Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)
National Institutes of Health (NIH)
Components of Participating Organizations

National Institute of Allergy and Infectious Diseases (NIAID)

Funding Opportunity Title
Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA) (U01 Clinical Trial Optional)
Activity Code
U01 Research Project – Cooperative Agreements
Announcement Type

Reissue of RFA-AI-13-006 and RFA-AI-12-005

Related Notices
April 28, 2020 - Notice of Clarification to Eligibility Information in RFA- AI-20-029. See Notice NOT-AI-20-045
July 26, 2019- Changes to NIH Requirements Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-128

August 23, 2019- Clarifying Competing Application Instructions and Notice of Publication of Frequently Asked Questions (FAQs) Regarding Proposed Human Fetal Tissue Research. See Notice NOT-OD-19-137

Funding Opportunity Announcement (FOA) Number
RFA-AI-20-029
Companion Funding Opportunity

None

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

93.855

Funding Opportunity Purpose

The purpose of this FOA is to solicit applications to participate in a clinical studies program to improve the long-term outcome of adult and pediatric transplant recipients (thoracic organ, abdominal organ, vascular composite tissue, and cellular replacement). The Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA) program will support cooperative, multi-institutional consortia for the conduct of interventional trials (Phase 1, 2, or 3) or observational clinical studies in organ, vascularized composite tissue, or cellular replacement allotransplantation. Each applicant institution must represent a consortium of 2 or more clinical sites. Each clinical study must include associated mechanistic studies that focus on immune-mediated processes that are relevant to the proposed clinical study. The goals of this research will be to further our understanding of and ultimately reduce immune- and infection-mediated morbidity and mortality of allotransplantation.

Key Dates

Posted Date

April 15, 2020

Open Date (Earliest Submission Date)
September 09, 2020
Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Date(s)

October 9, 2020

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).

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

February 2021

Advisory Council Review

May 2021

Earliest Start Date

July 2021

Expiration Date
October 10, 2020
Due Dates for E.O. 12372
Not Applicable
Required Application Instructions
It is critical that applicants follow the instructions in 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 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to solicit applications to participate in a clinical studies/clinical trials program to improve outcomes of recipients of thoracic or abdominal organ transplants, vascularized composite allografts (VCA), or cell replacement allografts (e.g., pancreatic islet or hepatocyte transplants). The goals of this research will be to improve our understanding of immune-mediated causes of morbidity and mortality in transplant recipients, evaluate interventions to address them, and ultimately improve transplant outcomes. The Clinical Trials in Organ Transplantation in Children and Adults (CTOT-CA) program will be a merger and renewal of two existing NIAID-sponsored consortia, the Clinical Trials in Organ Transplantation consortium (CTOT) and the Clinical Trials in Organ Transplantation in Children consortium (CTOT-C), and will support a cooperative, multi-institutional consortium for the conduct of interventional trials (Phase 1, 2, or 3) or observational clinical studies in allotransplantation. Each clinical study must include associated mechanistic studies that focus on immune-mediated pathologic processes in allotransplantation, including, but not limited to: mechanisms of immune activation and quiescence; biomarkers of immune activation, rejection, or tolerance; the interplay of alloimmunity and pathogen response; and mechanisms of susceptibility to/protection from infection that are particularly relevant to transplant recipients.

Background

The CTOT and CTOT-C consortia were established in 2004 and 2008, respectively, to conduct clinical research into the immune-mediated morbidity associated with organ transplantation in adults and children. Together, the two consortia currently include approximately 200 active clinical sites and immunology laboratories and have conducted 33 multi-center clinical studies in organ transplantation (nine randomized clinical trials, four phase 1-2 single arm interventional studies, 9 biomarker development/validation studies and 11 observational studies of immune mechanism/clinical outcomes) enrolling nearly 7000 adult and pediatric transplant recipients. The two consortia have similar governance structures and, on a yearly basis, convene together at the NIAID-sponsored "Mechanistic Studies in Transplantation Workshop." All CTOT and CTOT-C studies have some degree of harmonization 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.

These two consortia are being merged to conduct clinical research (observational studies and phase 1-3 clinical trials) addressing the immunologic and infectious barriers to long-term success of allotransplantation. Information about the current investigative sites and studies can be found at http://www.ctotstudies.org and at http://www.ctotc.org.

