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

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

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

The objective of this FOA is to support development of novel MPTs for the dual purpose of preventing pregnancy and HIV infection in women. MPTs must be composed of a combination of a licensed contraceptive and an anti-HIV drug delivered using drug delivery systems (DDS) with rheological/biophysical properties and product user perceptions compatible with current long-acting reversible contraceptive (LARC) strategies (look, feel, effectiveness, safety and duration of action). For the FOA the target population is females age 15 years and older desiring access to contraception and HIV prevention. Inclusion of specific sub-populations of females where MPTs may have particular benefit such as HIV-positive females, adolescent females, females in serodiscordant partnerships, specific ethnicities or races with genetic or cultural risks of HIV infection or pregnancy, intravenous drug users (IDUs) and alcohol users and abusers who desire the convenience of combined contraception and HIV prevention is encouraged.

Due to the high-risk, high-impact nature of the research, this FOA will use milestone-driven, phased research activities with investigator-provided milestones. Support will be provided for up to three (3) years for the R61 phase, and up to two (2) years of support may follow for the R33 phase. Prior the end of the R61 phase, awardees will submit the R33 transition package, which will be evaluated by NIH Program staff for completion of milestones. R33 transition decisions will be based on successful completion of negotiated transition milestones, Program priorities, and availability of funds. It is expected that approximately half of the projects supported during the R61 Phase will continue into the R33 Phase. A plan to submit a pre-IND to the FDA by the end of the fourth year is required in the application, and documentation of submission of the pre-IND is required to be eligible for year 5 funding.

The results of phase III non-vaccine biomedical prevention (nBP) HIV-1 clinical trials (Vaginal and Oral Interventions to Control the Epidemic, VOICE and A Study to Prevent Infection with a Ring for Extended Use, ASPIRE) have demonstrated conclusively that women experience multiple barriers to adherence when given access to vaginal coital, daily or 30-day sustained release products for HIV prevention. Multiple factors can contribute to low adherence with many of the barriers to use associated with user perception and the impact of the prevention product and its drug delivery system (DDS) in their lives. It has been postulated that coupling HIV prevention to contraception could create a highly desirable dual prevention strategy, relying on the individuals risk perception of pregnancy and familiarity with contraceptive practices to solve HIV prevention uptake and adherence issues. Several MPT candidates have been advanced to clinical testing as first generation MPTs using a drug development strategy focused on adapting the contraceptive drug to an existing anti-HIV microbicide DDS platform. This has resulted in a product pipeline dominated by MPTs consisting of intravaginal rings (IVRs) with the added capacity to deliver Levonorgestrel (LNG). Creation of MPTs with a range of contraceptive choices and anti-HIV drugs that retains the convenience and efficacy of the licensed contraceptive strategy alone will be a critical factor in getting women to substitute their proven contraceptive method for an MPT, since it is unlikely that reduced contraceptive efficacy and/or decreased convenience will entice substitution of an MPT for a more familiar and trusted pregnancy prevention regimen.

MPT approaches for development through this FOA MUST be purpose-designed as dual indication co-delivery products for sustained release of all active pharmaceutical ingredients (API) for extended (one month to years) prevention of pregnancy and HIV infection. Products must be the combination of a licensed contraceptive and an antiretroviral (ARV)or non-ARV anti-HIV drug. The proposed MPT must be new and not already in preclinical or clinical development.

It is expected that products will deliver APIs using delivery methods typically associated with LARCs (implant, injection, transdermal, IUD) and the LARC-like strategies will provide for a minimum of 90 days or 3 menstrual cycles of pregnancy prevention with an antiviral pharmacokinetic (PK) profile (tail) that covers periods of contraceptive non-use, e.g. planned removal for menstrual bleeding or between contraceptive doses.

