Part 1. Overview Information

Key Dates

It is critical that applicants follow the instructions in 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 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 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose

The purpose of this Funding Opportunity Announcement (FOA) is to support cooperative agreements to conduct large-scale digital clinical trials that test whether digitally-delivered (mHealth or online) primary HIV prevention interventions can reduce HIV incidence among key populations experiencing new HIV infections in the United States. Applicants are expected to submit applications proposing to advance and test innovative, digitally-delivered interventions that are designed to promote HIV risk reduction interventions that may include promoting use of PrEP. Digital interventions may stand alone or be a component of a comprehensive and scalable prevention program in the United States. The interventions must be remotely delivered to large samples from specific U.S. populations who experience a high epidemiologic burden of HIV infection: men who have sex with men (MSM) and transgender women and men. An application may focus on one of these groups or may propose stratified enrollment across the categories. Regardless of the population focus, it is expected that at least half of planned MSM participants will be individuals who self-identify as black, Latino, or of mixed race. Applicants are additionally encouraged to enroll or oversample (1) youth (age 13-34 years old with emphasis on age 18 or younger) and (2) rural populations, where clinic-based HIV prevention efforts are particularly difficult, because of low population density. Applications will require documented evidence of the ability to digitally recruit and retain cohorts of sufficient size to conduct a clinical trial powered on an HIV incidence outcome. Applicants are expected to implement their prevention interventions in the first 12 months of the award and to complete their trial within the 5-year project period.

The major goal is to support investigators who will use innovative electronic methods to recruit and retain large samples of persons at high risk of HIV infections, conduct digitally-delivered interventions that promote HIV risk reduction and/or pre-exposure prophylaxis (PrEP) use, and assess the resulting impact on HIV incidence through mailed HIV test kits or other remote means.

Background

There is a critical need to strengthen HIV prevention in the United States. While HIV incidence in the U.S. has declined modestly overall, progress has been uneven, and rates have risen among some subgroups. Recent epidemiologic data indicate that HIV cases among MSM in the U.S. increased from 2010 to 2016, with MSM accounting for 82% of new cases among males in 2017. Racial and geographic disparities are marked in the U.S. Compared to the incident rate of new HIV diagnoses per 100,000 white males in 2017, the rate was 7.6-fold higher for black males and 3.6-fold higher for Latinos. High HIV incidence rates have also been reported for transgender populations. Nearly twenty percent of HIV cases in the U.S. in 2016 were from rural areas or metropolitan statistical areas (MSA) with less than 500,000 residents; furthermore, the South accounted for 20,218 (52%) of all new HIV diagnoses in 2017. The Ending the HIV Epidemic: A Plan for America focuses mainly on the 50 primarily urban jurisdictions (48 counties and San Juan, P.R. and Washington, D.C) that account for about half the annual HIV incident cases in the U.S. Although the plan also targets the seven states with large numbers of rural cases, additional efforts are needed to reach the approximately 41% of annual HIV infections occurring in other, less densely populated areas of the country.

Potent tools to reduce HIV incidence are available and advancing. Widespread access to HIV treatment and improving rates of viral suppression bring concomitant benefits for HIV prevention. Expanded use of HIV pre-exposure prophylaxis (PrEP) stands to make a population-level impact on HIV incidence. The preventive impact of these biomedical prevention approaches, however, are impeded by substantial structural challenges that impede access to and use of biomedical HIV prevention. This is reflected in sharp racial/ethnic disparities in PrEP uptake and the late presentation of HIV-infected minorities to care. Effective engagement of hard-to-reach populations and impactful support for behavioral HIV risk reduction and biomedical prevention strategies will require novel approaches.

Smart phones, the internet, and other wireless technologies have dramatically changed the ways that people meet and interact. They also offer new approaches to track and gather information from diverse populations, as well as ways to deliver and test HIV prevention interventions. The LITE initiative (RFA-AI-16-031) has demonstrated the effectiveness of digital approaches for screening, recruiting, and retaining very large (i.e. more than 5,000 participants) observational cohorts of individuals at-risk for HIV infection, with enough HIV seroconversions occurring on study to provide adequate statistical power for digital clinical trials. LITE investigators have used postal mail and in-home HIV test kits to assess HIV-infection status, and various digital-based interventions have been used to reduce risks of HIV-infections.

