Part 1. Overview Information

Key Dates

It is critical that applicants follow the SBIR/STTR (B) Instructions in the SF424 (R&R) SBIR/STTR Application Guide except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance toall 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. Applicationsthat do not comply with these instructions may be delayed or not accepted for review.

Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

A. Overview

Recent advances in neuroscience offer unprecedented opportunities to discover new treatments for nervous system disorders. However, before a new chemical entity can be tested in a clinical setting, it must undergo a process of chemical optimization to improve potency, selectivity, and drug-like properties, followed by pre-clinical safety testing to meet the standards set by the Food and Drug Administration (FDA) for clinical testing. All of the necessary expertise and resources are not commonly available to small companies as these activities are largely the domain of large pharmaceutical and biotechnology companies and contract research organizations.

To facilitate drug discovery and development by the neuroscience community, the NIH Blueprint for Neuroscience Research (https://neuroscienceblueprint.nih.gov/) established the Blueprint Neurotherapeutics Network (BPN), which offers neuroscience researchers funding for drug discovery and development activities that can be conducted in their own laboratories. Researchers have the opportunity to collaborate with NIH-funded consultants and contract research organizations (CROs) that specialize in medicinal chemistry, pharmacokinetics, toxicology, formulations development, chemical synthesis under Good Manufacturing Practices (GMP), and Phase I clinical testing. A current list of BPN contractors and consultants is available at https://neuroscienceblueprint.nih.gov/bpdrugs/bpn_resources.htm.

This Funding Opportunity Announcement (FOA) invites applications for new BPN projects. The PD/PI will be responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools. A Program Director/Principal Investigator (PD/PI) with- for example medicinal chemistry expertise and resources may additionally request funding to conduct structure-activity relationship (SAR) studies in his or her own lab but collaborate with BPN contractors on in vitro ADMET, in vivo PK, drug manufacturing and IND-enabling toxicology studies. By contrast, a PD/PI with limited experience in drug discovery and development may opt to collaborate with all available BPN contractors. Applicants may propose to conduct all drug discovery and development activities themselves or collaborate with BPN contractors on activities of their choice.

For each project funded under this FOA, the NIH will assemble a customized Lead Development Team (LDT). The LDT will be co-chaired by the PD/PI and a BPN consultant and will include members of the PD/PI's team, additional BPN consultants, and NIH staff. The LDT will establish an overall strategy for the project, including milestones proposals, plan studies to be conducted by BPN contractors, and coordinate activities across different research sites.

Potential applicants are strongly encouraged to read Frequently Asked Questions (FAQs) on the BPN website (http://neuroscienceblueprint.nih.gov/bpdrugs/faqs.htm) and contact NIH Scientific/Research staff and participating NIH Institutes/Centers prior to preparing an application to discuss how they may best utilize BPN resources and whether their application fits the mission of a particular NIH IC.

For this FOA, Phase I clinical testing, studies or trials refer to the common phases of a clinical trial. U44 Phase I and II refer to the project phases of the SBIR program.

B. Scope

The BPN is dedicated to the discovery and development of small molecule compounds, of a size and structure that can be readily synthesized and chemically modified (if optimization is required). This program is not designed to support development of biologics or biotechnology products, including oligonucleotides and proteins, or devices. Applicants should contact NIH Scientific/Research staff regarding small peptides (typically less than 6 amino acids) and other complex chemical structures, as well as combination therapies, to determine suitability for optimization and development within the BPN.

To be eligible for this FOA, a project must focus on a nervous system condition that falls within the mission of one of the participating Institutes or Centers. Please see Section C below for more information on the interests of the participating Institutes and Centers and alternative programs to consider.

Projects can enter either at the Discovery stage, to optimize promising hit compounds through medicinal chemistry to the Development stage, to advance a single development candidate through Investigational New Drug (IND)-enabling toxicology studies and phase I clinical testing. Alternatively, projects can enter at the Development stage and progress in a shorter period to IND enabling toxicology studies and phase I clinical testing.

