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 (CTOT) (U01)

Activity Code

U01 Research Project – Cooperative Agreements

Announcement Type

Reissue of  RFA-AI-08-015

Related Notices

  • August 21, 2013: Removed reference to ASSIST in section IV.3, since ASSIST is currently only available for multi-project applications.

Funding Opportunity Announcement (FOA) Number

RFA-AI-13-006

Companion Funding Opportunity

None

Number of Applications

Only one application per institution is allowed.. See Section III. 3. Additional Information on Eligibility.

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

93.855, 93.856 

Funding Opportunity Purpose

This FOA invites applications from groups of two (2) or more institutions to participate in a clinical studies program to improve the long-term outcome of transplant recipients (thoracic organ, abdominal organ and vascular composite tissue). The Clinical Trials in Organ Transplantation (CTOT) program will support a cooperative, multi-institutional consortium for the conduct of interventional trials (Phase 1, 2, or 3) or observational clinical studies in organ or vascularized composite allotransplantation (VCA). Each clinical study must include associated mechanistic studies that focus on immune-mediated pathologic processes in allotransplantation or on mechanisms of immune activation and quiescence. The goals of this research will be to target immune-mediated causes of morbidity and mortality in transplant recipients and evaluate interventions to address them.

Key Dates
Posted Date

July 19, 2013

Open Date (Earliest Submission Date)

October 19, 2013

Letter of Intent Due Date(s)

October 19, 2013

Application Due Date(s)

November 19, 2013, by 5:00 PM local time of applicant organization.

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not Applicable

Scientific Merit Review

March, 2014

Advisory Council Review

May, 2014

Earliest Start Date

July, 2014

Expiration Date

November 20, 2013

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

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

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 or renewal applications from groups of two (2) or more institutions to participate in a clinical studies program to improve the long-term outcome of recipients of thoracic or abdominal organ transplants or vascularized composite allografts (VCA). The Clinical Trials in Organ Transplantation (CTOT) program will support a cooperative, multi-institutional consortium for the conduct of interventional trials (Phase 1, 2, or 3) or observational clinical studies in transplantation. Each clinical study must include associated mechanistic studies that focus on immune-mediated pathologic processes in allotransplantation or on mechanisms of immune activation and quiescence. The goals of this research will be to further our understanding of and ultimately reduce immune-mediated morbidity and mortality in thoracic and abdominal organ and VCA transplant recipients.

Background

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, 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. In addition, it is clear that there are substantial health disparities in transplant outcomes. The barriers to short- and long-term success of organ transplantation are predominantly due to immunologic incompatibility between donor and recipient that leads to acute and chronic rejection, and complications of long-term pharmacologic immune suppression.

More recently, vascularized composite allotransplantation (VCA) has emerged as an increasingly accepted therapy for individuals with limb loss or severe facial injuries not correctable using autologous tissue. The immunologic properties of grafts containing skin, muscle, bone and nerve are as yet poorly understood, and the optimal immunosuppressive regimen for VCA recipients is not known. Standard criteria for the diagnosis of rejection and identification of the best endpoints for clinical trials are yet to be developed. Inclusion of VCA in the CTOT program will make the resources and experience of the greater transplant research community accessible to those studying VCA, and in turn promote interest in VCA among transplant scientists who have not worked in this area.

The CTOT was established in 2003 to conduct clinical research into the immune-mediated morbidity associated with organ transplantation.  Information about the current CTOT investigative sites and studies can be found at http://www.CTOTstudies.org. Currently, 50 clinical sites and 22 immunologic laboratories are supported by and participating in the CTOT program; over 2500 subjects have been enrolled in CTOT trials. Current observational studies focus on enhancing understanding the mechanisms of and identifying candidate biomarkers for immunologic quiescence or activation in recipients of heart, liver, lung, and kidney transplant recipients. Interventional studies are evaluating the safety and efficacy of drugs not labeled for use in transplantation, new drug regimens, and drug minimization protocols. Other studies are directed at evaluating the reliability of candidate genomic and proteomic biomarkers.  The CTOT research laboratories perform a wide variety of tests on blood, urine and tissue samples from study subjects, including cellular assays, assays of antibodies and gene expression, genomic and proteomic studies, and histopathology. CTOT investigators have implemented an intensive effort to standardize procedures at all CTOT laboratories, and to understand the properties of specific laboratory approaches. All CTOT investigators collaborate with respect to clinical data collection and the timing of and methods used for mechanistic assays, thus creating a powerful data resource for exploratory and confirmatory analyses.

