It is critical that applicants follow the Research (R) 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.

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

This Funding Opportunity Announcement (FOA) solicits applications from currently funded Program Directors/Principal Investigators (PDs/PIs), Mechanistic Subcommittee members, core laboratory leaders and clinical site leaders in the "Clinical Trials in Organ Transplantation in Children (CTOT-C) program". The objectives of this limited competition FOA are to support mechanistic investigations that leverage unique CTOT-C resources to address hypothesis-driven mechanistic studies related to pediatric transplant outcomes. The primary objectives of this FOA are to use the unique CTOT-C clinical databases, linked biospecimens and histologic images to investigate underlying mechanisms of either pathological processes or therapeutic regimens relevant to pediatric transplantation, with a focus on discovery and validation of biomarkers for surveillance, diagnosis, use in personalized medical regimens, and use as surrogate endpoints in future clinical trials. Specimens and data from sources other than CTOT-C studies may be used in the proposed investigations if the investigator can document that they were collected, curated, and archived with a similar level of rigor.

Investigators are strongly encouraged to include new investigators, Early Stage investigators and Assistant Professors in the proposed research projects. The investigations supported under this FOA are expected to provide new and Early Stage investigators with exposure to and experience in critical research methods and/or laboratory techniques.

This FOA will result in synchronization of the funding cycles of the CTOT-C (pediatric consortium) and CTOT (adult consortium).

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, drug pharmacokinetics in children, and studies of immune mechanisms. The CCTPT succeeded in developing a reliable network of clinical centers for pediatric kidney transplant research. CCTPT trials demonstrated that obtaining research kidney biopsies in children was safe and that calcineurin inhibitor-free regimens provide effective protection from kidney rejection in children.

In 2008 the CCTPT was renewed as the CTOT-C and the scope expanded to include studies in all pediatric organ transplant recipients. One of the goals of CTOT-C was to develop and nurture a community of pediatric transplant research experts and clinician scientists in an arena traditionally limited by sample size, scale, and scope. CTOT-C was last renewed in 2013. It has supported clinical trials in pediatric kidney, heart, lung and liver transplantation. CTOT-C investigators work collaboratively with investigators in the Clinical Trials in Organ Transplantation (CTOT), a large NIAID-funded research consortium conducting clinical trials with associated studies of immune mechanism in adult transplant recipients. The two consortia share protocol templates and laboratory SOPs, and jointly conduct an annual Mechanistic Studies Meeting. Additional information about CTOT-C and CTOT can be found at http://www.ctotc.org and http://www.ctotstudies.org/, respectively.

Applications submitted in response to this FOA should propose a milestone and hypothesis-driven research program of mechanistic and biomarker studies designed to expand our understanding of the link between pediatric transplant recipient clinical phenotypes and basic mechanisms of allo-immunity, innate immunity and auto-immunity. These mechanistic studies may include, but are not limited to, imaging, histopathology, cellular assays (e.g., Elispot, flow cytometry), antibody assays (e.g., Luminex), gene expression studies, genomic and epigenomic and proteomic studies, or any other immunologic or molecular assays that will contribute to the scientific goals of the proposed studies. The funding of a milestone-based project beyond the first year is contingent upon satisfactory progress in meeting negotiated milestones.

Applications containing research covering the following topics will be considered non-responsive and will not be reviewed:

• Projects that do not propose mechanistic studies
• Projects that propose clinical trials
• Applications proposing more than one hypothesis-driven research project
• Studies of hematopoietic stem cell transplantation (HSCT)
• Studies of islet transplantation for treatment of type 1 diabetes
• Studies involving animal models
• Studies involving xenotransplantation
• Behavioral studies
• Data coordination and management and clinical trial support that duplicate services provided by the DAIT Statistical and Clinical Coordinating Center (SACCC) for the CTOT-C consortium

Steering Committee

A Steering Committee will continue to serve as the governing board for the CTOT-C consortium. The Steering Committee develops policies and procedures governing the activities of the consortium, and identifies scientific opportunities, emerging needs and impediments. In addition, this committee will evaluate the progress and direction of individual awards. Each PD(s)/PI(s) will serve as a voting member of the Steering Committee and will abide by all of its policies and procedures.

