Part I Overview Information


Department of Health and Human Services

Participating Organizations
National Institutes of Health (NIH), (http://www.nih.gov)

Components of Participating Organizations
National Institute of Allergy and Infectious Diseases (NIAID), (http://www.niaid.nih.gov/)

Title: Immunobiology of Xenotransplantation (U01, U19)

Announcement Type
This is a reissue of RFA-AI-04-042.

Update: The following update relating to this announcement has been issued:

Request For Applications (RFA) Number:  RFA-AI-09-035

Catalog of Federal Domestic Assistance Number(s)
93.855  

Key Dates
Release Date: August 11, 2009
Letters of Intent Receipt Date:  November 2, 2009
Application Receipt Date:  December 2, 2009
Peer Review Date:  April 2010
Council Review Date:  May 2010
Earliest Anticipated Start Date:  July 2010
Additional Information To Be Available Date (Url Activation Date): http://www.niaid.nih.gov/ncn/qa/revniaid.htm
Expiration Date:  December 3, 2009

Due Dates for E.O. 12372

Not Applicable

Additional Overview Content

Executive Summary

Table of Contents


Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

Section II. Award Information
1. Mechanism(s) of Support
2. Funds Available

Section III. Eligibility Information
1. Eligible Applicants
    A. Eligible Institutions
    B. Eligible Individuals
2.Cost Sharing or Matching
3. Other - Special Eligibility Criteria

Section IV. Application and Submission Information
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates and Times
    A. Receipt, Review and Anticipated Start Dates
         1. Letter of Intent
    B. Sending an Application to the NIH
    C. Application Processing

    D. Application Assignment
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
    A. Additional Review Criteria
    B. Additional Review Considerations
    C. Resource Sharing Plan(s)
3. Anticipated Announcement and Award Dates

Section VI. Award Administration Information
1. Award Notices
2. Administrative and National Policy Requirements
     A. Cooperative Agreement Terms and Conditions of Award
         1. Principal Investigator Rights and Responsibilities
         2. NIH Responsibilities
         3. Collaborative Responsibilities
         4. Arbitration Process
3. Reporting

Section VII. Agency Contact(s)
1. Scientific/Research Contact(s)
2. Peer Review Contact(s)
3. Financial/ Grants Management Contact(s)

Section VIII. Other Information - Required Federal Citations


Part II - Full Text of Announcement


Section I. Funding Opportunity Description


1. Research Objectives

Purpose 

The National Institute of Allergy and Infectious Diseases (NIAID) invites new or renewal 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 application of xenotransplantation in the clinic. This FOA solicits only applications for research projects studying porcine to non-human primate (NHP) models of islet, kidney, heart, lung, or liver xenotransplantation. All qualified investigators are invited to apply; prior funding under the IXCRP program is not required. 

Background 

Transplantation is often the preferred therapy for end-stage organ disease.  In 2008, about 26,000 organ transplants were performed in the United States, but over 100,000 patients were still on waiting lists.  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.  The success of the "Edmonton Protocol" has established pancreatic islet transplantation as a viable therapy for type 1 diabetes in patients whose disease cannot be effectively managed with exogenous insulin therapy.  As with solid organ transplantation however, the availability of human islets is sufficient for only a small fraction of patients who could potentially benefit from islet transplantation.  Xenotransplantation offers a potential solution to the severe shortage of human organs, tissues, and cells to treat patients with end-stage organ disease.  Currently, the swine is the primary species of interest as an unlimited source of donor organs, tissues, and cells 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, such as porcine endogenous retrovirus (PERV) to general population.

The first and most challenging hurdle to xenotransplantation has been hyperacute rejection, which is caused by preformed xenoreactive natural antibodies (XNA) that can destroy the xenograft within minutes to a few hours of implantation. The primary target of XNA is the gal epitope (galactosyl alpha-(1,3)-galactosyl beta-1,4-N-acetyl glucosaminyl), a non-reducing tri-saccharide synthesized by New World monkeys and lower mammals, but not by humans, apes, and Old World monkeys.

In recent years, researchers have developed several lines of genetically modified pigs designed for use as organ donors. Organs from these animals induce less severe hyperacute rejection. The genetic modifications include (1)  transgenic strains expressing various human complement regulatory proteins [e.g., decay accelerating factor (CD55), terminal complement inhibitor (CD59), and monocyte chemoattractant protein (CD56)] to minimize the deleterious effects of the complement cascade; (2)  transgenic strains expressing glycosyltransferases that compete with alpha-1,3-galactosyltransferase, the enzyme that generates the gal epitope, to decrease the gal antigen expression, and (3) transgenic pigs expressing a combination of a human complement regulatory protein and a glycosyltransferase.  These strategies dramatically reduce the frequency and severity of hyperacute rejection and prolong survival of some xenografts in porcine to NHP transplantation models from a few hours to a few weeks. However, the gal epitope still contributes to delayed acute vascular rejection.  To further reduce the risk of hyperacute rejection, two different strains of alpha-1,3-galactosyltransferase gene knockout pigs, which lack the expression of the gal epitope, were developed.  Genetically modified pigs also provide opportunities to address other 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 between organs, tissues, and cells within the xenogeneic environment is another potentially critical challenge to successful xenotransplantation.  Initial observations in studies using solid organs from transgenic pigs transplanted into NHP indicate that the xenografts may have basic physiological functions that are compatible with the recipient as long as the grafts survive. 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 any physiological obstacles to xenotransplantation and the development of novel therapeutic approaches to address those limitations. 

The third major barrier to xenotransplantation is potential transmission of a zoonotic infectious agent from the xenograft to the recipient and then more broadly to the general population.  The animals used as the source of xenografts can be bred in specific pathogen-free conditions, vaccinated, caesarian-derived, and routinely screened to eliminate most, if not all, known zoonotic agents.  However, endogenous retroviruses (e.g. PERV), whose DNA is integrated into the donor genome, or new and yet unidentified infectious agents may not be removed by conventional means.  Although the patients transplanted with porcine cells or tissues show no evidence of PERV infection thus far, the effects of long-term exposure to xenografts, especially in immunosuppressed recipients, are unknown.  Investigators have made significant progress in assessing the risk of PERV infection.  Polytropic (PERV-A, B, and A/C) and ecotropic (PERV-C) classes of PERV and human receptors for PERV-A have been identified.  Investigators have found recombinant PERV-A/C infects human cells in vitro and their proviruses integrated de novo in the genome of somatic pig cells, however, the proviruses have not been detected in pig germ line cells. Studies of PERV or other potential zoonotic agents or infections are beyond the scope of the current solicitation, other than monitoring donor organs and pigs and the NHP recipients for the presence or integration of provirus and for active PERV or other potential zoonotic infections. Therefore, while applicants can include plans to monitor for zoonotic agents in their proposed research model, they can not propose study of zoonoses as a primary research goal under this FOA.