Research Objectives and Scope

The objective of this FOA is to support multi-center interventional clinical trials and/or observational studies in adult candidates for and recipients of organ or vascularized composite allotransplantation. All clinical trials and studies must include associated studies of immunologic mechanisms performed on samples from study subjects and, if appropriate, human controls. These mechanistic studies may include cellular assays (ELISPOT, flow cytometry, etc.), antibody assays, gene expression studies, genomic studies, studies of the microbiome, or any other assays that will contribute to the scientific goals of the proposed studies.

Examples of clinical trials, observational studies and associated mechanistic studies include, but are not limited to, the following:

(1) enable accurate non- or minimally-invasive monitoring of the recipient’s immunoreactive state, so that therapy can be individualized and proactive, or

(2) act as reliable surrogates for important clinical transplant outcomes;

This FOA will NOT support research involving:

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

The CTOT consortium will work collaboratively with the Clinical Trials in Organ Transplantation in Children (CTOT-C) consortium (http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-12-005.html), a similar clinical studies program in pediatric organ transplantation. Applicants may include children under the age of 18 in their study if: (1) there is strong scientific justification for doing so, (2) the majority of the subjects in the proposed study will be adults, and (3) they have personnel with the appropriate pediatric expertise. If such a study is funded, the investigators will be required to establish a collaboration with investigators in the CTOT-C consortium (www.ctotc.org).

Milestones

General milestones addressing completion of subcontracts to clinical and laboratory sites, accrual of subjects, and time to last patient/last visit must be provided in the application as part of the research strategy.

Explicit, detailed, and quantitative yearly milestones will be used for assessing progress and success by NIAID program staff when recommending continued funding on an annual basis. Some of these milestones will be developed post award, when the final research protocols have been developed, and some will require steering committee input. In order to maximize utilization of CTOT 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 toward yearly Milestones.

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 and clinical coordinating center, the Statistical and Clinical Coordinating Center (SACCC) (see http://www.CTOTstudies.org).  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 CTOT Steering Committee (see below) and the SACCC. The quality and integrity of CTOT studies require that all analyses are performed on data from the central database, and that these analyses are performed or have oversight by the SACCC. The SACCC will provide technical assistance and data management services to CTOT 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. 

Each applicant team shall include one or more individuals qualified to provide biostatistical support for the proposed project.  SACCC statisticians will work collaboratively with study team statisticians to develop statistical analysis plans for protocols. The SACCC will also provide clinical site monitoring, regulatory support, and drug and specimen distribution. More information about SACCC responsibilities can be found at http://grants.nih.gov/grants/guide/rfa-files/RFA-AI-09-015.html.

CTOT Steering Committee

A Steering Committee will serve as the governing board to direct the collaborative work of the CTOT consortium.  All major scientific decisions will be made by the majority of the voting members of the Steering Committee. Voting members of the Steering Committee will include one CTOT Program Directors/Principal Investigators (PD(s)/PI(s)) from each awarded CTOT grant, one additional investigator from each awarded CTOT grant, a senior statistician from  the SACCC, and the Chair of the Mechanistic Studies Sub-Committee (see below). The NIH Project Scientist will be a non-voting member of the Steering Committee. CTOT Steering Committee responsibilities are described further under Section VI, below.

The CTOT Steering Committee will also recommend procedures to solicit applications for CTOT Ancillary Studies Fund support (described below), make recommendations to support specific applications through the Ancillary Studies Fund, recommend budget allocations for each project to be supported through the Fund, and monitor the progress of funded projects.

