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 to all 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. Applications that 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 biology offer unprecedented opportunities to discover new treatments for nervous system disorders. Biotherapeutic development, however, has inherent complexities with regards to characterization, manufacturing, delivery, and administration. Many academic laboratories and small business enterprises don t have the full scope of expertise and resources available; this program seeks to bridge those gaps. For instance, all therapeutic candidates including biologics, must obtain the requisite toxicology and safety pharmacology data package and undergo regulatory review by the Food and Drug Administration (FDA).

The NIH Blueprint for Neuroscience Research is a collaborative framework through which 14 NIH Institutes, Centers and Offices jointly support neuroscience-related research, with the aim of accelerating discoveries and reducing the burden of nervous system disorders (for further information, see http://neuroscienceblueprint.nih.gov/). To facilitate biotherapeutic discovery and development by the neuroscience community, the NIH Blueprint for Neuroscience Research established the Blueprint Neurotherapeutics Network for Biologics (BPN-Biologics), which includes biotechnology products and biologics-based therapies (e.g., peptides, proteins), gene (e.g., oligonucleotide- and viral-based) and cell therapies, and other novel emerging therapies (e.g., microbial and microbiome therapies). Within this network, neuroscience researchers can utilize funding for discovery and development activities that can be conducted in their own laboratories in collaboration with NIH-funded consultants and optionally also access NIH contracted research organizations (CROs) that specialize in manufacturing, pharmacokinetics, toxicology, and Phase I clinical testing. A current list of BPN-Biologics contractors and consultants is available at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/resources.

This Funding Opportunity Announcement (FOA) invites applications from small business concerns for new BPN Biologics-based therapy projects. Applicants may propose to conduct all experimental activities in their own labs or collaborate with BPN-Biologics CROs on activities of their choice. A Program Director/Principal Investigator (PD/PI) with some, but not all, required expertise and resources may request funding to conduct studies in his or her own lab and collaborate with BPN-Biologics CROs on any remaining studies. By contrast, a PD/PI with limited experience in biologics development may opt to collaborate with all available BPN-Biologics CROs. Regardless, the Program PD/PI will be responsible for conducting all studies that involve disease- or target-specific assays, models, and other research tools.

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-Biologics consultant and will include members of the PD/PI's team, additional BPN-Biologics consultants, and NIH staff. Projects are funded via a U44 Fast-Track cooperative agreement mechanism that is milestone-driven and involves the LDT’s participation in establishing the project plan, monitoring research progress, and setting appropriate go/no-go decision-making criteria. The LDT will develop an overall strategy for the project, including milestone proposals, plan studies to be conducted by BPN-Biologics contractors, and coordinate activities across different research sites. Progression from the U44 Phase I award to the U44 Phase II award will be based on administrative review and availability of funds (see Section D, Milestones).

Potential applicants are strongly encouraged to read Frequently Asked Questions (FAQs) on the BPN-Biologics website (https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/faqs) and contact NIH Scientific/Research staff and participating NIH Institutes/Centers prior to preparing an application to discuss how they may best utilize BPN-Biologics 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

BPN-Biologics is dedicated to the translation of biological therapeutics towards clinical testing by supporting the discovery and development of novel and promising biotherapeutic candidates for neurological diseases. This FOA is not designed to support discovery and development of small molecules (see Companion BPN Funding Opportunities). Applicants should contact NIH Scientific/Research staff regarding small peptides (less than 6 amino acids), natural products, and/or combination therapies to determine the fit for this FOA as well as suitability for discovery and development within the BPN.

To be supported by this FOA, a project must focus on a single 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.

The overall objective is that all projects should reach the clinical trial stage (regardless of entry point) within a maximum of 5 years of BPN-Biologics funding and support. A schematic of this project structure is available on the BPN-Biologics website at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/resources.

Projects can enter at either:

The Discovery stage to optimize a promising lead compound then transition into development with the goal on entering the clinic by the end of no later than the 5th year. Applications that propose entry with a Discovery stage biologic lead should include a Development work plan as well.

or

The Development stage to advance a single biologic candidate through Investigational New Drug (IND)-enabling toxicology studies, filing an IND package with the FDA, and an optional Phase I clinical trial.

Potential applicants are strongly encouraged to contact NIH Scientific/Research staff prior to preparing an application. The following sections describe the Discovery and Development stages in more detail.

