Department of Health and Human Services
Part 1. Overview Information

 

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Allergy and Infectious Diseases (NIAID)

Funding Opportunity Title

Immunobiology of Xenotransplantation (U19 Clinical Trial Not Allowed)

Activity Code

U19 Research Program – Cooperative Agreements

Announcement Type

Reissue of RFA-AI-14-047

Related Notices

None

Funding Opportunity Announcement (FOA) Number

RFA-AI-19-043

Companion Funding Opportunity

RFA-AI-19-042, U01  – Cooperative Agreements

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

93.855

Funding Opportunity Purpose

This Funding Opportunity Announcement (FOA) invites applications from institutions to participate in the Immunobiology of Xenotransplantation Cooperative Research Program (IXCRP), for the development of preclinical porcine-to-nonhuman primate (NHP) models of pancreatic islet, kidney, heart, lung, or liver xenotransplantation. The goals of this program are to: (1) delineate the cellular and molecular mechanisms of xenograft rejection and/or the induction of immune tolerance; (2) develop effective strategies to improve xenograft survival; and (3) characterize and address the physiological compatibility/limitations of xenografts. The long-term goal of this program is to develop strategies for application of xenotransplantation in the clinic.

Key Dates

 

Posted Date

May 30, 2019

Open Date (Earliest Submission Date)

August 16, 2019

Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Date(s)

September 16, 2019, 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 2020

Advisory Council Review

May 2020

Earliest Start Date

June 2020

Expiration Date

September 17, 2019

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.


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. Table of Contents

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

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


    Part 2. Full Text of Announcement
    Section I. Funding Opportunity Description
    Purpose

    This Funding Opportunity Announcement (FOA) invites applications from institutions to participate in the Immunobiology of Xenotransplantation Cooperative Research Program (IXCRP). The goals of this program are to: (1) delineate the cellular and molecular mechanisms of xenograft rejection and/or the induction of immune tolerance; (2) develop strategies to improve xenograft survival; and (3) characterize and address the physiological compatibility/limitations of xenografts. The long-term goal of this program is to develop strategies for the application of xenotransplantation in the clinic. This FOA solicits only applications for research projects studying swine-to-nonhuman primate (NHP) models of islet, kidney, heart, lung, or liver xenotransplantation. All qualified investigators are invited to apply.

    Background

    Transplantation is often the preferred or only therapy for end-stage organ disease, yet the number of patients on waiting lists greatly exceeds the number of available organs. In 2018, over 114,000 patients were on the United Network for Organ Sharing (UNOS) waiting lists, but ~34,000 organ transplants were performed in the United States. It is estimated that 20 people on average die each day while waiting for a transplant.  Xenotransplantation offers a potential interim or definitive solution to the severe shortage of human organs for transplantation or as a source of pancreatic islets for transplantation. The swine is the primary species of interest as an unlimited source of donor organs for xenotransplantation due to its favorable reproductive capacity, and anatomical and physiological similarities to humans. However, xenotransplantation poses significant challenges, including the immune response of the recipient against the xenograft (hyperacute, acute, and chronic rejection), the physiological limitations of organs, cells or tissues functioning in a xenogeneic environment, and potential transmission of zoonotic pathogens.

    To address these challenges, the IXCRP was established by the National Institute of Allergy and Infectious Diseases (NIAID) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in 2005 (RFA-AI-04-042) and renewed by NIAID in 2010 (RFA-AI-09-035) and in 2015 (RFA-AI-14-047 and RFA-AI-14-048).  NIAID is strongly committed to the long-range goal of the IXCRP, which is to translate preclinical models of xenotransplantation to clinical application. IXCRP investigators and other researchers in the field have made significant advances toward this goal over the past two decades, emphasizing the value of continued support in this challenging area of research.

    Historically, the most significant hurdle to successful xenotransplantation was hyperacute rejection, which is caused by preformed xenoreactive naturally-occurring antibodies (XNA) that can destroy the xenograft within minutes to a few hours of transplantation. The primary target of XNA is the gal epitope [(galactosyl alpha-(1,3)-galactosyl beta-1,4-N-acetyl glucosaminyl, (alpha-1,3 gal)], a non-reducing oligosaccharide not present in humans, apes, and Old World monkeys.  To overcome this hurdle, genetically-modified pigs deficient in alpha-1,3 gal expression were developed over a decade ago by knocking out the gene for alpha-1,3 glycosyltransferase, (GT), the enzyme that is required for alpha-1,3 gal expression. Xenografts from GT knockout (GTKO) pigs to NHPs elicit substantially less severe hyperacute rejection. Recently, additional XNA to pig antigens have been identified. While these XNA may not elicit as severe an immune response as alpha-1,3 gal, further genetic modifications in donor pigs have eliminated two of these xenogenic antigens, N-glycolylneuraminic acid (Neu5Gc), a product of the enzyme, cytidine monophosphate-N-acetylneuraminic acid hydroxylase, and SDa glycan, a product of the enzyme beta-1,4N-acetylgalactosaminyltransferase.

