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

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

The purpose of this FOA is to solicit applications for the Immune Tolerance Network. The major objective of the Network is to develop tolerogenic approaches for the treatment of disease in three clinical areas: asthma and allergic diseases; autoimmune diseases; and immune-mediated consequences of allotransplantation. The scope of research to be carried out by the Network includes:

1) the design and conduct of clinical trials at all phases to evaluate the safety and efficacy of investigational products and approaches for the induction and maintenance of immune tolerance in humans; 2) the design and conduct of mechanistic studies and the development of tolerance assays as integral components of the clinical trials undertaken; and establishment of biospecimen repositories 3) the provision of services on data management in collaboration with other resources provided by NIAID, bioinformatics analysis, and data sharing in a secure computing environment to support clinical trials and mechanistic studies. The Network may also support limited product development and nonclinical studies (e.g., toxicology, pharmacology, pharmacokinetics, etc.) essential for the subsequent evaluation of promising tolerance induction approaches in humans.

The successful induction of immune tolerance is a major therapeutic goal for the treatment of immune-mediated diseases, including asthma and allergic diseases; autoimmune disorders, such as rheumatoid arthritis and type 1 diabetes; and immune-mediated rejection of transplanted solid organs, tissues, and cells. Tolerance induction strategies aim to selectively block or prevent deleterious immune responses, while leaving protective immunity intact. More than two decades of highly intensive and productive basic research in immunology have provided a solid foundation of knowledge and understanding that will enable the application of promising tolerance induction strategies to the treatment of immune-mediated diseases and transplantation, and enhanced understanding of the underlying mechanisms of disease and therapeutic effect.

Asthma and allergic diseases are among the major causes of illness and disability in the U.S., affecting more than 1 in 5 Americans. Asthma afflicts over 26 million Americans or 7.9 percent of the U.S. population; atopic dermatitis affects up to 20% of children worldwide and, in many of them, it is considered the first step in later development of other allergic conditions, also known as the "atopic march"; allergic rhinitis is estimated to affect 60 million Americans and chronic rhinosinusitis more than 30 million. Food allergy was reported to afflict 5.6 million children under the age of 18 in 2019. In asthma and allergic diseases, the goal of tolerance research is to prevent the development of pathogenic immune responses (mostly Type 2 and IgE-mediated) against aeroallergens and food allergens or to shift such responses towards non-pathogenic states.

Autoimmune diseases are chronic disabling disorders in which immune responses are directed against host cells, tissues, and organs. More than 100 autoimmune diseases have been identified and, for reasons that are not clear, the prevalence of these diseases is rising. Collectively, autoimmune diseases affect approximately 23.5 million people in the U.S., and represent a significant physical, emotional, social, and fiscal burden for patients, their families, and society. These diseases can affect any organ or organ system, and all ages are affected, with onset from childhood to late adulthood. In autoimmune diseases, novel approaches are needed to block deleterious immune responses.

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. In 2018, 36,527 transplants were performed in the U.S., with approximately 114,000 candidates on the transplant waiting list. Although one-year survival after transplantation has improved markedly for every organ, barriers to long-term graft and patient survival include incompatibility between donor and recipient, acute rejection, chronic graft dysfunction, and complications of long-term use of immunosuppressive drugs. In transplantation, donor-specific immune tolerance - a selective blockade of immune responses directed against the graft - would enable long-term graft survival without the complications and risks of systemic immunosuppressive therapy (e.g., infection, malignancy, and atherosclerosis).

The NIAID has a long-standing commitment to supporting basic, translational and clinical research on immune tolerance with the ultimate goal of developing novel, efficacious therapies for the induction and maintenance of antigen-specific immune tolerance in humans. In 1999, the NIAID awarded a seven-year contract to establish the Immune Tolerance Network - a major program resulting from the scientific planning process, designed to: (1) develop a long-term scientific agenda for clinical trials and mechanistic studies; (2) design and conduct clinical trials at all phases to determine the safety, toxicity and efficacy of tolerogenic treatment strategies for multiple immune system diseases; and (3) design and conduct research to delineate the underlying mechanisms of immune tolerance as an integral part of the clinical trials undertaken by the Network, as well as clinical trials sponsored by other Federal and private sector organizations and companies. In 2007, the contract was recompeted and expanded to include limited nonclinical research and product development, as well as bioinformatics, data collection and analysis. In 2014, the Immune Tolerance Network program was recompeted under a cooperative agreement award.

Since the establishment of this Network in 1999, substantial progress has been made in evaluating diverse tolerogenic products and approaches for a broad range of immune-mediated diseases, enhancing our understanding of underlying mechanisms, and assessing the induction, maintenance and loss of tolerance through multiple assays. Achieving complete and durable tolerance in the setting of established disease has proven to be challenging; hence, studies that provide step-wise advances in achieving over-arching goals have been an important strategy in advancing tolerance research. The Network has initiated 65 clinical trials with associated mechanistic studies: 18 clinical trials in asthma and allergic diseases; 27 clinical trials in autoimmune diseases; and 20 clinical trials in transplantation. It is anticipated that 20 studies will be ongoing at the completion of the current contract and will be continued and completed during the new award period. Additional information about the research activities of the current Network, publications, the status of the studies, as well as information on organizational structure and membership, may be obtained from the Network website here (http://www.immunetolerance.org).

The Network will function as a cross-disciplinary, open consortium with proposed activities for clinical trials and integrated mechanistic studies accepted from investigators both within and outside of the Network and with support provided to Network and non-Network institutions and researchers.

For this FOA, immune tolerance is broadly defined as a clinical phenotype characterized by selective elimination of pathogenic immune responses to relevant antigens (e.g., alloantigens, autoantigens or allergens), with preservation of protective immunity, with no or minimal requirement for ongoing immunosuppression or other immune-based intervention. Approaches may include a variety of mechanisms such as deletion, induction of anergy, immune deviation, sequestration, exhaustion or suppression.