Past experience with BPN suggests that many otherwise excellent awarded projects often require additional proof of concept data or the generation of tools in order to meet the program's requirements for initiating medicinal chemistry or IND-enabling studies. For this reason, all BPN SBIR projects will begin with the U44 Phase I to conduct feasibility studies required to launch medicinal chemistry (if entering at the Discovery stage) or IND-enabling studies (if entering at the Development stage). During the U44 Phase I award, the NIH will form the LDT, which will identify and oversee the studies necessary to meet the BPN requirements for initiating medicinal chemistry or IND-enabling studies. The LDT will also design plans and go/no-go milestones for all subsequent Discovery and/or Development work. Progression from U44 Phase I to Phase II will be based on administrative review (see Section D., Milestones). A project that completes all U44 Phase I and Phase II Discovery activities and advances into Development will conduct all Development work (including Development feasibility studies) under the U44 Phase II award. After successful completion of the U44 Phase I, a project may proceed either to the U44 Phase II in either hit-to-lead/lead optimization (SAR) (the discovery phase) or to IND-enabling studies (the development phase).

A schematic of this project structure is available on the BPN website at https://neuroscienceblueprint.nih.gov/bpdrugs/bpn_resources.htm .

The following sections describe the Discovery and Development stages in more detail, including the program entry criteria, the program requirements for initiating medicinal chemistry and IND-enabling studies, and examples of activities that can be conducted during the U44 Phase I award. Potential applicants are strongly encouraged to contact NIH Scientific/Research staff prior to preparing an application to clarify which entry stage is most appropriate for their project and what to include in their plans for the U44 Phase I award.

Discovery

Projects that require medicinal chemistry to improve the potency and/or drug-like properties of promising bioactive compounds will enter the BPN at the Discovery stage. The process of understanding the structure-activity relationship (SAR) for desired drug properties typically requires dozens of rounds of compound synthesis and testing. Initially, medicinal chemistry will focus heavily on optimizing activity and potency of compounds in primary and secondary in vitro assays. Subsequently, SAR will increase emphasis on ADMET (absorption, distribution, metabolism, excretion, toxicity) properties of the compounds, with continued monitoring and optimization of bioactivity. The ultimate goal of the SAR effort is the selection of a development candidate with sufficient bioactivity, therapeutic index, and drug-like properties to proceed to IND-directed pre-clinical safety assessment with reasonable projected human doses.

Entry Criteria for Discovery Stage

Projects must meet the following requirements prior to entering Discovery:

• 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 < 1 M in biochemical assays and <10 M 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

Feasibility Studies for Discovery Stage (U44 Phase I)

All Discovery projects will begin with a U44 Phase I award of up to two years. The first 6-12 months should be used to prepare for SAR studies. The following are general expectations for a BPN project to initiate SAR studies:

• 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 (Z') =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 R?² 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

Examples of activities that can be supported include:

• Establishment of a project milestone plan, including milestones that must be met to initiate SAR studies and desired compound profiles (including prospective criteria) at completion of lead optimization
• Refinement of a compound testing funnel, including studies to correlate activity across different bioactivity assays to justify advancement criteria
• In vivo pharmacology and if applicable studies using established biomarkers to demonstrate 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
• Limited exploratory medicinal chemistry (approximately 2 medicinal chemists for 6 months) to enable demonstration/confirmation of synthetic route and bioactivity of proposed hit compounds
• Procurement of commercially available analogs ("SAR by catalog")
• After completing the preparatory activities, up to 1 year of SAR studies can be supported during U44 Phase I at which point the PD/PI is expected to demonstrate in vivo activity for a representative compound from the lead series, delivered by any route of administration

The PD(s)/PI(s) will be responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools. Applicants may propose to use BPN contractors for chemical synthesis and ADMET profiling or request funds to conduct this work themselves.

The Discovery U44 Phase I award typically supports the following activities :

• Design and synthesis of analogs for SAR studies
• Compound scale up for in vivo testing
• Testing of analogs in bioactivity assays and animal models
• Testing of analogs in selectivity and counter-screening assays
• Testing of analogs in ADMET assays (e.g., microsome stability, CYP induction and inhibition, solubility, permeability in MDCK or Caco-2 cells, plasma protein binding, brain/plasma ratio, pharmacokinetics [PK] in multiple species)

Discovery Activities after Feasibility Phase (U44 Phase II)

The BPN typically supports up to one additional year of medicinal chemistry to complete the SAR studies to identify a development candidate that meets the entry criteria for Development (below).

