Participating Organization(s)	National Institutes of Health (NIH)
Components of Participating Organizations	National Institute of Allergy and Infectious Diseases (NIAID)
Funding Opportunity Title	Pilot Clinical Trials to Eliminate the Latent HIV Reservoir (U01)
Activity Code	U01 Research Project Cooperative Agreements
Announcement Type	New
Related Notices	March 10, 2016 - This RFA has been reissued as RFA-AI-16-012. June 4, 2014 - Notice NOT-14-074 supersedes instructions in Section III.3 regarding applications that are essentially the same. November 25, 2013 - See Notice NOT-AI-14-014. Notice of Change in the Key Dates.
Funding Opportunity Announcement (FOA) Number	RFA-AI-13-055
Companion Funding Opportunity	None
Number of Applications	See Section III. 3. Additional Information on Eligibility.
Catalog of Federal Domestic Assistance (CFDA) Number(s)	93.855, 93.856
Funding Opportunity Purpose	This Funding Opportunity Announcement (FOA) solicits applications for support of pilot clinical trials to evaluate interventions aimed at the elimination of the HIV reservoir in HIV-infected adults who are on suppressive antiretroviral therapy. It is expected that the trials will be fully integrated with laboratory-based analytical tools to detect and measure elimination of latently-infected cells both in blood and in tissue.

Posted Date	October 24, 2013
Open Date (Earliest Submission Date)	(Extended to June 15, 2014 per NOT-AI-14-014), Originally February 7, 2014
Letter of Intent Due Date(s)	(Extended to June 15, 2014 per NOT-AI-14-014), Originally February 7, 2014
Application Due Date(s)	(Extended to July 15, 2014 per NOT-AI-14-014), Originally March 7, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
AIDS Application Due Date(s)	(Extended to July 15, 2014 per NOT-AI-14-014), Originally March 7, 2014, by 5:00 PM local time of applicant organization. Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
Scientific Merit Review	(Extended to November, 2014 per NOT-AI-14-014), Originally July, 2014
Advisory Council Review	(Extended to January, 2015 per NOT-AI-14-014), Originally October, 2014
Earliest Start Date	(Extended to June, 2015 per NOT-AI-14-014), Originally February, 2015
Expiration Date	(Extended to July 16, 2014 per NOT-AI-14-014), Originally March 8, 2014
Due Dates for E.O. 12372	Not Applicable

Required Application Instructions

It is critical that applicants follow the 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

Purpose

This Funding Opportunity Announcement (FOA) solicits pilot clinical trial applications to evaluate interventions aimed at the elimination of the HIV reservoir in HIV-infected adults who are on suppressive antiretroviral therapy. It is expected that the trials will be fully integrated with laboratory-based analytical tools to detect and measure elimination of latently-infected cells in both blood and tissue.

Background

HIV infection can be effectively treated with modern medical management but individuals require lifelong therapy. Early in the course of HIV infection a pool of latently infected cells is established, some of which are extremely long-lived. These cells contain integrated proviral DNA, some of which is replication competent. Integrated HIV provirus persists in latently infected cells and discontinuation of antiretroviral therapy leads to rapid virological rebound. Until recently it has been felt that the there was no hope of eradicating the reservoir of latently infected cells, however there have now been two reports of probable cure; one in an adult requiring stem cell transplantation, and the other in a child who was aggressively treated early in life. Other patients have been identified who may have had significant reductions in the HIV viral reservoir as a result of different interventions. These events have sparked renewed interest in identifying the steps that may be necessary in order to effect a cure of HIV and NIAID has prioritized this effort. Efforts have focused on the reversal of latency; it was hoped that the reversal of latency would cause the death of the latently infected cells by either cytopathic effects of HIV itself or by immune-mediated clearance. Current understanding suggests that reversal of latency is not enough to destroy the cells containing the virus. These infected cells may retain the capacity to both act as a reservoir and to produce viable virions. It has been shown in vitro that the activity of stimulated cytotoxic T cells can increase the elimination of cells that have had HIV reactivation. This finding has generated excitement about curing HIV infection using approaches that enhance the killing of latently infected cells, either alone or in combination with an activation step.