Research Scope: The scope of research to be performed by the Network includes:

• Clinical Trials. Design and conduct of Phase I-IV clinical trials to evaluate the safety and efficacy of investigational products, approaches and techniques intended to lead to a functional state of immune tolerance in three clinical areas: asthma and allergic diseases; autoimmune diseases; and immune-mediated consequences of allotransplantation. Tolerogenic strategies may include but are not limited to those that target antigen specific receptors co-stimulation pathways, homing molecules, or other relevant approaches; may use any of a variety of agents including but not limited to antigens, peptides, altered peptides, monoclonal antibody blockade, cytokines, molecularly engineered cells or tissues, DNA vectors, or other relevant molecules; and may be administered by a variety of routes. Tolerance studies may include projects that are intended to achieve incremental advances and are clear steps towards tolerance. In addition to new clinical trials, the successful applicant will continue oversight and implementation of ongoing clinical trials and associated mechanistic studies. Additional information on the scope and responsibilities for ongoing clinical trials and mechanistic studies may be found at the following link (http://www.itnstudies.org/) and (for clinical trials) at www.clinicaltrials.gov.
• Mechanistic Studies. Design and conduct on human specimens of mechanistic studies and development and evaluation of assays to measure/assess stages of disease and likelihood of progression as specifically relevant to immune tolerance, effect of treatment on immunological status and/or clinical outcome, maintenance of protective immunity, and safety of immunosuppression withdrawal, and identification and evaluation of potential immune/surrogate markers and predictors of the induction, maintenance, and loss of tolerance. These state-of-the-art and novel studies will be performed as integral elements of the Network research program.
• Bioinformatics Resources. Provision of services on data management in collaboration with other resources provided by NIAID within a secure computing environment required for the integration of Network clinical trials and mechanistic studies, conducting statistical and bioinformatics analysis of such data across Network clinical trials and mechanistic studies, facilitating communication of data and analysis results for investigators in distinct areas of expertise and from multiple-geolocations, and sharing data through appropriate public repositories and in compliance with NIH Data Sharing policies, FAIR Data Principles (Findable, Accessible, Interoperable and Reusable) and other community-based standards and best practices.
• Studies and Product Development. On a limited basis, support will be provided for product development activities and the design and conduct of nonclinical studies essential for the subsequent evaluation of promising tolerance induction strategies in humans. Such activities may include but are not limited to: in vivo or in vitro proof-of-principle studies; pharmacokinetics and pharmacodynamics animal studies; and nonclinical toxicity studies in suitable animal models and product characterization. Manufacturing and laboratory studies will be conducted under current Good Laboratory Practices (cGLP) or current Good Manufacturing Practices (cGMP) as appropriate.

Disease-specific Research Priorities: Research priorities within each of the three clinical areas include, but are not limited to, the following:

Allergic Diseases and Asthma

• Tolerance induction through innovative allergen-specific strategies, immunomodulatory agents and microbiome manipulations including but not limited to:
• Early life/early stage interventions aiming at the prevention or progression of allergic diseases
• Therapeutic interventions in established allergic diseases aiming at increasing the durability of response after treatment discontinuation

In pursuing the above priorities, research efforts should also be targeted towards improving the effectiveness, safety and patient acceptability of specific allergen immunotherapy using new forms of allergenic products, alternative routes of administration and combination with other immunomodulatory interventions.

• Human studies to elucidate the mechanisms leading to the development of allergic sensitization and reactivity (failure or loss of tolerance), as well as the natural loss of allergic sensitization or reactivity (induction of tolerance) that can occur over time.

Autoimmune Diseases

Innovative, immune-based approaches to restore tolerance, while preserving protective immunity, targeting cell subsets and pathways, including but not limited to:

• Co-stimulatory blockade strategies to inhibit T cell activation
• Cytokine modulation to induce immune deviation
• Strategies to promote or restore healthy immune homeostasis
• Antigen-specific therapies to modulate autoreactive immune responses

Transplantation

Innovative tolerogenic approaches to improve long-term graft survival and decrease the adverse immunologic consequences of allotransplantation and pharmacologic immunosuppression, including but not limited to:

• Cell-based therapies
• Use of novel molecules or biologic agents, or combination thereof, to induce T and/or B cell tolerance to alloantigens
• Other potentially tolerogenic strategies
• Studies designed to identify risk-stratifiers for or biomarkers of tolerance to alloantigens

The Immune Tolerance Network operates in a coordinated manner across four functional areas: Leadership, Clinical Operations, Core Laboratory, and Bioinformatics. These functional areas are integrally connected to all aspects of the Research Agenda for the prevention and treatment of immune-mediated diseases. The Network functions as a collaborative effort under the direction of the PD(s)/PI(s) with input from key personnel, Network clinical and basic science investigators, Executive and Steering committees, activity-specific subcommittees within the Network and NIAID.

The Leadership Group (LG), led by the PD(s)/PI(s), is responsible for the overall administrative leadership of the Network as well as oversight and evaluation of all Network Activities. The LG is also responsible for the following:

• Research Priorities. The LG will develop, implement and update the Research Agenda for the Immune Tolerance Network, approve and prioritize the research concepts for clinical trials and mechanistic studies, seek opportunities for outside collaborations to benefit the ongoing and planned research activities, and establish industry collaborations for product development and testing.
• Governance. The LG will develop and implement plans and procedures for effective governance of the Network in terms of the administration, operational standards, communications plans, and fiscal functions of the Network, and develop policies and guidance for internal decision making and collaborations within and outside the Network in support of implementation of the Research Agenda.
• Monitoring. The LG will monitor the implementation of the Research Agenda and evaluate the performance of the functional areas of the Network with respect to meeting targeted timelines and milestones associated with each research project, and Network activities in support of the Research Agenda.
• Quality Management. The LG will develop strategies for assuring quality management and develop risk assessment and mitigation strategies that are integrated within all research activities of the Network.
• Collaborative Responsibilities. The LG will actively seek opportunities for collaboration with other NIH-supported clinical networks, and other Federal and private sector clinical research programs. Such collaborations and interactions are essential for the development and implementation of a comprehensive research agenda that utilizes the strengths, experience, and expertise of various collaborating organizations. Sharing of expertise, resources, and procedures is expected in key areas, including harmonization of laboratory resources and specimen management and harmonization of common data elements and data entry interfaces.
• Communications. The LG will develop clear, effective and centralized communications plans for distributing and/or posting (e.g. secured web portal) relevant content for use by various entities within the Network and NIAID. In doing so, the LG will determine the optimal mode of communications for all needs, such as administrative, personnel, research, regulatory, laboratory, contract support, subcommittees and stakeholders.
• Executive Committee. The Executive Committee provides scientific leadership and overall governance of the Network and is responsible for the implementation of the Research Agenda.
• Network Steering Committee. The Steering Committee provides leadership and oversight for the Network functions, including clinical trials, mechanistic studies and tolerance assays, nonclinical research and product development, bioinformatics/data analyses, and assessment of additional clinical research capacity, as needed. The Steering Committee makes recommendations to the Executive Committee for changes in direction, scope or reprioritizing of the research.

