Part 1. Overview Information

Key Dates

It is critical that applicants follow the SBIR/STTR (B) Instructions in the How to Apply – Application Guide, except where instructed to do otherwise (in this NOFO or in a Notice from the NIH Guide for Grants and Contracts).

Conformance to all requirements (both in the How to Apply – Application Guide and the NOFO) is required and strictly enforced. Applicants must read and follow all application instructions in the How to Apply – Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the How to Apply – Application Guide, follow the program-specific instructions.

Applications that do not comply with these instructions may be delayed or not accepted for review.

IMPORTANT: Per NOT-OD-24-086 updated application forms (FORMS-I) will be used for this opportunity. The updated forms are not yet available and will be posted 30 calendar days or more prior to the first application due date. Once posted, you will be able to access the forms using one of the following submission options:

1. NIH ASSIST
2. An institutional system-to-system (S2S) solution
3. Grants.gov Workspace

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

Blueprint Neurotherapeutics Network for Biologics (BPN Biologics)

The NIH Blueprint for Neuroscience Research is a collaborative framework through which 13 NIH Institutes, Centers, and Offices jointly support neuroscience research, with the aim of accelerating transformative discoveries for the nervous system in health, aging, and disease. For further information, see: https://neuroscienceblueprint.nih.gov.

Recent advances in biologics-based therapeutics offer unprecedented opportunities to develop new treatments for nervous/neuromuscular system disorders across multiple emerging modalities, including gene and cell therapies, oligonucleotides, and novel antibody technologies. However, biotherapeutics development has inherent complexities with regard to characterization, manufacturing, delivery, and administration and requires specialized expertise and resources.

The Blueprint Neurotherapeutics Network for Biologics (BPN Biologics) program seeks to bridge this gap by providing awarded projects with:

• Grant funding for investigator-led discovery and development activities
• In-kind access to BPN Biologics contract resource organizations (CROs) that specialize in industry-standard manufacturing, nonclinical, and early phase clinical services
• Assistance from BPN Biologics-contracted consultants with industry expertise across drug development areas and therapeutic modalities
• Project management support and milestone and strategy planning resources

The overarching goal of the program is to accelerate the development of diverse biotherapeutic modalities for the treatment of nervous and neuromuscular system disorders by advancing therapies through early clinical development. 

For more information, please visit our website at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics.

A. Overview

The purpose of this Notice of Funding Opportunity (NOFO) is to support the development of biologics-based therapies for disorders affecting the nervous and neuromuscular systems. Activities supported by this NOFO include lead optimization through first-in-human phase 1 clinical trials. Applicants may propose to use grant funding to conduct all experimental activities or collaborate with BPN Biologics CROs on activities of their choice. The PD/PI will be responsible for conducting all studies involving disease- or target-specific assays, animal models, and other research tools. 

This NOFO uses a phased, milestone driven U44 Fast-Track cooperative agreement that involves close collaboration and regular interactions with NIH program staff (see Section VI.2). All projects must have two phases and start with a U44 Phase I award. The U44 Phase I may not exceed two years. Progression from U44 Phase I to Phase II will be based on administrative review and availability of funds (see Section I.H, Milestones). Note: For this NOFO, Phase 1 clinical testing, studies, or trials refer to the common phases of a clinical trial. U44 Phase I and II refer to the project phases of the SBIR program.

As part of the cooperative agreement, a multi-disciplinary and highly collaborative “Lead Development Team” (LDT) composed of the PD/PI’s research team, NIH staff, and NIH-contracted consultants will be assembled for each project. Consultants will be selected by NIH program staff based on the specific expertise needed. The LDT will meet once every two weeks at a fixed time throughout the funding period. Relevant project staff from BPN Biologics CROs will join when appropriate. The LDT will participate in:

• Developing the overall project strategy
• Refining milestone plans and advising on appropriate go/no-go decision criteria
• Designing study plans to be conducted by BPN Biologics CROs and coordinating activities across research sites
• Regularly presenting new project-related data and troubleshooting issues as they arise

B. Scope

Projects must focus on a single nervous or neuromuscular system condition that falls within the mission of participating NIH Blueprint Institutes and Centers (see Section I.C below).

Biologics-based therapeutic agents that are within scope of this program include, but are not limited to, antibodies, peptides, proteins, oligonucleotides, gene therapies, cell therapies, and other emerging therapeutic modalities (e.g., microbial or microbiome-based).

Note: This NOFO does not support small molecules drugs (see Companion BPN Funding Opportunities PAR-24-043 and PAR-24-063). 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 NOFO.

C. Institutes and Centers (IC) Interests and Guidance

For specific IC requirements and interest statements refer, to the BPN Biologics website at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/contacts.

D. Entry Criteria

All projects will begin with a U44 Phase I award regardless of therapeutic starting point. Applicants may enter the program at either the “Discovery Stage” after one or more lead biologic agent has been identified or at the “Development Stage” once a single clinical candidate has been selected.

At minimum, all projects entering the program must have a strong body of evidence linking the putative drug target/affected pathway to the proposed disease pathophysiology and compelling data suggesting the proposed mechanism or mode of action is likely to produce desirable outcomes for the intended patient population.  

Discovery-stage entry criteria
Projects entering at this stage must have:

• One or more lead agent(s) that have been sufficiently profiled for lead optimization and require no more than two years of further optimization to select a single clinical candidate
• Preliminary target engagement data (i.e., target binding or proximal downstream effects) with lead agent(s) in a relevant animal model
• Preliminary in vivo efficacy data (e.g., histological, functional, and/or behavioral outcomes) with lead agent(s) in a disease relevant animal model
• Readily available in vitro or ex vivo assays (e.g., binding, bioactivity, selectivity) with sufficient reliability and throughput to drive lead optimization in the PD/PI’s or collaborator’s lab
• Available animal model(s) that have been sufficiently validated and characterized and are ready for dosing with the proposed lead(s) in the PI/PD or collaborator’s lab
• No obvious legal (e.g., intellectual property) constraints to pursuing the proposed biologic agent(s), using the proposed assays and models for research purposes, and/or commercial development. If patents have not been filed at this stage, it is expected that a strategy is in place for future IP filings.

Development-stage entry criteria 
Projects must have selected a single clinical candidate prior to entering the program that:

• Requires no further optimization
• Has suitable pharmacokinetics (for gene and cell therapies, this may include biodistribution/tropism) and pharmacokinetic-pharmacodynamic (PK-PD) relationship with the planned route of administration
• Demonstrated in vivo target engagement and efficacy with defined minimal and optimal doses with the intended route of administration in the relevant animal model(s)
• Is protected by granted or pending patents and is unlikely blocked or impeded by legal (e.g., intellectual property) constraints

E. Activities Supported Through This Program

U44 Phase I activities
The U44 Phase I award supports lead optimization, candidate selection, and any remaining activities required to initiate Investigational New Drug (IND)-enabling studies. The U44 Phase I award must not exceed two years. Projects entering at the Development stage are expected to complete U44 Phase I activities within one year since they are further advanced.

The following are examples of in-scope U44 Phase I activities for projects entering at the Discovery stage:

• Optimization of lead agent(s) to improve bioactivity, selectivity, and ADME (absorption, distribution, metabolism, excretion) and reduce toxicity
• Research-grade synthesis of new analogs for in vitro and in vivo testing as part of lead optimization
• Characterization of identity and properties (e.g., cell phenotype, post-translational modifications, aggregation, epitope mapping, stability)
• In vivo pharmacology (e.g., dose-range, dosing regimen, treatment duration)
• In vivo efficacy studies assessing target engagement and functional outcomes in relevant animal model(s)
• Preliminary safety and tolerability
• Initial development of bioanalytical assays to measure drug levels in nonclinical and clinical PK studies
• Initial development of pharmacodynamic biomarkers to measure target engagement or downstream drug effects in nonclinical and clinical studies

The following are examples of in-scope U44 Phase I activities for projects entering at the Development stage:

• Replication of in vivo efficacy studies in the same or different animal model (if needed)
• Remaining qualification of bioanalytical assays and pharmacodynamic biomarker assays
• Pre-formulation studies (e.g., buffer compatibility, freeze-thaw, excipient screening)
• Initial process development for drug production
• Initial development of analytical methods (i.e., potency, purity, identity, and safety testing) to monitor quality and consistency of drug substance and drug product manufacturing
• Pre-IND package preparation and pre-IND meeting

U44 Phase II activities:
The U44 Phase II award supports completion of safety and pharmacology in compliance with Good Laboratory Practices (GLP), production of material under current Good Manufacturing Practices (cGMP) in support of IND filing, and a first-in-human (FIH) clinical trial. Progression from the U44 Phase I to Phase II award will be based on administrative review of milestones progress (see section I.H, Milestones). After successful completion of the U44 Phase I award, a project may proceed to the U44 Phase II award.

