrated microsystems are expected to mimic or simulate the complex physiology and biology of the human body, including vascularization and innervation, as well as hormonal, humoral and immunological signaling.  The integrated systems should also be able to mount physiologically relevant responses to metabolic challenges while providing simultaneous evaluation of primary and secondary effects of drugs, toxins, pathogens, particulates and other agents on different tissues. Ideally an integrated system should also capture developmental aspects of human biology and disease. Disease models should capture common disease processes, such as fibrosis, acute inflammation, chronic inflammation, etc. The integrated microsystem should not lose any of the characteristics of its components.

The criteria to determine which of the Phase I (UH2) projects will be continued into the UH3 phase will include the following:

1. Successful achievement of the defined milestones for the Phase I period of the project

2. Potential for meeting the goals of the initiative towards a fully integrated microsystem(s)

3. Ability to work within a consortium arrangement with other UH2 awardees to meet the goals of the initiative.

4. The availability of funds

5. Program balance

The UH3 phase of the grant application should address what microsystems will comprise the integrated platform, the rationale and value of the proposed combination of microsystems, the level of complexity that will be addressed, the plans for integration, as well as, consideration of the diverse readouts that can potentially arise when joining individual microsystems within a multisystem platform, including computational challenges that may arise when combining data from varied readouts and from integrated microsystems. The UH3 phase should also identify the characteristics or features of the platform that will be required for successful integration.

The UH3 plans should also include plans for validation of the system against known drugs that have succeeded in animal trials but failed in humans, or drugs that have the intended on-target effects but unacceptable side-effects on other organ systems.

C.  Milestones

Both the UH2 and UH3 must have a section labeled "Milestones" that includes milestones that are quantifiable and have clear go/no go decisions.  Milestones must address the critical areas identified for the UH2 phase of the application and outlined in Section 1 under Research Scope, UH2 Phase.  Milestones for the UH3 phase must address the integration of one or more microsystems within a multisystem platform.  Please see Section IV.6 for additional information.

The following are key aspects of this FOA:

Section II. Award Information
Funding Instrument

Cooperative Agreement

Application Types Allowed

New

The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

The total amount of funds available is $12 million total costs per year for the UH2 phase. In FY12-13, the UH2 phase will support between 10-15 awards. Following administrative review, it is anticipated that the UH3 phase will support between 3-5 awards made up of UH2 successful projects under a consortium agreement.  The total amount of funds available during the UH3 phase is $14 million total costs per year. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.

Award Budget

The expected direct cost amount for UH2 awards is approximately $450,000-$675,000 (total costs not to exceed $1.125 million) for each of the two years of the award. Budgets for the UH3 phase should reflect the complexity of integrating 1 or more microsystems into a multisystem platform developed under the DARPA initiative or an alternative platform that supports multisystem function and analysis. The estimated amount of funds available for support of the UH3 phase, with the anticipation that 3-5 projects will be awarded as a result of this announcement, is $2.8 million total costs per year.

Award Project Period

This FOA will use the UH2/UH3 cooperative agreement to support the development and integration of microphysiological systems representing tissue and organs of the human body.  The program will be funded in two phases, as allowed by this mechanism.  The initial two-year development phase (UH2) will support development of modular microsystems that will support development of integrated systems during the three-year scale-up phase (UH3). 

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Foreign Institutions

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.

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.   

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Requesting an Application Package

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the “Apply for Grant Electronically” button in this FOA or following the directions provided at Grants.gov.

2. Content and Form of Application Submission

It is critical that applicants follow the 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.

Letter of Intent

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

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

The letter of intent should be sent to:

Margaret Sutherland, PhD for the Regulatory Science Microsystems Working Group
Program Director, Neurodegeneration
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard.
Neuroscience Center, Room 2203
Bethesda, MD 20892
Telephone: (301) 496-5680
Fax: (301) 480-1080
Email: sutherlandm@ninds.nih.gov  

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

All page limitations described in the SF424 Application Guide and must be followed, with the following exceptions or additional requirement:

PHS 398 Research Plan Component

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

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies; GWAS) as provided in the SF424 (R&R) Application Guide, with the following modifications:

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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.

4. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

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

Applicants should include in their budgets sufficient funds to attend bi-annual workshops to be held in conjunction with investigators funded under the DARPA initiative https://www.fbo.gov/index?s=opportunity&mode=form&id=d12e2f420cb12f75d61a8682623c3a79&tab=core&_cview=1 and the FDA.  The yearly budget for the bi-annual workshops to be held in the greater Washington, D.C. metro area is not to exceed $6,000.

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (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.

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 SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD(s)/PI(s) Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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 Central Contractor Registration (CCR). 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 by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.  

Additional Submission Requirements

The applications sought in this FOA will propose to develop in vitro microsystems representative of human physiology for the assessment of drug or biologic candidate efficacy and toxicity. To fully assess the potential of the applicant to address the research questions, additional submission requirements and information are requested to be included within the page limits of the research strategy section of the application.

Intellectual property management plan

A primary objective for the Regulatory Science Microsystems Project is to maximize the public benefit of the data and resources produced under this project. Accordingly, awardees should manage intellectual property (IP) and data in a way that achieves this goal. The IP and data management plan may be included with the Plan for Sharing Research Data. 

Restrictive licensing and sharing practices for Regulatory Science Microsystems project data and resources could substantially diminish the value and public benefit provided by the coordinated NIH, DARPA and FDA Regulatory Science Microsystems Initiative. Management practices that would prevent or block access to, or use of Regulatory Science Microsystems project data and resources for research use will be considered to be hindering the goals of the Regulatory Science Microsystem Initiative. Applicants are encouraged to clearly demonstrate in an IP Management plan how their strategies will achieve the desired public benefit and programmatic goals through effective sharing of Regulatory Science Microsystem project data and tools.

The Government may, at its discretion, provide Authorization and Consent and/or Patent Indemnity clauses (see below) to the grantee at the time of the award.

Authorization and Consent".

(a)  The Government authorizes and consents to all use and manufacture of any invention described in and covered by a United States patent in the performance of this Cooperative Agreement.

Notice and Assistance Regarding Patent and Copyright Infringement.

(a) The Grantee shall report to the NIH Program Director, promptly and in reasonable written detail, each notice or claim of patent or copyright infringement based on the performance of this Cooperative Agreement of which the Grantee has knowledge.

(b) In the event of any claim or suit against the Government on account of any alleged patent or copyright infringement arising out of the performance of this Cooperative Agreement or out of the use of any supplies furnished or work or services performed under this Cooperative Agreement, the Grantee shall furnish to the Government, when requested by the Program Director, all evidence and information in possession of the Grantee pertaining to such suit or claim. Such evidence and information shall be furnished at the expense of the Government except where the Grantee has agreed to indemnify the Government.

(c) The Grantee agrees to include, and require inclusion of, this clause in all subawards and subcontracts at any tier for supplies or services (including construction and architect-engineer subawards and subcontracts and those for material, supplies, models, samples, or design or testing services).

Patent Indemnity.

(a) The Grantee shall indemnify the Government and its officers, agents, and employees against liability, including costs, for infringement of any United States patent (except a patent issued upon an application that is now or may hereafter be withheld from issue pursuant to a Secrecy Order under 35 U.S.C. 181) arising out of the manufacture or delivery of supplies or materials or the performance of services under this Cooperative Agreement, or out of the use or disposal by or for the account of the Government of such supplies or materials.

(b) This indemnity shall not apply unless the Grantee shall have been informed as soon as practicable by the Government of the suit or action alleging such infringement and shall have been given such opportunity as is afforded by applicable laws, rules, or regulations to participate in its defense. Further, this indemnity shall not apply to:

(1) An infringement resulting from compliance with specific written instructions of the Program Director; or

(2) An infringement resulting from an addition to, or change in, supplies or components furnished by commercial vendors or collaborators or construction work performed that was made subsequent to delivery or performance by commercial sources or contract research organizations.

