National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
National Eye Institute (NEI)
National Institute on Aging (NIA)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Dental and Craniofacial Research (NIDCR)
National Institute on Drug Abuse (NIDA)
National Institute of Mental Health (NIMH)
National Center for Complementary and Integrative Health (NCCIH)
All applications to this funding opportunity announcement should fall within the mission of the Institutes/Centers. The following NIH Offices may co-fund applications assigned to those Institutes/Centers.
Office of Behavioral and Social Sciences Research (OBSSR)
U44 Small Business Innovation Research (SBIR) Cooperative Agreements -Fast-Track applications
New
- April 23, 2021 - This PAR has been reissued as PAR-21-233.
- April 23, 2021 - Notice of Early Termination of PAR-21-162. See Notice NOT-NS-21-056.
PAR-21-163- Blueprint Neurotherapeutics Network (BPN): Biologic-based Drug Discovery and Development for Disorders of the Nervous System (UG3/UH3 Clinical Trial Optional)
PAR-20-122 - Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development of Disorders of the Nervous System (UG3/UH3 Clinical Trial Optional)
PAR-20-111 - Blueprint Neurotherapeutics Network (BPN): Small Molecule Drug Discovery and Development for Disorders of the Nervous System (U44 Clinical Trial Optional)
93.853, 93.213, 93.867, 93.866, 93.273, 93.286, 93.865, 93.279, 93.121, 93.242
The Blueprint Neurotherapeutics Network for Biologics (BPN-Biologics) provides support for biologic-based therapeutic discovery and development, from lead optimization through phase I clinical testing. This Funding Opportunity Announcement (FOA) supports preclinical discovery and development of potential therapeutic Biotechnology Products and Biologics including, but not limited to, large biologic macromolecules, (e.g., proteins, antibodies, and peptides), gene-based therapies (i.e., oligonucleotide- and viral-based), cell therapies, and novel emerging therapies (e.g., microbial and microbiome therapies). Applicants will collaborate with NIH-funded consultants and can augment their project with NIH contract research organizations (CROs) that specialize in manufacturing, scaling, pharmacokinetics, toxicology, and Phase I clinical testing. BPN-Biologics awardee institutions retain their assignment of IP rights and gain assignment of IP rights from the BPN-Biologics contractors (and thereby control the patent prosecution and licensing negotiations) for biotherapeutic candidates developed in this program.
30 days prior to the application due date
August 10, 2021, February 9, 2022, August 9, 2022, February 9, 2023, August 9, 2023, February 9, 2024
All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s).
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
September 5, 2021, April 5, 2022, September 5, 2022, April 5, 2023, September 5, 2023, April 5, 2024
All applications are due by 5:00 PM local time of applicant organization. All types of AIDS and AIDS-related applications allowed for this funding opportunity announcement are due on the listed date(s).
Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.
November 2021, June 2022, November 2022, June 2023, November 2023, June 2024
January 2022, October 2022, January 2023, October 2023, January 2024, October 2024
April 2022
Not Applicable
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.
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-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-frequently-asked-questions) 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-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.
Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.
New (Fast-Track)
Resubmission (all phases)
The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for the FOA.
Need help determining whether you are doing a clinical trial?
The number of awards is contingent upon NIH appropriations and the submission of a sufficient number of meritorious applications.
Application budgets are not limited but need to reflect the actual needs of the proposed project.
Applicants should rarely exceed up to $500,000 total cost per year for Phase I and up to $1,500,000 total cost per year for the Phase II. In all cases, applicants should propose a budget that is reasonable and appropriate for completion of the research project. Application budgets should only cover the work that will be performed by the PD/PI and his/her staff. The NIH will pay BPN contractors and consultants directly for their work; therefore, these expenses should not be included in the budget for this application.
Durations up to 2 years for Phase I and up to 3 years for Phase II may be requested.
NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.
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:
- 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;
- 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;
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- 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
- 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
- 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.
- 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.
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. This Transition Rate requirement applies to 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. For these companies, the benchmark establishes a minimum number of Phase II awards the company must have received for a given number of Phase I awards received during the 5-year time period in order to be eligible to apply for a new Phase I award Fast-Track, or Direct Phase II (if available). This requirement does not apply to companies that have received 20 or fewer Phase I awards over the 5 year period.
Companies that do not meet or exceed the benchmark rate 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. 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 benchmark minimum Transition Rate is 0.25.