There is an opportunity to evolve from digital cohorts to digital clinical trials. Digital clinical trials use remote methods (e.g., online surveys, postal mail, and package delivery) to collect participant data and samples, and they involve limited or no in-person visits. Digital clinical trials offer a number of advances relative to clinical trials conducted through brick-and-mortar locations or clinical trials units (CTUs): 1) the preponderance of U.S. persons, including those at risk for HIV, demonstrate ready access to the Internet and broad use of home-delivery services; (2) online recruitment is highly efficient and inexpensive for rapidly establishing very large cohorts (i.e., many thousands of participants); 3) the remarkably large study sizes attainable through digital enrollment allow clinical trials to be powered on an HIV incidence outcome, as well as on outcomes related to HIV incidence, such as PrEP use, self-reported behavior change, and STD incidence; 4) electronic cohorts facilitate engagement of participants in rural, underserved areas and can overcome geographic limitations to assemble large subgroups of MSM, such as adolescents, or groups such as transgender persons who are spread thinly throughout the U.S.; 5) the ability to rapidly enroll participants using smartphone apps and other electronic methods facilitates digital clinical trials that can be conducted more rapidly than clinic- or community-based clinical trials, and, thus, results can be more quickly available to inform resource allocation; 6) digital interventions are inherently scalable and can be implemented inexpensively if found useful.

A growing evidence base indicates that digital interventions, which are delivered online or through smartphones, can advance primary HIV prevention outcomes such as reduced sexual risk behavior, decreased sexually transmitted infections, and improved use of oral PrEP. Relative to brick-and-mortar based HIV prevention programs, digital HIV prevention interventions have the unique potential to rapidly scale their delivery to exceptionally large numbers of people in regionally diverse U.S. settings. Digital HIV prevention programs may also be helpful for reaching populations in underserved rural settings, as well as populations that experience substantial stigma and discrimination in the real world. Developing and fielding effective and scalable, digital HIV interventions, independent of geography, could importantly contribute to reducing the incidence of HIV in the United States.

Research Objectives and Scope

The primary goal of this FOA is to fund investigators to use electronic methods to recruit and retain large samples of MSM and/or transgender individuals in the U.S. who are at high risk of HIV-infection, to conduct digital interventions that promote HIV risk reduction, which may include encouraging PrEP use, and to remotely test the intervention’s impact on reducing HIV incidence through mailed HIV test kits or other means. Applicants should expect either to enroll 5,000 or more participants or to justify why fewer participants are needed based on expected HIV incidence. Applicants must demonstrate the capacity to digitally enroll large numbers of HIV-negative high-risk groups, with an emphasis on U.S. individuals at high risk of HIV seroconversion, such as youth (age 13-34 years, with emphasis on age 18 or younger), racial/ethnic minorities, and rural individuals. Applicants will be expected to establish and meet enrollment milestones for their studies, including overall enrollment goals, any benchmarks for stratified over-enrollment of youth, racial/ethnic minorities, and rural residents, and numbers of acute HIV infections at baseline as an indication of expected HIV incidence.

Studies of particular interest include:

• Development and testing of scalable, digitally-delivered primary HIV prevention interventions that promote HIV risk reduction and may include support for PrEP use among MSM and transgender persons through digital clinical trials that use incident HIV infections as the main study endpoint, and which rely on remote administration of study assessments and sample collection.