The Clinical Operations Group (COG) provides leadership for the development, implementation, and monitoring of clinical trials, performing clinical site feasibility assessments and other pre-study initiation requirements, development of clinical protocols, study implementation and safety oversight, and ensuring adherence to all standards for FDA, ICH, GMP and other regulatory compliance issues related to clinical trials and biospecimen collection.

The Core Laboratory Group (CLG) is responsible for: 1) designing and implementing mechanistic studies as integral elements associated with the clinical trials; 2) developing and implementing laboratory performance standards and metrics; and 3) implementing procedures for conducting quality assurance and quality control on mechanistic data and samples. In addition, the CLG will accept responsibility for and operate the existing Network repositories as directed, and if needed will establish and operate a repository for clinical specimens generated by Network clinical trials and mechanistic studies, including sample collection methods, tracking, storage, inventory, retrieval and packaging and shipment of specimens in support of the Research Agenda.

The Bioinformatics Group (BG) is responsible for collecting, validating and analyzing mechanistic data, integrating the mechanistic and clinical data, managing all data sources in a secure computing environment to support workflows of clinical trials and mechanistic studies, conducting integration, harmonization and analysis of such data across Network clinical trials and mechanistic studies and providing Web-access to data and analysis results, and sharing data through public repositories and complying with NIH Data Sharing policies and community-based best practices. The BG will also operate a data management system, provide capabilities of analysis and data sharing for mechanistic study data and de-identified clinical data while integrating data sharing with other Division of Allergy, Immunology and Transplantation (DAIT)-supported programs.

The NIAID will provide certain resources to support the design, development, implementation, oversight and monitoring of Network clinical trials, the conduct of mechanistic studies and the analysis of final study data. The Network will cooperate with NIAID to ensure that clinical research complies with all applicable regulatory requirements as well as NIAID policies and procedures. These resources include:

• Statistical and Clinical Coordinating Center(s) (SACCC) to provide a broad range of support services, including: the clinical and safety databases of record, assistance in the development of statistical design and analysis plans and other clinical protocol components (e.g., data and safety monitoring plans); a central data management system for the collection, storage, quality control and retrieval of clinical and other trial related data; a safety database system for the receipt, reporting and disposition of Serious Adverse Events (SAEs); and the analysis of final clinical study data and preparation of final clinical study reports.
• Clinical Site Monitoring Center to assist in monitoring the conduct of clinical trials in accordance with protocol-specific and regulatory requirements, including initial site assessments, interim site monitoring of ongoing clinical trials, and site and study close-out.
• Clinical Products Center for the receipt, storage, inventory, packaging/repackaging, quality assurance, distribution and disposal of study products.
• Regulatory Management Center to provide technical and administrative assistance for a broad range of regulatory support functions related to the conduct, compliance and oversight of clinical trials (e.g. preparation of regulatory submissions and safety reports; maintenance and management of Sponsor required essential clinical documents, see https://www.ich.org/).
• Immunology Database and Analysis Portal (ImmPort) to serve as the NIAID centralized immunologic data repository.
• Other Support Services. With rare exceptions, NIAID will serve as the regulatory sponsor for Network clinical trials conducted under Investigational New Drug (IND) Applications, Investigational Device Exemptions (IDEs), and international equivalents with full responsibility for carrying out sponsor regulatory obligations (e.g. Data management and statistical support, adverse event reporting, management of clinical agents and specimens and clinical monitoring and compliance auditing). The NIAID will assemble and coordinate the activities of independent Data and Safety Monitoring Boards (DSMBs).

The NIAID will provide funds to the Leadership Group (LG) to support centralized operational, administrative and research-related resources for all Network-affiliated clinical trials and mechanistic studies, including evaluation of proposed research concepts, study design and protocol development, study implementation, oversight and follow-up, and analyses of final integrated study data.

Note: For further information, please visit the following website for general information and questions and answers. https://www.niaid.nih.gov/grants-contracts/questions-answers-rfa-ai-19-068.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

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

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.
• o NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number 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.

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.

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

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

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.

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

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:

Julio Aliberti, PhD
Telephone: 301-761-7322
Fax: 301-480-2310
Email: [email protected]

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

The Research Strategy must consist of the following subsections with the indicated page limits:

Subsection A: Overview of the Immune Tolerance Network --one required -- 12 pages

Subsection B: Leadership Group -- one required -- 30 pages

Subsection C: Clinical Operations Group -- one required -- 30 pages

Subsection D: Core Laboratory Group -- one required -- 30 pages

Subsection E: Bioinformatics Group -- one required -- 12 pages

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

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

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

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

Facilities and Other Resources

Clinical Sites and Facilities: Describe the unique and necessary aspects of the facilities to be used for clinical care and clinical research that support the proposed Network research activities. Describe how the facilities will be monitored and secured based on the nature of the research performed therein.

Data Management Facilities: Describe the unique facilities and features of the data management section to support the processes for the reliable and accurate collection and recording of the data, and the features of the facilities that will enable rapid and secure transfer of all data types between the Network and NIAID's supporting awards.

Laboratory Resources and Facilities: Describe the unique and necessary aspects of the facilities related to acquisition, preparation and use of the biological samples to be used for mechanistic research studies. Describe the storage facilities appropriate for various specimens and how the facilities will be monitored and secured based on the nature of the data.

