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

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

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

This FOA solicits applications for the Clinical research program of the Autoimmunity Centers of Excellence (ACE). The companion FOA, RFA-AI-18-002 solicits applications to the Basic research program of the ACE. The goal of the ACE is to conduct insightful analyses of human immunology, as it applies to autoimmune disease(s), within and among collaborative Centers and especially in the context of Clinical Projects, i.e., clinical trials with integrated mechanistic studies. The members of the Clinical and Basic ACE will work together after award to design, develop, and conduct studies of autoimmunity and autoimmune diseases in humans. This approach is expected to advance our fundamental understanding of human autoimmunity, identify common and distinct mechanisms in the pathogenesis of autoimmune diseases, and clarify mechanisms of action of immune-modulating agents used in therapy or tested in clinical trials.

The ACE program was founded in 1999 to accelerate the discovery and translation from lab to clinic of therapies for autoimmune diseases. The ACE conducts cooperative clinical, mechanistic, and basic studies, fosters intellectual and material collaborations among scientists, and facilitates the study of clinical samples by research scientists. The ACE combines two research programs -- Basic and Clinical -- that align grant awards with responsibilities. The Clinical research program develops and conducts Clinical Projects (i.e., clinical trials with integrated mechanistic studies) as well as Collaborative Projects investigating fundamental human immunology. The Basic research program provides a solid scientific foundation and conducts advanced, collaborative investigations into human immunology.

The members of the Basic and Clinical programs will work closely together to fully develop and conduct Clinical Projects and other studies of mechanism and pathogenesis. The ACE has conducted Clinical Projects in systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis, Sj gren's Syndrome, ulcerative colitis, scleroderma, and pemphigus vulgaris (partial list: ClinicalTrials.gov). The collaborative ACE Research Plan and annual progress reports of the current ACE are available on the public ACE website.

Collaborations among basic and clinical scientists have been productive though challenging to initiate and maintain. A 2005 Trans-NIH Autoimmune Diseases Research Plan advocated for clinical trials with integrated mechanistic studies that "utilize materials and data from clinical trials to elucidate underlying mechanisms of drug activity and immune response." This Plan also acknowledged that clinical trials are lengthy, risky, and expensive, conceding "many agents that show promising results in preclinical studies do not advance to clinical trials" and noting that new treatments are sometimes discovered "when practitioners identify new uses for medications originally approved for other conditions." The importance of informative clinical trials in developing new therapies and evaluating existing therapies was also emphasized in a report from the Institute of Medicine, "Envisioning a Transformed Clinical Trials Enterprise in the United States: Establishing an Agenda for 2020:Workshop Summary". Well-designed clinical studies of immune-modulating agents can be fundamentally informative whether or not an investigational agent ultimately advances to licensure and clinical practice.

The objectives of the ACE are to accelerate the discovery and translation from lab to clinic of therapies for autoimmune diseases. The ACE program approaches these objectives by conducting cooperative basic, clinical, and mechanistic studies, fostering intellectual and material collaborations among basic and clinical scientists, and facilitating the study of clinical samples by basic research scientists. Projects designed to test explicit hypotheses are preferred though 'data-driven' projects are permitted. The program is expected to advance our fundamental understanding of human autoimmunity, identify common and distinct mechanisms in the pathogenesis of autoimmune diseases, and clarify mechanisms of action of immune-modulating agents used in therapy or tested in clinical trials.

Research Scope: All projects must investigate autoimmune disease in humans.

Clinical Projects: A Clinical Project is defined in this FOA as a clinical trial together with integrated mechanistic studies. The NIH defines a clinical trial as "a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes" (full definition here: NIH Clinical Trial). Mechanistic studies are designed to improve the understanding of the mechanism of action of the intervention or the pathogenesis of the disease. In addition to assessing practical questions about the intervention, such as whether the targeted cell or molecule has been affected, these studies should be designed to address fundamental questions about human immunology.

Clinical Projects developed by the ACE should be innovative and propose clear, testable hypotheses on underlying immune mechanisms. Mechanisms of interest include the intervention, the disease, and fundamental immunity. The proposed Clinical Projects may aim to generate initial evidence of efficacy and mechanism, using resources appropriate to the scope of the ACE network. A Clinical Project may not be shared between applications to this FOA. Only unique Clinical Projects will be selected for funding. Applicants may propose collaborations with other investigators (who may also be applicants), but the complete Clinical Project must be contained within a single application

Types of trials that may be proposed include but are not limited to the following:

• Combinations of approved drugs;
• Comparative effectiveness research using approved drugs;
• Repurposing drugs approved for other indications, based on the understood mechanism of the drug;
• Use of unapproved drugs with evidence of strong collaboration and endorsement from pharmaceutical partners though it is not the purpose of the ACE to support critical path development for industry;
• New tolerogenic and immunomodulatory approaches using individual or combined therapies including cellular therapies to treat or prevent autoimmune disease; and
• Novel approaches to therapy applying advances in fundamental immunity and biology, such as gene therapy, regulating gene transcription (epigenetics, methylation, acetylation), RNA metabolism (splicing, stability, miRNA, RNAi), antigen receptors or Natural Killer (NK) inhibitor receptors (KIR), lymphocyte subsets, dendritic cells, cytokines, chemokines, proteins mediating signal transduction (immune synapse, intracellular pathways), and the microbiome.

