When are applications due?
Upcoming application due dates for PAR-21-163 Blueprint Neurotherapeutics Network (BPN): Biologic-based Drug Discovery and Development for Disorders of the Nervous System (UG3/UH3 Clinical Trial Optional) are August 10, 2021 and February 9, 2022.
What are the entry criteria for Discovery-stage projects?
- A biologic or agent, in hand, that serves as a starting point for optimization with:
- Sufficient characterization so that parameters still to be optimized can be quantitatively specified
- Established preliminary in vivo efficacy* and target engagement data using the biologic or agent in relevant animal model(s)
- Selectivity for the intended target over closely related targets, if desired (and when the target is known)
- Rigorous data supporting the hypothesis that modulating the putative drug target/affected pathway will produce a desirable outcome for the intended disease indication. (it is not necessary to know the precise drug target or mechanism of action)
- Demonstrated availability and suitability of in vitro bioactivity assays that can be used for driving lead characterization and optimization studies that demonstrate sufficient reliability and throughput for their proposed use in the project
- Demonstrated availability of preclinical animal model(s) that can be used to assess in vivo efficacy* or target engagement (measurement of target binding or proximal downstream effects)
- Demonstrated availability of selectivity and counter-screening assays that can be used to identify interfering agents and other undesirable activities or artifacts, such as toxicity, immunogenicity or other off-target effects
- No obvious legal (e.g., intellectual property) constraints to pursuing the proposed agent(s) and using the proposed assays and models for research purposes and/or commercial development
* Proposals may be considered without in vivo/ex vivo efficacy, if there is a clear rationale backed-up with compelling in vitro data.
What are the entry criteria for Development-stage projects?
- A strong package of data linking the putative drug target/affected pathway to the proposed disease indication and supporting the hypothesis that altering the target activity as proposed will produce desirable outcomes for the disease
- The proposed biologic candidate must have in vitro and in vivo biological activity and ADMET properties appropriate for the intended clinical use (i.e., the disease indication, patient population, delivery mode, treatment duration, and treatment regimen)
- The candidate should have appropriate bioactivity, stability, manufacturability, and bioavailability by the intended route of administration for development
- The candidate should demonstrate target engagement with defined minimal and optimal doses by the intended route of administration.
- Applicants should show that their candidate therapeutic is efficacious when delivered by the intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.
- Projects with only in vitro data need compelling rationale supported by data that the in vivo studies are not necessary or appropriate.
- Demonstration that the ability of the PD/PI's institution to develop and commercialize the proposed biologic candidate is unlikely to be blocked or impeded by legal (e.g., intellectual property) constraints.
In addition, projects must be capable of initiating IND-enabling studies within two years of entering the BPN-Biologics program. The following are general expectations for a project to initiate IND-enabling studies:
- Dose-range finding toxicology studies show an acceptable safety margin.
- Manufacturing-related development processes, including compound assay release criteria (e.g. potency and stability indicating) have been established.
- Optimal delivery route has been determined and is feasible for the proposed indication and patient population.
What is a UG3/UH3 award, and how does it compare to an R01 grant?
The UG3/UH3 is a phased cooperative agreement mechanism. BPN-Biologics uses a UG3/UH3 award to pay for work that will be conducted by the Principal Investigator (PI). The UG3 supports the PI’s activities for lead optimization and characterization in preparation for IND-enabling studies and allows for formation of the Lead Development Team and project planning, including negotiation of go/no-go milestones, while the UH3 supports all subsequent work. BPN-Biologics applicants can request up to two years of UG3 support. The combined duration of the UG3 and UH3 awards cannot exceed five years.
NIH is more involved in the management and oversight of research funded by cooperative agreements than by typical grants. The cooperative agreement mechanism enables BPN-Biologics program staff and consultants to participate in Lead Development Teams and evaluate project milestones.
My project already meets the program requirements to initiate IND-enabling studies. Can I skip the UG3 phase?
All projects must begin with a UG3 phase to allow for NIH due diligence (confirmation that the project meets requirements for subsequent work) and project launch activities, but it can be shorter than one year. You should allow approximately three months for establishing a Lead Development Team and developing project plans, including milestones. We recommend budgeting for a minimum of a six-month preparatory phase. If preparatory activities are completed in less than six months, the project can be advanced sooner.
What kind of work can be done during the UG3 phase?
