Participating Organization(s)
National Institutes of Health (NIH)
Components of Participating Organizations
This Funding Opportunity Announcement (FOA) is developed as a Common Fund initiative (https://commonfund.nih.gov/) through the NIH Office of the NIH Director, Office of Strategic Coordination (https://commonfund.nih.gov/). All NIH Institutes and Centers participate in Common Fund initiatives. The FOA will be administered by the National Center for Advancing Translational Sciences (NCATS) and the National Cancer Institute (NCI) on behalf of the NIH.
Funding Opportunity Title
Advancing Extracellular RNA (exRNA) Communication Research: Improved Isolation and Analysis of exRNA-Carrier Subclasses (UG3/UH3 Clinical Trial Not Allowed)
Activity Code
UG3/UH3 Exploratory/Developmental Phased Award Cooperative Agreement
Announcement Type
New
Related Notices
None
Funding Opportunity Announcement (FOA) Number
RFA-RM-18-027
Companion Funding Opportunity

RFA-RM-18-026, U54 Specialized Center - Cooperative Agreement

RFA-RM-18-028, UG3/UH3 Exploratory/Developmental Phased Award -  Cooperative Agreements
Catalog of Federal Domestic Assistance (CFDA) Number(s)
93.310
Funding Opportunity Purpose
Circulating extracellular RNAs (exRNAs) can act as endocrine signaling molecules, both locally and systemically, representing a novel paradigm in intercellular communication. ExRNAs are transported in body fluids in association with a variety of carrier vehicles of varying complexity including extracellular vesicles (EVs), ribonucleoproteins (RNPs), and lipoproteins (LPPs).  These distinct carriers protect exRNAs from degradation and are thought to contribute to the biodistribution, uptake, and functional impact of exRNAs in target cells.  The overarching goal of this Funding Opportunity Announcement (FOA) is to develop and evaluate innovative separation tools, technologies, and approaches that will enable the scientific community to rapidly and reproducibly sort complex biofluids into homogenous carrier populations of EVs, (including EV subsets), RNPs, and LPPs, and that also support high-throughput isolation and analysis of their extracellular RNA content and associated molecular cargo.
Posted Date
August 6, 2018
Open Date (Earliest Submission Date)
September 23, 2018
Letter of Intent Due Date(s)

September 23, 2018

Application Due Date(s)
October 23, 2018, by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on this date.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)
Not Applicable
Scientific Merit Review
February/March 2019
Advisory Council Review

May 2019

Earliest Start Date

July 1, 2019

Expiration Date
October 24, 2018
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions
It is critical that applicants follow the instructions in 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 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.
  4. Table of Contents

Background

The NIH Common Fund Extracellular RNA Communication program (https://commonfund.nih.gov/exrna) was established in 2012 to uncover fundamental principles of exRNA generation, secretion, and transport; identify and develop a catalog of exRNA found in normal human body fluids; and investigate the potential for using exRNAs in the clinic as therapeutic molecules and/or biomarkers of disease. The Common Fund supports cross-cutting programs that are expected to have exceptionally high impact. All Common Fund initiatives invite investigators to develop bold, innovative, and often risky approaches to address problems that may seem intractable or to seize new opportunities that offer the potential for transformation of research processes.

ExRNAs can act as endocrine signaling molecules, both locally and systemically, representing a novel paradigm in intercellular communication. ExRNAs are transported in body fluids in association with an array of carrier vehicles of varying complexity including extracellular vesicles (EVs), ribonucleoproteins (RNPs), and lipoproteins (LPPs). While these carriers (EVs, RBPs, and LPPs) share the functional attribute of protecting exRNAs from degradation by ubiquitous extracellular RNAses, their respective contributions to biodistribution, uptake, and/or function of their respective exRNA cargo in target cells is less clear. In humans, exRNAs have been found in virtually all body fluids examined, including blood, saliva, urine, breast milk, cerebral spinal fluid (CSF), amniotic fluid, semen, ascites, and pleural effusions. Reports in the literature suggest that exRNAs can have both protective and pathogenic roles in a variety of human diseases, and concomitantly serve as biomarkers for disease states. Taken together, the above findings highlight the important role secreted exRNAs have in regulating human health and disease.

While significant strides have been made in the field of exRNA biology, specific technological challenges remain. For example, RNA concentrations in biofluids are significantly lower than in tissues, necessitating the development of improved methods for their isolation and analysis. Currently available separation approaches are time-consuming and do not adequately discriminate exRNAs encapsulated in EVs from exRNAs associated with non-vesicular RNPs or LPPs.  Ultimately, this can lead to unintended biases in exRNA population profiling based upon the specific isolation method used.  Further, little is known about the normal physiology of exRNAs, the functional consequences of exRNA uptake, or deficiency of uptake, by recipient cells, and the level of variation existing at the subpopulation level in both normal and disease states. These technological impediments limit the utility and impact of current efforts to catalog exRNAs and assess their contribution(s) to human health and disease.