Clinical Projects of particular interest to the ACE include, but are not limited to the following:

• Pathogenesis of human autoimmune disease;
• Mechanisms responsible for the initiation, maintenance, or loss of immune tolerance;
• Understanding existing therapies, including mechanism of action and why they may work better in subsets of patients;
• Understanding sex-based differences in autoimmune disease;
• Identification and evaluation of biomarkers for autoimmune disease status, including diagnosis, prediction or confirmation of remission or relapse, and measurement of therapeutic response or disease progression; and
• Stratification of patients into groups that benefit or not from particular therapies, accompanied by mechanistic studies to determine why this is so.

Applications proposing the following for Clinical Projects will be considered non-responsive and will not be reviewed:

• Mechanistic studies within industry-supported clinical trials;
• Non-interventional clinical studies;
• A clinical trial whose primary goal is to enable licensing;
• Research using animal models of human disease ("humanized" animals are not permitted);
• Projects without integrated mechanistic studies;
• Projects focused on primary immune deficiency or cancer (though studies of autoimmunity including these patient populations are responsive);
• Projects focused on HIV/AIDS;
• On-going clinical trials;
• Projects that do not investigate autoimmune disease in humans.

Collaborative Project: This Project may use samples from previously completed clinical trials or studies, but it may not support a clinical trial. Collaborative projects must be related to the overarching theme of the applicant's proposed Center.

Specific areas of interest for Collaborative Projects include, but are not limited to:

• Pathogenesis of human autoimmune disease;
• Mechanisms of action of existing therapies for autoimmune disease;
• Biomarkers for autoimmune disease status, including diagnosis, disease progression, prediction of remission or relapse, therapeutic response, and stratification;
• Sex-based differences in autoimmune disease;
• Mechanisms responsible for the initiation, maintenance, or loss of tolerance;
• Cellular diagnosis or cell therapy, including adult stem cells, regulatory B and T cells, and antigen-presenting cells;
• Single-cell or clonal analysis of genetic variation (including epigenetic) contributing to autoimmunity;
• Influence of histocompatibility genes (e.g., HLA) on autoimmunity; and
• Novel mechanistic approaches to therapy applying advances in fundamental immunity and biology, such as gene therapy, regulating gene transcription (epigenetics, methylation, acetylation), RNA metabolism (splicing, stability, miRNA, RNAi), antigen receptors or Natural Killer (NK) inhibitor receptors (KIR), lymphocyte subsets, dendritic cells, cytokines, chemokines, proteins mediating signal transduction (immune synapse, intracellular pathways), metabolomics and the microbiome.

Applications proposing the following for a Collaborative Project will be considered non-responsive and will not be reviewed:

• Large scale epidemiology;
• Research using animal models of human disease ("humanized" animals are not permitted);
• Clinical trial;
• Projects focused on primary immune deficiency or cancer (though studies of autoimmunity including these patient populations are responsive);
• Projects focused on HIV/AIDS;
• Collaborative Projects that do not investigate autoimmune disease in humans.

A Clinical ACE application must include two Clinical Projects (Primary and Alternate), a Collaborative Project, an Administrative Core, and an ACE Funds Management Core. These elements are described below:

Administrative Core: The administrative core is responsible for providing overall leadership to the Center, including management, coordination, and oversight for the Center activities.

ACE Funds Management Core (AFMC): This core will administer, on behalf of the entire ACE, two funds: the Clinical Project Fund for support of the Clinical Projects and the Collaborative Research Fund for support of the Collaborative Projects and additional studies required for achieving the aims of the ACE Research Agenda. One of the applicants will be selected by NIAID after award to administer the AFMC. Clinical and Collaborative Projects will be funded through the recipient of the ACE Funds Management Core.

Clinical Projects: Each Clinical ACE must propose two Clinical Projects:

• Primary Clinical Project;
• Alternate Clinical Project.

Both Clinical Projects should be ready for implementation soon after award. The Primary and Alternate Clinical Projects must address different diseases and have different leaders, though both projects may be within one clinical specialty. The Clinical Projects will be phased for development based on peer review and programmatic assessment, independent of the designation Primary or Alternate. Neither Clinical Project may include mechanistic studies within industry-supported clinical trials.