General Entry Criteria:

All projects must meet the following entry requirements:

• Identified one or more lead biologic agent(s) sufficiently profiled so that the parameters still to be optimized can be quantitatively specified.
• Established preliminary in vivo efficacy and target engagement data using agent(s) in relevant animal model(s). The agent(s) should show in vivo efficacy using clinically relevant outcome measures (e.g., biochemical, anatomical and/or functional, when possible) and in vivo target engagement (e.g., measurement of target binding or proximal downstream effects) at the clinically intended site of action, using sufficient experimental and statistical rigor in a relevant animal in vivo proof-of-concept model. Applications may be considered without an in vivo/ex vivo efficacy requirement if there is a clear rationale backed-up with compelling in vitro data.
• Demonstrated that the key in vitro and in vivo assays are suitable to drive the characterization and optimization of lead biologics in a rigorous fashion and are available in either the applicant’s or collaborator’s laboratories.
• The proposed approach is unlikely to be blocked by any 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.

Discovery Stage

Projects that require lead characterization and optimization to improve the potency and/or suitability for clinical testing will enter the BPN-Biologics at the Discovery stage. The BPN-Biologics supports a maximum of two years of lead optimization. Therefore, by the end of the U44 Phase I, the PD/PI should have identified a clinical candidate that meets the entry criteria for the Development stage (U44 Phase II).

Examples of activities that can be supported during the Discovery (U44 Phase I) stage include, but are not limited to:

• 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 U44 Phase II
• 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
• Initial development of pharmacodynamic biomarker assay(s)

The goal at the end of the Discovery stage is to select a clinical candidate with appropriate bioactivity, stability, manufacturability, and bioavailability by the intended route of administration for development. Other requirements include target engagement with defined minimal and optimal doses by the intended route of administration, other favorable properties consistent with the desired clinical application, and in vivo efficacy when applicable. Projects with only in vitro data need compelling data and rationale that the in vivo studies are not necessary or appropriate. Projects that meet this goal will enter Development in the U44 Phase II award, beginning with the preparatory activities listed below.

Development Stage

The Development stage includes all IND-enabling studies, cGMP synthesis of clinical trial material, and Phase I clinical testing. Applications for entry into the Development stage must have identified the candidate therapeutic.

Entry Criteria for the development Stage:

• A strong body of data linking the putative therapeutic target to the proposed disease indication and supporting the hypothesis that altering the target activity will produce desirable outcomes for the disease is required.
• The proposed therapeutic should have rationally laid out biological activity by the planned route of administration with exposure levels for activity being achievable based on absorption, distribution, metabolism, and excretion (ADME) properties appropriate for the intended clinical use.
• Demonstration that the ability of the PD/PI's institution to develop and commercialize the proposed biologic 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 (see Other Attachments in Section IV).

All applications proposing to enter at the Development stage will begin with a U44 Phase I award of up to two years, to prepare for the IND-enabling studies supported during the U44 Phase II award. Projects that began at the Discovery stage will conduct all Development stage preparatory and IND-enabling studies during their U44 Phase II.

Development stage U44 Phase I activities can include, but are not limited to:

• Any remaining optimization activities as listed above, if needed
• Non-GLP toxicology studies (e.g., dose-range finding toxicology)
• Formulation
• Scale up manufacture
• Replication of in vivo studies in the same or a different animal model
• A pre-IND meeting with FDA, if not already conducted

The following are general expectations for a project to initiate Development IND-enabling studies within BPN-Biologics:

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

Development Activities for the U44 Phase II award may include the following:

• cGMP manufacturing of material for IND-enabling and/or Phase I clinical testing
• IND-enabling safety pharmacology and toxicology studies to determine a basis for clinical dose extrapolation using a relevant animal model
• IND document preparation and filing with the FDA
• Phase I clinical trial (a single and/or multiple ascending dose study to characterize safety, PK, and PD) (See below for more information regarding clinical trials

The goal by the end of the Development stage is to begin a first-in-human Phase I clinical trial.

Note: Key studies should be sufficiently powered and controlled with experimental and statistical rigor to lend a high degree of confidence in the results, with detailed information available about study design, execution, analysis, and interpretation.

BPN-Biologics contractors can conduct the preclinical safety studies, cGMP manufacturing, formulation and other activities required to prepare for human testing. BPN-Biologics 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-Biologics contractors.

The PD/PI's Institution will be responsible for assembly and submission of the IND application and scheduling regulatory 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.