Sharing Research Resources

NIH policy expects that grant recipients make unique research resources readily available for research purposes to qualified individuals within the scientific community after publication (See the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm and http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part7.htm#_Toc54600131). Investigators responding to this funding opportunity should include a sharing research resources plan addressing how unique research resources will be shared or explain why sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by NIH Program staff when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each Non-Competing Grant Progress Report (PHS 2590). See Section VI.3., “Reporting.”

Applicants should discuss the following:

Availability of biological resources utilized and/or developed (cell lines, reporter systems);

Availability of technologies and protocols developed with funds from this award.

Other Special Performance Requirements

The research project will be a collaborative effort between the awardee and the NIH. The NIH will provide scientific and regulatory guidance in the implementation of the proposed projects.  To facilitate the DARPA, FDA and NIH partnerships, NIH will request that applicants also share outcomes of peer review, post award evaluations, and investigator submitted applications and reports in response to RFA RM-11-022 with these agencies.  Instructions on how to share the information will be posted at the NIH Regulator Science Website: http://commonfund.nih.gov/regulatoryscience/. At a minimum, the applicant must explicitly indicate their willingness to:

1. Work with NIH to participate in semi-annual meetings, during the course of the grant award to be held in the Washington, D.C. greater metro area;

2. Cooperatively interact with NIH in support of the project and activities;

3. Actively seek input from NIH regarding resource needs or expertise needs that may arise during the performance of the project;

4. If needed to work within a consortium agreement to meet the goals of the initiative;

5. Participate in quarterly conference calls with NIH, DARPA and FDA staff.

Applications Involving the NIH Intramural Research Program

The requests by NIH intramural scientists will be limited to the incremental costs required for participation.   As such, these requests will 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 or F&A costs).  These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses.  Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits. 

If selected, appropriate funding will be provided by the NIH Intramural Program.  NIH intramural scientists will participate in this program as PD(s)/PI(s) in accord with the Terms and Conditions provided in this FOA.  Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights. 

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application.  The intramural scientist may submit a separate request for intramural funding as described above.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115,

Section V. Application Review Information

1. Criteria

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.

Overall Impact

Reviewers will provide an overall impact/priority 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).

Scored Review Criteria

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.

Significance

Does the project address an important problem or a critical barrier to progress in the field? 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? Does the research address a critical need in developing the proposed microsystem for a given organ or tissue?    If the aims of the project are achieved, how will technological advances and/or health be improved? Will the new approach/methodology have a competitive advantage over existing/alternate approaches and have the potential to inform future medical product development? Does the microsystem have the potential to be readily adaptable in drug efficacy and toxicity testing?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or 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(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Do project team members and/or associated collaborators have prior experience and/or necessary qualifications to successfully execute and implement the proposed research including, where appropriate, the ability to partner and collaborate with other scientists or organizations? Are the relationships of the key personnel to the applicant organization and, if applicable, to other partnering organizations (e.g., Contract Research Organizations (CROs), Contract Manufacturing Organizations (CMOs), academic laboratories, clinical sites and/or strategic partners) appropriate for the work?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Does the research outcome have the potential to solve the identified problem and create significant value in informing the drug development pathway?  

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? 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? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Are the technologies or experimental approaches state of the art? Has the applicant adequately defined the disease or health state being represented in the microsystem? Is the proposed use of particular cell types sufficient to capture the complexity and normal physiology of the target organ or tissue? Does the application identify major technical risks, and are the proposed efforts to mitigate or address the risks clearly defined and feasible? Are the methods and procedures for characterizing and validating microsystems rational and clearly explained? Is the proposed transition plan to the UH3 transition phase complete and in a logical sequence to the elements of the phased UH2/UH3 as defined in Section 1? Do the evaluation plans, milestones and timelines proposed clearly identify successful completion of the UH2 and the appropriateness of advancement to the UH3 phase?    