These technology challenges will be addressed in the second stage of the NIH Common Fund exRNA Communication Program – Advancing Extracellular RNA (exRNA) Communication Research. Three companion FOAs will focus on the development of tools, technologies, and resources to catalyze the field of exRNA communication research.

  • RFA-RM-18-026:  Limited Competition: Data Management and Resource Repository (DMRR) on Extracellular RNA (U54 Clinical Trial Not Allowed).  This companion FOA will support the DMRR to curate and disseminate information regarding critical reagents, and resources as well as promote and facilitate cross-project collaborations
  • RFA-RM-18-027:  Advancing Extracellular RNA (exRNA) Communication Research: Improved Isolation and Analysis of exRNA-Carrier Subclasses (UG3/UH3 Clinical Trial Not Allowed). This FOA will specifically focus on improved separation technologies to rapidly and reproducibly sort exRNA carrier vehicles (EVs, RBPs, and LPPs) and identify their respective exRNAomes and associated molecular cargo. A full description of the goals of this FOA is below in Research Objectives.
  • RFA-RM-18-028:  Advancing Extracellular RNA (exRNA) Communication Research: Towards Single Extracellular Vesicle (EV) Sorting, Isolation, and Analysis of Cargo (UG3/UH3 Clinical Trial Not Allowed). This companion FOA will specifically focus on single EV isolation and analysis tools to assess exRNA heterogeneity and enable mapping exRNAs to their cell or tissue of origin.

Development of these tools, technologies, and resources will complement Stage 1 products and fill remaining knowledge and technology gaps. A consortium-structured grant mechanism is being used to support this research initiative to facilitate the generation of community accepted standards. Meeting the goals of the Stage 2 Initiatives will have a transformative effect on the field of exRNA biology as this will enable a greater understanding of the fundamental role of exRNAs in intercellular signaling and the translational potential to diagnose and treat diseases.

Research Objectives

Determining which exRNAs are transported by each specific carrier vehicle (EV, RNP, or LPP) is essential for elucidating exRNA sorting pathways, identifying associated cargo that may confer targeting or functionality, leading to a better understanding of the role of exRNA intercellular communication in human health and disease.  Ideally, a protocol(s) for separating exRNA-carrier complexes should be (1) rapid and reproducible, (2) yield highly enriched carrier-specific exRNAs with no cross-contamination, and (3) have the capacity for high-throughput isolation and characterization of carrier-specific genomic, proteomic, and lipidomic signatures. None of the separation technologies currently employed to isolate exRNAs from culture media or biofluid (i.e., precipitation, ultracentrifugation, sequential filtration, or immunoaffinity capture) meet all these performance standard. Thus, there is a critical need to develop and validate novel tools, technologies, and approaches to segregate exRNA carriers based on their unique biophysical characteristics and to rapidly and accurately sort homogeneous carrier-specific exRNAs from complex biofluids.  Further, these approaches should incorporate high-throughput capacity for downstream analysis of their respective exRNAs and associated molecular cargo.  

This FOA will use the UG3/UH3 cooperative agreement award mechanism. The UG3 phase will focus on technology development and feasibility using cell culture, animal models, or human biofluids. Support will be provided for up to two years for the initial proof of concept studies. Following NIH administrative review, the UH3 Phase will support activities to optimize, refine, and scale-up of validated separation technologies using human biofluids. Successful technologies, information on PD/PI-generated reagents, and associated protocols will be shared with the broader community via the exRNA Portal (exRNA.org). This will be the primary deliverable of this collaborative Common Fund-sponsored program.

To be responsive to this FOA, applicants are expected to:

  • Propose separation strategy/strategies for all three of the known exRNA carriers - EVs (and EV subsets), RBPs and LPPs.
  • Outline strategy/strategies that allow for high-throughput separation and analysis of carrier-specific molecular cargo including genomics, proteomics, and lipidomics.
  • Justify how the proposed separation strategy/strategies will improve the state of the art either by enabling purification of carrier types in a way that has previously not been possible or will dramatically improve (by at least 5-fold) our ability to purify carrier types with respect to increased purity, increased speed, or decreased cost. 
  • Propose using human biofluids in the UH3 Phase.
  • Incorporate approaches to share the strategies/tools developed with the broader scientific community. 

UG3/UH3 transitions and 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.