The following are examples of in-scope U44 Phase II activities:

• Non-GLP toxicology studies (e.g., dose range finding toxicology)
• IND-enabling safety pharmacology and toxicology in compliance with GLP
• Biodistribution and immunogenicity in vivo studies
• Tumorigenicity evaluations, particularly for gene and cell therapies
• Master and working cell bank development
• Manufacture of the candidate therapeutic for IND
• Formulation and stability studies
• IND preparation and submission
• FIH phase 1 clinical trial

The goal by the end of the U44 Phase II award is to reach the clinical trial stage (at minimum, IND filing). Applicants are encouraged to include a FIH clinical trial if feasible within the funding period.

Clinical trial activities 
FIH clinical trials supported in the U44 Phase II may use:

• Healthy subjects or subjects from the intended patient population
• Single dose or single ascending dose protocols, which may be placebo-controlled or open-label studies
• Safety, tolerability, pharmacokinetics, pharmacodynamics, and target engagement endpoints

Applicants are strongly encouraged to contact Scientific/Research staff to ensure their proposed clinical trial plan can be supported by the program.

F. Responsible parties for proposed activities

PD/PI’s team
Applicants may propose to use grant funding to perform all or some of the U44 Phase I and II research activities at the PD/PI’s institution and/or through collaborators/CROs selected and managed by the PD/PI through a sub-award. It is expected that grant funding will be used for the following:

• All activities using target- or disease-related assays (e.g., target binding, phenotypic assays, organoids) and animal models (e.g., transgenic, knockout, pharmacologically induced)
• Assembly and submission of regulatory meeting packages and the IND application. The PD/PI’s institution will be responsible for scheduling regulatory meetings with the FDA. Assistance from NIH-contracted consultants will be available to support preparation of regulatory materials.

BPN Biologics CROs
The use of BPN Biologics CROs is optional, and the costs are covered by NIH. Applicants may propose the number and types of activities that will be conducted through BPN Biologics contractors. These activities may include:

• Nonclinical studies, including bioanalytical and pharmacodynamic biomarker assay development and qualification, pharmacokinetics, biodistribution, and safety pharmacology and toxicology under non-GLP and GLP conditions
• Chemistry, Manufacturing, and Controls (CMC) activities including small-scale synthesis, process development, analytical methods development, cell bank development, formulations development, scale-up, and cGMP manufacturing
• FIH clinical trial study planning, coordination, conduct, data handling, and reporting. As the clinical trial needs/requirements of biologics therapeutics vary, applicants are strongly encouraged to contact NIH Scientific/Research staff (listed in Section VII) to discuss the types of human subject trials currently supported by BPN Biologics clinical contractors.

Any IP developed through these activities will be assigned to the applicant’s institution.

Consultants

• All awarded projects receive support from NIH-contracted consultants at no cost to the PD/PI. Consultants are selected after award based on the project needs. Consultant areas of expertise include assay development, pharmacokinetics, toxicology, CMC, regulatory, and medical writing
• Applicants may also use grant funding for consultants selected and managed by the PD/PI who have been integral parts of the project team.

A current list of BPN Biologics contractors and consultants is available at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/resources

G. Applications Not Responsive to this NOFO

Non-responsive or incomplete applications will not be reviewed.

The following activities are considered non-responsive to this NOFO:

• Basic research and studies of disease mechanism
• Animal model development and/or validation
• Mechanistic studies for how the proposed therapeutic acts at its target
• Stand-alone preclinical efficacy studies in animal models
• Development of in vitro screening assays for activity or selectivity
• Development of small molecule therapeutics (covered by PAR-24-043 and PAR-24-063)
• Development of diagnostics and medical devices
• Development of risk, diagnostic, prognostic, predictive, and safety biomarkers
• Stand-alone clinical trials
• Studies directed beyond a first-in-human (FIH) phase 1 study (including open-label extensions, and IND-enabling nonclinical toxicology to support longer-term dosing beyond the FIH trial)
• Natural history clinical studies

H. Milestones

The awards funded under this NOFO are cooperative agreements. Clear, definitive milestones that quantitatively measure success and form the basis for go/no-go decision-making will be established in collaboration with NIH staff. Prior to funding, milestone plans will be developed by NIH staff with input from the PD/PI based on the project aims and feedback from the review process. In some cases, NIH-contracted consultants may be engaged during milestone development for additional guidance.

The final agreed upon and approved milestone plan will be incorporated into the Notice of Award. Milestones may be updated as needed with input from the LDT.

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 will be discontinued (see Section VI.2).

U44 Phase I to Phase II Transition
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). Recommendations on whether projects will advance from the U44 Phase I to Phase II award will be made based on:

• Successful achievement of U44 Phase I 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

Clinical Trial Initiation (if applicable)
NIH requires the following for approval to commence a clinical trial (defined as signing of informed consent by the first prospective subject):

• Successful achievement of the defined nonclinical and manufacturing milestones
• Submission of an IND application with documentation of 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. This may be done in collaboration with an NIH-provided CRO.
• Agreement on updated timeline and milestones for the clinical trial
• Submission of all NIH Human Subjects documentation if not using the NIH-provided CRO 

I. Intellectual Property (IP)

Since the ultimate goal of this program is to bring new biotherapeutics to the market, the program expects that recipient institutions will file and maintain any IP developed around the biotherapeutic during the project period. Institutions retain their rights to existing IP and are assigned rights to any new IP developed within the program.

The PD/PI(s) are expected to work closely with technology transfer/business development officials at their 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. Recipients are 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.

J. Quality and Compliance Requirements

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

• IND-enabling nonclinical studies must be performed in a manner consistent with GLP and current FDA guidance.
• Investigational products for use in clinical trials must be produced under cGMP practices.
• All clinical trials must be performed following Good Clinical Practices (GCP) and in accord with NIH Policy for Data and Safety Monitoring and FDA guidelines.

K. Rigor and Transparency

NIH strives for rigor and transparency in all research it funds. For this reason, this NOFO explicitly emphasizes the NIH application instructions related to rigor and transparency and provides additional guidance to the scientific community. For example, this NOFO supports applications in which the biological rationale for the proposed experiments must be based on rigorous and robust supporting data, which means that data should be collected via methods that minimize the risk of bias and be reported in a transparent manner. If previously published or preliminary studies do not meet these standards, this NOFO will support applicants that address how the current study design addresses the deficiencies in rigor and transparency. This NOFO supports proposed experiments that are designed in a manner that minimizes the risk of bias and ensures validity of experimental results.

This NOFO intends to support applications with proposed clinical trials that must be based on robust and rigorous supporting data (e.g., from nonclinical in vivo and/or in vitro studies) and that demonstrate that there is an adequate scientific foundation to justify the proposed trial. This NOFO supports trial designs that also use rigorous and transparent approaches.

L. Pre-Application Consultation

Applicants are strongly encouraged to consult with the relevant Scientific/Research staff from the relevant NIH Institutes/Centers (see Section VII) when planning an application. Early contact provides an opportunity for staff to provide further guidance on program scope, goals, and how applicants may best utilize BPN Biologics resources. Ideally, applicants should contact program staff at least 12 weeks before a receipt date.