Research Objectives and Examples of Research Strategies

This FOA invites applications to specifically address interventions that will enhance elimination of latently infected cells containing integrated HIV DNA. Interventions might include drugs, biologics or both. An activation step may or may not be required; some approaches might directly target cells that are immunologically silent. The focus of this FOA is to facilitate the translation of basic research findings into novel approaches and mechanistic clinical studies that will enhance the elimination of latently infected cells in HIV infected adults on effective long-term suppressive therapy. In this FOA, the HIV reservoir is defined as the cells containing integrated HIV provirus that is transcriptionally silent, but replication competent. Recognition of these cells, detection of this reservoir, and measurement of quantitative changes in this reservoir, are needed. Novel methodologies and assays designed to assess these effects are encouraged. It is anticipated that these trials will lead to an increased understanding of the cell types, location, and numbers of latently infected cells; however applications that deal only with the detection and measurement of latently infected cells would not be responsive. Novel therapeutic vaccines and other immunological approaches that harness and enhance the patient’s immune response are of interest, but responsive applications must contain preliminary data that demonstrate that latently-infected cells can be eliminated by the proposed approach. Preliminary data that demonstrate how the approach will lead to cell death and measurements that quantify the reduction in latently infected cells in vivo or in vitro are required.

Significant questions still exist:

• What are the best interventions to enhance the activity of the innate and adaptive immune responses with the goal of eliminating latently infected cells?
• Is an activation step required for elimination of the HIV reservoir? Combination approaches that include an activation step may be proposed.
• Are there steps in the pathway maintaining latency and persistence that can be targeted, resulting in the death of latently infected cells? Successful applications must show that the proposed approach could result in the death of those cells.
• Does the interruption of mechanisms that allow HIV in latently infected cells to escape immune recognition lead to increased killing of these cells?

For this FOA, each application must propose one pilot interventional trial in HIV infected individuals on suppressive antiretroviral therapy. Subjects selected for this study must have sustained undetectable plasma viral load levels below the limit of detection (less than 50 copies/ml) for a minimum of 2 years. Patients known to have been treated during acute infection may be an attractive population to study because of the more limited reservoir size and preserved immunological function. The trials will be conducted at single sites with a small number of patients (30 subjects or fewer).

The NIAID defines a clinical trial as a 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. Clinical trials supported by this FOA must be hypothesis driven and designed to investigate the impact of an intervention with a proposed mechanism of action for the elimination of the latent HIV reservoir. The expectation is that these trials will generate hypotheses that can be tested later in larger clinical trials. Accordingly, state-of-the-art laboratory endpoints that quantify the reduction in the number of latently infected cells caused by the intervention (e.g. Quantitative Viral Outgrowth Assay or similar) should be employed within the study design. This is a rapidly evolving field, and superior assays for quantifying changes in the latent cell reservoir may soon be available and would be considered responsive. Applications must justify the choice of endpoints and thoroughly describe experiments to support the approach and the assay(s) used to quantify a reduction in the size of the latent reservoir. An application that does not meet these criteria will be considered non-responsive, and will not be reviewed.

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

• Novel therapeutic vaccines or other immune based strategies, such as antibody- or cell-based therapies, and gene therapies
• Strategies that target immunological mechanisms, including those that modulate the immune system’s activation or inhibition signaling pathways
• Other pharmaceutical approaches

Applications addressing the following areas will be considered non-responsive, and will not be reviewed:

• Trials proposing interventions that induce non-specific T-cell activation through general transcription activators
• Trials proposing interventions that focus solely on reversing latency (activation), and contain no elimination strategy
• Proposals that require the generation of preclinical data in order to support the hypothesis that the approach will eliminate latently-infected cells
• Drug discovery and development programs
• Trials intended to support a New Drug Application (NDA)
• Research on approaches already under extensive investigation in the HIV field.
• Trials conducted outside of the U.S.
• Studies performed in animal models
• Applications that include more than one clinical trial, or that include more than one clinical site

This FOA will NOT support clinical trial planning activities, 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 Product Package Insert

Investigators seeking support for the planning and design of clinical trials should refer to the NIAID Clinical Trial Planning (R34) Grant FOA (PAR-13-150).