    In the last decade, pigs with additional genetic modifications, including genetic deletions and expression of single or multiple human transgenes, have been developed to address many of the species-to-species incompatibilities. Most of the genetic modifications are on the GTKO background pig and result in more human-like organs. Modifications include, but are not limited to, insertion of human complement regulatory proteins to minimize the deleterious effects of the complement cascade in antibody-mediated rejection; human thrombomodulin and/or tissue factor pathway inhibitor to overcome coagulation pathway dysfunction; and human anti-inflammatory and/or immune suppressive genes to circumvent immune responses and graft rejection. These strategies have dramatically reduced the frequency and severity of hyperacute rejection and have prolonged survival in pig-to-NHP xenotransplantation models for as long as 2-3 years.  Application of CRISPR-Cas 9 technology combined with somatic cell nuclear transfer cloning has significantly accelerated the pace of multi-gene modification and donor pig production. Overall, genetically modified pigs provide opportunities to address the physiological and immunological barriers to xenotransplantation, including acute and chronic rejection, and to test regimens for immune tolerance induction to xenografts.

    Physiological incompatibilities within the xenogeneic environment, e.g. rate of xenograft growth, xenograft lifespan, and non-immunologic incompatibility, are areas that remain largely unexplored.  Success in prolonging xenografts survival will allow investigation of these issues. Transmission of zoonoses to the human recipient and then more broadly to the general population is a potential concern. To reduce this risk, animals used for xenotransplantation can be bred in specific-pathogen-free conditions, caesarian-derived, and routinely screened to eliminate most, if not all, known zoonotic agents. Historically, porcine endogenous retroviruses (PERV) have been a concern; however, with the advent of CRISPR-Cas9 technology, investigators have eliminated PERV proviruses from the pig's genome.   

    Research Scope

    This FOA will continue the IXCRP to develop and evaluate preclinical swine-to-NHP models of xenotransplantation. Research in this program will address immunological and physiological issues critical to the engraftment, survival, and function of xenografts. This FOA solicits only applications for research projects studying swine-to-NHP models of islet, kidney, heart, lung, or liver xenotransplantation. The research focus may include: (1) delineation of the cellular and molecular mechanisms of xenograft rejection and/or immune tolerance induction; (2) development of strategies to prolong xenograft survival, including immune tolerance induction; and (3) characterize and address the physiological compatibility/limitations of xenografts. 

    Examples of research topics may include, but are not limited to the following:

    • Elucidation of the mechanisms of and development of strategies to prevent hyperacute, acute and chronic rejection;
    • Characterization of the host innate and adaptive immune responses to the xenograft;
    • Evaluation of regimens to induce immune tolerance and/or delineation of mechanisms of tolerance induction;
    • Development and characterization of life-supporting models of xenotransplantation;
    • Development of effective strategies, including genetic modifications of organs/tissues/cells or utilization of encapsulation, to prolong xenograft survival and to eliminate or minimize the use of immunosuppressive drugs; and,
    • Characterization of physiological interactions between the xenograft and host, and development of strategies to overcome physiological incompatibilities.

    Applications including the following will be deemed non-responsive and will not be reviewed:

    • Swine-to-NHP xenotransplantation studies of any other organs except, pancreatic islets, kidney, heart, lung, or liver;
    • Small animal models of xenotransplantation, such as rodent models, unless the model is proposed only as an in- vivo bioassay of large animal immune function (e.g. trans in -vivo delayed type hypersensitivity assay);
    • Clinical trials or clinical/human studies of xenotransplantation.  However, using human cells/blood as an experimental tool in the NHP-swine model is allowed (e.g. perfusion of the pig organ with human blood); and,
    • Studies of zoonotic agents or infections, such as Porcine Endogenous Retrovirus (PERV), except for monitoring for the presence of zoonoses in the donor and/or recipient.

    Applicants are strongly encouraged to discuss the proposed research with the  Scientific/Research contact well in advance of the application submission deadline.

    Milestones

    Explicit, detailed, quantitative yearly milestones will be used by NIAID program staff in assessing progress and recommending continued funding on an annual basis.

    Steering Committee

    Program Directors/Principal Investigators (PD(s)/(PI(s)) of awards funded under this program will form a Steering Committee after award. The Steering Committee will serve as the main governing body of the IXCRP. Among other responsibilities, it will identify scientific opportunities, emerging needs, and impediments; ensure the timely release of data through publications, develop guidelines for the publication of collaborative research project results, and prepare cumulative consortium progress reports. For detailed information on the Steering Committee and related guidelines, see Cooperative Agreement Terms and Conditions of Award.   