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

Investigators proposing NIH-defined clinical trials may refer to the Research Methods Resources website for information about developing statistical methods and study designs.

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 NOFO.

Section III. Eligibility Information

1. Eligible Applicants

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

1. Is organized for profit, with a place of business located in the United States, which operates primarily within the United States or which makes a significant contribution to the United States economy through payment of taxes or use of American products, materials or labor;

2. Is in the legal form of an individual proprietorship, partnership, limited liability company, corporation, joint venture, association, trust or cooperative, except that where the form is a joint venture, there must be less than 50 percent participation by foreign business entities in the joint venture;

3.

i. SBIR and STTR. Be a concern which is more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), an Indian tribe, ANC or NHO (or a wholly owned business entity of such tribe, ANC or NHO), or any combination of these; OR

ii. SBIR-only. Be a concern which is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these. No single venture capital operating company, hedge fund, or private equity firm may own more than 50% of the concern, unless that single venture capital operating company, hedge fund, or private equity firm qualifies as a small business concern that is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States; OR

iii. SBIR and STTR. Be a joint venture in which each entity to the joint venture must meet the requirements set forth in paragraph 3 (i) or 3 (ii) of this section. A joint venture that includes one or more concerns that meet the requirements of paragraph (ii) of this section must comply with § 121.705(b) concerning registration and proposal requirements.

4. Has, including its affiliates, not more than 500 employees.

 SBIR and STTR. Be a concern which is more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), an Indian tribe, ANC or NHO (or a wholly owned business entity of such tribe, ANC or NHO), or any combination of these; OR  SBIR-only. Be a concern which is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these. No single venture capital operating company, hedge fund, or private equity firm may own more than 50% of the concern, unless that single venture capital operating company, hedge fund, or private equity firm qualifies as a small business concern that is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States; OR  SBIR and STTR. Be a joint venture in which each entity to the joint venture must meet the requirements set forth in paragraph 3 (i) or 3 (ii) of this section. A joint venture that includes one or more concerns that meet the requirements of paragraph (ii) of this section must comply with § 121.705(b) concerning registration and proposal requirements. 

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

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

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

Definitions:

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

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

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

Performance Benchmark Requirements

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

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

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

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

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

Non-domestic (non-U.S.) Entities (Foreign Organizations) are not eligible to apply.

Non-domestic (non-U.S.) components of U.S. Organizations are not eligible to apply.

Foreign components, as defined in the NIH Grants Policy Statement, may be allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply – 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. Failure to complete registrations in advance of a due date is not a valid reason for a late submission, please reference NIH Grants Policy Statement 2.3.9.2 Electronically Submitted Applications for additional information.

• 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.
  • Unique Entity Identifier (UEI) – A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• SBA Company Registry – See How to Apply – Application Guide for instructions on how to register and how to attach proof of registration to your application package. Applicants must have a UEI to complete this registration. SBA Company registration is NOT required before SAM, Grants.gov or eRA Commons registration.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; 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 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 diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019. 

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.

Under the SBIR program, for both Phase I and Phase II, the primary employment of the PD/PI must be with the small business concern at the time of award and during the conduct of the proposed project. For projects with multiple PDs/PIs, at least one must meet the primary employment requirement. Occasionally, deviations from this requirement may occur.
 

For the STTR program, the PD(s)/PI(s) may be employed with the SBC or the single, “partnering” non-profit research institution as long as s/he has a formal appointment with or commitment to the applicant SBC, which is characterized by an official relationship between the SBC and that individual. Such a relationship does not necessarily involve a salary or other form of remuneration The primary employment of the PD/PI must be with the SBC or the Research Institution (where they are PD/PI at) at the time of award and during the conduct of the proposed project. Each PD/PI must commit a minimum of 10% effort to the project.

The How to Apply – Application Guide should be referenced for specific details on eligibility requirements. For institutions/organizations proposing multiple PDs/PIs, see Multiple Principal Investigators section of the How to Apply – Application Guide.

2. Cost Sharing

This NOFO does not require cost sharing as defined in the NIH Grants Policy Statement Section 1.2 Definition of Terms.

3. Additional Information on Eligibility

Number of Applications

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

NIH will not accept similar grant applications with essentially the same research focus from the same applicant organization. This includes derivative or multiple applications that propose to develop a single product, or service that, with non-substantive modifications, can be applied to a variety of purposes. Applicants may not simultaneously submit identical/essentially identical applications under both this funding opportunity and any other HHS funding opportunity, including the SBIR and STTR Parent announcements.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. NIH Grants Policy Statement 2.3.7.4 Submission of Resubmission Application. 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 NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

A Phase I recipient  may submit a Phase II application either before or after expiration of the Phase I budget period, unless the recipient  elects to submit a Phase I and Phase II application concurrently under the Fast-Track procedure. To maintain eligibility to seek Phase II or IIB support, a Phase I recipient should submit a Phase II application, and a Phase II recipientshould submit a Phase IIB application, within the first six due dates following the expiration of the Phase I or II budget period, respectively. Recipients of Phase I and Phase II grants, cooperative agreements, or contracts are eligible to submit Phase II and Phase IIB grant applications, respectively, for this opportunity in accordance with each awarding component's guidance in the current SBIR/STTR Program Descriptions and Research Topics for the NIH, CDC and FDA.

Specific to this NOFO: Please note, the percentages listed below only refer to activities to be covered by grant funding and do not include BPN Biologics CROs. Costs for BPN CRO activities are not included in the calculations for the research or analytical effort carried out by the small business concern. 

In Phase I, normally, two-thirds or 67% of the research or analytical effort is carried out by the small business concern. The total amount of all consultant and contractual arrangements to third parties for portions of the scientific and technical effort is generally not more than 33% of the total amount requested (direct, F&A/indirect, and fee).

In Phase II, normally, one-half or 50% of the research or analytical effort is carried out by the small business concern. The total amount of consultant and contractual arrangements to third parties for portions of the scientific and technical effort is generally not more than 50% of the total Phase II amount requested (direct, F&A/indirect, and fee).

We encourage you to contact a program officer listed in Section VII with questions about this because occasionally, deviations from these requirements may occur, and must be approved in writing by the funding agreement officer after consultation with the agency SBIR Program Manager/Coordinator. In Phase I and Phase II, at least 40% of the research or analytical effort must be performed by the small business concern and at least 30% of the research or analytical effort must be performed by the single, “partnering” research institution. The basis for determining the percentage of work to be performed by each of the cooperative parties will be the total of direct, F&A/indirect costs, and fee attributable to each party, unless otherwise described and justified in “Consortium/Contractual Arrangements” of the PHS 398 Research Plan component of the SF424 (R&R) application forms.

A small business concern may subcontract a portion of its SBIR or STTR award to a Federal laboratory within the limits above.  A Federal laboratory, as defined in 15 U.S.C. § 3703, means any laboratory, any federally funded research and development center, or any center established under 15 U.S.C. §§ 3705 & 3707 that is owned, leased, or otherwise used by a Federal agency and funded by the Federal Government, whether operated by the Government or by a contractor.

The basis for determining the percentage of work to be performed by each of the cooperative parties in Phase I or Phase II will be the total of the requested costs attributable to each party, unless otherwise described and justified in “Consortium/Contractual Arrangements” of the PHS 398 Research Plan component of SF424 (R&R) application forms.

Additional details are contained in the SF424 (R&R) SBIR/STTR Application Guide.

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 NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the SBIR/STTR (B) Instructions in the How to Apply – Application Guide, except where instructed in this notice of funding opportunity to do otherwise. Conformance to the requirements in the How to Apply – Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

• Descriptive title of proposed activity
• Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
• Names of other key personnel
• Participating institution(s)
• Number and title of this funding opportunity

The letter of intent should be sent to:

Lauren Friedman, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-5065
Email: lauren.friedman@nih.gov

All page limitations described in the How to Apply – Application Guide and the Table of Page Limits must be followed.

