Part 1. Overview Information

Key Dates

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.

It is critical that applicants follow the instructions in the Research (R) Instructions in the SF424 (R&R) Application Guide,except where instructed to do otherwise (in this FOA or in a Notice from 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 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 UG3/UH3 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 UG3 award to the UH3 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.

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 agent 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 aswell.

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 UG3 phase, the PD/PI should have identified a clinical candidate that meets the entry criteria for the Development stage (UH3).

Examples of activities that can be supported during the Discovery (UG3) 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 UH3 phase
• Determination of optimal route of administration
• Lead optimization to improve effectiveness, diminish toxicity, and increase absorption (e.g., absorption, distribution, metabolism, and excretion (ADME))
• Demonstration of adequate/stage-appropriate preliminary safety, such as safety pharmacology and/or dose-range finding toxicology
• Initial development of pharmacodynamic biomarker assay(s)

The goal at the end of the Discovery stage (UG3) 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 UH3 phase, 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 or 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 UG3-funded preparatory phase of up to two years to prepare for the IND-enabling studies supported during the UH3 phase. Projects that began at the Discovery stage will conduct all Development stage preparatory and IND-enabling studies during their UH3 phase.

Development stage preparatory 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 after the preparatory phase (UH3) 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.

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 Disorders and 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 the following Innovation Grants to Nurture Initial Translational Efforts (IGNITE) funding opportunities: Neurotherapeutic Agent Characterization and In vivo Efficacy Studies PAR-21-122 (R61/R33) and Assay Development and Neurotherapeutic Agent Identification PAR-21-124 (R61/R33). Applicants seeking support only to conduct early stage clinical trials should consider applying for an NINDS Exploratory Clinical Trial, through PAR-18-420 (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 in the NINDS guidance Improving the Quality of NINDS-Supported Preclinical and Clinical Research through Rigorous Study Design and Transparent Reporting. 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 UG3 phase to the UH3 phase 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 biotherapeutic 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

Higher Education Institutions

• Public/State Controlled Institutions of Higher Education
• Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

• Hispanic-serving Institutions
• Historically Black Colleges and Universities (HBCUs)
• Tribally Controlled Colleges and Universities (TCCUs)
• Alaska Native and Native Hawaiian Serving Institutions
• Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

• Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
• Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

• Small Businesses
• For-Profit Organizations (Other than Small Businesses)

Local Governments

• State Governments
• County Governments
• City or Township Governments
• Special District Governments
• Indian/Native American Tribal Governments (Federally Recognized)
• Indian/Native American Tribal Governments (Other than Federally Recognized)

Federal Governments

• Eligible Agencies of the Federal Government
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations
• Non-domestic (non-U.S.) Entities (Foreign Institutions)

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, are 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 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.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS 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.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility

Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

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)

Section IV. Application and Submission Information

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

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:

Lauren Friedman, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-5065
Email: [email protected]

Kelly Sheppard, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-529-7469
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

Facilities & Other Resources:

All applicants should describe their institutions' existing or planned infrastructure for bringing the biologic agents 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 UG3/UH3-supported work, to ensure that IP remains unencumbered.

Other Attachments:

Applications must include an 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 therapeutic agents, 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, similar therapies 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 compounds. If the applicant's institution has filed pertinent patents, the applicant should indicate filing dates, the type of patent, and application status.

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R Budget

All instructions in the SF424 (R&R) 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. The UG3/UH3 award is intended to support studies to be conducted by the PD/PIs and associated personnel. The UG3/UH3 budget may not support biotherapeutic development activities that the applicant proposes to conduct through BPN-Biologics contracts. 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 UG3/UH3 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 will 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) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed.