    Each PD/PI (one PD/PI if multiple PDs/PIs) from each U01 or U19 award and an additional Project Leader (PL) from each U19 award will serve as voting members of the IXCRP Steering Committee, follow the policies and procedures developed and approved by the Steering Committee with NIAID Project Scientist concurrence.  Each Steering Committee and subcommittee member will participate in Steering Committee activities, teleconferences, and attend Steering Committee meetings to be held near Bethesda, MD, unless another location is agreed to by NIAID.

     
    The Immunology Database and Analysis Portal (ImmPort)

    The Immunology Database and Analysis Portal (ImmPort) program will provide support for public sharing of research data and experimental protocols of IXCRP. ImmPort is a data sharing platform funded by the NIAID, which has developed templates for data collection, standardization and sharing from various NIAID-supported research programs. The IXCRP awardees will participate with ImmPort in the development of data standards for IXCRP specific data types, where applicable, and be responsible for collecting and submitting data and documents into ImmPort. The IXCRP Steering Committee will provide information, consistent with the goals of the program and NIH policy, regarding research data and experimental protocol sharing within the IXCRP and with the public.

    The National Swine Resource and Research Center (NSRRC)

    The Office of Research Infrastructure Programs within the Division of Program Coordination, Planning, and Strategic Initiatives in the Office of the NIH Director supports the National Swine Resource and Research Center (NSRRC), which is co-sponsored by NIAID and the National Heart, Lung, and Blood Institute (NHLBI). The NSRRC was established in 2003 to develop the infrastructure needed to ensure that biomedical investigators across a variety of disciplines have access to critically needed swine models of human health and disease. The purpose of the NSRRC is to provide the biomedical research community enhanced access to critically needed swine models and to develop genetically modified swine when required for studies involving human health and diseases, including xenotransplantation. Therefore, NIAID encourages IXCRP-funded investigators to submit the relevant cell lines and animal models developed under this FOA to the NSRRC, where applicable.

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

    Section II. Award Information
    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
    Renewal

    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

    NIAID intends to commit $2.8 million in FY 2020 for the IXCRP to fund two to three (U01 and/or U19) awards.

    Award Budget

    Application budgets are not limited but need to reflect the actual needs of the proposed project. As a guideline, the approximate level of funding in direct costs for similar U19 awards has been approximately $1.2 million per year.

    Award Project Period

    Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. 

    The total award period requested for this FOA may not exceed five years.

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

    Section III. Eligibility Information
    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:

    o   Hispanic-serving Institutions

    o   Historically Black Colleges and Universities (HBCUs)

    o   Tribally Controlled Colleges and Universities (TCCUs)

    o   Alaska Native and Native Hawaiian Serving Institutions

    o   Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

    Nonprofits Other Than Institutions of Higher Education

    • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
    • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

    For-Profit Organizations

    • Small Businesses
    • For-Profit Organizations (Other than Small Businesses)

    Governments

    • State Governments
    • County Governments
    • City or Township Governments
    • Special District Governments
    • Indian/Native American Tribal Governments (Federally Recognized)
    • Indian/Native American Tribal Governments (Other than Federally Recognized)
    • Eligible Agencies of the Federal Government
    • U.S. Territory or Possession

    Other

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

    Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
    Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

    Foreign components, as defined in the NIH Grants Policy Statement, are not allowed.

    Required Registrations

    Applicant Organizations

    Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

    • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
    • System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
    • o   NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM. 
    • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. 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.

    An applicant may only serve as PD/PI on only one application in response to this FOA or its companion. However, a PD/PI may serve as a Senior/Key Personnel or Other Significant Contributor on another scientifically distinct application to this FOA or its companion.   

    2. Cost Sharing

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

    3. Additional Information on Eligibility
    Number of Applications

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

    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).
    Section IV. Application and Submission Information
    1. Requesting an Application Package

    The application forms package specific to this opportunity must be accessed through ASSIST or an institutional system-to-system solution. A button to apply using ASSIST is 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 Multi-Project (M) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise and where instructions in the Application Guide are directly related to the Grants.gov downloadable forms currently used with most NIH opportunities. 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.

    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:

    Zhuqing "Charlie" Li, PhD
    Telephone: 240-669-5068
    Fax: 301-480-2408
    Email: liz@niaid.nih.gov

    Page Limitations

    Available Component Types

    Research Strategy/Program Plan Page Limits

    Overall

    12

    Admin Core

    6

    Core (Scientific Core)

    6

    Research Projects

    12

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

    Instructions for the Submission of Multi-Component Applications

    The following section supplements the instructions found in the SF424 (R&R) Application Guide, and should be used for preparing a multi-component application.

    The application should consist of the following components:

    • Overall: required
    • Administrative Core: required, maximum of 1
    • Scientific Cores: optional, no minimum or maximum
    • Research Projects: required, minimum of 2 and no maximum
    Overall Component

    When preparing your application, use Component Type ‘Overall’.

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

    SF424 (R&R) Cover (Overall)

    Complete entire form.

    PHS 398 Cover Page Supplement  (Overall)

    Note: Human Embryonic Stem Cell lines from other components should be repeated in cell line table in Overall component.