The Discovery U44 Phase II award typically supports the following activities:

• Design and synthesis of analogs for SAR studies
• Compound scale up for in vivo testing, dose ranging finding toxicity (DRF) evaluation
• Testing of analogs in bioactivity assays and animal models
• Testing of analogs in selectivity and counter-screening assays
• Testing of analogs in ADMET assays (e.g., microsome stability, CYP induction and inhibition, solubility, permeability in MDCK or Caco-2 cells, plasma protein binding, brain/plasma ratio, pharmacokinetics [PK] in multiple species)

The PD/PI will be responsible for conducting primary in vitro biological assessment of compounds on a one-to-two week schedule to inform the design of subsequent iterations of compound synthesis. In addition to a regular testing schedule in the primary assay, the PD/PI will provide confirmation of the activity of select compounds in secondary and counter-screening assays and animal models relevant to the drug target and therapeutic indication.

BPN contractors can produce compound analogs for SAR testing, scale up compounds as needed for in vivo testing, and provide standard screening services to assess in vitro and in vivo ADMET characteristics of the compounds. Typically, BPN will assign four medicinal chemist FTEs to a project, generating approximately 4-8 compounds per week, plus additional staff to support computational chemistry modeling and ADMET studies as appropriate.

Compounds that meet the BPN's criteria for a development candidate can continue seamlessly on into Development.

Development

The Development stage includes IND-directed preclinical safety studies, GMP synthesis of clinical trial material, formulation development, and phase I clinical testing. Projects that have completed medicinal chemistry optimization and identified a development candidate may initiate Development activities within BPN. The BPN does not support SAR studies during Development.

Entry Criteria for Development Stage

Application for entry into the Development stage must have identified the candidate compound and cannot request additional medicinal chemistry resources. It may be acceptable to have 2 candidates that will be narrowed to a single candidate as part of the U44 Phase I activities (time and budget permitting).

Projects must meet the following requirements prior to entering the Development portion of the U44 Phase II:

• 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 compound 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 clinically 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 for the proposed indication is unlikely to be blocked or impeded by legal (e.g., intellectual property) constraints and that there is support from the institution to file and maintain the patents estate and necessary regulatory documents along with associated cost.

Feasibility Studies for Development

All applications proposing to enter at the Development stage at the start of the U44 Phase II will begin with a U44 Phase I award of up to two years, to prepare for IND-enabling studies, which will be supported under the U44 Phase II award. (Projects that began in Discovery will conduct these activities during their U44 Phase II award.) The following are general expectations for a project to initiate IND-enabling studies within BPN:

• Dose-range finding (DRF) toxicology studies (rodent and non-rodent) 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)

Examples of activities that can be supported during the Development preparatory activities 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 Phase I clinical trials (if applicable)
• Validation of ADMET data
• Replication/confirmation of key in vivo pharmacology data
• Scale-up synthesis (including required material amounts for DRF studies if not available at time of award)
• 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

The PD(s)/PI(s) is responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools. BPN contractors can perform all other work.

Development Activities after Feasibility Phase (U44 Phase II)

The Development U44 Phase II award may include the following:

• GMP manufacturing of material for phase I clinical testing
• IND-enabling toxicology studies
• IND document preparation
• Phase I clinical trial (a single and/or multiple ascending dose study to characterize safety, PK, and PD)

The PD/PI's Institution will be responsible for assembly and Submission of the IND application and scheduling meetings with the FDA and therefore should include support for this activity in their plan

. NIH staff and consultants on the LDT must be included in all meetings with the FDA.

The development of the protocol and management of the phase I clinical trial will be performed by a Clinical Development Team (CDT), which will evolve from the LDT and include the PD/PI, clinical consultants identified by the PD/PI and NIH, and NIH staff. The protocol, selected supporting trial documents, and regulatory documents will be submitted to NIH for administrative review (including internal and external experts) prior to commencement of the clinical trial (defined as signing of first informed consent).

BPN contractors can conduct the preclinical safety studies, GMP synthesis, formulation and other activities required to prepare for human testing. BPN contractors will provide data and reports in a format suitable for inclusion in an IND application and will assist in the development of the application. The phase I clinical trial can also be conducted through BPN contractors.