In 2003, the National Center for Research Resources established the National Swine Research and Resource Center (NSRRC; http://www.nsrrc.missouri.edu/), which is co-sponsored by the 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 requires IXCRP-funded investigators to submit the relevant cell lines and animal models developed under this FOA to the NSRRC.       

Research Objectives and Scope 

This FOA will continue the IXCRP to develop and evaluate pre-clinical porcine 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 porcine to NHP models of islet, kidney, heart, lung, or liver xenotransplantation. The research focus may include: (1) delineate 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: 

This FOA will not support 

Requirements of the IXCRP

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 milestones to be achieved during the project, 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.

Applications should demonstrate adequate data sharing and model organism sharing plans, and outline the plan for depositing all animal models and/or cell lines developed under this FOA funding into NCCR National Swine Research Center (NSRRC; http://www.nsrrc.missouri.edu/), if applicable. Applicants should also document the availability or expected availability of all critical non-commercially available reagents or therapeutic agents proposed, and the availability of an adequate number of animals for the proposed studies. A time frame for periodic deposition of reagents, animal models and cell lines should be specified in the application.

Steering Committee

A Steering Committee will be established to serve as the governing body of the IXCRP. The Steering Committee will consist of the PD/PI (or multiple PD/PIs) of the U01 and U19 applications, and Project Leaders (PL) from each research project under the U19 application, as well as one Project Scientist from NIAID. Voting members of the Steering Committee are comprised of one U01/U19 PD/PI from each award and one additional PL from each U19 award. Each U01 has one vote and each U19 has two votes. The function of the Steering Committee will be to: 

Steering Committee responsibilities are further described under Section VI.2.A.3.

Additional Information Specific to the Multi-Project (U19) Application:

The description of the U19 should include a clear and concise plan that depicts the interrelationships among the research groups, the relevant experience/expertise and the contribution of each individual; an organizational chart of the U19 cooperative group showing the name, organization, and scientific discipline of the PD/PI (or multiple PDs/PIs) and of all key scientific and technical personnel. If the application is from a consortium of institutions, the applicant should provide a plan to assure the maintenance of close cooperation and effective communication among members of the U19 cooperative group.  An Administrative Core is required, however, Scientific Cores are not required, but may be proposed if essential to the execution of the research projects. 

Research Project: Applications for the U19 multi-project award mechanism must contain at least two individual research projects organized around a common theme or hypothesis, with demonstrated synergy among the research projects, administrative core and scientific cores (if proposed).

Administrative Core (Required): Each application should provide for an Administrative Core headed by the contact PD/PI of the application who is responsible for the overall management, communication, coordination and supervision of the Program. The description of the Administrative Core should include plans for the oversight of the program; overall plans for the structure and roles of administrative staff; plans for collaborations and communications among the program PIs, PLs and CLs; how fiscal and other resources will be prioritized, allocated and managed; and how research-related travel, publications, communication expenses and training will be budgeted.

Scientific Cores (Optional): If proposed, a scientific core must support at least two projects within the U19 application.   A scientific core will be headed by a Scientific Core Leader and should present a clear picture of the facilities, techniques, and skills that the core will provide and describe the role of the Scientific Core Leader and each of the key participants.  The apportionment of dollars, or percentage of dollars, that will be required to support each component research project which will utilize each scientific core should also be presented.

See Section VIII, Other Information - Required Federal Citations, for policies related to this announcement.

Section II. Award Information


1. Mechanism of Support

This funding opportunity will use the U01 (single project) and U19 (multiple project) NIH cooperative agreement award mechanisms.  The Project Director/Principal Investigator (PD/PI) will be solely responsible for planning directing, and executing the proposed project. 

This FOA uses “just-in-time” information concepts. It also uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

This funding opportunity will use a cooperative agreement award mechanism. In the cooperative agreement award mechanism, the Project Director/Principal Investigator (PD/PI) retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described in Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award".

2. Funds Available

The NIAID intends to commit $2.5 million in total costs in FY2010 to fund two to four new and/or renewal applications in response to this FOA.  Future year amounts will depend on annual appropriations.  An applicant may request a project period of up to 5 years.

As a guideline, the approximate amount of funding in direct costs per IXCRP award is $1.2 million for U19 awards and $0.25 to $0.6 million for U01 awards.

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.  Although the financial plan of the NIAID provides support for this program, awards pursuant to this FOA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

Facilities and administrative costs requested by consortium participants are not included in the direct cost limitation, see NOT-OD-05-004. 

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.

At this time, it is not known if this FOA will be reissued.

Section III. Eligibility Information


1. Eligible Applicants

1.A. Eligible Institutions
 
The following organizations/institutions are eligible to apply:  

Foreign institutions are not eligible to apply as the primary applicant but may enter into a consortium that has a domestic institution as the primary applicant.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research as the PD/PI is invited to work with his/her institution 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.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application for projects that require a “team science” approach and therefore clearly do not fit the single-PD/PI model. Additional information on the implementation plans, policies and procedures to formally allow more than one PD/PI on individual research projects is available at http://grants.nih.gov/grants/multi_pi. All PDs/PIs must be registered in the NIH eRA Commons prior to the submission of the application (see http://era.nih.gov/ElectronicReceipt/preparing.htm for instructions).

The decision of whether to apply for a grant with a single PD/PI or multiple PDs/PIs is the responsibility of the investigators and applicant organizations, and should be determined by the scientific goals of the project. Applications for grants with multiple PDs/PIs will require additional information, as outlined in the instructions below. When considering multiple PDs/PIs, please be aware that the structure and governance of the PD/PI leadership team as well as the knowledge, skills and experience of the individual PDs/PIs will be factored into the assessment of the overall scientific merit of the application.  Multiple PDs/PIs on a project share the authority and responsibility for leading and directing the project, intellectually and logistically. Each PD/PI is responsible and accountable to the grantee organization, or, as appropriate, to a collaborating organization, for the proper conduct of the project or program, including the submission of required reports. For further information on multiple PDs/PIs, please see http://grants.nih.gov/grants/multi_pi.

