Part I Overview Information

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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: Coordinating Center for Organ Transplant Clinical Trials (U01)

Announcement Type

This is a re-issue of RFA-AI-04-046.

Request For Applications (RFA) Number:  RFA-AI-09-015

Catalog of Federal Domestic Assistance Number(s)
93.856, 93.855  

Key Dates
Release Date: April 1, 2009
Letters of Intent Receipt Date: June 22, 2009
Application Receipt Date: July 21, 2009
Peer Review Date: November 2009
Council Review Date: January 2010
Earliest Anticipated Start Date:  March 2010
Additional Information To Be Available Date (Url Activation Date): http://www.niaid.nih.gov/ncn/qa/revniaid.htm
Expiration Date: July 22, 2009

Due Dates for E.O. 12372
Not Applicable

Additional Overview Content

Executive Summary

• Purpose. The National Institute of Allergy and Infectious Diseases (NIAID) invites applications from institutions for renewal of a Statistical and Clinical Coordinating Center (SACCC) to support clinical studies in organ transplantation conducted by the following NIAID-sponsored clinical consortia: the Clinical Trials in Organ Transplantation (CTOT) Consortium, the Clinical Trials in Organ Transplantation in Children (CTOT-C) Consortium, and the Genomics of Transplantation Cooperative Research Program (GTCRP). The SACCC will provide statistical expertise, data management and clinical site monitoring, and will work with NIAID staff to ensure that studies are conducted in compliance with Good Clinical Practice (GCP) and the federal regulations governing human subjects research.
• Mechanism of Support. This FOA will utilize the cooperative agreement (U01) grant mechanism. 
• Funds Available and Anticipated Number of Awards. NIAID intends to commit approximately $3.8 million in FY 2010 to fund one new or competing renewal grant in response to this FOA.
• Budget and Project Period.  The total project period for an application submitted in response to this funding opportunity is 5 years. Direct costs less consortium F&A are limited to $2 - 2.5 million per year for a five-year period.
• Eligible Institutions/Organizations. Institutions/organizations listed in Section III, 1.A. are eligible to apply.  Foreign institutions/organizations are not eligible to apply.
• Eligible Project Directors/Principal Investigators (PDs/PIs). Individuals with the skills, knowledge, and resources necessary to carry out the proposed research are invited to work with their institution/organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
• Number of PDs/PIs. More than one PD/PI (i.e., multiple PDs/PIs), may be designated on the application.
• Number of Applications. Applicants may submit more than one application, provided they are scientifically distinct.
• Resubmissions.  Resubmission applications are not permitted in response to this FOA.   
• Renewals.  Renewal applications are permitted in response to this FOA
• Special Date(s). This FOA uses non-standard due dates. See Receipt, Review and Anticipated Start Dates
• Application Materials. See Section IV.1 for application materials.
• Hearing Impaired.  Telecommunications for the hearing impaired are available at: TTY: (301) 451-5936

Table of Contents

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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 and Information

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

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Section I. Funding Opportunity Description

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1. Research Objectives

The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), invites applications for the renewal of a Statistical and Clinical Coordinating Center (SACCC) to support clinical studies in organ transplantation conducted by three NIAID-sponsored clinical consortia: (1) Clinical Trials in Organ Transplantation (CTOT) Consortium http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-08-015.html , website https://www.ctotstudies.org/; (2) Clinical Trials in Organ Transplantation in Children (CTOT-C) Consortium http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-07-006.html , website https://www.ctotc.org/, and (3) Genomics of Transplantation Cooperative Research Program (GTCRP) http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-05-022.html . These three consortia, funded using the cooperative agreement (U01) mechanism,  implement clinical research with associated mechanistic studies designed to advance our knowledge of the immunobiology of organ transplantation and ultimately to improve the outcomes of organ transplantation. The SACCC will provide a broad range of services for these consortia, including expertise in the design, implementation, and analysis of clinical trials; technical and administrative support for each consortium's Steering Committee and for the NIAID Transplantation Data and Safety Monitoring Board (DSMB); clinical site monitoring and training; regulatory support; and drug and specimen distribution and tracking. The SACCC will also assist with preparing of DSMB reports, scientific manuscripts, and other reports and documents as needed to support the activities of the consortia, and will assist NIAID in fostering collaborations among the consortia.

Organ or tissue replacement is the treatment for end-stage organ failure when other therapies have failed or are not available, and when the person affected by organ failure is deemed likely to benefit from transplantation. The benefits of organ transplantation, as evidenced by prolonged survival and/or improved quality of life, have been clearly demonstrated for children and adults suffering from a wide range of congenital and acquired diseases. However, normal life expectancy and health-related quality of life are rarely, if ever, restored by organ transplantation. Although 1-year survival after organ transplantation has improved markedly over the last 15 years, there has been little success in reversing the decline in long-term graft and patient survival in recipients of any organ transplant. The prevalence of morbidities such as systemic hypertension, diabetes mellitus, renal insufficiency, and malignancy remain high in transplant recipients as compared with the general population. The barriers to short and long-term success of transplant procedures are predominantly the result of incompatibility between donor and recipient, acute and chronic rejection, and complications of long-term pharmacologic immune suppression.

