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

 The BRAIN Initiative

Since 2014, the Brain Research through Advancing Innovative Neurotechnologies® (BRAIN) Initiative has aimed to accelerate the development and application of innovative neurotechnologies, enabling researchers to produce a new dynamic picture of the brain that reveals how individual cells and complex neural circuits interact in both time and space. It is expected that these advances will ultimately lead to new ways to treat and prevent brain disorders.

As one of several federal agencies involved in the BRAIN Initiative, NIH's contributions to the BRAIN Initiative were initially guided by "BRAIN 2025: A Scientific Vision," a strategic plan that detailed seven high-priority research areas. This plan was updated and enhanced in 2019 by: "The BRAIN Initiative 2.0: From Cells to Circuits, Toward Cures" and "The BRAIN Initiative and Neuroethics: Enabling and Enhancing Neuroscience Advances for Society." This and other BRAIN Initiative Notices of Funding Opportunities (NOFOs) are based on this vision and issued with input from Advisory Councils of the 10 NIH Institutes and Centers supporting the BRAIN Initiative, as assisted by the NIH BRAIN Multi-Council Working Group and Neuroethics Working Group. 

The NIH BRAIN Initiative recognizes that diverse teams working together and capitalizing on innovative ideas and distinct perspectives outperform homogeneous teams. There are many benefits that flow from a diverse scientific workforce, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH BRAIN Initiative encourages inclusivity in research. Examples of structures that promote diverse perspectives include but are not limited to:

• Transdisciplinary research projects and collaborations among neuroscientists and researchers from fields such as computational biology, physics, engineering, mathematics, computer and data sciences, as well as bioethics.
• Engagement from different types of institutions and organizations (e.g., research-intensive, undergraduate-focused, minority-serving, community-based).
•  Individual applications and partnerships that enhance geographic and regional heterogeneity.
• Investigators and teams composed of researchers at different career stages.
• Participation of individuals from diverse backgrounds, including groups historically underrepresented in the biomedical, behavioral, and clinical research workforce (see NOT-OD-20-031).
• Project-based opportunities to enhance the research environment to benefit early- and mid-career investigators.
   

The NIH also encourages businesses to participate in the BRAIN Initiative. It is possible for companies to submit applications directly to BRAIN Initiative program announcements or to collaborate with academic researchers in joint submissions. Small businesses should consider applying to one of the BRAIN Initiative small business NOFOs.

The BRAIN Initiative requires a high level of coordination and sharing between investigators. It is expected that BRAIN Initiative awardees will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings and in other activities such as the annual PI meeting. The data sharing expectations for BRAIN Initiative awards can be found at NOT-MH-19-010.  

NIH BRAIN Initiative Public-Private Partnership Program

This Notice of Funding Opportunity (NOFO), along with its companion NOFO (RFA-NS-25-022 for UH3 clinical research applications), allows participation in an NIH BRAIN Public-Private Partnership Program (BRAIN PPP), which aims to facilitate partnerships between clinical investigators and manufacturers of latest-generation stimulating and/or recording devices that are FDA-designated as Class III (posing significant risk of harm), to conduct clinical research in the CNS. Through the BRAIN Initiative, NIH is interested in reducing barriers to negotiating such partnerships and ensuring that new clinical studies leverage manufacturers' existing data. Data demonstrating safety and utility of these devices are very costly to obtain and pose a substantial barrier to research progress.

Types of research NIH plans to support with these partnerships include:

• IRB-approved Non-Significant Risk (NSR) clinical research studies (Note: these types of applications are not covered by this NOFO)
• New Significant Risk (SR) clinical studies requiring amendments to existing Investigational Devices Exemptions (IDEs) from the FDA
• SR clinical studies in which a new IDE would require no or minimal additional non-clinical testing
• SR clinical studies in which a new IDE would require significant additional non-clinical testing but leverages existing company device data (Note: these types of applications are not covered by this NOFO).

The central feature of the BRAIN PPP is a set of template research agreements for collaborations between researchers, research institutions, and device manufacturers. These template agreements were generated with substantial input from industry partners, clinical researchers, the FDA and representatives from institutional tech-transfer and contracts offices, and refined from input at a workshop held on June 3-4, 2015, (video of the workshop is publicly archived at https://braininitiative.nih.gov/news-events/events/workshop-brain-initiative-program-industry-partnerships-facilitate-early-access.) and a public feedback from a Request for Information issued in the NIH Guide (NOT-NS-15-032). Through these templates the NIH aims to lower the barriers to utilizing latest-generation devices for early-stage clinical research and to broaden the knowledge base regarding the mechanisms of action and potential therapeutic possibilities of those devices.

