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

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

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

This Funding Opportunity Announcement (FOA) solicits applications that will advance understanding of vaccine regimens and immune responses that sustainably suppress virus in HIV-infected individuals. The FOA will support small, multi-arm, comparative clinical trials designed to identify correlations between levels of induced immune response and HIV virologic control. Vaccines may be combined with adjuvants and/or other modifiers of the immune response to HIV.

HIV-infected persons currently require lifelong treatment with combination antiretroviral therapy (cART). The development of therapeutic vaccines that induce HIV-controlling immune responses could end the need for lifelong treatment. However, it has proven exceptionally difficult to induce protective immune responses using vaccination strategies. Despite a number of clinical trials, effective products have not been developed.

Substantial evidence suggests immune responses can reduce viral loads (VL) in HIV-infected persons. Some individuals naturally suppress VL to low levels without cART. These elite controllers often produce CD8 T cell responses recognizing specific HIV peptides. Other individuals maintain low VL after cART is withdrawn. The CD4 T cells and natural killer (NK) cells in these post-treatment controllers display enhanced functional activity. Finally, some infected individuals develop broadly neutralizing HIV-specific antibodies (bNAb) that exhibit antiviral activity when cloned, manufactured and administered passively to infected persons. Together, these observations suggest HIV should be susceptible to vaccination-induced immune-mediated control. However, robust correlates of immune-mediated VL control in HIV-infected persons have yet to be identified, and there are sizable gaps in both our knowledge about the most effective mechanisms for suppressing HIV and how to sustainably maintain protective responses.

Chronic inflammation and immune dysregulation persist in HIV-infected persons despite VL suppression with cART. These conditions have a variety of effects on immunity that may interfere with vaccine responsiveness. One prominent aspect of the dysregulation is T cell exhaustion, characterized phenotypically by upregulated expression on T cells of checkpoint receptors like PD-1. In experimental models of HIV infection, and in human cancer patients, therapeutic blockade of checkpoint pathways can increase and/or broaden T cell responses. Thus, therapeutic vaccine strategies for HIV may benefit from co-administration of immunomodulatory or anti-inflammatory agents that antagonize suppressive checkpoint or inflammatory pathways.

The VL rebound that follows withdrawal of cART is thought to result from activation of HIV reservoirs comprised of latently infected cells containing integrated HIV DNA. The latently infected cells may be invisible to the immune system if they do not express sufficient levels of HIV antigens. It may be possible to expose these quiescent reservoirs through the use of latency reversing agents (e.g., HDAC inhibitors, PKC agonists, TLR agonists). However, some reservoirs may reside within sanctuaries that are inaccessible to cytotoxic T cells. Thus, therapeutic vaccine strategies targeting HIV reservoirs may benefit from co-administration of agents that induce expression of HIV antigens and/or disrupt the capacity of HIV to hide within sanctuary sites.

Perhaps the largest challenge to therapeutic vaccine strategies is the capacity of HIV to escape from immune responses. The dominant T cell responses elicited during acute HIV infection typically target regions of the virus that can mutate without substantially diminishing viral fitness, and the HIV reservoirs in patients on cART are replete with proviruses harboring mutations that have escaped from dominant T cell responses. Thus, therapeutic vaccine strategies may need to overcome the robust priming of these dominant but ineffective responses, perhaps by targeting conserved regions of HIV that are unable to mutate without compromising viral fitness.

HIV also escapes from B cell responses, making it difficult for antibodies to bind and neutralize its envelope glycoproteins. Nevertheless, some individuals produce measurable titers of bNAb that recognize many HIV variants. Researchers are designing sets of immunogens engineered to guide the de novo maturation of bNAb-producing B cells. While primarily designed for preventive HIV vaccines, some of these constructs may be useful in therapeutic settings as well. Non-neutralizing antibodies also appear to protect against HIV acquisition, perhaps via antibody-dependent cell-mediated cytotoxicity or phagocytosis. Thus, the induction or administration of HIV-specific antibodies may be an important component of HIV therapeutic vaccine strategies.

The goal of this FOA is to support research that will advance understanding of vaccine regimens and immune responses that sustainably suppress virus in HIV-infected persons. Specifically, it will support hypothesis-driven mechanistic studies utilizing small, comparative, multi-arm, clinical trials. Vaccination approaches that aim to sustainably elicit, boost and/or activate HIV-specific T cells, NK cells, antibodies, or other effector mechanisms are responsive to this FOA, as are approaches that aim to elicit combinations of protective mechanisms.