Requirements for this application include:

• Demonstrated ability to enroll sufficient numbers of high-risk individuals in the U.S. to obtain sufficient statistical power for the prevention trial. Studies planning to enroll fewer than 5,000 high-risk individuals need to justify their projected enrollment based on HIV incidence data for their sample population.
• Demonstrated ability to enroll large numbers of MSM participants who self-identify as black, Latino, or of mixed race.
• A digitally-delivered primary HIV prevention intervention, preferably with promising pilot data.
• A Planning Timeline and clinical trial milestone plan to complete all requirements to begin enrollment in the clinical trial within the first 12 months of the project period and to complete the trial within the five-year project period. The Planning Timeline may include plans to finalize and, if necessary, pilot the clinical trial protocol, to develop plans for statistical analysis, data management, and development of consent forms. Applicants must obtain NIAID approval of their prevention trial protocol in the first year of the award (NIAID protocol policy here).
• Awardees are required to refer all participants testing HIV-positive to treatment.

A secondary goal of this FOA is to facilitate interactions among awardees to share approaches, data, and methods, and to develop harmonization standards. Awardees will participate in regular project management calls and are encouraged to plan for and attend annual meetings focused on cohort enrollment, intervention development, and discussion of individual awardee program progress, as well as to foster collaborations among the funded investigators to share approaches, data, methods and data harmonization standards.

Projects may additionally explore:

• Characterization of subgroups of MSM and transgender persons who could be targeted for HIV prevention strategies.
• Descriptions of risk behaviors and risk determinants in these key populations that can inform onward interventions to reduce HIV incidence.
• Geospatial analyses of patterns of HIV infection in both rural and urban areas of the United States.
• Studies using the assembled cohorts to investigate patterns of HIV testing and mechanisms to optimize testing frequency and rapid linkage to treatment.
• Monitoring HIV PrEP awareness, uptake, and adherence and identifying associated determinants.
• Mental health as a determinant of HIV exposure risk and engagement in prevention strategies.
• Multi-level analyses of individual and social contextual determinants of HIV risk behavior or seroconversion in the United States.
• Efforts targeting youth populations as outlined in this announcement.

Applications including the following types of studies will be considered non-responsive and will not be reviewed:

• Studies of individuals living with HIV.
• Studies of subjects residing outside the United States or its territories.
• Studies not proposing the use of technology-focused approaches to establish and follow large numbers of HIV-negative individuals for epidemiologic and clinical trials research.
• Studies not focused on at least one of the high-risk groups targeted by this FOA: MSM and transgender men and women, where at least half of planned MSM participants are self-identified as black, Latino, or of mixed race.
• Applications proposing a clinical trial that requires an IND.

All clinical trial planning activities for the first trial must be completed and the trial must open to enrollment within 12 months of receiving the award.

This FOA may support clinical trial planning activities for the trial such as:

• Development of study design
• Identification of collaborators and methods of enrollment
• Development of the clinical protocol and informed consent
• Development of the statistical analysis plan
• Development of the data management plan
• Training of study personnel related to conduct of the trial
• Enrollment and recruitment of study subjects
• Data collection, management, and quality control
• 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
• Site monitoring

NIAID reserves the right to specify:

• Requirements for safety monitoring as applicable

Applicants should review the NIAID Clinical Terms of Award and associated guidance documents, policies, and procedures as they will be terms of these awards (https://www.niaid.nih.gov/grants-contracts/niaid-clinical-terms-award). Applicants should also review the DAIDS Clinical Research Policies and Standard Procedures Documents (https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures) that describe requirements for DAIDS-funded clinical research. Investigators are also referred to NIAID’s Clinical Research Toolkit website (https://www.niaid.nih.gov/research/trans-niaid-clinical-research-toolkit).

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. Each application must include a detailed planning timeline for the award period that allows the first clinical trial to open for enrollment within the first 12 months of the award and provides for completing the clinical trial within the period of award; these milestones will be incorporated into the terms of award. Funding levels beyond the first year are dependent on opening the first trial for enrollment by the end of the first 12 months. NIAID may re-negotiate a reduction of funding or period of performance based on lack of achievement of milestones.

In addition to the planning timeline for the award, the application requires specific milestones for the Study Timeline associated with the execution of the clinical trial.

Applications that lack the Planning Timeline will be considered non-responsive and not reviewed.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

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) 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 to register in eRA Commons.Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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)

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guideexcept 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.

Letter of Intent

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:

Chelsea Boyd, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-6664
Email: Chelsea.boyd@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 followed.

