Required Application Instructions

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

Part 1. Overview Information
Part 2. Full Text of the Announcement
Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

This Funding Opportunity Announcement (FOA) solicits applications 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 the induction of tolerance; (2) develop effective strategies to improve xenograft survival; and (3) characterize the physiological compatibility/limitations of xenografts. The long-term goal of this program is to develop novel and efficacious 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; prior funding under the IXCRP is not required.

Transplantation is often the preferred or only therapy for end-stage organ disease. In 2013, about 28,000 organ transplants were performed in the United States, but over 120,000 patients were still on the UNOS waiting list. Although active donor recruitment and primary care education programs have resulted in a gradual increase in the number of donated organs, the number of patients on waiting lists greatly exceeds the number of available organs. Transplantation of pancreatic islets is an emerging therapy for individuals with type 1 diabetes whose disease cannot be effectively managed with exogenous insulin therapy; however, the availability of human pancreases for the manufacture of islets for transplantation is severely limited. Xenotransplantation offers a potential interim or definitive solution to the severe shortage of human organs to treat patients with end-stage organ disease. Currently, the swine is the primary species of interest as an unlimited source of donor organs for xenotransplantation due to its favorable reproductive capacity, as well as anatomical and physiological similarities to humans. However, xenotransplantation poses significant challenges, including the immune response of the recipient against the xenograft (e.g. hyperacute, acute and chronic rejection), the physiological limitations of organs 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). 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 decade, 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, it is expected that additional genetic modifications may be required to address XNA incompatibilities.

In the last decade, pigs with genetic modifications expressing single or multiple human transgenes have been developed to address many of the species to species incompatibilities. The majority of the transgenes have been placed onto the GTKO background pig, resulting 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 thrombomoduline 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 prolonged survival in pig to NHP xenotransplantation models to as long as a year. Overall, genetically modified pigs provide opportunities to address many physiological and immunological barriers to xenotransplantation, including acute vascular and cellular rejection as well as chronic rejection, and to test regimens for immune tolerance induction to xenografts.

Physiological incompatibility within the xenogeneic environment is another potentially critical challenge to successful xenotransplantation. While the heart or kidney of a juvenile miniature swine is of suitable size for transplant into human, the rate and extent of graft growth as well as the lifespan of the xenograft beyond the pig’s natural lifespan of 15 years are undetermined. Successful strategies to overcome hyperacute rejection and prolong the survival of xenografts will allow opportunities to investigate whether physiological obstacles to xenotransplantation exist.

Xenotransplantation poses the potential risk of transmission of a zoonotic infectious agent from the xenograft to the recipient and then more broadly to the general population. To reduce this risk animals used as the source of xenografts can be bred in specific pathogen-free conditions, caesarian-derived, and routinely screened to eliminate most, if not all, known zoonotic agents. However, porcine endogenous retroviruses (PERV) whose DNA is integrated into the donor genome, or new and as yet unidentified infectious agents may not be removed by conventional means. Careful monitoring of xenograft recipients for evidence of transmitted zoonoses is essential.

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 tolerance induction; (2) development of effective strategies to prolong xenograft survival, including immune tolerance induction; and (3) characterization of the biology of the xenograft post-transplantation.

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

• Elucidation of the mechanisms of hyperacute, acute vascular and cellular rejection as well as chronic rejection of xenografts;
• Characterization of the host innate and adaptive immune responses to the xenograft post-transplantation;
• Evaluation of the immune responses to xenografts in different stages of development, (e.g., neonatal islet-like clusters vs. adult islets);
• Approaches to induce immune tolerance;
• Delineation of the mechanisms of immune 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 identification of and development of strategies to overcome physiological incompatibilities.

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

• Small animal models of xenotransplantation, such as rodent models, unless a rodent animal model(s) 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; and/or research using human samples.
• Studies of zoonotic agents or infections, such as PERV, except for monitoring for the presence or absence of potential zoonotic infectious agents 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.

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

PDs/PIs from 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, prepare cumulative progress reports as requested by the NIAID Program Officer. For detailed information on the Steering Committee and related guidelines, see Cooperative Agreement Terms and Conditions of Award.

The Immunology Database and Analysis Portal (ImmPort)

The NIAID Bioinformatics Information Support Contract (BISC) program will provide support for handling and housing research data and experimental protocols in ImmPort (https://immport.niaid.nih.gov/), a data sharing platform funded by the NIAID. BISC has templates for data collection from various assays and established procedures for data exchanges that can be adapted by NIAID supported research programs. The IXCRP awardees will participate with BISC 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 protocols sharing within the IXCRP and with the public.

The National Swine Resource and Research Center (NSRRC)

In 2003, the former National Center for Research Resources, now the Division of Program Coordination, Planning, and Strategic Initiatives, Office of the NIH Director (DPCPS), established a related program, the National Swine Resource and Research Center (NSRRC); http://www.nsrrc.missouri.edu/, which is co-sponsored by NIAID and the National Heart, Lung, and Blood Institute (NHLBI). The purpose of the NSRRC is to provide the biomedical research community enhanced access to critically needed swine models 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.