Multiple PDs/PIs may be designated on the primary U01 or U19 application. However, only one Project Leader (PL) or Core Leader (CL) may be designated for each project or core, respectively, for multi-project U19 applications.

A PD/PI, or PD/PI on multi-PI application, or U19 PL may serve as a collaborator for another application provided there is no scientific overlap with the application submitted by the PD/PI, multi-PD/PI, or U19 PL. However, an investigator may only be a PD/PI, multi-PD/PI, or U19 PL on one application.

The PD/PI is expected to commit substantial time and effort to ensure success of the program. A minimum effort of 1.8 calendar months for a U01 or U19 PD/PI (or multi-PD/PI), and a minimum effort of 1.2 calendar months for a U19 Project Leader (PL) is expected.

2. Cost Sharing or Matching

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

3. Other-Special Eligibility Criteria

Number of Applications.  Applicants may submit more than one application provided they are scientifically distinct. Individual PIs may only submit one application as PI or part of a multiple PI team  

Resubmissions.  Resubmission applications are not permitted in response to this FOA.

Renewals.  Renewal applications are permitted in response to this FOA.

Section IV. Application and Submission Information


1. Address to Request Application Information

The PHS 398 application instructions are available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. Applicants must use the currently approved version of the PHS 398. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov.

Telecommunications for the hearing impaired: TTY 301-451-5936.

2. Content and Form of Application Submission

Applications must be prepared using the most current PHS 398 research grant application instructions and forms. Applications must have a D&B Data Universal Numbering System (DUNS) number as the universal identifier when applying for Federal grants or cooperative agreements. The D&B number can be obtained by calling (866) 705-5711 or through the web site at http://www.dnb.com/us/. The D&B number should be entered on line 11 of the face page of the PHS 398 form.

The title and number of this funding opportunity must be typed in item (box) 2 only of the face page of the application form and the YES box must be checked. 

The exceptions from the PHS 398 instructions and detailed information on the application structure and components are provided in Section IV.6 “Other Submission Requirements”. 

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs

When multiple PD/PIs are proposed, use the Face Page-Continued page to provide items 3a – 3h for all PD/PIs. NIH requires one PD/PI be designated as the “contact PD/PI” for all communications between the PD/PIs and the agency. The contact PD/PI must meet all eligibility requirements for PD/PI status in the same way as other PD/PIs, but has no special roles or responsibilities within the project team beyond those mentioned above. The contact PD/PI may be changed during the project period. The contact PD/PI should be listed in block 3 of Form Page 1 (the Face Page), with all additional PD/PIs listed on Form Page 1-Continued. When inserting the name of the PD/PI in the header of each application page, use the name of the “Contact PD/PI, et. al.” The contact PD/PI must be from the applicant organization if PD/PIs are from more than one institution.

All individuals designated as PD/PI must be registered in the eRA Commons and must be  assigned the PD/PI role in that system (other roles such as SO or IAR will not give the PD/PI the appropriate access to the application records). Each PD/PI must include their respective eRA Commons ID in the eRA Commons User Name field.

All projects proposing Multiple PDs/PIs will be required to include a new section describing the leadership plan approach for the proposed project.

Multiple PD/PI Leadership Plan: For applications designating multiple PDs/PIs, a new section of the research plan, entitled “Multiple PD/PI Leadership Plan” must be included. A rationale for choosing a multiple PD/PI approach should be described. The governance and organizational structure of the leadership team and the research project should be described, and should include communication plans, process for making decisions on scientific direction, and procedures for resolving conflicts. The roles and administrative, technical, and scientific responsibilities for the project or program should be delineated for the PDs/PIs and other collaborators. 

If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should be delineated in the Leadership Plan. In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

Additional information is available in the PHS 398 grant application instructions.

More than one PD/PI, or multiple PDs/PIs, may be designated on the application.  However, only one Project Leader or Core Leader may be designated for each project or core for multi-project U19 applications.

3. Submission Dates and Times

Applications must be received on or before the receipt date described below (Section IV.3.A). Submission times N/A.

3.A. Receipt, Review and Anticipated Start Dates
Letters of Intent Receipt Date:  November 2, 2009
Application Receipt Date:  December 2, 2009
Peer Review Date:  April 2010
Council Review Date:  May 2010
Earliest Anticipated Start Date:  July 2010

3.A.1. Letter of Intent

Prospective applicants are asked to submit a letter of intent that includes the following information:

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.

The letter of intent is to be sent by the date listed in Section IV.3.A.

The letter of intent should be sent to:

Katrin Eichelberg, Ph.D.  
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3128, MSC-7616
6700B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Phone: 301-496-0818
Fax: 301-480-2408
Email:  keichelberg@niaid.nih.gov

3.B. Sending an Application to the NIH

Applications must be prepared using the forms found in the PHS 398 instructions for preparing a research grant application. Submit a signed, typewritten original of the application, including the checklist, and three signed photocopies in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)

Personal deliveries of applications are no longer permitted (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-040.html).

At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to:

Katrin Eichelberg, Ph.D.  
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3128, MSC-7616
6700B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Phone: 301-496-0818
Fax: 301-480-2408
Email: keichelberg@niaid.nih.gov

3.C. Application Processing

Applications must be received on or before the application receipt date) described above (Section IV.3.A.). If an application is received after that date, the application may be delayed in the review process or not reviewed.  Upon receipt, applications will be evaluated for completeness by the CSR and for responsiveness by the reviewing Institute Incomplete and/or non-responsive applications will not be reviewed.

The NIH will not accept any application in response to this funding opportunity that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to a funding opportunity, it is to be prepared as a NEW application. That is, the application for the funding opportunity must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application.

Information on the status of an application should be checked by the Principal Investigator in the eRA Commons at: https://commons.era.nih.gov/commons/.

4. Intergovernmental Review

This initiative is not subject to intergovernmental review.

5. Funding Restrictions

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

Pre-award costs are allowable. A grantee may, at its own risk and without NIH prior approval, incur obligations and expenditures to cover costs up to 90 days before the beginning date of the initial budget period of a new or renewal award if such costs: 1) are necessary to conduct the project, and 2) would be allowable under the grant, if awarded, without NIH prior approval. If specific expenditures would otherwise require prior approval, the grantee must obtain NIH approval before incurring the cost. NIH prior approval is required for any costs to be incurred more than 90 days before the beginning date of the initial budget period of a new or renewal award.

