Department of Health and Human Services

Part 1. Overview Information

Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Institute of Allergy and Infectious Diseases (NIAID)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

National Institute of Mental Health (NIMH)

Funding Opportunity Title
Long-Acting Drug Delivery Systems for ART Optimization in Children Living with HIV-1 II (LADDS II) (R61/R33 Clinical Trial Not Allowed)
Activity Code

R61/R33 Exploratory/Developmental  Phased Award

Announcement Type
New
Related Notices
  • August 31, 2022- Implementation Changes for Genomic Data Sharing Plans Included with Applications Due on or after January 25, 2023. See Notice NOT-OD-22-198.
  • August 5, 2022- Implementation Details for the NIH Data Management and Sharing Policy. See Notice NOT-OD-22-189.
Notice of Funding Opportunity (NOFO) Number
RFA-AI-23-061
Companion Funding Opportunity
None
Number of Applications

See Section III. 3. Additional Information on Eligibility.

Assistance Listing Number(s)
93.855, 93.242, 93.865
Funding Opportunity Purpose

The purpose of this Notice of Funding Opportunity (NOFO) is to accelerate the development of safe and effective long-acting drug delivery systems for improved, simplified treatment of HIV-1 in children. This NOFO invites applicants engaged in the development of existing long-acting platforms at early stages of development stages to perform specific preclinical activities that enable product optimization and accelerated translation to HIV-infected children. Collaborative research partnerships with industry are required. 

Key Dates

Posted Date
October 25, 2023
Open Date (Earliest Submission Date)
February 13, 2024
Letter of Intent Due Date(s)

30 days prior to the application due date

Application Due Dates Review and Award Cycles
New Renewal / Resubmission / Revision (as allowed) AIDS - New/Renewal/Resubmission/Revision, as allowed Scientific Merit Review Advisory Council Review Earliest Start Date
Not Applicable Not Applicable March 13, 2024 July 2024 October 2024 December 2024

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

Expiration Date
March 14, 2024
Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the Application Guide and the NOFO) 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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

  1. Use the NIH ASSIST system to prepare, submit and track your application online.
  2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.

  3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.


  4. Table of Contents

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Background

While some advances are being made in antiretroviral therapy (ART) coverage for pediatric populations, significant gaps remain. Currently available ART regimens for children have limitations and result in suboptimal viral suppression. Infants and young children achieve even lower rates of viral suppression and are more likely to experience subsequent viral rebound. Key factors underlying these suboptimal viral suppression outcomes include suboptimal regimen potency, poor adherence in all pediatric populations, often the result of poor regimen tolerability, lack of appropriate formulations, and poor palatability of many of the existing formulations. Additional factors contributing to limitations in treatment efficacy include high rates of pre-treatment drug resistance, hypervariable antiretroviral (ARV) drug exposures in early life due to ontogeny of drug metabolizing enzymes and transporters, significant and pervasive stigma, and non-disclosure of HIV status affecting mothers living with HIV, all of which can perpetuate poor virologic suppression rates and associated morbidity and mortality. While the roll out of a promising daily pediatric friendly oral dolutegravir formulation is underway in many low- and middle-income settings and presents the prospect of improving dismal viral suppression rates in this population, its impact is still limited by factors common to daily oral ART including stigmatization concerns and persistent adherence challenges.

Long acting ARVs represent a major therapeutic advance for people living with HIV across the age spectrum. They offer the prospect of enhanced treatment convenience and improved treatment adherence and stigma reduction, potentially removing a key barrier to maintenance of viral suppression. A combination of two long-acting injectable drugs has received regulatory approval for 2-monthly administrations for the treatment of HIV-1 in adults and adolescents and is being investigated in younger children. Another long-acting drug was also recently approved for 6-monthly administration in heavily treatment-experienced adults with multidrug resistant HIV-1 infection failing their current ART regimen. Despite such remarkable progress, further advances are needed to fully realize the promise of long-acting treatment for HIV treatment and sustained effort is necessary to accelerate their introduction in pediatric populations.

