Department of Health and Human Services

Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Allergy and Infectious Diseases (NIAID)

Funding Opportunity Title

Clinical Trials in Organ Transplantation in Children (U01) 

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of RFA-AI-07-006

Related Notices

  • January 26, 2012 - See Notice NOT-AI-12-024. Notice For Change in Receipt Date.

Funding Opportunity Announcement (FOA) Number

RFA-AI-12-005

Companion FOA

None

Number of Applications

Only one application per institution is allowed as defined in Section III. 3. Additional Information on Eligibility. Section III. 3. Additional Information on Eligibility.

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

93.855, 93.856

FOA Purpose

The National Institute of Allergy and Infectious Diseases (NIAID) invites new and renewal applications from institutions to participate in the “Clinical Trials in Organ Transplantation in Children” (CTOT-C) program. This funding opportunity will support a consortium of investigators to conduct clinical trials (Phase I,II, or III) and/or observational clinical studies, accompanied by mechanistic studies, in pediatric solid organ transplant recipients (subjects must be less than 21 years of age at the time of enrollment) who have undergone heart, lung, liver, small intestine, and/or kidney transplantation). Research supported under this FOA will focus on reducing long-term graft dysfunction and/or loss and immune-mediated morbidity and mortality unique to pediatric transplant recipients.

Key Dates
Posted Date

January 4, 2012

Open Date (Earliest Submission Date)

February 18, 2012  

Letter of Intent Due Date

March 18, 2012  

Application Due Date(s)

(Extended to May 4, 2012 per NOT-AI-12-024), Original Date April 18, 2012, by 5:00 PM local time of applicant organization.

AIDS Application Due Date(s)

Not Applicable.

Scientific Merit Review

September, 2012  

Advisory Council Review

January, 2013  

Earliest Start Date(s)

April, 2013  

Expiration Date

(Extended to May 5, 2012 per NOT-AI-12-024), Original Date April 19, 2012  

Due Dates for E.O. 12372

Not Applicable.  

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

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

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The National Institute of Allergy and Infectious Diseases (NIAID) invites new and renewal applications from institutions to participate in a clinical trials (phase I, II, and III) research program with embedded mechanistic investigations to improve long-term graft acceptance and patient/graft survival in pediatric solid organ transplant recipients who have undergone thoracic and/or abdominal organ transplantation (subjects must be less than 21 years of age at the time of enrollment). In light of progress in early transplant outcomes (e.g., graft and patient survival) and lack of progress in late outcomes; studies addressing late transplant outcomes in the pediatric allograft recipient are a priority of this FOA. The Clinical Trials in Organ Transplantation in Children (CTOT-C) program will support cooperative, multi-institutional research programs conducting multi-center clinical trials (Phase I, II, or III) and/or observational clinical studies with associated mechanistic studies, to promote understanding and reduce immune-mediated morbidity and mortality in vulnerable pediatric transplant recipients. In efforts to harness and exploit unique features of the immature and developing immune system in children these studies are designed to: (1) evaluate new therapies and approaches to overcome immunologic barriers to long-term graft and patient survival; (2) evaluate novel approaches to treat or prevent immune mediated complications in pediatric transplant patients; (3) investigate underlying mechanisms of action for pathological processes and therapeutic regimens under evaluation; (4) develop diagnostic and critical biomarkers that will facilitate routine surveillance, early diagnosis and ongoing monitoring of processes that contribute to post-transplant morbidity and mortality; (5) evaluate small bowel transplantation and the interplay of mucosal immunity and the alloimmune response; and (6) evaluate therapies promoting the development of allograft tolerance. 

NOTE: This FOA will NOT support: (1) studies of hematopoietic stem cell transplantation (HSCT) unless HSCT is a component of a study of organ transplantation; (2) studies of islet transplantation for treatment of type 1 diabetes; (3) studies involving animal models except where necessary as part of an assay linked to a clinical trial; and (4) studies involving xenotransplantation.

Background

Organ replacement is presently the optimal treatment for end-stage organ failure in the absence of suitable alternative therapy. In recent decades, organ transplantation in children was associated with improved early survival and quality of life, though these advances have sometimes lagged behind similar progress in adult populations. Early 1-year graft and patient survival is now approaching (or exceeding in some instances) 90 percent for most pediatric solid organ transplants.

