Executive Committee Oversight
When are applications due?
The next application due date for PAR20-122 (UG2/UH3) and PAR-20-111 (SBIR U44-1/II) is August 11, 2020.
What are the entry criteria for Discovery-stage projects?
- 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)
- A bioactive compound, in hand, that will serve as a starting point for optimization with:
- Proof of identity and purity (typically >95%, as determined by, e.g., NMR, melting point, or LC/MS, with no single impurity >0.5%)
- in vitro biological activity (typically <1µM in biochemical assays and <10µM in cell-based assays relevant to the drug target), confirmed by repeat dose-response testing, with more than one batch of compound
- Selectivity for the intended target over closely related targets, if desired (and when the target is known)
- Availability of primary and secondary in vitro bioactivity assays that can be used or optimized for driving SAR studies
- 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)
- Availability of selectivity and counter-screening assays to address potential activity at related targets and other undesirable activities or artifacts
- No obvious legal (e.g., intellectual property) constraints to pursuing the proposed chemical scaffold(s) and using the proposed assays and models for research purposes and/or commercial development
In addition, projects must be capable of initiating SAR studies within a year of entering BPN. The following are general expectations for a project to initiate SAR studies within BPN:
- Completion of an in vitro ADME and physicochemical profile for the starting compound that includes measures of aqueous solubility, microsome stability, CYP inhibition, and permeability (e.g., MDCK or Caco-2)
- Demonstration that the primary assay meets the following validation criteria to reliably rank compounds with similar activities:
- A statistical demonstration of reliability, e.g., a Z’ factor
- ≥0.5 and a coefficient of variation (CV) ≤20%
- Concentration response testing over at least 10 concentrations generates reproducible EC50 values within a 3-fold range for at least 4 compounds
- Blinded test-retest reliability with r2 of at least 0.75 on at least 8 compounds exhibiting EC50 values across a 100-fold range of potencies
- Throughput of at least 10 compounds per week, run with sufficient replicates to produce robust and reproducible 10-point dose-response curves
- Demonstration that the proposed secondary bioactivity assays and counter-screening and selectivity assays have sufficient reliability and throughput for their proposed use in the project
- Demonstration of a clear correlation between activity in the primary assay and activity in confirmatory assays and models, sufficient to justify advancement criteria in a testing funnel.
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
- Proposed compounds 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) and outcomes
- Applicants should show that their proposed compounds are efficacious when delivered by the intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.
- Proposed compounds should give defensible results in tests for Ames mutagenicity, hERG activity, microsome stability, CYP inhibition, plasma protein binding, and aqueous solubility.
- In cases where the molecular target of compound action is known, the applicant should demonstrate the degree of selectivity for the intended target over closely related targets.
- Counter-screening to determine selectivity across a broad panel of unrelated pharmacological targets (e.g., G protein-coupled receptors, kinases, etc.) is also required.
- Demonstration that the ability of the PD/PI's institution to develop and commercialize the proposed compound(s) 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 a year of entering BPN. The following are general expectations for a project to initiate IND-enabling studies within BPN:
- Dose-range finding toxicology studies show an acceptable safety margin (e.g., 5x if toxicity can be monitored, reversible, and has premonitory signs; 10x if toxicity is more severe but controllable/reversible; 30x if toxicity is unlikely to be easily monitored, controllable, reversible, or have premonitory signs)
- Viable synthetic route for manufacturing (acceptable cost, number of steps and purification techniques needed)
- Viable API (active pharmaceutical ingredient; salt and polymorph selection complete, acceptable stability to support initial clinical trial)
What is a UG3/UH3 award, and how does it compare to an R01 grant?
The UG3/UH3 is a phased cooperative agreement award. The BPN uses the UG3/UH3 award to pay for work that will be conducted by the Principal Investigator (PI). The UG3 supports the PI’s activities during the preparatory phase, while the UH3 supports subsequent work. BPN applicants can request up to one year 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 program staff and consultants to participate in Lead Development Teams and evaluate project milestones.
What is the purpose of the preparatory phase?