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?Is the applicant organization concentrating on its core competencies in order to maximize its chances of success?  Has the applicant established alliances/collaborative partnerships where they are appropriate or needed to facilitate achievement of the research goals? Does the project take advantage of various bioengineering tools and cell resources available to the scientific community?  Do the letters of collaboration and institutional support show strong commitment to the project?

Additional Review Criteria

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/priority score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the six 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 six 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 Human Subjects Protection and Inclusion Guidelines.

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

 Not Applicable

Renewals

Not Applicable

Revisions

Not Applicable

Additional Review Considerations

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/priority score.

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; 3) Resource Sharing Plan: and 4) Genome Wide Association Studies (GWAS). Are the plans adequate for public release of all types of data generated through this project, including protocols, procedures, devices and other tools and resources? Are there adequate plans for release or distribution of other resources, software, or technologies developed under this award? Does the applicant have a successful record in this regard?

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by the Center for Scientific Review (CSR)), in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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

Applications will be assigned 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 NINDS Advisory Councill. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons

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

Section VI. Award Administration Information

1. Award Notices

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 the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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.

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 Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), 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:

Intellectual Property

The successful development of organ microsystems 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 Regulatory Science Microsystem 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:

Awardees are expected to make new information and materials known to the research community in a timely manner through publications, web announcements, reports to the NIH Regulatory Science Microsystem Steering Committee, and other mechanisms.

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.

Publications

The Principal Investigator will be responsible for the timely submission of all abstracts, manuscripts and reviews (co)authored by project investigators and supported in whole or in part under this Cooperative Agreement. The Principal Investigator and Project Leaders are requested to submit manuscripts to the NIH Project Scientist within two weeks of acceptance for publication so that an up-to-date summary of program accomplishments can be maintained. Publications and oral presentations of work conducted under this Cooperative Agreement are the responsibility of the Principal Investigator and appropriate Project Leaders and will require appropriate acknowledgement of NIH support. Timely publication of major findings is encouraged.

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 DHHS, PHS, and NIH policies.

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

NIH Regulatory Science Microsystem Project Scientists will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination.  However, the role of NIH Regulatory Science Microsystem Project Scientists will be to facilitate and not to direct the activities. 

Each NIH Regulatory Science Microsystem Project Scientist shall participate as a member of the NIH Microsystems Steering Committee

The Project Scientists will:

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

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 Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report 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. 

Section VII. Agency Contacts

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

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Danilo A. Tagle, Ph.D. for the Regulatory Science Microsystems Working Group
Program Director, Neurogenetics
National Institute of Neurological Disorders and Stroke
6001 NSC/ Room 2114
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: (301) 496-5745
Email: tagled@ninds.nih.gov

Or

Margaret Sutherland, Ph.D. for the Regulatory Science Microsystems Working Group
Program Director, Neurodegeneration
National Institute of Neurological Disorders and Stroke
6001 Executive Boulevard.
Neuroscience Center, Room 2203
Bethesda, MD 20892
Telephone: (301) 496-5680
Fax: (301) 480-1080
Email: sutherlandm@ninds.nih.gov 

Peer Review Contact(s)

Examine your eRA Commons account for review assignment and contact information (information appears two weeks after the submission due date).

Tom Peterson, Ph.D.
Chief of Bioengineering Sciences and Technologies (BST) IRG
MSC 7849,
6701 Rockledge Dr.
Bethesda, MD 20892
Phone: 301-408-9694
Fax:     301-480-4184
Email: petersonjt@csr.nih.gov

Financial/Grants Management Contact(s)

Tijuana Decoster, MPA
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 3258
6001 Executive Boulevard
Bethesda, MD 20892
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: decostert@mail.nih.gov

Section VIII. Other Information

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.

Authority and Regulations

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 Parts 74 and 92.


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