Long-Acting Drug Delivery Systems (LADDS) that can overcome limitations of daily oral ART are needed to significantly simplify dosing requirements and optimize ART outcomes in infants and children through achievement and maintenance of consistent and effective drug levels and suppression of HIV replication. Stimulating critical optimization and preclinical activities at an earlier stage in the product development lifecycle could significantly facilitate and accelerate introduction of promising LADDS platforms to young pediatric populations, often the last ones to benefit from treatment innovations.

Purpose

The goal of this Notice of Funding Opportunity (NOFO) is to support development of LADDS for optimized treatment of HIV-1 in children. This initiative will stimulate the optimization and evaluation of LADDS formulations in suitable preclinical animal models, at an earlier stage of adult drug development. Supporting optimization and evaluation of LADDS formulations in suitable preclinical animal models could accelerate clinical translation in pediatric populations and improve HIV-1 treatment outcomes in children.

Research Objectives and Scope

Successful applications will need to propose:

  • A long-acting drug delivery platform which must include the following attributes:
    • Platform is already in development, ideally for ART use in adult populations, however, innovative platforms in development for non-pediatric or non-ART use are also acceptable. This should serve to increase future market prospects of any product developed as part of this program.
    • A single platform that can deliver a complete ART regimen (consisting of 2 or more ARVs) for HIV treatment. However, inclusion of a single ARV is allowable, if needed to meet the minimum required dosing interval, even if separate administrations of the ARVs are required, provided that a complete ART regimen is proposed as part of the application.   
    • LADDS are able to support a minimum dosing interval of 8 weeks delivering ARV exposures that are expected to match adult exposure associated with efficacy or that remain above four times the protein-adjusted IC90 (paIC90) for each ARV at the end of the dosing interval.
    • ARVs and ART regimen chosen should be clinically relevant and ideally supported by existing treatment guidelines or if in pre-approval stages, recognized as high priority ARVs with early data supporting their high potential for future development.
  • Platform development that targets pediatric populations aged less than 12 years of age and preferably children less than 6 years of age and are well suited to accommodate unique growth and development characteristics of the target pediatric population.
  • Innovative PB-PK modelling and other in silico approaches to inform optimization of LADDS formulations for pediatric use and ARV dose selection to be applied in future pediatric clinical studies.
  • Appropriate use of preclinical animal models including:
    • Pre-clinical in vitro studies to characterize potential platforms and select ARV candidates during the R61 phase of the award.
    • An animal antiviral efficacy study of the LADDS candidate in age/maturation-matched non-human primates (NHP)s during the R33 phase of the award.
  • Socio-behavioral studies initiated during the R61 phase to assess end-user preferences and inform final production design. Where possible, preferences from all stakeholders (e.g., caregivers, children, providers) should be considered. The methods should be appropriate to the stage of product development, and could involve qualitative methods, discrete choice surveys, or other novel product acceptability methods. Where possible, the research should be iterative; that is, behavioral research should occur throughout development to provide feedback on the product at each step and inform future iterations. A behavioral scientist with appropriate expertise in the proposed behavioral methods should be included.
  • An industry/drug development partner which could be an established company, startup biotech company or non-profit organization with knowledge and resources to support early product development and regulatory interactions to enable a possible future path to market.
  • Planning for a Pre- Investigational New Drug (pre-IND) meeting with the FDA before the end of the R33 Phase.

In addition, inclusion of a pediatric-focused Quality Target Product Profile (pQTPP) is recommended at the R61 stage to summarize long-acting drug product critical properties and targets for development, with attention to those properties of key relevance to pediatric populations living with HIV in Low- and Middle-Income settings. The pQTPP might describe the essential product attributes (product release profile and duration of action, target age, optimal dosing regimen, dose flexibility, acceptable duration of PK lag periods and tails, maximum and minimum PK targets, PD targets, stability and storage requirements, desirable acceptability/desirability-derived attributes, and cold chain/storage requirements, regulatory pathway) by identifying optimal and minimally acceptable attributes for the drug and its platform.