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: The Specific Aims section should include Aims delineated for the UG3 and UH3 phases. 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 UG3 and UH3 phases, 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 https://neuroscienceblueprint.nih.gov/sites/default/files/documents/Example_TPP_508C.pdf). 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 https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/resources) 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 UG3/UH3 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 applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property and licensing associated with this project and agreement to share confidentially with NIH details of any licensing agreements related to the proposed program relevant to determining feasibility of commercialization for the proposed disease area.
• If the applicants require a license for technology to proceed to commercialization, then a letter of support from the institution holding that intellectual property must be provided to enable freedom to operate.
• 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.

The following modifications also apply:

• 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.

The following modifications apply:

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.

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) 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) Application Guide must be followed.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions described throughout the SF424 (R&R) Application Guide.

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), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and Grants.gov

Part I. Overview Information contains information about Key Dates and times. 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) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) 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. See Section III of this FOA for information on registration requirements.

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. Additional information may be found in the SF424 (R&R) 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.

Requests of $500,000 or more for direct costs in any year

Applicants requesting $500,000 or more in direct costs in any year (excluding consortium F&A) must contact a Scientific/ Research Contact at least 6 weeks before submitting the application and follow the Policy on the Acceptance for Review of Unsolicited Applications that Request $500,000 or More in Direct Costs as described in the SF424 (R&R) Application Guide.

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

If FDA meetings have been held, documentation of meeting outcomes, agreements, disagreements, and action items should be summarized and submitted. Documentation can come from 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. Submission of these materials falls under the same timeline as other post-submission materials as outlined in the policy above.

Section V. Application Review Information

1. Criteria

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.

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

For this particular announcement, note the following:

• Risks should be evaluated in a stage appropriate fashion and the ability for the BPN-Biologics to mitigate those risks with milestones. Earlier-stage projects are inherently riskier than later-stage projects. Projects should be evaluated relative to expectations for their proposed entry stage, when assessing risk.
• The market size for the proposed biotherapeutic should not be considered in assessing the significance of a project.
• Projects should not be penalized if the mechanism of action of the agent is unknown. While this may add to the risk, the increased risk may be counterbalanced by increased novelty.
• Evaluation of the approach should focus on the biological rationale, the feasibility to identify a biologic with acceptable properties to potentially benefit the targeted patient population, competitive landscape (novelty), and strengths/weaknesses of studies to be conducted by the PD/PI. Work to be conducted by BPN-Biologics contractors (which may include Good Manufacturing Practices (GMP), pharmacokinetics, toxicology, and Phase I clinical testing) will be designed by NIH-provided consultants and contractors after award.

In addition, for applications involving clinical trials: A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this announcement:

• How significant an advantage does the proposed biologic offer over other treatments under development (in any therapeutic class)?
• What is the likelihood that completion of the research objectives will lead to a therapy for the intended disease (i.e., is there a clear path into the clinic)?
• How robust and rigorous are the data supporting the choice of biologic target and biologic for the proposed disease indication?
• For projects entering at the Discovery stage, does the proposed biologic have sufficient activity in assays that are relevant to the proposed disease indication?
• For projects entering at the Development stage, does the identified clinical candidate have sufficient bioactivity, stability, manufacturability, bioavailability, in vivo efficacy and/or target engagement using clinically relevant animal models and endpoints to warrant further development? Has the intended route of administration and formulation been defined and is it reasonable?
• Has the applicant provided convincing data that the candidate is efficacious when using the intended route of administration and formulation, at exposure levels that can likely be achieved clinically with the proposed human dosing regimen? Is the therapeutic window between the efficacious dose and the dose that leads to adverse effects sufficiently large and clinically reasonable?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this announcement:

• If the PD/PI's are proposing to perform work that could be performed by the BPN-Biologics Contract Support Network, then are the proposed expertise of the PD(s)/PI(s), collaborators, and other proposed researchers appropriate for the work they propose to conduct themselves, including process development and clinical trials? Note: the work performed by the BPN-Biologics contractors is assumed to be industry standard and not subject to review.

• Is there adequate statistical support for experimental design and data analyses?