SBA calculates individual company Phase I to Phase II Transition Rates daily using SBIR and STTR award information across all federal agencies. For those companies that have received more than 20 Phase I awards over the past 5 years, SBA posts the company transition rates on the Company Registry at SBIR.gov. Information on the Phase I to Phase II Transition Rate requirement is available at SBIR.gov.
Applicants to this FOA that may have received more than 20 Phase I awards across all federal SBIR/STTR agencies over the past five (5) years should, prior to application preparation, verify that their company’s Transition Rate on the Company Registry at SBIR.gov meets or exceeds the minimum benchmark rate of 0.25.
Phase II to Commercialization Benchmark
In accordance with guidance from the SBA, HHS, including NIH, 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. The Commercialization Rate Benchmark was published in a Federal Register notice on August 8, 2013 (78 FR 48537).
This requirement applies to companies that have received more than 15 Phase II awards from all agencies over the past 10 years, excluding the two most recently-completed Fiscal Years. 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. This requirement does not apply to companies that have received 15 or fewer Phase II awards over the 10 year period, excluding the two most recently-completed Fiscal Years.
Information on the Phase II to Commercialization Benchmark is available at SBIR.gov.
Applicants to this FOA that may have received more than 15 Phase II awards across all federal SBIR/STTR agencies over the past ten (10) years should, prior to application preparation, verify that their company’s Commercialization Benchmark on the Company Registry at SBIR.gov meets or exceeds the benchmark rate listed above.
Applicants that fail this benchmark will be notified by SBA annually and 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.
Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, may be allowed.
Applicant Organizations
Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.
- Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM, SBA Company registry, and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
- System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
- SBA Company Registry See Section IV. Application and Submission Information, SF424(R&R) Other Project Information Component for instructions on how to register and how to attach proof of registration to your application package. Applicants must have a DUNS number to complete this registration. SBA Company registration is NOT required before SAM, Grants.gov or eRA Commons registration.
- eRA Commons - Applicants must have an active DUNS number number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
- Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.
Program Directors/Principal Investigators (PD(s)/PI(s))
All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.
Under the SBIR program, for both Phase I and Phase II, the primary employment of the PD/PI must be with the small business concern at the time of award and during the conduct of the proposed project. For projects with multiple PDs/PIs, at least one must meet the primary employment requirement. Occasionally, deviations from this requirement may occur.
For the STTR program, the PD(s)/PI(s) may be employed with the SBC or the single, partnering non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant SBC, which is characterized by an official relationship between the SBC and that individual. Such a relationship does not necessarily involve a salary or other form of remuneration The primary employment of the PD/PI must be with the SBC or the Research Institution (where they are PD/PI at) at the time of award and during the conduct of the proposed project.
Each PD/PI must commit a minimum of 10% effort to the project.
The SF424 (R&R) SBIR/STTR Application Guide should be referenced for specific details on eligibility requirements. For institutions/organizations proposing multiple PDs/PIs, see Multiple Principal Investigators section of the SF424 (R&R) SBIR/STTR Application Guide.
2. Cost Sharing
This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.Applicant organizations may submit more than one application, provided that each application is scientifically distinct.
NIH will not accept similar grant applications with essentially the same research focus from the same applicant organization. This includes derivative or multiple applications that propose to develop a single product, process, or service that, with non-substantive modifications, can be applied to a variety of purposes. Applicants may not simultaneously submit identical/essentially identical applications under both this funding opportunity and any other HHS funding opportunity, including the SBIR and STTR Parent announcements.
The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:
- A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
- A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
- An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).
A Phase I awardee may submit a Phase II application either before or after expiration of the Phase I budget period, unless the awardee elects to submit a Phase I and Phase II application concurrently under the Fast-Track procedure. To maintain eligibility to seek Phase II or IIB support, a Phase I awardee should submit a Phase II application, and a Phase II awardee should submit a Phase IIB application, within the first six due dates following the expiration of the Phase I or II budget period, respectively.
In Phase I, normally, two-thirds or 67% of the research or analytical effort is carried out by the small business concern. The total amount of all consultant and contractual arrangements to third parties for portions of the scientific and technical effort is generally not more than 33% of the total amount requested (direct, F&A/indirect, and fee).
In Phase II, normally, one-half or 50% of the research or analytical effort is carried out by the small business concern. The total amount of consultant and contractual arrangements to third parties for portions of the scientific and technical effort is generally not more than 50% of the total Phase II amount requested (direct, F&A/indirect, and fee).