Mechanistic Studies Subcommittee

The CTOT Steering Committee shall appoint a Mechanistic Studies Subcommittee to review proposed mechanistic studies and make recommendations to the Steering Committee.  One representative from each awarded grant will 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 non-voting member. Responsibilities of the Mechanistic Studies Subcommittee are described further under Section VI, below.

Publications Subcommittee

The Steering Committee will establish a Publications Subcommittee to develop publication policies and procedures for the CTOT consortium.  See Section VI, below.

Ancillary Studies Fund

An Ancillary Studies Fund of up to $600,000 total costs per year for the entire program may be available, depending on the availability of funds. This amount includes the cost for the management of the Ancillary Studies Fund. These funds are to be used to support additional mechanistic studies (i.e., studies which are in addition to those proposed as an integral part of a clinical trial) performed on existing, archived biological specimens from CTOT studies or on prospectively collected specimens from a CTOT study. All projects supported by the Ancillary Studies Fund must be within the scientific scope of the parent grant. The CTOT Steering Committee will make recommendations to the awardee of the Ancillary Studies Fund as to the goals, priorities, and evaluation criteria for the use of the Fund. Any use of Ancillary Studies funds must comply with all applicable HHS/NIH policies. Use of these funds is limited to CTOT investigators or non-CTOT investigators who establish a collaboration with a CTOT investigator. After award, one awardee institution will be selected by the NIAID to manage the Ancillary Studies Fund for the entire CTOT program.

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.

Application Types Allowed

New
Renewal

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.

Funds Available and Anticipated Number of Awards

NIAID intends to commit $9.5 million yearly, to make 3 to 4 awards.

Award Budget

Application budgets are limited to $1.75M in direct costs per year. Budgets need to reflect the actual needs of the proposed project.

Award Project Period

The maximum project period is 7 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

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 not eligible to apply.

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

Required Registrations

Applicant Organizations

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

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

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

Eligible Individuals (Program Director/Principal Investigator)

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

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

The PD/PI must be a physician with substantial experience in the field of organ transplantation and in the design, implementation, and evaluation of clinical trials as evidenced by clinical experience and publication in peer-reviewed journals.

An individual may only be named as PD/PI on one application. An investigator identified as the PD/PI or as a collaborator on one application may appear as a collaborator on other application(s) provided there is no scientific overlap. 

The applicant team must contain two or more participating institutions working together with a designated PD/PI.

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 identified by having a unique DUNS number or NIH IPF number) is allowed.

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

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:

James T. Snyder, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
6700B Rockledge Drive, Room 3147, MSC 7616
Bethesda, MD   20892-7616
Zip Code for express couriers: 20817-1821
Telephone: 301- 435-1614
Fax: 301- 480-2408
Email: snyderji@mail.nih.gov

Page Limitations

All page limitations described in the SF424 Application Guide and must be followed, with the following exceptions or additional requirements:

Required and Optional Components

The forms package associated with this FOA includes all applicable components, required 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.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instruction:  The applicant team must contain two or more participating institutions working together with a designated PD(s)/PI(s).  

SF424(R&R) Other Project Information

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

Facilities and Other Resources: The applicant must document availability of facilities for performing and supporting administrative functions for the overall management of the applicant group.  

SF424(R&R) Senior/Key Person Profile

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

The PD(s)/PI(s) must be a physician with substantial experience in the field of organ transplantation and in the design, implementation, and evaluation of clinical trials as evidenced by clinical experience and publication in peer-reviewed journals. This information should be reflected in the accompanying Biographical Sketch for the PD(s)/PI(s).

The applicant team must contain two or more participating institutions working together with a designated PD(s)/PI(s). 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 (provided as a Letter of Support and note foreign clinical sites must provide equivalent documentation) 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, which should be reflected in the accompanying Biographical Sketch for the appropriate Senior/Key Personnel. 