This FOA will support both a primary trial and a follow-on trial designed to confirm the observed correlations between specific immune response and virologic control and further optimize the response. The goal is to incrementally develop effective therapeutic vaccination strategies by increasing our understanding of protective responses and working iteratively to improve the potency of those responses.

The target population is HIV-infected persons virologically suppressed by cART. Accordingly, the proposed readout assays must be able to quantify the effects of the therapeutic interventions on measures of persistent virus in this population (e.g., low-level viremia, cell-associated HIV RNA). The use of novel immune and virologic assays is encouraged, as is the use of functional assays (e.g., viral inhibition/suppression assays) and the extensive characterization of responses pre- and post-vaccination.

The proposed interventions must include vaccines, perhaps in combination with adjuvants and/or other modifiers of the immune response to HIV. To ensure timely initiation of studies, applicants are strongly encouraged to use agents already approved for human use or agents that are ready to be tested in clinical trials. The first trial must open to enrollment within 12 months of award and can be conducted at no more than 2 clinical research sites located within the United States.

Specific areas of interest

• Vaccination strategies designed to harness HIV-specific T cell, B cell, or NK cell effector functions, elicit de novo HIV-specific responses, or broaden existing HIV-specific responses
• Comparisons of vaccine vectors, HIV immunogen constructs, vaccine adjuvants, vaccine or adjunct dosages, or the order and timing of treatments
• Combinations of vaccines and immunomodulators, anti-inflammatory agents, latency-reversing agents, sanctuary-disrupting agents, or HIV-specific monoclonal antibodies
• Endpoints based on correlations between measures of immunity and virologic criteria
• Novel therapeutic vaccination approaches

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

• Animal models of HIV infection
• Vaccine strategies that primarily aim to boost dominant existing responses
• Comparisons of a single treatment arm versus a placebo arm
• Treatment interruptions as the only means to evaluate virologic control; treatment interruptions are permitted but not as the primary measure of virologic response
• Clinical trials that are conducted outside of the U.S.

Clinical Trial and Regulatory Support

All clinical trial planning activities for the first trial must be completed by the time of application submission. The first trial must open to enrollment within 12 months of receiving the award.

This FOA will NOT support clinical trial planning activities for the first trial, such as:

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

This FOA will support clinical trial planning activities for the second trial, such as:

• Development of the clinical protocol and informed consent
• Development of the statistical analysis plan
• Development of the data management plan
• Development of the Investigator’s Brochure

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

• Regulatory activities to support implementation of the trial
• 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: 1) whether an IND (Investigational New Drug)/IDE (Investigational Device Exemption) application should be submitted to an appropriate regulatory agency; 2) the entity (NIAID, primary awardee, etc.) who will hold the IND/IDE; and 3) the requirements for the establishment of a DSMB (Data Safety Monitoring Board)/SMC (Safety Monitoring Committee). In most cases, it is expected that the NIAID will not hold the IND/IDE.

Applicants should review the NIAID Clinical Terms of Award and associated guidance documents, policies, and procedures that will be made terms of these awards (https://www.niaid.nih.gov/grants-contracts/niaid-clinical-terms-award ), and 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. Milestones commensurate with opening enrollment within 12 months of award start date and completing both clinical trial(s) within the period of award will be incorporated into the terms of award. Funding will be provided for the first trial; funding for the second trial will be contingent upon the results from the first trial meeting criteria to warrant an additional trial aimed at further strengthening or focusing the relevant immune responses. NIAID may negotiate funds or the period of performance based on lack of achievement of milestones.

If requested by NIAID, a Scientific Advisory Board will be established by the applicant, approved by NIAID staff, and convened to review progress and provide the applicant with evaluations, advice, and recommendations concerning the ongoing and planned research activities.

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

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

Higher Education Institutions

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

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

• 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.

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

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, 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:

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.

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

Provide budgets for the entire project, including the primary clinical trial, the proposed follow-on trial and all data analysis. Clearly identify and justify all costs requested in Year 1 and justify any changes in costs in future years. In addition to funds required to support clinical trial conduct, budget sufficient funds to support independent study and site monitoring, regulatory submissions, and safety oversight activities, as appropriate. Note sources of support for the trial outside of this award in the budget justification and document by a letter of support (below). These outsource costs do not constitute cost sharing as defined in the current NIH Grants Policy Statement and should not be presented either as part of the requested budget or as Estimated Project Funding.