There are three sets of agreement documents associated with the program, which are available at the following website (https://braininitiative.nih.gov/research/neural-recording-modulation/public-private-partnerships-program).

Memoranda of Understanding (MOUs) agreed upon by NIH and device company partners to provide a framework under which the specified proprietary devices and associated support will be provided by these partners to BRAIN PPP awardees.

Template Confidential Disclosure Agreements (CDA) to be signed by researchers to initiate detailed discussions that may require knowledge of proprietary company information relevant to the devices and proposed research.

Template Collaborative Research Agreements (CRA) to be used as common starting points for negotiations of agreements between the device manufacturer, researcher, and research institution.

These template agreements have been developed to streamline interactions among the parties and expedite the formation of partnerships to conduct exploratory clinical research by creating a reasonable starting point for negotiations. The NIH recognizes that specific terms and clauses may need to be altered for specific projects by consensus agreement of the two parties.

Use of the BRAIN PPP is optional. Applicants that have already established formal collaborations with device manufacturers (that are part of the BRAIN PPP or otherwise) are also allowed to apply. Institutions or businesses that are developing their own devices are also welcome to apply to RFA-NS-25-022 and are not limited to working with companies participating in the BRAIN PPP. Likewise, institutions that have already established formal collaborations with device manufacturers (that are part of the BRAIN PPP or otherwise) are also allowed to apply. Institutions  and businesses that are pursuing translational activities beyond the regulatory activities supported by the UG3 phase of this NOFO are encouraged to apply to PAR-21-282 or its companion funding opportunity PAR-21-315. 

For applications proposing a collaboration with an BRAIN PPP or non-PPP industry partner, a successful application will be contingent on the applicant's ability to provide the NIH with documentation of company interest in allowing access to the selected device and associated data needed for conducting the proposed non-clinical studies and for filing an investigator-sponsored IDE in order to conduct the proposed exploratory clinical research study (e.g., an executed CRA or letter from the partner). Final negotiations need not be completed at the time of submission, but an executed CRA will be required before issuance of grant award.

A list of devices being offered as part of the BRAIN PPP, along with associated information, can be found at the following website: https://braininitiative.nih.gov/research/neural-recording-and-modulation/public-private-partnerships-program/devices-support.

A. Purpose

This NOFO seeks to encourage applicants to pursue milestone-driven translational and clinical projects for recording and/or stimulating devices to treat central nervous system (CNS) disorders and better understand the human brain. Studies seeking to develop technology which address central nervous system diseases and care across the lifespan are highly encouraged. This NOFO will support regulatory activities necessary to enable initial clinical studies of devices that advance clinical diagnostic or therapeutic applications and maximize their scientific research value, followed by a small first-in-human or early stage clinical study with such devices. These Significant Risk (SR) clinical studies will require an Investigational Device Exemption (IDE) from the FDA, such as chronic implants.

The incorporation of the ability to synchronize peripheral, ambulatory behavioral data signals in the proposed next generation device is strongly encouraged. These signals should be synchronized in real-time, but analysis may be done in an online or offline manner. Data does not have to be stored in the device but may be streamed out, as long as it does not interfere significantly with the naturalistic behavior (i.e., a participant must not be required to carry around a large personal computer with them for synchronization to occur). Data privacy of research participants and confidentiality of the data should also be addressed. Behavioral signals may be those captured by a phone (GPS, keyboard usage, accelerometer, etc.), a smartwatch, or related peripheral behavioral capture device.

B. Overview

This NOFO is related to the recommendations in Section III of the BRAIN 2025 Report and addresses the goal of developing "innovative technologies to understand the human brain and treat its disorders." The recent update to the report, The BRAIN Initiative® 2.0: From Cells to Circuits, Toward Cures, recommends continuation of these ongoing efforts within BRAIN stating the need for better neurotechnology to “understand and manipulate brain function”. The leap from animal studies to humans is large, and initial clinical studies are often necessary to address critical scientific questions about the function of a device in human patients and/or inform a final device design suitable for eventual FDA market approval. Initial demonstrations of novel device function in humans have become increasingly required to encourage the industry and venture capital investment necessary to develop a final safe, reliable, and efficacious device that can be manufactured at scale suitable for regulatory approval, yet at a price point viable for success given the constraints of the commercial markets and insurance reimbursement.  