The following areas of preclinical and behavioral research may be used to achieve the objective of creating the next generation of MPT candidates:

• Developing new and novel MPT strategies using not only LARC-associated DDS, but also DDS that represent new and novel concepts for delivery of dual indication MPTs.
• Understanding the relationship between MPT contraceptive and antiviral efficacy using animal models (simultaneously or in separate harmonized animal model protocols).
• Understanding the potential for and identifying/characterizing drug-drug interactions (DDI) that could compromise contraceptive and/or antiviral effectiveness.
• Understanding the PK of MPT products by mapping the antiviral and/or contraceptive duration, lag period (time to establish effective concentrations) and tails (time to loss of effective concentrations) during non-use periods such as menstruation or dose renewal.
• Understanding the ability of the MPT to deliver antiviral concentrations to both the female reproductive tract (FRT) and the gastrointestinal (GI) tract.
• Understanding Preferred User Characteristics (PUC), which will govern decisions made by individuals to use the MPT (look and feel), and whether to adopt and maintain use of longer duration MPT strategies. For this FOA, PUCs are defined as the rheological/biophysical properties of the MPT/DDS that invoke user judgments, leading to decisions for first, subsequent use or non-use and/or early termination.
• Advancing the MPT in the clinical pipeline by performing studies which position the MPT at the end of five years to either advance to clinical testing, undergo further iterative design or have its development terminated. Regulatory strategies that rely solely on demonstrating MPT contraceptive bioequivalence to the licensed contraceptive alone product are discouraged.

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

• Combination of a licensed contraceptive drug(s) with a single or combination antiviral drug(s) delivered by a method familiar to women for contraception delivery, e.g. injection, IUD, transdermal with a duration of action that approximates the contraceptive alone exemplar.
• Development of longer duration MPTs (>90 days or 3 menstrual cycles) with extended or alternative modes of use/action. Highest priority will be given to:
• non-IVR strategies with durations of 90 days or longer with or without removal periods for bleeding, modification of licensed copper or hormone IUDs to release an antiviral drug(s),
• or development of new non-IVR/IUD MPT mucosal delivery systems that protect both the FRT and GI tracts.,
• Use of broadly neutralizing antibodies or non-ARV HIV inhibitors as the anti-HIV component(s) of the MPT.
• IVRs with a duration of action of 90 days or longer (minimum 3 menstrual cycles of proposed contraceptive and antiviral activity).
• Novel delivery systems (mucosal or systemic), other than IVR, injection, transdermal or IUD with a minimum of 30 days (1 menstrual cycle) may also be proposed.
• Strategies to co-deliver the contraceptive and anti-HIV drugs may include co-formulation or co-packaging. DDS which compartmentalize the contraceptive and anti-HIV drug to address DDI and/or to create different release rates.
• Strategies/development that enable self-injection for injectable MPTs.
• In vitro or in vivo animal PK, pharmacodynamic (PD) and toxicokinetic (TK) studies to support the proposed duration of use. An understanding of both the contraceptive and anti-HIV moiety PK lag and tail as it relates to establishment of contraceptive and anti-HIV efficacy using animal models (PD).
• Nanotechnology approaches to specific problems related to MPT candidate sustained/extended release/duration, tissue/systemic distribution, safety, efficacy and adherence.
• Development of new animal models to simultaneously address the contraceptive and anti-HIV activity of MPT candidates. There is particular interest in models where size adaptation of the proposed MPT drug product is not needed for testing, and use of concurrent sample collection that upon analysis results in unequivocal evidence of contraceptive and antiviral efficacy.
• Hypothesis-driven assessments of the proposed MPT impact on the genital tract, specifically on mucosal barrier and immune function in animal models, which could lead to changes in HIV susceptibility, and/or decreased safety or efficacy. Approaches may include modulation of drug transporters (importers/exporters), inducible and non-inducible cellular drug-degradation and -metabolism pathways, as well as the impact of the API on epithelial cell function, mucosal wound repair, and/or immune cell trafficking.
• Assessments of PUCs for MPT rheological/biophysical attribute selection. Studies using established behavioral and social sciences tools associated with user look and feel optimization, such as perceptibility assessments, mental modeling, discrete choice studies and conjoint analysis. Approaches will focus on identifying factors which may influence an individual’s choice to use. Ethnography studies of potential users to identify factors that could inform on product and DDS attributes. Assessment of contraceptive user journeys when performed in the context of optimizing the physical properties of a proposed MPT DDS. Studies including potential prescribing physicians/Health givers in the U.S. that address physical and rheological/biophysical attributes of the MPT DDS, such as implant size, location and placement that could influence user perceptions of the product. PUC research using artificial tissue models to provide kinesic experience to enhance user experience with the DDS is encouraged.
• Limited clinical research focused on obtaining PUC information is allowable, if the proposed research meets the criterial outlined below.