    Research & Related Other Project Information (Overall)

    Follow standard instructions.

    Project/Performance Site Location(s) (Overall)

    Enter primary site only.

    A summary of Project/Performance Sites in the Overall section of the assembled application image in eRA Commons compiled from data collected in the other components will be generated upon submission.

    Research & Related Senior/Key Person Profile (Overall)

    Include only the Project Director/Principal Investigator (PD/PI) and any multi-PDs/PIs (if applicable to this FOA) for the entire application.

    A summary of Senior/Key Persons followed by their Biographical Sketches in the Overall section of the assembled application image in eRA Commons will be generated upon submission.

    Budget (Overall)

    The only budget information included in the Overall component is the Estimated Project Funding section of the SF424 (R&R) Cover.  

    A budget summary in the Overall section of the assembled application image in eRA Commons compiled from detailed budget data collected in the other components will be generated upon submission.

    PHS 398 Research Plan (Overall)

    Specific Aims: List in priority order, the broad, long-range objectives and goals of the proposed program.  Concisely and realistically describe the hypothesis or hypotheses to be tested.   

    Research Strategy:  This section summarizes the overall research strategy for the multi-component application.  The multi-component application should be viewed as a confederation of interrelated research projects, each capable of standing on its own scientific merit, but complementary to one another.  This is an important section as it provides the investigators an opportunity to give conceptual wholeness to the overall program, by giving a statement of the general problem area and by laying out a broad strategy for attacking the problems.  As the strategy develops, each project and core should be cited briefly as to its place in the overall scheme.  Summarize the special features in the environment and/or resources that make this application strong or unique.

    Applicants may describe in the Overview section synergy, how the individual components (research projects and shared resource cores) will be coordinated and work together to address the overall goals and aims of the program and indicate collaborations, shared expertise, and leveraging of resources (protocols, reagents, animal models etc.), as applicable. In addition, applicants may address optimizing interactions between projects and cores to achieve milestones and timelines of the program.  Schematics highlighting the interactions among the investigators and components and overall program milestones and timelines are encouraged. Also, describe general plans for overall staffing and effective project management of the program and its components.

    Letters of Support: If the proposed study includes biological samples, reagents, or animals obtained from another person, institution, or company or not currently in the possession of the PD/PI, the application should include a letter of support from the person, institution, or company controlling the animals/reagents indicating that these research tools or animals will be made available to the applicant and the timeline for availability, if applicable. 

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

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

    All investigators funded under this FOA will be expected to share their data publicly through ImmPort or other public portals approved by NIH. Therefore, the Data Sharing plan should include a summary of how the applicant will manage data submission and interactions with ImmPort. In addition, NIAID encourages IXCRP-funded investigators to submit all animal models and/or relevant cell lines developed under this FOA funding into the National Swine Resource and Research Center (NSRRC; http://www.nsrrc.missouri.edu), if applicable. NIAID expects IXCRP investigators to provide an outline of the plan, including timeframes for the periodic depositing of animal models and/or cell lines into the NSRRC or another repository, if applicable.

    Appendix:

    Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.   

    PHS Human Subjects and Clinical Trials Information (Overall)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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, there must be at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or a Delayed Onset Study record within the application. The study record(s) must be included in the component(s) where the work is being done, unless the same study spans multiple components. To avoid the creation of duplicate study records, a single study record with sufficient information for all involved components must be included in the Overall component when the same study spans multiple components.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

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

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

    PHS Assignment Request Form (Overall)

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

    Administrative Core

    When preparing your application, use Component Type ‘Admin Core.’

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

    SF424 (R&R) Cover (Administrative Core)

    Complete only the following fields:

    • Applicant Information
    • Type of Applicant (optional)
    • Descriptive Title of Applicant’s Project
    • Proposed Project Start/Ending Dates
    PHS 398 Cover Page Supplement (Administrative Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Administrative Core)

    Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

    Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Administrative Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Administrative Core)
    • In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Core Lead’ and provide a valid eRA Commons ID in the Credential field.
    • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.
    • The PD/PI or one of the PD/PIs of multi-PD/PI application must be also serve as Administrative Core Leader.
    • Multiple Core Leads are NOT permitted for an Administrative Core.   
    Budget (Administrative Core)

    Budget forms appropriate for the specific component will be included in the application package.

    Applicants should include appropriate travel budgets to accommodate travel by the PD(s)/PI(s), each Project Leader and one key personnel to the annual Steering Committee meeting in Bethesda, MD.

    Applicants should budget for a minimum of 0.6 person months per year for the Administrative Core Leader.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Administrative Core)

    Specific Aims: List in priority order, the broad, long-range objectives and goals of the Administrative Core. Describe the work to be completed to address issues of program coordination, communication, and management. In addition, state the core’s relationship to the goals and how it relates to the individual research projects or other cores in the application.      

