National Institutes of Health (NIH)
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 Center for Advancing Translational Sciences (NCATS) (http://www.ncats.nih.gov/) on behalf of the NIH Common Fund Program on Extracellular RNA Communication http://commonfund.nih.gov/extracellular_RNA/.)
Funding Opportunity Title
Clinical Utility of Extracellular RNA for Biomarker Development (UH2/UH3)
Funding Opportunity Announcement (FOA) Number
Companion Funding Opportunity
RFA-RM-12-010, U54 Specialized Center--Cooperative Agreements on "Data Management and
Resource Repository (DMRR) on Extracellular RNA (U54)"
Catalog of Federal Domestic Assistance (CFDA) Number(s)
Funding Opportunity Purpose
The NIH invites applications for projects that will identify and qualify extracellular RNA (exRNA)-based biomarkers derived from human body fluids, such as blood, saliva, urine, breast milk, amniotic fluid, cerebrospinal fluid, ascites and pleural effusions, in order to diagnose and monitor disease progression and response to therapy. The overall goal of this project is to develop reliable, well-defined and clinically relevant biomarkers derived from extracellular RNA that measure tangible benefits for patients in terms of how they feel, function, and survive in clinical trials. Appropriate studies under this FOA will identify and validate candidate exRNA-based biomarkers in well-defined patient populations, provide new technologies to monitor biomarkers or establish reliable assays for validated markers
Studies using existing human biospecimen collections are strongly encouraged. This FOA is only for studies related to human biomarkers; animal or other non-human disease model studies are not responsive to this FOA.
Funds from the NIH will be made available through the UH2/UH3 cooperative agreement award mechanism. The initial UH2 phase will support 1-2 year studies to identify and develop exRNA-based biomarkers from human body fluids. Transition to qualification and validation studies in the remaining 3-4 years will be supported during the UH3 phase. Awards funded under this FOA are anticipated to involve activities conducted by multidisciplinary teams of investigators.
August 3, 2012
Open Date (Earliest Submission Date)
October 12, 2012
Letter of Intent Due Date
October 12, 2012
Application Due Date(s)
November 13, 2012, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)
Scientific Merit Review
February - March, 2013
Advisory Council Review
Earliest Start Date(s)
November 14, 2012
Due Dates for E.O. 12372
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.
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
The concept that RNA molecules are secreted in the extracellular spaces and act as endocrine signals to alter the phenotypes of target cells, both locally and at distant sites, represents a novel paradigm in intercellular signaling. Recent advances in RNA sequencing technologies have identified a large and diverse population of extracellular RNA (exRNA) including microRNA and long non-coding RNA (lncRNAs). Given that approximately 60% - 80% of all protein encoding genes are regulated by microRNA and certain lncRNAs have been linked to regulation of the epigenome, extracellular delivery of these RNAs could have profound implications for a wide range of physiologic and pathologic processes.
In humans, exRNAs are found in all body fluids examined, including blood, saliva, urine, breast milk, cerebral spinal fluid (CSF), amniotic fluid, ascites, and pleural effusions. Recent reports in the literature suggest that exRNAs have both protective and pathogenic roles in a variety of human diseases. Further, functional plant- and microbe-derived exRNAs have been identified in human serum and cells, suggesting that trans-kingdom exRNA communication could explain some associations between environmental exposures and health or disease.
Taken together, the above findings highlight the transformative potential that secreted RNAs may have in the regulation of health and disease. However, to realize the potential that exRNAs may have as health/disease indicators and/or as therapeutic molecules, fundamental principles of their biogenesis, distribution, uptake, and function need to be defined. While exRNAs are known to be encapsulated in extracellular vesicles (EVs), recent studies have also demonstrated their presence in nuclease-resistant complexes with RNA-binding carrier proteins, such as HDL and Argonaut, in serum. A better understanding of exRNA sorting to different secretory pathways, regulation of secretion, mechanisms of targeting, and effector function in target cells would generate opportunities to identify novel strategies for prognosis, diagnosis, and intervention of many diseases.