• Is there sufficient clinical expertise to define the goals of the biotherapeutic development effort for the intended disease indication, even if the trial will be conducted by BPN-Biologics contractors?

• Does the team seem capable and sufficiently engaged to successfully complete the activities/assays/models needed to develop the therapeutic candidate?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?

Specific to this announcement:

Would the proposed biologic be expected to give significantly better clinical outcomes than have been observed in previous efforts focused on the same target?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address 1) the protection of human subjects from research risks, and 2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?

Specific to this announcement:

• Are the proposed studies appropriate, feasible, and consistent with the proposed Target Product Profile, and likely to advance the project to the desired endpoint within the proposed timeframe?
• Are proposed experimental designs and methodological approaches sufficiently rigorous to give meaningful results?

For projects entering at the Discovery Stage:

• Is the proposed biologic agent(s) suitable for optimization into a drug candidate?
• If applicable, is the plan to validate the target engagement assays at the site of action relevant to the proposed therapy development?
• For key critical experiments (such as in vivo demonstration of efficacy and target engagement with a dose response):
  • Are endpoints adequately described and is there sound rationale for the choice of endpoints, assays, and models?
  • Is there sufficient explanation for assumptions and reference to supporting data for the basis of power analyses?
  • Is the description of planned data analyses and data handling rules such as criteria for data inclusion/exclusion, replication, blinding, and randomization, appropriate?
  • Are appropriate minimal requirement(s) and assay(s) for the purity and activity of the reagents provided?
• Does the application adequately discuss feasibility and reproducibility of production of the candidate?
• Are the proposed in vivo studies and go/no-go criteria appropriate for declaring a development candidate?

For projects entering at the Development Stage:

• Is it feasible to scale up the proposed development candidate to levels required for IND-enabling studies and clinical trials?
• For applicants that propose to conduct Development work themselves, does their Development plan include all the appropriate studies for obtaining an IND? Are the timelines realistic?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

Environment

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Intellectual Property

• For Development-stage projects, has the applicant demonstrated the ability of his or her institution to develop and commercialize the proposed development candidate? Do the IP Strategy attachment and related letters of support address potential concerns? Has the applicant demonstrated that it is unlikely to be blocked or impeded by intellectual property constraints?
• If multiple institutions are proposed, is it clear how intellectual property will be shared or otherwise managed to avoid encumbering the IP, consistent with achieving the goals of the program? Are these plans acceptable?

Study Timeline

Specific to applications involving clinical trials
Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment? Is the projected timeline feasible and well justified? Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?

Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.

Resubmissions

For Resubmissions, the committee will evaluate the application as now presented, taking into consideration the responses to comments from the previous scientific review group and changes made to the project.

Renewals

Not Applicable

Revisions

For Revisions, the committee will consider the appropriateness of the proposed expansion of the scope of the project. If the Revision application relates to a specific line of investigation presented in the original application that was not recommended for approval by the committee, then the committee will consider whether the responses to comments from the previous scientific review group are adequate and whether substantial changes are clearly evident.

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Resource Sharing Plans

Reviewers will comment on whether the following Resource Sharing Plans, or the rationale for not sharing the following types of resources, are reasonable: (1) Data Sharing Plan; (2) Sharing Model Organisms; and (3) Genomic Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s), convened by NINDS, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications will receive a written critique.

Applications may undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.

Applications will be assigned on the basis of established PHS referral guidelines to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications. Following initial peer review, recommended applications will receive a second level of review by the appropriate national Advisory Council or Board. The following will be considered in making funding decisions:

• Scientific and technical merit of the proposed project as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.
• Feasibility of developing a strong intellectual property position for the project, consistent with achieving the goals of the program. The NIH will work with applicants to determine if intellectual property concerns raised by reviewers or by NIH staff can be addressed prior to program entry or within the program.
• Feasibility of conducting the work proposed within the BPN-Biologics structure.