Despite marked improvements in one-year survival and a reduced incidence of acute rejection, the average half-life of an allograft is only 10 - 12 years, varying from organ to organ.  Little progress has been made in reversing the inexorable long-term decline of graft function and reduced life expectancy of organ transplant recipients. This is largely due to morbidities associated with long-term pharmacologic immunosuppression, such as infection, hypertension, diabetes mellitus, renal damage, hyperlipidemia, cardiovascular disease and malignancy. Long-term effects of chronic steroid use and other immunosuppressive agents - stunting of growth, changes in body habitus, altered intellectual development, interruption of schooling, medical non-adherence, and psychosocial sequelae - are particularly deleterious in children. The adolescent age group still remains the most vulnerable to morbidity and mortality irrespective of the type of allograft.

There are over 120,000 individuals listed for organ transplantation in the United States. Approximately two percent are children under the age of 21 years. These children are exposed to the same pharmacologic and surgical interventions as their adult counterparts, but may have unique needs and characteristics including immunologic immaturity, naïveté to multiple infectious pathogens, differences in drug metabolism, and issues related to physical growth and psychological development. Furthermore, responses to antibody induction therapy in preparation for engraftment and subsequent immune reconstitution may differ from adults. Their relatively small number makes clinical investigation of pediatric transplant recipients quite challenging and also makes it unlikely that their specific needs will be addressed in the absence of continued focused initiatives.

In 1993, NIAID established the “Cooperative Clinical Trials in Pediatric Transplantation” (CCTPT) program, a consortium conducting clinical trials in pediatric kidney transplantation.  This endeavor focused on drug minimization in pediatric kidney recipients, pediatric pharmacokinetics, and studies of immune mechanisms. The CCTPT has succeeded in developing a reliable network of clinical centers for pediatric transplant research. CCTPT trials have demonstrated that research kidney biopsies can be performed safely in children and that calcineurin inhibitor-free regimens can provide effective protection from kidney rejection in children. In 2008 the CCTPT was renewed as the CTOT-C and expanded to include studies in all pediatric organ transplant recipients.

Ongoing clinical study protocols within the present CTOT-C consortium include studies of antibodies in heart transplant recipients, viral triggers of immunity in lung recipients, immunosuppression withdrawal to monotherapy in kidney recipients, immune development in kidney recipients and adherence in pediatric solid organ recipients. Information about the current CTOT-C investigative sites and studies can be found at http://www.ctotc.org.

The CTOT-C consortium will continue to work collaboratively with the Clinical Trials in Organ Transplantation (CTOT) consortium (www.CTOTstudies.org ) (http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-08-015.html), a similar clinical studies program in adult organ transplantation. The collaboration is expected to benefit both groups.  CTOT-C will provide the necessary pediatric expertise and advocacy for the CTOT; and, under certain conditions, may be able to leverage statistical power from concurrent studies in adults.  The CTOT-C and CTOT research laboratories perform a wide variety of tests in blood, urine and tissue samples from study subjects, including cellular assays, assays of antibodies and gene expression, genomic and proteomic studies, and histopathology.  The mechanistic committees of both consortia are presently standardizing the process and procedures for these assays.  All CTOT-C investigators collaborate with respect to clinical data collection and the timing of and methods used for mechanistic assays, thus creating an even more powerful and robust data resource for exploratory and confirmatory analyses.

Other collaborations, including the NIAID-funded Genomics in Transplantation Cooperative Research Program (RFA-AI-10-019) and the Immune Tolerance Network (ITN), are encouraged (http://www.immunetolerance.org).

Research Objectives and Scope

Responsive applications to this FOA must propose a milestone driven research program that includes multi-center clinical trials (Phase I, II or III) and/or observational clinical studies with associated mechanistic studies, to evaluate interventions reducing immune-mediated morbidity and mortality of solid organ transplantation in children and improving our understanding of the pathophysiology and mechanism of disease and dysfunction. All clinical trials and studies must include associated studies of immunologic mechanisms performed on samples from study subjects and, if appropriate, donors and human controls. Mechanistic studies should be designed to expand our understanding of the basic mechanisms of alloimmunity, innate immunity and autoimmunity in the transplant setting, and/or graft dysfunction. These mechanistic studies may include cellular assays (e.g., Elispot, flow cytometry), antibody assays (e.g., Luminex), gene expression studies, genomic and proteomic studies, or any other immunologic or molecular assays that will contribute to the scientific goals of the proposed studies. Projects will be milestone-based and funding of a project beyond the first year will be contingent upon satisfactory progress in meeting negotiated milestones. 