The following section supplements the instructions found in the How to Apply – Application Guide and should be used for preparing an application to this NOFO.

All instructions in the How to Apply – Application Guide must be followed.

All instructions in the How to Apply – Application Guide must be followed.

All instructions in the How to Apply – Application Guide must be followed with the following additional instructions:

Other Attachments:

1. SBIR Application Certification for small business concerns majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms

Applicant small business concerns that are majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms (e.g. majority VCOC-owned) are required to submit a Certification at time of their application submission per the SBIR Policy Directive.  Follow the instructions below. 

Applicants small business concerns who are more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), or any combination of these (i.e. NOT majority VCOC-owned) should NOT fill out this certification and should NOT attach it to their application package.

1. Download the “VCOC Certification.pdf” at the NIH SBIR Forms webpage. 

2. Answer the 3 questions and check the certification boxes.

3. The authorized business official must sign the certification.

4. Save the certification using the original file name.  The file must be named “SBIR Application VCOC Certification.pdf”.  DO NOT CHANGE OR ALTER THE FILE NAME.  Changing the file name may cause delays in the processing of your application.

5. When you are completing the application package, attach this certification as a separate file by clicking "Add Attachments" located to the right of Other Attachments field on the “Research and Related Other Project Information” form.

Gantt Chart (Required 1 page max)

Applications that do not include this attachment or that exceed the page limit will be withdrawn. This attachment should be entitled “Gantt.pdf”. Applicants must include a project timeline in the form of a Gantt chart that shows key activities proposed during the funding period, including both U44 Phase I and Phase II. Suggested Gantt format can be found at: http://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/resources.

Applicants must clearly indicate within the chart which activities will be conducted by the PD/PI and associated personnel (i.e., funded by the U44 award through a sub-award) and which activities will be conducted by BPN Biologics CROs.

Intellectual Property (IP) Strategy (Required 2 pages max)

Applications that do not include this attachment or that exceed the page limit will be withdrawn. This attachment should be entitled “IP Strategy.pdf”. Applicants are encouraged to prepare this section in consultation with their institution’s technology transfer officials, if applicable.

Applicants should describe any known constraints that could block or impede (1) therapeutic development including use of therapeutic agents (e.g. capsids), assays, or models for research purposes and/or (2) commercialization of the proposed agent(s), (e.g., certain restrictions under transfer or sharing agreements, applicant’s previous or present IP filings and publications, similar therapies that are under patent and/or on the market, etc.) and how these issues would be addressed.

Applicants should list all patents, granted or pending, related to the proposed project and include the filing dates, type of patent, and application status. If patents for the proposed technology have not been filed, applicants should also describe plans for future IP filings.

Applicants should describe the existing or planned infrastructure to support bringing technologies to application (e.g., filing and managing IP, licensing, and commercialization). For a multiple-PD/PI, multiple-institution application, applicants should describe how IP will be shared or otherwise managed, the infrastructure to support those activities, and coordinating these efforts (e.g., licensing, managing IP) among the institutions.

All instructions in the How to Apply – Application Guide must be followed.

All instructions in the How to Apply – Application Guide must be followed.

The application must include a budget for each year of the proposed project, including both the U44 Phase I and Phase II awards with appropriate justification. The budget should include all studies to be conducted by the PD/PI’s lab and by collaborators/CROs selected and managed by the PD/PI. Budgets may include institution costs associated with assembling and filing regulatory documents, including pre-IND meeting packages and the IND application.

The U44 budget should not include support for activities proposed to be conducted through BPN Biologics CROs.

The PD/PI must 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 with NIH staff about their anticipated budget in the early stages of preparing an application.

Equipment requests are allowed but not encouraged. Equipment requests should be considered only if necessary to the success of the project, cannot be supported by any other means, and is fully allocated to the project. This is likely to be a subject of negotiation before an award is made.

All instructions in the How to Apply – Application Guide must be followed.

All instructions in the How to Apply – Application Guide must be followed.

SBIR/STTR Information Form

All instructions in the How to Apply – Application Guide must be followed.

Specific Aims: 

The single Specific Aims attachment must include Aims delineated for both U44 Phase I and Phase II. All applications must include an aim for IND preparation and filing in the U44 Phase 2.  If a first-in-human (FIH) clinical trial is proposed, define the aims of the clinical study.

Research Strategy: 

The single Research Strategy attachment must include the following subsections:

A. Clinical Impact (Significance): 
Each application must only focus on a single neurological or neuromuscular disorder or disease, even if the proposed therapeutic agent is relevant for more than one.

• Briefly describe the current state of knowledge of the proposed disease etiology, clinical characteristics, and prevalence.
• Briefly discuss the unmet medical need by outlining available treatments (across all treatment modalities) and their limitations.
• Briefly describe current therapeutic development efforts in academia and industry for the intended patient population and how this relates to the proposed therapeutic approach.
• Provide a Target Product Profile (TPP) table that summarizes the minimal / ideal attributes for the eventual final marketed product. The TPP is intended to show the ultimate goals of the proposed drug development effort. Parameters include disease indication, patient population, delivery mode, dosage form, treatment duration and regimen, and standards for clinical efficacy. TPP examples can be found at: https://neuroscienceblueprint.nih.gov/sites/default/files/documents/Example_TPP_508C.pdf. Applications that fail to include a TPP will be considered incomplete.
• Briefly comment on the feasibility of conducting clinical trials in the target patient population (e.g., availability of patients for recruitment into clinical trials).
• Briefly describe possible clinical trial endpoints for efficacy and indicate if biomarkers are currently available or in development to measure target engagement in humans.
• Describe the group clinical expertise used to determine the goals of the biotherapeutic development program and clinical trial.

B. Biological Rationale and Therapeutic Agent Profile (Significance):
Note: Data presented from animal model studies to justify the choice of therapeutic target, support the drug candidate, and/or to determine efficacy must be in compliance with NIH guidance on rigor and reproducibility. Descriptions of supporting animal studies must include animal model(s), controls, group numbers (n), statistical analyses, and, if an intervention was administered, dose level, treatment duration and frequency, and delivery route.  

• Summarize the evidence from cellular or animal models and clinical studies linking the putative drug target or pathway to the proposed disease indication.
• Provide evidence that altering the putative target/pathway activity as proposed will give desirable outcomes for the proposed disease indication.
• Provide a Therapeutic Agent Profile Table that summarizes the known characteristics of the proposed lead(s) or candidate agent(s) (e.g., structure/identity, special formulation details (e.g., liposomes), in vitro activity/selectivity, in vivo activity/distribution/exposure, safety/tolerability). Note any potential liabilities. Example tables can be found at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/resources. Applications that fail to include a Therapeutic Agent Profile Table will be considered incomplete.
• Specify whether the project is proposed for entry at the Discovery or Development stage (refer to Section I.C).
• Present evidence that the proposed agent(s) meet the entry requirements (in Section I.C).
• For Discovery stage projects, show that the lead agent(s) proposed as the starting point for optimization engages the putative target (e.g., target binding or proximal downstream effects) and produces desired outcomes (e.g., histological, function, behavioral) in relevant disease model(s).
• For Development stage projects:
  • Show the candidate has suitable PK (for gene and cell therapies, this may include biodistribution/tropism), PK-PD relationship, and preliminary safety/tolerability with the planned route of administration and how these data support the clinical dosing regimen proposed in the TPP. Provide rigorous evidence that the agent is blood-brain-barrier penetrant, unless the agent is proposed to be delivered directly to the central nervous system or is intended to act in peripheral tissue (e.g., muscle).
  • Present data showing the minimal and optimal effective doses with target engagement and clinically relevant functional and/or histological outcome measures when delivered by the clinically intended route of administration and dosing regimen, and if applicable with special formulation (e.g., liposomes, nanoparticles, slow release).
  • Discuss the clinical relevance of the preclinical outcome measures and observed effect size.