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, outcomes vary by pre-transplant diagnosis, comorbidities, and organ transplanted. Normal life expectancy and health-related quality of life are rarely, if ever, achieved after organ transplantation. Although 1-year survival after organ transplantation has continued to improve, the prevalence of morbidities such as infection, systemic hypertension, diabetes mellitus, renal insufficiency, and malignancy remain high in transplant recipients as compared with the general population. The barriers to short- and long-term success of organ transplantation are predominantly due to immunologic incompatibility between donor and recipient that leads to acute and chronic rejection, and to the complications of long-term pharmacologic immune suppression.

Vascularized composite allotransplantation (VCA), defined as the transplantation of multiple tissues such as muscle, bone, nerve and skin, as a functional unit (e.g., a hand, or face) from a deceased donor to a recipient with a severe injury, has emerged as an increasingly accepted therapy for individuals with limb loss or severe facial injuries not correctable using autologous tissue. The unique immunologic properties of grafts containing skin, muscle, bone, blood vessels and nerve are still incompletely 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. As with organ transplantation, successful VCA requires life-long pharmacologic immunosuppression; unlike organ transplantation, these procedures are generally not life-saving, and thus the risk/benefit considerations are more nuanced. Inclusion of VCA in the CTOT-CA program will make the resources and experience of the greater transplant research community available to those studying VCA, promote interest in VCA among transplant scientists who have not worked in this area, and promote research into the immunologic properties and potential of VCA.

Cellular replacement therapies, such as pancreatic islet transplantation or hepatocyte transplantation, are investigational therapies aimed at replacing specific cellular functions rather than total organ replacement. Pancreatic islet transplantation has been demonstrated to be an effective therapy for individuals with autoimmune diabetes complicated by intractable severe hypoglycemic events. Hepatocyte transplantation has been used with some success in the treatment of non-cirrhotic metabolic diseases such as familial hypercholesterolemia and urea cycle defects. Neither islet nor hepatocyte transplant has yet resulted in a permanent "cure". In common with organ allografts, cellular allografts are subject to immunologic rejection that must be prevented by pharmacologic immunosuppression. In addition, cellular allografts are subject to cell loss at implantation due to innate immune responses, and to metabolic stress when implanted in a non-homologous environment (e.g., islets infused into the liver). Unlike organ transplantation, cellular transplantation involves complex manufacturing procedures that are an important component of clinical trial design and execution. Nevertheless, cellular allografts have great potential for alleviating disease and improving quality of life without some of the risks associated with whole organ transplant.

Infection is a leading cause of death in the first three years following any organ transplant. The development of curative drugs for hepatitis C will likely have an important positive impact on donor availability and transplant outcomes; however, many other infectious agents continue to contribute substantially to early and late mortality and morbidity after transplantation. In the immediate postoperative period, these include donor-derived (e.g., Cytomegalovirus, Epstein-Barr Virus, Herpes Simplex Virus, West Nile Virus, and Trypanosoma cruzi) and hospital-acquired (e.g., multiply-resistant Staphylococcus aureus, Vancomycin-resistant Enterococcus, and Clostridium difficile) infections. In the following year and beyond, additional pathogens of importance include polyomavirus, adenovirus, influenza, cryptococcus, varicella, mycobacteria, pneumocystis, toxoplasma, nocardia, aspergillus, and others. Treatments for these infections and antimicrobial/antiviral/antifungal prophylaxis and immunization to prevent them are frequently sub-optimally effective and can be associated with substantial toxicity, in part due to drug-drug interactions with immunosuppressive drugs. This FOA includes a specific emphasis on, and funding for, studies of infectious disease in transplant recipients.

Research Objectives and Scope

The objective of this FOA is to support multi-center interventional clinical trials and/or observational studies in adult and/or pediatric candidates for or recipients of allogeneic organ, vascularized composite tissue, or cellular replacement transplants requiring lifelong immunosuppression under the current standard of care. New elements of this FOA, as compared to prior CTOT and CTOT-C programs, include: (1) a merger of CTOT and CTOT-C into a single research consortium; (2) the addition of cellular allotransplantation to the scope of research supported; and (3) an expanded emphasis on infectious disease in allotransplantation.

All clinical trials and studies must include associated studies of immunologic and/or infectious disease 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/genetic studies, studies of the microbiome, metabolomics, proteomics, or any other assays that will contribute to the scientific goals of the proposed studies. In the case of studies that target infectious pathogens, mechanistic examination of correlates of risk or protection are encouraged. These studies may be hypothesis-driven or hypothesis generating. Studies of pharmacokinetics and/or pharmacodynamics should be included where appropriate to the understanding of test therapeutics.