To advance understanding of the immunobiology and genomics of transplantation, and to improve short- and long-term graft and patient survival, the NIAID supports three investigative consortia to conduct clinical and associated mechanistic studies that will lead to improved outcomes for transplant recipients –  the Clinical Trials in Organ Transplantation (CTOT) Consortium, the Clinical Trials in Organ Transplantation in Children (CTOT-C) Consortium and the Genomics of Transplantation Cooperative Research Program (GTCRP).

NIAID previously solicited applications for a Statistical and Clinical Coordinating Center for the CTOT and CTOT-C  http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-04-046.html . Pharmaceutical Product Development (PPD), Inc. successfully competed for this award and expires in June 2010. Although NIAID expects that the award in response to this FOA will overlap with the existing coordinating center grant in time only, NIAID will not support overlapping coordinating center activities by PPD, Inc. and the successful applicant to this FOA.  Upon termination of the current grant with PPD Inc, the awardee will assume all coordinating center responsibilities for the CTOT, CTOT-C, and GTCRP consortia. Transfer of existing activities will begin at the time of award. 

Research Objectives and Scope

The research consortia that will be supported by the SACCC are described below.

Clinical Trials in Organ Transplantation (CTOT): The cooperative, multi-site CTOT consortium, established in FY 2004 and renewed in FY 2009, develops and conducts interventional and observational clinical studies, accompanied by studies of immune mechanism, to enhance understanding and ultimately reduce the immune-mediated morbidity and mortality of abdominal or thoracic organ transplantation in adults. The CTOT collaborates with CTOT-C in the study of issues related to transplant recipients who are children.  At this time, the CTOT consortium includes 3 awardees that are conducting clinical studies of heart, lung, liver, and kidney transplantation at more than 40 clinical sites and core laboratories, and is conducting 5 multi-center clinical trials with an aggregate target enrollment of approximately 2500 transplant recipients. The CTOT studies encompass a broad range of issues, including the evaluation of new therapeutic regimens to overcome immunologic barriers to graft acceptance and/or long-term graft and patient survival; the evaluation of approaches to the treatment or prevention of immune-mediated complications of transplantation; investigation of the underlying mechanisms of action of the pathologic processes, agents or regimens under study; and the development of diagnostic tests and/or surrogate biomarkers that will facilitate routine surveillance, early diagnosis and ongoing monitoring of those processes that contribute to post-transplant morbidity and mortality.

Clinical Trials in Organ Transplantation in Children (CTOT-C): This cooperative, multi-site consortium was established in FY 2008 as an expansion of the Cooperative Clinical Trials in Pediatric Transplantation (CCTPT). Like CTOT, the CTOT-C investigators develop and conduct interventional and observational clinical studies, accompanied by studies of immune mechanism, to enhance understanding and ultimately reduce the immune-mediated morbidity and mortality of abdominal or thoracic organ transplantation in children. The CTOT-C consists of 4 awardees who are conducting clinical studies of heart, lung, and kidney transplantation at more than 20 clinical sites and core laboratories. In the aggregate these trials have a target enrollment of approximately 250 pediatric transplant recipients.

Specifically excluded from both the CTOT and the CTOT-C are studies involving: 1) hematopoietic stem cell transplantation (HSCT), unless HSCT is a component of a study of organ transplantation, 2) islet transplantation for treatment of Type 1 diabetes, 3) animal models, and 4) xenotransplantation. Examples of conditions to be studied include, but are not limited to, the following:

• Pre-existing immunologic barriers (such as anti-HLA antibodies or ABO incompatibility) to successful transplantation;
• Chronic, progressive allograft destruction (e.g., allograft nephropathy, obliterative bronchiolitis) after organ transplantation;
• Immunomodulatory interventions targeting innate immunity and/or autoimmunity in transplant donors or recipients;
• New, less toxic immunosuppressive agents or regimens, or innovative approaches to develop donor-specific tolerance;
• Prevention or treatment of post-transplant lymphoproliferative disorder and malignancy; and
• Susceptibility to, and prevention of, the adverse consequences (e.g., nephropathy, systemic hypertension, diabetes mellitus, malignancy) of current post-transplant immunosuppressive regimens.