The incurrence of pre-award costs in anticipation of a competing or non-competing award imposes no obligation on NIH either to make the award or to increase the amount of the approved budget if an award is made for less than the amount anticipated and is inadequate to cover the pre-award costs incurred. NIH expects the grantee to be fully aware that pre-award costs result in borrowing against future support and that such borrowing must not impair the grantee's ability to accomplish the project objectives in the approved time frame or in any way adversely affect the conduct of the project (see NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part6.htm.)

6. Other Submission Requirements

Supplemental Instructions for the Preparation of Multi-Project (U19) Applications

The following section supplements the instructions found in Form PHS 398 for preparing a multi-project grant application (U19).  Additional instructions are required because the Form PHS 398 is designed primarily for individual, free-standing research grant applications, and has no specific instructions for multi-project applications consisting of research projects interrelated by a common theme.  Applicants preparing single project applications (U01) should follow the PHS Form 398.

The supplemental instructions for multi-project (U19) applications are divided as follows:

A. General Instructions – addresses collaborative efforts among research projects, the administrative and organizational structure as well as the overall facilities and environment, and the overall budget.

B. Specific Instructions for Individual Projects – describes modifications to PHS Form 398 instructions on selected items to address the collaborative or interactive role of the project.

C. Specific Instructions for Core Units – Describes modifications to PHS Form 398 instructions on selected items to address the collaborative or interactive role of the project.

A. General Instructions

All applications must be submitted on Form PHS 398.  The multi-project grant application should be assembled and paginated as one complete document.

1. Form Page 1 - Face Page

Items 1 - 14: complete these items as instructed. This should be the first page of the entire application and all succeeding pages should be numbered consecutively.

When multiple PDs/PIs are proposed, use the Face Page-Continued page to provide items 3a-3h for all PDs/PIs.  The Contact PI should be listed on block 3 of Form Page 1-Face Page, with additional PDs/PIs listed on the Face Page-Continued.

2. Form Page 2

Using Page 2 of Form 398, provide a succinct but accurate description (abstract) of the OVERALL multi-project application addressing the major, common theme of the program.  Do not exceed the space provided.

List the performance sites where the research will be conducted.

Under "Key Personnel", list the PD(s)/PI(s) of the multi-project application, followed by the Project and Core Leaders of the component research projects and cores, and other key personnel and then other significant contributors.

3. Form Page 3 - Table of Contents

Do not use Form Page 3 of the PHS 398; a more comprehensive table of contents is needed for a multi-project application.

Bearing in mind that the application will be scientifically reviewed project by project and core by core, prepare a detailed Table of Contents that will enable reviewers to readily locate specific information pertinent to the overall application as well as to each component research project and core.  A page reference should be included for the budget for each project and each core.  Further, each research project should be identified by number (e.g. Project 1), title, and responsible Project Leader, and each Core should be identified by letter (e.g. Core A), title, and responsible Core Leader.  The page location of a COMPOSITE BUDGET should be indicated in the "Table of Contents."

4. Composite Budget

Do not use Form Page 4 of PHS Form 398.  Instead, using the suggested format presented below, prepare a Composite Budget For All Proposed Years of Support. (Justification for budget elements should not be presented here but in the individual budgets of the projects and cores.)

SAMPLE: Consolidated Direct Cost Budget for All Proposed Years of Support

Component

Year 1

Year 2

Year 3

Year 4

Year 5

All Years

Project 1. Invest.

125,000

130,000

135,200

140,608

146,232

677,040

Project 2. Study

125,000

130,000

135,200

140,608

146,232

677,040

Project 3. Develop.

100,000

104,000

108,160

112,486

116,985

541,631

Core A. Admin. Core.

50,000

52,000

54,080

56,243

58,493

270,816

Core B. DNA

25,000

50,000

52,000

54,080

56,243

237,323

Totals

425,000

466,000

484,640

504,025

524,185

2,403,850

 

 

 

 



5. Form Page 5

Complete the Total Direct Cost line entries for all requested budget periods (years) and the Total Direct Cost for Entire Period of Support entry. Detailed budgets are required within the descriptions of each project and core (see below).
If the FOA allows for budget requests beyond 5 years, use a second Form Page 5 to reflect the additional budget years requested. 

6. Biographical Sketch Format Page

Biographical sketches of all professional personnel for all components should be placed at the end of the application with the PI(s)/PD(s) first, followed by those of other key personnel in alphabetical order.

7. Resources Format Page

Do not complete.  Essential information is to be presented in the individual research project and core sections of the application.

8. Program Overview (Research Objectives and Strategic Plan)

This narrative section summarizes the overall research plan for the multi-project application and is limited to 25 pages.  The multi-project 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 for it provides the group of 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.

If the application is a renewal, this section should also highlight past performance and the major accomplishments from the prior funding period.  In addition to discussing results from individual projects, describe the synergy and collaborations that occurred.  For individual research projects that will be continued, additional details should be provided in the Progress Report section of the Research Plan within the application for the Research Project.

9.  Leadership Plan for Multiple PDs/PIs (required if applicable)

Applications designating multiple PDs/PIs for the overall Program must include a new section, entitled “Multiple PD/PI Leadership Plan”, as part of the Program Overview.  This Plan must describe: a rationale for choosing a multiple PD/PI approach; the governance and organizational structure of the leadership team and the research projects and cores; communication plans, processes for making decisions on scientific direction, and procedures for resolving conflicts; the administrative, technical, and scientific roles and responsibilities for the PDs/PIs and other collaborators.  If budget allocation is planned, the distribution of resources to specific components of the project or the individual PDs/PIs should also be delineated.  In the event of an award, the requested allocations may be reflected in a footnote on the Notice of Award.

10. Checklist

One Checklist, placed at the end of the application, is to be submitted for the entire application.

11. Appendix Materials

Refer to Section IV.6. “Appendix Materials” below, for instructions on submitting appendix materials.

For each project or core in the multi-project application, 3 publications plus other approved material are allowed.

B. Specific Instructions for Individual Research Projects

Except for the requirements below, follow the PHS 398 Specific Instructions found at http://grants1.nih.gov/grants/funding/phs398/phs398.doc#_Toc130797900 in preparing each research project.

For each individual Research Project, include: 

1. Cover Page

The Face Page of the 398 Form should not be used as a cover page for individual research projects within a multi-project application.  Instead, use the PHS 398 continuation page to create a "Cover Page" containing selected data about each individual research project.  This Cover Page will demarcate each individual research project and should contain the following information items (these are a subset of the information provided on a PHS 398 Face Page):

Project Number and Title:  (e.g., 1. Preclinical Evaluation of HIV Microbicides)

Name of Project Leader:  (e.g., Jones, Roberta A.)