Projects submitted to the FOA must include substantive investment by at least one industrial partner. For the purpose of this FOA, "industry is broadly defined as a for-profit or not-for-profit pharmaceutical, biotechnology, bioengineering, or chemical company that is large or small, domestic or foreign entity with an established record in product development. Substantive investment" is defined as a significant commitment of one or more resources to the project including, but not limited to: research and development plan support/guidance, product development support/guidance, personnel, in kind contributions of materials and/or reagents (e.g., adjuvant, innovative biotechnology platforms, scale up of GMP manufacturing, etc.), provision of animal or other laboratory models for evaluation, subcontracts, data management resources, regulatory support, or alterations/renovations of facilities or provision of equipment to address biohazard concerns. Inclusion of a commercial regulatory advisory group or consultants from outside the applicant’s organization to assist in preparation of the pre-IND package meets this requirement.

Industry applicants are not required to involve collaborators from academic and/or non-profit research organizations.

For the purposes of this FOA, animal antiviral and contraception efficacy studies are divided into two categories. The first category includes hypothesis-driven studies that are supportive of MPT development and address the impact of the MPT product or strategy on the FRT as part of a safety determination. The second category includes animal models for screening/testing MPT candidates to understand PK, contraceptive and antiviral relationships and/or DDI. Animal model testing of MPTs is complicated because simultaneous measurement of contraceptive and antiviral activity/interactions is difficult using a single animal model. However, antiviral efficacy models can still be used for contraceptive drug PK and DDI assessments with the appropriate design. If specific models are proposed for independently assessing contraceptive and antiviral efficacy and PK, then a careful consideration of the integration of the results is needed.

This FOA will only support clinical research and trials for assessing PUCs at a U.S. site. To meet the objectives of the FOA it is critical that PUC study outcomes are linked to selection of MPT rheological (look and feel) properties as part of the MPT development process.

Products for testing in PUC assessment must be managed for low potential risk when study participants are required to handle them during PUC studies. Licensed contraceptives may be used for a mano studies (handled during the study) if all label contraindications and potential allergic reactions associated with handling of the product are managed. Studies using any MPT candidate containing an antiviral drug (licensed or unlicensed for treatment or prevention) in any DDS will not be supported.

A low risk placebo DDS or MPT prototype may be developed and employed in studies where the device is used only for examination purposes, e.g. a mano studies. Human vaginal/rectal, parental dosing or implantation will not be supported. Any MPT prototype placebo manufactured specifically for use in a PUC study must be manufactured under Good Manufacturing Practices (GMP) with appropriate stability and sterility testing post-manufacture. Skin/dermal animal irritation/sensitization study should be performed to confirm potential safety of prototype placebos. For some placebo DDS there may be sufficient use of their components (excipients) in humans to justify forgoing specific skin/dermal sensitization/irritation testing, e.g. drug-free silicone and ethylene-vinyl acetate (EVA) IVRs and implants.

Handling of vaginal OTC products as surrogate MPT products by study participants is allowed, if there are no documented safety risks for vaginal use of the OTC product. Use of N-9 based or containing products will not be supported for PUC assessments. To maintain low-risk, repackaged OTC products will not be supported unless the appropriate package compatibility, stability and sterility studies have been performed on the repackaged product. Care should be taken when using OTC products, manufactured placebos or prototype MPTs in PUC studies that the rheological properties of products either span a range of potential user perceptions or match the rheological properties of the proposed MPT DDS.

Applications proposing the following areas of research will be considered non-responsive and will NOT be reviewed.