The applicant institution and each clinical site participating on the applicant’s team must document clinical experience which should be reflected in the accompanying Biographical Sketch for the appropriate Senior/Key Personnel.

Applications must name one or more individuals qualified to provide biostatistical support for the proposed project. These individuals will work collaboratively with the SACCC on study design, analysis plans, and the final study analysis. This information should be reflected in the accompanying Biographical Sketch for the appropriate Senior/Key Personnel,

The applicant must document availability of personnel capable of performing and supporting administrative functions for the overall management of the applicant group. This information should be reflected in the accompanying Biographical Sketch for the appropriate Senior/Key Personnel.

Applications including studies on subjects under the age of 18 should document appropriate pediatric expertise in the accompanying Biographical Sketch for the appropriate Senior/Key Personnel.

R&R Budget

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

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:

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

If a study requiring an Investigational New Drug (IND) application is proposed, the application should provide information regarding the costs associated with maintaining a legal entity in the foreign country, submission to the foreign health authority, and required insurance coverage for clinical trials and any other costs uniquely generated by non-U.S. clinical sites. All foreign sites must provide information about the availability and cost of clinical site monitoring in the foreign country.

A budget for the Ancillary Studies Fund should not be prepared and should not be included in the application.

PHS 398 Cover Letter

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Research Strategy:

Concept proposals for clinical studies

The application must include a detailed concept proposal for one or more interventional or observational clinical studies, each of which will have associated mechanistic studies that meet the objectives and scope of this FOA. Proposed studies must address questions with broad relevance in the field of transplantation. In addition applicants should discuss specifically how the associated mechanistic studies focus on immune-mediated pathologic processes in allotransplantation or on mechanisms of immune activation and quiescence. The applicant must explain how the results will have an impact on the field of transplantation, and must address any relevant health disparity issues. The proposed study or studies must not exceed the clinical and scientific resources of the applicant’s team of institutions (e.g., the applicant group must be able to recruit the required number of study subjects from within their own institutions) and must not exceed 5 years in duration (first subject enrolled to last subject last visit).  The concept proposal must be organized as specific aims, background and significance, preliminary studies, and research design and methods. The concept proposal must include the following information about the clinical study or studies:

The concept proposal should be presented in sufficient detail to allow reviewers to judge significance, approach, innovation and environment. Submission of a detailed, final clinical protocol is neither required nor encouraged.  A more detailed and complete SAP will be developed when studies are finalized post-award, with the assistance of the SACCC.

Post award, the CTOT Steering Committee (see Section VI Cooperative Agreement Terms and Conditions of Award: “Collaborative Responsibilities”) will review concept proposals from successful applicants and make recommendations for development of the full study protocol. The Steering committee review may result in recommendations for modification of the submitted proposals in order to avoid duplication of effort, adapt to scientific progress that may have occurred in the period between application submission and award, ensure alignment with the CTOT Scientific Agenda, or any other scientific or pragmatic considerations. Final protocols must be approved by majority vote of the Steering Committee prior to implementation.

Associated mechanistic studies

Each concept proposal must include investigations performed on biological samples from the study participants that address, at the tissue, cellular, or molecular level, the immunologic mechanisms underlying the observed clinical events and if appropriate human controls. Descriptions of proposed mechanistic studies must include:

Mechanistic studies will be weighed equally with the interventional or observational clinical studies in the review of the application, using the review criteria defined in Section V. 

Scientific Agenda

Applicants must briefly present their views of the important questions facing the field of transplantation and explain how their proposed research addresses these questions. These responses will assist the Steering Committee in creating a scientific agenda for the CTOT consortium.

Applicants should 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 Part 2. Section IV. “Cooperative Agreement Terms of Award, PD(s)/PI(s) Responsibilities and Areas of joint Responsibilities”, below.

Ancillary Studies

Ancillary Studies funds, if available, must be used to support additional mechanistic studies (i.e., studies which are in addition to those proposed as an integral part of a clinical trial) performed on existing, archived biological specimens from CTOT studies or on prospectively collected specimens from a CTOT study.