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

  • de novo LADDS engineering.
  • New molecular entity discovery work.
  • Applications proposing human clinical trials.
  • LADDS not meeting the minimum duration of action defined in the NOFO.
  • Use of any live biotherapeutic or vector system.
  • Development of broadly neutralizing antibodies.
  • LADDS and ARV combinations previously developed for pediatric populations.
  • Applications without an industry partner as defined above.
  • Applications without end-user preferences studies.

Phased Innovation Awards

Due to the high-risk, high-impact nature of the research, this funding opportunity will use the R61/R33 phased innovation grant award mechanism. Support will be provided for up to two years (R61 phase) for pre-clinical research to optimize the long-acting platform and ARV payload, characterize duration of action, setting up and initiating the end user preferences studies and other related activities. Up to three years of support may follow (R33 phase) for additional activities as appropriate, such as completion of end user preferences studies, evaluation of optimized delivery system in suitable NHP models, preparation of the pre-IND package and pre-IND meeting with the FDA. Proposed milestones will be reviewed and negotiated prior to award with NIH program staff.

Before the end of the R61 phase, awardees will submit the R33 transition package, which includes a detailed progress report describing advancement toward the initial milestones and a description of how the completed work justifies continuation with the originally proposed R33 studies. These materials will be evaluated by NIH Program staff; grants selected for continued funding will be transitioned to an R33 award without the need to submit a new application. Transition to the R33 phase is neither automatic nor guaranteed; R33 funding decisions will be based on the original R61/R33 peer review recommendations, successful completion of transition milestones, Program priorities, and availability of funds. It is expected that approximately one-half of the projects supported during the R61 Phase will continue into the R33 Phase. 

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

Section II. Award Information

Funding Instrument

Grant: A support mechanism providing money, property, or both to an eligible entity to carry out an approved project or activity.

Application Types Allowed
New

The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this NOFO.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials.

Funds Available and Anticipated Number of Awards

Issuing IC and partner components intend to commit an estimated total of $2,800,000 to fund 3-4 awards.

Award Budget

Applications budgets are not expected to exceed $850,000 in direct costs per year during the R61 Phase and $1,250,000 in direct costs per year during the R33 Phase. All F&A costs are excluded from this limit. Requested budgets should reflect the actual needs of the proposed project.

Award Project Period

Applicants may request up to two years of support for the R61 phase, and up to three years of support for the R33 phase. The maximum project period for an application submitted in response to this NOFO cannot exceed five years total.

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

Section III. Eligibility Information

1. Eligible Applicants

Eligible Organizations

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)

Local 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)

Federal Governments

  • 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)
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

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

Required Registrations

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • 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.
    • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
  • eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registrations; 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 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.

Eligible Individuals (Program Director/Principal Investigator)

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 their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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 NOFO 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, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

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 NOFO. 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 How to Apply - Application Guide except where instructed in this notice of funding opportunity 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:

Poonam Pegu, Ph.D.
Telephone: 240-292-0719
Email:  poonam.pegu@nih.gov 

Page Limitations

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

Instructions for Application Submission

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: Briefly describe in clearly demarked sections the overall objective(s) and specific aims for both the R61 and R33 phases of the proposed research plan.

Research Strategy: Describe how the proposed LADDS represents an advance beyond and is different from products currently being developed.

Describe how the proposed development pathway helps to establish the next generation of products for possible accelerated clinical testing in pediatric populations, and how achievement of the proposed R61 and R33 milestones enable product development. Clearly describe the justification for using the pediatric population/age range proposed for LADDS development.

LADDS Development:

Describe the LADDS pediatric development plans, including:

  • The ARVs selected, selection process, rationale and how the ARVs will be incorporated into the drug delivery system (DDS) to achieve the required durations of action, at the targeted exposures.
  • The strategy to ensure that the appropriate exposure target(s) are selected and outline plans to optimize exposure matching with levels associated with efficacy in adult populations or, if not yet available, plans to achieve exposures exceeding paIC90.
  • The approach to enable incorporation of a full HIV regimen in a single LADDS, or alternatively if a single ARV is incorporated in the LADDS, the strategy to develop a complete ARV treatment with more than one LADDS, that can generate end-user acceptance.
  • The rationale and approach to achieving the minimum duration of action (8 weeks) required for the LADDS.
  • Suitability of the proposed LADDS for the target age group(s) in relation to the development stage and trajectory.
  • TPP (optional): applicants may include a TPP to summarize sustained/extended-release drug product critical properties and targets for development. The TPP might describe the essential product attributes (product release profile and duration of action, optimal dosing regimen, acceptable duration of PK lag periods and tails, maximum and minimum PK targets, PD targets, stability and storage requirements, desirable acceptability/desirability-derived attributes, and cold chain/storage requirements) by identifying optimal and minimally acceptable criteria for the drug and its platform.