Implementation:

This FOA may provide resources to support activities related to the conduct of the clinical trial, including, but not limited to:

• Training of study personnel related to the conduct of the trial
• Enrollment and recruitment of study subjects
• Data collection, management and quality control for the trial only
• Laboratory work and data analysis
• Study management and oversight
• Establishment of committees to manage trial implementation activities
• Preparation of the final study report
• Other related post-enrollment activities
• Regulatory activities to support the implementation of the trial

It is not expected that these exploratory trials will achieve statistical significance, but will instead support or refute hypothesized approaches to eliminate the HIV reservoir.

All clinical trial planning activities must be completed by the time of application. It is expected that investigators will implement the proposed trial within 6 months of receiving the award.

NIAID reserves the right to specify: 1) whether an IND (Investigational New Drug)/IDE (Investigational Device Exemption) application should be submitted to the FDA; 2) the sponsor who will hold the IND/IDE; and 3) the requirements for the establishment of a DSMB (Data Safety Monitoring Board)/SMC (Safety Monitoring Committee).

In most cases, it is expected that the NIAID will not hold the IND/IDE.

Investigators are referred to the DAIDS Clinical Research Policies and Standard Procedures Documents for protocol templates and guidance and clinical research resources.

Milestones: Delineation of milestones is a key characteristic of this FOA. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity.

Funding Instrument	Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities.
Application Types Allowed	New The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
Funds Available and Anticipated Number of Awards	NIAID intends to commit $4 million in FY2015 to fund 1-3 awards.
Award Budget	NIAID estimates the award budgets will be $1.0 to 1.5 million in Direct Costs per year.
Award Project Period	The scope of the proposed project should determine the project 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
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

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

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (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 and should work with their organizational officials to either create a new account or to affiliate an existing account with the applicant organization’s eRA Commons account. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

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

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

NIH will not accept any application that is essentially the same as one already reviewed within the past thirty-seven months (as described in the NIH Grants Policy Statement), except for submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

U.S.-based institutions must receive primary awards through this FOA. Foreign collaborators are permitted if scientifically justified and feasible given the proposed study design, but the clinical site must be located in the United States.

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 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:

Peter Jackson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Room 3133, MSC-7616
6700B Rockledge Drive,
Bethesda, MD 20892-7616
Zip Code for express couriers: 20817-1821
Telephone: 301-496-8426
Email: [email protected]

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

The forms package associated with this FOA includes all applicable components, required 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.

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

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

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

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

Other Attachments: The following items are required for this FOA, and must be included as separate pdf attachments.

1. Milestone Plan

The filename Milestone plan.pdf should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The milestones will undergo peer review, are subject to negotiation prior to award and will be incorporated into the terms of award.

This section may not exceed 3 pages, and must include:

• Date by which pre-IND meeting with the FDA will occur, if it has not already, or a copy of the IND/IDE exemption letter from the FDA, if applicable
• Projected date of submission of completed protocol to NIAID for review at the DAIDS Scientific Review Committee
• Projected date of Recombinant DNA Advisory Committee (RAC) review, if applicable
• Expected receipt date of a safe-to-proceed letter from the FDA, if applicable
• Date of IRB approval of the clinical trial
• Timeline for finalizing agreements with collaborators (e.g. Materials Transfer or Clinical Trial Agreements), if applicable
• Date by which sites will receive the proposed study agent(s), if applicable
• Detailed recruitment plan with timeline for enrolling 50% and 100% of the targeted study population and a futility assessment if specified targets are not met
• Dates planned for meetings of the independent data and safety monitoring committee overseeing the trial
• Date by which site, pharmacy and laboratory will be ready to start trial
• Date by which data collection is expected to be complete
• Date by which the data analyses are expected to be completed
• Date of expected distribution of a final study report
• Detailed protocol-specific performance milestones, as applicable to the proposed trial. These milestones will be negotiated at the time of the award.

