Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Allergy and Infectious Diseases (NIAID)
Funding Opportunity Title	Targeting Inflammation and Immune Activation in HIV Disease (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	None
Funding Opportunity Announcement (FOA) Number	RFA-AI-12-007
Companion FOA	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.855; 93.856
FOA Purpose	This FOA solicits applications that propose small proof-of-concept clinical trials, with concurrent intensive laboratory studies, designed to evaluate the effect of an intervention on chronic immune activation or persistent inflammation in HIV-infected individuals who are taking effective antiretroviral therapy. The intervention must have a known mechanism of action. The goal of this initiative is to identify specific mechanisms or pathways that can be targeted to prevent or reverse persistent immune activation in HIV-infected individuals.

Posted Date	January 20, 2012
Open Date (Earliest Submission Date)	June 13, 2012
Letter of Intent Due Date	June 13, 2012
Application Due Date(s)	July 13, 2012, by 5:00 PM local time of applicant organization.
AIDS Application Due Date(s)	Not Applicable.
Scientific Merit Review	November, 2012
Advisory Council Review	January, 2013
Earliest Start Date(s)	April, 2013
Expiration Date	July 14, 2012
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the SF 424 (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

Purpose

This FOA solicits applications that propose small proof-of-concept clinical trials with concurrent, intensive laboratory studies to evaluate the effect of an intervention with a known mechanism of action on chronic immune activation and persistent inflammation in HIV-infected individuals on effective antiretroviral therapy. The goal of this initiative is to identify specific mechanisms or pathways that can be targeted to prevent or reverse chronic immune activation in HIV-infected individuals.

Background

Host defense against viral infection necessitates a highly regulated balance between eliminating or reducing the invading pathogen and minimizing damage to the host. The inflammatory response is initiated when triggering stimuli are detected by sensors that translate signals through complex molecular and cellular networks to ultimately mediate the response to affected tissues and systems. Once the inducing stimulus is removed, the acute inflammatory response is normally terminated, inflammation resolved and damaged tissue repaired. During acute HIV infection, the immune system is highly activated as expected, however as infection proceeds to the chronic phase, the inflammatory response is not resolved. This leads to a state of chronic immune activation thought to be central to AIDS pathogenesis. Characteristics of this persistent immune activation include elevated T cell activation and turnover, polyclonal B cell activation and increased levels of pro-inflammatory cytokines and chemokines. Concomitant with activation, there is a progressive loss of CD4+ T cells and an impairment of effector T cell function often referred to as immune exhaustion. Studies in untreated humans and animal models show that the levels of chronic immune activation are strong predictors of disease progression in untreated HIV/SIV infection. While the inducing stimuli of chronic immune activation in untreated infection are likely multi-factorial, ongoing viral replication is likely a primary driver.

While it is clear that the virus plays a central role in untreated infection, less understood are the factors that maintain immune activation during suppressive antiretroviral therapy (ART), which in most patients reduces HIV RNA levels to nearly undetectable levels. Despite the success of ART in significantly prolonging survival and improving quality of life in HIV-infected individuals, studies show that patients on long-term therapy continue to have abnormal levels of immune activation and inflammation. Chronic inflammation is known to be a major driver of disease and data suggest that treated HIV-infected individuals have a shorter life expectancy and are at higher risk for a number of non-infectious co-morbidities than age-matched HIV-uninfected persons. It appears that even in the context of viral suppression, HIV infection has emerged as an independent risk factor for early end-organ disease in the way that genetic and traditional risk factors play a role. While a number of factors including residual HIV replication, microbial translocation, co-infections, loss of immunoregulatory responses, homeostatic proliferation, lymphoid fibrosis, and others have been associated with markers of inflammation and morbidity, the causal contribution of specific mechanisms and pathways to chronic immune activation in treated individuals remains unknown.