Animal Models:

Describe how the animals proposed are appropriate (type, age, sex, and maturity) for the LADDS development in the target population; describe the study design features that allow for an assessment of potential safety and effectiveness of the LADDS strategy, including study design elements that support the integrity of the study endpoints.

End User Acceptance Acceptability:

Describe how Social Behavioral Studies (SBS) assess end user acceptance, and how they will be performed iteratively throughout the product development stages and inform final product design. Describe how the appropriate behavioral scientific expertise will be reflected within the research team.

Industry Partner:

In a clearly labeled section, describe the role of the industry partner as a collaborator, including the activities and processes conducted by the partner. If proposing the use of a CRO, clearly demonstrate how the CRO is making substantive contributions to the proposed research in terms of scientific input, as well as contributions to and involvement in strategic planning and development. Applications from industry should describe the advantages that sole industry sponsorship brings to the application. Industry applicants should describe how an academic collaborator(s), if proposed, will be integrated into the proposed research.

Regulatory Strategy and FDA Pre-IND Meeting:

In a clearly labeled section provide the strategy to collect the necessary data and put together the required package for a pre-IND meeting with the FDA during the R33 Phase. Describe how the meeting will contribute to product development and enable clinical testing in pediatric populations.

Milestones:

Applicants must submit a single application that includes both the R61 and R33 phases.

Relevant information or data to support the rationale/hypothesis should be provided as evidence that the proposed project is feasible and well-designed for the intended purpose.

In a clearly labeled section, provide milestones for BOTH the R61 and R33 phases of the award. Proposed milestones should describe research outcomes by providing quantifiable measures for success within the R61 and R33 phases. Milestones must be specific, scientifically rigorous, and not simply a restatement of the specific aims. Descriptions of the milestones must include Go/No-Go criteria to support critical parameters of the milestone that will determine whether the research should move forward or cease due to pediatric product development failures (transition milestones).

Milestones should address critical points required for sustained/extended-release products. The following milestones are examples that may be included:

  • Demonstration of proposed duration of action.
  • Definition of optimal dosing regimen including PK lag and tail.
  • Identification of active pharmaceutical ingredient (API), API-DDS (Drug Delivery System) and DDI (Drug-Drug Interaction).
  • Characterization of anti-HIV efficacy of the sustained/extended-release prototype in an animal model.
  • Socio-behavioral studies to assess end-user acceptability/desirability outcomes and integration into LADDS development for pediatric indications.

Letters of Support: Provide a letter of support indicating the availability of non-human primates for experiments in the R33 phase from a non-human primate facility that includes infant and juvenile animals and/or a breeding program.

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.

Other Plan(s): Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H application forms packages.

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

  • All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

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

  • No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined 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.

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.

PHS Assignment Request Form

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

Foreign Institutions

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

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 Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 form. 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 NOFO for information on registration requirements.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier 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 the National Institute of Allergy and Infectious Diseases, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials

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

For this particular announcement, note the following:

The R61/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R61/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R61 and R33 phases. 

Overall Impact

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).

Scored Review Criteria

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 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 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?

Specific to this NOFO: How well represented is behavioral expertise within the research team and is it well suited to successfully carry out the behavioral work proposed? 

 

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?

Specific to this NOFO: To what extent does the proposed LADDS have the potential to enable accelerated clinical testing in pediatric populations. 

 

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?

Specific to this NOFO: How well does the application describe the anti-viral selection process and how well does the strategy employed ensure that the clinically relevant exposure will be achieved? How likely is it that the proposed approach on the selected platform will achieve the minimum required duration of exposure for the selected ARVs? To what extent is the LADDS strategy appropriate and justified for use in the target population/age group?

