Required Application Instructions

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

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

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

The purpose of the Preclinical Innovation Program III (PIP) is to support novel, high-risk and under-explored strategies in the field of Non-vaccine Biomedical Prevention (nBP). Non-vaccine Biomedical Prevention strategies are composed of, but not limited to, topical microbicides and topical and/or systemic pre-exposure prophylaxis (PrEP), and Multipurpose Prevention Technologies (MPT). All of these strategies when applied topically to genital and gastrointestinal (GI) tract mucosa or delivered systemically (oral, implanted, transdermal, injection or by other means) to men and/or women can result in inhibition of the transmission/acquisition of HIV.

• MPT will be defined in this FOA as a combination of a HIV inhibitor(s) with an inhibitor of a Sexually Transmitted Infection (STI) or a licensed hormonal contraceptive method. STI inhibitory strategies eligible for support under this FOA as part of a proposed MPT must be for STIs clinically and/or epidemiologically associated/linked with increased susceptibility to HIV infection.

The dosing regimen(s) used to deliver the prevention product play a critical factor in the success of the prevention strategy. Evidence is accumulating that daily or coital-associated dosing may not be the optimal way to deliver prevention strategies to some at-risk populations. Analysis of self-reported adherence and plasma drug concentration from the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial where daily dosing in women with 1% Tenofovir vaginal gel or oral Tenofovir or Truvada showed that adherence was the primary driver for lack of efficacy in this trial. In parallel with the need to enable user adherence is the issue of providing nBP prevention to infants, children and adolescents. A key gap for these populations is the provision of prevention products that address weight and size variables in dosing. This gap is further exacerbated by the need to integrate dosing variables with physical and social maturation, e.g. puberty, menarche, etc. Thus, in an attempt to create new dosing schedules and regimens that may help individuals maintain adherence, this FOA will support the development of non-coital and sustained release drug delivery systems (DDS) and formulation of age appropriate formulation strategies (AFS) for sustained release use in infants, children and adolescents. 

For the purposes of this FOA the following non-coital and sustained release formulation definitions will be used:

• Non-coital delivery/release will be defined as an nBP product or DDS that will provide a window of at least one week (7 days) of protection against HIV transmission/acquisition after application.
• Sustained delivery/release will be defined as delivery of an nBP product that will prevent HIV transmission/acquisition for a minimum of one month after application. The one month window of protection may be achieved using either a single dose or continuous dosing strategy. A 30 day protection window enabled with multiple discrete doses during the 30 days is not considered sustained delivery/release.  

As part of the forward looking aspect of research supported under this FOA and its focus on building and maintaining a sustainable pipeline of prevention strategies and delivery systems, applications proposing products and/or DDS that provide for longer intervals (60 to 365 days) of protection are encouraged, if sufficiently justified and practical. 

Discovery, development and testing of new and innovative nBP candidates, mucosal and HIV inhibition targets and supporting technologies are complex processes that require multi-disciplinary resources and expertise. The PIP program is designed to assist in this effort by supporting the advancement of high-risk and innovative approaches that can substantially advance nBP in six general areas.

• Discovery and development of microbicides, PrEP and MPT products or strategies for use singly or in combination directed against HIV and/or sexually transmitted infections (STIs) linked to HIV acquisition,
• Development of non-coital (1 dose provides a minimum of a 7 day window of protection from HIV infection) and sustained release (single dose or continuous dose device provides > 30 day window of protection from HIV infection) formulations for prevention of HIV transmission,
• Development of new and emerging technologies, approaches and processes that contribute to the development of more efficient methods for assessing microbicide, PrEP, and MPT product safety, efficacy, acceptability and adherence,
• Development of quantitative biomedical methods to measure product and its appropriate placebo in tissues, secretions and plasma as a measure of product and/or DDS use/adherence,
• Development of pharmacokinetic (PK) and pharmacodynamic (PD) models to establish the linkage between secretion, plasma and tissue product concentrations and prevention of infection. This may be facilitated by development of novel and/or enhanced methods for detection of nBP products in tissues and secretions,
• Development of novel AFS approaches suitable for use in infants, children and adolescents to deliver sustained release prevention products.