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

  • Evaluation of improved, less toxic, or more specific immunosuppressive agents or regimens;
  • Protocols designed to minimize pharmacologic immune suppression, including the use of allo- or autogeneic immunologically active cells (for example, native or modified T regulatory cells or regulatory dendritic cells);
  • Interventions in the living or deceased donor that will result in improved recipient outcomes;
  • Identification and validation of biomarkers that will enable accurate non- or minimally-invasive monitoring of the recipient’s immunoreactive state, so that therapy can be individualized and proactive;
  • Identification and validation of biomarkers that will act as reliable surrogates for important clinical transplant outcomes or for risk stratification;
  • Studies designed to improve understanding of pathogen-specific immunomodulation or ?heterologous immunity in transplant recipients;
  • Implementing and validating strategies to improve surveillance, diagnosis, prophylaxis and/or treatment of infections in transplant recipients;
  • Prospective observational studies characterizing the course of viral, fungal or mycobacterial infections in the organ transplant population that address key unknowns and correlates of risk.
  • Studies that identify, develop or validate biomarkers of risk of, protection from or recovery from infectious disease in transplant recipients;
  • Studies designed to optimize the therapeutic or prophylactic dose of anti-infectives in transplant recipients, e.g., pharmacodynamic/pharmacokinetic studies of anti-infectives, studies that address critical drug-drug interactions, and studies that address optimization of treatment strategies (timing, dose, combination therapies) for a particular transplant population;
  • Studies of vaccine efficacy and safety in transplant candidates or recipients.

Applications proposing the following types of studies will be considered non-responsive to this FOA and will not be reviewed:

  • hematopoietic stem cell or mesenchymal stem cell transplant, except as a component of a study of organ transplantation, VCA, or cellular allotransplantation;
  • xenotransplantation;
  • uterine transplantation;
  • non-vascularized tissue transplant that does not require life-long immunosuppression, including but not limited to: cartilage, cornea, bone, tendon, heart valves;
  • stem cell therapy for regenerative medicine; for example, for tissue repair after myocardial infarction or for neurologic diseases;
  • autologous reconstructive surgery, autologous nerve grafts, or any other procedure involving use/regeneration of autologous tissue;
  • investigations in animal models, unless mechanistic assays specifically linked to a clinical study require the use of animals; e.g., a mouse footpad assay;
  • Studies that aim primarily to create or maintain a data registry;
  • Studies that focus on the treatment of drug-resistant bacterial infections.

Proposed studies may include adult and/or pediatric subjects. Applications may propose to study adults and children sequentially to demonstrate evidence of benefit in adults before enrolling children. Study personnel should have expertise appropriate to the patient population; specifically, studies enrolling children must have one or more pediatricians participating as the Program Director/Principal Investigator (PD(s)/PI(s)) or co-investigator; studies having an infectious disease-related primary or key secondary outcome must have an infectious disease expert as a PD(s)/PI(s) or co-investigator.

Milestones

This program is milestone-based, with the flexibility to quickly redirect or replace research projects during the funding period. Milestones will be negotiated with NIAID staff prior to award and reviewed on an annual basis.

Data Coordination and Management and Clinical Trial Support

Data coordination and management, site monitoring, statistical and study design support, and data analysis will be carried out by separate, NIAID-funded entities that will provide technical assistance and data management services to CTOT-CA participating institutions. Each participating clinical site and laboratory will be responsible for providing primary study data in real time to these entities for management, quality control and analysis; procedures for data submission will be developed by the NIAID-funded data management center, with input from the CTOT-CA steering committee and subject to NIAID approval. All primary CTOT-CA publications will be based on the data submitted to the central databases. Each applicant team must include one or more individuals qualified to provide biostatistical support for the proposed project, who will work collaboratively with the NIAID-funded data centers. NIAID and/or its designees will provide clinical site monitoring, regulatory support, sample tracking, and drug distribution.

CTOT-CA Steering Committee

A Steering Committee will serve as the governing board to direct the collaborative work of the CTOT-CA consortium, including management of the Ancillary Studies Fund. The Steering Committee will meet at least twice in the first year and annually thereafter in Bethesda, Maryland.

Mechanistic Studies Subcommittee

The CTOT-CA Steering Committee will appoint a Mechanistic Studies Subcommittee to review proposed mechanistic studies, including those proposed for the Ancillary Studies Fund and make recommendations to the Steering Committee.