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

Within the biosketch, the PDs/PIs should describe any experience they may have in the planning, direction and oversight of digital clinical trials. Moreover, the biosketches should describe the abilities of their research team to find, enroll, and follow the relevant populations and to conduct data analysis.

R&R or Modular Budget

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:

Provide the overall goals or hypotheses for the entire project period. The first year of the project should be used to prepare and, if necessary, test or pilot the digital prevention trial.

Research Strategy:

Clearly state the significance of the proposed trial and the importance of the research question in terms of advancing HIV prevention among HIV-negative U.S. persons at high risk of HIV seroconversion. Discuss how the trial will test the proposed hypotheses. Explain the need for and timeliness of the planned studies.

Without duplicating information in the biosketches, please describe any previous experience in performing the following activities: enrollment of high risk populations, including documenting their minority status, age, rural or urban status, and sexual risk status, as well as measuring retention rates, and annual HIV seroconversion rates.

Provide detailed descriptions of any supporting data and your experimental approach for the following:

• Enrollment of high-risk populations with minimal or no face-to-face interaction and use of primarily digital enrollment procedures.
• Approaches to reduce barriers associated with bias and loss to follow-up using a non-clinic based approach.
• Use of digital methods for recruitment and participant follow-up activities including the working definition of retention and the methods for qualitatively evaluating and improving the recruitment and retention process.
• In the context of a digital approach, strategies to access and enroll high-risk groups, including transgender persons and MSM, and for oversampling particular target populations such as youth, racial/ethnic minorities, and rural residents.
• In the context of a digital approach, strategies to access and enroll participants under age 18 years and any special considerations for enrolling and following this population.
• Strategies in digital settings to verify the race, sex, and age of participants, including strategies to ensure that participants are discrete, not duplicated, and to document the country of residence, for example, individuals living in the United States or its territories.
• Unique statistical analysis challenges posed by an HIV incidence endpoint and approaches to manage other expected study outcomes.
• Ways to determine co-enrollment of study participants in other studies or other clinical trials in the context of digital enrollment and intervention.
• Methods to determine the HIV status of participants in a non-clinic setting, for example use of screening programs, home-based tests, HIV self-tests, electronic medical records and self-report. Also methods to estimate time from HIV infection to study enrollment.
• Prediction of expected numbers of HIV seroconversions among study participants receiving or not receiving HIV prevention interventions.
• Approaches for referring HIV-positive participants for HIV treatment.
• In the context of digital enrollment and intervention, discuss the unique needs for assessment of HIV risks for participants, including measuring HIV risks, health seeking behaviors, and PrEP uptake and use.
• Strategy to assess contextual and other factors potentially associated with HIV seroconversion or its surrogate measures.

Describe plans to organize and convene a Scientific Advisory Board, including expertise composition but do NOT name or contact any potential members of the Board in the application.

Describe safeguards (e.g. processes, including institutional processes, encryption, hardware, software, and data storage locations ) in place to protect data privacy, security and integrity.

Planning Timeline. In a separate section titled, Planning Timeline, applicants must provide a well-defined Planning Timeline for the period from award until opening enrollment, which will be no later than the end of 12 months of the award. Activities in the planning timeline could include, but are not limited to developing, adapting, and piloting the proposed prevention intervention, piloting methods for providing laboratory support and testing, developing protocols for safety monitoring in a non-clinical based setting, and preparing and finalizing documentation required for a final protocol and IRB approval. Timelines for clinical trials, beginning with enrollment, will be described within Section 2.7. Study Timeline of the PHS Human Subjects and Clinical Trials Information.

Letters of Support:

• Provide all appropriate letters of support, including any letters necessary to demonstrate the support of collaborators, laboratories, other health providers.
• If co-funding or in-kind support is planned from non-NIH sources, include letters outlining details of the commitment (e.g., type, amount and source of support), signed by a business official on organization letterhead.
• If the project relies upon patentable ideas, trade secrets, privileged or confidential commercial information or materials that are not owned by the applicant, but are necessary for the trial itself, the applicant must include documentation of availability of data and/or resources to the applicant for the proposed clinical trial.