Development of the Clinical Projects will begin as soon as possible after award and will involve the ACE in the design and performance of the clinical trial and the mechanistic studies. The ACE is committed to developing and implementing one Clinical Project from each ACE Clinical Program, either the Primary or the Alternate Clinical Project. A second trial will be developed only if resources permit.

Collaborative Project: The Collaborative Project should be designed to test at least one specific hypothesis on the nature of human autoimmunity, exploit particular strengths of the applicant, and engage other members of the ACE after award. The goals should exceed the reach of a single Center and produce a greater-than-additive return. It is recognized that applicants will NOT know in advance with whom they will be collaborating because the members of the ACE will not be known before award; therefore, applicants should make reasonable assumptions as to the types of collaborations that will be available and build flexibility into their research plans. The ACE will fully develop the Collaborative Projects after award and they should be designed to become part of the ACE Research Agenda (see below). Collaborative Projects may be expanded or reduced after award, depending upon how well they are ultimately integrated within the ACE.

The ACE will coordinate the activities of the Clinical and Basic Research programs through the following elements:

Steering Committee: A Steering Committee will be formed with the PDs/PIs of the Basic and Clinical Research programs. The Steering Committee will have responsibility for collaboratively formulating the ACE Research Agenda, and for helping develop, finalize, and implement Clinical and Collaborative Projects.

ACE Research Agenda: The Steering Committee will formulate an ACE Research Agenda that includes overarching themes, goals, and approaches for the period of award. The Agenda will incorporate the best themes and goals from the individual Centers as well as the Clinical Projects and the Collaborative Projects. The Research Agenda of the current ACE cycle and their annual progress reports are posted on the public ACE website. The ACE will be responsible for on-going "legacy" Clinical Projects.

Plenary Meeting: The ACE will convene an annual plenary meeting, preceding one of the twice-annual face-to-face Steering Committee meetings, to exchange information and develop collaborations among the investigators. All key personnel, including project leaders, are expected to attend and participate by presenting the aims, status and highlights of their projects.

Resources Provided by NIAID

Statistical, Data Management, Site Monitoring, and Operations Support: NIAID will provide statistical, data collection and management, site monitoring, and clinical trial operations support through a separately-funded Statistical and Clinical Coordinating Center for Autoimmune Diseases Group (SACCC ADG) grant. Clinical product support will be provided as needed through the NIAID Division of Allergy, Immunology, and Transplantation (DAIT) Clinical Products Center (CPC). NIAID provides information and guidance for NIH funded clinical research in Research Rules & Policies, which includes a Clinical Research Toolkit, Guidance for the management and use of drugs is also provided within the linked DAIT Pharmacy Manual.

Note: For more information, please refer to the Questions and Answers web site for this FOA.

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 not allowed.

Applicant Organizations

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

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

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

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

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.

An individual may serve as PD/PI on an application to either this Clinical ACE program FOA or the companion Basic ACE program FOA (RFA-AI-18-002) but not both. An individual may serve as Project Leader or in another role (non-PD/PI) on applications to both FOAs.

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).

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

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

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

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

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

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

The letter of intent should be sent to:

Zhuqing "Charlie" Li, Ph.D.
Telephone: 240-669-5068
Fax: 301-480-2408
Email: liz@niaid.nih.gov

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

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

Section A. Overview of the proposed ACE Clinical Research Program--12 pages

Section B. Administrative Core--6 pages

Section C. ACE Funds Management Core--6 pages

Section D. Primary Clinical Project--12 pages

Section E. Alternate Clinical Project--12 pages

Section F. Collaborative Project--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 instructions:

Facilities & Other Resources

Describe the availability of all special services needed to complete the trial (e.g. investigational pharmacy, PET scanner facilities).

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

Each Clinical Research Project and Core must be led by one person; co-leaders of projects or cores are not allowed. A PD/PI may lead no more than one of the proposed Projects. The PD/PI (or one of the PDs/PIs if multiple PDs/PIs) should also lead the Administrative Core.

Describe the experience of the investigators in developing and conducting collaborative research and highlight any participation in clinical trials with mechanistic studies. Include the investigators' experience in clinical trials in the proposed study area and participation in investigator-initiated clinical trials. List accomplishments and describe the synergies and collaborations that occurred.

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

In the budget justification, provide budget breakouts for the individual Center elements; i.e., Administrative Core, ACE Funds Management Core, and Projects (Primary and Alternate Clinical Projects and the Collaborative Project).

Administrative Core:

Applicants may request up to $50,000 direct costs per year. Applicants must request at least 1.2 person months effort by the PD/PI (or 1.2 person months in total for multiple PDs/PIs). Additional effort may be requested within the relevant Clinical and Collaborative project(s). Funds must be budgeted for the PD(s)/PI(s) to attend the twice-yearly Steering Committee face-to-face meetings, one of which will overlap with the annual ACE plenary meeting, and for the PD(s)/PI(s) and all Project leaders to attend the annual ACE plenary meeting. Both meetings will be held in the Bethesda MD area.