The Common Fund Extracellular RNA Communication Program has been developed to address critical issues in this nascent field. Both fundamental scientific discovery and innovative tools and technologies will be required to advance the field. The key components (and associated FOAs) that need attention include: (a) defining the fundamental principles of exRNA biogenesis, distribution, uptake, and function, developing the molecular tools, technologies, and imaging modalities to enable these studies (RFA-RM-12-012 ), (b) generating a reference catalog of exRNAs present in the body fluids of normal healthy individuals that would facilitate disease diagnosis and therapeutic outcomes (RFA-RM-12-011), (c) demonstrating the clinical utility of exRNAs as therapeutic agents and/or biomarkers and developing the scalable technologies required for these studies (This FOA and RFA-RM-12-014); and (d) developing a community resource, the exRNA Atlas, to provide access to exRNA data, standardized exRNA protocols, and other useful tools and technologies generated by the exRNA consortium (RFA-RM-12-010). Awards funded under these FOAs are anticipated to involve activities conducted by multidisciplinary teams of investigators. Awardees from all 5 initiatives will form a consortium, with the overarching goal of determining fundamental principles associated with exRNAs. Comparisons across studies will be essential to establish these cross-cutting principles so investigators must be willing to act as part of the consortium.
This initiative is funded through the NIH Common Fund, which 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 rapid progress.
The goal of this FOA is to promote the identification and validation of exRNA-based biomarkers readily available from human body fluids, such as serum, plasma, saliva, urine, semen, breast milk, amniotic fluid, cerebrospinal fluid, ascites and bronchoalveolar lavage fluid, and to facilitate the assessment and qualification of biomarkers for their utility in the clinical setting. During the UH2 phase, support will be provided for proof of principle studies to develop biomarkers that are robust. i.e. have been shown to correlate with biological function, disease states or response to treatment, and readily available from existing human biofluid specimen collections. The proposed studies should include the comparative analysis of exRNAs produced from healthy vs patients. Following NIH administrative review, the UH3 phase will build upon successful UH2 projects and support qualification and validation studies wherein the biomarker has been demonstrated during the UH2 phase to reliably support a specified manner of interpretation and application in its declared “context of use (CoU)”.
A. Definition of Biomarkers
A biomarker can be defined as a physical, functional, or biochemical indicator of a normal physiological or disease process that has diagnostic and/or prognostic utility. A biomarker can be an indicator of a disease process, and can replace symptomatic or phenotypic clinical end points as a measure of the effect of new therapies. The ability to study and treat disease and to develop effective interventions are hampered by a lack of unique, reliable, quantifiable, easily measured biomarkers that correlate well with disease progression. Different types of biomarkers have been identified, including:
B. Research Scope
The UH2/UH3 phases must be submitted as a single application but the approach should be clearly organized into two stages: UH2 (phase 1) and UH3 (phase 2). UH2/UH3 applications are limited to 12 pages for the Research Strategy section including milestones, timeline, and future plans.
1. UH2 phase
During the UH2 phase, the NIH is interested in exploratory studies to identify novel biomarkers derived from exRNA obtained from human biofluids with characteristics unique to human disease conditions that might lead to potential clinical utility. An ideal biomarker can be measured in a minimally invasive way, can be measured repeatedly over time, is indicative of disease prognosis, and correlates well with progression and response to therapy. Priority will be given to those projects with high promise and technical feasibility for clinical use in the relatively near future.