This NOFO supports regulatory activities required to obtain IRB and FDA approval needed to conduct a small clinical study, and the subsequent study itself (e.g., Early Feasibility Study - https://www.fda.gov/regulatory-information/search-fda-guidance-documents/investigational-device-exemptions-ides-early-feasibility-medical-device-clinical-studies-including). All projects must have two phases: UG3 and UH3. The UG3 phase will support regulatory activities necessary to obtain an IDE and IRB approval for an SR clinical study. All projects will start at the UG3 phase. The duration of the UG3 phase must be one year. Only those UG3 phase projects that have acquired the necessary regulatory approvals will transition to the UH3 phase after NIH administrative review. The UH3 phase will support a small clinical study and can last one to four years, however, the total project period (including both the UG3 and UH3 phases) must not exceed five years. Projects for which only a clinical phase is proposed are outside the scope of this funding opportunity and are encouraged to apply to its companion NOFO RFA-NS-25-022.

This NOFO utilizes a UG3/UH3 cooperative agreement mechanism. As a cooperative agreement, this NOFO supports milestone-driven projects and involves NIH program staff’s participation in negotiating the milestone plan before award, monitoring the research progress, and making go/no-go decisions. The expectations of the program are in line with those of industry regarding the advancement of devices through the developmental and translational pipelines. As such, an inherent rate of attrition is possible within this program.

Applicants are strongly advised to contact the Scientific/Research contact listed below prior to submission.

C. Scope

Projects must focus on a single CNS condition that falls within the mission of one of the participating institutes of the BRAIN Initiative.

It is expected that devices within the scope of this program either:

• are very close to the 'final system' and manufactured using very close to the same manufacturing process as the device to be marketed or studied in a larger clinical trial following the completion of this project; or
• have received Pre-Submission feedback from the FDA (see https://www.fda.gov/medical-devices/products-and-medical-procedures/neurological-devices and https://www.youtube.com/watch?v=u0zPKPLW2mU for helpful resources);
• require early feasibility clinical data to inform the final device design or manufacturing processes.
• are already approved, but are being used for a novel indication, target, or patient population.

D. Entry Criteria

For entry to the program, projects should have:

• Comprehensive supporting data based on bench, in vitro, and/or in vivo models that are representative of the intended patient population and indication.
• Identified one or more clinically meaningful device outcome measures based on input from key stakeholders (e.g., clinicians, patients, and caregivers) as well as supporting literature.
• A compelling case for a successful IDE submission. All regulatory approvals must be in place prior to the start of the UH3 phase.

Applicants are encouraged, but not required, to consult with FDA via a Pre-Submission meeting, study risk designation request, and/or 513(g) submission prior to applying for funding through this grant mechanism. Applicants who do not have sufficiently relevant feedback from the FDA regarding all planned activities prior to application for funding will be expected to do so as the first milestone during the UG3 phase of the award. 

E. Phases

UG3 phase:

Examples of studies that may be proposed during the UG3 phase include, but are not limited to:

• Regulatory activities, including pre-submission meetings with FDA, IDE submission, or other FDA regulatory submissions (e.g., Humanitarian Device Exemption (HDE), Request for Risk Designation, 513(g) submission).
• Clinical trial planning activities, including finalizing the trial protocol and acquiring the necessary IRB approvals. 

       UH3 phase:

The UH3 phase will support a small clinical study that will lead to either:

• A marketing application if only a small clinical study or experience is needed to demonstrate the device is safe and effective;
• A larger clinical study that will lead to a marketing application; or
• Use of the clinical experience to inform device design decisions.

Examples of studies that can be proposed during the clinical phase include, but are not limited to:

• Optimization of the device design with respect to the human functional anatomy.
• Identification of the most simple, reliable, and cost-effective device configuration for more advanced clinical studies and eventual market approval.
• Basic proof-of-concept testing in human patients.
• Studies of the key physiological variables that may impact the function of the device in humans.
• Initial assessments of device safety, but only in conjunction with obtaining enabling data about device design or function.