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.

The following modifications also apply:

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

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

• Although not required, applicants may include a complete Clinical Protocol to support their ability to implement the clinical trial within 12 months. The filename Clinical Protocol pdf should be used and will be reflected in the final image bookmarking for easy access for reviewers. There is no page limit for this section, but applicants are urged to be succinct. The Clinical Protocol may include a schema and the Subject Informed Consent Form(s). When the final blank informed consent form is not available at the time of application, a draft blank subject consent form may be included.
• Investigators are referred to the DAIDS Protocol and Informed Consent Development website at https://www.niaid.nih.gov/research/daids-clinical-research-protocol-informed-consent.

When involving human subjects research, clinical research, and/or NIH-definedclinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Note: Applicants must include a Study Record for at least one Clinical Trial, which will begin no later than the 12th month of the award.

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Describe unique challenges and approaches to a digital non-clinic-based recruitment plan. Describe engagement and retention strategies in the context of digital strategies.

2.7 Study Timeline

All applicants must provide a Study Timeline for the entire duration of the award, including specific milestones for the following activities:

• Submission of the Clinical Protocol and Subject Informed Consent Form for NIAID review
• Completion of regulatory approvals for the Clinical Protocol as applicable
• Opening enrollment of the first trial (within 12 months of award)
• Enrollment of 25%, 50%, 75% and 100% of the study subjects
• Primary completion date for the trial
• Last participant off study (must be within period of award)
• Submission of study results to https://clinicaltrials.gov/ (must be within 12 months of the primary completion date)
• Within this section, discuss the feasibility of achieving and completing the milestones on-time, including alternate approaches and contingencies for dealing with potential problems and impediments.

2.8 Enrollment of First Subject

Inclusion Enrollment Report(s)

Applicants should create one Inclusion Enrollment Report (IER) or more than one IER to enable reporting depending on the scientific goals for the study and whether monitoring of inclusion enrollment would benefit from being combined or separated. NIAID recognizes that traditional definitions of a geographical site may not be relevant in this setting.

Section 3 - Protection and Monitoring Plans

3.3 Data and Safety Monitoring Plan

For this FOA, it is anticipated that a Safety Monitoring Committee should provide the appropriate level of monitoring. Additional guidance can be found at:

https://www.niaid.nih.gov/research/daids-clinical-research-event-reporting-safety-monitoring and https://www.niaid.nih.gov/sites/default/files/studyprogsafetymonitor.pdf

3.5 Overall Structure of the Study Team

Describe the management of the study team with respect to the various roles and responsibilities that are unique to implementation and conduct of digital clinical trials. In addition, include the role of non-traditional study team members (e.g. social media consultants, privacy in digital platforms, Scientific Advisory Board, etc.) in the study team functions.

Section 4 - Protocol Synopsis

Section 4.3 Outcome Measures

In addition to standard instructions, include innovative use of digital and remote assessment of trial measures and outcomes.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

For each required attachment, applicants must include the available information and describe the plan including the timeline/milestone for developing final versions in time to implement the clinical trial within the first 12 months.

1. Laboratory Measurement Assays

The filename Laboratory Assays Plan.pdf should be used and will be reflected in the final image with bookmarking for easy access for reviewers. There is no page limit for this section, but applicants are urged to be succinct.

• Describe the assays proposed to measure HIV status. Provide data or references supporting the reliability of the assays and the validity for their use. Describe plans to adhere to NIAID’s policies when proposing endpoint assays that are for investigational use only, and not approved by the FDA nor validated by the International Council for Harmonisation (ICH) or U.S. Pharmacopeia. If assay results will be used to determine participant eligibility for trials or treatment decisions during trials, address plans to ensure the relevant assays are CLIA compliant and performed in CLIA-certified laboratories. Address compliance with Good Clinical Laboratory Practices (GCLP) and for performing proficiency assessments. For guidance, see: https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures.
• Describe plans manage the quality of the assays by leveraging resources, collaborations, and/or sources of external support.