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: State the hypothesis, goals, and expected outcomes of the proposed intervention(s). Specific attention should be given to the rationale for the proposed vaccination strategy, including its capacity to elicit the desired immune responses, and the hypothesized mechanisms of action that will lead to a measurable virologic effect.

Research Strategy:

Significance: Clearly state the significance of the proposed trials and the importance of the research question. Discuss how the trials will test the proposed hypotheses and why there is clinical equipoise. Explain the need for and timeliness of the studies. Describe how results will impact clinical approaches for treating or curing HIV infection.

Approach: Provide detailed descriptions of the supporting data and the experimental approach, including:

• a hypothesis proposing a means to induce an immune response, or set of responses, that will exert a measurable virologic effect in HIV-infected humans taking effective antiretroviral therapy.
• the supporting data and rationale for the proposed immunotherapeutic intervention, or combination of interventions, chosen to induce or augment the desired immune responses. This rationale should justify the selection of the specific intervention and dose/schedule specified in the Clinical Protocol.
• the supporting data and rationale for the primary immunologic and virologic endpoints.
• the supporting data and rationale for the choice of the study population.
• the overall strategy, which must include a multi-arm clinical trial designed to induce the desired immune responses to varying degrees and demonstrate correlations between the levels of the induced immune responses and measures of virologic control. The strategy must also include plans for a follow-on trial that will further advance the goal of incrementally developing an effective therapeutic vaccination regimen by increasing understanding of protective responses and working iteratively to improve the potency of those responses. A detailed description of the follow-on trial is not required. Rather, the application must describe the rationale and general design for the follow-on trial. One goal of the follow-on trial must be to replicate any key findings observed in the first trial.
• the criteria for determining whether the results from the first trial warrant an additional trial aimed at further strengthening or focusing the relevant immune responses.

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 suppliers), 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 study agents or materials that are not owned by the applicant, but are necessary for regulatory approval or for the trial itself, the applicant must include documentation of availability of data and/or resources to the applicant for the proposed clinical trial.

If the project involves collaborations with NIH intramural scientists, refer to https://oir.nih.gov/sourcebook/ethical-conduct/research-ethics/nih-policies/intramural-extramural-collaborations and https://www.niaid.nih.gov/research/intramural-collaboration-extramural-funded.

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:

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

Include a complete Clinical Protocol. 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 should describe the first trial to be performed and must include a schema and the Subject Informed Consent Form(s).

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.

Applications that lack the Clinical Protocol are incomplete and will not be reviewed.

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

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.7 Study Timeline

Describe a series of milestones for completion of the clinical trial in a section entitled Milestone Plan. The milestones will undergo peer review and will be incorporated into the terms of award. The milestone plan is limited to 2 pages and should include a timeline for the following:

• Pre-IND meeting with the FDA, unless the FDA determined a meeting was not necessary or the FDA granted an IND exemption for the trial
• Submission of the first Clinical Protocol and Subject Informed Consent Form for NIAID review
• Completion of regulatory approvals for the first Clinical Protocol
• Recombinant DNA Advisory Committee (RAC) review, if applicable
• Opening enrollment of the first trial (within 12 months of award)
• Enrollment of 25%, 50%, 75% and 100% of the study subjects in the first trial
• Primary completion date for the first trial
• Submission of study results to ClinicalTrials.gov (must be within 12 months of the primary completion date)
• Opening enrollment of the follow-on trial
• Enrollment of 50% and 100% of the study subjects in the follow-on trial
• Primary completion date for the follow-on trial
• Last participant off study (must be within period of award)

Discuss the feasibility of achieving and completing the milestones on-time, including alternate approaches and contingencies for dealing with potential problems and impediments.

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

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, even for trials with two clinical sites. 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 study organization, administration, and management; roles of any advisory groups; oversight, responsibilities, and coordination of clinical and laboratory sites; and roles of any sub-contractors. Describe plans to organize and convene a Scientific Advisory Board, but do not name any potential members of the Board in the application or contact any potential members.

Section 4 - Protocol Synopsis

4.1 Brief Summary

Include the primary immunologic and virologic endpoints for the first trial to be performed.