Human Subjects: (Yes or No)

If Yes:

Exemption number, -or-

IRB Approval Date (e.g., 12/13/2006,or "Pending"), and  Federalwide Assurance (FWA) number

Vertebrate Animals: (Yes or No)

If Yes:

IACUC Approval Date (e.g., 11/17/2006, or Pending) and Animal welfare assurance number:

Proposed Period of Support:

From: (mmddyy - e.g., 07/01/2007)

To: (mmddyy - e.g., 06/30/2112)

Costs Requested for Initial Budget Period: (e.g. 07/01/2007-06/30/2008)

Direct Costs: (e.g., $ 150,000)

Total Costs: (e.g., $162,000)

Costs Requested for the Entire Budget Period: (e.g., 07/01/2007-06/30/2112)

Direct Costs: $700,000

Applicant Organization (full address)

2. Form Page 2

Provide a Description (abstract) of the research proposed in the project according to the instructions on Form Page 2 of PHS Form 398.  In addition, the abstract should contain a brief description of how the research project will contribute towards attainment of the multi-project program objectives.

List the performance sites where the research will be conducted.

Under "Key Personnel", list the Project Leader, followed by other key project personnel, and then other significant contributors.

3. Form Page 3

Prepare a Table of Contents for the research project using Form Page 3 of the PHS 398.

4. Budget Pages (PHS 398 Form Pages 4 and 5)

Prepare a detailed budget and justification for the research project using Form Pages 4 and 5 of the PHS 398.

5. Biographical Sketches

Do not repeat the biographical sketches of participating investigators since this information will be included at the end of the overall application (and therefore will be referenced in the Overall Table of Contents).

6. Resources Format Page

Provide information on resources available for the project.

7. Research Plan (Items 2-5 of the Research Plan cannot exceed 25 pages)

Item 2 -- Specific Aims: List in priority order, the broad, long-range objectives and goals of the proposed project. Concisely and realistically describe the hypothesis or hypotheses to be tested. In addition, state the project's relationship to the multi-project program goals and how it relates to other projects or cores. This section is typically one page.

Item 3 -- Background and Significance: Use this section to describe how the proposed research will contribute to meeting the program's goals and objectives and explain the rationale for selecting the methods to accomplish the specific aims. In addition to stating the biological significance of the research, indicate the project's relevance to the primary theme of the application.

Following Items 2-5 of the Research Plan, and within the 25 page Research Plan page limit, applicants should include responses to the following:

      i.        Timeline and Milestones: Clearly state the interim and long-term objectives and milestones to be achieved during the project, 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. 

    ii.        Clinical Applicability: Briefly discuss the applicability to future clinical applications.

   iii.        Reagent and Animal Availability:  Document availability or expected availability of all critical non-commercially available reagents or therapeutic agents proposed and document reasonable expectation of availability of animals and the numbers of animals required for the proposed studies in proposed timeframes.

   iv.        Experience and Qualifications:  Demonstrate scientific and technical expertise related to the design, conduct, analysis and interpretation of porcine/NHP studies.

C. Specific Instructions for Core(s) (if proposed)

Except for the requirements below, follow the PHS 398 Specific Instructions found at http://grants1.nih.gov/grants/funding/phs398/phs398.doc#_Toc130797900 in preparing each proposed core.

For each individual Core, include: 

1. Cover Page.  The Face Page of the 398 Form should not be used as a cover page for cores within a multi-project application.  Instead, use the 398 continuation page to create a "Cover Page" containing selected data about each individual core.  This Cover Page will demarcate each core and should contain the following information items (which are a subset of the information provided on a Face Page - see PHS 398):

Core Letter and Core Title:  (e.g., A. Monoclonal Antibody Production Core)

Name of Core Leader:  (e.g., Smith, Robert A.)

Human Subjects (Yes or No)

If Yes,

Exemption Number, -or-

IRB Approval Date (e.g., 5/14/06, or Pending), and Federalwide Assurance (FWA) number

Vertebrate Animals (Yes or No)

If Yes,

IACUC Approval Date (e.g., 4/15/07, or Pending), and Animal welfare assurance number

Proposed Period of Support

From: (mmddyy, e.g., 07/01/2007)

To: (mmddyy, e.g., 06/30/2012)

Costs Requested for Initial Budget Period

Direct Costs (e.g. $50,000)

Total Costs (e.g. $70,000)

Costs Requested for the Entire Budget Period

Direct Costs (e.g. $212,323)

Total Costs (e.g. $297,252)

Applicant Organization (ABC University; 111 Main Street; Anywhere, Else 99999)

The following are specific instructions for sections of the PHS 398 application form that are to be completed differently than usual.  For all other items in the core application, follow the usual PHS 398 instructions.

2. Form Page 2.  Provide a Description (abstract) of the core activities and services according to the instructions on Form Page 2 of the PHS 398. In addition, the abstract should contain a brief description of how the core services will contribute towards attainment of the multi-project program objectives.

List the performance sites where the core activities and services will be conducted.

Under "Key Personnel", list the Core Leader, followed by other key core personnel, and then other significant contributors.

3. Form Page 3.  Prepare a Table of Contents for the core using page 3 of Form PHS 398. 

4. Budget Pages (PHS 398 Form Pages 4 and 5)

Prepare a detailed budget and justification for the core using Form Pages 4 and 5 of the PHS 398.

5. Biographical Sketches

Do not repeat the biographical sketches of participating investigators since this information will be located at the end of the overall application (and therefore will be referenced in the Overall Table of Contents).

6. Resources Format Page

Provide information on resources available for the core.

7. Core Research Plan (Items 2-5 cannot exceed 10 pages for the Administrative Core and 10 pages for each Scientific Core)

Item 2 - Specific Aims: List in priority order the broad, long-range objectives of the proposed core.  In addition, state the core's relationship to the multi-project program goals and how it relates to the research projects or other cores in the application.

Item 3 - Background and Significance:  Use this section to describe how the proposed core activities will contribute to meeting the goals and objectives and explain the rationale for the selection of the general methods and approaches proposed to accomplish the specific aims.  In addition, this section should indicate the relevance of the core to the primary theme of the multi-project grant.

Additional information is available in the PHS 398 grant application instructions.

