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

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

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

Despite recent reductions in HIV-1 perinatal transmission, 1.8 million children live with HIV-1 globally. Early anti-retroviral therapy (ART) is life-saving and is effective in decreasing HIV-1 reservoirs. However, ART is not curative, does not result in HIV-1 remission, and when taken lifelong can be associated with toxicities that can result in decreased adherence. Poor adherence can lead to an increased risk of developing ART resistance and thus further limit already scarce ART options in children. There is a strong need to explore additional interventions targeting HIV-1 reservoirs and/or reactivating virus.

HIV-1 infection in infants is established in the context of a tolerogenic immune system with T cell responses biased towards Th2 and away from Th1 responses, a high proportion of T regulatory cells expressing high levels of FoxP3, a lower proportion of central memory T cells, and a strong predominance of na ve T cells in the peripheral circulation and tissues. This unique immune environment likely impacts HIV-1 viral pathogenesis, creating distinct dynamics of reservoir establishment and persistence and distinct host-pathogen interactions. An example is the difference in time to viral set point from just weeks after infection in adults compared to 2-4 years in children. The time required for maturation of CD8 T cell responses in childhood also may influence HIV-1 pathogenesis and reservoir development. Due to this unique immune environment in infants and children, immunomodulatory and other safe interventions may perform differently in children as compared to adults, and may result in a decrease in HIV-1 reservoir size. Conducting research on and exploring the feasibility of potential agents in children in parallel with ongoing adult investigation is critical to advancing scientific knowledge in the field of pediatric HIV-1 remission.

This FOA solicits applications proposing pilot clinical trials to evaluate therapeutic modalities to limit or reduce HIV-1 reservoirs in children (birth to 18 years of age at the time of enrollment). The specific populations of interest include:

• Early ART-treated children who are virally suppressed, or
• Children who are about to start or recently started ART for acute infection and may not yet be virally suppressed, or
• Children who started ART later in their disease course.

Proposed therapeutic modalities are expected to have an established safety profile with preclinical and/or clinical data to support a potential effect on HIV-1 reservoirs and may include interventions such as therapeutic vaccines or broadly neutralizing antibodies or a safe latency-reactivating agent. Studies may also include evaluation of immune activation or inflammation but must also include assessment of HIV-1 reservoirs.

Specific areas of interest

Examples of approaches for the clinical trial include, but are not limited to:

• Testing an immunotherapeutic intervention in children who received early ART due to perinatal infection
• Simultaneous administration of immunotherapeutic interventions with combination ART during very early infection
• Testing latency-reversing agents with immune-based treatment in virally suppressed children

Collaborations with laboratory experts or networks with laboratory capacity are encouraged; collaboration with experts in other disciplines (such as oncology or immunology) is encouraged.

Applications proposing any of the following research topics will be considered non-responsive and will NOT be reviewed:

• Preclinical studies
• Trials of early ART alone without an additional therapeutic modality
• Evaluation of immune activation alone without assessment of HIV-1 reservoirs
• First-in-human trials
• Phase 2B or Phase 3 efficacy studies

NIH defines a clinical trial as a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes. Each award made through this FOA will support one pilot clinical trial. The trial is expected to involve a small number of participants (e.g., 20 subjects or fewer).

Clinical trials supported by this FOA will be hypothesis-driven and designed to investigate the impact of an intervention(s) with a proposed mechanism of action for the elimination of the latent HIV-1 reservoir. State-of-the-art laboratory endpoints that attempt to quantify the HIV-1 reservoir should be employed within the study design.

NOTE: It is not expected that these exploratory trials will achieve statistical significance, but will instead support or refute hypothesized approaches to limit or reduce the HIV-1 reservoir.

All clinical trial planning activities must be completed by the time of application submission.

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 brochure or product package insert

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

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

Other Requirements

The clinical trial and informed consent forms are subject to review and approval by the NIH Program Official and Medical Officer, the DAIDS Clinical Science Review Committee, and other necessary external advisors before opening to enrollment and when amended. While preparing applications for submission under this FOA, applicants are encouraged to review the NIAID Clinical Terms of Award and associated guidance documents, policies, and procedures under which the award will be made. These include, for example: https://www.niaid.nih.gov/grants-contracts/niaid-clinical-terms-award and the DAIDS Clinical Research Policies and Standard Procedures Documents that describe requirements for DAIDS-funded research.