3. Anticipated Announcement and Award Dates

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information

1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient's business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration and results reporting of all trials whether required under the law or not. For more information, see https://grants.nih.gov/policy/clinical-trials/reporting/index.htm

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see https://www.hhs.gov/civil-rights/for-providers/provider-obligations/index.html and http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html.

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

• Recipients of FFA must ensure that their programs are accessible to persons with limited English proficiency. HHS provides guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see https://www.hhs.gov/civil-rights/for-individuals/special-topics/limited-english-proficiency/fact-sheet-guidance/index.html and https://www.lep.gov. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at https://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

• Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html.

• HHS funded health and education programs must be administered in an environment free of sexual harassment. Please see https://www.hhs.gov/civil-rights/for-individuals/sex-discrimination/index.html; https://www2.ed.gov/about/offices/list/ocr/docs/shguide.html; and https://www.eeoc.gov/eeoc/publications/upload/fs-sex.pdf. For information about NIH's commitment to supporting a safe and respectful work environment, who to contact with questions or concerns, and what NIH's expectations are for institutions and the individuals supported on NIH-funded awards, please see https://grants.nih.gov/grants/policy/harassment.htm.

• Recipients of FFA must also administer their programs in compliance with applicable federal religious nondiscrimination laws and applicable federal conscience protection and associated anti-discrimination laws. Collectively, these laws prohibit exclusion, adverse treatment, coercion, or other discrimination against persons or entities on the basis of their consciences, religious beliefs, or moral convictions. Please see https://www.hhs.gov/conscience/conscience-protections/index.html and https://www.hhs.gov/conscience/religious-freedom/index.html.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at https://www.hhs.gov/ocr/about-us/contact-us/index.html or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 75 , and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

The PD(s)/PI(s) will have primary responsibility for:

• Determining experimental approaches, designing protocols, conducting experiments, and analyzing and interpreting research data for studies funded through this UG3/UH3.
• Serving as co-chair of the project Lead/Clinical Development Team (LDT/CDT).
• Presenting project updates (including raw data, when requested) in conference calls and annual face-to-face meetings of the BPN-Biologics External Oversight Committee in the Washington, DC area.
• With the LDT/CDT, assisting in the development of a project milestone plan at the outset of the project.
• Coordinating and participating with NIH staff and NIH-contracted consultants in all aspects of scientific and technical management of the project.
• Collaborating and communicating effectively with NIH service contractors to achieve project goals.
• Providing goals and strategies for assay qualification/validation and quality control, to NIH Program staff as requested.
• Ensuring that data and assay protocols developed as a part of this project are deposited in a centralized BPN-Biologics database according to the timeline agreed upon by the LDT/CDT and the NIH Program Official and according to BPN-Biologics policies.
• Adhering to BPN-Biologics policies, including those regarding data release, intellectual property, and publications.
• Implementing all scientific and policy decisions approved by the LDT/CDT and the BPN-Biologics program.
• Submitting periodic milestone progress reports in a standard format, as agreed upon by the LDT/CDT and BPN-Biologics program.
• Preparing for annual administrative site visits by NIH Program staff and consultants.
• Working closely with his/her institution's technology transfer officials to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner
• Submission of the IND application and scheduling meetings with the FDA.
• Ensuring NIH staff and consultants on the LDT are included in all meetings with the FDA.
• Providing protocol, supporting clinical documents and regulatory documents required for administrative review prior to clinical trial
• Production of publication for clinical trial

All data or materials generated under this UG3/UH3 award and through collaborations of the PD/PI with other components of the Blueprint Neurotherapeutics Network will be owned by the respective awardee and the data will be considered to be confidential and business privileged information of the awardee, which nevertheless does not affect its obligations to share or deliver the material or data with the government as set forth elsewhere in the grant agreement or regulations.

