The purpose of this Funding Opportunity Announcement (FOA) is to stimulate the development of new and innovative sustained/extended release drugs and drug delivery systems (DDS) that can achieve extended durations (months to years) of HIV prevention in at-risk individuals. This FOA requires an industry partner, milestones linked to Go/No-Go decisions and year 5 funding requires submission of a pre-IND application to the FDA.
October 30, 2018
November 30, 2018, by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on this date.
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
November 30, 2018, by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on this date.
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
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
Purpose and Scope
The objective of this FOA is to support the development of new and innovative sustained/extended release HIV prevention products with rheological and biophysical properties that provide product user perceptions (look and feel) compatible with sustained/extended use of the drug delivery system (DDS) for people at-risk of HIV/AIDS infection. These products are needed to enable users to more easily adhere to HIV prevention dosing regimens by reducing dosing frequency while simultaneously increasing effectiveness through enabling longer durations of effective drug coverage. The ultimate sustained/extended release product should provide months to years of HIV prevention coverage, be reversible through removal of the DDS, while offering “set it and forget it” protection from HIV infection. For the purposes of this FOA, the target populations are males and females, including transgender and gender non-conforming populations (ages 14 years and older) desiring sustained/extended release products to prevent HIV acquisition /transmission. Populations of specific interest include men and women in serodiscordant partnerships, men who have sex with men (MSM), gay men, blacks, Hispanics, intravenous drug users (IDUs) and alcohol users and abusers.
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 to 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 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 or communication with 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 numerous non-vaccine biomedical prevention (nBP) clinical phase III trials have demonstrated conclusively that both adolescents and adult men and women face adherence barriers when required to use prevention products around coitus (pre- or post). This includes taking a daily pill, using a daily or sex-act associated vaginal gel or a 30-day intravaginal ring (IVR) for HIV prevention. Multiple user perception factors (individual, cultural, stigma-derived, DDS-related, etc.) have been identified that can contribute to low adherence for prevention products. In addition to user perceptions, biological and pharmacological barriers may also play a role in the effectiveness of prevention strategies where individual use decisions control adherence to the prevention regimen. In vitro modeling and direct observed therapy pharmacokinetic (PK) studies of daily oral emtricitabine/ tenofovir disoproxil fumarate (TDF/FTC pre-exposure prophylaxis (PrEP) have shown that approximately 28% adherence by men, and 85% adherence by women are required for a weekly pill-taking regimen to achieve sustained protective levels of Tenofovir-diphosphate (TFV-dp) and emtricitabine triphosphate (FTC-tp) in the blood and mucosal tissues. To increase adherence and potentially reduce its impact on prevention strategies, the nBP field has begun to evaluate anti-HIV drugs with longer durations of action. The most advanced of these are Phase III clinical trials of a q8 weeks injection of a nanocrystal formulation of the integrase inhibitor Cabotegravir for HIV prevention in men (HPTN 083) and women (HPTN084). Although injectable prevention strategies could potentially have a significant impact on the HIV pandemic, there is still room for improvement. There are several questions that remain to be answered and capabilities that may need to be incorporated into development of sustained/extended release HIV prevention strategies. These include: impact of excess drug exposure (drug burst) after dose initiation on safety and establishment of protection; impact of periods of suboptimal drug exposure (PK tail, time during which drug drops below effective levels) on efficacy and emergence of resistance; the inability to terminate dosing if adverse events occur when deviceless (e.g. injection) DDS strategies are used; identification of optimal dosing parameters (volume of injection, size/number of devices used/implanted, user friendly durations); and methods for renewing the dose (site of drug application, surgical procedures) that facilitate sustained use of the prevention strategy. Therefore, this FOA focuses on developing the next generation of new and innovative sustained/extended release drug products that are optimized not only for delivery of HIV prevention (PK profile, DDS, etc.), but also for their interaction with the user (look, feel and use) to increase the potential for initial uptake and continued use of adherence independent strategies (implant, injection, etc.) and enhancement of adherence for user removable strategies.