Applications should include a brief plan (up to 2 pages) that describes the management of  the Ancillary Studies funds, including procedures for fund disbursement, and reporting and monitoring of the fund expenditures. The use of these funds is limited to CTOT investigators or non-CTOT investigators who establish a collaboration with a CTOT investigator. Junior investigators are especially encouraged to apply for Ancillary Studies Funds.

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

Ancillary Studies Fund Management- All applicants must include a letter from the PDs/PIs and the Institution’s Signing Official agreeing to take fiscal responsibility for the management of the Ancillary Studies funds, if chosen by NIAID to do so.

Participation in United Network for Organ Sharing (UNOS) - Where applicable the applicant must provide documentation of a UNOS certified program in organ transplantation (foreign clinical sites must provide equivalent documentation as appropriate).

Letter(s) of commitment from suppliers of investigational drugs and/or devices, A letter from each Senior Investigator, indicating a commitment to participate in the CTOT consortium, including adhering to Steering Committee policies and decisions, and accepting the participation and assistance of NIAID staff in accordance with the guidelines described in Section VI. Cooperative Agreement Terms and Conditions of Award:  “Collaborative Responsibilities” must be included with the application.

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.

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 applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission.

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

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

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

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 SF424 (R&R) Application Guide.  Paper applications will not be accepted.

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

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

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

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

See more tips for avoiding common errors.

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

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 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 likely to result in new knowledge that will contribute to a decrease in late morbidity and/or mortality after solid organ transplantation or vascularized composite allotransplantation?  Is the project likely to contribute important information even if the primary clinical endpoint is not evaluable due to inability to accrue subjects, low event rates, or unforeseen problems? 

Investigator(s)    

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Does the PD(s)/PI(s) have experience in clinical transplantation and clinical trial design and management, documented in peer-reviewed publications? Do the site PD(s)/PI(s) have appropriate experience and expertise?  Is the level of effort of the PD(s)/PI(s) and senior investigator(s) sufficient to ensure success of the program? 

Innovation

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

Approach

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

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Does the application adequately address the plan for acquisition and handling of study agent(s); statistical analysis plan; endpoint(s) and data to be collected; sample size, and power calculation? Are the clinical trial/study and associated mechanistic studies appropriately emphasized for solid organ transplantation and vascularized composite allotransplantation in the grant application? Does the application adequately address potential safety/ethical issues related to research procedures in transplant patients? 

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? Is the subject population available in adequate numbers at the proposed clinical sites to enroll the project to target? Does each participating institution have appropriate facilities for solid organ transplantation/VCA and/or associated mechanistic studies to carry out the proposed work? Are appropriate letters of support and certifications (if applicable) included? Does the applicant describe measures and procedures for fund disbursement, and reporting and monitoring of the Ancillary Studies fund? 

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 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 score.

Milestones

Are the proposed milestones detailed, explicit, and quantitative , detailing an approach which is achievable each year of the Project?

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the NIAID, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

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. 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/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons

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

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, SAM 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:

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. The PD(s)/PI(s) must commit a minimum of 2.4 person months to this consortium.  In the case of multiple PDs/PIs, the contact PI must commit a minimum of 1.5 person months, and all other PDs/PIs on the grant must commit a minimum

of  one person month.

Monitoring Clinical Studies

NIAID policy requires that clinical 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. 

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 DHHS, PHS, and NIH policies.

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

An NIH Project Scientist will have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The NIH Project Scientist, with assistance from other NIH 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 research 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 that the NIAID staff participate in this process. The manner of reaching this consensus and the final decision-making authority will rest with the Principal Investigator and the CTOT Steering Committee.

The NIH Project Scientist will serve as a non-voting member 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 require the assistance of the NIAID Division of Allergy, Immunology and Transplantation (DAIT) Clinical Research Program, and be conducted under a NIAID Clinical Trials Agreement.