ACE Funds Management Core (AFMC):

The ACE Funds Management Core application budgets must include the following costs:

• The proposed budget for administrative costs for the AFMC is capped at $250,000 annual direct costs. Direct costs to include:
• A minimum of 1.2 person months PD/PI effort as the AFMC Leader.
• A minimum of 6 person months salary for an AFMC administrator and a maximum of 6 person months for Information Technology staff (if required by the AFMC) to be included in the Other Personnel category.
• IT computing services, if required by the AFMC.
• The AFMC will support ongoing "legacy" Clinical Projects in addition to new Clinical Projects and Collaborative Projects.
• The AFMC should plan to issue consortium agreements with up to approximately $3.2M in direct costs annually for all costs related to Clinical Projects and Collaborative Projects. For the purpose of the application, assume 100 consortium agreements with 50 different sites and that each site invoices at least $25,000 per year. The costs may be included in the Other Expenses category because all consortium agreement expenses will be unknown to applicants.
• Travel for either the AFMC administrator or staff member to attend one of the two annual "face-to-face" Steering Committee meetings in the Bethesda/Rockville, Maryland area.

Clinical Research Projects:

Clinical Projects are expected to require support for between 2 and 5 years with a maximum of $700,000 direct costs per year. Applicants may request support to complete development of the Primary Clinical Project in the first half year of award, followed by the full costs of implementation. The full costs of the Clinical Projects approved for development will be paid by the Clinical Project Fund that will be awarded separately to the AFMC. Budgets should be based on per-patient costs and include the other costs of performing the trial (clinical research tests, coordinator and PD/PI time, proposed study intervention costs, including drug costs, if applicable, pharmacy costs, mechanistic study costs, etc.).

The costs for data collection and management, statistical support and monitoring, and other costs associated with trial management will be borne by the Statistical and Clinical Coordinating Center for Autoimmune Disease Group (SACCC ADG). Full development will begin soon after award, with the involvement of the other ACE grantees and the help of NIAID and SACCC staff. After award, additional funds to support the development and implementation of clinical trials and associated mechanistic studies may be provided by the Clinical Project Fund.

Collaborative Project:

Applicants may request up to $150,000 annual direct costs for 5 years. The budget should include the anticipated costs of the proposed collaborations. Funding levels will be determined post-award and will be guided by the final form of the ACE Research Agenda. Funds for the Collaborative Project will be provided by the ACE Funds Management Core, once that has been established.

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: Briefly introduce and describe the approach of the Center to autoimmune disease research and therapy, specifically including the:

(1) theme and overall goals of the Center,

(2) most important questions in autoimmune disease research and therapy, and

(3) how the questions will be answered (outline here, provide details in the projects).

Research Strategy: The Research Strategy section must consist of sections A-F as designated below.

Section A. Overview of the Proposed ACE Clinical Research Program

In this narrative section, summarize the overall research strategy for the application and explain how the proposed Center satisfies the purpose and objectives of this FOA to accelerate the discovery and translation from lab to clinic of therapies for autoimmune diseases.

Describe how the proposed Primary and Alternate Clinical Projects and the Collaborative Project fit under the overarching Center theme. Explain how the Center addresses key roadblocks in the development of treatments for two different autoimmune diseases. Each project in this application must have its own scientific merit and complement the others. This section is an opportunity for the investigators to give conceptual wholeness to the overall program by stating the general problems and by presenting a comprehensive strategy for solving them. As the strategy develops, the projects and core should be placed in the overall scheme. Describe how the individual research projects and core coordinate and synergize towards fulfilling the central theme and objectives of the Program. Include a description of the advantages the proposed Center will gain from participating in the ACE Program and what the Center will contribute to the overall group.

Renewal applications may propose to renew and continue on-going Collaborative projects or else to begin entirely new research projects. On-going Clinical Projects cannot be proposed as renewals but will be continued to completion as 'legacy' projects. For research projects that will be continued as part of a renewal application, provide additional details in the progress report section of the Research Strategy within the appropriate research project.

Advisory Committee (optional): For applicants proposing to appoint an advisory committee, describe the expertise and responsibilities of the potential committee members. For new applications, do not name or contact potential members. For renewal applications, provide the names of current and former members.

Leadership Succession Plan: Briefly present your plan in the case the PD/PI moves to a different institution or is for any reason unable to continue as leader of the program.

Section B. Administrative Core

• Provide a Staffing and Administrative Plan for the program that includes a discussion of the structure and roles of administrative and scientific staff, the functions to be performed, and how resources will be prioritized, allocated and managed.
• Provide overall milestones, timelines and performance objectives for the program, which should include all Core activities.
• Provide a management plan for fiscal accountability and communication within the Center.