Sustained release for the purpose of this FOA is defined as continuous exposure to the anti-HIV drug from a DDS that is achieved using either a continuous release device or through creation of a tissue depot. Extended release is defined as providing protection from HIV infection/transmission for the minimum durations identified below. It is expected that products proposed for development will deliver active pharmaceutical ingredients (API) capable of preventing HIV replication and infection using DDSs compatible with sustained/extended HIV prevention, and achieving the minimal durations of action for the DDS below:
IVR strategies with durations of 3 months or longer with or without removal periods for bleeding.
Modification of licensed copper IUDs to release an antiviral drug(s) with a projected duration of at least 3 years.
Implants or Injectable prevention strategies with a minimal duration of 6 months.
Novel DDS with a minimum of 1-month duration, e.g. fast dissolve inserts or films, transdermal patch, etc.
Responsive DDS administration strategies include, but are not limited to, injection (depot and non-depot forming), implant (non-biodegradable or biodegradable), transdermal (continuous use or short exposure depot-forming), depot or nondepot forming mucosal intravaginal/intrarectal DDS, and other systems which may or may not be enabled using nanotechnology and engineering solutions to achieve the required minimal durations of action. Strategies/development which may enable self-administration are of interest also.
If the strategy is composed of a combination of antiviral drugs, all components must be delivered simultaneously. DDS which compartmentalize the drugs to address drug-drug interactions (DDI) and/or create different release rates are responsive, if delivered simultaneously from a single DDS.
The following areas of preclinical and behavioral research may be proposed to achieve the objective of creating the next generation of sustained/extended release candidates:
Development of new and innovative DDS which can deliver sustained/extended HIV prevention products composed of either a single antiviral or combinations of HIV antivirals.
Understanding the potential for and identifying/characterizing drug-drug interactions (DDI) that could compromise antiviral effectiveness.
Understanding the PK of sustained/extended release products by mapping the characteristics of the antiviral release including, drug bursts (initial and during biodegradation), lag period (time to establish effective concentrations), PK tails (time to loss of effective concentrations) and forgiveness intervals (dosing intervals during which the drug/DDS must be renewed to maintain efficacy).
Understanding the impact of continuous antiviral drug delivery on tissue depot sites which might alter drug effectiveness (activation of drug transporters, metabolism and excretion), foreign body reactions (wound healing, encapsulation of implants, etc.) and/or local and systemic distribution of drug to HIV target tissues.
Understanding the ability of the sustained/extended release strategies to deliver antiviral concentrations to both the female reproductive tract (FRT), male genitourinary system (MGS), and/or gastrointestinal (GI) tract of men and women.
Understanding Preferred User Characteristics (PUC), which will govern decisions made by individuals to use the sustained /extended release strategy (look and feel), and whether to adopt and maintain use of longer duration strategies. For this FOA, PUCs are defined as the rheological/biophysical properties of the sustained/extended release DDS that invoke user judgments, leading to decisions for first, subsequent use or non-use and/or early termination.
Advancing the sustained/extended release candidate in the clinical pipeline by performing studies which position the drug/DDS at the end of five years to either advance to clinical testing, undergo further iterative development or terminate its development.
Responsive Areas of Research Interest
Examples of the types of studies responsive to this FOA include, but are not limited to:
Research designed to identify an optimal DDS for delivery of a single or combination of anti-HIV small chemically-defined molecule(s) and/or protein(s), such as broadly neutralizing antibodies or non-antiretroviral (non-ARV) HIV inhibitors.
Development of longer duration sustained/extended release strategies that protect both the FRT, MGS, and/or GI tract of men and women.
Sustained/extended release strategies incorporating PK studies with activities critical to characterizing the DDS sustained/extended release characteristics and capacity such as:
Characterization of the PK tail sufficiently to allow selection of the dosing regimen with such factors as lag, duration and forgiveness interval taken into account
Optimizing to achieve forgiveness intervals for of no more than 1/3 of the proposed duration of action of the DDS, e.g. Forgiveness interval is defined as the interval in which redosing is recommended to avoid delivering drug below the effective concentration.
Studies of PK lag periods (time before establishment of real or predicted effective drug concentrations).
Characterizing and minimization of the interval between DDS drug exhaustion and full degradation of the DDS for biodegradable DDS.
In vitro or in vivo animal PK, pharmacodynamic (PD) and toxicokinetic (TK) studies to support the proposed duration of use and PK parameters. Of significant interest are PK studies that establish relationships between plasma and GI, MGS, and FRT (upper and lower) tissues/secretions, lymphoid tissues, and implant/dosing site drug concentrations. Understanding the impact of timely or delayed re-dosing (forgiveness) on efficacy and emergence of viral resistance is also of interest.