Applicants are expected to carefully read Section IV 2 for detailed application instructions.

Program Formation and Governance

The awards funded under this FOA will be cooperative agreements (see Section VI. 2. Cooperative Agreement Terms and Conditions of Award). Close interactions among the awardees and NIH will be required to maintain this complex program. The exRNA Communication Consortium (ERCC) governance will rest with the ERCC Program Steering Committee in collaboration with NIH Program Officials, with advice from a group of External Program Consultants (EPC) providing critical scientific and managerial insights, and subject to oversight by th?e? NIH ERCC Working Group. The NIH ERCC Working Group consists of NIH programmatic staff from multiple Institutes and Centers of the NIH and the NIH Office of the Director. This group will be primarily responsible for the stewardship of the ERCC program. The NIH ERCC Working Group is chaired by the Director of the National Center for Advancing Translational Science (NCATS) and Director for the Division of Cancer Biology, National Cancer Institute (NCI). It reports to the Directors of the Office of Strategic Coordination/Common Fund and the Division of Program Coordination, Planning, and Strategic Initiatives for final funding decisions.

By participating in the exRNA Communication Consortium, the awardees are expected to agree to:

Communication Plan

  • Participate in regular (monthly) conference calls with all consortium members
  • Coordinate efforts with other awardees, in particular with the DMRR
  • Participate and present findings at meetings convened by the NIH through the DMRR twice a year in the DC area
  • Jointly publish findings in a timely manner

Performance Requirements

  • Meet yearly milestones as defined by investigators and NIH Program Official at the time of award
  • Work with, cooperatively interact with, and actively seek input from NIH

Sharing Plan

  • Broad sharing of 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 academia and industry.

The Data Management and Resource Repository? (DMRR) and designated NIH databases will be utilized for the banking and distribution of biological and clinical data. Project PD(s)/PI(s) will be expected to harmonize all data and resource generation with the DMRR. The DMRR is expected to curate and disseminate information regarding critical reagents, and resources and promote and facilitate cross-project collaborations (see RFA-RM-18-026).

Technical Assistance Webinar

All applicants are strongly encouraged to contact NIH staff to discuss the alignment of their proposed work with the goals of this FOA and the ERCC program. A technical assistance webinar will be held for potential applicants. NIH staff will be available to answer questions related to this and companion FOAs.  Participation in the webinar is optional. No pre-registration is required, but participants are asked to submit questions ahead of time to exrnacommunication@mail.nih.gov. The slides as well as some frequently asked questions will be available at https://commonfund.nih.gov/exrna following the webinar.

Webinar Information:

The webinar will be held on August 24, 2018 from 2-3:30 PM, EST.

Join us via WebEx using this link:
https://nih.webex.com/nih/onstage/g.php?MTID=ef29317fb2d940f2f6f0c3c410e5df5ff

Call-in toll number (US/Canada): 1-650-479-3208 

Event number: 629 822 206

Event password: exRNA

See Section VIII. Other Information for award authorities and regulations.
Funding Instrument
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
Application Types Allowed
New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Clinical Trial?
Not Allowed: Only accepting applications that do not propose clinical trials

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards
The NIH Common Fund (Office of Strategic Coordination) intends to commit $2.5M per year in FY2019 and FY2020 and $5M per year in FY2021 and FY2022 to fund up to 5 awards. The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Award Budget
Application budgets must not exceed $300,000 direct costs per year for the UG3 Phase (FY2019 and FY2020) and $650,000 direct costs per year for the UH3 Phase (FY2021 and FY2022).
Award Project Period
The maximum project period is 4 years (FY19-FY22);each phase is a maximum of 2 years.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

1. Eligible Applicants

Eligible Organizations

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 , including the NIH intramural Program
  • 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)
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed. 
Required Registrations

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) (formerly CCR) – 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.
  • 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.

Eligible Individuals (Program Director/Principal Investigator)
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.

3. Additional Information on Eligibility

 

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)

1. Requesting an Application Package

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.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in 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.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
 
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
  • Descriptive title of proposed activity
  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
  • Names of other key personnel
  • Participating institution(s)
  • Number and title of this funding opportunity
 
The letter of intent should be sent to:
 
Kevin Howcroft, Ph.D.
Telephone: 240-276-6229
Email: Howcrofk@mail.nih.gov
Page Limitations
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed
Instructions for Application Submission
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.
SF424(R&R) Cover
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Project/Performance Site Locations
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Other Project Information
All instructions in the SF424 (R&R) Application Guide must be followed.
SF424(R&R) Senior/Key Person Profile
All instructions in the SF424 (R&R) Application Guide must be followed.
 