Special Requirements for all Single Project (U01) Applications and Individual Research Projects within Multi-Project (U19) Applications

Following items 2-5 of the Research Plan and within the 25 page Research Plan page limit of single project (U01) applications, and individual research projects in a multi-project (U19) application, applicants should include the following:

      i.        Timeline and Milestones: Clearly state the interim and long-term objectives and milestones to be achieved during the project, 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. 

    ii.        Clinical Applicability: Briefly discuss the applicability to future clinical applications.

   iii.        Reagent and Animal Availability:  Document availability or expected availability of all critical non-commercially available reagents or therapeutic agents proposed and document reasonable expectation of availability of animals and the numbers of animals required for the proposed studies in proposed timeframes.

   iv.        Experience and Qualifications:  Demonstrate scientific and technical expertise related to the design, conduct, analysis and interpretation of porcine/NHP studies.

Applicants are encouraged to contact NIAID program staff well in advance of the application submission date to discuss the proposed research program. This will allow staff to assess responsiveness to this FOA and provide appropriate guidance as needed with regard to this initiative.  Discussion with program staff does not guarantee funding of an application. 

For cooperative agreements, awardees must agree to the "Cooperative Agreement Terms and Conditions of Award" in Section VI.2.A "Award Administration Information".

Research Plan Page Limitations

See Section IV.2, “Content and Form of Application Submission” for Research Plan page limitations associated with single project applications and see text above for page limitations associated with components of multi-project applications.

Appendix Materials

All paper PHS 398 applications submitted must provide appendix material on CDs only. Include five identical CDs in the same package with the application. See http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-031.html.

Do not use the Appendix to circumvent the page limitations of the Research Plan component. An application that does not observe the required page limitations may be delayed in the review process.

Resource Sharing Plan(s)

NIH considers the sharing of unique research resources developed through NIH-sponsored research an important means to enhance the value of, and advance research. When resources have been developed with NIH funds and the associated research findings published or provided to NIH, it is important that they be made readily available for research purposes to qualified individuals within the scientific community. If the final data/resources are not amenable to sharing, this must be explained in Resource Sharing section of the application. See http://grants.nih.gov/grants/policy/data_sharing/data_sharing_faqs.htm.

(a) Data Sharing Plan: Regardless of the amount requested, investigators are expected to include a brief 1-paragraph description of how final research data will be shared, or explain why data-sharing is not possible. Applicants are encouraged to discuss data-sharing plans with their NIH program contact. See Data-Sharing Policy or http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html.

(b) Sharing Model Organisms: Regardless of the amount requested, all applications where the development of model organisms is anticipated are expected to include a description of a specific plan for sharing and distributing unique model organisms and related resources, or state appropriate reasons why such sharing is restricted or not possible. See Sharing Model Organisms Policy, and NIH Guide NOT-OD-04-042.

(c) Genome-Wide Association Studies (GWAS): Regardless of the amount requested, applicants seeking funding for a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible.  A genome-wide association study is defined as any study of genetic variation across the entire genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight) or the presence or absence of a disease or condition.  For further information see Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088, and http://grants.nih.gov/grants/gwas/.

Section V. Application Review Information


1. Criteria

Only the review criteria described below will be considered in the review process.

2. Review and Selection Process

Applications that are complete and responsive to the FOA will be evaluated for scientific and technical merit by an appropriate peer review group convened by NIAID and in accordance with NIH peer review procedures (http://grants1.nih.gov/grants/peer/), using the review criteria stated below.

As part of the scientific peer review, all applications will:

The following will be considered in making funding decisions:

The mission of the NIH is to support science in pursuit of knowledge about the biology and behavior of living systems and to apply that knowledge to extend healthy life and reduce the burdens of illness and disability.  As part of this mission, applications submitted to the NIH for grants or cooperative agreements to support biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system. 

Review Criteria for U01 (single project) Applications and Individual Research Projects within a U19 (multi-project) Application

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

Core Review Criteria.  Reviewers will consider each of the five review criteria below in the determination of scientific and technical 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 for future clinical xenotransplantation applications?

Investigator(s).  Are the PD/PIs, collaborators, and other researchers well suited to the project?  If Early Stage Investigators or New Investigators, 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 or U19 Project Leader sufficient to ensure success of the program? 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 clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Are there sufficient preliminary data to support the proposed research projects? For renewal applications, what are the accomplishments and progress achieved during the prior funding period?  Are the objectives and milestones clearly laid out for the project and are detailed timelines provided for the attainment of each goal?

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 facilities available to the investigators to carry out the proposed work?

In addition to the above review criteria, the following criteria will be applied to applications in the determination of scientific merit and the impact/priority score.

Review Criteria for Multi-Project (U19) Applications Only

Administrative Core: Reviewers will consider each of the criteria below in the determination of scientific and technical meritIs the administrative and organizational structure appropriate and adequate to the attainment of the objective(s) of the proposed program?  Is the management plan for fiscal accountability and communication within the program appropriate?  Are the plans for coordination, problem identification and resolution, and the establishment of a strong collaborative environment for the program appropriate? Are plans for communication among the members of the U19 adequate to facilitate collaborative activities?  Is the experience, level of commitment, and availability of the Administrative Core Leader and administrative staff adequate to manage the program?

Scientific Cores (if applicable):  Reviewers will consider each of the criteria below in the determination of scientific and technical merit: Is provision of resources and core services for the individual Research Projects critical and justified? Is the relationship of a scientific core to the central focus of the overall program strong?  Is the quality of the relevant facilities or services provided and criteria for prioritization and usage appropriate?  Are the qualifications, competence, and commitment of the Core Leader and key personnel appropriate?

Review Criteria for Evaluating the Overall U19 Application: The following items will be considered in the determination of the overall scientific and technical merit and priority score for the entire multi-project application:  Is the program as a whole scientifically compelling? Is there coordination and synergy of the individual research projects and cores towards the achievement of the central objectives of the program?  Are the overall program goals significant and focused on studies that meet the objectives of the FOA? Will the integration of the individual projects into a single program be more beneficial than pursuing each project independently?  Are the objectives and milestones clearly laid out for the project and are detailed timelines provided for the attainment of each goal? Does the PD/PI (multiple PDs/PIs) have the leadership and scientific ability to develop an integrated and focused research program?  Will the PD/PI (multiple PDs/PIs) and other Project/Core Leaders devote adequate time and effort to the program?  For renewal applications, what are the accomplishments and progress achieved during the prior funding period? Are the qualifications, experience, and commitment of investigators responsible for the individual research projects or cores and their contribution to the program, including their ability to devote time and effort to the program adequate? Is there adequate evidence of sufficient institutional support for the PD/PI (multiple PDs/PIs) in terms of laboratory space, equipment and other resources?  For applications designated multiple PDs/PIs, is the Leadership Plan both adequate and appropriate to ensure that there will be sufficient coordination and communication among the PDs/PIs?  Do the administrative plans for the management of projects including a plan for resolving conflicts appropriately?

