The purpose of this Funding Opportunity Announcement (FOA) is to accelerate development of safe and effective long-acting drug delivery systems (LA-DDS) for improved, simplified treatment of HIV-1 in children. This FOA invites applicants engaged in the development of existing LA-DDS platforms at early product development stages to perform specific preclinical activities that enable product optimization and accelerated translation to HIV-1 infected children. Collaborative research partnerships with industry are required.
Background
Despite significant advances in prevention of maternal-to-child transmission of HIV and antiretroviral (ARV) scale up in HIV-infected children, pediatric HIV still constitutes an important part of the global HIV burden. In 2017 there were approximately 1.8 million prevalent and 180,000 new infections in children less than 15 years old and 2.1 million prevalent infections and 260,000 new infections in children 10-19 years old. The proportion of HIV-infected children receiving antiretroviral treatment (ART) and achieving viral suppression worldwide continues to increase but, in most places, falls short of meeting UNAIDS’ 90-90-90 targets. Currently available ART regimens for children have limitations including: suboptimal viral suppression, poor adherence in all pediatric populations but particularly in adolescents, regimen toxicity, and decreased drug penetration at some anatomical sites (lymphoid tissue, central nervous system [CNS]) of HIV replication. In particular, infants and young children experience high rates of pre-treatment drug resistance, hypervariable ARV exposures in early life due to ontogeny of drug metabolizing enzymes (DME) and transporters, lack of appropriate formulations and poor palatability/tolerability of many of the existing formulations. Even in settings where ART is available, other barriers exist contributing to delay of ART administration to young children such as maternal fear of stigma and non-disclosure of HIV status. Pediatric ARV drug development experiences many challenges, and introduction of new ARVs in children lags behind their introduction in adults by years. Generation of preclinical data relevant to inform pediatric studies seldom occurs early in drug development, and product manufacturers are not required to do so. Submission of Pediatric Study Plans (PSP)/Pediatric Investigation Plans (PIP) to regulatory bodies is not required in most cases until the end of Phase II adult studies. Late initiation of development of age-appropriate formulations further delays initiation of studies in young children who are unable to swallow tablets. LA-DDS that can overcome these limitations are needed to significantly simplify dosing requirements and optimize ART outcomes in infants and children, through achievement and maintenance of consistent and effective drug levels in anatomical tissues of high HIV replication. Stimulating critical optimization and preclinical activities at a very early drug development stage could significantly accelerate introduction of promising LA-DDS platforms to pediatric populations across the age spectrum.
Research Objectives and Scope
The objective is to develop a LA-DDS for treating HIV-1 in one or more pediatric age groups. For the purposes of this FOA, the target pediatric age groups are defined as: infants (0-< 2 years), young children (2-< 6 years), older children (6-< 12 years) and adolescents (12-< 18 years). While all pediatric populations are of interest, recent FDA draft guidanceencouraging adolescent inclusion in adult studies of antiviral agents, could mean easier transition for these products to adolescents or older children where, limited or no formulation optimization activity may be required, compared to younger children. Therefore, additional emphasis in this FOA is placed in non-adolescent (infants and children) age groups, particularly infants. The proposed LA-DDS may be in preclinical testing or early human clinical testing phase (up to phase 2) in adults but should not have undergone any clinical testing or have imminent plans for such testing in pediatric populations for anti-HIV-1 indications.
Responsive applications must include:
- A proposed LA-DDS with:
- Incorporation and simultaneous delivery of a fully active ARV combination
- Minimum dosing interval of > 4 weeks
- Applicants who have experience with the proposed LA-DDS, in terms of the development of the LA-DDS for non-pediatric or non-ART applications.
- An industry partner as defined below.
- Plans to develop an LA-DDS strategy for one or more pediatric age groups (with particular emphasis on the infants and children age groups as defined above), appropriate for the development stage of the target age group(s) and build/optimize a formulation suitable for chosen age group(s).
- An animal antiviral efficacy study of the LA-DDS candidate in the R33 phase in non-human primates (NHP).
Areas of interest include but are not limited to:
- Sustained/extended release strategies incorporating pharmacokinetic (PK) studies with activities critical to characterizing the DDS sustained/extended release characteristics and capacity such as:
- Animal PK and pharmacodynamic (PD) studies to support the proposed duration of use and PK parameters.
- 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 of no more than 1/3 of the proposed duration of action of the DDS. 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).
- Administration strategies such as oral, injection (depot and non-depot forming), implant (non-biodegradable or biodegradable), transdermal (continuous use or short exposure depot-forming), and depot or nondepot forming systems, which may or may not be enabled using nanotechnology and engineering solutions to achieve the required minimal durations of action.
- Enhanced targeting of anatomical compartments (e.g., secondary lymphoid tissues, gut-associated lymphoid tissue (GALT)), and CNS.
- Antiviral efficacy and safety of the proposed product(s) within the LA-DDS in animal models.
- Early assessment of preferred user characteristics in the end user population as defined below is strongly encouraged.
Industry partnership and collaboration. Applications submitted in response to this FOA require substantial collaboration with 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 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. Applications from industry are not required to involve collaborators from academic and/or non-profit research organizations, but are encouraged to do so, where appropriate.
Preferred user characteristics (PUC) assessment in end user population. Studies using established behavioral and social sciences tools or other assessment approaches to focus on identifying factors that may influence an individual/caregiver’s preference for a LA-DDS strategy are strongly encouraged. Such studies must not include clinical trials. Such studies can take place either during the R61 phase or R33 phase.
Animal research. Animal studies for LA-DDS optimization in the R61 phase are allowed. Animal models other than NHP can be used for screening/testing LA-DDS candidates to understand overall PK of the antiviral compounds (e.g., PK tail, forgiveness and duration), safety and/or drug-drug interactions (DDI) leading up to the sentinel NHP efficacy study. For the purposes of this FOA, the R33 phase must include an animal antiviral efficacy study in an NHP animal model.
Non-responsive Areas of Research
The following activities are non-responsive and will not be reviewed:
- de novo DDS/small molecule discovery work
- cGMP manufacture activities
- Applications proposing development of LA-DDS with durations of action that do not meet the minimum durations defined in the FOA
- Intravenous infusion of any component of the LA-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 of broadly neutralizing antibodies
- LA-DDS platforms that are in late phases of clinical testing or planned clinical testing in pediatric populations
- Applications without an industry partner as defined in the FOA
Phased Innovation Awards
This FOA will use milestone-driven, phased research activities with investigator-provided milestones. Support will be provided for up to two (2) years for the R61 phase, and up to three (3) years for the R33 phase, if applicable. 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 transition milestones, Program priorities, and availability of funds. If selected for transition, R61 awards will transition to the R33 award without the need to submit a new application. It is expected that approximately half of the projects funded during the R61 phase will continue into the R33 phase
Deadline: February 13, 2019 (letters of intent); March 13, 2019 (full proposals)
URL: https://grants.nih.gov/grants/guide/rfa-files/RFA-AI-18-057.html
Filed Under: Funding Opportunities