F. Non-Responsive Activities: 

Applications that include the following activities will be considered non-responsive and will be withdrawn and not reviewed:

• Applications solely proposing Non-Significant Risk NSR studies in the UH3 phase.
• Basic research and studies of disease mechanisms.
• Research projects that involve any animal studies.
• Efforts to develop neurotechnology for fundamental study of the nervous system.
• Fundamental basic/applied research projects that employ existing market approved devices for their labeled uses.
• Delayed-onset clinical studies.
• Applications lacking a clinical study protocol synopsis included with the submission.
• Research projects that employ existing, market approved devices for their labeled uses
• Projects focused on technologies for augmentation of healthy individuals.
• Development of technologies intended exclusively for implant outside the CNS that do not treat or diagnose CNS disorders or provide knowledge about CNS function, including dorsal root ganglion, peripheral, or cranial nerve modulation for the treatment of peripheral nervous system disorders.
• Applications proposing pre-clinical tests beyond the regulatory activities required for obtaining IRB and FDA approval for the clinical study. 

Applications that are missing all required attachments are deemed to be incomplete and will be withdrawn and not reviewed:

• Include a Needs Assessment as an attachment, as described in Section IV.2.
• Include an Intellectual Property (IP) Strategy as an attachment, as described in Section IV.2.
• Include a Team Management Plan as an attachment, as described in Section IV.2.
• Include a Gantt chart as an attachment, as described in Section IV.2.
• Include a Long-term Care Plan for Patients as an attachment, as described in Section IV.2.

Attachments that exceed the maximum page limits listed for each attachment in Section IV.2 will be considered non-responsive and will be withdrawn.

G. Milestones

Because device development is inherently risky, it is anticipated that there may be attrition as projects move through the process. Applications must propose one or more milestones associated with each objective in each year of the project. Milestones are goals that measure success and efficacy that will be used for go/no-go decision-making for the project and should have quantitative success criteria associated with them (see below for details).

For each milestone, provide details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured). Specify the quantitative criteria for measuring success and the rationale used to develop and justify the quantitative criteria identified. Quantitative criteria should be robust and consistent with the state-of-the-art in the field. The timeline for each milestone should be specified and included on the Gantt chart (described below). Applicants are encouraged to read examples of milestones (https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/Devices-Milestones).

NIH program staff will contact the applicant to discuss and negotiate the proposed milestones and any changes suggested prior to funding the application. The final agreed upon and approved milestones will be specified in the Notice of Award (NoA). Progress towards achievement of the final set of milestones will be evaluated yearly by NIH program staff. Program staff may involve independent consultants or subject matter experts with relevant expertise. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, portfolio balance and program priorities, competitive landscape, and availability of funds.

NIH encourages increasing the rigor and reproducibility of observed results. In some cases, conducting additional critical experiments will be important for NIH to have confidence in making a funding decision.

UG3 phase to UH3 phase transition:

An administrative review will be conducted by program staff, with potential input by independent consultants, to decide whether a UG3 phase project will be transitioned into the UH3 phase based on the following:

• Successful achievement of the defined milestones for the UG3 phase of the project;
• Likelihood of success in clinical testing;
• Competitive landscape;
• Program balance;
• Availability of funds;
• Documentation of final or conditional approval of the IDE from the FDA;
• IRB approval(s);
• Submission of the final clinical protocol and supporting documents to NIH for administrative review, and notification of approval by NIH;
• Feedback on activities involving humans subjects obtained from the NINDS Safety and Risk Assessment Committee (SARAC);
• Agreement on updated timeline, milestones, and budget for the clinical study.

H. Quality and Compliance Requirement

The use of the Design Control and Quality Systems processes (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-control-guidance-medical-device-manufacturers) to the degree specified by the FDA is required. Intermediate steps in the Design Control process (e.g., design reviews, design verification, design validation, and design transfer activities), where appropriate, and IDE submission should be represented in the annual milestones. NIH recognizes that the degree to which Design Controls and Quality Systems processes are required by the FDA may vary substantially depending on the specific device. Investigators are encouraged to discuss these issues with the FDA and regulatory consultants prior to submitting an application so the extent to which these processes are required is clearly defined and verifiable in the application. Applicants should consider the Quality System requirements at the IDE stage (i.e., design controls) when preparing their device development activities. Applicants should consider Guidelines and Policies for Monitoring Clinical Research in the formation of a plan for data and safety monitoring as required by the appropriate IC.