We encourage you to contact a program officer listed in Section VII with questions about this because occasionally, deviations from these requirements may occur, and must be approved in writing by the funding agreement officer after consultation with the agency SBIR Program Manager/Coordinator. In Phase I and Phase II, at least 40% of the research or analytical effort must be performed by the small business concern and at least 30% of the research or analytical effort must be performed by the single, partnering research institution. The basis for determining the percentage of work to be performed by each of the cooperative parties will be the total of direct, F&A/indirect costs, and fee attributable to each party, unless otherwise described and justified in Consortium/Contractual Arrangements of the PHS 398 Research Plan component of the SF424 (R&R) application forms.
A small business concern may subcontract a portion of its SBIR or STTR award to a Federal laboratory within the limits above. A Federal laboratory, as defined in 15 U.S.C. 3703, means any laboratory, any federally funded research and development center, or any center established under 15 U.S.C. 3705 & 3707 that is owned, leased, or otherwise used by a Federal agency and funded by the Federal Government, whether operated by the Government or by a contractor.
The basis for determining the percentage of work to be performed by each of the cooperative parties in Phase I or Phase II will be the total of the requested costs attributable to each party, unless otherwise described and justified in Consortium/Contractual Arrangements of the PHS 398 Research Plan component of SF424 (R&R) application forms.
Additional details are contained in the SF424 (R&R) SBIR/STTR Application Guide.
1. Requesting an Application Package
The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.
2. Content and Form of Application Submission
It is critical that applicants follow the SBIR/STTR (B) Instructions in the SF424 (R&R) SBIR/STTR Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.
Letter of Intent
Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.
By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:
- Descriptive title of proposed activity
- Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
- Names of other key personnel
- Participating institution(s)
- Number and title of this funding opportunity
The letter of intent should be sent to:
Ann-Marie Broome PhD MBA
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email:[email protected]
All page limitations described in the SF424 (R&R) SBIR/STTR Application Guide and the Table of Page Limits must be followed.
The following section supplements the instructions found in the SF424 (R&R) SBIR/STTR Application Guide and should be used for preparing an application to this FOA.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed with the following additional instructions:
Other Attachments:
1. SBIR Application Certification for small business concerns majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms
Applicant small business concerns that are majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms (e.g. majority VCOC-owned) are required to submit a Certification at time of their application submission per the SBIR Policy Directive. Follow the instructions below.
Applicants small business concerns who are 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), or any combination of these (i.e. NOT majority VCOC-owned) should NOT fill out this certification and should NOT attach it their application package.
- Download the VCOC Certification.pdf at the NIH SBIR Forms webpage.
- Answer the 3 questions and check the certification boxes.
- The authorized business official must sign the certification.
- Save the certification using the original file name. The file must be named SBIR Application VCOC Certification.pdf . DO NOT CHANGE OR ALTER THE FILE NAME. Changing the file name may cause delays in the processing of your application.
- When you are completing the application package, attach this certification as a separate file by clicking "Add Attachments" located to the right of Other Attachments field on the Research and Related Other Project Information form.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed.
The application should include a budget for each year of both phases of the grant’s duration with appropriate justification. This award is intended to support studies to be conducted by the PD(s)/PI(s) and associated personnel. The budget may not support biotherapeutic development activities that the applicant proposes to conduct through BPN contracts. The NIH will pay BPN contractors and consultants directly for their work. Equipment requests are allowed but not encouraged. Equipment requests should be considered only if the equipment is necessary to the success of the project and cannot be supported by any other means. This is likely to be a subject of negotiation before an award is made. Some budget requests may be made for the PD/PI's Institution to assemble and file the IND.
The U44 budget may include travel costs for one or two trips per year to attend meetings of the BPN-Biologics External Oversight Committee or hold face-to-face meetings of the LDT/CDT.
The PD/PI is expected to dedicate at least 20% level of effort (2.4 person months) to managing a BPN-Biologics project. It is strongly recommended that potential applicants consult NIH staff about their anticipated budget in the early stages of preparing an application.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed.
Specific Aims: The Specific Aims section should include Aims delineated for the U44 Phase I and Phase II award. If a clinical study is proposed, define the aims of the clinical study.
Research Strategy: The Research Strategy section should include the entire project scope including plans for both the U44 Phase I and Phase II awards, respectively, and should include the following subsections:
- Clinical Significance
- Biological Rationale and Biologic Profile (Significance)
- Approach
- Innovation
- Table of proposed activities that provides the following information: Activity (optimization, assays, PK, etc.), source (PD/PI lab, sub awardee, BPN-Biologics Contractor), advancement criteria.