Projects Not Appropriate for this Announcement include:

• Screening to identify hit compounds
• Basic research and studies of disease mechanism
• Animal model development
• Development of risk, detection, diagnostic, prognostic, predictive, and prevention biomarkers as well as PET ligands
• Development of diagnostics and diagnostic devices
• Development of biologics and biotechnology products
• Studies directed beyond phase I clinical testing

C. NIH Institute and Center Interests and Guidance

National Institute on Aging (NIA)

NIA is interested in studies that will provide drug development expertise and infrastructure support to researchers interested in developing new small molecules aimed at modifying the behavioral symptoms in Alzheimer's disease (AD), delaying the onset or slowing the progression of AD, mild cognitive impairment (MCI), other dementias of aging and age-related cognitive decline. Ideally, this initiative is aimed at researchers who have promising small molecule compounds but lack the necessary outside expertise and infrastructure to advance these compounds to the clinic.

Researchers who may have the necessary drug development expertise and access to infrastructure to advance small molecules to the clinic should consider submitting an application to the Alzheimer's Drug Development Program (PAR-18-820) or its reissue. This program is also available to researchers who are interested in the preclinical development of biologics or repurposed drugs.

NIA and the AD scientific community recognize that one of the major challenges to the successful development of drugs for AD is the poor translation of preclinical efficacy from AD animal models to the clinic. Meta analyses of preclinical studies indicate that a key factor contributing to the poor predictive power of AD animal models is the lack of standards in the design, conduct, and data analyses. Therefore, to improve the quality and predictive value of animal model studies NIA urges applicants, describing supporting data or proposed animal model studies, to follow best practices guidelines as summarized at: http://alzres.com/content/3/5/28).

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Alcohol interacts directly and indirectly with a wide spectrum of molecular targets in the brain, and alcohol-seeking behaviors and alcohol use disorders (AUD) involve multiple neurotransmitter systems, neuromodulators, hormones, signal transduction pathways, etc. These include signaling systems and signal transduction pathways of opioids, serotonin, dopamine, glutamate, ?-aminobutyric acid (GABA), endocannabinoids, neuropeptides (e.g. corticotropin releasing factor (CRF), neuropeptide Y, substance P), and protein kinases A and C. Numerous therapeutic agents targeting these and other molecular systems have been studied preclinically and in clinical trials. NIAAA is interested in research aimed to develop new pharmaceuticals to provide effective therapy for AUD. Studies involving novel targets previously un-recognized or understudied for the treatment of AUD are particularly encouraged. Specific genetic variants that may contribute to the risk for alcoholism and/or render alcohol dependent individuals responsive to specific therapeutic agent have been discovered. NIAAA is interested in supporting research to develop pharmaceuticals targeting individuals with identified genotypic and phenotypic characteristics to improve efficacy and safety.

National Eye Institute (NEI)

The National Eye Institute (NEI) interest in BlueprintNeurotherapeutics is to develop novel therapies to treat diseases and disorders of the visual system, especially blinding eye diseases such as cataracts, glaucoma, age-related macular degeneration, retinitis pigmentosa, ocular pain and other conditions. The NEI is also interested in other visual system disorders such as strabismus and amblyopia that could be treated with pharmacological interventions. Each project should have a well-defined end-point, achievable within a five-year time frame, for developing a treatment for a specific disease or disorder of the visual system. The steps towards this goal should be clearly delineated in a series of milestones that support the development of a novel therapeutic that can then be tested in a clinical trial. If successful, a project funded under this program may lead to filing an IND-directed pharmacological and toxicological study, and Phase I clinical testing. Investigators are encouraged to contact NEI program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute.

National Institute of Dental and Craniofacial Research (NIDCR)

NIDCR is interested in neurotherapeutics development for painful disorders of the orofacial region including temporomandibular joint disorder, trigeminal neuropathies, burning mouth syndrome, oral cancer pain and other conditions. Recent advances in genomics and phenotyping of subjects with orofacial pain conditions have expanded the scope of potential targets to treat these conditions. Receptor systems, ion channels, and pro- and anti-inflammatory molecules have been implicated in chronic pain. NIDCR is interested in supporting research that will lead to highly efficacious and specific pharmacological treatments for individuals with orofacial pain disorders.

Investigators are encouraged to contact NIDCR program staff to discuss potential research projects prior to application submission to determine alignment of the planned studies with priorities of the Institute mission and strategic plan.

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

The NICHD is interested in supporting neurotherapeutic research aimed to discover small molecules and compounds, and develop novel and improved pharmacotherapies for developmental disorders, diseases and conditions in pediatric population.

