Part 1. Overview Information

Key Dates

All applications are due by 5:00 PM local time of applicant organization. 

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

It is critical that applicants follow the instructions in the Research (R) Instructions in the How to Apply - Application Guide , except where instructed to do otherwise (in this NOFO or in a Notice from NIH Guide for Grants and Contracts).

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

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

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 and 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 cooperative UG3/UH3 agreement that involves close collaboration and regular interactions with NIH program staff (see Section VI.2). All projects must have two phases and start in the UG3 phase. The UG3 phase may not exceed two years. Progression from the UG3 phase to UH3 phase will be based on administrative review and availability of funds (see Section I.H, Milestones).

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 UG3 phase 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

UG3 phase activities
The UG3 phase of this award supports lead optimization, candidate selection, and any remaining activities required to initiate Investigational New Drug (IND)-enabling studies. The UG3 phase must not exceed two years. Projects entering at the Development stage are expected to complete UG3 activities within one year since they are further advanced.

The following are examples of in-scope UG3 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 UG3 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

UH3 activities
The UH3 phase of this 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 UG3 award to the UH3 award will be based on administrative review of milestones progress (see section I.H, Milestones). After successful completion of the UG3 phase, a project may proceed to the UH3 phase.

The following are examples of in-scope UH3 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 UH3 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 UH3 phase 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 UG3 and UH3 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 Lead Development Team.

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).

UG3 to UH3 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 UG3 phase to the UH3 phase will be made based on:

• Successful achievement of UG3 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.  Recipient 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

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

Local Governments

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

Federal Government

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

Other

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

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

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the 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 the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • 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.
• 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 their 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 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.

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 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).

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 instructions in the Research (R) 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 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: [email protected] 

Page Limitations

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.

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments:

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 the UG3 and UH3 phases. 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 UG3/UH3 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.

SF424(R&R) Senior/Key Person Profile

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

R&R Budget

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 UG3 and UH3 phases 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 UG3/UH3 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.

Please see Section IV.7 if direct costs for any single year are expected to be $500,000 or more. 

R&R Subaward Budget

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

PHS 398 Cover Page Supplement

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

PHS 398 Research Plan

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

Specific Aims: 
The single Specific Aims attachment must include Aims delineated for both the UG3 and UH3 phases. All applications must include an aim for IND preparation and filing in the UH3 phase. 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 including 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 UG3/UH3 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 UG3 phase (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 UG3 phase that are required to commence IND-enabling activities. Note: Projects entering at this stage are expected to complete UG3 activities 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 or 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 applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property (IP) and licensing related to the project.
• 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), any limitations on sharing of data (including negative results), 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 Plan: 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 applications, regardless of the amount of direct costs requested for any one year, must address a Data Management and Sharing Plan.

Appendix: Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the How to Apply - Application Guide.

• No publications or other material, with the exception of blank questionnaires or blank surveys, may be included in the Appendix.

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.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the 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.

PHS Assignment Request Form

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

Foreign Organizations

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

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

4. Submission Dates and Times

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

Organizations must submit applications to Grants.gov (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and Grants.gov systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to Grants.gov on or before the application due date and time.  If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH 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 NIH Grants Policy Statement Section 7.9.1 Selected Items of Cost.

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. See Section III of this NOFO for information on registration requirements.

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.

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

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

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 [email protected].

Post Submission Materials

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 announcement, note the following:

• All projects must start in the UG3 award phase, 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, the UG3 phase provides recipients up to two years to de-risk projects by completing remaining activities required to start IND-enabling studies and GMP manufacturing, which are supported during the UH3 phase of the 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 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.

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). An application does not need to be strong in all categories to be judged likely to have a major scientific impact.

Review Criteria

Reviewers will consider Factors 1, 2 and 3 in the determination of scientific merit, and in providing an overall impact score. In addition, Factors 1 and 2 will each receive a separate factor score. 

Factor 1: Importance of the Research

Significance

• Evaluate the importance of the proposed research in the context of current scientific challenges and opportunities, either for advancing knowledge within the field, or more broadly. Assess whether the application addresses an important gap in knowledge in the field, would solve a critical problem, or create a valuable conceptual or technical advance.
• Evaluate the rationale for undertaking the study, the rigor of the scientific background for the work (e.g. prior literature and/or preliminary data) and whether the scientific background justifies the proposed study.

Innovation

• Evaluate the extent to which innovation influences the importance of undertaking the proposed research. Note that while technical or conceptual innovation can influence the importance of the proposed research, a project that is not applying novel concepts or approaches may be of critical importance for the field.
• Evaluate whether the proposed work applies novel concepts, methods or technologies, or uses existing concepts, methods, technologies in novel ways, to enhance the overall impact of the project.

Specific to this NOFO:

• Assess how well the expected goals in the applicant’s Target Product Profile (TPP) align with clinical practice for the intended disease indication.
• Assess 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).
• Evaluate the strength of the data supporting the biological rationale for the putative target/pathway for the proposed disease indication.
• For projects entering at the Discovery stage, evaluate the strength of 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, evaluate the strength and completeness of the data supporting the proposed clinical 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.
• Evaluate the potential advantages the proposed therapeutic offers 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.