• Phase I, II, III clinical trials, Phase 1 or first-in-human trials that propose trials on any topic other than PUC determinations.
• Conduct of clinical research/trial to assess PUC at a non-U.S. site.
• Further development of any MPT that is currently under preclinical or clinical development. MPTs currently under development may be found on the IMPT website in the MPT Product Development Database. This includes proposed MPTs without antiviral activity to HIV and not composed of a contraceptive(s) licensed for prevention of pregnancy in women.
• Development of new contraceptives, contraceptive strategies or chemically modifying licensed contraceptives for incorporation into a proposed MPT.
• Development of an MPT targeting a sexually transmitted infection (STI) or viral/microbial infection other than HIV.
• Applications proposing development of on-demand MPTs, durations less than 30 days. All proposed MPTs using LARC-like DDS must meet the minimal durations defined in the FOA.
• Applications proposing the use of broadly neutralizing antibodies, where the antibodies are confined to the female reproductive tract, delivered by any vector system and/or are administered using intravenous infusion.
• MPT approaches that use non-simultaneous administration of the contraceptive and anti-HIV drugs.
• Applications where animal model development is not linked to the proposed MPT candidate development or does not inform on the efficacy of both the contraceptive and anti-HIV components of the MPT. Proposing the addition of biomarkers, such as mucus quality, changes in epithelial thickness, etc. to an existing HIV/SIV/SHIV efficacy animal model is not considered to be the development of a new animal model.
• MPTs where the prevention strategy is based on:
• Oral dosing or intravenous infusion of any component of the MPT.
• Use of an unlicensed contraceptive drug.
• Cure or amelioration of bacterial vaginosis (BV) or vaginal dysbiosis by any chemical or biological means to reduce HIV susceptibility as part of an MPT strategy.
• Use of barrier contraceptive methods (male or female condoms, diaphragms, etc.) as the DDS, contraceptive method and/or anti-HIV strategy.
• Use of any vector system (viral, bacterial, fungal, etc.) to produce/deliver the anti-HIV component of the proposed MPT.
• Development or optimization of a Genetically Modified Organism (GMO) as a part of a MPT DDS or incorporation of bacteria selected or engineered for specific characteristics designed to create a "hostile microenvironment" for HIV in the MPT. This restriction includes replacement of abnormal microbiomes with "normal" bacteria by supplementation or transplantation as a method to modulate genital or GI micro- or macro-environments as the anti-HIV strategy.
• Use of non-specific agents/products/drugs/candidates as the anti-HIV component(s) of the MPT. For this FOA non-specific agents are defined as agents that display broad anti-microbial activity (nonspecific killing of viruses, parasites, yeast, and pathogenic and beneficial bacteria) and/or do not have a defined anti-HIV target. Non-specific anti-HIV inhibitors may be characterized as detergents or sulfonated polymers that act as either virucidal agents or inhibitors of HIV entry, respectively. Examples include, but are not limited to, N-9, BZK, C31G, and high molecular weight sulfonated polymers such as carrageenan, dextran sulfate, cellulose sulfate, and some dendrimers.
• Development of an uncharacterized or a complex-mixture natural product as the antiviral component of an MPT.
• Further development, or use of an over-the-counter (OTC) product (outside of PUC studies), or non-specific vaginal female health product, including OTC lubricants and sexual pleasure products as the DDS, or as the anti-HIV component of the MPT. This does not preclude developing a MPT strategy with rheological/biophysical properties that can act as a sexual lubricant.
• Random, bulk or high-throughput screening of chemical or natural product libraries or collections to discover anti-HIV candidates for incorporation into MPTs.
• Medicinal chemistry efforts on pre-identified screening leads or characterized anti-HIV APIs designed to optimize or create new anti-HIV compounds. Chemical modification of anti-HIV APIs may only be used to facilitate incorporation into and release from the MPT DDS of the antiviral.
• Applications proposing broad generalized global assessments in animal models or humans to identify biomarkers of MPT impact on the FRT or GI tract using genomic, proteomic, scriptomic, metabolomic, and/or microbiome analysis/technologies that do not directly support the development of the MPT candidate. This restriction includes hypothesis-generating or cataloging studies of contraceptive use alone studies to identify direct or indirect effects of contraceptives on susceptibility to HIV infection in animals and humans.
• Development of MPTs incorporating the following HIV antiretrovirals:
• The nucleoside reverse transcriptase inhibitors Tenofovir (TFV, PMPA, (R)-9-(2-Phosphonoylmethoxypropyl) adenine), Tenofovir Disoproxil Fumarate (TDF or Viread ) and/or Tenofovir Alafenamide fumarate (TAF). MPTs products composed solely of or combinations of TFV, TDF, and/or TAF. TFV, TDF or TAF may be a component of a combination strategy with a second retroviral other than Emtricitabine (FTC), if the proposed combination is not already in preclinical MPT development or phase I clinical testing.
• The non-nucleoside reverse transcriptase inhibitor dapivirine.
• Development of the following combination antiretrovirals as the anti-HIV component of an MPT: TFV, TDF or TAF combined with Emtricitabine (FTC).
• Incorporation of Rilpivirine (TMC-278), or Cabotegravir (GSK-744, GSK/S 1265744) singly or in combination as the anti-HIV component of an MPT. Rilpivirine, or Cabotegravir may be combined with another anti-HIV API in an MPT.
• Applications proposing any form of vaccine development (new mucosal vaccine, vector, insert, or delivery system), or use of vaccines as an immunomodulatory element of an MPT prevention strategy.
• Basic behavioral research designed to develop and inform on broad issues of MPT use as a generalized intervention to reduce HIV incidence. Surveys and studies designed to provide information on specific groups/ community/ individual attitudes/acceptability using hypothetical, conceptual or theoretical MPTs products. Education programs to support introduction of an MPT. Structural and/or behavioral interventions to enhance projected product use or prepare for product roll-out, implementation or introduction. Epidemiologic studies targeting individuals other than product users, such as healthcare providers, policymakers, government officials or any non-user stakeholder to determine general enthusiasm/ openness to the MPT concept.
• Activities that are intended solely for enabling/facilitating clinical studies to be conducted with non-NGM funds. This restriction includes GMP production of clinical supplies for use other than PUC or IND-enabling studies, and regulatory submissions other than a pre-IND and production of clinical supplies for future trials.