Infectious Disease Subcommittee

The CTOT-CA Steering Committee will appoint an Infectious Disease Subcommittee to review proposed infectious disease studies, including those proposed for post-award development, and make recommendations to the Steering Committee.

Publications Subcommittee

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

Ancillary Studies Fund (ASF)

To capitalize on emerging opportunities consistent with the goals of the CTOT-CA, an Ancillary Studies Fund (ASF) will be made available. This fund will be managed for the entire CTOT-CA consortium by one institution chosen by NIAID from among the successful applicants after award. The designated institution must agree to take responsibility for managing the ASF, to include establishment of an administrative structure, disbursement and tracking of funds, and reporting the status of funds and projects.

The Ancillary Studies Fund will 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 or study) performed on existing, archived biological specimens from CTOT, CTOT-C, or CTOT-CA studies; prospectively collected specimens from CTOT-CA studies; or using data and specimens from other sources, in which case the investigator must be able to demonstrate that those data and/or specimens were collected and stored under conditions with a level of rigor comparable to those used in CTOT, CTOT-C, and CTOT-CA. Such studies must be approved by the Mechanistic Studies Subcommittee and the Steering Committee. The Ancillary Studies Fund will also be used to support post-award infectious disease studies or trials that are approved by the Infectious Disease Subcommittee and the Steering Committee. All projects supported by the Ancillary Studies Fund must be within the scope of this FOA. Any use of Ancillary Studies funds must comply with all applicable HHS/NIH policies. Use of these funds is limited to CTOT-CA investigators or non-CTOT-CA investigators who establish a collaboration with a CTOT-CA investigator.
See Section VIII. Other Information for award authorities and regulations.

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. See Section VI.2 for additional information about the substantial involvement for this FOA.
Application Types Allowed
New

Renewal to RFA-AI-13-006 and RFA-AI-12-005

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?
Optional: Accepting applications that either propose or do not propose clinical trial(s)

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

NIAID intends to commit $17 million in FY 2021 to fund 5-7 awards and includes $4 million annually to support an Ancillary Studies Fund.

Award Budget
Application budgets are not limited but need to reflect the actual needs of the proposed project. NIAID anticipates that the yearly direct costs per award for clinical trials and/or studies will be approximately $2 million. This amount does not include the Ancillary Studies Fund (ASF). The budget for the ASF is limited to $4 million direct costs/year.
Award Project Period

The project period must be 7 years.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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
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.

  • 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) – 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.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons.Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. 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.

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 (or one of the PDs/PIs in the case of multiple PDs/PIs) must be a physician with substantial experience in the specific area of allotransplantation addressed by the application, and in the design, implementation, and evaluation of clinical trials, as evidenced by clinical experience and publication in peer-reviewed journals. Thus, applications for studies including pediatric subjects must have a pediatrician PD(s)/PI(s) or co-investigator; applications for studies addressing an infectious disease outcome must have an infectious disease specialist as a PD(s)/PI(s) or co-investigator.

An individual may be named as PD(s)/PI(s) or Multiple PIs on only one application. An investigator identified as the PD/PI on one application may be a collaborator on other application(s). An investigator may be a collaborator on more than one application.

2. Cost Sharing

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

3. Additional Information on Eligibility

 

Only two applications per institution (normally identified by having a unique DUNS number or NIH IPF number) are allowed

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)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace 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.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guideexcept 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.

 

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:

James T. Snyder, Ph.D.

Telephone: 240-669-5060

Email: James.Snyder@nih.gov

Page Limitations

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

, with the following exceptions or additional requirements:

For this specific FOA, The Research Strategy section is limited to 30 pages.

Instructions for Application Submission

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.

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 instructions:

The applicant team must contain two or more participating institutions (clinical sites). Additional participating sites may be clinical and/or mechanistic participants. Clinical sites, i.e., sites that intend to enroll transplant candidates, recipients, or donors, must provide documentation of a United Network for Organ Sharing (UNOS)-certified program in organ transplantation; note, foreign clinical sites must provide equivalent documentation. Sites participating exclusively as mechanistic study sites must have demonstrated expertise and the appropriate facilities to carry out the research techniques necessary for the proposed mechanistic studies.
SF424(R&R) Other Project Information

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

, with the following additional instructions:

Facilities and Other Resources: Clinical Sites and Facilities: Describe the unique and necessary aspects of the facilities to be used for clinical transplantation and/or associated mechanistic studies that support the proposed research activities. For clinical sites, include information about the site's experience with participating in multi-center transplant clinical research studies and the relevant transplant yearly volume.