Examples of associated studies of immune mechanism include, but are not limited to, the following:

• The underlying mechanisms of action of the therapeutic approaches under investigation;
• Development, evaluation, and validation of diagnostic tests for and/or surrogate markers of the relevant immunologic processes that will facilitate routine surveillance, early diagnosis and ongoing monitoring of those processes that contribute to post–transplant morbidity and mortality;
• Development of assays to define and monitor immunoreactivity in order to guide real-time dose adjustments of the immunosuppressive regimen; and
• Identification of genetic determinants of outcome or response to therapy in tissue and organ transplant recipients.

Genomics of Transplantation Cooperative Research Program (GTCRP): The GTCRP was established in FY 2004 and expanded in FY 2006 to support a cooperative research program using recipient and donor samples, as well as clinical data, for hypothesis-driven or hypothesis-generating, large-scale, broad-scope, prospective and/or retrospective genomic studies in clinical transplantation. At this time, the GTCRP supports two multi-project and one single project grants in kidney transplantation, with an aggregate target for sample collection from more than 10,000 individuals (Transplant donors and recipients). The GTCRP program supports only the genomic studies, integral proteomic studies where appropriate, and in some cases the procedural costs associated with specimen acquisition; the parent clinical studies must have independent financial support. The long-term goals of the program are (1) to understand the genetic basis of immune-mediated graft rejection and differences in transplant outcomes, and thereby provide a basis for development of more effective treatment and prevention strategies; and (2) to facilitate identification and development of genetic markers as diagnostic and prognostic tools. A renewal of the program is anticipated in FY 2011.

Examples of relevant research include, but are not limited to, the following areas:

• Determination of gene expression profiles of donor organs and recipients prior to transplantation, before clinical signs of rejection, and during acute and chronic rejection;
• Development of surrogate biomarkers of acute and chronic graft rejection;
• Identification of unique SNPs, haplotypes, and microsatellite polymorphisms in both donors and recipients, and correlation of these genetic variations with responses to immunosuppressive therapy;
• Determination of gene polymorphisms and/or expression patterns associated with race, age, and/or gender in graft rejection and responses to immunosuppressive therapeutics;
• Identification of DNA sequence-mediated regulation of gene expression associated with graft survival/rejection; and
• Development of noninvasive diagnostic/prognostic tests based on gene expression that will predict or confirm acute and chronic rejection

Consortia Steering Committees: Overall governance for these consortia is provided by their respective Steering Committees. The responsibilities of these committees vary somewhat among the consortia and may include: the development and ongoing review and modification of the consortium's scientific agenda; the establishment and implementation of procedures for the development, review and evaluation of concepts for clinical trials and mechanistic studies; setting priorities among proposed concepts; establishing standards for data collection, nomenclature, and scientific methodologies; monitoring and evaluating the progress of clinical and mechanistic studies; allocating resources; and assessing the need for redirection in scientific focus and implementing necessary changes to redirect resources in order to accommodate new knowledge and changing opportunities. For consortium-specific descriptions of steering committee structure and function, please see the respective FOAs (listed above). In addition, each consortium will have subcommittees that will make recommendations to the Steering Committee on scientific or administrative issues. The SACCC PI or delegate will be a voting member of the Steering Committee of each consortium.

Functions of the SACCC shall include, but not limited to, the following:

1. Provision of clinical study design and statistical expertise, including the performance of data analyses as specified by study protocols or as requested by the steering committee, the Data Safety Monitoring Board, or the NIAID Project Scientist;
2. Development of a Statistical Analysis Plan for each consortium study. Plans for the analysis of high throughput data requiring complex analyses (e.g., microarray data and genomic data) will be the primary responsibility of the clinical study PIs. However, the data center will provide data management assistance for these studies, including assistance with development of data dictionaries and definitions, data reconciliation, and provision of clinical data sets for analysis.
3. Participation as a voting member in all functions of the Steering Committees. the Mechanistic Study Subcommittees, and other subcommittees as determined by the Steering Committee;
4. Establishment of reliable and efficient electronic systems, compliant with pertinent regulations of the FDA or other Health Authorities, for electronic data capture and management of data generated by clinical and mechanistic studies;
5. Development and implementation of policies and procedures for quality control of study data;
6. Development of policies and procedures for quality assurance of clinical site performance, collection and tracking of regulatory/clinical documents, and performance of clinical site monitoring;
7. Training of clinical sites for specific protocols and in standards of Good Clinical Practice;
8. Preparation and distribution of protocol documents, manuals of procedures, and other materials necessary for implementation of studies;
9. Preparation of reports as directed by the Steering Committee or NIAID Project Scientist, and participation in the preparation of scientific manuscripts;
10. Preparation, labeling, delivery and tracking of study medications to clinical sites, as well as recovery of unused drug at study completion or at NIAID's direction
11. Provision of appropriate specimen tubes and packaging materials to clinical sites for the collection and transport of fluid and tissue samples of human origin;
12. Tracking of fluid and tissue specimens for laboratory studies;
13. Support of regulatory activities including adverse event reporting and tracking, document preparation and delivery for IND submissions or for other regulatory requirements of domestic or foreign Health Authorities. These functions may be performed by the applicant organization or by subcontract to the applicant organization;
14. Provide support as required for FDA/Health Authority meetings; and
15. In the event that there is a new awardee as a result of this FOA, or as a result of a future FOA,  coordinate with the incumbent awardee to implement an orderly, secure and efficient transition of data, documents, and materials related to CTOT, CTOT-C, and GTCRP. 