I. Intellectual Property (IP)

Since the ultimate goal of this program is to bring new therapeutic and diagnostic devices to the market, the program strongly encourages the awardees and/or their collaborators to obtain and retain any IP developed around the device during the project period (see instructions on attachment or letters to address IP issues in Section IV). Recipients of awards are encouraged to identify and foster relationships with potential licensing and commercialization partners early in the device development process. The PD/PI(s) are expected to work closely with technology transfer officials at their institution to ensure that royalty agreements, patent filings, and all other necessary intellectual property arrangements are completed in a timely manner and that commercialization plans are developed and updated over the course of the project. For rare or ultra- rare diseases where commercialization may be challenging, applicants are encouraged to discuss alternative strategies with Scientific/Research staff to get further guidance.

J. Health Equity

Health equity (HE) is the principle underlying the continual process of assuring that all individuals or populations have optimal opportunities to attain the best health possible. Applying the principle of health equity requires that barriers to promoting good health are removed and resources are allocated among populations and/or communities proportional to their need(s) (See more: NIMHD Health Equity).

The National Institute of Neurological Disorders and Stroke (NINDS) is dedicated to addressing neurological health inequities faced by groups adversely affected by health disparities as we work to improve the neurological health for all people. NIH-designated populations that experience health disparities (HDPs) include racial and ethnic minority populations (Native Americans, African Americans, Hispanic/Latino Americans, Asian Americans, Native Hawaiians and Pacific Islanders), socioeconomically disadvantaged populations, underserved rural communities, sexual and gender minority groups, and people living with disabilities.

Despite research advances and improvement of health outcomes overall, health disparities within the US as a whole and within neurological disorders and stroke in particular, persist. Disparities in neurological diseases can not be explained by biological risk factors alone and social determinants of health (SDOH) are increasingly recognized as important drivers of inequities in neurologic disease and outcomes (NINDS SDOH framework). Health disparities in neurological disorders exist across the lifespan. In pediatric populations, neurological health disparities in acute care settings such as the emergency room impact the diagnosis, treatment and long-term health and longevity from childhood through adulthood.

K. Pre-application Consultation

As a  UG3/UH3 cooperative agreement, NIH program staff will be involved in the negotiation and execution of the projects. Applicants are strongly encouraged to consult with NIH program staff when planning an application. Early contact provides an opportunity for staff to provide further guidance on program scope, goals, and developing appropriate milestones. When possible, applicants should contact program staff at least 12 weeks before a receipt date.

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

Plan for Enhancing Diverse Perspectives (PEDP)

The NIH recognizes that teams comprised of investigators with diverse perspectives working together and capitalizing on innovative ideas and distinct viewpoints outperform homogeneous teams. There are many benefits that flow from a scientific workforce rich with diverse perspectives, including: fostering scientific innovation, enhancing global competitiveness, contributing to robust learning environments, improving the quality of the research, advancing the likelihood that underserved populations participate in, and benefit from research, and enhancing public trust.

To support the best science, the NIH encourages inclusivity in research guided by the consideration of diverse perspectives. Broadly, diverse perspectives can include but are not limited to the educational background and scientific expertise of the people who perform the research; the populations who participate as human subjects in research studies; and the places where research is done.

This NOFO requires a Plan for Enhancing Diverse Perspectives (PEDP), which will be assessed as part of the scientific and technical peer review evaluation.  Assessment of applications containing a PEDP are based on the scientific and technical merit of the proposed project. Consistent with federal law, the race, ethnicity, or sex (including gender identify, sexual orientation, or transgender status) of a researcher, award participant, or trainee will not be considered during the application review process or when making funding decisions.  Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

The PEDP will be submitted as Other Project Information as an attachment (see Section IV).  Applicants are strongly encouraged to read the NOFO instructions carefully and view the available PEDP guidance materials. 

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) 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, 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
• Draft Specific Aims of the proposed project 
• 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:

Megan Frankowski, PhD

Email: NINDS-Devices@nih.gov

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 exceed this limit or do not include this attachment will be withdrawn. This attachment should be entitled "Gantt.pdf". Applicants should include a project timeline in the form of a Gantt chart (or similar) that includes all major tasks to be performed during the project. The chart should also include estimated start and completion dates for those tasks.