All BPN projects will start with a preparatory phase of up to one year. During the preparatory phase, the NIH will confirm that the project meets program requirements for initiating iterative medicinal chemistry (for Discovery stage) or IND-enabling studies (for Development stage). The PI can apply for funding and contract support during the preparatory phase to complete studies necessary to meet these requirements. In addition, the preparatory phase allows for formation of the Lead Development Team and project planning, including negotiation of go/no-go milestones.
My project already meets the program requirements to initiate medicinal chemistry/IND-enabling studies. Can I skip the preparatory phase?
All projects must begin with a preparatory 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 preparatory phase?
Examples of activities that can be supported during the Discovery preparatory 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
- Establishment of a compound testing funnel, including studies to correlate activity across different bioactivity assays to justify advancement criteria
- in vivo pharmacology studies to demonstrate binding or activity at the target (i.e., target engagement)
- Studies to develop or validate target engagement markers that will be used in critical-path experiments
- Optimization and validation of bioactivity, selectivity, and counter-screening assays
- Critical-path pharmacology studies to clarify the compound mechanism of action (e.g., agonist vs. positive allosteric modulator)
- ADMET profiling of starting compound(s) to identify liabilities to address through medicinal chemistry
Examples of activities that can be supported during the Development 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 data
- Salt and polymorph screening
- Compound stability studies
- Pre-formulation studies
- Multiple-dose rodent PK testing, with pharmacodynamic (PD) correlations if applicable
- Dose-range finding toxicology
- Metabolite identification
How many compounds can I propose for optimization or development?
Applicants can include several compounds for consideration in their applications. Due to budget limitations, only one scaffold can be optimized during Discovery and only one clinical candidate can be advanced into Development. The preparatory phase of the project can be used to conduct studies to prioritize among possible compounds.
I have a potent compound that shows good preclinical efficacy in a mouse model, but I haven’t tested the compound in Ames, hERG, microsome, or CYP assays. Can I apply for the Development stage and complete these studies during the preparatory phase of my project?
No. You must demonstrate that your lead compound is free of common liabilities before applying for BPN at the Development stage. You need to either find other sources of funding to support the remaining profiling work or apply to the BPN at the Discovery stage, with assays in hand to support medicinal chemistry. If you enter the BPN at the Discovery stage, and profiling does not reveal any liabilities, your project can quickly advance 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 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 Lead Development Team (LDT) is the project leadership team responsible for planning and coordinating work conducted by the PI and BPN contractors. The LDT typically will be co-chaired by the Principal Investigator (PI) and a BPN consultant and will include members of the PI’s team, additional BPN consultants, and NIH staff. The LDT will hold a face-to-face meeting at the beginning of the project and typically will meet every two weeks by teleconference.
If I’m not using BPN contractors and I don’t need BPN 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 and a testing funnel for Discovery projects, and a Gantt chart and development plans for Development projects. For projects that do not involve BPN 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 contractors are paid directly by the NIH). Budgets for the cooperative agreement generally should not exceed $300K direct costs for the preparatory phase and $1.5M direct costs per year for Discovery/Development, assuming all work is conducted by the Principal Investigator (PI). If the PI proposes that any work be conducted by BPN contractors, the UG3/UH3 budget should be offset accordingly.
What does a target product profile look like?
A Target Product Profile (TPP) is a planning tool for therapeutic candidates based on FDA Guidance for Industry and Review Staff Target Product Profile — A Strategic Development Process Tool (pdf, 454 kb). Download the Target Product Profile Worksheet (pdf, 37.36 kb) 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 compound profile table look like?
For your BPN application, please fill out a compound profile table that summarizes available data for each of the parameters listed in the following example. If a parameter has not been measured, indicate “not done.” Name vendors used for any outsourced activities.
Please note: compounds can enter BPN at the Discovery stage (requiring medicinal chemistry) without having any SAR, DMPK, or toxicology data. However, compounds that enter at Development (ready for IND-enabling studies) should have a completed profile table with no apparent liabilities.
Download the Example Compound Profile Table (pdf, 207.4 kb)