Sample Repository Facilities: Describe the unique and necessary aspects of the facilities needed for the receipt, identification, handling (e.g., aliquot, sample-specific preparation), labeling and storage of the Biological samples. Describe the storage facilities appropriate for various specimens or reagents, and how the facilities will be monitored and secured based on the nature of the data.

Other Attachments: Applicants must provide a Quality Management Plan as described below as a single file attachment for this section.

Quality Management Plan

Provide a full Quality Management Plan including quality control, quality assurance and quality improvement.

• Describe the overall quality management plans for the Network research. Include a discussion of strategies for assuring quality management, to ensure that risk assessment and mitigation strategies are an integral part of all research activities within the Network.
• Describe the approach to quality management for LG activities and LG-coordinated management of efforts of the COG, CLG, and BG needed for achieving and maintaining compliance with ICHE6, 21CFR Part 11, Good Clinical Practice (GCP) ICHE6(R2) , Good Documentation Practice (GDP), Good Manufacturing Practice (GMP), DAIT Clinical Research Policies and Standard Operating Procedures (SOPs), and other standards.
• Describe how the LG oversight of quality management will be integrated throughout the Network to include laboratory quality management procedures, risk assessments, site selection, clinical operations, data sharing platform(s), and biorepositories.
• Describe the process for determining when quality assurance assessments are needed for each Network function.
• Describe what metrics will be captured in assessing quality and how these metrics will be communicated within the Network and to NIAID.

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

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

Applicants must budget for the following:

• A minimum of 3.6 person months per year for the PD/PI. If two or more PD(s)/PI(s) are named, each PD/PI must devote at least 1.8 person months of effort to the project. In the budget justification provide a detailed apportionment of the PD(s)/PI(s) time to administration, management and research activities associated with the Network functions.
• One (1), two (2) day initial Kick-Off Meeting within the first 6 months of the award in the Bethesda MD area for the PD(s)/PI(s) and key personnel.
• Two (2), three (3) day meetings per year rotating between the Bethesda MD area and a location to be determined for the PD(s)/PI(s) and key personnel to update NIAID on progress and future directions.

Applicants must request all necessary funds to support the infrastructure and operations of the entire Network. For budgeting purposes, applicants should plan according to the information provided below:

• At the time of award, 80% of funds (direct costs) will support ongoing clinical trial and associated mechanistic studies consisting of 150 sub-agreements. Examples of current costs for ongoing clinical trials and associated mechanistic studies can be found here (https://www.immunetolerance.org/sites/default/files/itn-trials-timeline.pdf) and clinical trial details for these studies can be found at www.clinicaltrials.gov. Budget an annual decline in support for studies ongoing at initiation at a rate of 20% per year.
• Assume one (1) new clinical trial and associated mechanistic study in each of the three disease areas (total three (3) trials/studies) in the first budget year and three (3) additional new clinical trials and associated mechanistic studies in each of the following proposed years of support.
• In the budget justification, for all new activities, provide a budget breakout under each group in clearly labeled sections: Leadership Group, Clinical Operations Group, Core Laboratory Group, and Bioinformatics Group for all proposed activities. Examples of breakout activities include implementation and support of clinical trials and mechanistic studies, laboratory functions (including sample collection, storage and shipping to the repository), and bioinformatics functionality and security; detailed budget for the planning, implementation and completion of new clinical trials and the mechanistic studies; detailed budget for the infrastructure and core support functions, including Network personnel, consultants and related research support resources, required to carry out and complete both new and ongoing clinical trials and mechanistic studies.

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

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

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

Specific Aims: Provide the specific aims for the Network and describe how they support the overall proposed Network Research Agenda.

Research Strategy: The Research Strategy section must consist of a single attachment consisting of subsections A-E, as designated below.

Subsection A. Overview of the Immune Tolerance Network

Describe the overall Network structure and function with respect to advancing immune tolerance induction strategies through clinical trials and integration of studies of underlying mechanisms of the induction, maintenance and loss of tolerance. From a high-level perspective, describe approaches to integrating all Network functional areas (Leadership Group, Clinical Operations Group, Core Laboratory Group and Bioinformatics Group), and plans for coordinating with the clinical sites participating in approved studies to create a fully-integrated, collaborative organization in support of the immediate and long-range goals of the Network research. The use of organizational charts, diagrams or other tools to represent the Network are encouraged. Discuss how the proposed organization will facilitate decision-making and the ability to drive studies through to completion and highlight any innovative aspects for the integration of a large, complex clinical research program.

Subsection B: Leadership Group (LG)

In this subsection, describe the organization of the LG and discuss how the organizational structure promotes effective leadership of the overall Network and proposed activities. Provide tables, diagrams, flow charts or organizational charts as appropriate to reflect the organization of the Network’s four functional areas Leadership (LG), Clinical Operations (COG), Core Laboratory (CLG) and Bioinformatics (BG) and any additional activities, such as executive, steering or subcommittees proposed. Include the following information:

Network Structure and Governance:

• Describe the general plans for LG management and oversight of Network activities, including discussions on overall planning, priority setting and decision making, operational support and resource planning, and coordination for all research projects, including the clinical trials and mechanistic studies.
• Describe the proposed staffing plans for the LG, including lines of authority, and discuss how the staffing will contribute to an effective governance structure.
• Describe the approach to governance of the Network including establishment of internal committees and their composition, roles, responsibilities and decision-making authorities. Do NOT name potential committee members who are not already key personnel within the application.
• Describe specific plans to establish effective project management for high-level scientific and administrative decisions for the LG, including research prioritization, reassessment, and redirection. Include a discussion of the involvement of key stakeholders in these decisions.
• Describe how project management will be used to develop, record and monitor individual project and higher-level program milestones, timelines and contingency plans.
• Describe plans for Network communications, including communications within and across the Groups, support contract staff (as appropriate), SACCC, NIAID, and other stakeholders. Describe how the LG will communicate with the scientific community, patient advocacy groups, and the general public. Include plans for communicating the solicitation for potential research concepts to be supported by the Network. Describe the internal communications plan to disseminate information to all or specific functional areas of the Network.
• Discuss process, procedure and plans, including frequency, of the LG to meet to share scientific and programmatic information, to assess scientific progress, and to identify new research opportunities and potential avenues of collaboration, both within the Network and with other stakeholders.
• Describe how the LG will coordinate and collaborate effectively within the Network, with NIAID and with other Federal and private sector research organizations/programs. Describe proposed plans to identify opportunities for such collaborations and to establish joint sponsorship arrangements to capitalize on non-Network clinical research resources in specific scientific areas.
• Describe the structure and function of the Executive Committee, and how the individuals will be selected for service. DO NOT NAME OR CONTACT SPECIFIC INDIVIDUALS AS MEMBERS IN THE APPLICATION.
• Describe the structure and function of the Steering Committee, and how the individuals will be selected for service. DO NOT NAME OR CONTACT SPECIFIC INDIVIDUALS AS MEMBERS IN THE APPLICATION.