Milestones

Delineation of milestones is a key characteristic of clinical trial awards made under this announcement. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. Awards will include a Milestone Plan that includes completion of the clinical trial within the period of award. The milestones will be incorporated into the terms of award.

NIAID may reduce funds or the period of performance based on lack of achievement of yearly milestones.

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

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made 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)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are 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.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

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

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

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time.  This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

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

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions 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 R. Jackson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5049
Email: pjackson@niaid.nih.gov

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

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 followedwith the following additional instructions:

Other Attachments: The following items are required for this FOA and must be included as separate PDF attachments. Applications that lack any of these attachments will be considered incomplete and not reviewed.

Clinical Protocol Synopsis

The filename Clinical Protocol Synopsis.pdf should be used.

The clinical protocol synopsis must include the following information:

• Title
• Participating Site(s)
• Hypothesis
• Intervention(s)
• Study Design, including schema showing schedule of interventions, procedures and evaluations
• Study population, including sample size and subject inclusion/exclusion criteria
• Primary immunologic and virologic endpoints
• Brief rationale for the trial, including justification for the selected endpoints and intervention(s)

Milestone Plan

The filename Milestone plan.pdf should be used.

Applications must have a milestone plan that includes milestone goals for implementing and, if needed, modifying the trial based on new information generated by the trial or the field. A milestone is defined as a scheduled event in the project timeline, signifying the completion of a major project stage or activity. The milestones are subject to negotiation prior to award and will be incorporated into the terms of award. Continuation of funding for these trials will be based upon satisfactory progress in meeting negotiated milestones.

This section must include:

• If applicable, communication(s) with the FDA regarding the IND submission
• Estimated date for readiness to submit clinical trial protocol and informed consent form to NIAID for review at one of the DAIDSs Scientific Review Committees
• Projected date of Recombinant DNA Advisory Committee (RAC) review, if applicable
• Estimated timeline for completion of regulatory approvals
• Estimated date of completion of Clinical Trial Agreements (CTAs), if applicable. If not required please explain and provide a justification.
• Detailed recruitment plan with timeline for enrolling the first subject, and for enrolling 25%, 50% and 100% of the targeted study population, including a futility assessment if specified targets are not met
• Planned frequency for meetings of the independent data and safety monitoring committee overseeing the trial
• Estimated date by which site(s), pharmacy(ies) and laboratory(ies) will be ready to start trial
• Estimated date by which data collection is expected to be complete
• Estimated date by which the data analyses is expected to be completed
• Estimated date of expected distribution of a final study report

Complete Clinical Protocol and Informed Consent Form

The filename Clinical Protocol.pdf should be used.

Investigators are referred to the following website for templates and clinical protocol guidance https://www.niaid.nih.gov/research/daids-clinical-research-protocol-informed-consent.

Regulatory Activities

The filename Regulatory.pdf should be used.

NIAID reserves the right to specify: 1) whether an IND application should be submitted to the FDA; 2) who will serve as sponsor to hold the IND; 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 NIAID will not hold the IND.

If the applicant proposes an approach that would require input from the FDA, a regulatory strategy and plan for FDA submissions must be included. If an IND submission is needed, applicants are expected to have received positive feedback from the FDA on the proposed clinical trial prior to the time that their U01 grant application is submitted. Applicants must possess or hire appropriate regulatory support to manage regulatory submissions to the FDA if the approach requires FDA input. If an IND is necessary, then applicants must state the name of the institution or company they propose to serve as the IND holder.

Applicants must also describe an approach for data management that is consistent with current FDA guidance, regulations for Electronic Signatures described in 21 CFR Part 11, and predicate rules set forth in the PHS Act. Applicants are encouraged to also consider the FDA requirements for providing regulatory submissions in electronic format. Limited information on both of these requirements can be found at the websites below:

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=11&showFR=1&subpartNode=21:1.0.1.1.8.3

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm.

All communications with the FDA must be submitted for review 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.

Management and Staffing Plan

The filename Management Staffing Plan.pdf should be used.