C. Innovation:

• Comment on the novelty of proposed therapeutic approach, biological target/pathway, assays, or models.
• Describe how the proposed therapeutic is expected to result in improved clinical outcomes, such as efficacy, safety, and/or reduced patient burden (e.g., improved side effects profile, less invasive route of administration, reduced dosing frequency), compared with available treatments or therapeutics currently in clinical development for the intended patient population.
• Describe what differentiates the proposed therapeutic from similar agents, in development and/or marketed, for the same disease indication and/or drug target.

D. Approach: 
Please see Section I.E for guidance on entry stage and U44 award phase-appropriate activities.

• For all research activities, clearly indicate which will be conducted with grant funding (under the direction of the PD/PI) or by BPN Biologics CROs.
  • For PD/PI-led activities, including those conducted by sub-awarded collaborators/CROs), applicants must describe detailed experimental designs and justifications in the text for all studies covered by grant funding.
  • For BPN Biologics CRO activities, applicants should describe activities and expected deliverables at a high level. Detailed study designs for BPN CRO activities should not be included in the application. These studies will be designed in collaboration with NIH staff and consultants after award.
• Demonstrate project readiness for assays, models, and research tools if they will be used as part of the proposed Aims, specifically:
  • Include assay validation data for in vitro or ex vivo bioactivity assays that are proposed to drive lead optimization. This should include metrics of robustness (such as Z' score, batch-to-batch variability, etc.) and throughput that is sufficient for the intended use.
  • Provide evidence that the proposed animal model(s) is well-validated and reflective of the human condition.
• For projects entering at the Discovery stage, include a Testing Funnel as a figure that lists all in vitro and in vivo assays proposed to down-select leads to nominate a clinical candidate within the U44 Phase I award (up to two years). Example testing funnels can be found at: https://neuroscienceblueprint.nih.gov/neurotherapeutics/bpn-biologics/resources.
  • Show how proposed assays will be ordered and grouped into testing tiers, indicating which parameters (e.g., binding, activity, selectivity, cellular uptake, transduction efficiency, distribution, clearance, dose-response) will be optimized. 
  • Include proposed quantitative criteria for advancement at each step.  Note: Advancement criteria will be finalized with input from the Lead Development Team after award.
• For projects entering at the Development stage, describe the remaining activities (e.g., qualification of bioanalytical assays, initial process development) to be performed during the U44 Phase I award that are required to commence IND-enabling activities. Note: Projects entering at this stage are expected to complete U44 Phase I within one year since they are further advanced.
• For in vivo efficacy studies proposed in relevant disease model(s):
  • Provide details on the study design, including animal model(s), controls, group numbers (n), dosing (route of administration, treatment duration, dose level), and outcomes as well as 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 for candidate selection)
  • Study descriptions must be in compliance with NIH guidance on rigor and reproducibility.
  • It is expected that these activities will be performed by the PI/PD or through grant subawards
• If applicable, describe plans to develop and qualify bioanalytical assays (e.g., to measure drug levels in nonclinical and clinical PK studies) and pharmacodynamic biomarkers (e.g., to measure target engagement or downstream drug effects in nonclinical and clinical studies) 
• Describe plans for manufacturing material for IND-enabling activities, including process development, scale-up, formulation, and analytical methods development to evaluate potency, purity, identity, and safety of the drug substance and drug product. If this will be done through BPN Biologics CROs, this description can be high-level.
• Describe plans for conducting non-GLP and GLP nonclinical studies including IND-enabling toxicology and safety pharmacology, tumorigenicity, immunogenicity, and biodistribution as needed. If this will be done through BPN Biologics CROs, this description can be high-level.
• If a FIH clinical trial is proposed during the funding period:
  • Provide a brief description of the clinical trial plan, including study population and estimated group numbers, type of design (e.g., single ascending dose, randomized or open-label), expected dosing (including route of administration and frequency), and main outcomes (e.g., safety, PK/PD). We anticipate the details of the trial are likely to change during therapeutic development. If this will be done through BPN Biologics CROs, this description can be high-level.

Letters of Support:

Applicants must include letters of support from consultants, contractors, and collaborators not provided through NIH.

• If collaborating with other institutions, include a letter of support from each sub-awarded organization that clarifies how IP will be shared or otherwise managed across institutions, to ensure IP remains unencumbered, consistent with achieving the goals of the program. 
• If collaborating with a private entity, include a letter of support that addresses any agreement to provide agent(s), any limits on the studies that can be performed with said agent(s), and whether a licensing agreement(s) will be needed and in place once the project is funded. This letter must come from a high official within the private entity who has authority to speak on these issues.

Resource Sharing Plans:

Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the How to Apply – Application Guide.

Other Plan(s)

All instructions in the How to Apply – Application Guide must be followed, with the following additional instructions:

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

Appendix:

Note that Phase I SBIR/STTR Appendix materials are not permitted.  Only limited items are allowed in the Appendix of other small business applications.  The instructions for the Appendix of the Research Plan are described in the How to Apply – Application Guide; any instructions provided here are in addition to the How to Apply – Application Guide Instructions.

The following modifications apply (if applicable):

Applicants who have held meetings with the FDA related to the proposed project must include a summary of the meeting outcomes, agreements, disagreements, and action items in a single Appendix document (2-page maximum). This includes pre-IND meetings and INitial Targeted Engagement for Regulatory Advice on CBER producTs (INTERACT) meetings.

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

When involving human subjects research, clinical research, and/or NIH-defined clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the How to Apply - 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 How to Apply - Application Guide must be followed.

Note: For this NOFO, only answer “Yes” to the question “Are Human Subjects Involved?” in the R&R Other Project Information form if human subjects work is proposed and will be conducted with grant funds. Answer “No” if proposing to use BPN Biologics contractors to conduct human subjects research. If a first-in-human trial is proposed, please code your application as “Delayed Onset”.
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.

Delayed Onset Study

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 How to Apply - Application Guide must be followed.

All instructions in the How to Apply - Application Guide must be followed.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 2. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. contains information about Key Dates and time. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

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 How to Apply – Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the Section 7.9.1 Selected Items of Cost.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the How to Apply - 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 form. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH.

The applicant organization must ensure that the unique entity identifier provided on the application is the same identifier used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the How to Apply - 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.

Recipients or subrecipients must submit any information related to violations of federal criminal law involving fraud, bribery, or gratuity violations potentially affecting the federal award. See Mandatory Disclosures, 2 CFR 200.113 and NIH Grants Policy Statement Section 4.1.35.

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at grantdisclosures@oig.hhs.gov. 

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

If FDA meetings have been held in the intervening time between application submission and review, applicants should submit a summary of meeting interactions as described in see Section IV. Appendix. 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

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 NOFO, note the following:

• All projects must start with a U44 Phase I award, but may enter the program at either the “Discovery stage” with lead(s) that require further optimization or at the “Development stage” once a clinical candidate has been selected. Regardless of starting point, U44 Phase I provides recipients up to two years to de-risk the project by completing remaining activities required to start IND-enabling studies and GMP manufacturing, which are supported during the U44 Phase II award. 
• Projects entering at the Discovery stage, which have less data and more unknowns, are inherently more risky than those entering at the Development stage; therefore, projects should be evaluated relative to expectations for their proposed entry stage. Note: Risks will be managed through the establishment of milestones by NIH staff pre- and post-award, close interactions with NIH staff as part of the cooperative agreement, and regular meetings with the Lead Development Team, which is composed of the PD/PI’s research team, NIH staff, and NIH-contracted consultants.
• Evaluation of the project should focus on the unmet medical need, potential patient benefit, competitive landscape (novelty), biological rationale, the potential for identifying and/or advancing a safe and effective clinical candidate, and strengths/weaknesses of the proposed PD/PI-directed studies to be conducted with grant funding.
• Reviewers should evaluate study plans for all PD/PI-led activities (including those to be conducted by sub-awarded collaborators/CROs); however, activities to be conducted by BPN Biologics CROs (which may include bioanalytical and pharmacodynamic biomarker assay development, pharmacokinetics, toxicology, manufacturing, and first-in-human clinical testing) do not need to be described in detail in the application or included in the budget. These studies will be designed in collaboration with NIH staff and consultants after award.
• Note: The market size for the proposed biotherapeutic should not be considered in assessing the significance of a project.