Nanotechnology approaches to solve specific problems related to the sustained/extended release DDS, candidate duration of action, tissue/systemic distribution, safety, and/or efficacy.
Hypothesis-driven studies focused on the impact of the sustained/extended release drug on the genital/GI tract and tissue at the site of dosing, specifically on mucosal barrier and immune function as it relates to the safety/efficacy of the proposed sustained/extended release drug product and its use. This may include impact on drug transporters, inducible and non-inducible cellular drug-degradation and metabolism pathways, as well as the impact of the DDS/drug on epithelial cell function, mucosal wound repair, and immune cell trafficking. Understanding the impact of prolonged exposure of the drug on innate, adaptive and cellular immunity, which may control susceptibility to HIV infection is also of interest.
Assessments of PUCs for sustained/extended release strategy rheological/biophysical attribute selection. Studies using established behavioral and social sciences tools associated with user look and feel optimization, such as ethnographic studies, perceptibility assessments, mental modeling, user journeys, discrete choice studies and conjoint analysis. Approaches will focus on identifying factors which may influence an individual’s choice to use. Studies involving potential prescribing physicians/Health givers in the U.S. that result in identification of physical and rheological/biophysical attributes of the sustained/extended release 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. PUC studies should be designed and implemented to inform on the rheological and biophysical property (ies) choices made for the sustained/extended release strategy.
Limited clinical research focused on obtaining PUC information is allowable, if the proposed research meets the criteria outlined below.
Applications submitted to the FOA must demonstrate substantial collaboration by at least one industrial partner. An industrial partner/collaborator is broadly defined as participation in the application of an individual, group, or unit from a for-profit or not-for-profit pharmaceutical, biotechnology, bioengineering, or chemical company that is large or small, domestic or foreign with an established record in product development. Substantive collaboration 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, provision and testing in animal or other laboratory models for evaluation, data management resources and/or regulatory support. 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. However, inclusion of a Contract Research Organization (CRO) to provide fee-for-service deliverables without significant participation/scientific collaboration in the research agenda does not meet the definition of an industry partner.
Industry applicants are not required to involve collaborators from academic and/or non-profit research organizations, but are encouraged to do so, where appropriate.
Animal Models for Efficacy and PK Determinations
For the purposes of this FOA, animal antiviral efficacy studies are divided into two categories. The first category includes hypothesis-driven studies that are supportive of sustained/extended release drug development and address the impact of the product or strategy on the FRT, MGS, and GI track as part of a safety determination. The second category includes animal models for screening/testing sustained/extended release candidates to understand overall PK (e.g. PK tail, forgiveness and duration), antiviral activity (e.g. Pharmacodynamics, PD), safety and/or DDI.
Clinical Trials and Clinical Studies
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 sustained/extended release drug product rheological/biophysical (look and feel) properties as part of the development process. The outcome from the PUC studies should support/guide the rheological and biophysical property (ies) choices made for the sustained/extended release strategy.
Products for testing in PUC assessment must be managed for low potential risk when study participants are required to handle them during PUC studies. A mano studies (handled during the study) with commercial or licensed products may be carried out if all label contraindications and potential allergic reactions associated with handling of the product are managed.
A low risk placebo DDS or 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 prototype or 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 studies should be performed to confirm safety. 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 over-the-counter (OTC) products as surrogate products by study participants is allowed, if there are no documented handling safety risks and potential allergic reactions are managed. Use of nonoxynol-9 (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 sustained/extended release devices in PUC studies that the rheological/biophysical properties of products either span a range of potential user perceptions or match the biophysical and rheological properties of the proposed DDS.
Non-responsive Areas of Research
Applications proposing the following areas of research will be considered non-responsive and will NOT be reviewed:
Phase I, II, III clinical trials, except for clinical research involving a mano PUC studies.
Conduct of clinical research/trial to assess PUC at a non-U.S. site.
Applications proposing development of sustained/extended release strategies with durations of action that do not meet the minimal durations defined in the FOA.