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

Section II. Award Information

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1. Mechanism of Support

This funding opportunity will use the Cooperative Agreement (U01) award mechanism.
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 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 under the Section VI. 2. Administrative Requirements, "Cooperative Agreement Terms and Conditions of Award". Plans beyond the current funding period are indefinite.

2. Funds Available

The estimated amount of funds available for support of one project awarded as a result of this announcement is $3.8 million for fiscal year 2010.  Future year amounts will depend on annual appropriations. The expected direct cost amount for individual awards is between $2-2.5 million. An applicant may request a project period of up to five years.

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

Although the financial plans of the IC(s) provide support for this program, awards pursuant to this funding opportunity are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications.

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.

Section III. Eligibility Information

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1. Eligible Applicants

1.A. Eligible Institutions

The following organizations/institutions are eligible to apply:

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education
• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Small Businesses
• For-Profit Organizations (Other than Small Businesses)
• State Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribally Designated Organizations
• County Governments
• City or Township Governments
• Special District Governments
• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• U.S. Territory or Possession
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Regional Organizations
• Other(s):
  • Eligible Agencies of the Federal Government
  • Faith-based or Community-based Organizations.

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. The NIH review criteria for approach, investigators, and environment have been modified to accommodate applications involving either a single PD/PI or multiple PDs/PIs. 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.

The Principal Investigator(s) must have appropriate expertise and capability in biostatistics, data management, data analysis, clinical trial design and protocol development, and project management. The Principal Investigator(s) must possess a doctoral degree in an appropriate field, e.g., biostatistics or bioinformatics, and must commit a total of at least 40% effort to the SACCC.  

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 each application is scientifically distinct.

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

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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) 710-0267, Email: [email protected].

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.

SPECIAL INSTRUCTIONS

Applications with Multiple PDs/PIs 

When multiple PDs/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.

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: June 22, 2009
Application Receipt Date: July 21, 2009
Peer Review Date: November 2009
Council Review Date: January 2010
Earliest Anticipated Start Date: March 2010

3.A.1. Letter of Intent

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

• Descriptive title of proposed research
• Name, address, and telephone number of the Principal Investigator
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

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:

Priti Mehrotra, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases 
Room 3138, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817-7616 (for express/courier service; non-USPS service)
Telephone: (301) 435-9369
FAX: 301-480-2408
Email: [email protected]

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:

Priti Mehrotra, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases 
Room 3138, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817-7616 (for express/courier service; non-USPS service)
Telephone: (301) 435-9369
FAX: 301-480-2408
Email: [email protected]

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 and Information

SUPPLEMENTARY INSTRUCTIONS:

For the purposes of budget planning and resource allocation, the applicant should assume that the three consortia being supported will be simultaneously implementing a total of 15 clinical studies with associated studies of immunologic mechanism, of which 3 will be randomized clinical trials, 5 will be phase 1 or 2 clinical trials, and 7 will be observational studies or assay studies. (The actual number may be different, and may change over the life of the grant.)

The Research Plan section of the application should include the following information:

1. Overview
2. Description of relevant capabilities and experience, including but not necessarily limited to database development and electronic data capture, biostatistics, protocol development, multi-site project management , and oversight of human subjects research
3. Research plan detailing the strategy to be used in executing the responsibilities of the SACCC

All three sections must be included within the page limit for the Research Plan as specified in the PHS 398 application instructions http://grants.nih.gov/grants/funding/phs398/phs398.html , except for specific materials, identified in the list below, which should be submitted as appendices. 

(1) Overview

The application should provide a brief discussion of the applicant's understanding of the nature and magnitude of the functions required to support the clinical research programs in general, and research programs in organ transplantation and other immune-mediated diseases in particular. Potential problems and obstacles, as well as proposed approaches to overcome problems/obstacles, should be identified.