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 as appropriate for the stage of research, 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 and commercial impact. For example, a project that by its nature is not innovative may be essential to advance a field.

Significance

Does the project and proposed product or service address an important problem, a critical barrier to progress, or unmet need 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 and commercialization of the resulting product or service change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the proposed project have commercial potential to lead to a marketable product, process or service? (In the case of Phase II, Fast-Track, and Phase II Competing Renewals, does the Commercialization Plan demonstrate a high probability of commercialization? How strong is the described market opportunity in the Commercialization Plan including: (i) the product or service being developed; (ii) target customers; and (iii) how the product will solve a demonstrated customer need?

For a Phase I, does the proposed project have commercial potential to lead to a marketable product or service? 

For Phase II (all types) and Fast-Track applications, does the Commercialization Plan demonstrate a high probability of commercialization? How strong is the described market opportunity in the Commercialization Plan including: (i) the product or service being developed; (ii) target customers; and (iii) how the product or service will solve a demonstrated customer need?)   

Specific to this NOFO:

• How well do the expected goals in the applicant’s Target Product Profile (TPP) align with clinical practice for the intended disease indication?
• 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 strong are the data supporting the biological rationale for the putative target/pathway for the proposed disease indication?
• For projects entering at the Discovery stage, how strong are the in vitro and in vivo data supporting the proposed lead(s) as starting point(s) for optimization?
• For projects entering at the Development stage, does the applicant have a well-profiled and fully optimized candidate with regards to in vitro and in vivo activity, PK, PK-PD relationship, and preliminary safety/tolerability that is appropriate for the intended clinical use?

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 the proposed product or service?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project and will they provide a meaningful contribution to successfully complete the proposed aims? Do the PD(s)/PI(s) have appropriate experience and training to lead this project? If so, have they demonstrated an ongoing record of accomplishments in 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? For projects in later stages, does the team have expertise to commercialize the product  or service?

Specific to this NOFO:

• If the PD/PI(s) are proposing to perform work that otherwise could be conducted by BPN Biologics CROs, does the investigator’s team (including collaborators/CROs supported by grant funding) have the appropriate expertise to support those studies? Note: the work performed by the BPN Biologics CROs is assumed to be industry standard and not subject to review.
• Is the PD/PI's leadership experience suitable to manage the activities across research sites in collaboration and regular interaction with NIH staff and NIH-contracted consultants?

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

How does the proposed product or service represent an innovative solution to important problem, barrier to progress, or unmet need in research or clinical practice? Does the product or service proposed in application challenge and seek to shift current research or clinical practice paradigms? What meaningful competitive advantages does the end product or service proposed offer over existing approaches, instrumentation, or interventions or those in development?

For Phase II (all types) and Fast-Track applications, does the small business present a reasonable plan to create a temporal barrier against other companies aiming to provide a similar solution, including protecting the intellectual property relevant to the product or service being studied or used during the project?

Specific to this NOFO:

• How significant of an advantage does the proposed therapeutic offer in terms of improved clinical outcomes (e.g., efficacy, safety, reduced patient burden) over those observed with available treatments or therapeutics currently in clinical development for the intended patient population?

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 research aims appropriate for the current stage of development? Do the aims represent the necessary steps to further advance the development of the product or service? Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included any 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?

For Phase I applications, will the strategy establish feasibility, and will particularly risky aspects be managed? Are there clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II?

For Fast-Track applications, Are there clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II? Will successful completion of the research aims significantly advance development of the proposed product or service toward eventual commercialization?

For Phase II (all types) applications, will successful completion of the research aims significantly advance development of the proposed product or service toward eventual commercialization? How well does the application demonstrate progress toward meeting the Phase I (or equivalent) objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity?

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 NOFO:

• For projects entering at the Discovery stage:
  • Is the proposed biologic agent(s) a suitable starting point for optimization into a drug candidate within two years? Note: projects are expected to complete optimization activities and identify a clinical candidate by the end of U44 Phase I, which may not exceed two years.
  • Are the in vitro and in vivo assays suitable and the proposed advancement criteria appropriate to down-select leads and declare a clinical candidate? How well does this relate to the desired drug properties presented in the Target Product Profile? Note: Advancement criteria will be finalized with input from the Lead Development Team after award.
  • How strong are the bioactivity assay validation data to support its use in driving lead optimization?
• For projects entering at the Development stage:
  • Do the proposed U44 Phase I activities address the remaining deficiencies (e.g., qualification of bioanalytical assays, initial process development) in a rigorous and complete way to enable entering IND-enabling studies in U44 Phase II? Note: Projects entering at this stage are expected to complete U44 Phase I activities within one year since they are further advanced.
• For applicants proposing to conduct IND-enabling nonclinical and/or manufacturing activities with grant funding, does their plan include all the appropriate studies for IND submission and 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 and business environment in which the work will be done contribute to the probability of success and eventual commercialization? Are the small business 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 arrangement?

For Phase I applications, does the small business concern have appropriate business expertise and resources, or have they identified appropriate business resources, to accomplish the aims of this project and support commercialization of the proposed product or service?

For Phase II (all types) or Fast-Track applications, does the applicant have access to the business experts and resources needed to accomplish the aims of this project and to commercialize the proposed product or service?

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?

Specific to this NOFO:

• Intellectual Property (IP):
  • Are potential issues regarding the IP landscape for the proposed biotherapeutic and means for addressing any IP hurdles/barriers addressed in the application? Do the IP Strategy attachment and related letters of support address potential concerns?
  • Are there known constraints that could impede development of the biotherapeutic?
  • Are IP filing plans appropriate for the current stage of development?
  • If multiple institutions/companies are involved, is IP sharing adequately addressed?

Commercialization Plan (Phase II and Fast-Track Only)

For Phase II (all types) and Fast-Track applications, reviewers will consider the following:

How well does the application present the market opportunity, including market segments, that its product or technology will address? Does the applicant understand the barriers to commercialization of its product or service (e.g., regulatory approval, insurance reimbursement, competitive products, customer preferences)? Does the application have appropriate strategies to address these barriers?

Does the application provide appropriate post-SBIR product development and commercialization milestones and explain how these milestones will be achieved? Does the application present a plan for funding the development and commercialization of the product or service? If applicable, did the applicant obtain letters of interest or commitment for such funding and/or resources?

Are the executives, management team, and business experts well suited to advance the development and commercialization of the proposed product or service? If not, is there a plan in place to add the necessary expertise as the product advances towards commercialization?

Is there a sound strategy for driving product adoption and generating revenue from the product or service (e.g., product sales, licensing, partnerships)?

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 three points: (1) a complete description of all proposed procedures including the species, strains, ages, sex, and total numbers of animals to be used; (2) justifications that the species is appropriate for the proposed research and why the research goals cannot be accomplished using an alternative non-animal model; and (3) interventions including analgesia, anesthesia, sedation, palliative care, and humane endpoints that will be used to limit any unavoidable discomfort, distress, pain and injury in the conduct of scientifically valuable research. Methods of euthanasia and justification for selected methods, if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals, is also required but is found in a separate section of the application. For additional information on review of the Vertebrate Animals Section, please refer to the Worksheet for Review of the Vertebrate Animals 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.

Phase IIB Competing 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 with Foreign Components

Reviewers will consider whether work to be performed outside of the United States is thoroughly justified, based on a rare and unique circumstance, and necessary to the overall completion of the project.

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 Resource Sharing Plan(s) (e.g., Sharing Model Organisms) or the rationale for not sharing the resources, is reasonable.

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.

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 and within the proposed time frame
• Security risk as assessed by the HHS Due Diligence Program.

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 Section 2.5.1. Just-in-Time Procedures. This request is not a Notice of Award nor should it be construed to be an indicator of possible funding.