Given the high-innovation and high-risk research targeted by the PIP program, the identification of a SINGLE Go/No-Go criterion as an initial judgment to measure the potential for success of the proposed research is required. The Go/No-Go criterion will be used to understand the feasibility of the proposed research by peer review, and by NIAID to determine whether the award will be continued after year 2 (See Section IV). The Go/No-Go criterion will be referenced in the notice of award.

Examples of the types of studies that are considered responsive to this FOA include, but are not limited to:

• Development and validation of new non-coital or sustained release nBP products. Applicants are encouraged, if applicable, to use chemical, physical, and in silico tools, i.e. computational measures of drug Absorption, Distribution, Metabolism, Excretion (ADME), to assist in product design. The approaches suggested in the U.S. Food and Drug Administration (FDA) guidance's for preclinical development of antiviral products and for development of topical microbicides may also be used to characterize products proposed for development.
• Development of accurate and reproducible biomedical, electronic, and/or analytical technologies that are independent of subject reporting biases to quantify adherence to drug product and placebo, when used either remotely by trial participants or during clinical study visits.
• Discovery and/or development of novel non-coital and sustained release DDS. Applicants are encouraged to conduct appropriate in vitro or in vivo animal PK, PD and toxicokinetic (TK) determinations to support the scientific rationale for the chosen nBP delivery route/device and proposed release profile. A Targeted Product Profile (TPP) may be used to identify critical properties and targets for development of a successful DDS.
• Nanotechnology approaches to solve specific problems related to nBP candidate non-coital and sustained release, tissue/systemic distribution, safety, efficacy and adherence.
• Engineering adaptations (instrumentation, software, hardware, etc.) focusing on creative solutions to minimize sample volumes to quantitatively and/or dynamically analyze the interaction of nBP products/DDS with the male and female genital and GI tracts.
• Development of new animal models to address the role of wound healing/resolution and/or genital or GI tract inflammation in HIV susceptibility and prevention.
• Hypothesis-driven studies into genital and GI tract mucosal immune function and repair, including immune cell trafficking, characterization of tissue-specific immune cells or regulatory cells and their effector function, the role of Toll-Like Receptors (TLRs) and inflammasome(s) in HIV infection/prevention, and how the microbiome may alter genital and GI mucosa integrity and susceptibility to HIV infection. Following the prevention of infection with an nBP strategy, the fate of tissue-associated virus and its effect on the immune response and tissue integrity are also of interest. The role of the duration of the nBP non-coital and sustained release product exposure (acute, chronic, and episodic) in modulation of these factors is an additional interest.
• Development of combination nBP products/strategies. This may include combinations of individual products into a single DDS or combining discrete nBP strategies into a prevention package. Proposed combination strategies that include activity against an STI linked to HIV susceptibility/transmission/acquisition must demonstrate and maintain antiviral efficacy against HIV.
• Development of new MPT strategies using combinations of anti-HIV retrovirals and hormones. If the non-contraceptive component is an anti-STI drug, then it must meet the definition for MPT composed of STIs given above. Modification of copper or hormone releasing intrauterine devices (IUDs) to release an antiviral drug is responsive.
• Assessments of baseline behavioral and social parameters that could directly affect the decision to use a nBP product or strategy by potential users. This may include development of specific tools or measures designed to identify the properties of nBP products and/or DDS that will promote/enable the user product selection process. Studies using established tools associated with product optimization and Quality by Design approaches such as perceptibility assessments, incorporation of discrete choice modeling and conjoint analysis are essential for these studies. Structural ethnography of potential users to identify factors that could inform on product and DDS attributes and identify user preferred properties of prototypic dosage forms and method of dosing are acceptable.
• Limited clinical research in allowable age populations may be proposed if the proposed research meets the following criteria:
  • Clinical research must be low risk to participants with limited human exposure to test products. For the purposes of this FOA, low risk is defined to be the use of clinical sample collection procedures, i.e. biopsy, Cytobrush, or swabbing.
  • All products proposed for testing must have established and documented safety risks. To meet the latter part of this definition, the only allowable test products are: (1) A licensed product, i.e. licensed contraceptive, used only for its approved use or (2) A low-risk placebo. An antiretroviral licensed only for treatment and proposed for use for HIV prevention does not meet this definition. A low-risk placebo is defined as a clinical trial quality product with phase 2B or 3 safety data demonstrating minimal or no impact on the integrity or inflammatory state of the genital and/or GI mucosa. Any placebo manufactured for a study must be manufactured under Good Manufacturing Practices (GMP) with appropriate stability and sterility testing post-manufacture to support the proposed study(s). A low risk placebo may also be an Over-the-Counter (OTC) product with no known (medical or research) or suspected safety issues. The OTC product may not be repackaged for use unless the appropriate package compatibility, stability and sterility studies have been performed for the repackaged product.
  • Studies involving behavioral/social research are limited to no more than 50 participants per proposed study, and must contain a justification to support the proposed research's responsiveness to this FOA.
  • Applicants may propose multiple studies per application, but are cautioned that poorly justified or duplicative studies could reduce reviewer enthusiasm for the application. Study cohorts may include HIV-positive, specific at-risk populations, such as men who have sex with men (MSM), transsexuals, post-menopausal women, specific ethnicities or races, intravenous drug users (IDUs) and alcohol users and abusers when scientifically appropriate.