- Timeline of proposed activities
A. Clinical Significance: Each application generally should focus on only one disorder or disease, even if the therapeutic agent proposed for development shows activity in models for more than one disorder. This is because the target patient population and intended use guide the design of the therapy, the path for an IND, and the nonclinical IND-enabling studies. Levels of tolerated toxicities may also differ between different disorders especially if the proposed treatment is chronic versus acute.
- Briefly describe the current state of knowledge of the etiology, clinical characteristics, and prevalence of the proposed disease indication.
- Briefly discuss available treatments (if any), their limitations, and how the proposed project would provide an advantage over all existing therapies, regardless of therapeutic class (i.e., discussion only on within class comparisons is not sufficient).
- Discuss how the proposed project relates to therapy development efforts underway in academia and industry.
- Provide a Target Product Profile (TPP), a table based on an FDA template that summarizes the minimal/ideal profile of the final marketed product and shows the ultimate goals of the proposed biologic drug development effort, such as disease indication, patient population, delivery mode, treatment duration, treatment regimen, and standards for clinical efficacy (see guidance and example of suggested format at http://neuroscienceblueprint.nih.gov/resources/target-product-profile.htm).Explain the rationale behind the minimally acceptable and ideal parameters for the clinical population.
- In addition to a TPP, outline the plans for the first clinical proof-of-concept study that aligns with the proposed TPP and comment on feasibility of conducting the trial(s). Briefly comment on the contribution of conducting clinical trials toward the goals in the TPP (e.g., availability of patients for clinical trials).
- Describe the group clinical expertise used to determine the goals of the biotherapeutic development program and the clinical trial.
B. Biological Rationale and Biologic Profile (Significance): This section contains, but is not limited to, comprehensive data that support the scientific premise and that justify that the application meets the entry criteria.
- Describe the intended biological target/pathway and provide the evidence that links this target to the proposed disease indication.
- Provide the evidence that altering target activity as proposed will give desirable outcomes for the proposed disease indication.
- Provide evidence that the agent(s) modulates the target(s) in vitro and in vivo.
- Provide an Agent Profile Table (see guidance and example of suggested format at http://neuroscienceblueprint.nih.gov/resources/example_compound_profile_table.htm) that summarizes the known characteristics of the agent(s) proposed for optimization or as the development candidate (structure/identity, selectivity/specificity, bioactivity, stability, bioavailability, and other modality- specific characteristics).
- Show structure/identity such as cell identity for cell therapies, purity, aggregation, epitope mapping, glycosylation, or other post-translational modification for proteins. Note any potential liabilities.
- For Discovery projects, show that the agent(s) proposed as the starting point for optimization alters the activity of the putative target as intended and/or produces desired outcomes in disease models, with sufficient detail to allow reviewers to evaluate the rigor of the experimental design. Explain the choice of models, assays, and endpoints for these studies.
- For Development projects, show that the proposed development candidate has clinically relevant in vivo activity, when delivered by the clinically intended route of administration, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen.
- Present data showing the minimal effective dose, optimal effective dose, time and duration of treatment. These should have been determined in relevant in vivo assays using clinically relevant functional and/or anatomical outcome measures, and/or in vivo target engagement assays, using a candidate that is sufficiently pure [This normally should have been done using the clinically intended route of administration and special formulations if proposed (such as slow release, liposomes, nanoparticles, etc.), unless justified to use other routes of administration in which case the dose-response must have been reliably bridged by pharmacokinetics measurements].
- Present data on pharmacokinetics, CNS penetration, and pharmacokinetic-pharmacodynamic relationship.
- Describe bioactivities of the candidate in vitro (e.g., binding affinities, IC50 in relevant in vitro model). Show evidence that the candidate modulates the targets or pathway in vitro.
- Describe the supporting in vivo biology study design in detail, including the power analysis and associated assumptions for the determination of sample size, statistical handling of the data (such as criteria for data inclusion or exclusion), procedures used for blinding and randomization, and whether studies were replicated.
- Discuss the clinical relevance of the preclinical outcome measures and observed effect size.
- Show the data that demonstrate the relationship between agent exposure and activity and explain how these data support the clinical dosing regimen proposed in the TPP.
C. Approach: Specify whether the project is proposed for entry at the Discovery or Development stage. Clearly indicate within a table which activities will be conducted by the PD/PI and associated personnel (i.e., funded by the U44 award) and which activities will be conducted by BPN-Biologics contractors. Include experimental designs and justification for all studies that will be conducted by the PD/PI and associated personnel. Activities that will be conducted by BPN-Biologics contractors need not be described in detail in the application, since these will be planned after award by the LDT. Potential pitfalls and alternative strategies to knowable issues should be addressed.