4.4 Statistical Design and Power

Describe the statistical methods, including sample size and power calculations and the underlying assumptions (and data) used to link these calculations to the endpoints and to the hypothesis being tested. Even for small, exploratory studies seeking preliminary data to guide further research, justify cohort sizes using either power calculations or non-statistically powered justifications. If not highly powered, explain how the study aims to establish correlations between immune and virologic responses. Efforts to minimize intra-subject variability (e.g., replicate measures around key time points) should be highlighted. Although this initiative requires multiple active arms in each trial, it is acceptable to define success based on within arm results (e.g., a mean increase in Gag-specific CD8 T cells by more than 25% indicates success). Controls should be described and justified. The use of placebo arms may be appropriate both to facilitate safety assessments and to determine whether reasonable thresholds were chosen to indicate response/success.

4.6 Will the study use an FDA-regulated intervention?

4.6.a If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) Status

State whether an IND/IDE is necessary for the proposed trial. If an IND/IDE is necessary, identify the sponsor. Describe a plan and timeline for acquiring study products. If the interventions planned for the follow-on study are not yet ready for testing in humans, describe plans to ensure that those interventions will be ready in time for the trial.

See the Letters of Support section for instructions regarding documentation of availability of study agent and documentation of co-funding from partners.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

Applications that lack the attachments below are incomplete and will NOT be reviewed.

1. Laboratory Assays for Measuring Vaccine-Induced Responses

The filename Laboratory Assays.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 the assays proposed to measure vaccine-induced immune and virologic responses. Provide data or references supporting the reliability of the assays and 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 to maximize the number of immune/virologic endpoints measured and the quality of the assays by leveraging resources, collaborations, and/or sources of external support.

2. Clinical Site Monitoring

The filename Clinical Site Monitoring.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. 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.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 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 regulatory support for the development and implementation of the clinical trial.

Describe previous and planned interactions with the FDA on the proposed clinical trial. If a pre-IND meeting request was 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 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, or
• a copy of the FDA letter granting an IND/IDE exemption letter for the proposed 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

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.

Delayed Onset Study

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

Justification Attachment

Provide the Justification attachment for the follow-on study.

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

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

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

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

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

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

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

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?

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?

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

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

Does the application adequately address the following, if applicable?

Study Design

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

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

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

Data Management and Statistical Analysis

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

Specific to this FOA

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

Is it likely that the first trial can open to enrollment within 12 months of the award? Is the Regulatory Plan realistic and feasible? Does the application adequately address plans for independent clinical site monitoring?

Will the chosen interventions and approaches test the hypothesis? Will the studies advance understanding of the immunological mechanisms that can be induced by vaccination to sustainably suppress viral loads in HIV-infected humans? Are the endpoints appropriate? Is sufficient data provided or referenced in the Laboratory Assays attachment to support the reliability of the proposed assays? Will the assays measure the impact of the induced immune response(s) on virologic control? Did the applicant 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, did the applicant address plans to ensure the relevant assays are CLIA compliant and performed in CLIA-certified laboratories? Did the applicant describe plans to maximize the number of immune/virologic endpoints measured and the quality of the assays by leveraging resources, collaborations, and/or sources of external support?

Does the analysis include an appropriate sample size justification and power calculation, or an acceptable non-statistically powered justification? Will the proposed follow-on trial replicate key observations from the first trial and further advance the HIV therapeutic vaccine field? Were appropriate criteria proposed for determining whether the results from the first trial warrant an additional trial aimed at further strengthening or focusing the relevant immune responses? Is the overall proposed strategy consistent with an iterative approach to improving HIV therapeutic vaccine regimen?

Does the Clinical Protocol include, among other information, the study objectives, study design, population to be studied, study product/intervention, study procedures/evaluation, safety assessment, clinical management, statistical considerations, and data handling? Are the Clinical Protocol and Subject Informed Consent Form(s) for the first trial developed sufficiently to permit submission to institutional review boards and the FDA within the timeline in the Milestone Plan?

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

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

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

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

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

Specific to this FOA

Is there sufficient support, either internally or through consortium agreements, to comply with NIAID policies for regulatory activities, clinical trial oversight, laboratory and pharmacy activities, site monitoring, and data and safety monitoring?

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

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 listed in the Milestone Plan for each trial appropriate and feasible? To what extent are the milestones achievable and aligned with the Study Design and Regulatory Plan?

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.