The Management Staffing Plan describes the organization of the proposed program, the clinical research locations (sites) where the research participants will be seen, and its management structure. The plan must include:

• A description of how the organization of the pilot clinical trial and its management structure will form a cohesive, integrated and efficient unit that provides scientific and administrative oversight of the proposed trial.
• An overview of how the trial will be coordinated and managed to answer the scientific questions and hypotheses proposed within this application.
• A Staffing Plan that describes the roles of the staff including a project manager and/or study coordinator and administrative and scientific staff involved with this project.

Evidence of Permission to Access Proprietary/Privileged Information Required to Accomplish the Study Aims, if applicable

The filename Permissions.pdf should be used.

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 clinical 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 signed Material Transfer Agreement must be included in the application. 

Laboratory Methods for the Proposed Assay to Measure HIV-1 Reservoirs

The filename Laboratory Assay.pdf should be used.

The laboratory protocol for the assay to measure HIV-1 reservoirs 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. Applicants must address plans for assuring compliance with Good Clinical Laboratory Practices (GCLP) and for performing proficiency assessments. If assay results will be used to determine participant eligibility or treatment decisions during the clinical trial, address plans to ensure the relevant assays are CLIA compliant and performed in CLIA-certified laboratories. For guidance, see:

https://www.niaid.nih.gov/research/daids-clinical-research-laboratory-specimens-management

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.

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 reduction or limitation of the HIV-1 reservoir. The application should specify the primary endpoint(s) to be measured and provide justification for their inclusion.

Research Strategy: Provide an overview of the state of the science, current status and relevance of the clinical 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 reduce or limit HIV-1 reservoirs (include preliminary data).
• A description of and a rationale for the proposed study design with an emphasis on how the clinical 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 clinical trial, including a description of the assay(s) used to quantify a reduction in the size of the HIV-1 reservoir.
• A discussion of how the intervention will exert an effect (reduction and/or elimination) on cells and tissues that are believed to comprise the HIV-1 reservoir. Applicants should provide a rationale for how positive or negative results could provide meaningful information to advance the field.
• An explanation of why the study population is an appropriate population to study the research question(s) posed. Applicants using adolescent participants should discuss expected differences in results between adolescents and young adults who would be eligible for adult remission studies.
• A justification for the proposed sample size using either power calculations or non-statistically powered justifications for small, exploratory studies seeking preliminary data to guide further research.
• A rationale as to why the proposed intervention can justify potential risks to participants as well as the resources and effort required to implement the clinical trial.
• A description of capability to assess HIV-1 reservoirs. If relevant, discuss the capability for in-depth assessment of immune correlates of HIV-1 reservoir effect.

Data Safety Monitoring (DSM) Plan: All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions: The DSM Plan must address the following areas:

• Where the monitoring will occur;
• How the reportable events will be managed and reported; and
• How site(s) and participating facilities (e.g., laboratories, pharmacies) will be monitored.

Applications that lack the DSM Plan are incomplete and will not be reviewed.

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.

Refer to https://www.niaid.nih.gov/research/intramural-collaboration-extramural-funded for considerations for NIH intramural scientist collaborations. If NIH intramural scientists are substantially involved, document their Institute/Center’s concurrence with the proposed activities by including letters of support signed by the Scientific Director of the Institute/Center.

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

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

Appendix:

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

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

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

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

Applicants are strongly encouraged to consult with NIH as plans for an application are being developed. Early contact provides an opportunity for NIH 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. NIH staff will not evaluate the technical and scientific merit of the proposed trial; technical and scientific merit will be determined during peer review using the review criteria indicated in this FOA.

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

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

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

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

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

Are the 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 this trial? Does the project include an experienced project manager and/or a study coordinator to oversee and manage study implementation activities?

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

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

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

Is the approach likely to substantially reduce the reservoir, and are the plans for measuring the effect reasonable? Does the analysis include an appropriate sample size justification and power calculation, or an acceptable non-statistically powered justification? Does the application provide adequate justification for the selected population? Are the regulatory approaches and project milestones and timeline feasible and appropriate for timely completion of the clinical trial?

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

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

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.

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

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

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

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

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

Not Applicable

Not Applicable

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.