For Discovery-stage projects:
- Describe how each parameter (such as potency, selectivity, stability etc.) will be optimized. If multiple parameters are to be optimized, whether this will be done sequentially, in parallel, or in an iterative process.
- Propose experiments such as demonstration of in vivo efficacy, target engagement with dose-response, bioavailability at the site of action (including brain penetration), and pharmacokinetic-pharmacodynamics relationships.
- Present a table that lists all the in vitro and in vivo assays that will be executed by the PD/PI and associated personnel. The table should include descriptive names of the assays, the assay specifications, and the proposed acceptance criteria for each assay.
- Show assay validation data or present plans to optimize and validate assays.
- For the in vivo bioactivity study required to declare a development candidate, provide details on the study design, including power analysis and associated assumptions for sample size estimation, the process for blinding and randomization, and data handling rules, such as criteria for inclusion and exclusion of data. Describe plans for data analysis and interpretation, including what effect size would be considered minimally acceptable and clinically relevant (i.e., what constitutes a go/no-go decision for advancement into Development).
- If there is anticipated toxicity based on the proposed therapeutic target, provide a plan for preliminarily evaluating toxicity.
- Describe how the production and reproducibility of production of the candidate will be optimized or evaluated. Discuss feasibility of production and reproducibility of production of the candidate.
For Development-stage projects:
- If requesting funding to conduct preclinical Development activities, include a graphical timeline that lays out each step (e.g., GMP synthesis, formulations development, and IND-enabling studies).
- If applicable, present a plan for all preparatory work for IND-enabling studies such as CMC activities, preliminary safety studies, validation of target engagement assays to support future human clinical trials, final characterization of the manufactured material intended for nonclinical IND-enabling toxicology studies, etc.
- Present a plan for how nonclinical studies that are consistent with or per regulatory guidance will be achieved. These include IND-enabling toxicology, tumorigenicity evaluations as needed, immunogenicity evaluations as needed, biodistribution studies as needed, large animal study to assess biocompatibility of means of clinical delivery of the candidate, etc.
- Provide a brief description of the clinical trial strategy. We anticipate that details of the trial are likely to change during therapeutic development. As appropriate, applicants are encouraged to make use of the following resources for clinical research including:
- Clinical and Translational Science Award (CTSA) program (https://ctsacentral.org/);
- NeuroQOL (http://www.healthmeasures.net/explore-measurement-systems/neuro-qol);
- NIH Toolbox (http://www.healthmeasures.net/explore-measurement-systems/nih-toolbox);
- PROMIS (http://www.healthmeasures.net/explore-measurement-systems/promis); and
- NINDS Common Data Elements (https://www.commondataelements.ninds.nih.gov/#page=Default).
D. Innovation: Explain how the project offers a novel approach to treating the proposed disease indication.
- If therapeutics that target the same molecule, pathway, or cellular process have been tested in clinical trials for the proposed disease indication, explain why the proposed approach would be expected to provide a benefit over those therapeutics.
- If similar drugs have been tested in clinical trials for the proposed disease indication, explain why the proposed biologic would be expected to give significantly better clinical outcomes.
- If the therapy is an improvement over an earlier generation agent(s) that has not been marketed, discuss what advantages the proposed new agent will have. Include results from previous clinical trials with related agents.
- Comment on the novelty of proposed approach, target, pathway, assays or models.
Letters of Support:
- If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property (IP) will be shared or otherwise managed across the institutions, to ensure that the IP remains unencumbered, consistent with achieving the goals of the program.
Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:
- All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan. If patent protection is being sought, investigators should explain how data will be shared after filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.
Appendix:
Note that Phase I SBIR/STTR Appendix materials are not permitted. Only limited items are allowed in the Appendix of other small business applications. The instructions for the Appendix of the Research Plan are described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide Instructions.
If FDA meetings have been held, documentation of meeting outcomes, agreements, disagreements, and action items should be summarized and included as an Appendix document. These meetings can include pre-IND meetings and, earlier in development, INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) meetings. Early, nonbinding regulatory advice can be obtained from the FDA through an INTERACT meeting, which can be used to discuss issues such as a product’s early preclinical program, and/or through a pre-IND meeting prior to submission of the IND.