2. Clinical Protocol Synopsis

The filename "Clinical Protocol Synopsis.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The clinical protocol synopsis must include the following information:

• A description of the study population, including subject eligibility and inclusion/exclusion criteria;
• Sampling, recruitment and enrollment plans, including a discussion of the availability of subjects for the proposed study and the ability of enrollment center(s) to recruit and retain the proposed number of subjects;
• The process to be used for obtaining informed consent and, if applicable, assent;
• Approaches to be used for retention, cooperation and follow-up of subjects and to address any anticipated changes in the composition of the study population over the course of the trial;
• Methods of assignment of subjects to study groups and of randomization;
• If appropriate to the study, a description and justification for the selection of the dose, frequency and administration of the intervention(s);
• A description of each enrollment site and how data from the site(s) will be obtained, managed, and protected;
• Descriptions of all clinical, laboratory, physiological, and/or behavioral tests to enable the research questions to be answered; and
• A description of the data management and quality control plan, including methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; and data confidentiality and subject privacy.

3. Statistical Analysis Plan

The filename "Statistical Analysis Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

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.

4. Data and Safety Monitoring (DSM) Plan

The filename "Data and Safety Monitoring Plan.pdf" should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The DSM plan should be commensurate with the risk level of the proposed clinical research and 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 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 manage and conduct the monitoring;
• What will be monitored;
• Proposed monitoring time points;
• Where the monitoring will occur;
• How the reportable events will be managed and reported; and
• How sites/centers, and participating facilities (labs, pharmacies) will be monitored.

5. Complete Clinical Protocol

The filename Complete Clinical Protocol.pdf should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The Complete Clinical Protocol, including the Informed Consent Form(s), must be included immediately after the Milestone Plan. Investigators are referred to the Trans-NIAID Clinical Research Toolkit website for templates and clinical protocol guidance.

6. Regulatory Planning

The filename Regulatory.pdf should be used and will be reflected in the final image bookmarking for easy access for reviewers.

Applicants must show the capability to provide full regulatory support for the development and implementation of the clinical trial. A regulatory support plan must be submitted, including point-of-contact information, and a list of INDs, IDEs and other evidence supporting sufficient regulatory experience to qualify the institution to hold an IND.

Applicants are asked to state whether or not an IND/IDE is necessary for the proposed trial. If an IND/IDE is deemed to be necessary, then applicants must state the name of the party they propose to serve as the IND/IDE holder. In most cases, it is expected that the NIAID will not hold the IND/IDE.

Applicants are expected to seek feedback from the FDA on the proposed clinical trial prior to the time that their U01 grant application is submitted to the NIH so that the trials can commence within 6 months of the award. The status of discussions with the FDA must be submitted as part of the application. If a pre-IND meeting request is granted by the FDA, applicants must include the list of questions posed to the FDA and the official meeting minutes, if they are available. Applicants who have requested an IND/IDE exemption must submit either:

• a copy of the letter that was sent to the FDA requesting an IND/IDE exemption for the proposed trial, and information about the status of the FDA’s review (e.g. decision pending as of XX date, queries received on XX date); OR
• a copy of the FDA letter granting an IND/IDE exemption letter for the proposed trial

7. A Laboratory Protocol for the Proposed Assay to Measure Elimination of Latently-infected Cells

The filename Laboratory Assay.pdf should be used and will be reflected in the final image bookmarking for easy access for reviewers.