Section C. ACE Funds Management Core (AFMC)

List in priority order the proposed activities and services of the AFMC. The ACE Funds management plan must include:

• an administrative structure and plans for staffing;
• plans to negotiate, write, review, revise as needed, execute, and administer budgets and consortium agreements;
• a description of a draft template for Clinical Project consortium agreement budgets.
• plans to receive, review, revise as needed, approve and pay invoices in a timely manner;
• plans to identify and resolve problems;
• plans for accountability and communication with the Steering Committee and with NIAID;
• a description of a draft template of a quarterly report to NIAID on the status of the Clinical Project and Collaborative Project Funds.
• IT support for the maintenance and/or development of an internal website, if required.

Sections D and E: Primary and Alternate Clinical Projects.

Describe both the Primary and Alternate Clinical Projects in separate sections, based on the following instructions (Section D: Primary; Section E: Alternate). Note that for each clinical trial, applicants will provide specific information in a matching PHS Human Subjects and Clinical Trials Information (Study Record) section which should not be duplicated in the Research Strategy section. Each Clinical Project must have matching PHS Human Subjects and Clinical Trials Information section (Study Record).

Introduce the hypothesis or hypotheses to be tested in the Clinical Project and outline the approach to testing the hypothesis/hypotheses. Explain the importance of anticipated results, alternative results, and approaches to the interpretation of results (e.g., what anticipated results support or disprove your hypothesis?). In addition to stating the biological and clinical significance of the research, indicate the project's relevance to the theme of the application.

This section should include:

• Background summaries of the studies that led to this proposed clinical trial and information or data from preliminary studies that address the need for and the feasibility of the trial;
• Explanation of the significance of the problem being studied and the potential impact of the results of the trial and the mechanistic studies, as well as how the trial and studies will test each hypothesis;
• Research plan for the mechanistic studies with justification, preliminary data, and approach;
• Description of the study organization and administration, including, but not limited to: a description of committee structures needed to manage the complexity of the trial; the oversight, responsibilities, and coordination of any sites or cores proposed; and the role of any sub-contractors or service providers for personnel or facilities. If an advisory committee is planned, applicants should not contact or name potential advisory committee members.

Section F. Collaborative Project

Describe and explain the strategy to test the proposed hypothesis or hypotheses for the Collaborative Project. Outline the approach and explain the rationale for selecting the methods proposed to test the hypothesis/hypotheses. In addition to stating the biological and clinical significance of the research, indicate the project's relevance to the theme of the applicant's proposed Center and how it relates to other projects. Since applicants will not know in advance what other ACE Centers may be funded, applicants may consider proposing projects that start from their own specific expertise and disease focus and later seek to generalize observations and mechanisms to other autoimmune diseases. This could be accomplished with collaborators who have complementary strengths and skills. The Collaborative Project must be coherent, but it may lack some details if they can be reasonably developed with additional ACE collaborators after award. The Collaborative Project must include a research proposal for the entire project period and plans for formulating annual benchmarks for evaluating progress on the research project.

The ACE will fully develop the Collaborative Projects after award and they should be designed to become part of the ACE Research Agenda. Collaborative Projects may be expanded or reduced after award, depending upon how well they are ultimately integrated within the ACE.

Letters of Support

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 individuals who have the authority to make fiduciary commitments on behalf of the institution. 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 or as Estimated Project Funding.

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.
• All investigators funded under this FOA will be expected to share their data publicly through ImmPort or other public portals approved by NIH. Therefore, the Data Sharing plan should include a summary of how the applicant will manage data submission and interactions with ImmPort, or other NIH-approved public portal.

Appendix:

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

Applicants must include the following:

• As the first attachment, for the Primary Clinical Project, attach the draft "Primary Clinical Project - Clinical Trial Protocol".
• As the second attachment, for the Primary Clinical Project, attach the draft "Primary Clinical Project - Informed Consent Form"(s) and, if applicable, draft "Assent Form"(s).
• As the third attachment, for the Alternate Clinical Project, attach the draft "Alternate Clinical Project - Clinical Trial Protocol".
• As the fourth attachment, for the Alternate Clinical Project, attach the draft "Alternate Clinical Project - Informed Consent Form"(s) and, if applicable, draft "Assent Form"(s).
• As the fifth attachment, for the AFMC, attach a file named "Clinical Trial Budget Template" showing a draft template for budgets supporting Clinical Project consortium agreements.
• As the sixth attachment, for the AFMC, attach a file named "Quarterly Funds Report" showing a draft template for reporting to NIAID the status of Clinical Project and Collaborative Project funds.

Investigators are referred to the Trans-NIAID Clinical Research Toolkit website for clinical protocol guidance and templates (https://www.niaid.nih.gov/research/trans-niaid-clinical-research-toolkit ). Investigators are urged to be succinct.