    Research Strategy: Provide a plan addressing the short- and long-term management of the program, including: a discussion of the structure and roles of administrative and scientific staff; prioritization of project goals; communication between project leaders; internal data and resource sharing; and fiscal management. Include a discussion on the rationale and feasibility of the proposed timelines and performance objectives outlined in the management plan.   

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

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

    All investigators funded under this FOA will be expected to share their data publicly through ImmPort or other public portals approved by NIH. Therefore, the Data Sharing plan should include a summary of how the applicant will manage data submission and interactions with ImmPort. In addition, NIAID encourages IXCRP-funded investigators to submit all animal models and/or relevant cell lines developed under this FOA funding into the National Swine Resource and Research Center (NSRRC; http://www.nsrrc.missouri.edu), if applicable. NIAID expects IXCRP investigators to provide an outline of the plan, including timeframes for the periodic depositing of animal models and/or cell lines into the NSRRC or another repository, if applicable.

    Appendix:

    Only limited items are allowed in the Appendix.Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.   

    PHS Human Subjects and Clinical Trials Information (Administrative Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

    Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

    Scientific Core

    When preparing your application, use Component Type ‘Core.’

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

    SF424 (R&R) Cover (Scientific Core)

    Complete only the following fields:

    • Applicant Information
    • Type of Applicant (optional)
    • Descriptive Title of Applicant’s Project
    • Proposed Project Start/Ending Dates
    PHS 398 Cover Page Supplement (Scientific Core)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Scientific Core)

    Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

    Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Scientific Core)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Scientific Core)
    • In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Core Lead’ and provide a valid eRA Commons ID in the Credential field.
    • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used. 
    • Multiple Core Leads are NOT permitted for a Scientific Core.   
    Budget (Scientific Core)

    Budget forms appropriate for the specific component will be included in the application package.

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Scientific Core)

    Specific Aims: List in priority order the broad, long-range objectives and goals of the proposed core. In addition, state the core’s relationship to the goals and how it relates to the individual research projects or other cores in the application.      

    Research Strategy: Use this section to describe how the proposed Core activities will contribute to meeting the Program’s goals and objectives in two or more projects and explain why the core resources are not otherwise available. In addition, this section should indicate the relevance of the Core to the primary theme of the application. The application must indicate the specific projects to be served by the Scientific Core(s). The activities of Scientific Cores must not overlap with those of a proposed project. Scientific Cores should provide broad-based support for routine activities that individual projects may need to accomplish the goals.  Scientific Cores must provide support to at least two Research Projects. If applicable discuss how work would be prioritized and expected usage of the core services for the overall program.    

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

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

    • All investigators funded under this FOA will be expected to share their data publicly through ImmPort or other public portals approved by NIH. Therefore, the Data Sharing plan should include a summary of how the applicant will manage data submission and interactions with ImmPort. In addition, NIAID encourages IXCRP-funded investigators to submit all animal models and/or relevant cell lines developed under this FOA funding into the National Swine Resource and Research Center (NSRRC; http://www.nsrrc.missouri.edu), if applicable. NIAID expects IXCRP investigators to provide an outline of the plan, including timeframes for the periodic depositing of animal models and/or cell lines into the NSRRC or another repository, if applicable.

    Appendix:

    Only limited items are allowed in the Appendix. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.   

    PHS Human Subjects and Clinical Trials Information (Scientific Core)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

    Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

    Research Projects

    When preparing your application, use Component Type ‘Project.’

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

    SF424 (R&R) Cover (Research Projects)

    Complete only the following fields:

    • Applicant Information
    • Type of Applicant (optional)
    • Descriptive Title of Applicant’s Project
    • Proposed Project Start/Ending Dates

    PHS 398 Cover Page Supplement (Research Projects)

    Enter Human Embryonic Stem Cells in each relevant component.

    Research & Related Other Project Information (Research Projects)

    Human Subjects: Answer only the ‘Are Human Subjects Involved?’ and 'Is the Project Exempt from Federal regulations?’ questions.

    Vertebrate Animals: Answer only the ‘Are Vertebrate Animals Used?’ question.

    Project Narrative:  Do not complete. Note: ASSIST screens will show an asterisk for this attachment indicating it is required. However, eRA systems only enforce this requirement in the Overall component and applications will not receive an error if omitted in other components.

    Project /Performance Site Location(s) (Research Projects)

    List all performance sites that apply to the specific component.

    Note: The Project Performance Site form allows up to 300 sites, prior to using additional attachment for additional entries.

    Research & Related Senior/Key Person Profile (Research Projects)

    • In the Project Director/Principal Investigator section of the form, use Project Role of ‘Other’ with Category of ‘Project Lead’ and provide a valid eRA Commons ID in the Credential field.
    • In the additional Senior/Key Profiles section, list Senior/Key persons that are working in the component.
    • Include a single Biographical Sketch for each Senior/Key person listed in the application regardless of the number of components in which they participate. When a Senior/Key person is listed in multiple components, the Biographical Sketch can be included in any one component.
    • If more than 100 Senior/Key persons are included in a component, the Additional Senior Key Person attachments should be used.   
    • Multiple Project Leads are NOT permitted for a Research Project.
    Budget (Research Projects)

    Budget forms appropriate for the specific component will be included in the application package.