The application must include a concept proposal for one or more interventional and/or observational clinical studies with embedded mechanistic studies. Proposed studies may include a single type of organ transplant or may be designed to address a transplant-related immunologic problem that will be studied in a diverse group of pediatric allograft recipients. Increasing our understanding of late and long-term outcomes after pediatric solid organ transplantation is a priority of this FOA. The applicant must clearly state how anticipated study results will contribute to improvements in patient/graft survival. Clinical and mechanistic studies should have equal emphasis in the application and this will be taken into account in the evaluation of the application.

Applications must be comprised of an applicant team consisting of three or more participating institutions, or must provide evidence that the resources of fewer centers are sufficient to support the clinical and mechanistic studies described in the application. Member institutions may be clinical participants, in which case they must provide documentation of a United Network for Organ Sharing (UNOS) certified program in organ transplantation (see Part 2 section IV.2 PHS 398 Plan Component Letters of Support), or they may be mechanistic study participants, in which case they must have demonstrated expertise in the research techniques necessary for the proposed mechanistic studies and research agenda.   Applications must name a single Senior Investigator for each participating institution in the applicant’s group or team that will be responsible for on-site clinical and scientific implementation, direction and management of the clinical protocols, and the coordination of requirements for mechanistic studies of underlying mechanisms and immune/surrogate markers.

The applicant should discuss plans to ensure the maintenance of close cooperation and effective communication among members of the applicant’s group and provide evidence of the capability of the applicant organization and each institution in an applicant group to participate and interact effectively in cooperative, multi-center clinical trials.

Each clinical study proposed (See Section IV.6.2. Application and Submission Information-Other Submission Requirements) must include associated mechanism of disease and/or therapeutic action studies.   Examples of Phase I, II, and III clinical trials, observational studies and associated mechanistic studies include, but are not limited to:

This FOA will not support:

Applications proposing such studies will be considered non-responsive and will not be reviewed.

Data Coordination and Management and Clinical Trial Support

Data coordination and management, and clinical trial support will be carried out by a separately funded data coordinating center, the Statistical and Clinical Coordinating Center (SACCC) (http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-09-015.html). The SACCC provides this function and service for both adult and pediatric consortia (see http://www.CTOTC.org and/or http://www.CTOTstudies.org). Each participating institution will be responsible for providing primary study data to the SACCC. Timeliness and accuracy of submitted data will be monitored by the SACCC and evaluated by the Steering Committee.  Quality control and data analysis will follow procedures and standards determined by the CTOT-C Steering Committee (see below) and the SACCC.  The quality and integrity of CTOT-C studies requires all analyses are performed on data from the central database, and these analyses are performed or have oversight by the SACCC. The SACCC will provide technical assistance and data management services to CTOT-C 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. The SACCC will provide expert assistance in the design, implementation, and analysis of clinical trials. The SACCC will develop the statistical analysis plan for each approved study protocol that will be reviewed and approved by the CTOT-C Steering Committee. The SACCC will provide assistance to CTOT-C in preparing abstracts, presentations and manuscripts. The SACCC will also provide clinical site monitoring, regulatory support, and drug and specimen tracking and distribution. The SACCC will prepare periodic reports (e.g., safety, efficacy and performance) for the NIAID-Transplantation Data and Safety Monitoring Board (DSMB) and NIAID Program staff as required.  The SACCC will also assist NIAID in fostering collaborations among the consortia. More information about responsibilities can be found at http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-09--015.html

SACCC responsibilities are further described under Section VI 2.A.3. Cooperative Agreement Terms and Conditions of Award – “Collaborative Responsibilities.”

Steering Committee

A Steering Committee will serve as the governing board for the CTOT-C consortium; its actions and decisions will be determined by majority vote. The Steering Committee will develop policies and procedures governing the activities of the consortium. The Steering committee responsibilities include identifying scientific opportunities, emerging needs, and impediments, and establishing and overseeing group collaborations. The Steering Committee will evaluate the progress and direction of individual awards and make recommendations for the continuation, replacement, redirection, or discontinuation of studies on an ongoing basis and in consultation with NIAID. All major scientific and budgetary decisions will be made by the majority of the voting members of the Steering Committee. Other voting members will include the NIH Project Scientist and one representative from the SACCC supporting the CTOT-C consortium. Steering Committee responsibilities are further described under Section VI 2.A.3. Cooperative Agreement Terms and Conditions of Award – “Collaborative Responsibilities.” 