Additional Review Criteria.  As applicable for the project proposed, reviewers will consider the following additional items in the determination of scientific and technical merit, 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.

Inclusion of Women, Minorities, and Children.  When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children.

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.

Renewal Applications.  When reviewing a Renewal application (formerly called a competing continuation application), the committee will consider the progress made in the last funding period.

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.

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

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

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 (http://grants.nih.gov/grants/policy/data_sharing/data_sharing_guidance.htm); 2) Sharing Model Organisms (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html); and 3) Genome Wide Association Studies (GWAS) (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-07-088.html).

3. Anticipated Announcement and Award Dates

Not Applicable.

Section VI. Award Administration Information


1. Award Notices

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.

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant. For details, applicants may refer to the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization. The NoA signed by the grants management officer is the authorizing document. Once all administrative and programmatic issues have been resolved, the NoA will be generated via email notification from the awarding component to the grantee business official (designated in item 12 on the Application Face Page). If a grantee is not email enabled, a hard copy of the NoA will be mailed to the business official.

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. See Also Section IV.5. Funding Restrictions.


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 (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_Part4.htm) and Part II Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities (http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part9.htm).

The following Terms and Conditions will be incorporated into the award statement and will be provided to the Principal Investigator as well as to the appropriate institutional official, at the time of award.

2.A. Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS 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.

2. A.1. Principal Investigator Rights and Responsibilities

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

The PD/PI (multiple PDs/PIs) agrees that although NIAID intends to support the peer-reviewed studies/specific aims proposed in the awarded grant applications, under special circumstances (e.g. duplicative or overlapping specific aims between two awardees), the Steering Committee will establish guidelines and review procedures for modification of the peer-reviewed aims or initiation of new projects, and will evaluate and determine opportunities for collaboration with outside investigators and redirection of resources when applicable and necessary. This policy is in keeping with the terms and conditions of the cooperative agreement mechanism. Any recommendations that result in a change in the scope of a research project must be approved by the NIAID Program Official and Grants Management Specialist.  

The PD/PI (multiple PDs/PIs) agrees 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 (multiple PDs/PIs) are requested to submit all manuscripts with studies funded by the IXCRP to the Program Officer at least one week prior to journal submission and within at least two weeks of acceptance for publication so that an up-to-date summary of the cooperative program accomplishments can be maintained and NIAID press release can be prepared, if applicable.  Publications or oral presentations of work performed under this Agreement are the responsibility of the PD/PI (multiple PDs/PIs) and appropriate Project Leaders, and will require appropriate acknowledgement of NIAID support. Timely publication of major findings is required by the NIH Public Access Policy

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

2. A.2. NIH Responsibilities

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 assist with scheduling the meetings and teleconferences of the Steering Committee and subcommittees, and ensure coordination of Steering Committee activities and implementation of its recommendations, decisions, and policies. 

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.  However, awardees will retain custody of and have primary rights to all data developed under these awards.

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 milestones. It is recognized that project goals may require revision and re-negotiation during the course of the project period.  The NIAID reserves the right to terminate or curtail a study (or any individual award) in the event of a substantial shortfall in study milestones or other major breach of the approved project.  

2.A.3. Collaborative Responsibilities 

Steering Committee:

A Steering Committee will serve as the governing body of the IXCRP. The Steering Committee will consist of the PDs/PIs (multiple PDs/PIs) of the U01 and U19 awardees, the PLs from U19 awards, and the NIAID Project Scientist. Each U01 will have one vote and each U19 will have two votes. The NIAID Project Scientist will be non-voting members. Voting members of the Steering Committee are as follows: a single PD/PI from each U01 or U19 (including from multi-PDs/PIs awards) and one PL from each U19. The PL voting member is determined by the PD(s)/PI(s) of the U19 and may be rotated on an annual basis among each PL from the funded research projects, as determined by the U19 PD(s)/PI(s).  Each voting member will have one vote. In addition, selected scientists other than the awardees may serve as non-voting members when additional expertise is required for committee breadth and balance, to be determined by majority vote of the Steering Committee. The NIAID may appoint up to two external scientists to be non-voting members of the Steering Committee. A Chairperson will be selected by majority vote from among the voting members.

The NIAID Project Scientist will work with the Chair of the Steering Committee to schedule the meetings of the Steering Committee and actively participate in developing the meeting agendas. The Steering Committee will meet at least annually. Unless agreed to by the NIAID Project Scientist, annual meetings will be held in Bethesda, MD. Proposed budgets should include funds to cover travel costs for these meetings. Each Steering Committee member will be expected to participate in all meetings and activities, e.g., conference calls and special subcommittees as required.

All members of IXCRP consortium are required to accept and implement common guidelines and procedures approved by the Steering Committee.

The Steering Committee or a designated subcommittee will prepare a cumulative group progress report, when requested by the NIAID Project Scientist and generally at the completion of the second year of funding and either annually or biannually after the first report. This cumulative group progress report will, at a minimum, containing the following information: project overviews; cumulative progress of ongoing and newly-initiated projects; manuscripts published, in press, and in preparation; presentations at regional, national, and international meetings; other activities of the group; and future plans.  The first such report will be submitted to the NIAID Project Scientist no later than four months after the NIAID Project Scientist requests a report, or a time agreed upon by the NIAID Project Scientist and the Steering Committee Chair.

The Steering Committee will: 

Cooperation with Other NIH-Sponsored Programs

In order to most efficiently utilize research resources and rapidly exchange scientific information to promote xenotransplantation objectives, it is anticipated that cooperation or opportunities to collaborate with other NIH funded programs will be initiated in future years and will be coordinated and facilitated by the NIAID Project Scientist.

Each full member will have one vote (with the exception of the NIH, which is a nonvoting member). Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. 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 arbitration. 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 regulations 42 CFR Part 50, Subpart D and HHS regulations 45 CFR Part 16.

3. Reporting

Awardees will be required to submit the Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, invention statement, and Financial Status Report are required when an award is relinquished when a recipient changes institutions or when an award is terminated.