Network Operations:

• Describe the Network operations structure, management and oversight, and illustrate the extent to which Network operations are centralized to achieve efficiency and effectiveness.
• Provide an organizational chart demonstrating how the centralized operational support for the implementation and management of research-related policies and procedures (e.g., submission, distribution and review of proposed clinical trials/studies, publications, conflict of interest, and agreements with Federal, non-Federal and industry collaborators) will be conducted and managed.
• Describe the plan for determining the soundness, feasibility, and anticipated contributions of proposed projects. Outline the plan for soliciting, evaluating, awarding and managing clinical trials, mechanistic studies, bioinformatics projects, and sub-agreements; assessing performance, resolving problems or barriers, and termination of projects.
• Describe the proposed time frames/milestones associated with carrying out Network operations.
• Describe the fiscal management plan for the Network to administer and track the Network budget and associated expenditures and reports; provide plans for oversight of Network resources, including access, authority, decision making, tracking and reporting processes. Describe procedures for calculating the amount of study-specific funds, including any formulas or templates to be used.
• Describe in detail the plans for management and administration of all business activities of the Network and discuss the extent to which the staff composition for this activity will result in effective oversight to monitor costs in a timely manner.
• Provide proposed plans and procedures for ensuring the adequacy of clinical research capacity for supported clinical trials, including, for example, the number of clinical sites, access to a diverse and representative sample of subjects, recruitment and retention capabilities. Provide plans for recruiting additional clinical research capacity, and how the location, feasibility and funding of that capacity will be approved.

Network Evaluation and Improvement:

• Describe how the overall performance of the Network will be evaluated and improved during the award period.
• Describe proposed policies, methods, and approaches for evaluating the operational performance of the overall Network, including financial management of resources. Include a discussion of metrics that may be used to determine both productivity and quality of the results generated by the Network and how findings will impact adjustments to Network activities and follow up evaluations.
• Describe methods and approaches for monitoring implementation of clinical research conducted by the selected sites.
• Discuss the plans for implementation of a formal process to review and assess progress, and identify risks associated with completion of trials and studies (for example, early signals obtained from informal milestones, soft Go/No-Go juncture points, or impact of potential outcome on the scientific field or relevance to clinical practice).
• Describe proposed processes for the resolution of performance problems and proposed processes for the development of remediation/improvement plans at all levels of the Network functions.

Network Research Agenda:

Present the proposed Network Research Agenda to advance immune tolerance induction strategies through clinical trials and to integrate studies of underlying mechanisms of the induction, maintenance and loss of tolerance. Consider the following elements:

• Provide a detailed description of research priorities for both clinical trials and mechanistic studies and the rationale for their selection with respect to the significance, soundness and innovation of approaches, strategies and techniques designated as high priority.
• Describe the key parts of the Research Agenda with respect to how current state of the art research, techniques, approaches and models help shape the structure, direction and future activities of the Network research.
• Describe how the proposed approaches build on prior work in immune tolerance and take this research in new directions.
• Provide an overview of the approach to identifying research gaps, opportunities, and prioritizing research that will be incorporated into the agenda, centering on research strategies to induce tolerance in human clinical studies through underlying mechanisms, and scientific opportunities relevant to the clinical application of tolerance induction strategies in human immune-mediated diseases and transplantation.
• Indicate the frequency, timing and plans for reviewing progress of the Research Agenda and incorporating new information into the Research Agenda.
• Discuss how the concepts for research will be solicited, developed, evaluated, prioritized and approved for funding by the Network. Include the delineation of promising investigational tolerogenic approaches for the treatment of asthma, allergic and autoimmune diseases, and for the prevention of immune-mediated rejection of solid organ, tissue and cell transplants through clinical trials or mechanistic studies.
• Identify the decision-making process for implementing the Network Research Agenda as it relates to timelines, milestones, and solutions to overcome potential barriers to meeting major objectives of the Network Research Agenda.

Subsection C: Clinical Operations Group (COG)

• Describe the organizational structure, proposed staffing plans, and lines of authority for the COG. Demonstrate how this organization will implement the Research Agenda for the Network and provide oversight of the Network clinical research. Provide tables, diagrams, flow charts and organizational charts to connect all operations within COG, including pre-study implementation, feasibility assessment, and protocol development.
• Describe project management approaches, including the establishment of timelines/milestones for all activities within the purview of the COG, and the process and metrics associated with the evaluation of COG performance.
• Discuss the processes and procedures to establish effective project management of COG activities. Discuss how the work will be divided among the staffing plans to meet clinical research timelines and milestones (with appropriate metrics), develop contingency plans and redirect efforts, as needed.
• Describe the communication processes within the COG and between the COG, the LG and other Network functional areas, including NIAID and NIAID supported contractors.
• Describe the decision-making processes and methods to identify and resolve operational issues.
• Describe the methods used to plan and manage resources with respect to the clinical research operations.
• Describe plans and procedures to ensure the efficient, timely, and effective review of protocol documents by the single IRB of choice.