(2) Description of relevant capabilities and experience. The following items should be addressed:

• Describe the experience, training and expertise of the proposed key personnel in clinical trial design, implementation and monitoring, as well as biostatistics, data management, data analysis, and project management. Provide an organization chart showing the proposed staffing plan, lines of authority, and proposed level of effort for each person, along with a brief description of the roles and responsibilities of all key personnel. This chart should indicate the use of dedicated project teams for each of the three consortia.
• Identify previous or ongoing collaborations in multi-center research, especially in transplantation or other surgically treated or immune-mediated diseases, within the last five years. Describe the contributions of the applicant organization to the successful design, implementation and analysis of the studies supported.
• Provide examples of the following items, prepared by the applicant organization, for previous multi-center clinical trials: protocol flow diagram and timeline, schedule of events, blood table, case report forms, manual of procedures, materials for investigator meetings, and graphical representations of study data. These items should be included as appendix 1.
• Provide examples of the following reports prepared by the proposed SACCC team for previous multi-center clinical trials: study progress reports; clinical site performance reports; site monitoring reports. These items should be included as appendix 2.
• Provide citations of publications and samples of those that are non-publically available co-authored by SACCC personnel, resulting from previous multi-center clinical research in which the applicant organization had substantial participation. These items should be included as appendix 3.
• Describe in detail logistical services (sample tracking and provision of study medications) arranged by the proposed SACCC team in support of previous multi-center clinical research.
• Describe the approach to clinical site training in protocol implementation and Good Clinical Practices. Provide relevant documents (training manuals, slide presentations, etc) in appendix 4.
• Describe examples of support provided for regulatory activities, including examples of IND submissions and processes for reporting and tracking of adverse events.
• Describe the available and/or planned facility, and how it has been or will be used to support multi-center clinical research. This should include a description of data system capabilities, computer graphics capabilities, and data and document storage facilities.
• Describe the organizational systems used by the proposed SACCC to assign and adjust its resources to participate in multi-center clinical and/or basic research.
• Provide an example of the calculation of costs by the applicant organization for their management of a specific research protocol conducted in a multicenter setting during the past five years. The sample size, quantity of data accumulated and analyzed, and the number of publications should be specified.
• Provide a plan for the transition of responsibilities from PPD, Inc. (“Initial Transition”), using the following assumptions (actual numbers may be different): Ten clinical protocols, one of which is done under IND, will be transferred from PPD, Inc to the successful applicant. The number of sites involved in each study ranges from 3 to >20; target accrual in each study ranges from 10 to >1000 subjects. Five studies will be in the subject accrual stage; 4 will be in the subject follow-up stage; and one will have completed accrual and follow up and will be entering data clean-up and analysis. The transition plan should include:
• draft protocols for clinical trials in development, final protocols and protocol amendments for ongoing clinical trials, and final protocols and protocol amendments for completed clinical trials;
• all study-related materials for ongoing and completed clinical trials, as well as clinical trials in development;
• data and other information contained in study-specific websites and procedures for access control;
• materials prepared for meetings, teleconferences and responses to inquiries from the FDA and other regulatory authorities;
• users’ manuals and written instructions for utilization of the data management system; and
• instructions and standard operating procedures for safety reporting.
• Provide a plan as described above for transition of responsibilities from your group to a new awardee or to the government (“Final Transition”) at the end of the 5-year funding period.

(3) Research Plan

• Include a statement of intent to collaborate in a manner consistent with the terms of the award.
• Provide generic plans and estimated timelines for protocol development, review, and implementation.
• Describe plans for staff allocation to meet the demands of the plans and timelines described above.
• Propose methods to be used to facilitate communication between SACCC staff, consortium investigators, NIAID and the Clinical Centers and Mechanistic Research Sites.
• Describe any planned modifications in the organizational systems to assign and adjust resource allocation during protocol performance. This should include any potential for outsourcing to increase efficiency or to meet short-term needs.
• Describe procedures to increase operational efficiency and decrease costs while protecting the integrity of the data and the quality of the analyses.
• Describe the method to be used by the proposed SACCC to calculate all operational costs per protocol and per enrolled patient for all SACCC functions.
• Propose a staffing pattern for providing SACCC functions from protocol design through analysis. This should include provisions for adjusting staff time commitments during the life of a study.
• Propose administrative and management functions that would assure continuing attention to cost-efficiency and productivity. This should include adjustment of resource allocation during protocol performance and the potential for outsourcing to improve efficiency or to meet short-term needs.