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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

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

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

Applicant Organizations

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

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

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

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

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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

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

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Nancy V zquez-Maldonado, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases (NIAID)
Room 3F52B, MSC 9823
5601 Fishers Lane
Rockville, MD 20892-9823
(For Express Couriers: 20852-9823)
Telephone: 240-669-5044
Email: [email protected]

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

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

Facilities and other Resources:

• Applicants should provide the source of, and timelines for, the availability or expected availability of all critical non-commercially available reagents or therapeutic agents proposed.
• Applicants should provide documentation for the timely availability of an adequate number of animals for the proposed studies and the availability of suitable facilities to perform the proposed animal studies.

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

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

• Applicants should include appropriate travel budgets to accommodate travel by the PD(s)/PI(s) and one key personnel to the annual Steering Committee meeting in Bethesda, MD.
• Applicants should budget for a minimum of 1.8 calendar months per year for the individual leading the research effort or in a multi-PD/PI application for the contact PD/PI.

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

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

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

Research Strategy: All applications for the IXCRP should provide a clear research strategy 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 and milestone. Proposed projects should demonstrate applicability to future clinical applications.

Provide a detailed description of, and rationale for, the proposed acquisition and preparation of the solid organs, tissues or cells to be used in the studies and the proposed methods, source, and number of NHP samplings/biopsies required.

Provide a discussion of, and justification for, the numbers of animals used per experiments, with a discussion of statistical considerations and statistical soundness of the proposed experiments within the bounds of limited resources and budgetary constraints. Address the conclusions that can be drawn given the number of animals used.

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(s)/PI(s), the application should include a letter of support as an attachment 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 timetable 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.
• 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 other repository, if applicable.

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

Not Applicable

Not Applicable

Part I. Overview Information contains information about Key Dates. 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.

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? What is the likelihood that the results of the proposed studies will be translated into, or contribute to, new approaches and knowledge that are relevant to future clinical and preclinical xenotransplantation application?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/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? Is there adequate scientific and technical expertise related to the design, conduct, analysis, and interpretation of porcine/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? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Are there sufficient data to support the proposed research project? Are the objectives, annual milestones, and timelines clearly laid out, sufficiently detailed, appropriate, and reasonably attainable? Are the research approaches sufficiently detailed? 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 to carry out the proposed work?

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 six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

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

Inclusion of Women, Minorities, and Children

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

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable

Renewals

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

Revisions

Not Applicable

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

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) Genome Wide Association Studies (GWAS).

Budget and Period of Support

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by 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.
• Progress under any current IXCRP award, if applicable.
• Timely availability of critical reagents and resources.
• Compliance with data and resource sharing under current IXCRP, if applicable.

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.

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

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

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

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

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

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

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

The 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) agrees 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 prior to or 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 Steering Committee and other experts, as required, may review the PD/PI’s proposal for replacement or redirection of projects or for significant modification of yearly milestones and provide recommendations to the NIAID.

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 (http://www.nsrrc.missouri.edu/) 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 this program. PD(s)/PI(s) will participate with BISC 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 (https://immport.niaid.nih.gov/).

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. The assigned Program Officer may also serve as the Project Scientist. 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. However, awardees will retain custody of and have primary rights to all data developed under these awards.

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 and the Grants Management Specialist to approve redirection or replacement of research projects during the funding period as long as the revised projects remain within the scope of the original research project. In addition, in order to maximize utilization of program resources, the NIH Project Scientists may re-budget individual award funds based on NIAID assessment of availability of funds and grant progress. This policy is in keeping with the terms and conditions of the cooperative agreement mechanism. Future year funding is dependent on meeting the annual milestones.

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.

Each Steering Committee and subcommittee member will participate in all meetings, teleconferences, and activities of those committees, and attend the annual Steering Committee meeting to be held in Bethesda, MD, unless another location is agreed to by the NIH Program Officer.

The Steering Committee will:

• Serve as the main governing board;
• Identify scientific opportunities, emerging needs, and impediments;
• Identify opportunities for and encourage collaborations between 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 recommendations regarding the modification of the peer-reviewed aims, yearly milestones, and 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 BISC 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 progress reports, as requested by the NIH Program Officer;
• Establish subcommittees as needed to provide recommendations on shared aspects of the cooperative research group, including but not limited to the activities listed above.

Additional details and responsibilities of the Steering Committee will be negotiated at the time of award or post-award.

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.

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

A final progress report, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone: 301-710-0267
Email: [email protected]

Nasrin Nabavi, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3538
Email: [email protected]

Nancy V zquez-Maldonado, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5044
Email: [email protected]

Julia Shriner
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2972
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.