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

For studies involving the use of identifiable human biospecimens collected from independently funded clinical research or clinical trials, applicants should include both historical and current study information that is clearly distinguishable within the information requested in the study record forms.

Section 2 - Study Population Characteristics

2.5. Recruitment and Retention Plan

Attach a document that describes the following:

• The availability of the overall research population. Include a discussion of the standard of care alternatives to trial participation and likelihood of acceptance by study populations of the proposed interventions (e.g. intravenous administration, required hospitalization, or requirement for procedures such as biopsies, bronchoscopies or repeated imaging).
• The competing clinical trials underway in the community and their potential influence on recruitment;
• The interventions with similar mechanism of action currently under development and their potential influence on the availability of potential eligible study participants and expected enrollment goals for each site over the period of the proposed trial;

2.7. Study Timeline

Describe a series of milestones for completion of the clinical trial and provide contingency plans should there be delays in attaining them. This section must include timelines for, as applicable:

• Completion of regulatory approvals;
• Enrollment of the first subject;
• Enrollment of 25%, 50%, 75% and 100% of the projected recruitment time period for all study subjects, including women, minorities and children (as appropriate);
• Completion of data collection time period;
• Completion of primary endpoint and secondary endpoint data analyses time period;
• Completion of final study report; and
• Any protocol-specific milestones.

Section 4 - Protocol Synopsis

4.1 Brief Summary

In the brief summary of the protocol, clearly state the study hypothesis.

4.2 Study Design

4.2.a Narrative Study Description

In a synopsis of the protocol, include descriptions of the following:

• The study design, including a discussion of potential biases or challenges in the protocol and how they will be addressed, a brief overview of procedures without duplicating information in section 3.1 Protection of Human Subjects, and evaluations.

4.2.c Interventions

The description of the intervention should include the availability of the proposed study intervention and schema showing the schedule of interventions.

4.4 Statistical Design and Power

Attach a description of the plans for how the statistical analysis will be designed, as well as clarify the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis(es) being tested. This plan is critical to knowing whether applicants have selected the correct cohort size based on proper power calculations and/or are using the most appropriate methods to analyze the resulting data and make correct conclusions at the end of the study. The ability to make conclusions of primary outcomes other than safety will be particularly important in small studies. The final Statistical Analysis Plan will be developed by the ACE and SACCC after award.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

Provide a description of the plans to implement and monitor Good Clinical Practices (GCP), Good Laboratory Practices (GLP) and Good Manufacturing Practices (GMP), as appropriate.

Delayed Onset Study

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

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.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Applicants are required to follow the instructions for post-submission materials, as described in the policy. 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. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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). While each application will be evaluated in its entirety based on one overall impact score per application, the Primary Clinical Trial, the Alternate Clinical Trial, the Collaborative Research project, and the Administrative core within each application will also each receive a separate impact score

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

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the 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 Program scientifically compelling as a whole? Are the overall Program goals significant and focused on studies that accelerate the discovery and translation from lab to clinic of therapies for autoimmune diseases? Will the integration of the individual projects into a single Program be more beneficial than pursuing each project independently?

Primary and Alternate Clinical Projects

Do the proposed Clinical Projects address important clinical questions? Are they likely to result in important clinical or fundamental knowledge? Is there a clear statement of the question(s) that the trial and studies will address? Is sufficient information provided to determine the significance and timeliness of, as well as the need to perform, the trial and studies? Will the results of the mechanistic studies illuminate the mechanism of action or disease pathogenesis? If successful, will the proposed trials benefit health care or our understanding of autoimmunity? In the case of competitive interventions, are they thoroughly and fairly presented, including their clinical and economic advantages and disadvantages?

Collaborative Project

Does the Collaborative Project address an aspect of the Center's theme? Does the Project seek to answer broader questions beyond the abilities of a single Center?

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 Projects exploit the strengths of the applicants? For applications designated multiple PDs/PIs, is the Leadership Plan adequate and appropriate to ensure that there will be sufficient coordination and communication among the PDs/PIs? Is the Leadership Succession Plan adequate and feasible? Have the applicants and collaborators made a significant impact on the field of autoimmune diseases? Have the applicants and collaborators successfully developed and conducted collaborative research projects? Do(es) the PD(s)/PI(s) have the leadership and scientific ability to develop an integrated and focused research Program?

Primary and Alternate Clinical and Collaborative Projects

For all potential site investigators, including the Clinical Project leader, are their professional training and experience appropriate? Is the experience of the PD(s)/PI(s), Clinical Project leaders, and key personnel in directing clinical trials with integrated mechanistic studies adequate and appropriate?

Administrative Core

Is the Staffing and Administrative Plan appropriate for the objectives of the proposed Program? Are the experience, level of commitment, and availability of the Core Leader adequate to manage the overall Program?