Mechanistic Studies Subcommittee

The Steering Committee must appoint a Mechanistic Studies Subcommittee to review proposed mechanistic studies and make recommendations to the Steering Committee. Each PD/PI shall select one representative from his/her team to serve as a voting member of the Mechanistic Studies Subcommittee; additional non-voting members may be nominated and approved by the Steering Committee. The NIH Project Scientist will serve as a voting member.  This committee works closely with a similar group from CTOT to standardize and harmonize timing of sample procurement, process and assays. Mechanistic Studies Subcommittee responsibilities are further described under Section VI.2.A.3. Cooperative Agreement Terms and Conditions of Award – “Collaborative Responsibilities.”

Milestones

Explicit, detailed, and quantitative yearly milestones must be included in each U01 application for assessing progress and success. These annual milestones will be used by NIAID program staff in evaluating progress and recommending continued funding. Completion of research reports and preparation of peer-reviewed manuscripts are required milestones when individual study end points are met.

Based on an Awardee’s own evaluations and assessment by the NIAID Project Scientist and/or CTOT-C Steering Committee, replacement or redirected projects may be proposed at any time by the PD/PI for review by the CTOT-C Steering Committee and other experts, as required.  The CTOT-C Steering Committee will provide recommendations regarding approval or disapproval of proposals for replacement or redirection to the NIAID Program Scientist. In order to maximize utilization of CTOT-C program resources, the NIAID may re-budget individual U01 funds based on recommendations of the Steering Committee and/or based on NIAID assessment of availability of funds or progress towards yearly milestones

Publications Subcommittee

The Steering Committee will establish a Publications Subcommittee to develop publication policies and procedures for the CTOT-C consortium. The NIAID Project Scientist and a representative from the SACCC will serve on this committee. The Publications Subcommittee, along with NIAID and the SACCC, will oversee the completion of research reports and peer-reviewed publications. Publications Subcommittee responsibilities are further described under Section VI.2.A.3. Cooperative Agreement Terms and Conditions of Award – “Collaborative Responsibilities."

Section II. Award Information
Funding Instrument

Cooperative Agreement

Application Types Allowed

New
Renewal
The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NIAID intends to commit $4.3 million in total costs to fund 3 to 4 awards in FY2013.

Award Budget

Application budgets are not limited, but need to reflect actual needs of the proposed project.

Award Project Period

The total project period for an application submitted in response to this funding opportunity may not exceed five years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

Higher Education Institutions

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

Nonprofits Other Than Institutions of Higher Education

For-Profit Organizations

Governments

Other

Although applicant organizations may submit only one application, they may participate on one or more applicant team.

Foreign Institutions

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

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

Required Registrations

Applicant organizations must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

Eligible Individuals (Program Director(s)/Principal Investigator(s))

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

Multi-PD(s)/PI(s) are not allowed.

This FOA will NOT support multiple PD(s)/PI(s). A single PD/PI should be named for the overall application.

A PD/PI may serve as PD/PI on only one application. A PD/PI may serve as a collaborator on another application(s) provided there is no scientific overlap. 

The PD(s)/PI(s) must be a physician with substantial experience in pediatric organ transplantation and in the design, implementation, and evaluation of clinical trials.

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

 Only one application per institution (normally defined by having a unique DUNS number or NIH IPF number) is allowed. 

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Section IV. Application and Submission Information

1. Requesting an Application Package

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

2. Content and Form of Application Submission

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

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

Letter of Intent

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

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

The letter of intent should be sent to:

Priti Mehrotra, M. Sc., Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases (NIAID)
Room 3138, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7616
For Express Couriers: 20817-1824
Phone: 301-435-9369, 301-496-2550
FAX: 301-480-2408
Email: pm158b@NIH.GOV

Required and Optional Components

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate “optional” components.