Other Attachments: Applicants must provide an Ancillary Studies Fund (ASF) Management Plan, as described below, as a single file attachment for this section.

The ASF management plan must include:

• an administrative structure;

• tracking and monitoring of timely submission and payment of invoices, and plans for handling consortium agreement administration delays;

• plans for interacting with the institutions that will receive ASF funds;

• reporting on the status of the funds and consortium agreements awarded;

• an administrative assistant to coordinate these activities;

• a statement of commitment from the Institution’s signing official agreeing to take fiscal responsibility for the management of the Ancillary Studies Funds, if chosen by NIAID to administer the fund.

This section should only include information about the management of the ASF and should NOT include any ASF proposed research projects.
SF424(R&R) Senior/Key Person Profile

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

, with the following additional instructions:

Biosketches for Senior/Key Personnel should reflect scientific expertise that aligns with the proposed scientific focus of the application.
 

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

, with the following additional instructions:

All applicants must propose 7-year budgets.

All costs required for the clinical and mechanistic studies must be included in the application and must be fully justified. These include the costs of the proposed clinical research: drug acquisition and/or cell manufacture, patient recruitment and follow-up, mechanistic assays, data collection, and participation in on-site quality assurance audits.

Include in the budget:

For single PD/PI applications, the PD/PI must commit an overall minimum of 2.4 person-months. For multi-PD/PI applications, one of the PD(s)/PI(s) must commit a minimum of 2.4 person-months.

Support for a clinical study coordinator at each clinical site, with effort proportional to study complexity and the anticipated volume of patient enrollment at that site.

Funds for travel to the Bethesda, Maryland area for: (1) In year 1 of the award, a one-day Steering Committee "kick-off" meeting and a 2-day combined Steering Committee and Mechanistic Studies Meeting; (2) in subsequent years, a 2-day combined Steering Committee and Mechanistic Studies Meeting. The PD(s)/PI(s) and a senior investigator from each participating institution, at a minimum, are expected to attend the Steering Committee Meeting, and all members of the Mechanistic Studies Committee are expected to attend the Mechanistic Studies meeting.

Applications should include the cost of the Ancillary Studies Fund ($4 million total costs, including applicable F&A costs) and in the Budget Justification applicants should note the cost of, and justification for, administration of the fund.
R&R Subaward Budget

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:

Subsection A: Overview

The applicant should include a brief, but clear and concise description in narrative and diagrammatic form that depicts the interrelationships among the members of the team or group, their respective contributions, how their experience/expertise will contribute to the fulfillment of the proposed scientific program and how that aligns to the goals of this FOA. Within this discussion, the applicant should also discuss the selection of the participating institutions in the consortium and how the group as a whole will work together to further the scientific aims of the program. Include plans for communication and cooperation among the member institutions and well as with NIAID-funded management centers on study design, analysis plans, and final study analysis to ensure exchange of information and enhanced collaboration.

A description of general milestones addressing completion of subcontracts to clinical and laboratory sites, time to first patient/first visit, accrual to target, and last patient/last visit should be provided in in this subsection, along with a contingency plan to be put in place if it appears that milestones will not be met. In order to maximize utilization of CTOT-CA program resources, NIAID may re-budget individual U01 funds based on NIAID's assessment of availability of funds, progress toward yearly milestones, or other scientific priorities.

Provide a statement summarizing the key clinical and mechanistic scientific advances expected from the trial or study. Summarize the major risks and benefits of the proposed trial or study. Explain how the anticipated results will address an important question facing the field of transplantation and may result in new knowledge that will contribute to a decrease in late morbidity and/or mortality in transplant recipients.

Subsection B: Clinical Study or Trial

Submit a plan for a single clinical trial or study that meets the objectives and scope of this FOA, in one of the following areas: organ transplantation, VCA, cellular replacement transplantation, or transplant infectious disease. The plan should be organized as specific aims, background and significance, preliminary studies, and research design and methods.

The plan should be presented in sufficient detail to convey the goals of and approach to the trial or study. Submission of a detailed, final clinical protocol is neither required nor encouraged, as a complete protocol and statistical analysis plan (SAP) will be developed when studies are finalized post-award, with the assistance of the NIAID-supported statistical center and NIAID program staff.