    Applicants should include travel budgets to accommodate travel by the Project Leader and one key personnel to the annual Steering Committee meeting in Bethesda, MD.

    Applicants should budget for a minimum of 1.2 person months per year for the Project Lead

    Note: The R&R Budget form included in many of the component types allows for up to 100 Senior/Key Persons in section A and 100 Equipment Items in section C prior to using attachments for additional entries. All other SF424 (R&R) instructions apply.

    PHS 398 Research Plan (Research Projects)

    Specific Aims: List, in priority order, the Specific Aims of the proposed project. Concisely and realistically describe the hypothesis or hypotheses to be tested. In addition, state the individual Research Project’s relationship to the Program goals and how they relate to other Research Projects or Cores in the application.

    Research Strategy: All applications for the IXCRP should provide a clear research plan and project goals to be completed during the award period. The applicant should clearly state the interim objectives and explicit, detailed, and quantitative annual milestones to be achieved during the project for assessing progress and success; identify impediments or critical decision points that could require a revision in the work plan; and provide a detailed timeline for the attainment of each goal. Proposed

    projects should demonstrate applicability to future clinical applications.

    Discuss the proposed approach and rationale behind the proposed acquisition and preparation of the solid organs, tissues, or cells to be used in the studies.  Within the bounds of limited resources and budgetary constraints, provide a discussion of, and justification for, the numbers of animals used per experiment, with a discussion of statistical considerations and statistical soundness of the proposed experiment.  In addition, address the conclusions that can be drawn given the number of animals used.

    Letters of Support: If the proposed research includes biological samples, reagents, or animals obtained from another person, institution, or company or not currently in the possession of the PD(s)/PI(s), the application should include a letter of support from the person, institution, or company controlling the animals/reagents indicating that these research tools or animals will be made available to the applicant and the timeline for availability, if applicable. 

    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:

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

    All investigators funded under this FOA will be expected to share their data publicly through ImmPort or other public portals approved by NIH. Therefore, the Data Sharing plan should include a summary of how the applicant will manage data submission and interactions with ImmPort. In addition, NIAID encourages IXCRP-funded investigators to submit all animal models and/or relevant cell lines developed under this FOA funding into the National Swine Resource and Research Center (NSRRC; http://www.nsrrc.missouri.edu), if applicable. NIAID expects IXCRP investigators to provide an outline of the plan, including timeframes for the periodic depositing of animal models and/or cell lines into the NSRRC or another repository, if applicable.

    Appendix:

    Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide instructions.

    PHS Human Subjects and Clinical Trials Information (Research Projects)

    When involving NIH-defined human subjects research, clinical research, and/or clinical trials 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 a Delayed Onset Study record.

    Study Record: PHS Human Subjects and Clinical Trials Information

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

    Delayed Onset Study

    Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed

     
    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) using ASSIST or other electronic submission systems. 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.

    For information on how your application will be automatically assembled for review and funding consideration after submission go to: http://grants.nih.gov/grants/ElectronicReceipt/files/Electronic_Multi-project_Application_Image_Assembly.pdf.

    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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

    Important reminders:

    All PD(s)/PI(s) and component Project Leads 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.

    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 (SAM). 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.

    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.

    Section V. Application Review Information
    1. Criteria

    Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

    Overall Impact - Overall

    Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the program 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 program proposed).

    Scored Review Criteria - Overall

    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 program that by its nature is not innovative may be essential to advance a field.

    Significance

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

    Specific For this FOA:

    Does the proposed overall research plan demonstrate applicability to future clinical applications for xenotransplantation? 

    Investigator(s)

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

    Specific For this FOA:

    Does the PD/PI have sufficient time, effort, leadership ability, and scientific talent to develop a program of integrated research projects with a well-defined central research focus? 

    Innovation

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

    Approach

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

    If the program involves human subjects and/or NIH-defined clinical research, are the plans to address:

     1) the protection of human subjects from research risks, and

     2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?   

    Specific For this FOA:

    Are the Management and Staffing Plans appropriate to facilitate attainment of the objectives of the proposed Program?

    Are the proposed timelines and performance objectives if included for the overall Program adequate and realistic to achieve the Program goals?

    Is the proposed program cohesive as evidenced by proposed projects and cores contributing to a common theme and as appropriate are measures in place to optimize sharing of data and resources between projects?

    Environment

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

    Specific For this FOA:

    Are the plans for coordination, problem identification and resolution, and the establishment of a strong collaborative environment for the program appropriate?

    Are the individual research projects and cores well-coordinated to achieve the goals, milestones, and timelines of the program? Will collective scientific gains of the program be beyond those achievable by each project if they were pursued independently?  