Investigators are strongly encouraged to contact NICHD program staff to discuss their potential research projects prior to application submission to determine alignment of their planned studies with the NICHD's priorities and strategic plan.

National Institute of Mental Health (NIMH)

NIMH supports neuroscience research to discover the causes of mental illness and to develop more effective and safer treatments. The NIMH is interested in applications proposing development of therapies aimed at novel molecular and clinical targets for the treatment of mental disorders, especially treatment-resistant depression, bipolar disorder, schizophrenia, PTSD, and autism spectrum disorder. Studies aimed at the development of new ligands for targets where a probe or therapeutic already exists are generally of lower priority.

NIMH will only support projects entering the BPN at the Discovery (optimization of validated small molecule hits and promising lead compounds through medicinal chemistry) stage. NIMH will not support projects entering the BPN at the Development (IND enabling/GMP synthesis or Phase I trials) stage. Projects at the Development stage should consider applying to the NIMH SBIR/STTR Programs. Projects at the early clinical trials phase should consider the NIMH SBIR/STTR Programs.or the First in Human and Early Stage Clinical Trials of Novel Investigational Drugs or Devices for Psychiatric Disorders (U01) PAR-18-427. Investigators are strongly encouraged to discuss their research plans with NIMH Scientific/Research contact prior to submission to determine alignment of the planned studies with NIMH priorities and to assess whether this or other NIMH funding opportunities are most appropriate. Investigators are also encouraged to review the following NIMH drug discovery FOAs: Drug Discovery for Nervous System Disorders PAR-19-147 (R01) and PAR-19-146 (R21), Assay development and screening for discovery of chemical probes or therapeutic agents PAR-17-484 (R01), Discovery of in vivo Chemical Probes for Novel Brain Targets PAR-17-336 (R01), Discovery of Cell-based Chemical Probes for Novel Brain Targets PAR-17-335 (R21), National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-18-230 (U01) and PAR-18-231 (U19).

Consistent with NIMH's Research Domain Criteria (RDoC) initiative, research projects directed towards ameliorating pathophysiology that is potentially more proximal to specific functional deficits (domains) than DSM diagnostic entities are encouraged. Additional information about the RDoC approach can be found at the RDoC website. The testing of functional domains not included specifically in RDoC may also be considered, if well justified. In vivo preclinical screening assays in animals should be carefully selected based on proposed brain targets and mechanisms of therapeutic action (see NOT-MH-19-053).

High-quality and reproducible studies that are reported to the scientific community in a transparent manner are an essential cornerstone of the research enterprise. Attention to principles of study design and transparency are essential to enable reviewers, the scientific community, and NIH to assess the quality of scientific findings. In support of this important goal, investigators must follow instructions to address Rigor and Reproducibility (http://grants.nih.gov/reproducibility/index.htm).

Further information on NIMH research priorities can be found in the NIMH Strategic Plan, Strategic Research Priorities, and Interventions Workgroup Report. Applicants are strongly encouraged to discuss applications with NIMH staff listed in Section VII - Agency Contact(s) Scientific/Research Contacts.

National Institute of Neurological Disorder sand Stroke (NINDS)

A list of diseases that is relevant to the research mission of the NINDS can be found at https://www.ninds.nih.gov/Disorders/All-Disorders ; applicants are encouraged to contact the NINDS to discuss disease areas of interest.

This FOA serves as the primary support mechanism at NINDS for the discovery and development of small molecule drugs. Researchers focused on the development of biologics and biotechnology products should consider the CREATE-Bio program (https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/CREATE-BIO ). Applicants seeking support only to conduct early stage clinical trials should consider applying for an NINDS Exploratory Clinical Trials R01, through PAR-18-420, which provides additional flexibility in budget and time, as well as the option of including a phase II trial.

There is growing recognition that the quality and reproducibility of both preclinical and clinical research depend on the rigor with which researchers conduct studies, control for potential bias, and report essential methodological details. Examples of critical elements of a well-designed study are summarized on the NINDS website http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf. NINDS urges applicants to this program to consider these elements when describing supporting data and proposed studies.

National Center for Complementary and Integrative Health (NCCIH)

NCCIH is interested in supporting research aimed at compounds and small molecules from natural products (e.g., cannabinoids, venoms, conotoxins, melatonin, prebiotics, probiotics, herbs, etc.) that may be used or developed to modulate CNS-based symptoms with priority given to pain and pain related symptoms including sleep, stress, and mood disorders. Investigators are strongly encouraged to discuss their research plans with the NCCIH Scientific/Research contact prior to submitting their applications.