Research Objectives and Examples of Research Strategies

Non-infectious co-morbidities of treated HIV disease are a major concern of the U.S. HIV community and a research priority for the Division of AIDS, NIAID. This FOA is intended to stimulate novel clinical trials that will inform the future development of therapeutic interventions to reduce or alleviate co-morbidities associated with chronic immune activation in treated HIV disease. While basic research studies in animal models and HIV-infected individuals have informed many areas of HIV pathogenesis, outstanding questions remain regarding chronic immune activation in HIV infected individuals on fully suppressive ART. For example, in the setting of fully suppressive ART:

• What are the inducers of chronic immune activation and persistent inflammation?
• Which cell types and pathways sense and mediate these signals?
• Are the relevant cells tissue-specific and can they be found in blood?
• Which cells and pathways could promote the resolution of inflammation and how are they affected in chronic HIV infection?
• At which point in the inflammatory cascade is it most feasible to intervene?

A translational research gap exists between basic studies of the biology of chronic inflammation in treated HIV disease and larger scale clinical studies. Small pilot clinical trials testing interventions with known mechanisms of action can be used to elucidate the importance of different activation pathways in HIV disease.

For this FOA, each application must propose one proof-of-concept treatment trial in HIV infected individuals on effective ART. The trial will be conducted at a single site, and it is anticipated that the sample size will be small (50 patients or fewer). The NIAID defines a clinical trial as prospective study of human subjects designed to answer questions about biomedical or behavioral interventions, e.g., drugs, treatments, devices, or new ways of using known treatments to determine whether they are safe and effective. An application that does not fit this definition of clinical trial will be considered non-responsive and will not be reviewed. Patients selected for the study must be on stable antiretroviral therapy with HIV RNA levels consistently below the level of detection by standard clinical assay for a minimum of 12 months prior to initiating the trial. Studies should be hypothesis-driven and designed to investigate the impact of an intervention with a known mechanism of action on parameters of chronic immune activation and persistent inflammation. Concurrent with the trial, it is expected that pathogenesis-oriented research will provide directly relevant data to improve the understanding of mechanisms mediating immune activation and HIV pathogenesis. The proof-of-concept studies should employ surrogate biochemical or physiological endpoints rather than major clinical endpoints for end organ disease. Applications should clearly justify the choice of endpoints used to determine the effect(s) of the intervention and thoroughly describe experiments to investigate pathogenesis. Close interaction between clinical and basic researchers is recommended to promote translation of basic science ideas into the clinical setting and to expand on ideas from clinical observations that can be pursued in the basic laboratory. In this regard, multiple PD(s)/PI(s) are encouraged to maximize the interaction and idea exchange. While trials are limited to a single site, laboratory-based studies that support pathogenesis research may be conducted by an investigator at a separate institution through a consortium agreement. These studies should be well-justified and relate directly to the primary research question.

Within this framework, appropriate areas include but are not limited to interventions that:

• Target inducers of persistent immune activation/inflammation
• Interrupt pathways sensing or mediating inflammation
• Enhance T cell renewal
• Reverse immune exhaustion

Applicants are strongly encouraged to include studies in relevant tissues as well as blood to determine the effect(s) of the intervention on chronic immune activation. Where appropriate, applicants are encouraged to evaluate the effect of the intervention on the viral reservoir.

The following areas will be considered non-responsive and will not be reviewed:

• Trials of broadly immunosuppressant interventions
• Interventions without a clear mechanism of action
• Behavioral research, including development of prevention measures of acceptability, compliance, or other behavioral parameters
• Studies in animal models       
• Studies in persons who can suppress HIV to levels below the limits of detection of standard clinical assays without antiretroviral drugs
• Drug discovery and development programs
• Large scale Phase III efficacy studies

Implementation:

This FOA provides implementation support defined as support for activities related to the conduct of the clinical trial, including, but not limited to:

• training of study personnel;
• enrollment and recruitment of study subjects;
• data collection, management and quality control;
• laboratory work and data analyses;
• study management and oversight;
• establishment of committees to manage the complexity of the trial
• preparation of the final study report; and
• other related post-enrollment activities.