Within the plans for the proposed trial or study discuss how the applicant will work within and not exceed the clinical and scientific resources of the PD(s)/PI(s)’s team of institutions (e.g., the applicant group should be able to recruit the required number of study subjects from within their own institutions) and within 5 years in duration from first subject enrolled to last subject last visit. Applicants should state whether a shortfall in recruitment might be addressed by adding additional clinical sites, and may include a discussion of contingency plans should they have difficulty with recruitment.

Note: Specific details for clinical trials and clinical studies will be captured using the PHS Human Subjects and Clinical Trials Information Form. Do not duplicate information requested under the PHS Human Subjects and Clinical Trials Information.

For applications that propose an observational clinical study (with no intervention), the following information should be included, in addition to the information required in PHS Human Subjects and Clinical Trials Information, Study Record (Sections 1 - 3): A description of the hypothesis and study objectives, the needed target population, the planned study design and sample size, the primary statistical test that will be applied to the primary endpoint.

For all applications, provide the number of relevant organ transplants performed at each participating clinical site for the last 5 years. For applications including VCA or cellular transplantation, provide the site’s experience with performing these procedures and, in the case of cellular transplant, manufacturing the cellular product. Finally, describe each clinical site's experience in cooperative research or multicenter clinical trials.

Subsection C: Mechanistic Studies Plan


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

  • The hypothesis to be tested and how it relates to the proposed interventional clinical trial or observational study;
  • A statement addressing how the results of the proposed mechanistic studies might ultimately contribute to improved outcomes in clinical transplantation;
  • Identification of and rationale for any immune, genetic, and/or surrogate markers selected, including background data from animal and/or human studies;
  • The source, quantity, and number of subject samples required;
  • Proposed approach to the collection and storage of samples;
  • A brief data analysis plan, including power calculations, for the primary mechanistic endpoint(s); and
  • Identification of any safety and/or ethical issues associated with obtaining the specified samples for mechanistic studies, and a plan for addressing those issues.

In addition to the key mechanistic endpoint(s), exploratory analyses are encouraged.

Subsection D: Multi-Site Infectious Disease Study or Trial Concept (if applicable)

Applications proposing a study in organ transplant, cellular replacement transplant, or VCA (i.e., those that do not have transplant infectious disease as the primary focus of inquiry) must include a plan for a multicenter clinical study or trial of transplant infectious disease with associated mechanistic studies that may be developed collaboratively post-award and funded through the Ancillary Studies Fund. "Multi-Site ID Plans" should not include a detailed clinical protocol. Include a study title, a general statement of the study objective(s), a description of the characteristics of the target population, a brief description of the study design, a description of the type of mechanistic studies that would be informative, and a descriptive estimate of costs. These study/trial concepts will be evaluated post-award by the CTOT-CA Infectious Disease Subcommittee, the CTOT-CA Steering Committee, the CTOT-CA Mechanistic Studies Committee, and NIAID to determine which if any will be implemented. NIAID will make the final determination about implementation based on availability of funds, responsiveness, current gaps in the NIAID transplant portfolio, and peer review comments generated in the review of the original application.

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

  • Participation in United Network for Organ Sharing (UNOS) - provide documentation that each proposed clinical site has UNOS-certification (foreign clinical sites must provide equivalent documentation as appropriate).
  • Letter(s) of commitment from suppliers of investigational drugs and/or devices.

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.

The following modifications also apply:

  • All applicants, regardless of the amount of direct costs requested for any one year, are expected to agree to a Data Sharing Plan in which clinical study data submitted to the NIAID-funded statistical management center will be made public in IMMPORT (https://immport.org) or another NIAID-designated portal within two years of the date that the study data set is locked, as appropriate and consistent with achieving the goals of the program. This period may be extended under unusual circumstances with NIAID's concurrence. The NIH data sharing policy is available at https://grants.nih.gov/grants/policy/data_sharing/.
Appendix:
Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.
PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered “Yes” to the question “Are Human Subjects Involved?” on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

, with the following additional instructions:

Section 3 - Protection and Monitoring Plans

3.1 Protection of Human Subjects

3.1.2 Adequacy of Protection Against Risks

Include a plan for the informed consent process that describes the involvement of a study physician and provides potential study subjects with the opportunity to consider the risks and benefits of study participation in advance of organ availability (that is, prior to the day that an organ becomes available for transplant.)