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

PDs/PIs are required to attend an initial kick-off meeting and bi-annual Consortium Meetings in the Washington, D.C. area. Funds to support travel of the PD(s)/PI(s) and any necessary staff to attend the kick-off and bi-annual Consortium Meetings should be included in the budget.
R&R Subaward Budget
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Cover Page Supplement
All instructions in the SF424 (R&R) Application Guide must be followed.
PHS 398 Research Plan
All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: In the single Specific Aims attachment, 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:
The UG3/UH3 phases must be submitted as a single application but the aims and approaches should be clearly organized into two stages:  UG3 Development (phase 1) and UH3 Optimization (phase 2). All projects should be milestone-driven with clear go/no-go criteria that are quantifiable.
Milestones and the timeline for each stage must be provided in a separate heading at the end of the Approach section for each UG3 and UH3 component and include the following:

  • Provide detailed quantitative criteria by which milestone achievement will be assessed.
  • Provide a detailed timeline (Gantt chart) for the anticipated attainment of each milestone and the overall goal.
  • Provide a description of the hypothesis to be tested in the UH3 phase of the study.
  • Yearly quantitative milestones are required to provide clear indicators of a project's continued success or emergent difficulties.
  • 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 phase at the end of Year 2 and transition to the UH3 phase for 2 years of additional funding.

Appropriate benchmarks for assessing milestones and project transitions will be negotiated between the NIH and applicant prior to funding decisions and will be specified in the Notice of Award.

The UG3 Development Phase:Transition Milestone for transition from the UG3 Phase to the UH3 Phase

UG3 projects will support feasibility and proof of principle studies of novel separation technologies using in vitro cell culture media and human or animal model biofluids. Studies will focus on identifying and validating biophysical attributes that can be applied in separating distinct exRNA carrier populations with high fidelity and establishing thresholds for purity (i.e., percent contamination from other carriers). Molecular tools as well as genetic and/or barcoding-based systems that allow assessment of separation performance (i.e., recovery, purity, functional output) of specific carrier subclasses are also encouraged.  The emphasis of the UG3 phase is to develop separation technologies capable of rapidly separating EV, RNP and LPP carriers into highly pure populations from a single sample biofluid.  While one integrated separation protocol is preferred, UG3 investigators will need to be flexible in the design and execution of their specific proposals through collaboration with other UG3 groups in identifying the optimum protocol(s) for each carrier subclass and to develop best practices specific for each carrier type. Applicants should:

  • Provide a description of the hypothesis to be tested in the UG3 phase of the study.
  • Provide a description of a protocol(s) for separating exRNA-carrier complexes (EVs and their subsets, RBPs, and LPPs) that is (1) rapid and reproducible, (2) yields highly enriched carrier-specific exRNAs with no cross-contamination, and (3) has the capacity for high-throughput isolation and characterization of carrier-specific genomic, proteomic, and lipidomic signatures.
  • Include an approach that incorporates high-throughput capacity for downstream analysis of exRNA-carrier complexes and their respective exRNAs and associated molecular cargo including genomics, proteomics, and lipidomics.
  • Provide justification for how the proposed separation strategy/strategies will improve the state of the art either by enabling purification of carrier types in a way that has previously not been possible or will dramatically improve (by at least 5-fold) our ability to purify carrier types with respect to increased purity, increased speed, or decreased cost.
  • Incorporate approaches to share the strategies/tools developed with the broader scientific community via the exRNA Portal (exRNA.org).
  • Transition to the UH3 Optimization Phase:

    UG3 projects that have met specific scientific milestones and other requirements (listed below) will be eligible for transition to the second UH3 Optimization Phase after NIH administrative review. 

    • Successful achievement of the defined milestones (including go/no-go conditions) for the UG3 Development Phase of the project.
    • Potential for meeting the goals of improved isolation and analysis of exRNA-carrier subclasses.
    • Evidence of interacting with the DMRR; work with the outside community and disseminate resources or tools generated in an expedient manner.
    • Availability of funds.
    • Program priorities.
    • Consistent with recent NIH guidance on rigor and reproducibility in research (https://grants.nih.gov/reproducibility/index.htm), the most important milestone for the transition will be independent validation of any separation tools/technologies/approaches. To achieve this milestone, each applicant must set-aside approximately 10% (Direct Costs) of year 2-4 funds to establish a collaboration(s) with a group(s) who will independently validate and provide an assessment of the potential utility of the tools/technologies/approaches.
    • These awards will be assessed and renewed on an annual basis, with renewal contingent on successful attainment of goals and milestones.