Strategies or antiviral candidates without demonstrated antiviral activity to HIV. Although anti-HIV antivirals identified for development as sustained/extended release strategies may have activity against other sexually transmitted infections (STI), the objective of this FOA is the development of sustained/extended release anti-HIV products, not sustained/extended release products with activity against additional/other STIs. Strategies targeting multiple pathogens (HSV, HCV, HPV, bacterial, yeast, mycoplasma, etc.) are acceptable but should be justified and described solely for their development to prevent HIV infection. Inclusion of additional agents (other than excipients and carriers) without a significant contribution to anti-HIV activity is highly discouraged.
Random, bulk or high-throughput screening of chemical or natural product libraries or collections to “discover” anti-HIV candidates (discrete inhibitors or natural product mixtures) for incorporation into sustained/extended release DDS. This includes medicinal chemistry efforts on screening leads or characterized anti-HIV active pharmaceutical ingredients (API) designed to create new anti-HIV compounds. Chemical modification of anti-HIV APIs may only be used to facilitate incorporation into and release from the proposed DDS.
Broad, generalized global assessments in animal models or humans to identify biomarkers of sustained/extended release drug/DDS impact on the FRT, MGS, or GI tract using genomic, proteomic, scriptomic, metabolomic, and/or microbiome analysis/technologies that do not directly support the development or characterization of the impact of a sustained/extended release candidate/product.
Intravenous infusion of any component of the sustained/extended release drug.
Cure or amelioration of bacterial vaginosis (BV) or vaginal dysbiosis by any chemical or biological means to reduce HIV susceptibility as part of a sustained/extended release strategy.
Sustained/extended release strategies employing a female or male condom, diaphragm or hormone containing IUD as the DDS.
Use of any live biotherapeutic or vector system (viral, bacterial, fungal, etc.) to produce/deliver the anti-HIV component of the proposed drug product.
Development or optimization of a Genetically Modified Organism (GMO) as a part of a sustained/extended release DDS or incorporation of bacteria selected or engineered for specific characteristics designed to create a "hostile microenvironment" for HIV. 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). 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 chemically characterized as detergents or sulfonated polymers that act as either virucidal agents or inhibitors of HIV entry. 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 a strategy.
Further development of an OTC product or a non-specific vaginal female health product, including OTC lubricants and sexual pleasure products as the DDS for the sustained/extended release strategy, or as the anti-HIV component. This does not preclude developing a strategy with rheological/biophysical properties that can act as a sexual lubricant or pleasure product.
Development of sustained/extended release products incorporating the following HIV antiretrovirals:
Sustained/extended release products composed solely of or combinations of Tenofovir (TFV, PMPA, (R)-9-(2-Phosphonoylmethoxypropyl) adenine), Tenofovir Disoproxil Fumarate (TDF or Viread®) and/or Tenofovir Alafenamide fumarate (TAF),
The non-nucleoside reverse transcriptase inhibitor dapivirine as a single agent or in combination with TFV, TDF, TAF or Emtricitabine (FTC),
Development of the following combination antiretrovirals as the anti-HIV component of a sustained/extended release strategy: 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 in an injectable or implantable DDS. Development of combinations of these drugs with other active pharmaceutical ingredients (APIs), except as noted above, is responsive.
Vaccine development of any form (new mucosal vaccine, vector, insert, or delivery system) and/or use of a vaccine as the antiviral or efficacy-enhancing element of a sustained/extended release prevention strategy.
Basic behavioral research designed to develop and inform on broad issues of sustained/extended release product 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 products. Education programs focused on any potential stakeholder population to support introduction of a sustained/extended release product. 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 product or concept of sustained/extended release.
Activities that are intended solely for enabling/facilitating clinical studies to be conducted with non-SRI funds. This restriction includes GMP production of clinical supplies for use other than PUC or IND-enabling studies, and regulatory submissions other than the milestone required 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.
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types.
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.
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.
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.
Letter of Intent
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
Specific Aims: Briefly describe in clearly demarked sections in the single Specific Aims attachment the specific aims for the R61 and R33 phases of the proposed research.