Study Feasibility Assessment:

• Describe proposed plans and procedures for assessing the adequacy and appropriateness of the capabilities of clinical sites approved for participation in Network clinical trials, including the staffing, data management systems, and clinical, laboratory and pharmacy facilities at each location.
• Describe how additional sites will be proposed, selected for consideration and evaluated for trial or study preparedness in the event of circumstances associated with an emergency need.
• Discuss how the proposed staffing of the clinical assessment teams will contribute to the rapid and accurate assessment of study site feasibility and associated timelines to implement.
• Describe the process for identifying appropriate actions to improve clinical research capabilities when necessary, assist clinical sites in implementing appropriate actions, and coordinating clinical site assessment activities and actions with the NIAID Clinical Site Monitoring Center and responsible NIAID staff.
• Discuss how site performance will be measured and managed, including processes and procedures to ensure the timely initiation, conduct and completion of clinical site assessments.
• Describe the plans to evaluate the proposed investigational product(s) (IP), including, availability of IP and quantity to complete the clinical trial; ability to meet FDA and ICH regulatory document requirements related to the IP including the proposed protocol's IND Sponsor requirements; ability to identify risks associated with IP sourced from various entities.

Protocol Development:

• Discuss how the protocol development teams will be assembled to be inclusive of all areas of need and expertise. Discuss the range of responsibilities the assembled teams will need to have in order be optimally responsive to the Network research.
• Describe the proposed approach to developing clinical research concepts into protocols and associated documents.
• Describe how decisions at each step in the protocol development process will be made. Include a discussion of the process for fast tracking development of high priority concepts. Provide flow charts/diagrams to delineate the steps and timelines involved in the protocol development and implementation process. Discuss who will need to be involved in the development and approval of each step in the preparation of draft and final clinical protocols and protocol-related documents and coordinating their review and modification.
• Describe how performance will be measured and managed, including processes and procedures to ensure adherence to approved protocol timelines/milestones, identify and resolve obstacles to timely protocol development, and develop and implement contingency plans when necessary.

Protocol Implementation and Oversight:

• Describe the staffing plans necessary for the implementation and oversight of Network-approved clinical trials.
• Describe the processes and quality management oversight to be applied to the timely clinical trial initiation and conduct in accordance with NIAID and Network policies and procedures, monitor subject accrual and retention, assess adherence to approved protocol timelines/milestones, identify problems/obstacles, and develop and implement actions to resolve identified problems/obstacles.
• Describe how decisions will be made with respect to protocol readiness for implementation in terms of the availability of preclinical safety data, relevant scientific data, study product availability, fiscal and human resources, and an evaluation of site readiness and feasibility.
• Discuss the procedures and process required to address criteria for protocol approval by NIAID, operational futility, methods for monitoring study progress and participant safety (in collaboration with the NIAID SACCC), receipt of status reports, and dissemination of results to study participants and the research community.
• Discuss how protocol development management plans will be developed, tracked, and monitored. Include a discussion of establishing realistic milestones and go/no-go criteria, evaluation of established plans, actual data, and future projections. Include discussion of the development of contingency plans and the processes to adjust project plans.
• Describe how performance will be measured and managed, including processes and procedures to assess clinical site progress, study deviations, corrective action plans and staff effectiveness and productivity.
• Discuss the process for developing documents to support the protocol.

Subsection D: Core Laboratory Group (CLG)

• Describe the CLG organizational structure including staffing plans and lines of authority. Include tables, diagrams, flow charts and organizational charts to indicate the functional structure and organization integrating the CLG with other areas of the Network.
• Describe the approach for making decisions on the selection of laboratories to perform specialized assays, including determining laboratory readiness and ensuring ongoing quality.
• Discuss how the proposed staffing of the CLG will address all areas of specialized need within this Group, and how the CLG team composition will facilitate the implementation of the Network Research Agenda.
• Describe the types of services to be provided. Discuss the CLG research approach and expected contributions to the field. Include plans for the development of any new/innovative assays that further the goals of the Network Research Agenda.
• Describe the plan to design and implement mechanistic studies as integral elements associated with the clinical trials.
• Describe processes to determine the nature and type of biological samples to be collected, and how the samples will be processed, labeled, inventoried and stored according to standardized procedures appropriate to sample type until needed. Include plans for shipping and shipment tracking.
• Describe the approach for conducting ancillary studies using pre-existing stored samples when available from Network-affiliated clinical research.
• Describe the approach to sharing and distribution of samples, specimens and other laboratory materials outside the Network. Address compliance with applicable laws.
• Describe the methods for specimen shipping and handling, in terms of specimen acquisition, processing, shipping, tracking, testing, labeling, storage and retrieval. Describe the plans for utilization of a laboratory data management system and discuss how samples will be identified/deidentified and the security of Personally Identifiable Information will be maintained.
• Describe any proposed subcommittees, including the structure and roles of each proposed committee and the procedures for establishing new committees and disbanding those that are no longer needed. Do NOT name potential committee members that are not already key personnel within the application.
• Describe how performance will be measured and managed, including processes and procedures to ensure adherence to approved timelines/milestones, identify and resolve obstacles to the timely initiation, conduct and completion of laboratory studies, and develop and implement contingency plans when necessary.
• Describe the processes for developing, implementing and updating laboratory processes and the plan for developing and implementation of protocol-specific laboratory documents and processes.
• Provide a plan for obtaining additional expertise, engaging new laboratory programs, and integrating state-of-the-art procedures into the CLG as the science progresses.
• Describe how new assays will be assessed and implemented for use with clinical specimens from clinical trials, including how decisions will be made on the use of new and non-FDA- approved test methods for IND and non-IND studies, and procedures for transitioning from existing to new technologies. Discuss the plans for conducting manufacturing activities and laboratory studies under current Good Laboratory Practices (cGLP) or current Good Manufacturing Practices (cGMP), as appropriate.
• Discuss the approach to making decisions on the selection of specialized assays, procedures, and analyses for performance of protocol-specific testing.

Quality Management, Evaluation and Improvements:

• Describe laboratory quality management procedures. Include general quality assurance (QA) and quality control (QC) procedures, as well as CLG requirements for external quality assurance (EQA), validations, reference range studies and laboratory audits.
• Describe the process for determining the need for and development and implementation of alternative EQA.