2. Clinical Site Monitoring

The filename Clinical Site Monitoring Plan.pdf should be used and will be reflected in the final image bookmarking for easy access for reviewers. There is no page limit for this section, but applicants are urged to be succinct.

• Describe plans to conduct independent clinical site monitoring as appropriate. Refer to https://www.niaid.nih.gov/research/daids-clinical-site-implementation-operations, especially the policy Requirements for On-Site Monitoring. (https://www.niaid.nih.gov/sites/default/files/onsitemonitor_reqs.pdf.)

3. Good Clinical Practices, Good Laboratory Practices, and Good Manufacturing Practices

The file name GCP, GLP, GMP Plan.pdf should be used and will be reflected in the final image bookmarking for easy access for reviewers. There is no page limit for this section, but applicants are urged to be succinct.

• Describe plans to implement and monitor Good Clinical Practices (GCP) (see NOT-OD-16-148), Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP), as appropriate.

4. Regulatory Plan

The filename "Regulatory Plan.pdf" should be used and will be reflected in the final image with bookmarking for easy access for reviewers. There is no page limit for this section, but applicants are urged to be succinct.

• Describe plans and capability to provide appropriate regulatory support for the development and implementation of the clinical trial.
• Describe plans to comply 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.

5. Data Management Plan

The filename Data Management Plan.pdf should be used and will be reflected in the final image with bookmarking for easy access for reviewers. There is no page limit for this section, but applicants are urged to be succinct.

• Include a description of the approach to data management and validation, including data management systems, methods of data entry and cleaning, event tracking and logistics, case report forms, and methods for monitoring the quality and consistency of the intervention(s) and data collection; policies and methods for ensuring blinding of study results; data confidentiality and subject privacy; adjudication of events (as needed); and data reports. Indicate plans for storage of data in a suitable data repository.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.

Note: Applicants must not propose a delayed onset study.

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

3. Unique Entity Identifier and System for Award Management (SAM)

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

4. Submission Dates and Times

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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.

7. Other Submission Requirements and Information

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

For this particular announcement, note the following:

Applicants are required to provide a Study Record. NIAID anticipates that applicants will vary in the quantity and nature of detail they can provide in various sections of the study record at the time of application submission. Applications will be evaluated on the feasibility to open to enrollment by the end of the first year of the award and not on the completeness of the study record alone. Applicants are not expected to be at identical stages of trial readiness at the time of application submission.

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? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Specific to this FOA:

• To what degree does the trial target U.S. populations at high risk for HIV infection?
• Does the proposed intervention hold promise for reducing HIV incidence through promotion of HIV risk reduction and/or PrEP use? To what degree is there promising pilot data regarding the intervention acceptability, feasibility, and potential impact?
• Does the study design allow changes in HIV incidence to be attributed to the intervention proposed? Is the proposed intervention scalable for implementation to reduce HIV infections in the U.S.?

Investigator(s)

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

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Specific to this FOA:

Do the PDs/PIs and the research team demonstrate experience in the conducting of digital research and interventions? Has this team digitally recruited and retained large numbers of U.S. persons at high risk for HIV?

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?

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Specific to this FOA:

To what degree does the research methodology reflect innovative use of digital and remote assessment of trial measures and outcomes?

Approach

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

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

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Specific to this FOA:

• Is the proposed digital intervention feasible and acceptable for use in the targeted populations? Does innovative use of digital and remote assessment of trial measures and outcomes support the goal?
• How feasible is the plan to enroll a group of MSM where at least half MSM participants are self-identified as black, Latino, or of mixed race and/or the plan to enroll transgender individuals?
• Do milestones include targets for overall enrollment, enrollment of key subgroups, groups such as transgenders, youth and rural populations?
• How well does the research plan address stratified enrollment or over-enrollment of key groups such as transgenders, youth and rural populations? Does the design adequately consider duplicate enrollment?
• How well is the proposed enrollment size justified based on HIV incidence data in the sample population?
• Does the study adequately consider other HIV prevention activities that may be occurring independently in the targeted populations in terms of the effect on HIV incidence?
• Is the Planning Timeline for the first year of the award likely to allow the intervention to begin by the end of the first year of the award? Are critical needs included in the timeline? Are contingency plans provided to address possible obstacles to achieving planning timelines?
• Do milestones include targets for overall enrollment, enrollment of key subgroups, and baseline seroprevalence?
• Are plans for laboratory measurement assays, clinical site monitoring, GCP/GLP/GMP practices, regulatory support and data management appropriate and well-described?
• Are sufficient safeguards (e.g. processes, including institutional processes, encryption, hardware, software, and data storage locations ) in place to protect data privacy, security and integrity