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

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

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

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

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

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

As part of the scientific peer review, all applications:

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

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

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

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

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

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

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

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

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

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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

Cooperative Agreement Terms and Conditions of Award

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

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

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

• 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 NIH policy requiring that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. The full policy, including terms and conditions of award, is available at: https://www.niaid.nih.gov/grants-contracts/niaid-clinical-terms-award
• Providing periodic Study Update and Safety Monitoring Reports to the NIH Medical Officer and NIH Program Official no less than quarterly (every 3 months) for the entire grant project period. These reports should include administrative updates, progress towards important study milestones, accrual data, and aggregated adverse event data that is not sorted by treatment arm.
• Submitting adverse event reports on an expedited basis to the Project Scientist at the same time that they are sent to the FDA and/or IRB.
• 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 NIH prior to protocol implementation
• developing post-study follow-up plans, contingent upon study results, that are incorporated within the protocol and are reviewed by the DAIDS Clinical Science 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) and/or the NIAID Clinical Research Management System (NIAID CRMS)
• Accomplishing negotiated milestones. Awardees who do not accomplish negotiated milestones shall submit a milestone report, including a discussion of why the milestones were not met in the agreed upon timeframe, and proposing a corrective action plan. The corrective action plan shall include: amended milestones, plans to achieve the amended milestones and any additional items required by NIH staff.
• Submitting a close-out plan to NIH staff within 2 months of a decision either by NIH 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.
• Except for licensing of patents or copyrights, notifying NIH and obtaining NIH concurrence for support or other involvement by industry or any other third party in the study.

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

• The Project Scientist(s) (who also may be a 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, and may serve as a member of the protocol team.
• Having access to data generated under this Cooperative Agreement and periodically reviewing the data and progress reports. NIH staff may use information obtained from the data for the preparation of internal reports on the activities of the study. 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.
• Providing guidance in the development, assembly, and submission of all required regulatory documents for the FDA (e.g., those regarding the use of investigational drugs).
• Serving 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, advising in management and technical performance, or assisting in the preparation of publications.
• Providing medical monitoring. A Project Scientist (who also may be a Medical Officer) will monitor the clinical trial and serve as the Medical Monitor. Should a pharmaceutical or biotechnology company sponsoring a clinical trial choose to name its own Medical Monitor, then the Project Scientist (who also may be a Medical Officer) will work with the company-assigned Medical Monitor (as needed). The Project Scientist (who also may be a Medical Officer) may also serve as a member of the protocol team.
• Overseeing the adequacy of adverse event management and reporting, and having regular communications with the PD/PI and study team, which may include attendance at safety monitoring and related committee meetings.

• Reviewing the progress of the study, and of each participating clinical research site, as needed, 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.
• Monitoring progress of study milestones. As with any award, continuation, even during the period recommended for support, is contingent upon satisfactory progress. Continuation of funding will be dependent upon the awardee’s ability to show adequate progress towards accomplishing milestones identified in the application and negotiated prior to award.
• Closing the study for lack of progress following review and consideration by NIH staff. NIH reserves the right to terminate or curtail the study (or an individual award) in the event of (a) failure to meet recruitment milestones as per criteria established pre-award, (b) failure to obtain regulatory approval, (c) failure to implement the study protocol, (d) a substantial shortfall in participant recruitment, follow-up, data reporting and dissemination, quality control, or other major breach of the protocol, (e) substantive changes in the agreed-upon protocol with which NIH does not concur, (f) reaching a major study objective substantially before schedule with persuasive statistical evidence, or (g) human subject ethical issues that may dictate a premature termination.

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.

Areas of Joint Responsibilities Include:

• Have access to data generated under this Cooperative Agreement and may periodically review the data and progress reports. NIH 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

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 Protocol 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.

Applicable

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

A final 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.

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

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

eRA Service Desk (Questions regarding ASSIST, eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: GrantsInfo@nih.gov (preferred method of contact)
Telephone: 301-710-0267

Judi Miller
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-292-4801
Email: jmillera@niaid.nih.gov

Peter R. Jackson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5049
Email: pjackson@niaid.nih.gov

Laura Pone
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-2951
Email: ponel@niaid.nih.gov

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

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