Applications proposing research in the following areas will be considered non-responsive to this FOA and will not be reviewed:

• Applications proposing Phase I, II, III or "first in human" studies in subjects of any age or clinical research on infants, children (less than or equal to 16 years of age).
• Studies exceeding the above criteria listed for limited clinical research will be categorized as clinical trials and will not be reviewed.
• Applications proposing development of a vaginal or rectal coital (duration of less than 7 days protection from a single dose) PrEP, topical microbicide and/or MPT. Development of new or novel DDS that are not for non-coital and sustained release DDS.
• Activities that are intended solely for enabling/facilitating clinical studies to be conducted with non-PIP funds. This includes activities that support the administrative preparation/submission of a an Investigational New Drug (IND), Investigational Device Evaluation (IDE) and/or New Device Exception (NDE) application to the FDA or other US or foreign regulatory bodies, or to produce clinical supplies for future trials. This does not preclude research aimed at optimizing specific nBP production processes, such as developing unique and innovative methods to produce/manufacture a product and/or DDS. Nor does it preclude proposing research or testing that could contribute to and/or be included in a future regulatory submission, such as preclinical virology or animal testing.
• Development of new animal models of HIV or STI infection for safety or efficacy determinations.
• Approaches using cure of bacterial vaginosis (BV) by antibiotics, chemical means and/or replacement of abnormal microbiomes with "normal" bacteria as a method to modulate genital or GI micro- or macro-environments to prevent HIV infection.
• Generalized or wholly descriptive studies which use exogenous or endogenous hormone exposure in cell lines, animals, or humans to assess changes which might be a potential factor in HIV susceptibility. Applications focused on mechanistic interactions of endogenous and exogenous hormones with the genital and GI mucosa and their impact on epithelial integrity, receptor usage, signaling and cross-talk, and interaction with the immune system to define specific cellular and/or genital and GI tissue responses to exogenous and endogenous hormones are responsive.
• Random or bulk screening of chemical or natural product libraries or collections to discover nBP candidates, including development of an uncharacterized natural product consisting of a complex mixture of potentially active and inactive ingredients.
• Development of non-specific agents/products/drugs/candidates as nBP. Non-specific agents for the purposes of this FOA are defined as agents that display broad anti-microbial activity, in the absence of pathogen specificity (nonspecific killing of viruses, parasites, yeast, and pathogenic and beneficial bacteria). A specific agent for the purposes of this FOA is any agent that has a defined mechanism of action, non-toxic to beneficial Lactobacilli spp. and does not induce tissue immune cell infiltration and inflammation. Applicants proposing a "specific agent" nBP having chemical, biophysical and/or antimicrobial properties that maybe potentially identified as a "non-specific agent" by peer review are strongly encouraged to include appropriate preliminary mechanistic safety and/or efficacy data demonstrating the above criteria for specificity.
• Applications proposing broadly generalized global assessments using genomic, proteomic, scriptomic, and/or microbiome analysis/technologies to identify potential targets, biomarkers for or responses to nBP are discouraged. Applications proposing use of these technologies should implement them in a focused manner designed to support a specific observation and/or scientific hypothesis, in contrast to using the above methods to find/hunt for possible immune, metabolic or organism interaction pathways or biomarkers that might correlate to an observed phenomena.
• New development or additional development of the following products:
  • Tenofovir (TFV, PMPA, (R)-9-(2-Phosphonoylmethoxypropyl) adenine), Tenofovir Disoproxil Fumarate (TDF or Viread ) and Tenofovir Alafenamide fumarate (TAF) as a single topical microbicide or for topical or systemic delivery as PrEP for non-coital, or sustained release. MPTs products composed solely of only or combinations of TFV, TDF and/or TAF are not responsive. TFV, TDF or TAF may be a component of a combination strategy with a second retroviral, if the proposed combination is not already in phase 1 clinical testing. TFV, TDF or TAF single products may be used as controls or probes to show equivalence to existing delivery approaches using PK and PD endpoints.
  • Development of Truvada (Viread plus Emtricitabine, TFV/FTC) as a topical microbicide, systemic or topical PrEP or MPT product.
  • Further development /testing of Rilpivirine (TMC-278), Cabotegravir (GSK-744, GSK/S 1265744) singly or in combination. Development of combinations with other active pharmaceutical ingredients (APIs) is responsive,
  • Development of new hormonal or non-hormonal contraceptive or spermicidal products,
  • Development of MPTs using levonorgestrel (LNG) as the contraceptive hormone.
  • Development or use of over-the-counter products (OTC) or non-specific vaginal and/or female/male rectal health products, including lubricants, to prevent HIV transmission. This does not preclude developing a topical microbicide, topical PrEP or MPT strategy with rheological properties that can act as a sexual lubricant,
  • Development of sulfonated polysaccharides or other large molecular weight charged polyanions as a single prevention product. Strategies using these entities in combination with other nBP candidates will be considered responsive to this FOA,
  • N-9 (Nonoxynol-9).
• The following DDS are not supported:
  • Aqueous or lipid hydrogels where the API is suspended in gelling components for any indicated duration.
  • Use of Intravaginal Rings (IVR) composed of silicon, polyurethanes or ethylene vinyl acetate (EVA) to deliver a single microbicide or topical PrEP agent. Development of IVR delivered MPTs that are composed of a single anti-HIV API. IVRs may be used to delivery combinations of antiviral products, other than Truvada.
• Applications proposing nBP strategies or candidate development without antiviral activity to HIV. Or, propose development microbicides for environmental decontamination or control. Or, development of microbicides or PrEP for treatment of STIs and bacterial infections associated with oral, pulmonary or iatrogenic infections or control of these infections.
• MPT strategies which use a barrier device with or without addition of a gel as the primary method for HIV prevention. Use of condoms (male or female), as the HIV prevention component in an MPT, are not responsive.
• Studies proposing the development or optimization of a Genetically Modified Organism (GMO) as a DDS for delivery of a single or multiple nBP products or use of bacteria selected or engineered for specific characteristics designed to create a "hostile microenvironment" to HIV and/or STIs.
• Applications proposing any form of vaccine development (new mucosal vaccine, vector, insert, or delivery system), or use of vaccines as an immunomodulatory element of a combination microbicide, PrEP or MPT prevention strategy.
• Use of Adenovirus or any vector to produce/deliver in tissue sites broadly neutralizing antibodies as a HIV prevention strategy. Broadly neutralizing antibodies may be incorporated into a responsive non-coital or sustained release strategy.
• Basic behavioral research designed to develop broadly usable measures of nBP use, or generalized interventions to reduce HIV incidence. Including surveys and studies to provide information on community/ individual attitudes/acceptability using hypothetical or theoretical nBPs products. Education programs to support introduction of an nBP. Structural and/or behavioral interventions to enhance projected product use or prepare for product roll-out or introduction. Epidemiologic studies targeting individuals other than product users, such as healthcare providers, policymakers, government officials or any non-user stakeholder. Studies including potential prescribing physicians that address physical attributes of the nBP and/or DDS that would influence their willingness to administer the strategy may be part of an ethnography study.
• Development of methods to quantify adherence that depend on the use of radioisotopes or unassisted visual assessments of a dye stained applicator. Applications proposing detection of mucosal secretions on applicators using a staining approach must incorporate a quantifiable analytical endpoint.