Examples of activities that can be supported during the Discovery UG3 phase include:
- Establishment of a project milestone plan, including milestones that must be met to initiate SAR studies and desired compound profiles at completion of lead optimization
- Characterization of identity and properties (e.g., cell phenotype, aggregation, epitope mapping, glycosylation or other post-translational modification, number of unpaired cysteines, oxidation, deamination, isomerization, proteolytic sites, sequences, viscosity, stability)
- Optimization and/or qualification of appropriate assays for pharmacokinetic, target engagement markers, biodistribution, or other assays to monitor safety available to be used in the UH3 phase
- Determination of optimal route of administration
- Lead optimization to improve effectiveness, diminish toxicity, and increase absorption (e.g., absorption, distribution, metabolism, and excretion (ADME))
- Demonstration of adequate/stage-appropriate preliminary safety, such as safety pharmacology and/or dose-range finding toxicology
Examples of activities that can be supported during the Development (UG3) preparatory phase include:
- Establishment of a preclinical development plan, including milestones for advancement into IND-enabling studies and the desired profile for a development candidate
- Design and planning for the first-in-human clinical trial (if applicable)
- Validation of ADMET data
- Replication/confirmation of key in vivo pharmacology or efficacy data
- Scale up manufacture and stability studies
- Formulation studies
- Dose-range finding toxicology
How many biologic agents can I propose for optimization or development?
Discovery stage applications can include several agents for consideration. The UG3 phase of the project can be used to conduct studies to prioritize among possible biologic agents for a single disease condition. Due to budget limitations, however, only one biologic or agent can be optimized during the Discovery stage and only one clinical candidate can be advanced into Development.
Can I request funding to do all of the work myself and/or with CROs that I select and pay directly?
Yes. However, we strongly encourage you to take advantage of the availability of BPN-Biologics consultants to add to your own expertise. In our experience, projects benefit from the perspectives of multiple experts.
What is a Lead Development Team?
The BPN-Biologics Lead Development Team (LDT) is the project leadership team responsible for planning and coordinating work conducted by the Principal Investigator (PI) and BPN-Biologics contractors. The LDT will typically be co-chaired by the PI and a BPN-Biologics consultant and will include members of the PI’s team, additional BPN-Biologics consultants, and NIH staff. The LDT will hold a face-to-face meeting at the beginning of the project and typically will meet every few weeks by teleconference.
If I’m not using BPN-Biologics contractors and I don’t need BPN-Biologics consultants, do I still need to have a Lead Development Team?
Yes. Your funding will be provided under a cooperative agreement, which requires that your project be conducted in collaboration with the NIH. Since you will not be collaborating with NIH contractors, your LDT will focus more on the broad project strategy than on day-to-day activities. At the beginning of your project, your LDT will hold a face-to-face meeting to agree on project plans, including go/no-go milestones, optimization goals for Discovery projects, and a Gantt chart and development plans for Development projects. For projects that do not involve BPN-Biologics contracts, the LDT is expected to meet at least quarterly to discuss project progress and update project plans accordingly.
Are there budget limits for UG3/UH3 awards?
There are no hard budget caps for UG3/UH3 awards, but budget requests must be well-justified and reflect the work that will be conducted by the PI (BPN-Biologics contractors are paid directly by the NIH). If the PI proposes that any work be conducted by BPN-Biologics contractors, the UG3/UH3 budget should be offset accordingly.
Note: Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.
What does a target product profile look like?
A Target Product Profile (TPP)(pdf, 189 KB) is a planning tool for therapeutic candidates based on FDA Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool. Download Target Product Profile Worksheet examples based on the FDA guidance that defines the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed therapy development effort.
What does a target agent profile table look like?
For your BPN-Biologics application, please fill out an agent profile table that summarizes available data for each of the parameters listed in the following example(s). If a parameter has not been measured, indicate “not done.” Name vendors used for any outsourced activities.
Note: agents can enter BPN-Biologics at the Discovery stage, i.e., requiring optimization. However, biologic agents that enter the Development stage, i.e., ready for IND-enabling studies, should have a completed profile table with no apparent liabilities.
Download Examples of Target Agent Profiles:
What types of clinical trials can BPN-Biologics contractors conduct?
BPN-Biologics contractors can conduct Phase I clinical trials for investigational agents that may include large biomacromolecules, e.g., peptides, proteins, or oligonucleotides. Depending on the project, target populations may be healthy volunteers or demographic subsets of healthy volunteers. Applicants proposing Phase I clinical trials involving subjects with conditions of interest or clinical trials testing biotherapeutic modalities other than those listed above should contact NIH program staff.