Applicants must propose a time-sensitive, milestone-driven clinical trial and describe the clinical trial stages, criteria for completion of the stages and contingency plans for each stage. Applicants must present a clear plan to acquire the study product(s) for use in the clinical trial. Any anticipated impediments that could require a revision in the timeline must be identified and accompanied by a discussion of alternative approaches. The clinical trial must be hypothesis driven and have clear primary and secondary endpoints. A description of the study population, why it is an appropriate group to study the research question(s) posed, subject eligibility, inclusion and exclusion criteria, and a feasible recruitment and enrollment plan must also be included. A description of anticipated risks associated with the intervention and other aspects of the trial must be included as well as a description of steps that will be taken to mitigate risks. Statistical methods appropriate for the study design, and adequate plans for data and safety monitoring are required. An overview of the state of the science, current status and relevance of the trial, and discussion of the clinical protocol must be presented in the application.

All clinical trial planning activities must be completed by the time of application submission and investigators must be ready to implement the proposed trial shortly after the time of award.

NIAID reserves the right to specify: 1) whether an IND/IDE application should be submitted to an appropriate regulatory agency; and 2) the entity (NIAID, primary awardee, etc.) that will hold the IND/IDE.

Investigators are referred to the DAIDS Clinical Research Policies and Standard Procedures Documents at http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Pages/Default.aspx for protocol templates and guidance and clinical research resources.

Prior to initiation, pilot interventional trials are subject to review by the NIAID/DAIDS Clinical Science Review Committee. Larger scale studies will not be supported under this FOA. 

For additional information about NIAID’s investigator-initiated clinical trial program, please see http://www.niaid.nih.gov/researchfunding/sci/human/pages/iict.aspx.

Milestones:

Delineation of milestones is a key characteristic of the NIAID Clinical Trial Implementation (U01) Cooperative Agreement. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity.

Applications must include a series of milestones for completion of the clinical trial and provide contingency plans should there be delays in attaining them. The milestones will undergo peer review and will be incorporated into the terms of award.

This FOA will NOT support clinical trial planning tasks such as:

• Development of study design
• Identification of collaborators and enrollment site
• Development of the clinical protocol and informed consent
• Development of the statistical analysis plan
• Development of the data management plan
• Development of the Investigator’s brochure or equivalent

Investigators seeking support for the planning and design of clinical trials should refer to the NIAID Clinical Trial Planning (R34) Grant FOA (PAR-10-185).

Special attention must be paid to enabling the trial to get through the administrative processes at a reasonable pace so that the conduct of the study, analysis of data, and dissemination of results are not delayed.

Consultation with NIH Program Staff:

Applicants are strongly encouraged to consult with NIAID as plans for an application are being developed. Early contact provides an opportunity for NIAID to discuss the program scope and goals, and to provide information and guidance on how to develop an appropriate milestone plan. Other aspects of an application that are unique to this program are also discussed. Consultations may include both an introductory call and a conference call with NIAID staff.

Funding Instrument	Cooperative Agreement
Application Types Allowed	New The OER Glossary and the SF 424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	The number of awards is contingent upon NIH appropriations, and the submission of a sufficient number of meritorious applications. NIAID intends to commit $2,300,000 in FY 2013 to fund 2-4 awards.
Award Budget	Application budgets are not limited, but are anticipated to be in the range of $350,000 to $750,000 in direct costs per year and should be in accordance with the actual needs of the proposed project.
Award Project Period	The scope of the proposed project should determine the award period. The total project period may not exceed 5 years.

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

Higher Education Institutions

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

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

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

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 must complete the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. Applicants must have a valid Dun and Bradstreet Universal Numbering System (DUNS) number in order to begin each of the following registrations.

• Central Contractor Registration (CCR) must maintain an active registration, to be renewed at least annually
• Grants.gov
• eRA Commons

All Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must also work with their institutional officials to register with the eRA Commons or ensure their existing eRA Commons account is affiliated with the eRA Commons account of the applicant organization.

All registrations must be completed by the application due date. Applicant organizations are strongly encouraged to start the registration process at least 4-6 weeks prior to the application due date.

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 PD(s)/PI(s), visit the Multiple Program Director(s)/Principal Investigator(s) Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF 424 (R&R) Application Guide.