Communications and Clinical Site Laboratory Capacity/Training:

• Describe procedures for interactions among CLG laboratories, with other Network Groups, and with participating clinical site laboratories for performing routine, non-specialized testing, and for collecting, processing and shipping specimens.
• Discuss the capacity of the CLG to perform testing and provide training on specific assays for laboratory personnel of other Federal and non-Federal clinical research programs.
• Describe how the CLG will establish and maintain communication and transmission of assay information and data between the CLG and the Bioinformatics Group.
• Describe and discuss the proposed data input methodology for clinical site laboratories, how assay capacity assessment and clinical site training will be accomplished, how clinical site laboratories will be evaluated, and problem resolution processes and procedures.

Subsection E: Bioinformatics Group (BG)

Structure and Governance:

• Describe the proposed organization, including all proposed functional needs. Identify the nature and type of expertise required to facilitate optimal operations and how such expertise will lead to the success of the Network research.
• Describe the structure and function of the Bioinformatics Group (BG) in terms of the overall implementation of the Research Agenda for the Network. Tables, diagrams, flow charts and organizational charts are strongly recommended.
• Describe proposed plans for the governance of the BG, including: lines of authority, project management approaches, including the establishment of timelines/milestones and the evaluation of BG performance, decision-making processes, and methods to identify and resolve operational issues.
• Describe the communication processes within the BG and among the BG and other Network functional areas, and NIAID and NIAID support contractors.
• Described how the BG will develop and incorporate new technologies for data analyses, data visualization, and methods for ensuring accuracy, confidentiality and integrity of data transferred among the Network members.

Data Management System:

• Describe plans for establishing and operating a data management system for the nature and volume of data collected by the Network.
• Describe the system procedures and workflows for the collection, storage, access, backup, archiving, and exchange of data from mechanistic studies and clinical data derived from the Network SACCC, including but not limited to genetic, cellular, and molecular data.
• Describe the software proposed for data capture, storage, query and analysis, as well as for disseminating data to investigators, NIAID, and the scientific community.
• Describe plans for an integrated electronic data repository that includes research subject samples and/or relevant scientific data for each research subject and discuss how this plan will permit rapid and efficient production of files for analysis.
• Provide proposed procedures for data quality control and verification in collaboration with originating laboratories and the Network SACCC.
• Describe system security and plans for long-term maintenance and survival of data and the data system.
• Provide a plan for tracking consents for sample use and for sample de-identification and/or destruction when necessary.

Primary and Secondary Analyses:

• Provide plans for interacting with investigators, the Network SACCC, and the NIAID for the development, review and implementation of proposed studies/sub-studies, including assessing feasibility.
• Discuss relevant statistical methods and study designs for the analysis of mechanistic data and combined mechanistic and clinical data within the context of previous similar analyses performed.
• Describe the range of services offered by the BG in support of the Network research, for example: data analyses, determining sample size, or assistance with manuscript preparation.

Letters of Support:

The Letters of Support attachment should begin with a table of letter authors, their institutions, and the type of each letter (institutional commitment or resources; collaboration or role in the project; potential or current user of a resource or service proposed in the application).

Provide all appropriate letters of support, including any letters necessary to demonstrate the support of consortium/site participants, cores, laboratories, pharmacies and other collaborators. If parts of the costs of the trial are to be borne by sources other than NIH, these contributions must be presented in detail as part of supporting letters signed by Authorized Organization Representative. These outsource costs do not constitute cost sharing as defined in the current NIH Grants Policy Statement and should not be presented either as part of the requested budget.

To document their commitment, include letters in support of the following:

• Study sites and laboratories
• The availability of study agents
• Co-funding of clinical trials from partners, if applicable

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

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

Appendix:

Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When involving human subjects research, clinical research, and/or NIH-defined clinical 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:

Although applicants must be prepared for clinical trials, definite plans for such involvement will not be available at the time of application submission. A study record must not be completed.

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, with the following additional instructions:

All applicants must add and complete the Delayed Onset Study record and must check box "Anticipated Clinical Trial?"

Study Title-- use: "Multiple Delayed-Onset Studies"

Justification Attachment: Indicate each clinical study protocol developed during the project period will be subject to approval through a procedure that involves an initial concept submission and subsequent review by the Immune Tolerance Network. If the concept receives approval, the next stage will be development of the protocol, which also must undergo review and approval prior to implementation through the Immune Tolerance Network.

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

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

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

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

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

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

This initiative is not subject to intergovernmental review.

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

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

• Awards issued under this FOA will be incrementally funded awards for project periods of seven years. Multi-year funded grants will not be awarded.
• 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.

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.

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.

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.

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.

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

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

Does the project address an important problem or a critical barrier to progress in the field? Is 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?

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?

Specific to this FOA:

Is the Network scientifically compelling as a whole? To what extent will the Network Research Agenda address the current state-of-the-art research, techniques, approaches and models, and will it shape the structure, direction and future activities of the Network research? How well does the proposed Research Agenda build on prior work in immune tolerance while advancing the science in new directions? Does the Research Agenda identify current research gaps and opportunities, and prioritize research activities?

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?

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?

Specific to this FOA:

Do the PD(s)/PI(s) and the key personnel provide the appropriate balance of leadership and technical expertise necessary to succeed in the implementation of the network? Have the PD(s)/PI(s) committed a sufficient amount of time and effort to the development, implementation and oversight of the network administration, management and research activities?

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?

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?

Specific to this FOA:

How well does the Network research agenda incorporate innovative and creative research approaches to the planned research? For example, are there innovative approaches to reach, recruit and retain a diverse and representative population of patients with immune tolerance diseases? Will the proposed innovative approaches significantly influence the immune tolerance community?

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?

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?

