Coordinating Center for Organ Transplant Clinical Trials

RFA Number: RFA-AI-04-046

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

• April 2, 2009 - This RFA has been reissued as RFA-AI-09-015.

Key Dates

Release Date: September 29, 2004
Letters Of Intent Receipt Date: December 10, 2004
Application Receipt Dates(s): January 11, 2005
Peer Review Date(s): April, 2005 Council Review Date(s): June, 2005
Earliest Anticipated Start Date: July, 2005 Additional Information To Be Available Date (URL Activation Date): http://www.niaid.nih.gov/ncn/budget/QA/rfa-04-046.htm (October 1, 2004)
Expiration Date: January 12, 2005

Due Dates for E.O. 12372 Not Applicable

This initiative will establish a Statistical and Clinical Coordinating Center (SACCC) to support clinical studies in organ transplantation to be conducted by two NIAID-sponsored clinical consortia, the Clinical Trials in Organ Transplantation (CTOT) Consortium and the Cooperative Clinical Trials in Pediatric Transplantation (CCTPT) Consortium. NIAID intends to commit approximately $3 million in FY 2005 to fund one new grant in response to this RFA. This RFA will use the NIH cooperative agreement (U01) funding mechanism. Eligible organizations include for-profit or non-profit organizations; public or private institutions, such as universities, colleges, hospitals, and laboratories; units of State and local governments; and eligible agencies of the Federal government. Foreign institutions are not eligible to apply. The applicant organization must have special expertise in 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. In addition, it must have the facilities necessary for electronic data submission and data management; tracking and distribution of study medications and samples; and secure storage of regulatory and clinical documents. Eligible principal investigators include any individual with the skills, knowledge, and resources necessary to carry out the proposed research. The Principal Investigator must have appropriate expertise and capability in biostatistics, data management, data analysis, and project management, and must possess a doctoral degree in an appropriate field. Submit one application per applicant. Application materials available at http://grants.nih.gov/grants/forms.htm

Table of Contents

Part I Overview Information

Part II Full Text of Announcement

Section I. Funding Opportunity Description
1. Research Objectives

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

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

Section IV. Application and Submission and Instructions
1. Address to Request Application Information
2. Content and Form of Application Submission
3. Submission Dates
A. Receipt and Review and Anticipated Start Dates
1. Letter of Intent
B. Sending an Application to the NIH
C. Application Processing
4. Intergovernmental Review
5. Funding Restrictions
6. Other Submission Requirements

Section V. Application Review Information
1. Criteria
2. Review and Selection Process
3. Merit Review Criteria
A. Additional Review Criteria
B. Additional Review Considerations
C. Sharing Research Data
D. Sharing Research Resources

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. Award Criteria
4. 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

1. Research Objectives

PURPOSE:

The National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), invites applications for the establishment of a Statistical and Clinical Coordinating Center (SACCC) to support clinical studies in organ transplantation to be conducted by two NIAID-sponsored clinical consortia, the Clinical Trials in Organ Transplantation (CTOT) Consortium and the Cooperative Clinical Trials in Pediatric Transplantation (CCTPT) Consortium. 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. The SACCC will also assist with the preparation of DSMB reports, scientific manuscripts, and other reports and documents as needed to support the activities of the consortia.

RESEARCH OBJECTIVES:

Background

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 improve short- and long-term graft and patient survival, the NIAID supports two investigative consortia to conduct clinical and associated mechanistic studies that will lead to improved outcomes for transplant recipients the Cooperative Clinical Trials in Pediatric Transplantation (CCTPT) Consortium, and the Clinical Trials in Organ Transplantation (CTOT) Consortium. RFA-AI-02-004 provided for the renewal of the CCTPT Consortium ( http://grants2.nih.gov/grants/guide/rfa-files/RFA-AI-02-004.html .) RFA-AI-04-003 provides for the establishment of the CTOT Consortium in FY 2004 (http://grants1.nih.gov/grants/guide/rfa-files/RFA-AI-04-003.html .)