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

Primary and Alternate Clinical Projects

Does the applicant propose innovative approaches to reach, recruit and retain a diverse and representative population of patients with autoimmune diseases necessary for ACE Program to have a significant impact for the community of the patients with autoimmune diseases? Does the trial design incorporate a cutting-edge approach(es) to autoimmune diseases therapy or prevention?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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

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

Does the application adequately address Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP) compliance if applicable?

Primary and Alternate Clinical Projects

Are the proposed mechanistic studies insightful and well-integrated into the clinical trial? Are the mechanistic studies hypothesis-driven? Are the full clinical trial protocols, draft consent and, if applicable, draft assent forms appropriate?

Collaborative Project

Does the proposed Collaborative Project have a good probability of establishing useful, productive collaborative investigation?

Administrative Core

Are the plans for coordination, problem identification and resolution and the establishment of a strong collaborative environment for the program appropriate? Are the proposed timelines, milestones and performance objectives for the Core adequate? Is the management plan for fiscal accountability and communication within the Program appropriate?

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

Primary and Alternate Clinical Projects

Are there adequate, available and appropriate clinical facilities and ancillary facilities to provide the clinical care required to support the autoimmune clinical trials? Is there evidence demonstrating strong past institutional performance in autoimmune diseases research? Does the application describe a cohesive structure and range of support services to support autoimmune diseases trials and/or collaborative project research?

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)?

Specific to this FOA

Are the milestones feasible and well justified?

ACE Funds Management Core

Are the administrative structure and plans for staffing appropriate to manage the program funds? Have adequate plans been made to receive, review, and implement budgets and execute consortium agreements? Have adequate plans been made to receive, review, pay invoices, and report status to NIAID in a timely manner? Are the clinical trial budget and quarterly reporting templates appropriate?

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

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

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

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

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

Not Applicable

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 of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as 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 http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

• Advancing and coordinating the activities at their Center, scientifically and administratively;
• One PD/PI from each Center will attend meetings and serve as a voting member of the Steering Committee;
• Participating actively in the formulation and implementation of the ACE Research Agenda;
• Implementing policies approved by the Steering Committee or emplaced by NIAID;
• Providing the SACCC with all clinical study data for management, quality control, and analysis, using procedures and standards determined by NIAID;
• Sharing all data publicly through ImmPort, ImmuneSpace, or other public portals designated by NIAID, as appropriate and consistent with achieving the goals of the program. The PD/PI will establish procedures within the center to ensure that all members of that center, including any scientists added via AFMC support, conform to the data sharing and other resource-sharing plans;
• Complying with the NIAID Clinical Terms of Award. The full policy, including terms and conditions of award, is available at: https://www.niaid.nih.gov/grants-contracts/niaid-clinical-terms-award.

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

• An NIAID Program Officer will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice. NIAID staff assistance will be provided by DAIT Project Scientists along with other NIH staff. They will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination, including participation in periodic on-site monitoring with respect to compliance with Federal regulations, quality control, accuracy of data recording, sample accrual, etc.;
• Facilitate collaborations with and access to other NIAID-supported research resources and
• Services;
• Serve as liaison/facilitator among awardees and with the data portals ImmPort and ImmuneSpace;
• Provide oversight for human subjects protections and provide monitoring for any studies that
• involve more than minimal risk for participants or that involve vulnerable populations;
• Provide assistance to the Steering Committee in the development of procedures for evaluating the performance of research studies and monitoring any Clinical Trials;
• Participate on the Steering Committee as a voting member and coordinate Steering Committee activities and implementation of its recommendations, decisions, and policies;
• Share information regarding promising new agents, strategies, and developments when appropriate;
• Identify scientific gaps and organize meetings to facilitate exchange of scientific and regulatory information, including during meetings;
• Oversee resources that:
• provide statistical and data management support,
• provide regulatory support services,
• conduct external site monitoring, and
• manage and distribute investigational agents.
• Participate in the presentation of research results, including publications;
• Oversee clinical site operations to include development of template informed consent documents as well as site specific consents for IRB submission, operational activation of ACE clinical sites, and review and evaluation of site monitoring reports.

Trial Sponsorship. NIAID staff will have the option to independently file an IND on investigational agents or an IDE on investigational devices evaluated in NIAID-supported clinical studies. NIAID will advise the investigators on the specific regulatory requirements for IND sponsorship. In situations where NIAID is the IND sponsor, NIAID through its contractors will also assemble, review, and submit the required regulatory documents to the FDA. When holding an IND or IDE, NIAID has responsibility for the reporting of safety information in accordance with FDA requirements and preferences. In order to provide for consistent reporting of serious adverse experiences across the NIAID-supported clinical trial Networks, NIAID will provide current policies and procedures that govern the reporting of adverse events in NIAID-supported trials. Final disposition of serious adverse event (SAE) reports will be decided by NIAID staff for all IND studies held by NIAID.