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

Higher Education Institutions

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

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

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Governments

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

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

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

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

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

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

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

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

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

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

Applicants must obtain the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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.

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:

Research Strategy:

Go/ No-Go Criterion

Applicants must provide a section labeled Single Go/No-Go Decision Criterion with a clearly identified Go/No-Go decision criterion. The Go/No-Go section may be placed at the end of the Research Strategy Section, and applicants may consider the use of a timeline and/or Gantt chart to support the Go/No-Go decision.

The Go/No-Go criterion chosen by the applicant must identify a critical parameter that is essential for the success of the proposed research in subsequent years. The Go/No-Go criterion should be specific to the proposed research and represent a quantifiable outcome. A restatement of an application specific aim is not considered an adequate Go/No-Go criterion, and lack of a sufficiently robust Go/No-Go criterion may reduce enthusiasm of the peer review panel for the proposed research. 

Selected examples of possible Go/No-Go criterion are:

• The identified lead candidate will have (Fill in blank) potency and/or have the following specific (Fill in blank) characteristics.
• The formulated candidate will demonstrate (Fill in blank) potency and/or (Fill in blank) specific safety outcomes in animal model(s).
• The candidate, formulation and/or device will achieve a target tissue concentration of (Fill in blank).
• The proposed DDS and/or formulated candidate will deliver/release drug for (Fill in blank) hours/ days/weeks /months and at (Fill in blank) concentration,
• The technology proposed will measure (Fill in blank) under the following conditions (Fill in blank) with (Fill in blank) precision, or
• The proposed research will be enabled by (Fill in blank) administrative approval(s). This Go/No-Go criterion maybe be used in cases where obtaining IRB or other regulatory approvals to allow adolescent involvement and sampling is critical to enable research in later years of the award.

In these examples "Fill in blank" denotes an applicant chosen, single specific criterion that is essential for the success of the proposed research in subsequent years.

Targeted Product Profile (TPP)

If the application includes a Targeted Product Profile (TPP) to be used to support the development and validation of products and/or a DDS, the TPP may be placed as a table in the Research Strategy Section. Applicants are encouraged to capture properties in table format that lists the product attributes and both the optimal and minimally acceptable chemical and physical properties of the product or DDS. Examples of potential product attributes that can be captured are: product release profile of the DDS, delivery/injection/implant volume, pharmacokinetic (PK) maximums and minimums, stability and storage requirements, desirable physical attributes, acceptability, cold chain requirements and feasibility of GMP production. Applicants are advised that the proposed TPP should be used as a tool for identifying the optimal characteristics of the product/DDS proposed in this application, and therefore is less complicated and comprehensive than the FDA required TPP used to map and guide regulatory responses for the complete product development pathway from nonclinical studies to licensure.

Clinical Research

There are specific limits for inclusion of clinical trials and clinical research on selected age groups in the FOA.

If the research strategy includes clinical research with the indicated populations, applicants should include a discussion as to how this research meets the FOA-defined criteria for low risk.

Use of Animal Models

Applicants may include research that uses animal models such as humanized mice and/or nonhuman primates (NHP) for safety and/or efficacy determinations of the nBP strategies or candidates. For the purposes of this FOA, animal models should be pre-existing with studies divided into two categories. The first category includes studies that address the basic and developmental science issues of virus transmission within the context of the nBP products and/or DDS which may alter HIV susceptibility, acquisition and dissemination, such as genital and GI tract injury/trauma, age, hormone and immune status. The second category is the use of animal models for screening/testing of candidates to support their plausibility as clinical candidates. For this latter case the NIAID/DAIDS prevention program strongly encourages and makes the following recommendations to enhance the rigor of the animal model when efficacy results are proposed as a mechanism to prioritize nBP product or DDS development.

• Superiority assessments of the drug product(s)/DDS being tested should be used and include appropriate positive control and placebo arms.
• Sufficient numbers of animals should be included in all groups to allow for endpoint statistical analysis and a statistical analysis plan should be provided. Applicants are cautioned that underpowered studies can reduce reviewer enthusiasm for the application.
• When testing APIs in a proposed DDS, the product should be characterized for API stability and release. The use of unformulated products and vehicle admixtures without establishing some level of drug stability and release is strongly discouraged.
• Where appropriate, the inclusion of secondary endpoints to support the proposed prioritization such as PK, PD and safety measurements (colposcopy, histology, vaginal pH, microbiome analysis and/or the immune response, etc.) is encouraged. However generalized or broad use of omics technologies to identify potential biomarkers for potential safety biomarkers is discouraged.