NIAID previously solicited proposals for a Statistical and Clinical Coordinating Center contract for the CCTPT (RFP-NIH-NIAID-DAIT-01-08, http://www.niaid.nih.gov/contract/archive/rfp0108.pdf ). The EMMES Corporation successfully competed for this award. Further information on the CCTPT is provided at the EMMES website at http://spitfire.emmes.com/study/cctpt/index.htm . This contract expires in March 2006. Although NIAID expects that the award in response to this RFA will overlap with the existing CCTPT coordinating center contract in time only, NIAID will not support overlapping coordinating center activities by independent awardees. Upon termination of the current contract with the EMMES Corporation, the awardee will assume all coordinating center responsibilities for the CCTPT. Transfer of existing activities will begin no later than six (6) months prior to the termination of the EMMES contract.

Objectives and Scope:

CCTPT: The CCTPT is an established clinical consortium conducting pilot interventions and randomized clinical trials of immunosuppressive regimens in children undergoing kidney transplantation. There are currently 7 active CCTPT protocols, each of which has between 3 and 20 participating clinical sites. Each of these clinical investigations has associated mechanistic studies, which are currently being performed at 4 sites. SACCC responsibilities for the CCTPT will transfer from the current contractor, EMMES, to the successful applicant beginning no later than 6 months prior to termination of the EMMES contract. .

CTOT: The new cooperative, multi-site CTOT, to be established in FY 2004, will design and conduct interventional or observational clinical studies, accompanied by mechanistic studies, to enhance understanding and ultimately reduce the immune-mediated morbidity and mortality of abdominal or thoracic organ transplantation in adults and children. It is anticipated that 3 awards will be made, resulting in participation of approximately 20 clinical sites and 5 mechanistic study sites. The CTOT studies will 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.

Specifically excluded from both the CCTPT and the CTOT 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.

Participating Clinical Centers: It is anticipated that most of the investigators and clinical centers participating in these consortia will be located within the United States; however, participation of clinical centers located in other developed countries is permitted. The scope of these clinical studies precludes participation by sites located in developing countries.

Clinical centers from both consortia will participate in multi-site clinical trials and/or observational studies, with associated mechanistic studies, to improve our understanding of and/or evaluate interventions to reduce the immune-mediated morbidity and mortality of organ transplantation. 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.

Each clinical study will have associated mechanistic studies. Examples of associated mechanistic studies include, but are not limited to, the following:

1. The underlying mechanisms of action of the therapeutic approaches under investigation;
2. 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;
3. Development of assays to define and monitor immunoreactivity in order to guide real-time dose adjustments of the immunosuppressive regimen; and
4. Identification of genetic determinants of outcome or response to therapy in tissue and organ transplant recipients..

Consortia Steering Committees: Overall scientific leadership and direction for CTOT and CCTPT studies is provided by their respective Steering Committees. The responsibilities of these committees 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; 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. In addition, each consortium will have a Mechanistic Studies Subcommittee that will review proposed mechanistic studies and make recommendations about additional or alternative mechanistic studies.

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

1. Provision of clinical study design and statistical expertise to the CCTPT and CTOT, 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 Scientific Coordinator;
2. 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;
3. Establishment of reliable and efficient electronic systems, compliant with pertinent regulations of the FDA or other Health Authorities, for the collection and management of data generated by clinical and mechanistic studies;
4. Development and implementation of policies and procedures for quality control of study data;
5. 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;
6. Training of clinical sites for specific protocols and in standards of Good Clinical Practice;
7. Preparation and distribution of protocol documents, manuals of procedures, and other materials necessary for implementation of studies;
8. Preparation of reports as directed by the Steering Committee or NIAID Scientific Coordinator, and participation in the preparation of scientific manuscripts;
9. 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
10. Provision of appropriate specimen tubes and packaging materials to clinical sites for the collection and transport of fluid and tissue samples of human origin;
11. Tracking of fluid and tissue specimens for laboratory studies;
12. 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;
13. Provide support as required for FDA/Health Authority meetings; and
14. Transition of the above functions from the EMMES Corporation in FY 2006.

Section II. Award Information

The NIH (U01) are cooperative agreement award mechanisms. In the cooperative agreement mechanism, the Principal Investigator 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 and National Policy Requirements, "Cooperative Agreement Terms and Conditions of Award".

The total project period for applications submitted in response to the RFA may not exceed five years. At this time, the NIAID has not determined the manner by which the research activities will be continued beyond the present RFA.