Section VII. Agency Contacts



We encourage your inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues:

1. Scientific/Research Contacts:

Nasrin Nabavi, Ph.D.
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Diseases
Room 3045, MSC-6601

6610 Rockledge Drive
Bethesda, MD 20892-6601
Telephone: (301) 435-3567
FAX: 301-496-5598
Email:
nnabavi@niaid.nih.gov

2. Peer Review Contacts:

Katrin Eichelberg, Ph.D.  
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3128, MSC-7616
6700B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service or regular mail)
Bethesda, MD 20817 (for express/courier service; non-USPS service)
Phone: 301-496-0818
Fax: 301-480-2408
Email:  keichelberg@niaid.nih.gov 

3. Financial or Grants Management Contacts:

Kimberly Chatman 
Division of Extramural Activities

National Institute of Allergy and Infectious Diseases
Room 2241, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614 (express zip 20817-7614)
Telephone: 301-402-6580
Fax: 301-493-0597
E-mail: chatmank@niaid.nih.gov

Section VIII. Other Information


Required Federal Citations

Use of Animals in Research:
Recipients of PHS support for activities involving live, vertebrate animals must comply with PHS Policy on Humane Care and Use of Laboratory Animals (http://grants.nih.gov/grants/olaw/references/PHSPolicyLabAnimals.pdf) as mandated by the Health Research Extension Act of 1985 (http://grants.nih.gov/grants/olaw/references/hrea1985.htm), and the USDA Animal Welfare Regulations (http://www.nal.usda.gov/awic/legislat/usdaleg1.htm) as applicable.

Human Subjects Protection:
Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained (http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm).

Data and Safety Monitoring Plan:
Data and safety monitoring is required for all types of clinical trials, including physiologic toxicity and dose-finding studies (phase I); efficacy studies (Phase II); efficacy, effectiveness and comparative trials (Phase III). Monitoring should be commensurate with risk. The establishment of data and safety monitoring boards (DSMBs) is required for multi-site clinical trials involving interventions that entail potential risks to the participants (NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and Contracts, http://grants.nih.gov/grants/guide/notice-files/not98-084.html).

Sharing Research Data:
Investigators submitting an NIH application seeking $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible (http://grants.nih.gov/grants/policy/data_sharing).

Investigators should seek guidance from their institutions, on issues related to institutional policies and local IRB rules, as well as local, State and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score.

Policy for Genome-Wide Association Studies (GWAS):
NIH is interested in advancing genome-wide association studies (GWAS) to identify common genetic factors that influence health and disease through a centralized GWAS data repository. For the purposes of this policy, a genome-wide association study is defined as any study of genetic variation across the entire human genome that is designed to identify genetic associations with observable traits (such as blood pressure or weight), or the presence or absence of a disease or condition. All applications, regardless of the amount requested, proposing a genome-wide association study are expected to provide a plan for submission of GWAS data to the NIH-designated GWAS data repository, or provide an appropriate explanation why submission to the repository is not possible. Data repository management (submission and access) is governed by the Policy for Sharing of Data Obtained in NIH Supported or Conducted Genome-Wide Association Studies, NIH Guide NOT-OD-07-088. For additional information, see http://grants.nih.gov/grants/gwas/.

Access to Research Data through the Freedom of Information Act:
The Office of Management and Budget (OMB) Circular A-110 has been revised to provide access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this funding opportunity in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award.

Sharing of Model Organisms:
NIH is committed to support efforts that encourage sharing of important research resources including the sharing of model organisms for biomedical research (see http://grants.nih.gov/grants/policy/model_organism/index.htm). At the same time the NIH recognizes the rights of grantees and contractors to elect and retain title to subject inventions developed with Federal funding pursuant to the Bayh Dole Act (see the NIH Grants Policy Statement http://grants.nih.gov/grants/policy/nihgps_2003/index.htm). All investigators submitting an NIH application or contract proposal, beginning with the October 1, 2004 receipt date, are expected to include in the application/proposal a description of a specific plan for sharing and distributing unique model organism research resources generated using NIH funding or state why such sharing is restricted or not possible. This will permit other researchers to benefit from the resources developed with public funding. The inclusion of a model organism sharing plan is not subject to a cost threshold in any year and is expected to be included in all applications where the development of model organisms is anticipated.

Inclusion of Women And Minorities in Clinical Research:
It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

Inclusion of Children as Participants in Clinical Research:
The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all clinical research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them.

All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects (http://grants.nih.gov/grants/funding/children/children.htm).

Required Education on the Protection of Human Subject Participants:
NIH policy requires education on the protection of human subject participants for all investigators submitting NIH applications for research involving human subjects and individuals designated as key personnel. The policy is available at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

Human Embryonic Stem Cells (hESC):
Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (http://escr.nih.gov). It is the responsibility of the applicant to provide in the project description and elsewhere in the application as appropriate, the official NIH identifier(s) for the hESC line(s) to be used in the proposed research.

NIH Public Access Policy Requirement:
In accordance with the NIH Public Access Policy (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-08-033.html) investigators must submit or have submitted for them their final, peer-reviewed manuscripts that arise from NIH funds and are accepted for publication as of April 7, 2008 to PubMed Central (http://www.pubmedcentral.nih.gov/), to be made publicly available no later than 12 months after publication. As of May 27, 2008, investigators must include the PubMed Central reference number when citing an article in NIH applications, proposals, and progress reports that fall under the policy, and was authored or co-authored by the investigator or arose from the investigator’s NIH award.  For more information, see the Public Access webpage at http://publicaccess.nih.gov/.

Standards for Privacy of Individually Identifiable Health Information:
The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule", on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR).

Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html.


URLs in NIH Grant Applications or Appendices:
All applications and proposals for NIH funding must be self-contained within specified page limitations. For publications listed in the appendix and/or Progress report, internet addresses (URLs) must be used for publicly accessible on-line journal articles.  Unless otherwise specified in this solicitation, Internet addresses (URLs) should not be used to provide any other information necessary for the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site.

Healthy People 2010:
The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This FOA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.

Authority and Regulations:
This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372. 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 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm.

The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

Loan Repayment Programs:
NIH encourages applications for educational loan repayment from qualified health professionals who have made a commitment to pursue a research career involving clinical, pediatric, contraception, infertility, and health disparities related areas. The LRP is an important component of NIH's efforts to recruit and retain the next generation of researchers by providing the means for developing a research career unfettered by the burden of student loan debt. Note that an NIH grant is not required for eligibility and concurrent career award and LRP applications are encouraged. The periods of career award and LRP award may overlap providing the LRP recipient with the required commitment of time and effort, as LRP awardees must commit at least 50% of their time (at least 20 hours per week based on a 40 hour week) for two years to the research. For further information, please see: http://www.lrp.nih.gov.


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