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

    Applications must be supported by clearly identified Go/No-Go transition milestones for completion of the UG3 phase at the end of Year 2 and transition to the UH3 phase and timelines for assessing progress.

    The UH3 Optimization Phase:

    The UH3 Optimization Phase of the proposal should focus on the optimization, refinement, and scale-up of validated separation technologies and must include the use of human biofluids.  Projects should determine the exRNA cargo associated with each highly purified carrier class. Resulting datasets should be compared against previously deposited exRNA Atlas datasets (http://exrna-atlas.org/) to determine the contribution of each carrier subclass to the bulk exRNA recovered from each biofluid.  Activities supported in by the UH3 phase include, but are not limited to:

    • Optimizing tools/technologies/approaches developed during the UG3 Phase using one or more human biofluids.
    • Developing reagents/tools/assays to detect and isolate exRNA carriers based on their specific biophysical attributes or modifications.
    • Cataloging extracellular RNPs capable of transporting exRNAs and their specific exRNAomes.
    • Identifying biophysical attributes capable of improving separation of carrier subsets.
    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.

    The following modifications also apply:

    • All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. 
    • Applicants should indicate their willingness to abide by all data deposition, quality control metrics, standardization, metadata requirements, data and software release, and public copyright license policies developed by the exRNA Program Steering Committee and approved by NIH staff.  A primary goal of the exRNA program is to facilitate discoveries by the broad scientific community. Restrictive licensing terms and sharing practices for exRNA-generated data, tools, and resources could substantially diminish their value and public benefit. Accordingly, awardees should manage data, resources, protocols, tools, and software in a way that achieves this goal. Sharing practices that would hinder, prevent or block access to or use of exRNA program data, tools, and resources for research purposes will be considered to be hindering the goals of the exRNA program. The development of policies, methods, and standards for such sharing is critically important.  The NIH expects that the awardees, through the exRNA Program Steering Committee, will develop such policies, methods, and standards in concert with the NIH.  These policies, methods, and standards will remain consistent with NIH-wide policies on data and resource sharing.
    • Specific Plan for Data Sharing: Consistent with achieving the goals of this program, the NIH expects that information such as collected data (e.g. metabolomic, lipidomic, proteomic, etc.), technical protocols, and any other data or metadata collected under this FOA is to be deposited as appropriate into existing, publicly available data repositories that are easily accessible, and in machine readable format. Applicants must adhere to FAIR data principles (Findable, Accessible, Interoperable, and Reusable), data standards and processes to be determined by the NIH Data Commons, and evolving NIH data policies. Where appropriate, applicants should identify such repositories and plans for deposition. For datatypes that lack suitable public repositories, applicants should indicate their willingness to identify an appropriate alternative solution that is consistent with achieving the goals of the program. Data should also be made available as appropriate via the exRNA Portal that will serve as the central access point for information regarding data, critical tools, protocols and reagents being developed by the exRNA program.
    • Genomic Data Sharing Plan:  If applicants propose to generate transcriptomic or other types of genomic data, they must indicate their willingness to abide by the NIH Genomic Data Sharing Policy (https://gds.nih.gov/) and should indicate their agreement to it in the data sharing plan.
    • Specific Plan for Protocol, Tool, and Reagent Sharing: As one of the primary goals of this program is to advance research through development, establishment, broad dissemination and use of community resources across the research community, NIH intends that protocols, tools, and reagents generated by the exRNA program be broadly available and distributed at minimal cost, and without undue intellectual property constraints, so that they can be as widely used as possible for research purposes by the larger scientific community.  For all applications and where otherwise applicable, the applicant should discuss plans for sharing and distribution of non-data resources that will be generated by the proposed project, including protocols, instrument design specifications, animal strains, plasmids, viruses, antibodies, chemical compounds, biomaterials, and other reagents. 
    • The exRNA DMRR will work with all exRNA program investigators to collect, curate, and disseminate information regarding tools and reagents being developed by the program and to disseminate this information through the exRNA Portal and other sources as appropriate and consistent with achieving the goals of the program.
    • Specific Plan for Sharing Software:  A software dissemination plan, with appropriate timelines, is expected in applications that are developing software.  There is no prescribed single license for software produced in this project; however, reviewers will be asked to evaluate the software sharing and dissemination plan based on its likely impact. A dissemination plan guided by the following principles is thought to promote the largest impact:
        • The software should be freely available to biomedical researchers and educators in the non-profit sector, such as institutions of education, research institutions, and government laboratories.
        • The terms should also permit the dissemination and commercialization of enhanced or customized versions of the software, or incorporation of the software or pieces of it into other software packages.
        • To preserve utility to the community, the software should be transferable such that another individual or team can continue development in the event that the original investigators are unwilling or unable to do so.
        • The terms of software availability should include the ability of researchers outside the project and its collaborating projects to modify the source code and to share modifications with other colleagues.  An applicant should take responsibility for creating the original and subsequent "official" versions of a piece of software.
        • Applicants are asked to propose a plan to manage and disseminate the improvements or customizations of their tools and resources by others.  This proposal may include a plan to incorporate the enhancements into the "official" core software, may involve the creation of an infrastructure for plug-ins, or may describe some other solution.
        • Any software dissemination plans represent a commitment by the institution (and its subcontractors as applicable) to support and abide by the plan.
    • Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds (NIH Research Tools Policy (http://grants.nih.gov/grants/intell-property_64FR72090.pdf) and other related NIH sharing policies at http://sharing.nih.gov).