Not Applicable

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see 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 http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://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 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 https://www.hhs.gov/ocr/about-us/contact-us/index.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 the study, including any modification of study design, conduct of the study, quality control, data analysis and interpretation, preparation of publications, dissemination of data, tools, and technologies, and collaboration with other investigators. The awardee agrees to accept close coordination, cooperation, and participation of NIAID staff in those aspects of scientific and technical management of the study as stated in these terms and conditions.
• Meeting NIAID policy requiring that studies be monitored commensurate with the degree of potential risk to study subjects and the complexity of the study. The full policy, including terms and conditions of award, is available at: https://www.niaid.nih.gov/grants-contracts/niaid-clinical-terms-award.
• Complying with DAIDS Clinical Research Policies and Standard Procedures, available at: https://www.niaid.nih.gov/research/daids-clinical-research-policies-standard-procedures
• Establishing Clinical Trials Agreements necessary to conduct the proposed trial.
• Ensuring that each clinical research site will follow the procedures required by the protocol regarding study conduct and monitoring, volunteer management, data collection, and quality control.
• Collecting and, if requested, providing NIAID or a designee with samples that may be used for cross-trial comparisons or inter-trial evaluations.
• Participating in conference calls convened by NIAID for the purpose of sharing information and data, including relevant unpublished data, among other HIV vaccine researchers.
• If requested by NIAID, establishing a Scientific Advisory Board (SAB) that will review progress and provide the applicant and NIAID staff with evaluations, advice, and written recommendations concerning the PD(s)/PI(s) ongoing and planned research activities.
• Accomplishing negotiated milestones. If negotiated milestones are not met, submitting a milestone report that includes a corrective action plan with amended milestones and plans to achieve them. The plan shall be provided to NIAID staff no later than 2 months following the missed milestone.
• Submitting a plan to close-out a clinical trial following a decision either by NIAID staff or the grantee that the clinical trial is no longer feasible. The plan must be approved and signed by the Institutional Official and the PD(s)/PI(s) listed on the award prior to submission.
• Awardees will retain custody of and have primary rights to the data and software developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.

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

NIAID Project Scientists will be responsible for:

• Accessing data generated under this Cooperative Agreement and periodically reviewing the data and progress reports. NIAID staff may use information obtained from the data for the preparation of internal reports on the activities of the study.
• Serving as a resource to provide scientific/programmatic support during the study period 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 regulatory documents and publications.
• Providing medical monitoring. A NIAID Project Scientist will monitor the clinical trials 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 NIAID Project Scientist will work with the company-assigned Medical Monitor. A NIAID Project Scientist may also serve as a member of the protocol team.
• Overseeing the adequacy of adverse event management and reporting and maintaining regular communications with the PD/PI and study team, which may include attendance at safety monitoring and related committee meetings.
• Approving members of the SAB, convening the SAB meeting, and receiving the SAB meeting report.
• 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. While the IND/IDE sponsor is responsible for clinical site monitoring, NIAID reserves the right to audit the site.
• Assessing progress of study milestones; as with any award, continuation, even during the period recommended for support, is contingent upon satisfactory progress. Progress will be monitored by an internal panel with outside consultants as needed and determined by NIAID. The schedule for these interim reviews will be based upon the duration of the clinical trial period. Continuation of funding will be dependent upon the awardee’s ability to show adequate progress towards accomplishing milestones identified in the application and negotiated prior to award.
• Closing clinical trials for lack of progress following review and consideration by NIAID staff. NIAID reserves the right to terminate or curtail a clinical trial; for example, in the event of (a) failure to meet recruitment milestones as per criteria established pre-award, (b) failure to obtain regulatory approval within 9 months, (c) failure to open the trial to enrollment within 12 months, (d) a substantial shortfall in data reporting and dissemination, quality control, or other major breach of the protocol, (e) substantive changes in the agreed-upon protocol with which the NIAID 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 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:

A Steering Committee (SC) composed of the PD/PI(s), Key Personnel, representatives from sites, representatives from laboratories, and the NIAID Project Scientist (Medical Monitor) will have primary responsibility for facilitating the conduct and monitoring of studies and reporting study results. As the components of the SC may be geographically dispersed, the SC should meet with monthly conference calls, supplemented as necessary by face to face meetings. Each full member of the SC will have one vote. A NIAID Project Scientist (Medical Monitor) will have voting membership. Awardee members of the SC will be required to accept and implement policies approved by the SC. Additional details and responsibilities of the SC may be negotiated at the time of award or post-award.

Dispute Resolution:

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

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

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

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

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

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

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

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

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

Stephen Smiley, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-627-3071
Email: stephen.smiley@nih.gov

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

Tseday Girma
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-747-7388
Email: tseday.girma@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.