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

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

NIH will not accept any application in response to this FOA that is essentially the same as one currently pending initial peer review unless the applicant withdraws the pending application. NIH will not accept any application that is essentially the same as one already reviewed.

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

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

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

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 research
• Name, address, and telephone number of the PD(s)/PI(s)
• Names of other key personnel
• Participating institutions
• Number and title of this funding opportunity

The letter of intent should be sent to:

Peter R. Jackson, Ph.D.
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases (NIAID)
Room 3133, MSC-7616
6700-B Rockledge Drive
Bethesda, MD 20892-7624
Telephone: (301)-496-8426
FAX: (301)-480-2310
Email: [email protected]

The forms package associated with this FOA includes all applicable components, mandatory and optional.  Please note that some components marked optional in the application package are required for submission of applications for this FOA. Follow all instructions in the SF424 (R&R) Application Guide to ensure you complete all appropriate optional components.

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

Milestone Plan and Complete Clinical Protocol

A Milestone Plan and Complete Clinical Protocol must be included as a separate pdf attachment to item #12 of the Other Project Information component of the SF424 application and will not count toward the page limit for the Research Plan.  Applications that lack the Milestone Plan or the complete clinical protocol will not be reviewed. Special attention must be paid to enabling these important studies to get through the administrative processes at a reasonable pace so that the conduct of the study, analysis of data, and dissemination of results are not delayed.

Milestone Plan

Applicants are required to provide detailed project performance and timeline objectives in a section entitled Milestone Plan . This section may not exceed 3 pages and must include:

• a timeline for the following general milestones, 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
• detailed protocol-specific performance milestones and timeline; these milestones will be negotiated at the time of the award, if appropriate.

Complete Clinical Protocol

The Complete Clinical Protocol must be included as a separate pdf file immediately after the Milestone Plan. Investigators are referred to the DAIDS Clinical Research Policies and Standard Procedures Documents at http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Pages/Default.aspx for clinical protocol guidance and templates. Investigators are urged to be succinct.

Certification of IRB approval for the proposed clinical protocol will not be required prior to review or prior to award, (note: IRB approval of the overall grant is required prior to award). However, protocols need to be well developed with the necessary regulatory and other approvals in place or underway so that the clinical trial can be initiated shortly after award. Applicants need not have their clinical protocols reviewed by a Scientific Review Committee also known as a Protocol Review Committee at their institution prior to submission, however, since approval by this Committee is needed prior to award, the clinical protocol should be well developed at the time of application submission.

For products that are not FDA approved, sufficient preclinical/toxicity, and manufacturing data must exist to support an Investigational New Drug application (IND). Although these data do not need to be made available for review at the time of application, they are required to be available prior to implementation of the trial, therefore the application should indicate that they are available, whether from the applicant directly or from a third party (e.g. company). If these data will be supplied by a third party, a letter of agreement from that party stating willingness to supply these data should be included as a separate pdf attachment in the appendix. Applicants will be expected to complete the requirements for regulatory filing, e.g., an IND application or Investigational Device Exemption (IDE) application, prior to or within 6 months of the award; the status of discussions with the FDA should be documented in the application.

R&R Budget Component:

This FOA uses non-modular budget formats described in the PHS 398 application instructions (see http://grants.nih.gov/grants/funding/phs398/phs398.html).

Because all applications must include detailed scientific and operational plans, funding needs for the entire trial and data analysis period must also be included. Investigators must submit a complete, justified, individual budget for each year of support requested. All costs requested and all changes in budgets after the first year should be clearly identified and justified. Separate itemized budgets must be prepared for each subcontract and/or for each collaborating site or core, if multiple sites or cores are proposed. If parts of the costs of the trial are to be borne by sources other than NIH, these contributions must be presented in detail along with 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.

Further information concerning budget preparation may be obtained from the Office of Grants Management contact listed in Section VII. 3. Financial/Grants Management Contact(s).