Applicants are encouraged to contact the Scientific/Research Contact(s) located at the end of this FOA to discuss planned strategies for developing an application.

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

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

Higher Education Institutions

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

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

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o 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.

Individuals involved in NIH-funded clinical trials must meet the requirements for documented ICH-Good Clinical Practice (GCP) training. Documented means GCP training that provides a certification/documentation of completion indicating that the training requirement has been successfully completed.

Appropriate personnel are those individuals responsible for the design or conduct of the study, including all personnel of participating consortia and performance sites participating in the clinical trial. The description of GCP training for new key personnel or GCP refresher training for other personnel should be part of the progress report submitted as a prerequisite to award. GCP refresher training should occur every 3 years for the length of the trial.

The GCP training of choice must meet the GCP Principles of ICH E6.

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

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

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

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

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

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

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

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Peter Jackson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5049
Email: [email protected]

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

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

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

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

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

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

Under personal statement, senior/key personnel should indicate how their experience in areas outside of HIV and contraceptive fields will contribute to the overall success of the proposed research.

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

Applicants should include costs for oversight of quality control/ quality assurance of GLP or GMP studies, if a Contract Research Organization (CRO) or Contract Manufacturing Organization (CMO) is proposed.

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

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

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

Specific Aims: Briefly describe in clearly demarked sections the specific aims for the R61 and R33 phases of the proposed research. A single specific aims attachment must be provided.

Research Strategy:

MPT Specific Criteria: Describe the individual components of the MPT strategy, and how they meet the requirement of creating an MPT composed of a licensed contraceptive (hormone, combination of hormones or IUD) and one or more anti-HIV drug. All contraceptives proposed for incorporation into MPTs must be licensed for prevention of pregnancy, while use of anti-retrovirals licensed for HIV treatment is optional. The MPT development plans should describe means to assure:

• the efficacy, safety and duration of action of the licensed contraceptive component is preserved.
• the anti-HIV API is being adapted to the licensed contraceptive DDS platform. Candidate MPTs must use a simultaneous administration of the contraceptive and anti-HIV drug(s) describing either co-formulation in the DDS or co-delivery from a common package. If a co-delivered MPT is proposed, then appropriate packaging stability and extractable/leachable studies should be described.
• the drug development pathway in terms of the proposed regulatory strategy and how the required R61 and R33 milestones enable future development.
• the duration of action of the proposed MPT and its relationship to the duration of action of the licensed contraceptive or its parent LARC strategy. Approaches to shortened duration of an established longer duration will significantly weaken the MPTs impact. Strong justification is needed for the shorter use interval such as PUC or other behavioral data. Applicants are reminded that less than 90 days or 3 menstrual cycles for LARC-like, less than 90 days for IVR and less than 30 days for novel non-LARC strategies are the minimal acceptable durations for any MPT proposed for development.
• the potential DDI and how they will be dealt with for the contraceptive and antiviral component(s) and how interactions with the DDS will be identified. If a hormone containing MPT uses an anti-HIV strategy which includes cytochrome p450 inhibition, e.g. Cobicistat or other drug/metabolic enhancer combination designed to boost the anti-HIV efficacy of the MPT, then the use of this strategy should be adequately described in the context of known effects of Cytochrome P450 modulation on the safety and efficacy of the contraceptive strategy used.
• regulatory considerations and requirements for both contraceptive and anti-HIV product development are reflected throughout the planning and development of the MPT product.
• real or potential conflicts of interest between industry partners and applicant institutions are addressed to avoid delays in product development, clinical research and eventual regulatory approval.

Animal models for efficacy and PK determinations: Animal studies should contain design features which promote understanding of the interaction/impact of the MPT, such as:

• Inclusion of appropriate positive control and placebo arms needed to assess superiority of MPT prototypes. Designs with the individual drugs tested in parallel with the MPT are highly informative.
• Use of MPT DDS characterized for API stability and release. Use of unformulated products and vehicle admixtures without establishing some level of drug stability and release are strongly discouraged.
• Development of PK studies that are sufficiently robust (time points and types of samples collected) to allow conclusions regarding duration, burst effects and achievement of drug efficacy targets and exposure to the GI tract.
• Inclusion of additional safety measurements (colposcopy, histology, vaginal pH, microbiome analysis and/or the immune responses, etc.) to characterize MPT candidate impact on the FRT.

PK studies: PK studies should be adequately described and contain sufficient sampling to allow characterization/description of any PK lag, tail and the duration for all APIs in the MPT. Applicants should describe strategies for rectal sampling for the anti-HIV API(s) in all PK studies. Applicants also are urged, if feasible, to optimize antiviral release/dose in a manner that might provide protection for both the FRT and GI tract from HIV infection. This requirement IS NOT meant to require the addition of males to PK studies, but rather inclusion and analysis of rectal samples in female animals.

Reengineering IUDs as MPTs: Applications proposing modification of a copper or hormone IUD should describe the process to convert a contraceptive IUD into a MPT product, and how contraceptive efficacy will be maintained. Compare the new IUD proposed duration of action to that of marketed/licensed IUDs, and address any disparities in proposed duration of use. Applications should describe how IUD-induced endocervical irritation in proposed animal studies will be experimentally addressed with respect to any changes in efficacy and/or safety (HIV or contraception) of the MPT product.

Duration of IVRs: If applicable, describe how the PUC studies will inform the use of longer duration IVRs by their targeted population.

Use of genomic, proteomic, scriptomic, and/or microbiome analysis/technologies: Describe how any proposed genomic, proteomic, scriptomic, and/or microbiome analysis/technologies will be employed to address specific questions for the proposed MPT development.

PUC Studies: If applicable, describe how the outcome from the PUC studies will support/guide the rheological and biophysical property(ies) choices made for the MPT candidate during the development process.

Milestones (required): In a clearly labeled section, applicants must include 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 of the award, and define criteria for success and consideration of the R33 phase. Milestones that are a restatement of application Specific Aims do not meet the definition of milestones used here.