The Chief of the DAIT Office 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, devices or products, to the Food and Drug Administration or other Health Authorities. NIAID will act as the IND sponsor for multi-center studies carried out by the CTOT consortium, or will be responsible for delegating the sponsor responsibility to another qualified party (i.e., a pharmaceutical industry sponsor) subject to the Program Director’s/Principal Investigator’s approval.

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 program official will monitor program progress, and must approve changes involving key personnel, addition or deletion of clinical sites or mechanistic laboratories, and protocol changes that have resulted in a substantive change in scope, goals, or human subjects risk as compared with a previously approved protocol. The NIAID program official will have access to data generated under these awards and may use information obtained from the data for the preparation of internal reports on the activities of the group.

All protocols developed in the CTOT consortium will be reviewed by NIAID program staff and the NIAID Transplant Data Safety Monitoring Board.

Areas of Joint Responsibility include:

Steering Committee

The Steering Committee is the governing body of the CTOT. All participants in the CTOT consortium are bound by the policies and procedures developed by the Steering Committee; adoption of such policies and procedures requires a majority vote.

Membership of the Steering Committee will include, at a minimum: one CTOT PIs from each grant awarded; a senior statistician from the  SACCC; one additional Senior Investigator from each awardee group, selected by the contact PD/PI; the Chair of the mechanistic studies subcommittee; and the NIH Project Scientist.  Each member will have one vote, except for the NIH Project Scientist, who will be a non-voting member. Additional members may be added by majority vote of the Steering Committee. Steering Committee decisions are binding upon CTOT consortium participants. The first Steering Committee meeting will be scheduled by the NIH Project Scientist. A Steering Committee Chair will be elected by majority vote from among the CTOT PDs/PIs at the first Steering Committee meeting. The Steering Committee may choose to rotate the position of Steering Committee Chair among the CTOT PDs/PIs. The Steering Committee Chair will be responsible for scheduling and developing the agenda for subsequent Steering Committee meetings and for promoting collaborative productive research among the members of the CTOT consortium.

Steering Committee responsibilities will include: development of a scientific agenda for the CTOT consortium; approval of study protocols prior to their implementation (study protocols implemented by the consortium may differ from the clinical studies proposed by the awardees in response to this FOA); and development of policies and procedures governing the activities of the CTOT consortium, including but not limited to ongoing evaluation of site performance, presentation and publication of study findings, evaluation of new proposed studies, addition of new clinical sites, and management of conflicts of interest.

In addition, the Steering Committee will oversee the Ancillary Studies Fund for the consortium, including establishment of a policy for acceptance and review of Ancillary Studies Fund applications and ongoing review of progress of the Ancillary Studies. Receipt of applications for and a review of progress of Ancillary Studies-funded projects shall occur at least yearly at a CTOT Steering Committee meeting. This Steering Committee activity will be coordinated through the institution responsible for the Ancillary Studies Fund management, and be included as part of the institution’s annual progress report.

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

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 group 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 non-voting member.  The Mechanistic Studies Subcommittee may 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 consortium.

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 and clinical 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 quality and integrity of CTOT studies requires that all analyses are performed on data from the central database, and that these analyses are performed or have oversight by the SACCC. The SACCC will provide 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. 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 NIAID Transplant Data Safety Monitoring Board 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 PDs/PIs 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 annual Non-Competing Progress Report (PHS 2590 or RPPR) and financial statements as required in the NIH Grants Policy Statement.

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

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

Section VII. Agency Contacts

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

Application Submission Contacts

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

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: commons@od.nih.gov

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

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: 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

Scientific/Research Contact(s)

Nancy D. Bridges, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-451-4406
Email: nbridges@niaid.nih.gov

Peer Review Contact(s)

James T. Snyder, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301- 435-1614
Email: snyderji@mail.nih.gov

Financial/Grants Management Contact(s)

Roberta Dunlap Wolcott
National Institute for Allergy and Infectious Disease (NIAID)
Telephone: 301-451-2685 
Email: wolcottr@niaid.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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