Intellectual Property (IP) Strategy (Required – 3 pages max):

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

A goal of this program initiative is to advance research towards the development of products that will benefit the public. Accordingly, applicants should describe the IP landscape surrounding their therapeutic device. This should include any known constraints that could impede the development of their therapeutic device or diagnostic (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar technologies that are under patent and/or on the market, etc.) and how these issues could be addressed as appropriate and consistent with achieving the goals of the program.

• If the applicant proposes using a device or technology whose IP is not owned by the applicant's institution, either an investigational therapeutic, FDA-approved therapeutic, or other licensed product, the applicant should address any questions that may constrain or impede its ability to operate and move the technology forward consistent with achieving the goals of the program.
• Applicants should include a letter (see Letters of Support) from the entity that owns the IP indicating whether the entity will provide the device or technology, if there are any limits on the studies that can be performed with that device or technology, and if there is agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.
• If patents pertinent to the therapeutic device being developed under this application have been filed, the applicants should indicate the details of filing dates, what types of patents are filed, application status, and associated United States Patent Office (USPTO) links, if applicable.
• Applicants should also discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe how IP will be shared or otherwise managed, and the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions in the Team Management Plan (see below).

Needs Assessment (Required – 3 pages max):

Applications that exceed this limit or do not include this attachment will be withdrawn. This attachment should be entitled "Needs Assessment.pdf". The Needs Assessment should:

• establish performance requirements with clear, quantifiable metrics and identify significant issues faced by stakeholders (patients, clinicians, caregivers, customers), which is a key step in the design control process and will be evaluated for adequacy;
• critically evaluate primary or secondary data that have been used to identify deficiencies in current capabilities and the origins of the problem or critical barrier;
• describe the beneficiaries of the proposed work and how their needs have been identified;
• distinguish "wants" from "needs" and outline the involvement of those who will benefit in the development of a solution;
• describe how finite resources can best be deployed to develop and disseminate a feasible and applicable solution; and
• identify any human factors (i.e. ergonomics) incorporated into the proposed research that optimize human interaction, productivity, and understanding while using the technology.

Long-term Care Plan for Patients (Required – 3 pages max):

Applications that exceed this limit or do not include this attachment will be withdrawn. This attachment should be entitled "Long-term Care.pdf" which will be reflected in the final image. First, applicants should describe the anticipated care needs of participants after a trial has ended, which are related to their trial participation (e.g., continued access to the device, device maintenance, and/or device explant). Where relevant, it is recommended that applicants consider various post trial scenarios, such as device and trial failure or success, regulatory approval options, and decisions by device manufacturers to commercialize or discontinue a product.

Second, applicants must describe a plan for the care of patients at the end of the study and after the study period, if appropriate, related to the potential care needs. These plans may vary from project to project, depending on, for example, whether patients are likely to have other ways to access this care, the anticipated risks and benefits of lacking this care, and the feasibility of facilitating this care. Plans might include, for example:

• explant of indwelling devices once the approved study period is complete,
• surgical removal of batteries and ‘capping’ the exposed metals from leads/IS-1 connectors,
• manufacturer-supported device maintenance for patients responding to therapy,
• manufacturer support for filing of compassionate use exemptions for device maintenance, etc.

All plans should include information regarding post-trial obligations (e.g., explantation, hardware and software maintenance and/or updates, or device-related medical expenses).

Schematics (Optional – 1 page max):

Applications that exceed this limit will be withdrawn. This attachment should be entitled “Schematics.pdf”. This attachment may include images, photos, drawings, engineering schematics, design specifics, and associated labeling and captions.

Communications with the IRB (Optional – 5 pages max):

Applications that exceed this limit will be withdrawn. This attachment should be entitled “IRB Communications.pdf”. Applicants should submit relevant approval letters and associated attachments.

Plan for Enhancing Diverse Perspectives (PEDP)

• In an "Other Attachment" entitled "Plan for Enhancing Diverse Perspectives," all applicants must include a summary of strategies to advance the scientific and technical merit of the proposed project through expanded inclusivity. 
• Applicants should align their proposed strategies for PEDP with the research strategy section, providing a holistic and integrated view of how enhancing diverse perspectives and inclusivity are buoyed throughout the application.
• The PEDP will vary depending on the scientific aims, expertise required, the environment and performance site(s), as well as how the project aims are structured.
• The PEDP may be no more than 2 pages in length and should include:
  • Actionable strategies using defined approaches for the inclusion of diverse perspectives in the project;
  • Description of how the PEDP will advance the scientific and technical merit of the proposed project;
  • Anticipated timeline of proposed PEDP activities;
  • Evaluation methods for assessing the progress and success of PEDP activities.