National Institute on Drug Abuse (NIDA)

Through participating in this FOA, NIDA aims to provide drug development expertise and infrastructure to support the addiction researchers interested in developing new molecular entities for the treatment of substance use disorders (SUD). Projects focused on opioid use disorder, cocaine, methamphetamine and marijuana use disorders are of high priority for NIDA.

NIDA will only support the projects to develop the innovative pharmacological approaches entering the BPN at the Discovery stage. Specifically, NIDA is interested in using the BPN mechanism to support the addiction researchers in the "hit to lead optimization" stages with a well-justified proposal for the development stage as well.

NIDA applicants are strongly encouraged to take full advantage of the opportunities the BPN affords, including collaboration with BPN consultants and NIH-supported contract research organizations (CROs) that specialize in medicinal chemistry, pharmacokinetics, toxicology, formulations development, chemical synthesis under Good Manufacturing Practices (GMP). Researchers, who possess the drug development expertise and access to the necessary infrastructure to advance small molecules to the clinic, should consider submitting their applications to specialized NIDA-administered programs.

Investigators are strongly encouraged to discuss their research plans with NIDA program staff prior to submission to determine alignment of the planned studies with NIDA's interest and priorities. NIDA staff will also provide help in assessing whether this or other NIDA funding opportunities would be the most appropriate.

D. Milestones

Because drug discovery and development are inherently high risk, it is expected that there will be significant attrition as projects progress. Go/No-Go milestones (typically every six months) will be established by the LDT at the start of each project and updated as needed.

An administrative review will be conducted by NIH program staff, with technical input from an External Oversight Committee (composed of senior non-federal scientists who are not directly involved in BPN projects), to decide which projects will advance from the U44 Phase I to the Phase II award and progress after each subsequent milestone based on:

• Successful achievement of milestones
• The overall feasibility of project advancement, considering data that may not have been captured in milestones
• Competitive landscape for the disease indication and drug target
• Program priorities
• Availability of funds

Approval for commencement of a clinical trial (defined as signing of informed consent by first prospective subject) will include the following:

• Successful achievement of the defined preclinical development milestones;
• Submission of an IND with documentation for one of the following: 1) acceptance of clinical protocol by FDA; 2) elapse of the 30-day post filing waiting period without comment from the FDA; 3) completion of protocol changes or amendments requested by FDA.
• Submission of the clinical protocol and supporting documents to NIH for administrative review and notification of NIH approval;
• Agreement on updated timeline and milestones for the clinical trial.

Please Note: If a funded project does not make sufficient progress toward the agreed upon milestones at any stage, funding for the project and access to BPN contract resources may be discontinued (see section VI.2.).

E. Quality and Compliance Requirements

Since the goal of this program is to generate therapeutics which will be eligible for FDA approval, adherence to compliance and quality criteria is required.

• It is expected that all IND enabling nonclinical studies will be performed in a manner consistent with Good Laboratory Practices (GLP) and current FDA guidance.

• All clinical trials must be performed following Good Clinical Practices (GCP) and in accord with NIH Policy for Data and Safety Monitoring (https://osp.od.nih.gov/clinical-research/nih-data-and-safety-monitoring-policies/).

Investigational products for use in clinical trials must be produced under current Good Manufacturing Practice (cGMP) practices.

F. Intellectual Property (IP)

Since the ultimate goal of this program is to bring new drugs to the market, the creation and protection of intellectual property (IP) that will make drug candidates attractive to potential licensing and commercialization partners are a significant consideration in designing research strategies and prioritizing projects for funding. This program is structured so that the small business concern retains their assignment of IP rights and gains assignment of IP rights from the BPN contractors (and thereby control the patent prosecution and licensing negotiations) for drug candidates developed through this program. It is expected that the small business concern will take responsibility for patent filings, maintenance and licensing efforts toward eventual commercialization. The PD/PI is expected to work closely with technology transfer/business development officials at his or her institution to ensure that royalty agreements, patent filings, and all other necessary IP arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project. Award recipients will be encouraged to identify and foster relationships with potential licensing and commercialization partners early in the drug development process, consistent with the goals of the BPN.