SPECIAL REQUIREMENTS

• See Section1.B. for PI eligibility and special requirements. The PI must have the experience and knowledge necessary to provide leadership in all of the areas described below.
• Special Expertise: The SACCC must have special expertise in the following areas: clinical trial design, including approaches to the study of small and/or heterogeneous patient populations; organ or tissue transplantation; implementation of multi-center clinical trials; clinical research involving vulnerable populations; and established procedures for monitoring of clinical research sites.
• Facilities Required: The SACCC must have the facilities necessary for: electronic data submission and data management; the generation and electronic transmission of graphic representations of study data and data analyses; the preparation and delivery of study medications to clinical sites; the tracking of fluid and tissues samples for laboratory testing. Reporting Requirements: The SACCC must generate monthly reports on subject enrollment for all active clinical protocols; quarterly reports on enrollment and clinical site performance; reports of Steering Committee Meetings, Subcommittee Meetings, and DSMB meetings, and special reports as required by the Steering Committees of the NIAID Project Scientist or Program Official. The SACCC must also have the facilities and equipment to secure and preserve electronic data captured for the studies and all personnel involved in data management and storage must be trained in how to handle sensitive patient data.
• Meeting Coordination and Participation: The SACCC will organize and participate in Steering Committee Meetings and Investigator Meetings. Steering Committee meetings will occur at least annually for each consortium, with additional meetings scheduled as necessary. Investigator meetings will also occur at least once annually for each consortium, with additional meetings as necessary. The SACCC will also provide support for meetings with the FDA and other Health Authorities.

The SACCC must provide a data sharing plan to make available to the public the results and accomplishments of the research. Requirements for a data sharing plan are described in the “Final NIH Statement on Sharing Research Data” at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html

Research Plan Page Limitations

All three above sections must be included within the page limit for the Research Plan as specified in the PHS 398 application instructions http://grants.nih.gov/grants/funding/phs398/phs398.html , except for specific materials, identified in the above list, which should be submitted as appendices. 

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: Investigators seeking $500,000 or more in direct costs in any year 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/.

The SACCC shall collaborate and coordinate activities in conjunction with other NIAID and bioinformatics groups, including but not limited to the following:

a) Deposit all clinical and mechanistic data to the NIAID-funded Bioinformatics Integration Support Contract (BISC) data repository http://www3.niaid.nih.gov/about/organization/dait/bisc.htm ) (www.immport.org)  Clinical data will be deposited once the clinical study has been closed and the initial findings have been published. In accordance with the NIH Data Sharing Policy http://grants.nih.gov/grants/policy/data_sharing/index.htm , both clinical and mechanistic data residing in the SACCC database will be deposited to BISC no later than sixty (60) days after the initial publication of study results. 

b) All data will have all patient identifiers removed before deposition to BISC. The BISC system is able to accept most standard file formats that are produced in scientific research. The BISC is responsible for mapping data coming from the consortium studies into the BISC data model.  The format of the data files and of the data transfer methods from Network to BISC will be determined at the time of award. Examples of formats used by other groups can be found at  http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html)

c) Work with BISC to develop standards and formats that will lead to ease of interoperability among bioinformatics tools, databases and software developed by the Network, BISC and other NIH-funded programs.

d) Provide use cases or specifications, as the need arises in the Network, to the BISC project for novel tools for analysis or for existing tools to be incorporated into the systems developed by BISC.

Section V. Application Review Information

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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:

• Undergo a selection process in which only those applications deemed to have the highest scientific and technical merit, generally the top half of applications under review, will be discussed and assigned a priority score.
• Receive a written critique.
• Receive a second level of review by the National Advisory Allergy and Infectious Diseases Council.

The following will be considered in making funding decisions:

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

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. 

Overall Impact. Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following 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?   

Investigators.  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?  Are the PD/PIs and key personnel experienced and knowledgeable with respect to 1) the design, implementation and publication of complex multicenter clinical trials, and 2) the development of clinical studies and statistical analysis plans to address the correlation of clinical findings with detailed immunologic assays or mechanistic studies? 3) are there physicians with the appropriate background and expertise to review medical events occurring in clinical trials in organ transplantation? And 4) are the PD/PIs and key personnel knowledgeable and experienced with respect to Human Subjects Protections, Good Clinical Practice, and monitoring and reporting adverse events and serious adverse events?

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? Does the applicant present comprehensive, effective, and practical approaches for 1) the organizational plan and administrative and operational structure including clear delegation of responsibilities for the different tasks required (e.g., protocol development, project management, FDA compliance, Case Report Form development, programming, etc, as described in section I under the heading “Research Objectives and Scope”)?; 2) development of statistical analysis plans, and implementation of those plans, for all studies carried out within the three clinical consortia?; 3) collaboration with DAIT program staff in all aspects of clinical study development, implementation, and analysis?; 4) logistical support services for drug distribution and specimen tracking; and  5) an efficient plan for transition of studies from PPD, Inc, and to a subsequent awardee as necessary?

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 the data entry and management systems, organizational structure, and human resources described in the application adequate for the tasks described in this FOA?   

2. A. Additional Review Criteria:

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. Follow the instructions of PHS 398 for renewal applications http://grants.nih.gov/grants/funding/phs398/phs398.html

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 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

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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 Principal Investigator will have the primary responsibility for: defining the research objectives, approaches and details of the projects within the guidelines of the FOA and for performing the scientific activity. Specifically, the awardee has primary responsibility as described below.