The UH2 phase of the grant application should address the following critical areas: 1) plans to identify leads for potentially useful biomarkers; 2) plans to prioritize identified leads; 3) computer modeling or simulations and/or statistical justification for the number of subjects/samples proposed; clear scientific rationale for the range and types of subjects/samples to be used and involvement of key personnel with statistical expertise; 4) attention paid to variability in patient demographics, histology, prognosis, stage, and mode of detection; 5) matching of control subjects with case subjects; 6) outcome measures or primary data items for analysis reflecting sensitivity and specificity metrics; 7) sampling variability; and 7) plans for confirmatory or cross validation studies with a new set of bio-specimens. The successful conduct of confirmatory studies might form the basis for a successful transition into the UH3 phase.
2. UH3 phase
The UH3 phase will support validation and qualification studies of biomarkers resulting from a successful UH2 phase. Validation has been described as the process of linking a biomarker to clinical or behavioral endpoints. The process of validation is complex, but includes assay characterization and establishing the clinical utility and superiority of a new biomarker relative to standard tests. It also involves multidisciplinary expertise. In addition to an understanding of the employed technology and clinical knowledge of the disease of interest, the expertise needed to validate clinical biomarkers may include assay development and quality control, epidemiology and biostatistics. Qualification refers to the process where the biomarker has been demonstrated to reliably support a specified manner of interpretation and application in its declared “Context of Use (CoU)”
Projects supported during the UH3 phase will include: 1) studies in human subjects to determine whether a biomarker correlates well with pathogenesis, disease processes, progression or regression of disease, response to therapy, accepted clinical endpoints, symptom management, etc.; 2) studies to design or improve the biomarker assay system to be robust, quantitative, reliable, and translatable to many laboratories, or to fall within costs that are appropriate for clinical use. Clinical assay must be shown to distinguish subjects with disease from control subjects; 3) studies to establish sampling or biomarker monitoring strategies that are non-invasive and/or amenable to patients and clinical staff; 4) studies to determine the relationship between biomarker measurements made from biofluids compared to those measurements obtained from tissues; 5) studies to assess factors, such as sex, age, smoking behavior, etc., that are associated with biomarker status or level in control subjects; 6) studies to assess factors associated with biomarker status or level in case subjects—in particular, disease characteristics such as stage, histology, grade, and prognosis; and 7) studies to evaluate, as a function of time before clinical diagnosis, the capacity of the biomarker to detect preclinical disease, i.e. assess the impact of covariates on the discriminatory abilities of the biomarker before clinical diagnosis, including demographics, disease-related characteristics, and other clinical information about the subject.
Certain validation studies appropriate for this FOA may require the resources of a funded or completed clinical trial as ancillary studies. As appropriate, all ancillary study applications must include a letter or statement documenting that the patients, samples, data, and/or materials are available from the parent clinical trial and that the proposed ancillary study has the approval of the parent study’s investigators.
3. Transition from UH2 to UH3 phases
The criteria to determine which of the Phase I (UH2) projects will be continued into the UH3 phase will include the following:
I. Successful achievement of the defined milestones for the Phase I period of the project
II. Potential for meeting the goals of the initiative
III. Ability to work within a consortium arrangement with other awardees to meet the goals of the initiative.
IV. The availability of funds
V. Program balance
C. ExRNA Consortium Agreement
A key component of this program is the formation of consortium partnerships amongst all awardees. Each Notice of Grant Award will require the execution of an Inter-Institutional Agreement by the grantee. A template for Inter-Institutional Agreements should serve as a guidance document to provide a framework under which consortium relationships are established. This and other templates, such as for Confidential Disclosure Agreements (CDAs) and Collaborative Research Agreements (CRAs), have been developed by the NIH Office of Technology Transfer). By participating in the consortium, the awardees are expected to agree to:
The 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 Data Management and Resource Repository (DMRR). The DMRR is expected to curate and disseminate information regarding critical reagents, and resources as well as promote and facilitate cross-project collaborations (see RFA-RM-12-010).
Application Types Allowed
Funds Available and Anticipated Number of Awards
The total amount of funds for the UH2 phase is $4 million total costs per year.