The laboratory protocol for the assay to measure elimination of latently-infected cells must be provided. Data to support the reliability of the assay, and validity for use as a surrogate marker of latent cell elimination must also be provided. Investigators should try to adhere as closely as possible to NIAID’s policies on the use of non-FDA approved, investigational-use only study endpoints when developing, implementing and reporting their findings. The following website describes NIAID’s requirements for the use of endpoints that are for investigational use only, and are not approved by the FDA nor validated by the International Concurrence on Harmonization (ICH) or U.S. Pharmacopeia:

http://www.niaid.nih.gov/LabsAndResources/resources/DAIDSClinRsrch/Pages/reqUSLab.aspx

Applications that lack any of the applicable application attachments described in the listed attachments #1-7 above, will be deemed non-responsive, and will not be reviewed.

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.

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. Specific attention should be given to the rationale for the proposed intervention(s), including the hypothesized route or mechanism(s) of action that lead to the elimination of latently-infected cells. Applicants should specify the primary endpoint(s) to be measured and justify their inclusion.

Research Strategy: The Research Strategy includes the Significance, Innovation and Approach sections. Provide an overview of the state of the science, current status and relevance of the trial, and a description of the clinical trial. The Research Strategy should include:

• A clear hypothesis(es) stating the proposed mechanism by which the interventions or approaches will eliminate latently infected cells in HIV-infected individuals who are taking effective antiretroviral therapy (include preliminary data)
• A description of and a rationale for the proposed study design with an emphasis on how the trial will clearly test the stated hypothesis(es)
• A concise description of the overall strategy, methodology, and analyses to be used to accomplish the goals and specific aims of the trial
• A discussion of how the intervention will exert an effect on cells and tissues that are believed to comprise the latent HIV reservoir
• A description of the study population and explanation of why it is an appropriate population to study the research question(s) posed
• A description of the anticipated risks to subjects and a plan for how the risks will be minimized

Propose a time-sensitive, milestone-driven clinical trial and describe the clinical trial stages and criteria for completion of each stage. Present a clear plan and timeline to acquire the study product(s) for use in the clinical trial. 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 plans for both recruitment/enrollment and futility assessments must also be included.

Protection of Human Subjects: Provide a scientific justification for any risks that the trial may pose to subjects in the background of the protocol, and explain what steps will be taken to mitigate risks to subjects.

Letters of Support: Provide all appropriate letters of support, including any letters necessary to demonstrate the support of laboratories and other collaborators. If co-funding or in-kind support is planned from non-NIH sources (e.g. from drug supplier(s)), letter(s) outlining details of the commitment (e.g. type, amount and source of support), signed by a business official on organization letterhead, must be included in the Letters of Support.

If the application relies upon patentable ideas, trade secrets, privileged or confidential commercial information or study agents or materials that are not owned by the applicant, but are necessary for regulatory approval or for the trial itself, the applicant must include a letter of agreement from the collaborators stating willingness to supply these data and/or resources to the applicant for the proposed clinical trial. Alternatively, a Material Transfer Agreement must be signed and included in the application.

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 modification:

Provide the following in the Appendix:

• The Investigator’s Brochure or Package Insert for the study product(s), if applicable
• The Table of Contents of the Manual of Procedures
• The Laboratory Plan
• Documentation of availability of study agents and support for acquisition and administration of study agent(s)

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

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

Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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.

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 by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete and/or nonresponsive will not be reviewed.

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 may also be discussed. Consultations may include both an introductory call and a conference call with NIAID staff.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

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

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

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

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?

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/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project? Do the PD(s)/PI(s) have sufficient time and expertise to implement a complex, high-risk trial?

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?