Specific to this FOA:

• Are the organizational structure and governance plans for the Network Groups appropriate to achieve the goals?
• Are communications plans within the Network and between functional groups, governance structures, clinical and laboratory sites, NIAID and stakeholders adequate to maintain a bi-directional flow of information?
• Are overall project management plans adequate to monitor and evaluate progress for high-level scientific and administrative decisions for the Network, including research prioritization, reassessment, and redirection?
• Is the process for forming committees, naming members and conducting committee business (for both named committees and those committees that may be formed after award) well described and complete? Is the need for the committees adequately justified?
• Are the plans for promoting and supporting collaborations within and outside of the network adequate and feasible? How well do those plans take advantage of opportunities arising from collaborations and establish joint sponsorship arrangements that capitalize on non-Network clinical research resources in specific scientific areas?
• Are the plans and procedures to assure clinical research capacity adequate for network supported trials, including the plans to increase clinical research capacity in response to unexpected need?
• Is the process to evaluate the performance of Network Groups appropriate to the scope of the network functions? Are the plans and approaches for Network Groups improvement appropriate?
• How well defined is the process for developing clinical research concepts into protocols, and are the timelines for protocol development and implementation easily monitored, evaluated and adjusted?
• Are the plans to evaluate the proposed investigational product(s) (IP) appropriate and feasible including classifications of risk?
• Is there a suitable process to review and assess research progress, and identify risks associated with completion of trials and studies across the Network?
• Are the overall quality management plans for the Network research complete and reasonable?
• Are the proposed plans and procedures sufficient for assessing the readiness and capabilities of clinical sites approved for participation in Network clinical trials, including the staffing, standard operating procedures, data management systems, and clinical, laboratory and pharmacy facilities at each location assessed?
• Are the proposed plans to design and implement mechanistic studies as integral elements associated with the clinical trials appropriate?
• Are the plans and procedures described for the review of protocols and related documents by the sIRB likely to result in efficient, timely and effective review?
• Are the plans for establishing and operating a data management system appropriate for the nature and volume of data collected by the network researchers? Does the data management system provide breadth and depth of functions to collect, store, retrieve, archive and exchange mechanistic data and the capability to integrate those data with those from clinical data?
• Is there an adequate plan for tracking consents for sample use and for sample de-identification and/or destruction when necessary?

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

If 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?

Specific to this FOA:

Are there adequate, available and appropriate clinical, mechanistic and repository facilities for the clinical care and research required to support the Network? Are the proposed repository facilities and equipment adequate for the scope and volume of work anticipated?

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.

Study Timeline

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 the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the 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

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.

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.

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

As part of the scientific peer review, all applications:

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

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

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

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

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

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

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

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

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

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

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).

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. 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. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

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

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

• The scientific leadership, administration and coordination of all Network activities.
• Identifying and implementing a network research agenda that addresses research areas of highest priority in promoting research on new tolerogenic approaches for the treatment or prevention of asthma and allergic diseases, autoimmune diseases, and immune-mediated rejection of transplanted solid organs, tissues and cells.
• Chairing the Network Executive Committee and Steering Committee while ensuring the effective implementation of Committee responsibilities.
• Collaborating with NIAID and the Network SACCC to set Network clinical research priorities in accordance with available SACCC resources.
• Establishing policies and procedures for decision-making that are adaptable to changing research priorities.
• Participating in the design, conduct, analysis, and publication of clinical trial and mechanistic research findings/results.
• Establishing procedures and metrics for the assessment of Network progress and productivity in achieving the objectives of the Research Agenda.
• Ensuring the participation and appropriate training of Network investigators.
• Developing and implementing procedures for selecting and prioritizing proposed clinical trials and mechanistic studies.
• Managing the communications between the Network and the sIRB.
• Providing all Network personnel, consultants and research support services necessary for the continuation and completion of ongoing clinical trials and mechanistic studies being supported by the current Network.
• Ensuring that all operational, regulatory and site-specific requirements are met prior to protocol initiation and that all protocol documents are developed collaboratively with the input of investigators, statisticians, and NIAID staff.
• Establishing and providing bylaws, policies and standard operating procedures to the NIAID Program staff within a timeline to be determined after issuance of an award and description of lines of authority and communication within the Network.
• Implementing procedures for regular assessment of performance, to include processes for the addition, reduction, increase or elimination of Network trial sites and laboratories.
• Submitting required information to NIAID in order to meet administrative, oversight, and regulatory requirements including DAIT Regulatory review.
• Notification to NIAID of any audit specific to this award conducted by regulatory health authorities.
• Developing a plan for sharing of archived laboratory specimens obtained during the conduct of Network clinical studies across Network investigators, as well as for external investigators.
• Obtaining NIAID approval prior to submission of publications.
• Setting laboratory priorities for mechanistic studies that are based on Network research priorities and integrated in clinical trials.
• Engaging, where appropriate, non-Network expert investigators and laboratories and other supported resources when identifying, evaluating and implementing new tests, reagents and instruments for mechanistic studies of tolerance promoting strategies.
• 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:

NIAID Program Officials and Project Scientists along with other NIH staff will coordinate the activities below and will be identified at the time of award.

• Ensure that Network research efforts are consistent with that of the NIAID agenda for immune tolerance clinical research, and complement those of other NIH and NIAID programs.
• Facilitate coordination among the NIAID- and other NIH-supported clinical trials Networks and other research groups.
• Communicate the NIAID scientific priorities and how they impact Network priorities.
• Serve as members of protocol teams in the roles of Medical Monitors, Project Scientists, Project Managers and Regulatory Officers.
• Track protocol development, implementation, and study conduct.
• Share information regarding promising new agents, strategies, and developments when appropriate.
• Identify scientific gaps and facilitate exchange of scientific and regulatory information, including during Network meetings.
• Oversee resources that:
• Provide statistical and data management services
• Provide regulatory services
• Provide a centralized immunologic data repository
• Conduct external site monitoring
• Manage and distribute investigational agents
• Collect SAE reports
• Participate on committees as voting members.
• Participate in the presentation of research results, including publications.
• Monitor progress of medical, laboratory, and operational aspects of clinical trials.
• Oversee clinical site operations to include development of template informed consent documents as well as review of site-specific consents for IRB submission; operational activation of Network clinical sites; and review and evaluation of site monitoring reports.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• Implementing, monitoring, and updating the clinical research plan for the Network to ensure consistency and relevance with the NIAID scientific priorities.
• Reviewing the Network's research activities and goals on an agreed upon schedule.
• Ensuring the quality and scientific integrity of publications resulting from Network studies.

Dispute Resolution:

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

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final 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 agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission 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: [email protected] (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: [email protected]

Leighton Thomas
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3522
Email: [email protected]

Julio Aliberti, PhD
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-7322
Email: [email protected]

Tseday Girma
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-747-7388
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75 .