SBIR/STTR Information
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed, with the following additional instructions:
Commercialization Plan: All applicants are expected to describe a realistic plan (extending beyond the U44 Phase II), which outlines how and when full commercialization can be accomplished. The full commercialization of the product/technology should be carried out with non-SBIR funds.
The following subsections with the headings must be included within the Commercialization Plan, in addition to the requirements listed in the SF424 Application Guide:
1) Statement of Need
Applicants must provide a concise "Statement of Need". This statement is expected to provide answers to the questions listed below:
- What is the perceived "Valley of Death" for the product/technology under development?
- To what extent would a possible award under this FOA advance the product or technology far enough to attract sufficient, independent third-party financing and/or strategic partnerships to carry out full commercialization?
2) SBIR/STTR Commercialization History
Applicants should provide an SBIR/STTR Commercialization History that addresses the questions listed below. The following questions should be addressed for all SBIR/STTR awards received from any Federal agency:
- Has the company gone through any name changes within the past five years? If so, then all previous company names should be listed in the application.
- Is the company a subsidiary or a spin-off? If so, then the name of the parent company should be provided.
- What percentage of the company's revenue was derived from SBIR/STTR funding during each of the past 5 years, including both Phase I and Phase II awards? Applicants should report a percentage value for each year individually.
- What is the total number of SBIR/STTR Phase II awards that the company has received from the Federal government? For each award, companies should provide the award number, the award amount, project duration, and the name of the awarding agency.
- What are the total revenues that have been generated to date as a result of the commercialization of the SBIR/STTR projects funded within the past 5 years?
3) Intellectual Property (IP) Strategy
Applicants are encouraged to prepare this section in consultation with their institutions' technology transfer officials.
- For Discovery stage projects, applicants should describe any constraints of which they are aware that could impede their use of compounds, assays, or models for research purposes and/or commercial development (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present intellectual property filings and publications, compounds with similar structures that are under patent and/or on the market, etc.) and how these issues would be addressed. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.
- For Development stage projects, applicants should describe their efforts to confirm that there are unlikely to be IP or other legal constraints that could block or impede development or commercialization of the proposed biologic. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.
- All applicants should describe their institutions' existing or planned infrastructure for bringing the biotherapeutics to practical application (e.g., licensing for further biologic drug development, managing IP, commercializing discoveries) consistent with achieving the program goals. For a multiple-PD/PI, multiple-institution application, applicants should describe the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing intellectual property) among the institutions consistent with achieving the goals of the program. Applicants should clarify how IP will be shared or otherwise managed if there are multiple PD/PIs and institutions involved in the U44-supported work, to ensure that IP remains unencumbered.
When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:
If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.
Study Record: PHS Human Subjects and Clinical Trials Information
All instructions in the SF424 (R&R) Application Guide must be followed.
Note: Applications in which all human subject work is proposed to be conducted by BPN-Biologics CROs (i.e. not part of the grant budget) should not indicate that their applications involve human subjects.
Section 2 - Study Population Characteristics
2.5 Recruitment and Retention Plan
Applicants should provide a detailed recruitment and retention plan for the study. The recruitment plan should demonstrate how clinical sites will engage the community and ensure representation of a diverse study population.
Section 4 - Protocol Synopsis
4.1. Study Design
4.1a. Detailed Description
Include determination of dose levels.
4.1c. Interventions
For "Intervention Description", include route of administration.
4.2. Outcome Measures
At least one outcome measure should include PK assessments, with attention to demonstration of CNS penetration (if appropriate) and target engagement or modulation.
Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start). All instructions in the SF424 (R&R) Application Guide must be followed.
All instructions in the SF424 (R&R) SBIR/STTR Application Guide must be followed.
3. Unique Entity Identifier and System for Award Management (SAM)
See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), eRA Commons, and Grants.gov
4. Submission Dates and Times
Part I. Overview Information contains information about Key Dates and time. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.
Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.
Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.
Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) SBIR/STTR Application Guide.
5. Intergovernmental Review (E.O. 12372)
This initiative is not subject to intergovernmental review.
6. Funding Restrictions
All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.
Pre-award costs are allowable only as described in the NIH Grants Policy Statement.
7. Other Submission Requirements and Information
Applications must be submitted electronically following the instructions described in the SF424 (R&R) SBIR/STTR Application Guide. Paper applications will not be accepted.
Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.
For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.
Important reminders:
All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.
The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management (SAM). Additional information may be found in the SF424 (R&R) SBIR/STTR Application Guide.
See more tips for avoiding common errors.
Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.
and Human Services (HHS)