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?

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

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

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Study Timeline

Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate? Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Specific to this FOA:

Are the milestones proposed in the Clinical Trial Study Timeline feasible and justified?

Protections for Human Subjects

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

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

Inclusion of Women, Minorities, and Individuals Across the Lifespan

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

Vertebrate Animals

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.

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) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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.

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.

2. Review and Selection Process

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 on the basis of established PHS referral guidelines 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 appropriate national Advisory Council or Board. 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.

3. Anticipated Announcement and Award Dates

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.

Section VI. Award Administration Information

1. Award Notices

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

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

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

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

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

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.

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.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-individuals/section-1557/index.htmlhttps://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see https://www.hhs.gov/civil-rights/for-individuals/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.htmlor 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.

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

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

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

• The planning, direction, and execution of the proposed research, including: definition of objectives and approaches; implementation; data management and analysis, interpretations and publication of results.
• Referring all subjects testing HIV-positive to treatment. Information about referral efforts of all subjects who seroconvert on study is also required in annual progress reports.
• Making drafts of manuscripts available for review (electronically) to the NIH Project Scientists and other NIH staff at the time they are circulated to co-authors and when the final manuscripts are submitted for publication. This ensures that NIH program officials can maintain an up-to-date summary of program accomplishments and can prepare for press-releases of findings if warranted.
• 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:

During performance of the award, the NIH Project Scientists, with assistance from other NIH scientific staff will provide appropriate assistance, advice and guidance in the design of the activities; the analysis of data; management and technical performance; and preparation of publications. The Project Scientists will serve as a resource for scientific and policy information related to the goals of the awardee's research. However, the role of NIH staff will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus and that NIH staff will be given the opportunity to offer input into this process. The manner of reaching consensus and final decision-making authority will rest with the Principal Investigator.

The NIH Project Scientists will also:

• Monitor study results and quality assurance across all research sites to ensure the production of high-quality, unbiased results.
• Facilitate access to technical resources to increase harmonization and interoperability of study datasets.
• Periodically request research data for use in preparing internal reports on award activities.
• Additionally, an agency program official or IC program director will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.

Areas of Joint Responsibility include:

• Participating in the planning for meetings of the award recipients, to focus on cohort enrollment, study initiation and study results.
• Working to facilitate shared goals, to enhance resource sharing and to foster collaborations.
• Developing a data structure that results in a findable, accessible, interoperable, and reliable dataset to be made available for controlled access public use at the end of the program.
• Coordinating and facilitating access to datasets.
• Providing input and generating research presentations and publications of D-LITE research findings.

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.

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement. A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreementsare 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.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants. eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threatensubmission by the due date, and post-submission issues)

Finding Help Online:http://grants.nih.gov/support/(preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

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

Grants.gov Customer Support(Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email:support@grants.gov

Gerald B. Sharp, Dr.P.H.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3217
Email: GSharp@niaid.nih.gov

Michael J. Stirratt, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 240-627-3875
Email: stirrattm@mail.nih.gov

Sonia Lee, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-594-4783
Email: leesonia@mail.nih.gov

Chelsea Boyd, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-6664
Email: Chelsea.boyd@nih.gov

Annie Grimes
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-7315
Email: annie.grimes@niaid.nih.gov

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone:?301-443-2805
Email: siscor@mail.nih.gov

Bryan’s Clark, MBA
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-435-6975
Email: clark1@mail.nih.gov

Section VIII. Other Information

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.