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions:

R&R Budget Component

Additional submission requirements for the preparation of the Detailed Budget:

Study Costs

All costs required for the concept proposals and mechanistic studies must be included in the application and must be fully justified. These include the costs of the proposed clinical research, costs for patient recruitment and follow-up, mechanistic studies, data collection, and participation in on-site quality assurance audits.

The budget must include support for a clinical study coordinator at each clinical site, with effort proportional to the anticipated volume of patient enrollment at that site, but in no case less than 2.4 person months per site.

Mandatory Meetings

Requested budgets should also include funds for: (1) travel to the Bethesda, MD area for two Steering Committee meetings during the first 12 months, and annually thereafter, for the PD(s)/PI(s) and one Senior Investigator from each participating institution, and (2) travel to the Bethesda, MD area for two Mechanistic Studies Subcommittee meetings per year for the PD(s)/PI(s) and one representative from the applicant’s group.

Foreign Institutions

Applications from groups that include foreign institution components or collaborations must provide the following information as part of the study budget:

PHS 398 Research Plan Component

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

Research Strategy

Include the following information (a-e) as part of the Research Strategy (must be contained within the 30 page limit):

a. Overview

The applicant should include a clear and concise description, in narrative and diagrammatic form that depicts the interrelationships among the members of the team or group, their relevant experience/expertise, and the contribution of each to fulfillment of the Specific Aims of this FOA.  This should include a brief presentation of the applicant’s views of the important questions facing the field of pediatric transplantation and explain how their proposed research addresses these questions.  These responses will assist the Steering Committee in creating a scientific agenda for the overall CTOT-C consortium post award.  The applicant should also discuss the selection of the participating applicant team (three or more participating institutions), or provide evidence that the resources of fewer centers are sufficient to support the clinical and mechanistic studies described in the application. Applications must name a single Senior Investigator for each participating institution in the applicant’s team that will be responsible for on-site clinical and scientific implementation, direction and management of clinical protocols, and the coordination of requirements for studies and assays of underlying mechanisms and immune/surrogate markers and document the qualifying characteristics of his/her institution

b. Concept proposals for clinical studies

Research plans for multi-center clinical trials (Phase I, II or III) or observational clinical trials/studies with associated mechanistic studies must be in the form of a detailed concept proposal, organized as specific aims, background and significance, preliminary studies, and research design and methods.

1. Concept proposals must be presented in sufficient detail.  To allow reviewers to judge significance, approach, innovation, and environment, methods of data analysis and sample size justification for the proposed clinical study must be included. Submission of a detailed, final clinical protocol is neither required nor encouraged, as the choice of studies to be performed and final protocol development will be accomplished subsequent to award, under the guidance of the Steering Committee.

2. The concept proposal must include the following information about the clinical trial/study:

The applicant institution and each institution participating in the applicant’s team must document clinical experience, capacity to recruit and retain pediatric study participants, and provide a description of the population currently available for each proposed study. This information should include annual numbers of all pediatric organ transplants performed (by organ) at each clinical site for the last five years.

c. Associated mechanistic studies

Descriptions of proposed mechanistic studies must include: identification of and rationale for the immune, genetic, and/or surrogate markers selected, including data from animal and/or human studies; the source, quantity, and number of patient samples required; methodologies proposed to collect and analyze samples; and how the results of the proposed mechanistic studies will improve the capacity to utilize immune, genetic and/or surrogate markers to predict patient outcome, or will otherwise enhance our understanding of mechanisms of disease, or of therapeutic interventions in the transplant setting.

Each proposed mechanistic study must include:

d. Yearly Milestones

Provide detailed, explicit, and quantitative milestones that should be achieved each year of the Project. While the peer review panel will evaluate and provide comments on these yearly milestones they will not be scored and are subject to negotiation with the NIAID Project Officer prior to and/or after award.  For additional information see Part 2.  Section 1. “Funding Opportunity Description, Milestones” above and Part2. Section IV.2. “Cooperative Agreement Terms of Award, PD(s)/PI(s) Responsibilities and Areas of joint Responsibilities”, below.

e. Collaboration with the CTOT

The applicant must describe how the CTOT-C consortium will establish a productive collaboration with the CTOT. Information about the CTOT is available at http://www.ctotstudies.org, and at (http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-08-015.html).

f. Organization

The applicant must include organizational chart of the team or group showing the name, organization, and scientific discipline of the Principal Investigator and all key scientific, technical and administrative personnel. In addition, the applicant must document availability of personnel capable of performing and supporting administrative functions for the overall management of the applicant group.