The UH2 phase will support between 6-8 awards. The total amount of funds available for the UH3 phase is $6-8 million total costs per year. Following administrative review, it is anticipated that the UH2 awardees who have met their milestones will be eligible to transition to the UH3 phase. Awards issued under this FOA are contingent upon the availability of funds and the submission of a sufficient number of meritorious applications.
Applicants may request up to $500,000 total costs for the UH2 phase and $1,000,000 total costs for the UH3 phase.
Award Project Period
This FOA will use the UH2/UH3 cooperative agreement mechanism to support the development and validation of biomarkers derived from exRNA obtained from human biofluids. The program will be funded in two phases, as allowed by this mechanism. The initial development phase (UH2) can be for 1-2 years, and the second phase (UH3) can support qualification and validation studies for 3-4 years. The maximum period of support for the combined UH2 and UH3 phases is 5 years.
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.
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
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.
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
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.
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.
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.
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.
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.
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.
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:
Danilo A. Tagle, Ph.D.
Associate Director for Special Initiatives
National Center for Advancing Translational Sciences (NCATS)
Democracy I Building, Room 992
6701 Democracy Blvd.
Bethesda, MD 20892 USA
Telephone: (301) 594-8064
FAX (301) 480-3661
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.
All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:
Milestones and Timeline:
A timeline (Gantt chart) including milestones is required for all studies. Milestones are goals that create go/no-go decision points in the project and must include clear and quantitative criteria for success. Yearly quantitative milestones are required in order to provide clear indicators of a project's continued success or emergent difficulties and will be used to evaluate the application not only in peer review but also in consideration of the awarded project for funding of non-competing award years. The application must include clearly-specified, well-defined milestones, quantitative go/no go decision points, and timelines for assessing progress in both the UH2 and UH3 stages, including specific milestones and timeline for progressing from the UH2 stage to the UH3 stage. Milestones and the timeline for each stage must be provided in a separate heading at the end of the Approach section for each UH2 and UH3 component.
a) Provide detailed quantitative criteria by which milestone achievement will be assessed.
b) Provide a detailed timeline for the anticipated attainment of each milestone and the overall goal.
c) Identify any impediments that could require an addendum to the research plan, milestones, or timeline with a discussion of alternative approaches.
Milestones and UH2/UH3 Transition
i) Prior to funding an application, the Program Official will contact the applicant to discuss the proposed UH2 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 UH2 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 UH2 stage and progress towards interim milestones in the UH3 stage.
ii) For funded UH2 applications, projects that have met the scientific milestones and feasibility requirements will be eligible for rapid transition to the second UH3 stage after NIH administrative review. Awardees will submit a progress report to both the Grants Management Specialist and the Program Official upon completion of the UH2 milestones and any revisions to the proposed UH3 aims. Prior to initiation of the UH3 stage, an updated human subject's protection plan (e.g., protocol amendment, IRB approval of amendments to the protocol or consent form, etc.) and a detailed data and safety monitoring plan (DSMP) if appropriate, must be approved by NIH. Receipt of this progress report will trigger an administrative program review that will determine whether or not the UH3 should be awarded.
iii) The release of UH3 funds will be based on successful completion of the approved scientific milestones, program priorities, and the availability of funds. UH3 milestones will be the basis for judging progress towards and completion of interim milestones in the UH3 stage.
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 modification:
Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
Foreign (non-US) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.
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.
This initiative is not subject to intergovernmental review.
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
Applicants should include in their budgets sufficient travel-related funds to attend bi-annual workshops to be held in conjunction with investigators funded under this Common Fund program on Extracellular RNA Communication. 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.
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.
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/PI 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.
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.
Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.
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.
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).
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? 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: Does the biomarker/delivery approach have the potential to be readily adaptable in the clinical setting? If successfully established, will the biomarker have significant impact on the relevant disease or condition and will it represent a substantial improvement over existing methods for assessing health status?
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?