• For-profit or non-profit organizations
• Public or private institutions, such as universities, colleges, hospitals, and laboratories
• Units of State government
• Units of local government
• Eligible agencies of the Federal Government
• Foreign institutions are not eligible to apply

Foreign institutions are not eligible to apply as the primary institution, but may enter into a consortium or subcontract with a domestic institution as the primary applicant.

1.B. Eligible Individuals

Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their 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 programs.

2. Cost Sharing

Not Applicable http://grants.nih.gov/grants/policy/nihgps_2003/nihgps_Part2.htm#matching_or_cost_sharing

Section IV. Application Submission Instructions

Letters Of Intent Receipt Date(s): December 10, 2004
Application Receipt Dates(s): January 11, 2005
Peer Review Date(s): April, 2005
Council Review Date(s): June, 2005
Earliest Anticipated Start Date: July, 2005

• 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 at the beginning of this document.

The letter of intent should be sent to:

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: 301-402-2636
FAX: 301-402-2638
Email: [email protected]

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: 301-402-2636
FAX: 301-402-2638
Email: [email protected]

All 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 http://grants.nih.gov/grants/policy/policy.htm (See also Section VI.3. Award Criteria)

SUPPLEMENTARY INSTRUCTIONS:

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

1. Overview
2. Description of relevant capabilities and experience
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, 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 in particular. Potential problems and obstacles, as well as proposed approaches to overcome problems/obstacles, should be identified. In addition, provide a summary of the capabilities and commitment of the applicant organization to collaborative, multi-center clinical and mechanistic research in organ transplantation.

(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, biostatistics, data management, data analysis, and project management, including specific ongoing or completed projects involving the provision of support for multi-center clinical research.
• 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.
• Identify previous 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 examples of manuscripts 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 in detail 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 detailed plan for the transition of responsibilities for CCTPT studies from The EMMES Corporation, using the following assumptions: Six clinical protocols, each involving an IND, will be transferred from the EMMES Corporation to the successful applicant. The number of sites involved in each study ranges from 4 to 27; target accrual in each study ranges from 35 to 300 subjects. Two studies will be in the subject accrual stage; 3 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.

(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 and other components of the CCTPT and CTOT, including 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 an administrative and operational structure, in diagrammatic form, for providing and coordinating all SACCC functions for several CCTPT and CTOT protocols simultaneously. This should include lines of responsibility/authority for professional staff.
• 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.
• Describe any modifications in the applicant's current processes used to provide SACCC functions that may be made if the applicant were to be selected as the SACCC for the CCTPT and CTOT.
• 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 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. In addition, the SACCC facilities must include a secure, fire-protected storage area for regulatory/clinical documents.
• 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 Scientific Coordinator or Program Official.
• Meeting Coordination and Participation: The SACCC will organize and participate in Steering Committee Meetings and Investigator Meetings for the CCTPT and CTOT. Steering Committee meetings will occur at least twice annually for each consortium, with additional meetings scheduled as necessary. Investigator meetings will also occur at least twice 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 CCTPT and the CTOT. 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 .

Specific Instructions for Modular Grant applications.

Not Applicable

Specific Instructions for Applications Requesting $500,000 (direct costs) or More per Year.

Not Applicable

Plan for Sharing Research Data
The precise content of the data-sharing plan will vary, depending on the data being collected and how the investigator is planning to share the data. Applicants who are planning to share data may wish to describe briefly the expected schedule for data sharing, the format of the final dataset, the documentation to be provided, whether or not any analytic tools also will be provided, whether or not a data-sharing agreement will be required and, if so, a brief description of such an agreement (including the criteria for deciding who can receive the data and whether or not any conditions will be placed on their use), and the mode of data sharing (e.g., under their own auspices by mailing a disk or posting data on their institutional or personal website, through a data archive or enclave). Investigators choosing to share under their own auspices may wish to enter into a data-sharing agreement. References to data sharing may also be appropriate in other sections of the application.

All applicants must include a plan for sharing research data in their application. The data sharing policy is available at http://grants.nih.gov/grants/policy/data_sharing. All investigators responding to this funding opportunity should include a description of how final research data will be shared, or explain why data sharing is not possible.