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

Section II. Award Information

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

Section III. Eligibility Information

1. Eligible Applicants

Only United States small business concerns (SBCs) are eligible to submit applications for this opportunity. A small business concern is one that, at the time of award of Phase I and Phase II, meets all of the following criteria:

1. Is organized for profit, with a place of business located in the United States, which operates primarily within the United States or which makes a significant contribution to the United States economy through payment of taxes or use of American products, materials or labor;
2. Is in the legal form of an individual proprietorship, partnership, limited liability company, corporation, joint venture, association, trust or cooperative, except that where the form is a joint venture, there must be less than 50 percent participation by foreign business entities in the joint venture;
3. 1. SBIR and STTR. Be a concern which is more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), an Indian tribe, ANC or NHO (or a wholly owned business entity of such tribe, ANC or NHO), or any combination of these; OR
   2. SBIR-only. Be a concern which is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these. No single venture capital operating company, hedge fund, or private equity firm may own more than 50% of the concern, unless that singleventure capitaloperating company,hedge fund, orprivate equity firmqualifies as a small business concern that is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States; OR
   3. SBIR and STTR. Be a joint venture in which each entity to the joint venture must meet the requirements set forth in paragraph 3 (i) or 3 (ii) of this section. A joint venture that includes one or more concerns that meet the requirements of paragraph (ii) of this section must comply with 121.705(b) concerning registration and proposal requirements.
4. Has, including its affiliates, not more than 500 employees.

   If the concern is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these falls under 3 (ii) or 3 (iii) above, see Section IV. Application and Submission Information for additional instructions regarding required application certification.

   If an Employee Stock Ownership Plan owns all or part of the concern, each stock trustee and plan member is considered an owner.

   If a trust owns all or part of the concern, each trustee and trust beneficiary is considered an owner.

   Definitions:

• Hedge fund has the meaning given that term in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The hedge fund must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
• Portfolio company means any company that is owned in whole or part by a venture capital operating company, hedge fund, or private equity firm.
• Private equity firm has the meaning given the term "private equity fund" in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The private equity firm must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
• Venture capital operating company means an entity described in 121.103(b)(5)(i), (v), or (vi). The venture capital operating company must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
• ANC means Alaska Native Corporation.
• NHO means Native Hawaiian Organization.

SBCs must also meet the other regulatory requirements found in 13 C.F.R. Part 121. Business concerns, other than investment companies licensed, or state development companies qualifying under the Small Business Investment Act of 1958, 15 U.S.C. 661, et seq., are affiliates of one another when either directly or indirectly, (a) one concern controls or has the power to control the other; or (b) a third-party/parties controls or has the power to control both. Business concerns include, but are not limited to, any individual (sole proprietorship) partnership, corporation, joint venture, association, or cooperative. The SF424 (R&R) SBIR/STTR Application Guide should be referenced for detailed eligibility information.

Small business concerns that are more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these are NOT eligible to apply to the NIH STTR program.

Performance Benchmark Requirements

Phase I to Phase II Transition Rate Benchmark: In accordance with guidance from the SBA, the HHS SBIR/STTR Program is implementing the Phase I to Phase II Transition Rate benchmark required by the SBIR/STTR Reauthorization Act of 2011 and the SBIR and STTR Extension Act of 2022. The benchmark establishes a minimum number of Phase II awards the company must have received relative to a given number of Phase I awards received during the 5-fiscal year time period. The Transition Rate is calculated as the total number of SBIR and STTR Phase II awards a company received during the past 5 fiscal years divided by the total number of SBIR and STTR Phase I awards it received during the past 5 fiscal years excluding the most recently-completed year. The Transition Rate requirement, agreed upon and established by all 11 SBIR agencies, was published for public comment in a Federal Register Notice on October 16, 2012 (77 FR 63410) and amended on May 23, 2013 (78 FR 30951).

• For SBIR and STTR Phase I applicants that have received more than 20 Phase I awards over the past 5 fiscal years (excluding the most recently-completed fiscal year): Companies that do not meet or exceed the benchmark minimum Transition Rate of 0.25 will not be eligible to apply for a Phase I, Fast-Track, or Direct Phase II (if available) award for a period of one year from the date of the application submission. This requirement does not apply to companies that have received 20 or fewer Phase I awards over the prior 5-fiscal year period.
• For application deadlines that fall on or after April 5, 2023: For SBIR and STTR Phase I applicants that have received more than 50 Phase I awards over the past 5 fiscal years (excluding the most recently-completed fiscal year): Companies that do not meet or exceed the benchmark minimum Transition Rate of 0.5 will not be eligible to receive more than 20 total Phase I and Phase II awards for a period of one year from the date on which such determination is made. This requirement does not apply to companies that have received 50 or fewer Phase I awards over the 5-fiscal year period.