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

Specific Aims

The hypothesis(es), goals and expected outcome(s) of the trial should be concisely stated in the

Specific Aims section which is limited to 1 page. Specific attention should be given to the rationale for the proposed intervention, its mechanism of action and how the intervention is hypothesized to affect parameters of chronic immune activation in infected individuals who are taking effective antiretroviral therapy. Applicants should specify the primary and major secondary endpoints to be measured in the trial with a brief explanation of their value in determining the effect(s) of the intervention on chronic immune activation in HIV-infected individuals who are taking effective antiretroviral therapy.

Research Strategy

The Research Strategy includes the Significance, Innovation, and Approach sections. The Research Strategy may not exceed 12 pages and should include:

• a clear hypothesis(es) stating the proposed mechanism by which the intervention will affect chronic immune activation in HIV-infected individuals who are taking effective antiretroviral therapy;
• a clear rationale for the proposed intervention that incorporates its specific mechanism of action, a discussion of studies that led to the proposed trial and information from preliminary studies that address the need for and feasibility of the trial;
• a clear plan for how the study product for the clinical trial will be obtained;
• a description of, and a rationale for the proposed study design with emphasis on how the trial will clearly test the stated hypothesis(es);
• a thorough justification of the chosen endpoints used to determine the effect of the intervention on chronic immune activation in HIV-infected individuals who are taking effective antiretroviral therapy;
• a concise description of the overall strategy, methodology and analyses to be used to accomplish the goals and specific aims of the trial;
• a justification of the proposed experiments to investigate pathogenesis and how they relate directly to the primary research question;
• if appropriate, a discussion of how the proposed studies will evaluate the effects of the intervention in relevant tissues that may drive chronic immune activation;
• if appropriate, a discussion of how the proposed intervention may affect the viral reservoir;
• a description of the protocol to be followed in each arm of the trial, including a discussion of potential biases or challenges in the protocol and how they will be addressed;
• a description of the study population and why it is an appropriate group to study the research question(s) posed;
• a description of the anticipated risks and a plan for how they will be minimized;
• statistical methods that are appropriate for the study design, including sample size and power calculations and the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis(es) being tested; and
• a description of the study organization and administration

Requirements for the Human Subjects Section

Instructions in the PHS398 Part II Supplemental Instructions for Preparing the Protection of Human Subjects Section of the Research Plan should be closely followed.

Data and Safety Monitoring (DSM) Plan

A Data and Safety Monitoring (DSM) Plan that is commensurate with the risk level of the proposed clinical research must be included for all clinical trials (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html). All applications or study protocols must include a general description of the monitoring plan, policies, procedures, responsible entities, and approaches to identifying, managing and reporting reportable events (adverse events and unanticipated problems), to the applicable regulatory agencies (e.g., Institutional Review Board (IRB), the NIAID/NIH, the Office of Biotechnology Activities (as appropriate), the Office of Human Research Protections, the Food and Drug Administration, and the Data and Safety Monitoring Board (if one is used)). The DSM Plan must address the following areas:

• who will be responsible for overseeing and conducting the monitoring
• what will be monitored
• proposed monitoring time points
• how adverse events, serious adverse events and unanticipated problems will be managed and reported

The application should also include a description of how the clinical research site and participating facilities (lab, pharmacies) will be monitored. Although it is not required at the time of application, the development of a Site Quality Management Plan will be required prior to implementation of the clinical trial. Investigators are referred to the DAIDS Clinical Research Policies and Standard Procedures Documents http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Pages/Default.aspx for guidance related to clinical sites.

Resource Sharing Plan

Individuals are required to comply with the instructions for the Resource Sharing Plans (Data Sharing Plan, Sharing Model Organisms, and Genome Wide Association Studies (GWAS)) as provided in the SF424 (R&R) Application Guide, with the following modification:

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

Appendix

Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide, with the following modifications:

The following additional documents must be included in the Appendix material:

• the informed consent form(s) and, if applicable, assent form(s)
• the regulatory statistical analysis plan
• identification and qualifications of clinical trial site, pharmacies and laboratories
• the Investigator’s Brochure or equivalent for the study products(s)
• the Table of Contents of the Manual of Procedures
• a comprehensive Laboratory Plan
• documentation of availability of study agents and support for acquisition and administration of study agent(s)
• the Data Management Plan

Part I. Overview Information contains information about Key Dates. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission.