Prior to making an award, NIH reviews an applicant’s federal award history in SAM.gov to ensure sound business practices. An applicant can review and comment on any information in the Responsibility/Qualification records available in SAM.gov.  NIH will consider any comments by the applicant in the Responsibility/Qualification records in SAM.gov to ascertain the applicant’s integrity, business ethics, and performance record of managing Federal awards per 2 CFR Part 200.206 “Federal awarding agency review of risk posed by applicants.”  This provision will apply to all NIH grants and cooperative agreements except fellowships.

Disclosure Requirements Regarding Ties to Foreign Countries

SBIR and STTR applicants under consideration for award will be required to submit the U.S. Small Business Administration (SBA) Required Disclosures of Foreign Affiliations or Relationships to Foreign Countries form (referred to as the "Disclosure Form" hereafter), during the JIT process.  Applicants are required to disclose all funded and unfunded relationships with foreign countries, using the Disclosure Form, for all owners and covered individuals. A “covered individual” is defined as all senior key personnel identified by the SBC in the application (i.e., individuals who contribute to the scientific development or execution of a project in a substantive, measurable way). 

Upon request, applicants must submit the completed Disclosure Form and any additional agency-specific information electronically in eRA Commons via the Just-In-Time (JIT) process as described in the NIH Grants Policy Statement Section 2.5.1. Applicants must continue to comply with NIH Other Support disclosure requirements as provided in NIH GPS Section 2.5.1 and may be required to provide similar information on the Disclosure Form for covered individuals identified in the application. Applicants that fail to submit a completed Disclosure Form during the JIT process will not be considered for funding. If participating in this NOFO, SBC applicants applying to CDC and FDA will follow each agency’s policies for submitting additional documents during the pre-award process. 

Denial of Awards

Applicants are encouraged to consider whether their entity’s relationships with foreign countries of concern will pose a security risk. Prior to issuing an award, NIH, CDC, and FDA will determine whether the SBC submitting the application:

• has an owner or covered individual that is party to a malign foreign talent recruitment program;
• has a business entity, parent company, or subsidiary located in the People’s Republic of China or another foreign country of concern; or
• has an owner or covered individual that has a foreign affiliation with a research institution located in the People’s Republic of China or another foreign country of concern.

A finding of foreign involvement with countries of concern will not necessarily disqualify an applicant. Final award determinations will be based on the above finding of foreign involvement and whether the applicant’s involvement falls within any of the following risk criteria, per the Act:

• interfere with the capacity for activities supported by NIH, CDC, or FDA to be carried out;
• create duplication with activities supported by NIH, CDC, or FDA;
• present concerns about conflicts of interest;
• were not appropriately disclosed to NIH, CDC, or FDA;
• violate Federal law or terms and conditions of NIH, CDC, or FDA; or
• pose a risk to national security.

Generally, NIH, CDC, and FDA will not provide SBC applicants the opportunity to address any identified security risks prior to award. NIH, CDC, and FDA will not issue an award under the SBIR/STTR program if the covered relationship with a foreign country of concern identified in this guidance is determined to fall under any of the criteria provided.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access their Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement Section 2.4.4 Disposition of Applications.

Section VI. Award Administration Information

1. Award Notices

A Notice of Award (NoA) is the official authorizing document notifying the applicant that an award has been made and that funds may be requested from the designated HHS payment system or office. The NoA is signed by the Grants Management Officer and emailed to the recipient’s business official.

In accepting the award, the recipient agrees that any activities under the award are subject to all provisions currently in effect or implemented during the period of the award, other Department regulations and policies in effect at the time of the award, and applicable statutory provisions.

Recipients must comply with any funding restrictions described in Section IV.6. Funding Restrictions. Any pre-award costs incurred before receipt of the NoA are at the applicant's own risk.  For more information on the Notice of Award, please refer to the NIH Grants Policy Statement Section 5. The Notice of Award and NIH Grants & Funding website, see Award Process.

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 recipient 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

The following Federal wide and HHS-specific policy requirements apply to awards funded through NIH:

• The rules listed at 2 CFR Part 200, Uniform Administrative Requirements, Cost Principles, and Audit Requirements for Federal Awards.
• All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the terms and conditions in the Notice of Award (NoA). The NoA includes the requirements of this NOFO. 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. 
• If a recipient receives an award, the recipient must follow all applicable nondiscrimination laws. The recipient agrees to this when registering in SAM.gov. The recipient must also submit an Assurance of Compliance (HHS-690). To learn more, see the Laws and Regulations Enforced by the HHS Office for Civil Rights website.
  • HHS recognizes that NIH 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 NOFO.

All federal statutes and regulations relevant to federal financial assistance, including those highlighted in NIH Grants Policy Statement Section 4 Public Policy Requirements, Objectives and Other Appropriation Mandates.

Recipients are responsible for ensuring that their activities comply with all applicable federal regulations.  NIH may terminate awards under certain circumstances. See 2 CFR Part 200.340 Termination and NIH Grants Policy Statement Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support. 

The Office of Inspector General Hotline accepts tips from all sources about potential fraud, waste, abuse and mismanagement in Department of Health & Human Services programs. The reporting individual should indicate that the fraud, waste and/or abuse concerns an SBIR/STTR grant or contract, if relevant. Report Fraud.

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 (HHS) grant administration regulations at  2 CFR Part 200, 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 recipients 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 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 recipients for the project as a whole, although specific tasks and activities may be shared among the recipients and NIH as defined below.

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

• Defining objectives and approaches, and planning, conducting, analyzing, interpreting, and drawing conclusions on the studies funded through this U44 award
• Serving as co-chair and actively participating in bi-weekly, virtual meetings with the project’s Lead Development Team (LDT) comprised of the PD/PI’s research team, NIH staff, and NIH-contracted consultants
• Collaborating with NIH staff in developing and refining rigorous milestones that will be achieved during the project period
• Regularly presenting project updates (including preliminary data, study plans, troubleshooting) at LDT meetings or assigning presentations to the PD/PI’s research team
• Collaborating and communicating effectively with NIH staff to coordinate studies with BPN Biologics CROs to achieve project goals
• Ensuring that all project-related data, study designs, and protocols are deposited in a centralized, secure BPN Biologics database according to the timeline agreed upon by the LDT
• Presenting annual milestone updates to the External Oversight Committee
• Providing progress reports and milestone updates with a completeness that includes experimental design with rigor, including assumptions for the study designs, the results of the investigations, interpretations of the results, and for concluding whether milestones have been achieved. In cases when NIH program staff request raw data, recipients agree to provide the data
• 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
• Submitting regulatory meeting packages and the IND application and scheduling meetings with the FDA
• Communicating regulatory meeting dates and agenda to the NIH program staff and LDT members and invite their participation
• Providing protocol, clinical, and regulatory documents required for administrative review prior to clinical trial initiation
• Preparing for occasional in-person visits to the PD/PI’s site, if and when needed, by NIH Program staff and consultants
• Retaining custody of and having all rights to the data and technology developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies

All data or materials generated under this U44 award and through collaborations between the PD/PI with other components of the BPN Biologics program will be owned by the respective recipient. Data will be considered to be confidential and business privileged information of the recipient, 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 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 and may have substantial programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination above and beyond the levels required normally for program stewardship of grants, and will be responsible for:
  • Assigning BPN Biologics consultants to the LDT who can provide relevant strategic and technical guidance
  • Coordinating and participating in LDT meetings
  • Assisting in the development of a project milestone plan in collaboration with the LDT at the outset of the project
  • Serving as scientific liaison among the recipient and other NIH program staff
  • Facilitating collaboration and data exchange between the recipient, NIH-contracted consultants, and BPN Biologics CROs
  • Coordinating reports and presentations of project progress to the External Oversight Committee
  • Reporting periodically on the progress of the project to NIH leadership
  • With the NIH Contracting Officer and CO Representative, handle processing, award, and management of all BPN Biologic CROs contracts
• Each project will have the support of one or more NIH staff from the funding Institute/Center, who are consulted based on their expertise in the disorder(s) being studied and/or the implementation of the proposed translational research.
• NIH program staff, in consultation with the PD/PI, may in rare occasions add critical experiments that need to be conducted prior to or during the award as an additional milestone(s). In some cases, these studies will be supported by additional funds from NIH.
• NIH program staff attend PD/PI meetings with regulatory agencies related to the funded project.
• NIH program staff may consult as necessary with independent consultants or specialists with relevant expertise.
• In certain, well-justified instances, future-year milestones may be renegotiated based on data and information obtained during the previous year.
• If based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued.
• Leadership of the Institute/Center funding the project will make decisions on project continuation in coordination with BPN Biologics staff, 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
  • Emerging and published literature on competition for the disease indication and biologic drug target
  • Program priorities
  • Availability of BPN Biologics resources
  • Availability of funds