Additional Information regarding Clinical Trials

Applicants are strongly advised to discuss plans with NIH program staff prior to submitting their application to determine whether a clinical trial is feasible within the proposed funding timeframe and/or available BPN-Biologics contract resources. In the event that only diseased patients are expected to be enrolled, the applicants own clinical site(s) must be proposed.

Clinical Trial Design: Single dose or single ascending dose treatment which may be placebo-controlled or open-label studies; multiple ascending dose may be requested only if agent has a short half-life. Clinical trial outcomes may include safety, tolerability, pharmacokinetics and pharmacodynamics, target engagement and target modulation endpoints.

The development of the protocol and management of the Phase I 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 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).

Applications Not Responsive to this FOA

Non-responsive applications include those that involve any of the following activities:

• Basic research and studies of disease mechanism
• Animal model development
• Early discovery research, such as identifying and validating targets and generation of preliminary agents that are not suitable for human testing
• Development of small molecule compounds (covered by PAR-20-122 and PAR-20-111)
• Development of diagnostics and medical devices
• Development of risk, detection, diagnostic, prognostic, predictive, and prevention biomarkers as well as PET ligands
• Stand-alone clinical trials
• Studies directed beyond first-in-human Phase I clinical testing

Non-responsive applications will not be reviewed.

C. NIH Institute and Center Interests and Guidance

National Institute on Aging (NIA)

NIA is interested in projects that will provide drug development expertise and infrastructure support to researchers interested in developing new biologics 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. 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). Regarding therapeutic approaches, NIA is interested in traditional biotherapeutic modalities such as gene and immunotherapies and other modalities such as genome editing, gene silencing, and PROTAC. 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 to follow best practices guidelines as summarized at: https://grants.nih.gov/reproducibility/module_1/presentation_html5.html.

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Without a specific "receptor", alcohol has numerous molecular targets in the brain, and alcohol-seeking behavior and alcoholism are influenced by multiple neurotransmitter systems, neuromodulators, hormones, and signal transduction pathways. Many potential target sites for which new pharmaceuticals may be developed have, therefore, been identified. These include neurotransmitter systems related to opioids, serotonin, dopamine, glutamate, ?-aminobutyric acid (GABA), endocannabinoids, the hypothalamic-pituitary-adrenal (HPA) axis, adenosine, neuropeptide systems (for example, neuropeptide Y, corticotropin releasing factor), signal transduction pathways (such as protein kinase A and protein kinase C); and gene transcription factors (such as delta Fos B and cAMP response element-binding protein [CREB]). NIAAA is interested in research aimed to develop pharmaceuticals targeting new molecular sites to provide effective therapy to a broader spectrum of alcoholic individuals. Recent research has discovered specific genetic variants that may contribute to the risk for alcoholism and/or render alcohol dependent individuals responsive to specific therapeutic agent. NIAAA is interested in supporting research to develop pharmaceuticals targeting individuals with identified genotypic and phenotypic characteristics to improve efficacy and safety.

Research shows that diverse teams working together outperform homogenous teams. Scientists and trainees from diverse backgrounds and with different life experiences bring different perspectives, creativity, and individual enterprise to address complex scientific problems. Diverse teams of scientists will lead the way to develop more innovative inclusive research that will more broadly enhance public health. Fostering diversity by addressing underrepresentation in the scientific research workforce is a key component of the NIH strategy to identify, develop, support, and maintain the quality of our scientific workforce. It is expected that the Alcohol Research Centers will include a diverse group of scientists, including individuals from underrepresented backgrounds as per NOT OD 20-031 (Notice of NIH's Interest in Diversity). NIAAA is especially interested in enhancing representation from racial, ethnic and gender minorities and early-stage investigators.

National Eye Institute (NEI)

The National Eye Institute (NEI) interest in BPN-Biologics 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 and other conditions. The NEI is also interested in other visual system disorders such as strabismus and amblyopia that could be treated with biologics-based interventions. Each project should have a well-defined endpoint, 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 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 BPN Biologics development for craniofacial disorders and painful disorders of the orofacial region including temporomandibular joint disorders, trigeminal neuropathies, burning mouth syndrome, oral cancer pain, dental 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 of subjects with orofacial pain disorders.

Awardees will be required to comply with the NIDCR Clinical Terms of Award for activities that involve human subjects research that have been determined by NIDCR to need additional oversight. 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 research aimed to develop novel pharmacotherapies for the treatment of developmental disorders, diseases and conditions in pediatric population. Investigators are strongly encouraged to discuss their research plans with NICHD Scientific/Research contact prior to submitting their application.