Data Coordination and Management Support

Data coordination, data management and statistical support is provided by a separately funded data coordinating center, the Statistical and Clinical Coordinating Center. Each participating institution is responsible for providing primary study data to the SACCC. The SACCC will provide expert assistance in the design, implementation, and analysis of mechanistic studies, and in preparing abstracts, presentations and manuscripts.

Publications Subcommittee

Publication policies and procedures for the CTOT-C consortium are proposed by the Publications Subcommittee and approved by the Steering Committee. The Publications Subcommittee, along with NIAID and the SACCC, will oversee the completion of research reports and peer-reviewed publications.

Mechanistic Studies Subcommittee

The Steering Committee will appoint the Mechanistic Studies Subcommittee to review proposed mechanistic studies and make recommendations to the Steering Committee. The Mechanistic Studies Subcommittee will oversee the process and mechanism for exchange of biospecimens between laboratories, the process for determining the quality of banked specimens, and procedures for linking the clinical data to the biospecimen along with the SACCC post-award. This committee will continue to work closely with a similar group from CTOT to standardize and harmonize timing of sample procurement, process and assays.

See Section VIII. Other Information for award authorities and regulations.

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.

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)
• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are 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.

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.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
• NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. 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.

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.

Only current CTOT-C PDs/PIs, current members of the CTOT-C Mechanistic Studies subcommittee, current core laboratory leaders, and current clinical site leaders are eligible to apply as the PD/PI for this FOA. Non CTOT-C investigators may be included on applications, but not as the PD(s)/PI(s).

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

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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.

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:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Zhuqing Charlie Li, Ph.D.
Telephone: 240-669-5068
Fax: 301-480-2408
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

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

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

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

Other Attachments: Include the following information, if applicable:

• For applications using CTOT-C data and biospecimens provide the following information:
• The protocol from the study that is the source of the specimens and/or data to be used, informed consent form(s) indicating that participants consented to the use of their data and specimens for future use at the time that they consented to the study, and copies of IRB approvals or documentation that the samples and/or data have already been de-identified (e.g., data publically available from IMMPORT). Provide a justification and plan for relinking de-identified clinical data from completed studies in publically accessible databases (e.g., IMMPORT) to appropriate matching biospecimens and necessary IRB approvals and or consent form(s), if required to implement the specific aims of the proposed study.
• For applications using any non-CTOT-C data and biospecimens provide the following information:
• A justification for why non-CTOT-C data (including clinical phenotypes) and/or specimens are appropriate for use in the proposed project.
• The parent protocol from the study that is the source of the specimens and/or data to be used, informed consent form(s) indicating that participants consented to the use of their data and specimens for "future use" at the time that they consented to the study, and copies of IRB approvals, or documentation that the samples and/or data have already been de-identified, if applicable. Provide a justification and plan for relinking de-identified clinical data from completed studies in publically accessible databases to appropriate matching biospecimens and necessary IRB approvals and or consent form, if required to implement the specific aims of the proposed study.
• SOPs for non CTOT-C biospecimen procurement, processing, handling, and storage, including monitoring of storage facilities. This may include agreements, if any, related to the collection or transfer of these materials.
• Documentation of the measures taken to link the biospecimens to the clinical data and to protect patient confidentiality.
• A description of the procedures used to build, maintain, and protect a non-CTOT-C database that will be the source of clinical data for the proposed mechanistic study, including procedures used to verify data accuracy, completeness and quality.
• For all applications provide the following information:
• Discuss how the involvement of new or Early Stage investigators will be encouraged in the research activities.

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

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

• If the proposed budget includes the purchase or lease of laboratory equipment, provide a justification and documentation of context of use, how the request fits within the scope of the CTOT-C objectives, where the equipment will reside (e.g., at the applicant institution or other institution) and information about who will share this equipment.
• For essential equipment purchased or leased for the proposed project provide budget details regarding annual equipment maintenance.Include costs for collection, storage and shipping of specimens. Include costs associated with review and processing of requests for specimens and data, including special handling costs that may be incurred.
• Include costs directly associated with storage and manipulations of non-CTOT-C data; (however the costs of organizing new data centers will NOT be covered).
• Include costs and justification for Early Stage and new investigators (e.g., travel, techniques, and mechanistic assays).
• For mandatory meetings include costs for: (1) travel to the Rockville, 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 the CTOT/CTOT-C combined Mechanistic Studies Meetings, annually, for the PD(s)/PI(s) and one representative from the PD/PI's group.