Factor 2. Rigor and Feasibility

Approach

• Evaluate the scientific quality of the proposed work. Evaluate the likelihood that compelling, reproducible findings will result (rigor) and assess whether the proposed studies can be done well and within the timeframes proposed (feasibility).

Rigor:

• Evaluate the potential to produce unbiased, reproducible, robust data.
• Evaluate the rigor of experimental design and whether appropriate controls are in place.
• Evaluate whether the sample size is sufficient and well-justified.
• Assess the quality of the plans for analysis, interpretation, and reporting of results.
• Evaluate whether the investigators presented adequate plans to address relevant biological variables, such as sex or age, in the design, analysis, and reporting.
• For applications involving human subjects or vertebrate animals, also evaluate:
  • the rigor of the intervention or study manipulation (if applicable to the study design).
  • whether outcome variables are justified.
  • whether the results will be generalizable or, in the case of a rare disease/special group, relevant to the particular subgroup.
  • whether the sample is appropriate and sufficiently diverse to address the proposed question(s).
• For applications involving human subjects, including clinical trials, assess the adequacy of inclusion plans as appropriate for the scientific goals of the research. Considerations of appropriateness may include disease/condition/behavior incidence, prevalence, or population burden, population representation, and/or current state of the science.

Feasibility:

• Evaluate whether the proposed approach is sound and achievable, including plans to address problems or new challenges that emerge in the work. For proposed studies in which feasibility may be less certain, evaluate whether the uncertainty is balanced by the potential for major advances.
• For applications involving human subjects, including clinical trials, evaluate the adequacy and feasibility of the plan to recruit and retain an appropriately diverse population of participants. Additionally, evaluate the likelihood of successfully achieving the proposed enrollment based on age, racial, ethnic, and sex/gender categories.
• For clinical trial applications, evaluate whether the study timeline and milestones are feasible.

Specific to this NOFO:

• For projects entering at the Discovery stage:
  • Evaluate the suitability of the proposed biologic agent(s) as a 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 the UG3 phase, which may not exceed two years.
  • Evaluate the suitability of in vitro and in vivo assays and the appropriateness of the proposed advancement criteria to down-select leads. Evaluate how well this relates 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.
  • Evaluate the strength of the bioactivity assay validation supporting its use in driving lead optimization.
• For projects entering at the Development stage:
  • Evaluate whether the proposed UG3 activities adequately 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 the UH3 phase. Note: Projects entering at this stage are expected to complete UG3 activities within one year since they are further advanced.
• For applicants proposing to conduct IND-enabling nonclinical and/or manufacturing activities with grant funding, evaluate whether their plans include all the appropriate studies for IND submission and whether the timelines are realistic.

Factor 3. Expertise and Resources

Investigator(s)

Evaluate whether the investigator(s) have demonstrated background, training, and expertise, as appropriate for their career stage, to conduct the proposed work. For Multiple Principal Investigator (MPI) applications, assess the quality of the leadership plan to facilitate coordination and collaboration.

Environment

Evaluate whether the institutional resources are appropriate to ensure the successful execution of the proposed work.

Specific to this NOFO:

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

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

Specific to this NOFO:

• Intellectual Property:
  • Evaluate whether the applicants adequately describe potential issues regarding the IP landscape for the proposed biotherapeutic and the means for addressing any IP hurdles/barriers. Assess how well the IP Strategy attachment and related letters of support address potential concerns.
  • Assess the known constraints that could impede development of the biotherapeutic.
  • Evaluate the appropriateness of the IP filing plans for the current stage of development.
  • If multiple institutions are involved, evaluate whether IP sharing is adequately addressed. 

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, 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, 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.

Vertebrate Animals

When the proposed research includes Vertebrate Animals, evaluate the involvement of live vertebrate animals according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animals Section.

Biohazards

When the proposed research includes Biohazards, evaluate whether specific materials or procedures that will be used are significantly hazardous to research personnel and/or the environment, and whether adequate protection is proposed.

Resubmissions

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

Renewals

Not Applicable

Revisions

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

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

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

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

2. Review and Selection Process

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

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

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

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

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.

3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her 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 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 UG3/UH3
• 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 have 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 UG3/UH3 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.

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.

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.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement Section 8.6 Closeout. 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 Part 200.301.

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: [email protected] (preferred method of contact)
Telephone: 301-480-7075

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

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

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

Tony D. Gover, Ph.D. 
National Eye Institute (NEI)
Telephone: (301) 529-7370
Email: [email protected]

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

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

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

Melissa Ghim, Ph.D.
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-529-6570
Email: [email protected]

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

Jonathan Hollander, Ph.D.
National Institute of Environmental Health Sciences (NIEHS) 
Telephone: 984-287-3269
E-mail: [email protected]

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

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

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

Shellie Wilburn, M.B.A.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1974
Email: [email protected]

Section VIII. Other Information

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

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 2 CFR Part 200.