    Sharing within the ERCC

    The ERC program aims to maximize the benefits of sharing, while protecting the intellectual property of the data generators. Prepublication sharing of data within the consortium will allow collaboration across initiatives and further the progress of the ERC Program towards its goals and objectives. Therefore, the ERC program requires that data, metadata, and resources generated from ERC funding be made available to other ERCC members immediately upon being considered “shareable”. When ERC-generated material under embargo is shared within the ERCC, it will be considered confidential with the understanding that the information will not be used or disclosed by ERCC members unless explicitly agreed upon by the originator of the data under mutually acceptable terms. That is, Consortium members may not publish using material generated by other consortium members without a collaboration or other agreement, or until the material in question has been made available to the public . As such, ERCC investigators accessing embargoed material only available to members of the ERCC must sign a non-disclosure form agreeing to these terms.

    Prior to funding, NIH Program Staff may negotiate modifications to the Sharing Plan with the applicant.

    Appendix:
    Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
    PHS Human Subjects and Clinical Trials Information
    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

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

    PHS Assignment Request Form
    All instructions in the SF424 (R&R) Application Guide must be followed.
     
    Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
     

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

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

    4. Submission Dates and Times

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

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

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

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

    5. Intergovernmental Review (E.O. 12372)

    This initiative is not subject to intergovernmental review.

    6. Funding Restrictions

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

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

    7. Other Submission Requirements and Information

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

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

    For assistance with your electronic application or for more information on the electronic submission process, visit 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.

    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 Common Fund through the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs 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.
    Post Submission Materials
    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.

    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.

    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 need not have substantial preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the UG3 and UH3 Phases.

    Overall Impact
    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).
    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.

     

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

    Specific to this FOA:

    • How well has the applicant addressed potential hurdles in the development of technology for carrier separation and characterization?  
    • Does the UG3 phase focus on technology development and feasibility using cell culture, animal models, or human biofluids? 
    • Does the UH3 phase include at least one human biofluid? Are the methods scalable? 
    • If the proposed aims of the project are fully successful, will the strategy or technology dramatically change the ability of the scientific community to measure exRNA carriers and their cargo?

     

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

    Specific to this FOA:

    • Has the PD/PI or investigative team previously shown the ability to participate in, or lead, large complex projects? 
    • Does the PD/PI have experience in working collaboratively within a consortium or comparable groups?
    • Does the PD/PI or investigative team have a proven record of technology innovation?
    • Does the PD/PI or investigative team have expertise in exRNA isolation in human and animal biofluids?

     

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

    Specific to this FOA:

    • Will the proposed separation strategy/strategies improve the state of the art either by enabling purification of carrier types in a way that has previously not been possible or by dramatically improving (by at least 5-fold) our ability to purify carrier types with respect to increased purity, increased speed, or decreased cost?

     

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

    Specific to this FOA: 

    • Are the technologies and experimental approaches state of the art?  Will the expected results lead to advances in technologies for carrier sorting and characterization?
    • Will the separation tools, technologies, and approaches rapidly and reproducibly sort complex biofluids into homogenous carrier populations?  Will the proposed protocols yield highly enriched carrier-specific exRNAs with no cross-contamination?  Do the methods have the capacity for high-throughput isolation and characterization of carrier-specific genomic, proteomic, and lipidomic signatures? 
    • Are the proposed approaches, tools and technologies scientifically justified in relation to cell/biofluid source? Are the methods and procedures for sorting and characterizing carriers scientifically sound and clearly explained?
    • Does the application identify major technical risks, and are the proposed efforts to mitigate or address the risks clearly defined and feasible?
    • Are appropriate, quantitative milestones provided for the UG3 and UH3 stages clearly defined? Are the UG3 and UH3 milestones feasible, well developed and quantifiable with regard to the specific aims of each stage?  Is the timeline feasible and appropriate for the UG3 and UH3 stages?  Are the critical decision points (i.e. go/no go decision points) appropriate?  Are adequate criteria provided in the UG3 stage to assess milestone completion in order to make a decision to advance studies to the UH3 stage? 
    • Is the proposed transition plan to the UH3 validation phase complete and in a logical sequence to the elements of the phased UG3/UH3? Do the evaluation plans, milestones and timelines proposed clearly identify successful completion of the UG3 and the appropriateness of advancement to the UH3 phase? Is at least one human biofluid used in the UH3 Phase? 
    • Are data submission, management and support procedures described sufficiently to allow efficient and timely upload of data to the DMRR?