Organizations must submit applications via 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.

Applicants are responsible for viewing their application 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 SF 424 (R&R) Application Guide.  Paper applications will not be accepted.

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

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

Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF 424(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.

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 Central Contractor Registration (CCR). Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

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

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-10-115.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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

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

Significance

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

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or New Investigators, or in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD(s)/PI(s), do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Is the proposed effort of the PD(s)/PI(s) sufficient for the proposed research plan?

Innovation

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

Approach

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

If the project involves clinical research, are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Does the application present one or more clear, well-reasoned hypotheses stating the proposed mechanism(s) by which the intervention will affect chronic immune activation in HIV-infected individuals who are taking effective antiretroviral therapy? Is there an appropriate and feasible approach for testing the hypothesis(es)? Is there an adequate justification for the proposed intervention that incorporates the specific mechanism(s) of action? Do adequate preclinical or clinical data exist to justify the proposed intervention(s)?

Does the application include appropriate and well justified endpoints to evaluate the effect of the intervention on chronic immune activation? Do the proposed mechanistic experiments to investigate pathogenesis relate directly to the primary research question? Is the ieffectof the intervention in relevant tissues adequately considered and discussed? Does the application adequately consider the effect of the intervention on the viral reservoir and if applicable, are the proposed methodologies to evaluate the reservoir appropriate?

Is there an appropriate plan for managing risks associated with the approach? Does the application adequately address potential ethical issues? Are the plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed?

Is the proposed clinical trial sufficiently well-planned, developed and organized to be enrolling patients soon after award? Does the application provide adequate description or discussion of the following: the intervention, study agent(s), and mode of delivery; plan for acquisition and handling of study agent(s); the nature and availability of the eligible study population; plans for recruitment outreach, enrollment, and retention; the statistical hypothesis and data analysis plans; the proposed endpoint(s), the data to be collected and the data management plans; the sample size, power calculation, and duration of the trial; and the inclusion/exclusion criteria.  Does the application provide adequate milestones?

Environment

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

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/priority score, but will not give separate scores for these items.

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Children 

When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the Human Subjects Protection and Inclusion Guidelines.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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

Resubmissions

Not Applicable.

Renewals

Not Applicable.

Revisions

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/priority score.

Integration and Interaction

Close interaction between clinical and basic researchers is suggested to promote translation of basic science ideas into the clinical setting and expand on ideas from clinical observations that can be pursued in the basic laboratory. Is there evidence that the basic research component of the application is well integrated with the clinical site? Do the proposed experiments have the opportunity to identify specific mechanisms or pathways that can be targeted to prevent or reverse persistent immune activation in HIV-infected individuals?

Applications from Foreign Organizations

Not Applicable.

Select Agent Research

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

Resource Sharing Plans

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

Budget and Period of Support

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

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group) convened by NIAID., in accordance with NIH peer review policy and procedures, using the stated review criteria. Review assignments 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/priority 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 Counciil. 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(s)/PI(s) will be able to access his or her Summary Statement (written critique) via the eRA Commons. 

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

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

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

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

Any application awarded in response to this FOA will be subject to the DUNS, CCR Registration, and Transparency Act requirements as noted on the Award Conditions and Information for NIH Grants website.

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

• All aspects of their study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators. The awardee agrees to accept close coordination, cooperation, and participation of NIAID staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.
• Meeting NIAID policy requiring that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. NIAID policy was published in the NIH Guide on July 8, 2002 and is available at: http://grants.nih.gov/grants/guide/notice-files/NOT-AI-02-032.html. The full policy, including terms and conditions of award, is available at: http://www.niaid.nih.gov/researchfunding/sci/human/pages/clinterm.aspx
• Required regulatory filings or delegation of this responsibility to a third party following notification of and concurrence by NIAID.
• Upon implementation of the protocol, ensuring that each field center, whether a single institution or a consortium of institutions, will follow the procedures required by the protocol regarding study conduct and monitoring, volunteer management, data collection, and quality control.
• Support or other involvement of industry or any other third party in the study--e.g., participation by the third party; involvement of project resources or citing the name of the project or the NIAID support; or special access to project results, data, findings, or resources--may be advantageous and appropriate. However, except for licensing of patents or copyrights, support or involvement of any third party will occur only following notification of and concurrence by NIAID.
• Putting all study materials and procedure manuals into the public domain. Awardees are expected to publish and publicly disseminate results, data, and other products of the study, concordant with governance policies and protocols. Publications and oral presentations of work performed under this agreement will require appropriate acknowledgment of support by the NIAID/ NIH.
• Following Good Clinical Practice guidelines

Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies.

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

• Have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIAID staff may use information obtained from the data for the preparation of internal reports on the activities of the study. However, awardees will retain custody of and have primary rights to all data developed under these awards, subject to Government rights of access consistent with HHS, PHS, and NIH policies.
• Provide guidance and support in the development, assembly, and submission of all required regulatory documents, e.g., those regarding the use of investigational drugs, to the Food and Drug Administration.
• Serve as a resource to provide scientific/programmatic support during the accomplishment of the research by participating in the design of the activities, advising in the selection of sources or resources (e.g., determining where a particular reagent can be found), provision of research resources and reagents available from NIAID grantees and contractors, advising in management and technical performance, or participating in the preparation of publications.
• Oversee the adequacy of adverse event management and reporting, and have regular communications with the PD(s)/PI(s) and study team, which may include attendance at the safety monitoring (or DSMB) and related committee meetings.
• Review the progress of the study, and of each participating facility, through consideration of the annual reports, site visits, volunteer logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting.
• Monitor progress of study milestones; as with any award, continuation, even during the period recommended for support, is contingent upon satisfactory progress. Progress will be monitored by an internal panel with outside consultants as needed and determined by the NIAID. The schedule for these interim reviews will be based upon the duration of the clinical trial period. Continuation of funding will be dependent upon the awardee’s ability to show adequate progress towards milestone accomplishment.
• At each scheduled interim review, compare actual enrollment to the benchmarks and criteria identified in the application and negotiated prior to award; awardees who do not accomplish the negotiated milestones shall submit a milestone report which will include a discussion of why the milestones were not met in the agreed upon timeframe, and propose a corrective recruitment action plan. The corrective recruitment action plan shall include: amended milestones, plans to achieve the amended milestones and any additional items required by NIAID staff. The plan shall be provided to NIAID staff no later than 2 months following the missed milestone.

Studies in which recruitment milestones are not met as per criteria established pre-award, or for which regulatory approval has not been met within one year, and are deemed unlikely to improve sufficiently to bring the study to completion within an acceptable budget or time frame, may be closed for lack of progress following review and consideration by NIAID staff.

If a study is finally determined to lack feasibility and will no longer accrue subjects, awardees are required to submit a close-out plan to NIAID staff in 2 months timeframe of a decision either by NIAID staff or the grantee that an awarded study is no longer feasible. The plan must be approved and signed by the Institutional Official and the PD(s)/PI(s) listed on the award prior to submission.

NIAID reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to implement the study protocol in a timely matter, (b) a substantial shortfall in participant recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol, (c) substantive changes in the agreed-upon protocol with which NIAID does not concur, (d) reaching a major study objective substantially before schedule with persuasive statistical evidence, or (e) human subject ethical issues that may dictate a premature termination.

Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

None.

Dispute Resolution:
Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to dispute resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the Steering Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure 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 Non-Competing Continuation Grant Progress Report (PHS 2590) annually and financial statements as required in the NIH Grants Policy Statement.

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

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

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

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Telephone 301-710-0267
TTY 301-451-5936
Email: [email protected]

eRA Commons Help Desk(Questions regarding eRA Commons registration, tracking application status, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)
TTY: 301-451-5939
Email: [email protected]

Alan Embry, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-435-3751
Email: [email protected]

Peter R. Jackson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: (301)-496-8426
Email: [email protected]

Ann Devine
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-5601
Email: [email protected]

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Parts 74 and 92.