The Principal Investigator is expected to cooperate with the CTOT, CTOT-C and GTCRP clinical investigators, the NIAID Project Scientist and Program Official, and other participating NIAID staff in the design and conduct of protocols, analysis of data, and reporting of results of research undertaken by the research consortia.

The Principal Investigator will agree to accept the participatory and cooperative nature of the collaborative research process. The SACCC grant will provide research support services to the Clinical and Laboratory Sites comprising the CTOT, CTOT-C and GCTRP. These services will include establishment and maintenance of a centralized information management system to store, clean, and analyze data that will be used in publications and public presentations of research performed in the three consortia. The SACCC will serve as a central repository for data on all collaborative projects. The SACCC will assist the NIAID Project Scientist, Project Official, and the Steering Committees in monitoring research progress, and will work to ensure data integrity, accuracy, security, and accessibility.

Specifically, the SACCC will:

Support the activities of the Steering Committees and the NIAID Transplant Data and Safety Monitoring Board (DSMB) through provision of materials and documentation, meeting planning and logistics, and conference call coordination;

Provide advice on study design, data collection, data analysis, and publication development in all CTOT, CTOT-C, and GTCRP research projects;

Prepare, design, and disseminate operations manuals, data collection forms, databases, and results summaries for CTOT, CTOT-C and GTCRP projects and protocols;

Compile for the Steering Committee, the DSMB, the NIAID Project Scientist and Program Official site visit reports, monthly and quarterly reports of research activities (including, but not limited to, subject enrollment), meeting summaries, quarterly research site performance reports from each Clinical Center, and other reports as needed;

Provide, in concert with the NIAID Project Scientist and Program staff, support necessary to ensure that sites and investigators fully comply with federal regulatory requirements, including but not limited to those relating to human subjects protections, informed consent, and reporting of adverse events;

Provide training at study sites for personnel as needed for standardization of collaborative protocols across sites and for accurate and timely data entry;

In coordination with the NIAID Project Scientist and Program staff, develop a monitoring plan and provide periodic, on- and/or off-site quality control monitoring at study sites;

When determined by the NIAID Project Scientist or Program staff to be necessary, provide appropriate specimen tubes and labeling and packaging materials to clinical sites for the collection and transport of fluid and tissue samples;

Provide tracking of fluid and tissue samples;

Prepare and deliver study medications to clinical sites; and

Provide support for regulatory activities, including adverse event reporting, document preparation for IND submissions and other regulatory requirements of domestic or foreign Health Authorities.

Any of the above functions may be performed by the applicant organization or by subcontract to the applicant organization.

Awardees will retain custody of and have primary rights to the 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. 

NIAID staff assistance will be provided by the Chief of the Transplantation Immunobiology Branch, NIAID or his/her designee, who will serve as the NIAID Project Scientist. The NIAID Project Scientist will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond normal program stewardship for grants, as described below.

During performance of the award, the NIAID Project Scientist, with assistance from other scientific program staff who are designated based on the research topic and their relevant expertise, may provide appropriate assistance, advice, and guidance by: participating in the design of the activities; advising in the selection of sources or resources (e.g., determining where a particular reagent can be found); coordinating or participating in the collection and/or analysis of data; advising in project management and technical performance; and participating in the preparation of publications. The NIAID Project Scientist will serve as a liaison/facilitator between the awardee, pharmaceutical and biotech industries, and other government agencies (e.g., FDA, USDA, CDC) and will serve as a resource of scientific and policy information related to the goals of the awardee's research. However, the role of NIAID will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus and the NIAID staff will be given the opportunity to offer input into this process. The manner of reaching this consensus and the final decision-making authority will rest with the Principal Investigator.

The NIAID Project Scientist, together with the SACCC and the Steering Committee, will review the progress of each participating institution through consideration of the annual reports, site visits, patient logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting patient enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.

A NIAID Program Official will be assigned to perform normal program stewardship responsibilities for this award, including monitoring program progress, approving changes and concurring in proceeding into study implementation stage. 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. NIAID staff 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.

The NIAID reserves the right to terminate or curtail any study or any individual award in the event of (a) substantial shortfall in participant recruitment, follow-up, data reporting, quality control, or other major breach of the protocol, (b) substantive changes in the consensus protocol to which the NIAID does not agree, (c) reaching a major study endpoint substantially before schedule with persuasive statistical significance, or (d) human subject ethical issues that may dictate a premature termination.

Certain organizational changes require the prior written approval of the NIAID Program Official. These changes include the addition or replacement of a physician, scientific investigator, affiliate, component, or research base that is associated with this study. A change in the PI, or in any key personnel identified on the Notice of Award, must have the prior written approval of the NIAID Grants Management Specialist in consultation with the NIAID Program Official.