Trial Monitoring. NIAID staff will oversee clinical site monitoring that evaluates GCP, regulatory compliance, protocol implementation, internal quality assurance, and test article accountability at the network clinical sites. The site monitors, with or without accompanying NIAID staff, will visit ACE clinical sites periodically to review selected protocols, provide training on general protocol conduct, review internal QA/QC plans, and audit pharmacies.

Protocol review. NIAID staff will review all protocols and approval is required for initiation. The Program Scientist or designee will return comments and recommendations to the ACE protocol team after review. The protocol team must address in writing all safety, regulatory, ethical, and conflict of interest concerns raised by NIAID to the satisfaction of NIAID before participant enrollment can begin. If a protocol is disapproved, NIAID will not provide investigational products or permit expenditure of NIH funds for the proposed investigation. If a protocol is not initiated within twelve months of NIAID approval, re-review and approval by NIAID will be required.

Safety Monitoring. NIAID staff will participate in the development of appropriate safety monitoring plans for all planned clinical trials and must approve the plan for all trials involving investigational drugs, devices, biologics, or other clinical interventions. The frequency and intensity of safety monitoring will be based on individual study characteristics and past experience with study products and may require review by an Independent Safety Monitor, Safety Monitoring Committee (SMC) or Data and Safety Monitoring Board (DSMB). NIAID Medical Monitors will be part of the organized protocol safety review teams to monitor the safety and efficacy of the intervention(s) for ongoing studies, and will be provided with appropriate reports. Approval of the final monitoring plan, including the composition of the review committee, by NIAID is required prior to study initiation. NIAID independently supports Data and Safety Monitoring Boards (DSMB) that oversee clinical trials at the discretion of NIAID.

Clinical Study Termination. NIAID staff reserves the right to terminate or curtail a clinical study for any reason. Examples include, but are not limited to, risks to subject safety, failure to achieve recruitment goals, and reaching a major study endpoint substantially before schedule with persuasive statistical significance.

Clinical Data Access. NIAID has the right of access to all clinical data generated (raw and analyzed) and may periodically review it. This includes data as recorded on the case report forms and in the central databases, and external checking against the original source documentation as required by federal regulation and NIAID as the IND sponsor. NIAID staff may request from ACE protocol teams specific data analysis needed for programmatic activities or for issues related to NIAID plans with other partners.

Areas of Joint Responsibilities include:

Steering Committee

A Steering Committee will serve as the coordinating body for the ACE research program. It will be formed by a single PD/PI from each ACE U19 and each ACE UM1 and representatives from the SACCC and from NIAID. It will be chaired by a PD/PI chosen by a majority vote of the Steering Committee, with terms determined by the committee. Each member of the Steering Committee will have one vote. The SACCC and NIAID representatives will be voting members, but will not serve as the Chair of the Steering Committee. All participants in the ACE program are bound by the policies and procedures developed by the Steering Committee.

The Steering Committee responsibilities include:

• Composing soon after award an ACE Research Agenda establishing goals and priorities for the entire program term. The Agenda will be based on the Clinical and Collaborative Projects but may include additional plans in order to foster collaborations among all of the members of the ACE. The Agenda will include but is not limited to the following items:
• Overall goals and Specific Aims,
• Clinical and Collaborative Projects to be initiated within the coming year, and
• Benchmarks and Timelines for accomplishing the work.
• Composing an annual collaborative group report and posting it along with the ACE Research Agenda on the public ACE website (www.autoimmunitycenters.org);
• Helping to develop and implement the Clinical Projects, including the associated mechanistic studies and the Collaborative Projects;
• Determining how data from multiple Centers collaborating on a study will be shared and analyzed: investigators wishing to perform their own analysis of local data or of single site studies must obtain approval for the planned analysis from the Steering Committee;
• Developing policies for use of the ACE Clinical Project Fund and the Collaborative Research Fund;
• Establishing procedures for reporting results of ACE trials/studies, including composing and approving a Publications Policy governing the initial public release of ACE clinical trial-related information;

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 arbitration. An Arbitration Panel composed of three members will be convened. The members shall be: (1) one designee of the Steering Committee chosen without NIH staff voting, (2) one NIH designee, and (3) one designee with expertise in the relevant area who is chosen by the other two members. In the case of individual disagreement, the first member may be chosen by the individual awardee. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulations 42 CFR Part 50, Subpart D and HHS regulations 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 registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)

Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

Email: support@grants.gov

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

David Johnson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-496-7104
Email: DRJohnson@niaid.nih.gov

Zhuqing "Charlie" Li, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5068
Email: liz@niaid.nih.gov

Cheryl Y. Wall
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2956
Email: wallcy@niaid.nih.gov

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.