3.3 Data and Safety Monitoring Plan

For clinical trials, upload an attachment that states: NIAID monitors the conduct of all clinical trials and will convene the Safety Oversight Committee and develop the monitoring plan. No other information should be provided.

3.4 Will a Data and Safety Monitoring Board be appointed for this study?

Answer "yes". A NIAID-supported independent DSMB will monitor studies funded under this FOA.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

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

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. 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.

  • Awards issued under this FOA will be incrementally funded awards for project periods of seven years.
  • Grants awarded under this FOA will be excluded from automatic carryover – all carryover requests must be approved.
  • Grants awarded under this FOA will not be provided the authority to automatically extend the final budget period one time for up to 12 months beyond the original expiration date shown in the Notice of Award – all extensions, including the first extension, will require approval.
  • Progress and financial reporting will be required and reviewed annually.
  • All funds must be expended within the approved project period.

7. 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 How to Apply – Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. 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.

Post Submission Materials

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

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

In addition, for applications involving clinical trials: A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

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.

 

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? 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?

Specific to this FOA:

Is the project likely to result in new knowledge that will contribute to a decrease in late morbidity and/or mortality in transplant recipients?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

 

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

Specific to this FOA:

Does the PD(s)/PI(s) have experience in clinical transplantation and clinical trial design and management, documented in peer-reviewed publications? Do the PD(s)/PI(s) and site PD(s)/PI(s) have appropriate experience and expertise for the specific questions and population addressed in the proposed study? Is the level of effort of the PD(s)/PI(s) and senior investigator(s) sufficient to ensure success of the program?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

 

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?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

 

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed 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 individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this FOA:

For observational clinical studies, are the study endpoints, sample size justification, and primary statistical analyses adequately described? Are the proposed mechanistic studies appropriate to the overall goals of the project, and do they include hypothesis-driven studies? Is the choice of study sites clearjustified? Are the communication plans effective, the milestones appropriate and the plans for obtaining obtaining informed consent in advance of the day of transplant well-described?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

 

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?

Specific to this FOA:

Is the subject population available in adequate numbers at the proposed clinical sites to enroll the project to target within the proposed milestones? Does each participating institution have appropriate facilities for clinical transplantation and/or associated mechanistic studies to carry out the proposed work?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

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.

Specific to applications involving clinical trials

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

 

For research that involves human subjects but does not involve one of thecategories 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 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 individuals of all ages (including children and older adults) 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

 

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

 

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.

Ancillary Studies Fund (ASF):

  • Is provision of the proposed ASF management services to the “program” described in sufficient detail?Is sufficient justification provided for the management methods proposed for the ASF?
  • Are the personnel charged with managing the ASF appropriate?

 

Not Applicable

 

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.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by the National 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:
  • 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.

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.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.

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 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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain “applicable clinical trials” on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

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.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

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.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

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 Parts 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:

providing scientific leadership and subject matter expertise; determining and coordinating the scientific and administrative project activities; setting project goals and timelines to achieve the proposed goals; attending Steering Committee meetings, serving as a voting member of the Steering Committee, and accepting and implementing policies and procedures developed by the Steering Committee; providing primary study data to the NIAID-funded data management center for management, quality control, and analysis; participating in the cooperative nature of the CTOT-CA; and maintaining a level of productivity that justifies continued funding.

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: https://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The full policy, including terms and conditions of award, is available at: https://www.niaid.nih.gov/grants-contracts/niaid-clinical-terms-award.

All investigators are expected to agree to a Data Sharing Plan in which clinical study data submitted to the NIAID-funded statistical management center will be made public in IMMPORT (https://immport.org) or another NIAID-designated portal.

  • 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:

The NIAID 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; and 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-CA 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) Office of Regulatory Affairs and be conducted under a NIAID Clinical Trials Agreement.

Health Authority Regulation: NIAID DAIT reserves the right to specify whether an IND (Investigational New Drug)/IDE (Investigational Device Exemption) application should be submitted to an appropriate regulatory agency, and with other NIAID program staff and the PD(s)/PI(s), will determine whether NIAID should be the regulatory sponsor of a study. In the case that NIAID is the Regulatory Sponsor, the Chief of the DAIT Office of Regulatory Affairs (ORA) or designee will be responsible for providing guidance and assistance in the development, assembly and submission of all required regulatory documents 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-CA consortium, or will, along with the NIAID Project Scientist and the PD(s)/PI(s), delegate the sponsor responsibility to another qualified party (e.g., a pharmaceutical industry sponsor).