Does the application propose a trial that is designed to elucidate mechanisms that can identify, eliminate or substantially reduce the number of cells latently infected with HIV? Is the study hypothesis-driven and designed to investigate the impact of an intervention with a proposed mechanism of action intended to eliminate or substantially reduce the HIV reservoir? Did the applicant describe and justify the proposed patient population, and are they an appropriate group to study in order to address the research question(s) proposed in the application? Will the assays proposed quantify the elimination or reduction in cells latently infected with HIV caused by the intervention? Are there sufficient data to support the proposed assay(s)? Are the endpoints relevant? Can the necessary regulatory and other milestones be met so that the trial can begin within 6 months of the award?

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?

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? Does the applicant possess sufficient support internally or through consortium agreements to support the regulatory activities, trial oversight, laboratory and pharmacy activities, site oversight, and data and safety monitoring?

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.

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 Guidelines for the Review of Human Subjects.

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 Guidelines for the Review of Inclusion in Clinical Research.

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 score.

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(s) convened by NIAID, 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.

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, SAM 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 primary responsibility for:

• Providing periodic Study Update and Safety Monitoring Reports for the DAIDS Project Scientist (Medical Monitor) and Program Official on no less than a quarterly (every 3 months) basis for the entire grant budget period. These reports should include administrative, study progress towards important study milestones, accrual and aggregated adverse event data that is not sorted by treatment arm.
• Submitting adverse event reports on an expedited basis to the DAIDS Project Scientist (Medical Monitor) and Program Official at the same time that they are sent to the FDA and/or IRB.
• Establishing Clinical Trials Agreements necessary to complete the proposed clinical trial.
• Ensuring that protocol implementation and oversight adhere to the following policies and requirements:
  • establishing criteria for determining the futility of answering the research question within a pre-defined time boundary
  • obtaining protocol approval by NIAID prior to protocol implementation
  • developing mechanisms for monitoring study progress and participant safety, and provision of status update reports to NIAID on an agreed upon schedule
  • developing post-study follow-up plans, contingent upon study results, are incorporated within the protocol that is reviewed by the DAIDS Scientific Review Committee
  • providing results to study participants upon un-blinding, if applicable and to the community as soon as can be accomplished
  • providing timely information required by all DAIDS offices to facilitate activities such as accrual and milestone tracking in the DAIDS-Enterprise System (a database used by NIAID to support DAIDS-funded trials)
• Participating in an annual conference call for the purpose of information and data sharing among other cure researchers
• 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 action plan. The corrective 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.
• 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.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

Medical Officer Responsibilities:

The Project Scientist(s) or Medical Officer will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination above and beyond the normal program stewardship role for grants:

• May serve as a member of the protocol team

Program Official Responsibilities:

• Review the progress of the study through consideration of the update reports, site visits, volunteer logs, etc. This review may include, but is not limited to, compliance with the study protocol, meeting implementation milestones and enrollment targets, adherence to uniform data collection procedures, and the timeliness and quality of data reporting
• Monitor progress with input from an internal panel with outside consultants as needed and determined by the NIAID. NIAID will schedule these interim reviews based upon the duration of the clinical trial period
• At each scheduled interim review, compare actual achievement of study implementation milestones and criteria identified in the application and negotiated prior to award
• Close studies for a lack of progress, following review and consideration by NIAID staff, for those studies in which recruitment milestones are not met as per criteria established pre-award, or for which regulatory approval has not been met within 9 months, and are deemed unlikely to improve sufficiently to bring the study to completion within an acceptable budget or time frame

Areas of Joint Responsibilities Include:

• 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
• Attend and interact with the study team during meetings, site visits, and conference calls

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

Dispute Resolution:

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

When multiple years are involved, awardees will be required to submit the annual Non-Competing Progress Report (PHS 2590 or RPPR) 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.

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Phone: 301-402-7469 or 866-504-9552 (Toll Free)

Web ticketing system: https://public.era.nih.gov/commonshelp
TTY: 301-451-5939
Email: [email protected]

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

Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
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]

Tia Morton, R.N., M.S.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3073
Email: [email protected]

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

Jen Schermerhorn

National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-451-2649
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.