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

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

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

Specific Aims: Describe the proposed goals of the application, including the hypothesis to be tested, as well as a discussion of how the proposed project will result in the development of important surrogate endpoints and/or biomarker targets for diagnosis, monitoring, and therapeutics in pediatric transplantation.

Research Strategy: Describe the overall strategy, rationale, study design, methodology and analyses used to accomplish the goals of the study. Include the following information:

• A discussion of the linkage and integration of biospecimens to clinical data;
• A description of the study subjects from whom the phenotype data and/or samples were derived, the data collected and the protocols followed, including a discussion of potential biases or challenges in the protocols and how they will be addressed;
• A description of any archived specimens and/or data to be used, the consenting process, procurement, processing, storage, and the proposed assays and analyses to performed;
• A table detailing the source and physical location of all clinical data and biospecimens to be used in the proposed project;
• A discussion of proposed mechanistic or biomarker investigations, including the source, the quantity, and number of patient samples required; methodologies proposed to collect and analyze samples; and how the results of the proposed mechanistic or biomarker studies will enhance our understanding of mechanisms of disease, or predict patient outcomes in transplantation;
• A description of the need, quantity, amount, and process for acquisition of any specimens, and determining the quality of the specimens for the proposed mechanistic studies;
• A description of the timeline for collection and transmission of study data linked to the specimens, and archived specimens, to the appropriate mechanistic laboratories for analysis;
• A discussion of the statistical methods appropriate for the study designs, including sample size and power calculations and the underlying assumptions (and data) used to link these calculations to the endpoints and to the tested hypothesis;

Milestones: Include detailed and quantitative yearly milestones for assessment of progress and success. The timeline for preparation and completion of peer-reviewed manuscripts should be included among the milestones. Provide a summary flow diagram of these milestones fulfilling the specific aims over the project period.

Letters of Support: Provide the following information:

• For applications using CTOT-C data and biospecimens, provide letter(s) from the appropriate CTOT-C PD(s)/PI(s) and SACCC confirming sufficient (e.g., material, volume, cells, weight, images and histology) available biospecimens (linked to clinical data) required for the proposed study. In addition, the letter(s) must state that the use of CTOT-C biospecimens does not compromise the requirements of on-going parent CTOT-C studies, and that the specimen/data owner agrees to supply the resource.
• For applications using any non-CTOT-C data and biospecimens provide letter(s) confirming that the investigator has access to data and samples required for the proposed studies. The letter(s) should indicate the owner and location of the data and/or biospecimens, and express the owner's willingness to supply the resource.
• A letter from the PD(s)/PI(s) confirming that the current clinical trials agreement (CTA) will not prevent the use of the biospecimens and/or data for the proposed studies.
• Documentation of Commitment to the CTOT-C Collaborative Group. The application must include a written commitment, signed by the PD(s)/PI(s) and the applicant institution, to participate in the CTOT-C consortium, 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.2. Cooperative Agreement Terms and Conditions of Award: Collaborative Responsibilities.
• A statement from the PD(s)/PI(s) confirming willingness to fully share non-CTOT-C datasets pertinent to studies under this FOA with NIAID and the SACCC as appropriate and consistent with achieving the goals of the program.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.

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.

When conducting clinical research, follow all instructions for completing PHS Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. 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. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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 and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

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.

This initiative is not subject to intergovernmental review.

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.

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. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues. For assistance with application submission, contact the Application Submission Contacts in Section VII.

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 and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Applicants are required to follow the instructions for post-submission materials, as described in the policy.

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.

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).

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.

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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?

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 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? Is there potential for development of important surrogate endpoints and/or biomarker targets for diagnosis, monitoring, and therapeutics in pediatric transplantation?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of children, justified in terms of the scientific goals and research strategy proposed?

Are the samples and biospecimens well chosen, well-linked and integrated to clinical data for the proposed project? Is the plan for procurement and transfer of biospecimens linked with clinical data feasible?

For applications using any non-CTOT-C data and specimens: is there a strong justification for the use of these biospecimens and clinical phenotypes including: appropriate informed consent for use of data and specimens; clinical database characteristics, including procedures used to verify data accuracy, completeness and quality; methods of specimen processing and storage, including monitoring of storage facilities; and measures taken to link the biospecimens to the clinical data, and to protect patient confidentiality?