The NIAID Program Officialwill 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 the 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-CA consortium will be require review and approval by NIAID program staff and the NIAID Transplant Data and Safety Monitoring Board. NIAID reserves the right to terminate or curtail a clinical study or clinical trial or ancillary study for any of the following reasons:

  • Risk to subject safety
  • Occurrence of unforeseen safety issues or emerging data indicating a presence of unanticipated toxicity
  • Risks that cannot be adequately quantified
  • The scientific question is no longer relevant, or the objectives will not be met
  • Failure to comply with cGCP, federal regulations, or Terms and Conditions of Award
  • Failure to remedy deficiencies identified through site monitoring
  • Unreliable data
  • Inadequate progress in meeting study milestones
  • Slow accrual that may jeopardize study completion within the time frame of the award or negatively influence the scientific validity of the study
  • Reaching a major study endpoint substantially before schedule with persuasive statistical significance
  • 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.

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 toward achieving the previously agreed upon research goals.

Areas of Joint Responsibility include:

Steering Committee

The Steering Committee is the governing body of the CTOT-CA. All participants in the CTOT-CA 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-CA PD/PI from each grant awarded; a senior statistician from the DAIT-supported statistical center; 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-CA consortium participants.

Steering Committee responsibilities will include: development of a scientific agenda for the CTOT-CA 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-CA 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 will occur at least yearly at a CTOT-CA 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.

Mechanistic Studies Subcommittee

The Steering Committee will appoint a Mechanistic Studies Subcommittee to review proposed mechanistic studies and make recommendations to the Steering Committee; it will also have primary responsibility for planning, with DAIT program staff, the yearly Mechanistic Studies in Transplantation Workshop. Each PD/PI will 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 or reviewers if additional expertise in specific areas is needed. The Mechanistic Studies Subcommittee will elect a Chair from among non-Federal members. The Mechanistic Studies Subcommittee will meet at least twice yearly and its members will participate in meetings, conference calls and other subcommittee activities. The Mechanistic Studies Subcommittee will develop policies and procedures for the review of applications involving studies of mechanism or requests for laboratory equipment to the Ancillary Studies Fund, and will make recommendations to the CTOT-CA Steering committee for funding of such applications.

Infectious Disease Subcommittee

The Steering Committee will appoint an Infectious Disease Subcommittee to review proposed infectious disease studies and make recommendations to the Steering Committee. Each Principal Investigator will select one representative from his/her group as a voting member of the Infectious Disease Subcommittee; additional non-voting members may be nominated and approved by the Steering Committee. An NIH Project Scientist will serve as non-voting member. The Infectious Disease Subcommittee may appoint ad hoc subcommittee members if additional expertise in specific areas is needed. The Infectious Disease Subcommittee will elect a Chair from among non-Federal members and will meet at least twice yearly. Its members will participate in meetings, conference calls and other subcommittee activities. The Infectious Disease Subcommittee will also develop policies and procedures for the review of proposed Multi-Site Infectious Disease Studies or Trials, and will make recommendations to the CTOT-CA Steering committee for funding of such applications.

Publications Subcommittee

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

Data Coordination and Management, and Clinical Trial Support

Data coordination and management, and clinical trial support will be carried out by one or more separately funded data management and statistical centers. Each participating institution will be responsible for providing primary study data to a central database for management, quality control and analysis using procedures and standards determined by the Steering Committee, DAIT, and the data management center. The quality and integrity of CTOT-CA studies requires that all analyses are performed on data from the central database, and that these analyses are performed or have oversight by the statistical center. The data management and statistical center(s) 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. They will also 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 statistical center. All participating sites will have access to all data originating from their sites. 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 data management center; 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 Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.
A final RPPR, 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 agreementsare 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.

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 Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission by the due date, and 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)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email:GrantsInfo@nih.gov(preferred method of contact)
Telephone: 301-945-7573

Grants.gov Customer Support(Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email:support@grants.gov

Scientific/Research Contact(s)

Nancy D. Bridges, MD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3535
Email: nbridges@niaid.nih.gov

Jonah Odim, MD, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3540
Email: odimj@niaid.nih.gov

Peer Review Contact(s)
James T. Snyder, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5060
Email:James.Snyder@nih.gov
Financial/Grants Management Contact(s)

Roberta Dunlap Wolcott, JD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2964
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 Part 75.


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