Applications proposing modification of a copper or hormone IUD should address product loading and the expected durations of action for the new DDS. Applicants should compare the new IUD proposed duration of action to that of marketed IUDs and address any disparities in proposed duration of use.  

Applications which propose development of biomedical, electronic, and/or analytical technologies/techniques to quantify adherence must in the experiment plan propose approaches to quantitate both the drug product and its corresponding placebo.

Applications proposing baseline behavioral and social parameters that could directly affect the decision to use a prototypic or actual nBP product or strategy by potential users should address the relevance and need for the studies to support the development of the proposed nBP. Studies based on hypothetical/theoretical products should not be proposed.

Applications that include potential prescribing physicians in quality by design and or ethnography studies to assess/address nBP and/or DDS physical attributes that might influence their willingness to administer the strategy should be appropriately justified and the critical role of these studies in determining nBP /DDS product attributes should be discussed.

If experience and/or preliminary data from an alternative research field, e.g. sustained DDS development in cancer, Alzheimer's, Parkinson's disease, diabetes etc., is being used to support the Research Strategy explain how the expertise/preliminary data enables the proposed research.

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

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

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

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

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

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

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

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

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

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

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

This initiative is not subject to intergovernmental review.

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

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

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

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

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

Important reminders:

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

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

See more tips for avoiding common errors.

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

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

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

For this particular announcement, note the following:

The R01-based PIP program is intended to identify high-risk and high-innovation research that can contribute significantly to the support of the preclinical nBP prevention pipeline. Accordingly, evaluation of the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge and understanding of nBP-mediated prevention will be critical to achieving the goals of this program. Preliminary data play a significant role in providing a justification or rationale for the approach taken and the projected impact of proposed research. However, the high level of innovation and risk requested for PIP applications may not be supported by extensive preliminary data that is specific or all-inclusive for the proposed product, DDS and/or technology. Judgments regarding potential success for the proposed research may require reliance upon inclusion of specific expertise in an unrelated scientific area and/or inferential data/results from non-nBP prevention resources to establish the potential for research impact/success rather than substantial experimental data directly supporting application proposed specific aims.

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

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

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

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

If experience in a related research field, e.g. sustained DDS development in cancer, Alzheimer's, Parkinson's disease, diabetes etc., is being used to support a specific research agenda where minimal preliminary data is provided, do the proposed investigators have the expertise needed to support the proposed nBP approach(s)?

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

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

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

Are the roles of study participants to be enrolled in quality by design and ethnography studies appropriately described and will their participation lead to information required to identify critical physical attributes of the product, DDS, dosing method, etc. required for successful use of the strategy?

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?

Given the critical nature of the Go/No-Go criterion in supporting a considered analysis of the potential of the research and for continuation of funding past year 2 of the award, is the proposed Go/No-Go decision criterion well-defined with a quantifiable and measurable outcome appropriate for assessing potential experimental success and measuring the success of the first 2 years of the application? Is the Go/No-Go decision criterion sufficiently described to enable a clear decision about its attainment? Given the potential benefits and innovation of the proposed research, is the applicant provided Go/No-Go decision criterion commensurate with the overall projects proposed advancement of the candidate, target, technology or strategy?

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

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

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

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

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

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

Not Applicable

Not Applicable

Not Applicable

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

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

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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

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

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

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

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

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

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

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

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

Not Applicable

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

Year 2 Go/No-Go Criterion

In the Year 2 progress report, awardees must address the status of the project in regards to the single Go/No-Go decision criterion identified in the application. Achievement of the stated goal is required for future year funding.

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

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

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

eRA 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 CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: support@grants.gov

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

Jim A. Turpin, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-451-2732
Email: jturpin@niaid.nih.gov

Robert Freund, Ph.D.
Center for Scientific Review (CSR)
Telephone: 301-435-1050
Email: freundr@csr.nih.gov

Ann Devine
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-402-5601 
Email: adevine@niaid.nih.gov

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

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