The adequacy of the resources sharing plan and any related data sharing plans will be considered by Program staff of the funding organization when making recommendations about funding applications. The effectiveness of the resource sharing will be evaluated as part of the administrative review of each non-competing Grant Progress Report. (PHS 2590). See Section VI.3. Award Criteria.

Applications that are complete and responsive to the funding opportunity announcement will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NIAID in accordance with the review criteria stated below.

As part of the initial merit review, all applications will:

• Undergo a selection process in which only those applications deemed to have the highest scientific 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 review by the National Advisory Allergy and Infectious Diseases Council

The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of these criteria in assigning the application's overall score, weighting them as appropriate for each application.

• Significance
• Approach
• Innovation
• Investigator
• Environment
• Additional Review Criteria

The application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.

Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field?

Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics?

Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)?

Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support?

3.A. Additional Review Criteria:

In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score:

Relevant capabilities and experience: As evidenced by previous collaborations in multi-center research, especially in transplantation, surgery, or immune-mediated diseases, and by the capacity to (a) estimate appropriate and reasonable resources needed for individual projects in its role as the Data Center for multicenter research, (b) manage those resources efficiently during the research, (c) adjust the assigned resources as needed during the research project period, (d) report these resource allocations to NIAID periodically, and (e) sub-contract with outside organizations in order to supplement its own resources, as needed. Reviewers will also look for evidence of previous success in a) managing projects of similar complexity and scope, b) managing multiple subcontracts and/or consultants, and c) the implementation and monitoring of clinical studies and clinical site training.

1. The experience, training, commitment and expertise of proposed key personnel: The Principal Investigator, and other staff, must have appropriate expertise and capability in biostatistics, data management, data analysis, and project management. The Principal Investigator must possess a doctoral degree in an appropriate field and be willing to commit at least 30 percent effort to SACCC. The PI should provide a detailed plan as to how he/she will provide adequate leadership and technical support to the project. Specific expertise in transplant-specific study design, the approach to protocol and timeline development, and evidence of leadership ability, will be evaluated.
2. Quality of work, as evidenced by examples provided of reports, manuscripts, case report forms, meetings materials, and other requested supplementary materials.
3. Adequacy of facilities, including electronic data systems, computer graphics capabilities, and data and document storage facilities.
4. Comprehensiveness, effectiveness, and practicality of the proposed organizational plan and administrative and operational structure.
5. Comprehensiveness, effectiveness, and practicality of the proposed logistical support services for drug distribution and specimen tracking.
6. Comprehensiveness, effectiveness, practicality, and efficiency of proposed plan for transition of studies from the EMMES Corporation.

Protection of Human Subjects from Research Risk: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. See also Section VIII - Other Information.

Inclusion of Women, Minorities and Children in Research: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. See also Section VIII-Other Information .

Care and Use of Vertebrate Animals in Research: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed.

1. Award Notices

After the peer review of the application is completed, the Principal Investigator will also receive a written critique called a Summary Statement.

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 http://grants.nih.gov/grants/policy/nihgps_2003/NIHGPS_part4.htm

A formal notification in the form of a Notice of award will be provided to the applicant organization. The notice of award signed by the grants management officer is the authorizing document.

Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NGA (Notice of Grant Award) are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Notice of grants award will be transmitted via US mail and/or electronically via email.

2. Administrative and National Policy Requirements

All NIH Grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the notice of grant award. 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.

Monitoring Clinical Studies

When clinical studies or trials are a component of the research proposed, NIAID policy requires that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. AN UPDATED NIAID policy was published in the NIH Guide on July 8, 2002 and is available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html . The full policy, including terms and conditions of award, is available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf .

2.A.1. Principal Investigator Rights and Responsibilities
The Principal Investigator will have the primary responsibility for: d efining the research objectives, approaches and details of the projects within the guidelines of the RFA and for performing the scientific activity. Specifically, the awardee has primary responsibility as described below.

The Principal Investigator is expected to cooperate with the CCTPT and CTOT clinical investigators, the NIAID Scientific Coordinator 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 CCTPT and the CTOT.