    Overall Impact – Research Projects

    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 five scored review criteria, and additional review criteria (as applicable for the project proposed).

     
    Scored Review Criteria - Research Projects

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

    Significance

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

     
    Investigator(s)

    Are the Project Lead, 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?   Is the level of effort of the PD/PI sufficient to ensure success of the project? 

    Specific to the FOA

    Is there adequate scientific and technical expertise related to the design, conduct, analysis, and interpretation of porcine-to-NHP studies?

    Innovation

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

    Approach

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

    If the project involves human subjects and/or NIH-defined clinical research, are the plans to address: 1) the protection of human subjects from research risks, and

    2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?  

    Specific to this FOA

    Are  adequately detailed research approaches provided to support clear objectives, annual milestones, and timelines demonstrating appropriate, and reasonably attainable project goals?

    Are reagents, animals or therapeutics available, or is it reasonable to assume they will be developed or become available in the proposed time-frame?

    Environment

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

    Overall Impact – Administrative and Scientific Core(s)

    Reviewers will provide an overall impact score to reflect their assessment of the likelihood for each core 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 core proposed).

     
    Review Criteria – Administrative and Scientific Core(s)

    Reviewers will consider each of the review criteria below, as appropriate for the individual core, in the determination of scientific merit and provide an overall impact score for each Core but will not give separate scores for these items.

    Administrative Core

    Is the management plan for fiscal accountability and communication within the Program appropriate?

    Are plans adequate and appropriate to ensure sufficient both formal and informal communications and coordination among the investigators? 

    Is the administrative and organizational structure appropriate and adequate for the attainment of the objectives? 

    Are the experience, level of commitment, and established competence in organizing multi-project and cores demonstrated, and availability of the Administrative Core Leader and administrative staff adequate to manage the overall program?

    Scientific Core (s)

    Are the proposed Scientific Cores justified and relevant to the theme of the overall Program?

    Are the qualifications, competence, and commitment of the Core Leader and key personnel appropriate?

    Are the quality of the facilities or services provided and criteria for prioritization and usage appropriate?

    Additional Review Criteria - Overall, Research Projects, Administrative Core and Scientific Core(s)
     

    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.

    Protections for Human Subjects

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

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

    Inclusion of Women, Minorities, and Individuals Across the Lifespan  

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

    Vertebrate Animals

    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.

    Biohazards

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

    Resubmissions

    Not Applicable

    Renewals

    For Renewals, the committee will consider the progress made in the last funding period.

    Revisions

    Not Applicable

    Additional Review Considerations - Overall

    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.

    Applications from Foreign Organizations

    Not Applicable

    Select Agent Research

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

    Resource Sharing Plans

    Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: 1) Data Sharing Plan; 2) Sharing Model Organisms; and 3) Genomic Data Sharing Plan .


    Authentication of Key Biological and/or Chemical Resources

    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.

    Budget and Period of Support

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

    2. Review and Selection Process

    Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NIAID 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 National Advisory Allergy and Infectious Diseases Council. The following will be considered in making funding decisions:

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

    Section VI. Award Administration Information
    1. Award Notices

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

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

    Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

    Any application awarded in response to this FOA will be subject to 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.

    For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

    Cooperative Agreement Terms and Conditions of Award

    The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

    The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

    The PD/PI (multi-PDs/PIs) will have primary responsibility for: defining the research plan, approaches, and goals; setting project milestones and timelines to achieve the proposed goals; overseeing/performing the scientific activities; ensuring successful completion of yearly milestones within the timeframe and budget proposed; cooperating with NIAID programmatic, technical, and administrative staff; and administratively managing the award. Each PD/PI (one PD/PI if multiple PDs/PIs) from each U01 or U19 award and an additional Project Leader (PL) from each U19 award agree to serve as a voting member of the IXCRP Steering Committee, participate in all Steering Committee activities, attend Steering Committee meetings, and follow the policies and procedures developed and approved by the Steering Committee with NIAID Project Scientist concurrence.

    Although NIAID intends to support the peer-reviewed studies/specific aims, the PD(s)/PI(s), upon acceptance of an award, agrees that the awards are milestone-based and dependent. Under special circumstances (e.g., duplicative or overlapping specific aims between two awardees; lack of critical reagents; need to modify annual milestones), and at any time after award, studies, project goals, or yearly milestones may require revision by the PD/PI and re-negotiation based on peer-review, and/or NIAID Project Scientist assessment.

    The PD(s)/PI(s) agree to provide new information and materials, including research samples, tools, materials, methods, data, and animal models developed under the IXCRP to the research community and other members of this program in a timely manner through publications, web announcements, and reports to the NIAID or other mechanisms, subject to the rights described below. The PD/PI is encouraged to submit the relevant cell lines and animal models developed under this FOA to the NSRRC  or make suitable alternative arrangements for sharing of cell lines and animal models developed under this FOA, if applicable and consistent with achieving the goals of the program.  PD(s)/PI(s) will participate with ImmPort in the development of data standards for IXCRP-specific data types, where applicable, and be responsible for collecting and submitting data and documents into ImmPort.