To what extent are the animal models appropriate (e.g., age, sex, and maturity) for the development of the proposed LADDS?

To what extent is the approach to determine end user preferences for a long-acting drug delivery system (either from prior studies in related populations or proposed in the target population including caregivers as appropriate) appropriate to inform the development of the product for this population?

To what extent are the proposed milestones and timelines for both the R61 and R33 phases including the transition milestones, well-defined with specific, quantifiable measures that are scientifically rigorous, and feasible? How well do they reflect the Go/No-Go criteria proposed?

To what extent does the proposed collaboration with industry provide the opportunity for meaningful scientific contribution as well as involvement with strategic product development from the industry partner?

If the application is from an industry applicant, how well is the contribution of an academic collaborator described, or if there is no academic collaborator, how strong are the advantages of the sole industry partnership?

To what extent does the applicant outline a strategy to collect data and produce a pre-clinical package that would enable a pre-IND meeting with the FDA during the R33 phase?

 

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?

Specific to this NOFO: To what extent does the applicant have access to non-human primate facilities with infant and juvenile animals? 

Additional Review Criteria

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

 

For research that involves human subjects but does not involve one of the 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 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 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.

 

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 Animals 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 

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

 

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

 

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

 

Reviewers will comment on whether the Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

 

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.

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 policies and practices, 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 will receive a written critique.

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.

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

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 NOFO. Following initial peer review, recommended applications will receive a second level of review by the 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.

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 2.4.4 Disposition of Applications.

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 recipient's business official.

Recipients must comply with any funding restrictions described in Section IV.6. 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 NOFO 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.

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

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, Recipients, and Activities, including of note, but not limited to:

If a recipient is successful and receives a Notice of Award, in accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Should the applicant organization successfully compete for an award, recipients of federal financial assistance (FFA) from HHS will be required to complete an HHS Assurance of Compliance form (HHS 690) in which the recipient agrees, as a term and condition of receiving the grant, to administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, age, sex and disability, and agreeing to comply with federal conscience laws, where applicable. This includes ensuring that entities take meaningful steps to provide meaningful access to persons with limited English proficiency; and ensuring effective communication with persons with disabilities. Where applicable, Title XI and Section 1557 prohibit discrimination on the basis of sexual orientation, and gender identity. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and https://www.hhs.gov/civil-rights/for-individuals/nondiscrimination/index.html.

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 NOFO.

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.

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 and 2 CFR Part 200.206 “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

Not Applicable

3. Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

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

In addition, the NIAID Program staff would require periodic virtual meetings where progress and challenges can be discussed, and the team might be asked to present at internal meetings for NIH staff.

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. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 45 CFR Part 75.301 and 2 CFR Part 200.301.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for recipients of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later.  All recipients 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 the threshold.  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 2 CFR Part 200.113 and Appendix XII to 45 CFR Part 75 and 2 CFR Part 200, 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 and 2 CFR Part 200 – Award Term and Condition 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.

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: https://www.era.nih.gov/need-help (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: 301-637-3015

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

Scientific/Research Contact(s)

Tania B. Lombo Rodriguez, Ph.D.
National Institute of Allergies and Infectious Diseases (NIAID)
Telephone: 301-761-7612 
Email: tania.lombo@mail.nih.gov 

Sai Majji, Ph.D.
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-661-9816 
Email: sai.majji@nih.gov 

Teri Senn, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-761-7852 
Email: teri.senn@nih.gov 

Peer Review Contact(s)

Poonam Pegu, Ph.D.
National Institute of Allergies and Infectious Diseases (NIAID)
Telephone: 240-292-0719
Email: Poonam.pegu@nih.gov  

Financial/Grants Management Contact(s)

Mark Hodor
National Institute of Allergies and Infectious Diseases (NIAID)
Telephone: 240-669-5712 
Email: mark.hodor@nih.gov 

Margaret Young
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Telephone: 301-642-4552
Email: margaret.young@nih.gov




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

Authority and Regulations

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 and 2 CFR Part 200.

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