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? Will the new approach/methodology have a competitive advantage over existing/alternate approaches and have the potential to inform future medical product development and clinical intervention? Does the research outcome have the potential to solve the identified problem and create significant value in informing the development of biomarkers for the defined disease condition?
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?
Specific to this FOA: Are the technologies or
experimental approaches state of the art? Will the expected results lead
to advances in technologies used in the diagnosis and treatment of human
diseases? If the application focuses on a particular disease model, are the
proposed approaches, tools and technologies scientifically justified? 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 biomarkers scientifically sound
and clearly explained? Is the proposed transition plan to the UH3 validation
phase complete and in a logical sequence to the elements of the phased UH2/UH3?
Do the evaluation plans, milestones and timelines proposed clearly identify
successful completion of the UH2 and the appropriateness of advancement to the
UH3 phase?? Are data submission, management and support procedures described
sufficiently to allow efficient and timely upload of data to the DMRR? Are
appropriate, quantitative milestones provided for the UH2 and UH3 stages
clearly defined? Are the UH2 and UH3 milestones feasible, well developed and
quantifiable with regard to the specific aims of each stage? Is the timeline
feasible for the UH2 and UH3 stages? Are the critical decision points (i.e.
go/no go decision points) and timelines appropriate for the UH2 and UH3 stages?
Are adequate criteria provided in the UH2 stage to assess milestone completion
in order to make a decision to advance studies to the UH3 stage?
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? If the UH3 phase involves studies ancillary to a funded or completed clinical trial, is there sufficient documentation indicating that the patients, samples, data, and/or materials are available from the parent clinical trial and that the proposed ancillary study has the approval of the parent study’s investigators?
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 the best available tools and resources available to the scientific community? Do the letters of collaboration and institutional support show strong commitment to the project?
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.
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.
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.
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
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.
Select Agent Research
Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).
Resource Sharing Plans
Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genome Wide Association Studies (GWAS).
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.
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. 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 on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:
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.
If the application is under consideration for funding, NIH
will request "just-in-time" information from the applicant as
described in the NIH Grants
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.
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:
The successful development of biomarkers and/or therapeutics from exRNA 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 Extracellular RNA Communication Program. NIH recognizes that intellectual property rights may 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 Common Fund Extracellular RNA Communication Steering Committee, and other mechanisms.
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.
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.
NIH staff has substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:
NIH Common Fund Extracellular RNA Communication 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 Common Fund Extracellular RNA Communication Project Scientists will be to facilitate and not to direct the activities.
Each NIH Common Fund Extracellular RNA Project Scientist shall participate as a member of the NIH Common Fund Extracellular RNA Communication Steering Committee.
The Project Scientists will:
Areas of Joint Responsibility include:
A Steering Committee will serve as the main governing board of the Extracellular RNA Communications Consortium. The Steering Committee 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 Steering Committee. The Project Scientists may vote, but the total votes will count as a maximum of one-third of the total number of votes. The Steering Committee Chair will not be an NIH staff member. Additional members may be added by action of the Steering Committee. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions. The Steering Committee will:
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.
External Scientific Consultants:
The External Scientific Consultants (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 Consultant Panel is composed of four to six senior scientists with relevant expertise who are not PIs of a cooperative agreement involved in 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.
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.
We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.
GrantsInfo (Questions regarding application instructions and
process, finding NIH grant resources)
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)
Danilo A. Tagle, Ph.D.
Associate Director for Special Initiatives
National Center for Advancing Translational Sciences (NCATS)
Democracy I Building, Room 992
6701 Democracy Blvd.
Bethesda, MD 20892 USA
Telephone: (301) 594-8064
FAX (301) 480-3661
Richard Panniers, Ph.D.
Genes, Genomes and Genetics
Center for Scientific Review (CSR)
Phone: (301) 435-1741
Office of Grants Management
National Center for Advancing Translational Sciences
Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.
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