Letters of Support

Include the following information as part of the Letters of Support section: 

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

Appendix

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

3. Submission Dates and Times

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via Grants.gov, the online portal to find and apply for grants across all Federal agencies. Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration.

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

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

4. Intergovernmental Review (E.O. 12372)

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.

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

6. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF 424 (R&R) Application Guide.  Paper applications will not be accepted.

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

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

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(R&R) Application Package. Failure to register in the Commons and to include a valid PD(s)/PI(s) Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

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

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness by the Center for Scientific Review and responsiveness by the National Institute of Allergy and Infectious Diseases, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.  

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Section V. Application Review Information

1. Criteria

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

Overall Impact

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

Scored Review Criteria

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

Significance

Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Is the project as a whole significant and sufficiently focused on the goals of the FOA? What is the likelihood the results of the proposed studies will translate or contribute to new strategies relevant to future studies in pediatric solid organ transplantation? Will the results of the proposed studies positively affect long-term graft and patient survival? Are the proposed studies timely?

Investigator(s)    

Are the PD/PI, collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Is the level of effort of the PD/PI and senior investigator (s) sufficient to ensure success of the program? Is the pediatric and transplantation expertise of the key personnel sufficient to ensure success of the program? Is the plan for communication between members of the team appropriate?

Innovation

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

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? 

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Are the drugs, biologics, cells, reagents or therapeutics needed for the conduct of the study available or is it reasonable to assume they will be developed or become available in the proposed timeframe?  Are the approaches timely and justified for solid organ transplantation research in children? Are the clinical trial/study and associated mechanistic studies appropriately emphasized in the grant application?  

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? Does each participating institution have appropriate facilities and expert staff in pediatric solid organ transplantation and/or associated mechanistic studies to carry out the proposed work? Are appropriate letters of support and certifications (if applicable) included?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items.

Protections for Human Subjects

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

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

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. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

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

Biohazards

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

Resubmissions

Not Applicable.

Renewals

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

Revisions

Not Applicable.

Additional Review Considerations

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

Yearly Milestones

Reviewers will assess the adequacy and appropriateness of the yearly milestones for each of the Research projects, including the adequacy of the level of details provided and likelihood of attaining the milestones.  The evaluation of the milestones will not affect the overall impact scores.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Institutes of Allergy and Infectious Disease, in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Allergy and Infectious Disease Council l. The following will be considered in making funding decisions:

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons

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

Section VI. Award Administration Information

1. Award Notices

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

2. Administrative and National Policy Requirements

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

The PD(s)/PI(s) will have primary responsibility for: (1) determining and coordinating the project activities scientifically and administratively; (2) setting project goals and timelines to achieve the proposed goals, (3) attending Steering Committee meetings, serving as a voting member of the Steering Committee, and accepting and implementing policies and procedures developed by the Steering Committee; (4) providing primary study data to the SACCC for management, quality control, and analysis; (5) submitting data to NIH-supported and/or public databases in accordance with policies agreed upon and established by the Steering Committee and the NIH data sharing policy available at: http://grants.nih.gov/grants/policy/data_sharing/; and (6) participating in the cooperative nature of the group.  It is recognized that goals may require revision and re-negotiation during the course of the project period. Release of each funding increment by NIAID will be based on a review of progress towards achieving the previously agreed upon research goals.

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, and terms and condition of award, are available at: http://www.niaid.nih.gov/ncn/pdf/clinterm.pdf. Local institutional review boards and the NIAID Data and Safety Monitoring Board (DSMB) must approve clinical protocols before initiation.

Data

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.  However, awardees must be committed to making the biological samples, diagnostic products, and other research tools, methods, data, and materials that are developed under CTOT-C awards available to the CTOT-C and the research community.

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

During performance of the award, the NIH Project Scientist, with assistance from other scientific/medical/regulatory 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; coordinating or participating in the collection and/or analysis of data; advising in management and technical performance; or participating in the preparation of publications. 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 and the Steering Committee.

The NIH Project Scientist will serve as voting members of the Steering Committee and the Mechanistic Studies Subcommittee, schedule the first meeting of the Steering Committee, and ensure coordination of Steering Committee activities and implementation of its recommendations, decisions, and policies.