    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 children, justified in terms of the scientific goals and research strategy proposed?

     

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

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

     

    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 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 children 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
    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 score.

     

    Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

     

    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.

    2. Review and Selection Process

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

    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 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 appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
    • Scientific and technical merit of the proposed project as determined by scientific peer review.
    • Availability of funds.
    • Relevance of the proposed project to program priorities.

    3. Anticipated Announcement and Award Dates

    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.

    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 terms and conditions found on the Award Conditions and Information for NIH Grants website.  This includes any recent legislation and policy applicable to awards that is highlighted on this website.

    2. Administrative and National Policy Requirements

    All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General  and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

    Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency.  HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

    In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements.  FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award.  An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS.  The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

    For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/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 http://www.hhs.gov/ocr/civilrights/understanding/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.

    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.

    Definitions

    NIH exRNA Communication Working Group (WG): Consists of NIH programmatic staff from multiple Institutes and Centers of the NIH. This group will be primarily responsible for the stewardship of the exRNA Communication Program.

    Steering Committee (SC): The SC will provide coordination activities for the exRNA Communication Program. The SC will include PDs/PIs of each of the awards and NIH exRNA Communication WG members. The SC will be chaired by two PD/PIs that are nominated by the SC and approved by the NIH. The SC will establish subcommittees to oversee the development and implementation of consortium policies including data release.  The number of NIH votes may not exceed one third of the total number of votes on the SC. The number of votes from a multiple PI award will be one. Votes will inform recommendations to the NIH.

    External Scientific Consultants (ESC): The NIH exRNA Communication WG will recruit outside experts (4-6 senior scientists; non-awardees) of relevance to the exRNA Communication Program. The ESC will be responsible for reviewing and evaluating the progress of the exRNA Communications Consortium toward meeting their individual and collective goals. The ESC will be appointed by and provide recommendations to the NIH about continued support of the components of the Consortium. The membership of the ESC may be enlarged permanently, or on an ad hoc basis, as needed. The ESC will meet at least once a year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the ESC to interact directly with the awardees. Annually, the ESC will provide comments regarding progress of the Consortium and on any changes that may be necessary to the NIH.

    ExRNA Communication Consortium (ERCC): The ERCC will be made up of exRNA Communication awardees, the NIH exRNA Communication WG and other scientists and groups the SC agrees to include within the Consortium. The Consortium structure is meant to enable the overall goals of the exRNA Communication Program.

    The PD(s)/PI(s) will have the primary responsibility for:

    • Determining experimental approaches, designing protocols, setting project milestones and conducting experiments;
    • Adhere to the NIH policies regarding intellectual property, data release and other policies that might be established during the course of this activity;
    • Submit quarterly progress reports during the two year UG3, in a format as agreed upon by the exRNA Communication SC.  Projects that are selected for continued support through the UH3 mechanism will submit progress reports on a regular basis, at least biannually;
    • Accept and implement any other common guidelines and procedures developed for the NIH exRNA Communication WG and approved by the exRNA Communication SC;
    • Accept and participate in the cooperative nature of the ERCC;
    • Attend bi-annual workshops organized by the NIH and the Data Management and Resource Repository (DMRR).

    Publications

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

    Intellectual Property

    • The awardee is solely responsible for the timely acquisition of all appropriate proprietary rights, including intellectual property rights, and all materials needed for the applicant to perform the project.
    • Before, during, and subsequent to the award, the U.S. Government is not required to obtain for the awardee any proprietary rights, including intellectual property rights, or any materials needed by the awardee to perform the project.
    • The awardee is required to report to the U.S. Government all inventions made in the performance of the project, as specified by 35 U.S.C. Sect. 202 (Bayh-Dole Act).
    • Awardees will retain custody of and have primary rights to the data and resources developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

    NIH Project Scientists:

    • Participate (with the other Steering Committee 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. The Project Scientists will assist and facilitate the group process but not direct it;
    • Serve as a liaison between the awardees, the Advisory Councils for those Institutes that plan to administer elements of the NIH Common Fund Extracellular RNA Communication Program and the larger scientific community;
    • Coordinate the efforts of the awardee with others engaged in exRNA research, including other awardees under this FOA and those awardees involved in related NIH programs;
    • Attend all Steering Committee 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, NIH Institutes involved in the NIH Common Fund Extracellular RNA Communication Program and the Directors of the Division of Program Coordination, Planning, and Strategic Initiatives and Office of Strategic Coordination;
    • 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 Program Consultants.
    • Serve as liaison between the Steering Committee and the Program Consultants;
    • Serve on subcommittees/working groups of the Steering Committee as appropriate;
    • Provide advice in the management and technical performance of the investigation;
    • Assist in promoting the availability of data and resources developed in the course of this project to the scientific community at large;
    • Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action;
    • Retain the option to recommend the withholding or reduction of support from any cooperative agreement that either substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award.

    Areas of Joint Responsibility include:

    A SC will serve as the main governing board of the ERCC. The SC membership will include NIH Project Scientists and the PD/PI of each awarded cooperative agreement. The PD/PI of each award (or designee) will have one vote on the SC. The Project Scientists may vote, but the total votes will count as a maximum of one-third of the total number of votes.  The SC Chairs will not be NIH staff members. Additional members may be added by action of the SC. Other government staff may attend the SC meetings, if their expertise is required for specific discussions. The SC will:

    • Discuss progress in meeting the goals of various exRNA projects;
    • Develop recommendations for uniform procedures and policies necessary to meet the goals of the Research Network, for example for data quality measures and assessment, conventions for data deposition, or measuring costs and throughput. Adoption of procedures and policies developed by the SC will require concurrence by ESC.
    • The SC will also serve as a venue for coordination on the improvement of exRNA scientific methods, for example by disseminating best practices and collectively evaluating new procedures, resources, and technologies.
    • The SC will consider collective goals for the ERCC, will determine how joint publication of results will contribute toward the goals of the exRNA Program, and will coordinate joint publication as needed to demonstrate overarching principles of exRNAs. It will schedule the time for, and prepare concise (2 to 4 pages) summaries of, the SC meetings, which will be delivered to members of the group within 10 business days after each meeting.
    • Each full member will have one vote.  Awardee members of the SC will be required to accept and implement policies approved by the SC.

    Communication Plan

    • Participating in regular (monthly) conference calls with all NIH exRNA Communication WG members.
    • Coordinating efforts with other awardees, especially in circumstances where synergy of efforts and resources is beneficial to the overall goals of the exRNA Communication 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 exRNA Communication WG, and other mechanisms.

    Performance Requirements

    • Meeting yearly milestones as defined by investigators and NIH program at the time of award.
    • Working with, cooperatively interacting with, and actively seeking input from NIH.
    • Sharing broadly data and biological specimens within the Consortium and with the broader scientific community, using established data sharing guidelines , as appropriate and consistent with achieving the goals of the program .
    • 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 institutes supporting the awards. The workshop will go over Terms and Conditions of Award for the UG3/UH3, ERCC 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, DC area.
    • Attending one in-person “closeout meeting” at the end of the award period; this meeting will serve as a summary of accomplishments completed in the project period.
    • The NIH will enlist additional scientific experts as necessary from within the NIH, other government agencies, such as the FDA and NIST whose function will be to assist the NIH exRNA Communication WG in carrying out the goals and aims of the approved studies.
    • Consistent with recent NIH guidance on rigor and reproducibility in research (https://grants.nih.gov/reproducibility/index.htm), the most important milestone for the transition will be independent validation of any separation tools/technologies/approaches. To achieve this milestone, each applicant must set-aside approximately 10% (Direct Costs) of year 2-4 funds to establish a collaboration(s) with a group(s) who will independently validate and provide an assessment of the potential utility of the tools/technologies/approaches.

    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 Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
    A final RPPR, 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.

    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.
    Application Submission Contacts
    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

    Scientific/Research Contact(s)
    Kevin Howcroft, Ph.D.
    National Cancer Institute (NCI)
    Telephone: 240-276-6229
    Email: Howcrofk@mail.nih.gov

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

    Peer Review Contact(s)

    Maqsood Wani
    Center for Scientific Review (CSR)
    Telephone: 301-435-2270
    Email: wanimaqs@csr.nih.gov

     
    Financial/Grants Management Contact(s)
    Crystal Wolfrey
    National Cancer Institute (NCI)
    Telephone: 240-276-6277
    Email: wolfreyc@mail.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.
    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 Part 75.


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