Do the required letters of support demonstrate feasibility of the proposed research? Are the informed consent processes, clinical protocols, and the biospecimen and clinical phenotype linkages (if applicable) appropriate and acceptable?

Is there an adequate plan to ensure accurate collection and timely transmission of study data and archived biospecimens to the appropriate mechanistic laboratories for analysis? Is there a sound biostatistical analysis plan for the mechanistic investigation(s)?

Are the proposed milestones reasonable, achievable, appropriate, and adequately justified? Is a timeline for preparation and completion of peer-reviewed manuscripts included among the milestones? Is an adequate summary flow diagram of these milestones provided?

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? If applicable, are an adequate rationale and justification provided for lease or purchase of equipment?

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.

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 Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Not Applicable

Not Applicable

Not Applicable

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.

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.

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).

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) Genomic Data Sharing Plan (GDS).

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National Institute of Allergy and Infectious Diseases, 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:

• May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
• Will receive a written critique.

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 Diseases Council. The following will be considered in making funding decisions:

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

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. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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 terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

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 Part 75, 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:

• Proposing replacement or redirected projects to the Steering Committee and/or other experts for review, based on milestone evaluations and assessment by the NIAID Project Scientist and/or the Steering Committee. Replacement or redirected projects must not propose a change in scope from the original research project.
• Providing primary study data to the SACCC for management, quality control, and analysis. 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.
• Submitting data to NIH-supported and/or public databases in accordance with policies agreed upon and established by the Steering Committee.
• Participating in the cooperative nature of the CTOT-C program.
• Submitting to review by the NIAID Transplantation Data Safety and Monitoring Board (DSMB), if a DSMB is needed.
• 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:

• 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, and ensure coordination of Steering Committee activities and implementation of its recommendations, decisions, and policies.
• Collaborations with industry may require the assistance of the NIAID Division of Allergy, Immunology and Transplantation (DAIT).
• The NIAID reserves the right to terminate or curtail a study or any individual award in the event of: (a) inability to carry out the proposal due to substantial shortfall in available quality biospecimens, or biospecimens linked to relevant clinical data, data reporting, quality control, or other impediments; (b) substantive changes in the proposed studies to which the NIAID does not agree; or (c) human subject ethical or safety issues that may dictate a premature termination.
• 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.

Areas of Joint Responsibility include:

• Steering Committee - The CTOT-C Steering Committee will provide suggestions regarding replacement or redirection of proposals to the NIAID Project Scientist. Membership of the Steering Committee will include, at a minimum: the CTOT-C PD(s)/PI(s); the SACCC PD(s)/PI(s); and the NIH Project Scientist. Each member will have one vote. Additional members may be added by majority vote of the Steering Committee. Steering Committee responsibilities will include:
• Development of a scientific agenda for the CTOT-C consortium
• Approval of study protocols prior to their implementation. The study protocols implemented by the consortium may not reflect the studies proposed by any single awardee in response to this FOA.
• Providing suggestions regarding replacement or redirection of proposals to the NIAID Project Scientist.
• Development of policies and procedures governing the activities of the CTOT-C consortium, including but not limited to ongoing evaluation of site performance, presentation and publication of study findings, evaluation of new proposed studies, and addition of new collaborating sites.
• Development of quality control and data analysis standards, along with the SACCC.
• Mechanistic Studies Subcommittee - The Mechanistic Studies Subcommittee will review proposed mechanistic studies and make recommendations to the Steering Committee. The Mechanistic Studies Subcommittee may ask the Steering Committee to appoint ad hoc subcommittee members if additional expertise in specific areas is needed. Each PD/PI will select one representative from his/her team to serve as a voting member of the Mechanistic Studies Subcommittee; additional non-voting members are nominated and approved by the Steering Committee. The NIAID Project Scientist and a representative from the SACCC serve on this committee. 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. The NIAID Project Scientist (non-voting) and a representative from the SACCC serve on this committee.
• 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 provide 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. All participating sites will have access to all data originating from their sites. 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.

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-710-0267

Jonah Odim, M.D., Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3540
Email: [email protected]

Zhuqing Charlie Li, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5068
Email: [email protected]

Roberta Wolcott
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2964
Email: [email protected]

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.

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 Part 75.