National Institute of Mental Health (NIMH)

NIMH supports neuroscience research to discover the causes of mental illness and to develop more effective and safe treatments. NIMH has interest in applications proposing the development of biologics as an approach for the treatment of mental disorders, including treatment-resistant depression, bipolar disorder, schizophrenia, PTSD, and autism spectrum disorder.

Researchers with expertise and interest in advancing small molecules to the clinics should consider submitting an application to the BPN-small molecules Program (PAR-20-111 and PAR-20-122), small molecules 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 interested in the development of small molecule projects 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-20-271 (R01), Discovery of in vivo Chemical Probes for Novel Brain Targets PAR-21-029 (R01), Discovery of Cell-based Chemical Probes for Novel Brain Targets PAR-21-028 (R21), National Cooperative Drug Discovery/Development Groups (NCDDG) for the Treatment of Mental Disorders, Drug or Alcohol Addiction PAR-20-118 (U01) and PAR-20-119 (U19).

For this initiative, NIMH will only support projects entering the BPN-Biologics at the Discovery stage for monogenetic severe neurodevelopmental health disorders (e.g., Autism Spectrum Disorders). NIMH will not support projects entering the BPN-Biologics at the Development (IND enabling/GMP synthesis or Phase I trials) stage. NIMH is interested in gene-based therapies such as genome-editing modalities and viral gene deliveries. NIMH is not interested in therapies based on large biologic macromolecules, (e.g., proteins, antibodies, and peptides) or oligonucleotides. 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.

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.

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)

NIMH has published a Note with guidelines and priorities for potential applicants considering animal neurobehavioral approaches in research relevant to mental illnesses, investigators are strongly to follow the guidelines summarized at NOT-MH-19-053 if proposing to include behavioral measures.

Further information on NIMH research priorities can be found in the NIMH Strategic Research Plan 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)

Examples of diseases 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 as this list is not exhaustive.

This FOA serves as the primary support mechanism at NINDS for the optimization and development biologics and biotechnology products. Applicants seeking support for early drug discovery research are encouraged to review NINDS SBIR/STTR programs. Applicants seeking support only to conduct early stage clinical trials should consider applying for an NINDS Exploratory Clinical Trial, through PAR-18-618 (or its reissue), which provides additional flexibility in budget and time, as well as the option of including a phase II trial.

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 on development of novel biologics from natural products (e.g., venoms and conotoxins) and microbial and microbiome therapies to modulate symptoms on nervous system disorders including pain, sleep disorders, anxiety disorders, mild depression, and stress etc. 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 biotherapeutics for substance use disorders (SUD). Projects focused on cocaine, methamphetamine and marijuana use disorders are of high priority for NIDA because there are currently no FDA-approved treatments for these indications. NIDA will only support projects to develop innovative pharmacological approaches entering the BPN-Biologics at the Discovery stage. Specifically, NIDA is interested in using the BPN-Biologics mechanism to support (academic) addiction researchers in the "lead optimization" stages. NIDA applicants are strongly encouraged to take full advantage of the opportunities the BPN-Biologics affords, including collaboration with BPN-Biologics consultants and NIH-supported contract research organizations (CROs) that specialize in pharmacokinetics, toxicology, and manufacturing. Researchers who possess the drug development expertise and access to the necessary infrastructure to advance biotherapeutics 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 biotherapeutic discovery and development are inherently high risk, it is expected that there will be attrition as projects progress. Go/No-Go milestones will be established by the NIH with input from the LDTs 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-Biologics projects), to assess milestone progress and recommend which projects will advance from the U44 Phase I to the Phase II and assess 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 biotherapeutic target
• Program priorities
• Availability of funds

Note: If a funded project does not make satisfactory progress toward the agreed upon milestones at any stage during the funding period, access to BPN-Biologics contract resources and future year grant funding may be discontinued (see Section VI.2).

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.

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.

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 biotherapeutics to the market, the creation and protection of intellectual property (IP) that will make biologic 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 awardee institution retains their assignment of IP rights and gains assignment of IP rights from the BPN-Biologics contractors (and thereby control the patent prosecution and licensing negotiations) for biologic drug candidates developed in this program. It is expected that the awardee institution 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-Biologics.

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 single venture capital operating company, hedge fund, or private equity firm qualifies 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.