Milestones should address critical points required for dual indication 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 and/or Characterization of contraceptive and anti-HIV API and API-DDS DDI interactions.
• Characterization of both contraceptive and anti-HIV efficacy of the MPT product in an animal model.
• PUC outcomes and integration into MPT product development.

Industrial Partner: In a clearly labeled section, describe the role of the industrial partner, including what resources and facilities they provide to the MPT program. The activities, other resources and processes that would not otherwise be available to the program should be described, referencing but not repeating information submitted on Facilities & Other Resources. Describe the role of any CRO serving as the industry partner in terms of scientific input, contribution and involvement in the MPT strategic planning and development process that supports their participation and fulfils a critical role in the development team. Applications derived solely from industry need to describe the advantages that sole industry sponsorship brings to the application.

Targeted Product Profile (TPP) (optional): In a clearly labeled section, applicants may include a TPP to summarize MPT critical properties and targets for development. Describe the essential MPT product attributes by identifying optimal and minimally acceptable criteria for the MPT and its DDS. Product attributes include 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 physical and PUC-derived attributes, cold chain/storage requirements.

Timelines and/or Gantt charts (optional): In a clearly labeled section, applicants should provide descriptive timelines and/or Gantt charts for the proposed studies. If provided, applicants are encouraged to consider linking the timelines/Gantt chart elements to the proposed milestones.

Quality and Regulatory Strategy: Describe the quality and regulatory strategy needed to submit a pre-IND to the FDA by the end of year 1 of the R33 award. Describe how these activities will be integrated into the overall MPT development process. If a fee-for-service CRO or Contract Manufacturing Organization (CMO) is proposed to carryout GLP studies or GMP manufacturing activities for inclusion in the pre-IND, then describe the process used for quality oversight of the CRO/CMO.

Animal Models for Efficacy and PK Determinations: Describe the use of any animal models and the risks and benefits to the MPT dual indication context. When different animal models are proposed for independently assessing contraceptive and antiviral efficacy and PK, discuss the plan for how the results will be integrated and used to guide candidate development.

Clinical research (optional): If clinical trials, studies or research are proposed, in a clearly labeled section, justify the need for the studies and their impact on the proposed MPT development pathway.

Letters of support: Letters of support may be provided to document access to use of licensed compounds.

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

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

Appendix:

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

Pre-IND drafts should not be placed in the appendix.

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

All clinical research and clinical trials must be conducted at U.S. sites.

Delayed Onset Study

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

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 the policy.

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

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 focus their evaluation on 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.

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

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

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

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

Review criteria specific to this FOA:

Does the proposed MPT represent an advancement beyond the MPTs currently being developed, and will the proposed development help to establish the next generation of MPT products in the MPT pipeline?

If the proposed MPT development relies on fields outside traditional biology, pharmacology and pharmaceutical products, is the strategy well supported and integrated? Do the resources described provide a plausible basis for the MPT approach?

Specific to applications proposing clinical trials:

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

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

Review criteria specific to this FOA:

Does the application combine the expertise in anti-HIV drug and contraceptive drug development required to support the development of a dual indication MPT product?

Is the role of the industrial partner well defined and integral to the development of the proposed MPT?

Has sufficient consideration of regulatory requirements been included for both contraceptive and anti-HIV product development?

Have real or potential conflicts of interest between industry partners and applicant institutions been addressed and mitigated to avoid delays in product development, clinical research and eventual regulatory approval?

If academic investigators are included in an application led by industry are they well integrated into the proposed research?

Specific to applications proposing clinical trials:

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

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

Review criteria specific to this FOA:

Does the outlined development program embody innovation by leading to and supporting the creation of a new/novel MPT product for HIV and pregnancy prevention? Is this new product in line with the objective of creating the next generation of MPT strategies?

Specific to applications proposing clinical trials:

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

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

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

Review criteria specific to this FOA:

Does the overall MPT development strategy adequately address retention of contraception and anti-HIV efficacy, the role of PK lag and tail in developing an effective dosing regime and the potential for DDI for both the drug components and interaction of the drugs with the DDS? Are efforts proposed to quantitate the antiviral component in the GI tract?