Research Strategy: Applicants must discuss how the proposed sustained/extended release product represents an advancement beyond the products currently being developed, and how the proposed development pathway helps to establish the next generation of products for possible clinical testing. If a novel sustained/extended release DDS with a one-month duration is proposed, applicants should discuss the innovative/novel nature of the DDS and why this duration is important for its current stage of development and its potential for longer durations, if successful. If the proposed sustained/extended release development approach/rationale relies on research in fields outside the current biology, pharmacology and pharmaceutical research and development of prevention products, the applicant should discuss their relevance to the proposed sustained/extended release approach and how progress in these fields enable the proposed product.
Sustained/extended Release Product Specific Criteria: Describe whether the development plans for the sustained/extended release product include licensed or unlicensed HIV antivirals (though applicants are reminded that the only licensed antivirals for prevention is the combination of TDF and FTC and this combination is not supported by this FOA). Describe the sustained/extended release product development plans, including:
The process for how the antiviral was selected and how the antiviral will be incorporated into the DDS to achieve the required durations of action.
The drug development pathway in terms of the proposed regulatory strategy and how the required R61 and R33 milestones enables future development.
The rationale and approach to achieving the duration of action proposed for the sustained/extended release product.
How the time to full degradation of biodegradable DDS, if applicable, will be determined, and its relationship to the drug release profile.
The forgiveness interval to be incorporated into the sustained/extended release strategy and how it will be verified experimentally.
The potential for DDI and how they will be dealt with. If the anti-HIV strategy includes metabolic boosters, e.g. Cobicistat or other drug/metabolic enhancers designed to boost the anti-HIV efficacy of the antiviral drug, 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 other drugs which may be used, e.g. hormone contraceptives and chronic disease treatment drugs.
Animal models for efficacy and PK determinations: Applications proposing animal studies should describe design features incorporated into the study which promote understanding of the potential safety and effectiveness of the sustained/extended release strategy and wherever possible, study design elements and features that support the integrity of the study endpoints. These include descriptions of:
The positive control and placebo arms and their role in the study outcome,
How the drug products were characterized for stability, drug content and release,
How time points and the samples for analysis at these time points were chosen for studies,
and how this supports the requirement for drug exposure to the FRT, MGS, and male and female GI tracts.
How ancillary studies, e.g. colposcopy/endoscopy, histology of mucosa and injection/implant sites, vaginal/rectal pH, microbiome analysis, etc. are used to support the safety of the sustained/extended release strategy.
PK studies: If PK studies are included in the application, describe and justify the samples collected and the timing of sample collection for PK in the context of describing and characterizing critical PK features of the sustained/extended release product, such as duration, lag, tail, and forgiveness. Applicants should describe strategies for rectal and genital secretion and/or tissue sampling for the anti-HIV API(s) in PK studies where appropriate.
Use of genomic, proteomic, scriptomic, and/or microbiome analysis/technologies: If applicable, describe how any proposed genomic, proteomic, scriptomic, and/or microbiome analysis/technologies will be employed to address specific questions in a hypothesis-driven manner to inform on the sustained /extended release strategy safety and efficacy.
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 sustained/extended release strategy.
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. Milestones that are a restatement of application Specific Aims do not meet the definition of milestones used here. Descriptions of the milestones must include Go/No-Go statements to support critical parameters of the milestone that will determine whether the research should move forward or cease due to product development failures.
Milestones should address critical points required for sustained/extended release products. The following milestones are examples that may be included:
Demonstration of proposed duration of action.
Definition of optimal dosing regimen including PK lag and tail.
Identification of API and API-DDS DDI interactions.
Characterization of anti-HIV efficacy of the sustained/extended release product in an animal model.
PUC outcomes and integration into sustained /extended release product development.
Applicants must include a milestone for communication with or submission of a pre-IND package to the FDA by the end of year 1 of the R33. Describe this strategy, and how this outcome will be integrated into the R61 research agenda. Descriptions of this process should demonstrate knowledge of the appropriate considerations for this requirement. Applicants should not include pre-IND drafts or outlines of the required sections of the pre-IND contents in the application but should demonstrate knowledge of the process through a general description of the process they will follow.
Industrial Partner: In a clearly labeled section, describe the role of the industrial partner as a collaborator, including the activities and processes that would not otherwise be available to the program. Reference, but do not repeat, information submitted in the Facilities section. Describe the role of any CRO serving as the industry partner in terms of scientific input, contribution and involvement in 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. If an academic collaborator is proposed in an application from an industry source, describe how the academic collaborator(s) is(are) integrated into the proposed research. If the industrial /pharmaceutical company is proposing a virtual effort (contracting out all or part of the research), describe the oversight for the contracted elements of the plan.