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

    An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below.

    A program official from the NIAID Division of Allergy, Immunology, and Transplantation (DAIT) will serve as the NIAID Project Scientist for this program.  In conjunction with other NIAID scientific program staff and the IXCRP Steering Committee (see below), the NIAID Project Scientist will serve as facilitator of IXCRP activities and scientific endeavors and provide advice, technical assistance, and guidance on technical and management issues, such as reviewing progress, subcommittee requirements, identifying potential sources of reagents or other resources, and identifying potential collaborations to further the goals of the IXCRP.  However, the role of the NIAID Project Scientist will be to facilitate and not to direct the IXCRP activities.

    The NIAID Project Scientist will serve as a non-voting member of the Steering Committee and will provide assistance to the Steering Committee and subcommittees and ensure coordination of Steering Committee activities and implementation of its recommendations, decisions, and policies. It is anticipated that decisions in most Steering Committee activities will be reached by consensus, and the NIH Project Scientists will be given the opportunity to offer input into the process, but the manner of reaching this consensus and the primary decision-making responsibility will rest with the Steering Committee, except where stated in this FOA. 

    Additionally, a NIAID Program Officer will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the Notice of Grant Award. This stewardship role will include monitoring program progress and approving changes. The Government, via the NIAID Program Official, will have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports.  The NIAID Program Officer may use information obtained from the data for the preparation of internal reports on the activities of the study. Furthermore, the NIAID Program Officer will serve as a liaison/facilitator among awardees and with the ImmPort staff.  

    NIH Program Officers may also coordinate and facilitate opportunities to cooperate or collaborate with other NIH funded programs, as they arise in future years, in order to efficiently utilize research resources and rapidly exchange scientific information to promote NIH objectives in xenotransplantation research.

    Release of each annual funding increment by NIAID will be based on an NIAID Program Official review of progress towards achieving the previously agreed upon research goals, interim objectives and annual milestones. As detailed under PD/PI Responsibilities above, NIAID intends to support the peer-reviewed studies/specific aims proposed in the awarded grant applications. However, the awards are milestone-based, and the program includes the flexibility for the NIAID Project Scientist to approve redirection or renegotiation of research projects during the funding period if the revised projects remain within the scope of the original research project. This policy is in keeping with the terms and conditions of the cooperative agreement mechanism.

    Areas of Joint Responsibility include:
    Steering Committee
    • A Steering Committee will serve as the governing board of the IXCRP.  All consortium investigators will be required to accept and implement common guidelines and procedures approved by the Steering Committee. 
    • The voting members of the Steering Committee will include one PD/PI from each U01 award and two from each U19 award.  Additional PDs/PIs, Project Leaders, and NIH Program Officer(s) will serve as non-voting Steering Committee members.
    • NIH may appoint up to two external scientists or additional staff to the Steering Committee as non-voting members.  The Steering Committee may appoint additional non-voting members by majority vote.
    The Steering Committee will:
    • Serve as the main governing board;
    • Identify scientific opportunities, emerging needs, and impediments;
    • Identify opportunities for and encourage collaborations among consortium members;
    • Review progress of xenotransplantation projects at the annual Steering Committee meetings and provide guidance and recommendations to investigators regarding study implementation and conduct;
    • Establish guidelines and review procedures to provide NIAID with recommendations regarding the modification of the peer-reviewed aims, yearly milestones, and/or redirection of resources within the scope of the project, when applicable and necessary and when requested by the NIH Program Officer;
    • Establish policies for data handling and interaction with ImmPort staff, if appropriate, including protocols and standards for data collection, analysis, and management;
    • Establish protocols and subcommittees, as needed, for the review, development, and/or evaluation of   potential pilot or collaborative projects or potential resource sharing opportunities, if applicable; 
    • Develop guidelines and policies for publications, including collaborative project publications;
    • Prepare cumulative consortium progress reports, if requested by the NIH Program Officer; and,
    • Establish subcommittees as needed to provide recommendations on shared aspects of the cooperative research group, including but not limited to the activities listed above.
    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.

    Section VII. Agency Contacts

    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 submission by the due date, 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 instructions, 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)

    Nasrin Nabavi, PhD 
    National Institute of Allergy and Infectious Diseases (NIAID)
    Telephone: 240-627-3538
    Email: nnabavi@niaid.nih.gov

    Peer Review Contact(s)

    Zhuqing "Charlie" Li, PhD
    Telephone: 240-669-5068
    Fax: 301-480-2408
    Email:  liz@niaid.nih.gov

    Financial/Grants Management Contact(s)

    Kelvin Lyons
    National Institute of Allergy and Infectious Diseases (NIAID))
    Telephone: 240-627-3513
    Email:  lyonskd@niaid.nih.gov

    Section VIII. Other Information

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

    Authority and Regulations

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

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