If the applicant proposed PUC studies using a licensed contraceptive, placebo prototype or OTC product to identify preferred rheological/biophysical properties for the proposed MPT, is the range of properties represented by the surrogate appropriate, and will they inform on development of the rheological/biophysical properties of the new MPT?

If the application uses preliminary data or experimental approaches derived from an alternative research field (e.g. topical microbicides, contraception research, DDS development in cancer, Alzheimer's, Parkinson's disease, diabetes, etc.) to justify development, does it add significantly to the proposed MPT development approach?

If the applicant is using a CRO/CMO to provide research to support MPT development or for generation of data for inclusion in the pre-IND, have the applicants provided a plan for quality oversight of the CRO/CMO?

Is the strategy proposed likely to allow filing a pre-IND with FDA by the end of the first year of the R33 phase of funding?

If an animal model is proposed for development, do the specific endpoints allow concurrent sample collection to provide unequivocal evidence of contraceptive and antiviral efficacy?

If a TPP is included, does it identify physical, biological and rheological features of the proposed MPT and are the features achievable, and will they lead to an optimal MPT product?

Specific to applications proposing clinical trials:

Does the application adequately address the following, if applicable?

Study Design

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

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

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable? Does the application adequately address Good Clinical Practices (GCP), Good Laboratory Practices (GLP), and Good Manufacturing Practices (GMP) compliance if applicable?

Data Management and Statistical Analysis

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

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?

Review criteria specific to this FOA:

Are the required contraception, HIV prevention and DDS-development resources available to the project? Are the environment and resources provided by the industrial partner well integrated into the project to ensure a successful outcome?

If the application is derived solely from an industrial /pharmaceutical company, are the physical resources adequately described? If the industrial /pharmaceutical company is proposing a more virtual effort (Contracting research), is the company infrastructure appropriate to oversee the development plan?

Specific to applications proposing clinical trials:

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

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

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

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

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

Milestones (required), TPP (optional), Gantt Chart (optional), and Timelines (optional)

Review criteria specific to this FOA:

Are the milestones appropriate, adequately described, feasible, quantifiable and achievable within the proposed time frame for the research elements they support? Are the Go/No-Go criteria appropriate for the described testing and integrated into the milestones? Are the milestones well-integrated into the research strategy? Do the proposed milestones include those critical to submission of a pre-IND package to the FDA at the end of the first year of the R33 been proposed?

If applicable, are the TPP, Gantt chart and/or timelines to support product development integrated with the milestones, and do they support achieving the desired product properties in the proposed timeframes?

Study Timeline and Milestones

Specific to applications proposing clinical trials:

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

Are appropriate, evaluative milestones clearly defined for the aims associated? Are the milestones feasible and quantifiable with regard to specific aims and timeline? Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

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

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

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

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

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

Not Applicable

Not Applicable

Not Applicable

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

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

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

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

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

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

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

As part of the scientific peer review, all applications:

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

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

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA . Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

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

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.

Additionally, ICs may specify any special reporting requirements for the proposed clinical trial to be included under IC-specific terms and conditions in the NoA. For example: If the proposed clinical trial has elevated risks, ICs may require closer programmatic monitoring and it may be necessary to require the awardee to provide more frequent information and data as a term of the award (e.g., to clarify issues, address and evaluate concerns, provide documentation). All additional communications and information related to programmatic monitoring must be documented and incorporated into the official project file.

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

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH encourages registration of all trials

whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

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

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

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

Milestones: Future support of a study funded under this FOA is contingent upon adequate participant recruitment based on projected milestones.

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

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

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

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

Cooperative Agreement Terms and Conditions of Award

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.

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

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

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

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

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

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact Center Telephone: 800-518-4726
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

Jim A. Turpin, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-451-2732
Email: [email protected]

Teri Senn, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-761-7852
Email: [email protected]

Peter Jackson, Ph.D.
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 240-669-5049
Email: [email protected]

Jenna Briggs
National Institute of Allergy and Infectious Diseases (NIAID)
Telephone: 301-761-5137
Email: [email protected]

Rita Sisco
National Institute of Mental Health (NIMH)
Telephone: 301-443-2805
Email: [email protected]

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 .