Targeted Product Profile (TPP) (optional): In a clearly labeled section, applicants may include a TPP to summarize sustained/extended release drug product critical properties and targets for development. Describe the essential product attributes by identifying optimal and minimally acceptable criteria for the drug 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 may 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 communicate with and/or 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 drug 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.
Clinical research/trials: If clinical trials or research are proposed, justify the need for the studies and their impact on the proposed sustained/extended release product development pathway in a clearly labeled section.
Letters of support: Letters of support are strongly recommended to document access to use of licensed compounds
All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
Important Update: See NOT-OD-18-228 for updated review language for due dates on or after January 25, 2019.
For this particular announcement, note the following:
The R61/R33 phased innovation grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. An R61/R33 grant application need not have preliminary data, extensive background material or preliminary information; however, they may be included if available. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or, when available, from investigator-generated data. Accordingly, reviewers will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the R61 and R33 phases.
In addition, for applications involving clinical trials:
A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.
Specific to this FOA: Does the proposed sustained/extended release strategy represent an advancement beyond ones currently being developed, and will the proposed development help to establish the next generation of sustained/extended release products in the pipeline?
If the proposed sustained/extended release development relies on fields outside traditional biology, pharmacology and pharmaceutical prevention products, is the strategy well supported and described within these fields? Do the resources described provide a plausible basis for adaptation of the sustained/extended release approach to HIV prevention?
In addition, for applications involving 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?
Specific to this FOA: Does the application adequately combine the expertise in anti-HIV drug and DDS development required to support the development of a sustained/extended release product?
Are the industrial partner(s) and their participation well integrated with the development of the proposed sustained/extended release product?
If academic investigators are included in an application led by industry are they well integrated into the proposed research?
In addition, for applications involving 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?
Specific to this FOA: Does the outlined development program embody innovation by leading to and supporting the creation of a new and innovative sustained/extended release product for HIV prevention? Is this new product in line with the objective of creating the next generation of sustained/extended release strategies?
In addition, for applications involving 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?
Specific to this FOA: Does the overall sustained/extended release development strategy adequately address the required durations, the role lag, forgiveness, and tail in developing an effective dosing regime and the potential for DDI? Are efforts proposed to quantitate the antiviral component in secretions and/or tissues of the FRT, MGS, and GI tracts and at dosing sites?
If the applicant proposed PUC studies using a placebo prototype or OTC product to identify user preferred rheological/biophysical properties for the proposed sustained/extended release strategy, are the range of properties represented by the surrogate appropriate, and will they adequately inform on development of the rheological/biophysical properties of the new product?
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, do the information and preliminary data support its porting to sustained/extended release for HIV prevention?
If the applicant is using a CRO/CMO to provide research to support sustained/extended release development or for generation of data for inclusion in the pre-IND, is/are the plan(s) for quality oversight of the CRO/CMO adequate?
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?
Have regulatory considerations been adequately addressed and integrated into the proposed sustained/extended release product development plan, and are these considerations adequate?
If a TPP is provided, does the TPP adequately identify physical, biological and rheological features of the proposed sustained/extended release product and are the features achievable, and will they lead to an optimal drug product?
In addition, for applications involving clinical trials: Does the application adequately address the following, if applicable:
Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is? the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?
Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?
Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?
Data Management and Statistical Analysis
Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?
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), are the plans appropriate to oversee the development plan?In addition, for applications involving clinical trials: If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?
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?
Study Timeline: Milestones (required), TPP (optional), Gantt Chart (optional), and Timelines (optional)
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 communication with and/or submission of a pre-IND package to the FDA at the end of the first year of the R33?
If applicable, do the TPP, Gantt chart and/or timelines provided support the proposed product development, and are they integrated with the milestones?Do they support achieving the desired product properties in the proposed timeframes?
Specific to applications involving 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 potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?
All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.
Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.
In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 “Federal awarding agency review of risk posed by applicants.” This provision will apply to all NIH grants and cooperative agreements except fellowships.
For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/index.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and https://www.hhs.gov/civil-rights/for-providers/laws-regulations-guidance/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.
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