The NIAID Project Scientist will serve as a voting member of the Steering Committee and will participate in all Committee activities. The NIAID Project Scientist will also serve on the Mechanistic Studies Subcommittee.

Protocol Development

As a member of the Steering Committee, the NIAID Project Scientist will serve as a resource with respect to the design of the protocol and will, along with the SACCC, assist the Steering Committee in protocol development.

Publication and Presentation of Study Findings

The NIAID Project Scientist may contribute, through review, comment, analysis, and/or co-authorship, to reporting results of the study to the investigator community and other interested scientific and lay organizations. Co-authorship by the NIAID Project Scientist will be subject to approval in accordance with NIH policies regarding staff authorship of publications resulting from extramural awards.

Regulatory Affairs

The Chief of Regulatory Affairs, Division of Allergy, Immunology, and Transplantation will be responsible for providing guidance and assistance in the development, assembly, and submission of all required regulatory documents, e.g. those regarding the use of investigational drugs, to the Food and Drug Administration.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

2.A.3. Collaborative Responsibilities

Steering Committee. The SACCC Principal Investigator shall serve as a voting member of the CTOT, CTOT-C and GTCRP Steering Committees, which serve as the main governing bodies of their respective cooperative research programs. All major scientific decisions will be determined a consensus-driven process and confirmed by majority vote of the Steering Committee. The NIAID and the SACCC are limited to one vote each on the Steering Committees. The NIAID Project Scientist and the PI of the SACCC are not eligible to be the Steering Committee Chair.

Data and Safety Monitoring Board (DSMB).  Clinical research conducted by CTOT, CTOT-C, and the GTCRP is reviewed prior to implementation by an independent DSMB, appointed by the NIAID. The DSMB acts in an advisory capacity to NIAID. The DSMB review will focus on the safety, ethics, and scientific and statistical integrity of the studies.

Data Coordination and Management. Data Coordination and Management will be carried out by the SACCC. Each participating institution will be responsible for providing primary study data to NIAID via the SACCC for management, quality control, and analysis, using procedures and standards determined by the Steering Committees and the SACCC. The SACCC and NIAID Project Scientist will provide the following: technical assistance and data management services to the participating institutions with respect to quality control, uniformity of data collection, management of the collective database, and data analysis; centralized data collection and management; and quality assurance. Specific analyses to be performed will be directed by the Steering Committees. The results of those analyses will be delivered to the appropriate Steering Committee, which is responsible for determining how the results are interpreted, whether the results should influence ongoing data collection, and how the findings should be disseminated. In the event of a specific safety concern, the DSMB may also request specific analyses from the SACCC. All participating sites will have access to all data originating from their sites. The awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies. Each of the consortia’s clinical and laboratory sites will be responsible for on-site data collection and transmittal.

Publication and Presentation of Study Findings. Timely publication of major findings is encouraged. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of the participating institutions and NIAID support. Analyses to be performed using the collective data from all participating institutions will be determined and directed by the appropriate Steering Committee. Participating institutions wishing to perform analyses of local data will inform the Steering Committees of any such analyses prior to initiation in order to avoid duplication; the SACCC shall confirm Steering Committee and NIAID approval prior to initiation of any data analyses. Review and approval by the Steering Committee may be required for all completed analyses prior to publication or presentation according to criteria that will be developed by the individual Steering Committees. The Steering Committees may establish Publications Subcommittees to carry out this function.

Monitoring Study Progress. The Steering Committees will establish mechanisms for assessing the performance of the participating institutions, including institutions participating in consortia arrangements, with particular attention to accrual of adequate numbers of eligible patients, timely submission and quality of required data and specimens and conscientious observance of protocol requirements.

Each full member will have one vote. Awardee members of the Steering Committee will be required to accept and implement policies approved by the Steering Committee.

2.A.4. Arbitration Process

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. An Arbitration 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 arbitration procedure in no way affects 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

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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:

Nancy D. Bridges, M.D. 
Division of Allergy, Immunology, and Transplantation
National Institute of Allergy and Infectious Disease
Room 3035, MSC-6601
6610 Rockledge Drive 
Bethesda, MD 20892-6601
Telephone: (301) 451-4406
FAX:  (301) 402-0175
Email: [email protected]   

2. Peer Review Contacts:

Priti Mehrotra, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases 
Room 3138, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616 (U.S. Postal Service Express or regular mail)
Bethesda, MD 20817-7616 (for express/courier service; non-USPS service)
Telephone: (301) 435-9369
FAX: 301-480-2408
Email: [email protected]

3. Financial or Grants Management Contacts:

Mildred J. Qualls
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2125, MSC-7614
6700-B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 402-6611
FAX:  (301) 493-0597
Email: [email protected]

Section VIII. Other Information

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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.