On June 1 of each year, SBA will identify the companies that fail to meet minimum performance requirements.SBA calculates individual company Phase I to Phase II Transition Rates using SBIR and STTR award information across all federal agencies. SBA will notify companies and the relevant officials at the participating agencies. More information on the Phase I to Phase II Transition Rate requirement is available at SBIR.gov.

Phase II to Commercialization Benchmark: In accordance with guidance from the SBA, the HHS SBIR/STTR Programs are implementing the Phase II to Commercialization Rate benchmark for Phase I applicants, as required by the SBIR/STTR Reauthorization Act of 2011 and the SBIR and STTR Extension Act of 2022. The Commercialization Rate Benchmark was published in a Federal Register notice on August 8, 2013 (78 FR 48537), with a reopening of the comment period published on September 26, 2013 (78 FR 59410).

• For companies that have received more than 15 Phase II awards from all agencies over the past 10 fiscal years (excluding the two most recently completed fiscal year): Companies that meet this criterion must show an average of at least $100,000 in revenues and/or investments per Phase II award or at least 0.15 (15%) patents per Phase II award resulting from these awards during the past 10- fiscal year period. Applicants that fail this benchmark will not be eligible to apply for New Phase I, Fast-track or Direct Phase II (if applicable) awards for a period of one year. This requirement does not apply to companies that have received 15 or fewer Phase II awards over the 10-fiscal year period, excluding the two most recently-completed fiscal years.
• For application deadlines that fall on or after April 5, 2023: For companies that have received more than 50 Phase II awards from all agencies over the past 10-fiscal years (excluding the two most recently completed Fiscal Year): Companies that meet this criterion must show an average of at least $250,000 of aggregated sales and investment per Phase II award over the past 10-fiscal year period. Applicants that fail this benchmark will not be eligible to receive more than 20 total Phase I and Phase II awards for a period of one year from the date on which such determination is made. This requirement does not apply to companies that have received 50 or fewer Phase II awards over the 10-fiscalyear period, excluding the two most recently-completed fiscal years.
• For application deadlines that fall on or after April 5, 2023: For companies that have received more than 100 Phase II awards from all agencies over the past 10-fiscal years (excluding the two most recently completed Fiscal Year): Companies that meet this criterion must show an average of at least $450,000 of aggregated sales and investment per Phase II award over the past 10-fiscal year period. Applicants that fail this benchmark will not be eligible to receive more than 20 total Phase I and Phase II awards for a period of one year from the date on which such determination is made. This requirement does not apply to companies that have received 100 or fewer Phase II awards over the 10-fiscalyear period, excluding the two most recently-completed fiscal years.

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing (DMS) Plan will be attached in the Other Plan(s) attachment in FORMS-H subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.

Other Plan(s):

Note: Effective for due dates on or after January 25, 2023, the Data Management and Sharing Plan will be attached in the Other Plan(s) attachment in FORMS-H and subsequent application forms packages. For due dates on or before January 24, 2023, the Data Sharing Plan and Genomic Data Sharing Plan GDS) will continue to be attached in the Resource Sharing Plan attachment in FORMS-G application forms packages.

All applicants planning research (funded or conducted in whole or in part by NIH) that results in the generation of scientific data are required to comply with the instructions for the Data Management and Sharing Plan. All Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) applicants are required to address a Data Management and Sharing Plan, regardless of the amount of direct costs requested for any one year. However, SBIR and STTR recipients may retain the rights to data generated during the performance of an SBIR or STTR award for up to 20 years after the award date, per the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Program Policy Directive. An acceptable Data Management and Sharing plan can reference and incorporate these data rights. Further information about SBIR and STTR data rights are enumerated in the NIH GPS.

Note: Effective for due dates on or after January 25, 2023, the Data Sharing Plan and Genomic Data Sharing Plan (GDS) as part of the Resource Sharing Plan will not be evaluated at time of review.

Authority and Regulations