NIH staff have substantial scientific and programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

An NIH Project Collaborator will be assigned to the project, with substantial scientific and programmatic involvement that is above and beyond the normal stewardship role in awards:

• Providing the LDT/CDT with BPN-Biologics consultants who can provide strategic and technical guidance.
• Coordinating and participating in LDT/CDT meetings to discuss project status, planning, and implementation.
• With the LDT/CDT, assisting in the development of a project milestone plan at the outset of the project.
• Approving the final milestone language for incorporation into the award notice.
• Providing a perspective on the priorities of the NIH Blueprint for Neuroscience Research and BPN-Biologics.
• Facilitating collaboration and data exchange among the awardee, NIH-contracted consultants, and service providers.
• Enhancing the project progress by providing access to various NIH resources when appropriate.
• Providing technical assistance, advice, and coordination to the project, although the dominant role and responsibilities for the activities funded by the UG3/UH3 reside with the awardee.
• Coordinating reports and presentations of project progress to the BPN-Biologics External Oversight Committee.
• Coordinating review of clinical trial by internal NIH clinical and safety experts.
• Serving as scientific liaison among the awardee and other NIH program staff.
• Reporting periodically on the progress of the project to NIH leadership.

Leadership of the Institute/Center funding the project will make decisions on project continuation with input from NIH staff and the External Oversight Committee, based on:

• Successful achievement of milestones
• The overall feasibility of project advancement, considering data that may not have been captured in milestones
• Based on emerging and published literature on competition for the disease indication and biologic drug target
• Program priorities
• Availability of funds

Areas of Joint Responsibility include:

Project Lead Development Team (LDT): The LDT typically will be co-chaired by the PD/PI and an NIH-contracted drug development consultant and will include additional members from the PD/PI's group, consultants and NIH staff. This team will collaboratively set strategic direction and guide the workflow for the project on an ongoing basis. The LDT will meet approximately every two weeks via teleconference to analyze and interpret data from the PD/PI and contracted laboratories and to formulate the subsequent experimental plan. The LDT will propose milestones and produce progress reports for evaluation by the External Oversight Committee and program staff as needed.

If a clinical trial is performed, the LDT will be replaced by a Clinical Development Team (CDT), which will include the PD/PI, clinical consultants and NIH staff. The role and activities of the CDT during clinical development will be comparable to that of the LDT in earlier stages of the project.

The members of this collaborative effort are all made aware of the requirement for confidentiality due to the intent of the awardee to pursue commercialization of any qualified outcomes. Contractors and consultants of NIH will be made aware of the confidential nature of work done under this collaborative effort. The handling and disposition of this confidential data and business privileged information may be covered by the Trade Secrets Act, 18 U.S.C. Section 1905.

Dispute Resolution

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee of the External Oversight Committee chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of individual disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

Data Management and Sharing

Note: The NIH Policy for Data Management and Sharing is effective for due dates on or after January 25, 2023.

Consistent with the NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

3. Reporting

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-480-7075

Grants.gov Customer Support (Questions regarding Grants.gov registration and Workspace)
Contact Center Telephone: 800-518-4726
Email: [email protected]

Lauren Friedman, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-5065
Email: [email protected]

Kelly Sheppard, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-529-7469
Email: [email protected]

Melissa Ghim , Ph.D.
National Institute Of Dental & Craniofacial Research (NIDCR)
Phone: 301-496-7853
Email: [email protected]

Enrique Michelotti, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-5415
Email: [email protected]

Thomas N. Greenwell, Ph.D.
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: [email protected]

Neeraj Agarwal, Ph.D.
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: [email protected]

Paek Lee, Ph.D.
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: [email protected]

Qi-Ying Liu, MD, MSci
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-2678
Email: [email protected]

Jason Sousa, Ph.D.
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-5919
Email: [email protected]

Hye-Sook Kim, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-827-6910
Email: [email protected]

Tony Gover Ph.D.
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: [email protected]

Shreaya Chakroborty, Ph.D.
National Institute on Aging (NIA)
Telephone: 301-827-4019
Email: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: [email protected]

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.