Collaborations with industry will usually require the assistance of the NIAID Division of Allergy, Immunology and Transplantation (DAIT) Clinical Research Program, and be conducted under an NIAID Clinical Trials Agreement.

The NIAID reserves the right to terminate or curtail a 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  or safety issues that may dictate a premature termination.

The NIAID DAIT Chief of Regulatory Affairs or designee 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. The assigned program director may also serve as an NIH Project Scientist. The program official will monitor program progress, approve changes, and have access to data generated under these awards. NIAID staff may use information obtained from the data for the preparation of internal reports on the activities of the group.

Data and Safety Monitoring Board (DSMB)

An independent DSMB, appointed by NIAID, will review progress at least annually and report its findings to the NIH Project Scientist. 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 safety, ethics, scientific and statistical integrity of the studies.

Cooperation with Other NIH-Sponsored Programs

In order to most efficiently utilize research resources and rapidly exchange scientific information to promote organ transplantation objectives, it is anticipated that awardees will collaborate with other NIAID funded programs, such as the CTOT.  The NIH Project Scientist will facilitate liaison activity for collaborations, and provide assistance with access to NIAID-supported resources and services.

Areas of Joint Responsibility include:

Steering Committee

The Steering Committee will meet at least twice in the first year and annually thereafter in Bethesda, MD.

Mechanistic Studies Subcommittee

The Steering Committee shall appoint a Mechanistic Studies Subcommittee to review proposed mechanistic studies and make recommendations to the Steering Committee. Each Principal Investigator shall select one representative from his/her consortium as a voting member of the Mechanistic Studies Subcommittee; additional non-voting members may be nominated and approved by the Steering Committee. The NIH Project Scientist will serve as voting members.  The Mechanistic Studies Subcommittee may ask the Steering Committee to appoint ad hoc subcommittee members if additional expertise in specific areas is needed. The Mechanistic Studies Subcommittee shall elect a Chair from among non-Federal members. The Mechanistic Studies Subcommittee will meet at least twice yearly and its members will be expected to participate in all meetings, conference calls and other subcommittee activities.

Publications Subcommittee

The Steering Committee will establish a Publications Subcommittee to develop publication policies and procedures for the CTOT-C consortium.

Data Coordination and Management

Data coordination and management will be carried out by a separately funded data coordinating center, the Statistical and Clinical Coordinating Center (SACCC). Each participating institution will be responsible for providing primary study data to the SACCC for management, quality control and analysis using procedures and standards determined by the Steering Committee and the SACCC. The SACCC will provide technical assistance and data management services to 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. The SACCC will develop a statistical analysis plan for each approved study protocol that will be reviewed and approved by the Steering Committee. 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 their data developed under these awards subject to government rights of access consistent with HHS, PHS and NIH policies. The participating institutions will be closely involved with these centralized data collection and management services, and are responsible for on-site data collection and transmittal. The performance of participating institutions with respect to data submission, data quality, and protocol compliance will be monitored by the SACCC using criteria developed by the Steering Committee; these data will be provided to the PD(s)/PI(s) and evaluated by the Steering Committee at regular intervals.

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required to submit the 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 the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

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

Section VII. Agency Contacts

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

Application Submission Contacts

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading or navigating forms)
Contact Center Phone: 800-518-4726
Email: support@grants.gov

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-435-0714
TTY 301-451-5936
Email: GrantsInfo@nih.gov

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: commons@od.nih.gov

Scientific/Research Contact(s)

Jonah Odim, M.D., Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases (NIAID)
Room 6227, MSC-6601
6610 Rockledge Drive
Bethesda, MD 20892-6601
Telephone:  301-496-5598
Email:  odimj@niaid.nih.gov

Peer Review Contact(s)

Priti Mehrotra, M. Sc., 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
For Express Couriers: 20817-1824
Phone: 301-435-9369, 301-496-2550
FAX: 301-480-2408
Email:  pm158b@NIH.GOV

Financial/Grants Management Contact(s)

Mildred Qualls
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Room 2125, MSC-7614
6700B Rockledge Drive
Bethesda, MD 20892-7614
Telephone: (301) 402-6611
FAX: (301) 493-0597
Email:  boggsl@mail.nih.gov

Section VIII. Other Information

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

Authority and Regulations

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


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