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 Centers and Mechanistic Study Sites comprising the CCTPT and the CTOT. These will include establishment and maintenance of a centralized information management system to help the clinical and mechanistic study sites, the Steering Committee, and NIAID to edit, store, analyze, publish, and disseminate results from the shared research. The SACCC will serve as a central repository for data on all collaborative projects. The SACCC will assist the NIAID Scientific Coordinator, 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 CCTPT and CTOT research projects;
• Prepare, design, and disseminate operations manuals, data collection forms, databases, and results reporting summaries for CCTPT and CTOT projects and protocols;
• Compile for the Steering Committee, the DSMB, the NIAID Scientific Coordinator 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;
• For CCTPT and CTOT collaborative studies, provide support, in concert with the NIAID Scientific Coordinator and Program Official, as necessary, to ensure that all CCTPT and CTOT sites and investigators fully comply with NIH regulatory requirements, including Human Subject Protections, informed consent, reporting of adverse events, and human and subject safety and welfare protections;
• Provide training at all Clinical Center and Mechanistic Study sites for personnel as needed for standardization of collaborative protocols across sites;
• In coordination with the NIAID Scientific Coordinator and Program Official, provide periodic, on-site quality control monitoring at the Clinical Center and Mechanistic Study research sites for CCTPT and/or CTOT studies being performed at that site;
• 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 of regulatory activities, including adverse event reporting, document preparation for IND submissions or for other regulatory requirements of domestic or foreign Health Authorities.

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

2.A.2. NIH Responsibilities

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

NIAID staff assistance will be provided by the Chief, Clinical Transplantation Section, NIAID or his/her designee, who will serve as the NIAID Scientific Coordinator. The NIAID Scientific Coordinator 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 Scientific Coordinator, 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 Scientific Coordinator 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 Scientific Coordinator, 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 Program Official may serve as the Scientific Coordinator.

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

Protocol Development

As a member of the Steering Committee, the NIAID Scientific Coordinator 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 Scientific Coordinator 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 Scientific Coordinator 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/Office of Clinical Activities/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.

2.A.3. Collaborative Responsibilities

Steering Committee . The SACCC Principal Investigator shall serve as a voting member of the CCTPT and the CTOT Steering Committees, which serve as the main governing body of their respective cooperative research programs. All major scientific decisions will be determined by majority vote of the Steering Committee. The NIAID and the SACCC are limited to one vote each on the Steering Committee. The first two meetings of the CTOT Steering Committee will be convened by the NIAID Scientific Coordinator. At the second meeting, the group will elect a Chairperson from among the Steering Committee members; the NIAID Scientific Coordinator and the PI of the SACCC are not eligible to be the Steering Committee Chair. 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.

Data and Safety Monitoring Board (DSMB). An independent DSMB, appointed by the NIAID, will review progress at least annually on each study implemented by the CCTPT and CTOT, and report their findings to the NIAID Program Official. Clinical protocols and mechanistic studies will be subject to review by the DSMB, in an advisory capacity, prior to implementation. 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 Committee and the SACCC. The SACCC and NIAID Scientific Coordinator 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 Committee. The results of those analyses will be delivered to the 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. Although the participating institutions will be closely involved with these centralized data collection and management services, the participating institutions 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 Steering Committee. Participating institutions wishing to perform analyses of local data will inform the Steering Committee of any such analyses prior to initiation in order to avoid duplication. Review and approval by the Steering Committee will be required for all analyses prior to publication or presentation according to criteria that will be developed by the Steering Committee. The Steering Committee may establish a Publications Subcommittee 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 conscientious observance of protocol requirements.

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.

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

Awardees will be required to submit the PHS Non-Competing Grant Progress Report, Form 2590 annually: http://grants.nih.gov/grants/funding/2590/2590.htm and financial statements as required in the NIH Grants Policy Statement. (Add any IC specific reporting requirements not in the GPS or 2590)

Madelon Halula, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 3116, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
Telephone: 301-402-2636
FAX: 301-402-2638
Email: [email protected]

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, June 12, 1998: 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, 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.

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://grants1.nih.gov/grants/guide/notice-files/NOT-OD-04-042.html ). 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 that is available at 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 .

Public 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 public 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 PA 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.

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. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to 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 PA 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 Catalogue of Federal Domestic Assistance at http://www.cfda.gov/ in the following citations: No. 93.855, Immunology, Allergy, and Transplantation Research, No. 93.856, Microbiology and Infectious Diseases Research and No. 93.393-93.396, Cancer Cause and Prevention Research. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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.

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