Joint Responsibilities:

• Setting strategic direction and guiding the workflow through the LDT on an ongoing basis
• Clarifying and negotiating the milestones and timelines
• Coordination of site visits, if needed, at critical milestones or transition points of the award

The members of this collaborative effort are all made aware of the requirement for confidentiality due to the intent of the recipient 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 and are contractually required to maintain confidentiality and assign IP rights to the recipient institution. 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 recipients and NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened: a designee of the Steering 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 recipient. This special dispute resolution procedure does not alter the recipient's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and HHS regulation 45 CFR Part 16.

3. Data Management and Sharing

Consistent with the 2023 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. SBIR and STTR recipients may retain the rights to data generated during the performance of an SBIR or STTR award for up to 20 years after the award date, per the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) Program Policy Directive. An acceptable Data Management and Sharing plan can reference and incorporate these data rights. Further information about SBIR and STTR data rights are enumerated in the NIH GPS.

4. Reporting

When multiple years are involved, recipients will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement Section 8.4.1 Reporting.  To learn more about post-award monitoring and reporting, see the NIH Grants & Funding website, see Post-Award Monitoring and Reporting. 

NIH requires that SBIR/STTR recipients submit the following reports within 120 days of the end of the grant budget period unless the recipient is under an extension.

• Final RPPR 
• Final Invention Statement and Certification (HHS 568)
• Annual Invention Utilization Reports
• Federal Financial Report (FFR)
• SBIR.gov

Failure to submit timely final reports may affect future funding to the organization or awards with the same PD/PI. NIH NOFOs outline intended research goals and objectives. Post award, NIH will review and measure performance based on the details and outcomes that are shared within the RPPR, as described at 2 CFR 200.301.

Disclosure of Foreign Relationships Reporting Requirements

Recipients are responsible for monitoring their relationships with foreign countries of concern post-award, for any changes that may impact previous disclosures. SBCs receiving an award under the SBIR/STTR program are required to submit an updated Disclosure Form to report any of the following changes to NIH, CDC, and FDA throughout the duration of the award:

• any change to a disclosure on the Disclosure Form;
• any material misstatement that poses a risk to national security; and
• any change of ownership, change to entity structure, or other substantial change in circumstances of the SBC that NIH, CDC, and FDA determine poses a risk to national security.

Regular, annual updates are required at the time of all SBIR/STTR annual, interim, and final Research Performance Progress Reports (RPPRs). For changes that occur between RPPR submissions, recipients must request prior approval from NIH for legal actions such as merger, acquisition, and successor-in-interest or any other change in ownership, entity structure, covered individual, or other substantive changes in circumstances no later than 30 days before the proposed change. See NIH Grants Policy Statement 8.1.3 Requests for Prior Approval and NIH Grants Policy Statement 18.5.2.2 Change in Organization Size & Change of Recipient Institution Actions for more details. Disclosure Forms are required for any changes as described above. Recipients are required to upload these updated disclosures using the Additional Materials (AM) tool in eRA Commons.

If the recipient reports a covered foreign relationship that meets any of the risk criteria prohibiting funding described in this NOFO, NIH, CDC, and FDA may deem it necessary to terminate the award for material failure to comply with the federal statutes, regulations, or terms and conditions of the federal award. Refer to NIH GPS Section 8.5.2 Remedies for Noncompliance or Enforcement Actions: Suspension, Termination, and Withholding of Support for more information. Recipients are encouraged to monitor their covered foreign relationships post-award and avoid entering into relationships, both funded and unfunded, that may pose a security risk and jeopardize their ability to retain their award.

Agency Recovery Authority and Repayment of Funds

An SBC will be required to repay all amounts received from NIH, CDC, and FDA under the award if either of the following determinations are made upon assessment of a change to their disclosure:

• the SBC makes a material misstatement that NIH, CDC, and FDA determine poses a risk to national security; or
• there is a change in ownership, change in entity structure, or other substantial change in circumstances of the SBC that NIH, CDC, and FDA determine poses a risk to national security.

The repayment requirements and procedures provided in Section 8.5.4 Recovery of Funds of the NIH GPS apply and may also be subject to additional noncompliance and enforcement actions as described in Section 8.5.2 of the GPS. Recipients are required to follow the repayment procedures provided in the Guidance for Repayment of Grant Funds to the NIH.

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: https://www.era.nih.gov/need-help  (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: GrantsInfo@nih.gov (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: support@grants.gov

SBA Company Registry (Questions regarding required registration at the SBA Company Registry and for technical questions or issues)
Website to Email: http://sbir.gov/feedback?type=reg

Lauren Friedman, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-827-5065
Email: lauren.friedman@nih.gov

Kelly Sheppard, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-529-7469
Email: kelly.sheppard@nih.gov

Jonathan Hollander, PhD
NIEHS - NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
Phone: 984-287-3269
E-mail: jonathan.hollander@nih.gov

Paekgyu Lee
NEI - NATIONAL EYE INSTITUTE
Phone: (301) 435-8164
E-mail: paek.lee@nih.gov

Qi-Ying Liu, M.D.
National Institute On Alcohol Abuse And Alcoholism (NIAAA)
Phone: 301-443-2678
E-mail: liuqiy@mail.nih.gov

Enrique Michelotti, Ph.D.
National Institute of Mental Health (NIMH)
Telephone: 301-443-5415
Email: michelottiel@mail.nih.gov

Hye-Sook Kim, Ph.D.
National Center for Complementary and Integrative Health (NCCIH)
Phone: 301-827-6910
Email: hye-sook.kim@nih.gov

Shreaya Chakroborty, Ph.D.
Division of Neuroscience (DN)
National Institute on Aging (NIA)
Phone: 301-827-4019
Email: shreaya.chakroborty@nih.gov

Jason Carlos Sousa
NIDA - NATIONAL INSTITUTE ON DRUG ABUSE
Phone: (301) 827-5919
E-mail: jason.sousa@nih.gov

Melissa Ghim, PhD
​​​​​​​National Institute of Dental and Craniofacial Research (NIDCR)
Phone: 301-529-6570
Email: melissa.ghim@nih.gov

Eric Tucker, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: eric.tucker@nih.gov

Shellie Wilburn, M.B.A.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1974
Email: shellie.wilburn@nih.gov

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 2 CFR Part 200.

The SBIR Program is mandated by the Small Business Innovation Development Act of 1982 (P.L. 97-219), reauthorizing legislation (P.L. 99-443) P.L. 102-564, P.L. 112-81 (SBIR/STTR Reauthorization Act of 2011), as reauthorized and extended under P.L. 114-328, Section 1834, P.L. 115-232, and P.L. 117-183. The basic design of the NIH SBIR Program is in accordance with the Small Business Administration (SBA) SBIR and STTR Policy Directive.

The STTR Program is mandated by the Small Business Reauthorization Act of 1997 (P.L. 105-135), and reauthorizing legislation, P.L. 107-50, P.L. 112-81 (SBIR/STTR Reauthorization Act of 2011), as reauthorized and extended under P.L. 114-328, Section 1834, P.L. 115-232, and P.L. 117-183. The basic design of the NIH STTR Program is in accordance with the Small Business Administration (SBA) SBIR and STTR Policy Directive.