Examples of items that advance inclusivity in research and may be appropriate for a PEDP can include, but are not limited to:

• Partnerships with different types of institutions and organizations (e.g., research-intensive; undergraduate-focused; HBCUs; emerging research institutions; community-based organizations).
• Project frameworks that enable communities and researchers to work collaboratively as equal partners in all phases of the research process.
• Outreach and planned engagement activities to enhance recruitment of individuals from diverse groups as human subjects in clinical trials, including those from underrepresented backgrounds.
• Description of planned partnerships that may enhance geographic and regional diversity.
• Outreach and recruiting activities intended to diversify the pool of applicants for research training programs, such as outreach to prospective applicants from groups underrepresented in the biomedical sciences, for example, individuals from underrepresented racial and ethnic groups, those with disabilities, those from disadvantaged backgrounds, and women.
• Plans to utilize the project infrastructure (i.e., research and structure) to enhance the research environment and support career-advancing opportunities for junior, early- and mid-career researchers.
• Transdisciplinary research projects and collaborations among researchers from fields beyond the biological sciences, such as physics, engineering, mathematics, computational biology, computer and data sciences, as well as bioethics.

Examples of items that are not appropriate in a PEDP include, but are not limited to:

• Selection or hiring of personnel for a research team based on their race, ethnicity, or sex (including gender identity, sexual orientation, or transgender status).
• A training or mentorship program limited to certain researchers based on their race, ethnicity, or sex (including gender identity, sexual orientation, or transgender status).

For further information on the Plan for Enhancing Diverse Perspectives (PEDP), please see PEDP guidance materials.

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 budget should include funds necessary for travel for up to two key personnel to participate in biennial BRAIN investigator meetings, lasting not more than two days and including up to two overnight stays per meeting.

Examples of allowable items include, but are not limited to:

• Device hardware
• Technical/consulting support from the device provider or industry partner
• Surgical implantation and explantation costs

PEDP implementation costs:

Applicants may include allowable costs associated with PEDP implementation (as outlined in the Grants Policy Statement section 7): https://grants.nih.gov/grants/policy/nihgps/html5/section_7/7.1_general.htm.

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

In the single Specific Aims attachment, include aims delineated for the non-clinical testing and the clinical study.

Research Strategy

The single Research Strategy attachment must include the following subsections:

Significance

A. Clinical Impact and Feasibility

Please note that each application must focus on only one CNS disorder or disease, even if the device proposed for development could be used for more than one. The target patient population and intended use should guide the design of the device and the proposed clinical activities.

• Describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed disease indication.
• Briefly discuss available treatments, their limitations, and how the proposed project would address an unmet clinical need or provide a benefit over existing therapies, regardless of therapeutic or diagnostic class (i.e., agents and devices).
• Describe the significant advantages of the proposed device over early generations that may or may not have been marketed and why this iteration is likely to succeed where the prior iterations were insufficient (if applicable).
• Identify one or more clinically robust and meaningful device outcome measures based on input from both clinicians and patients and supporting literature.
• Discuss how the proposed project would affect clinical practice and how it relates to current therapy development efforts or significant efforts underway in academia and industry, including agents, neurotherapeutics, and devices.
• Describe the minimally acceptable and ideal results of the proposed clinical study and explain the rationale for each.

B. Supporting Data for Entry

The Supporting Data for Entry section should contain, at a minimum, comprehensive data and information that validate the feasibility of conducting studies to address the specific aims. When presenting preliminary results, details about study design, execution, analysis, and interpretation must be included. PD(s)/PI(s) should explain the choice of models or assays used to collect preliminary data, and primary, secondary and exploratory endpoints collected and how they are clinically relevant.

• For novel devices, proof-of-concept data of device function are required. These data must be obtained using a prototype device that is close to the final device design anticipated for clinical testing, ideally tested in an in vivo animal model representative of the intended patient population. Sufficient detail of the device design should be included such that a comparison between the device used to collect preliminary data and the proposed device can be made.
• For any device, the supporting data for entry should include a description of the device and its capabilities with sufficient detail for reviewers to assess if the device is appropriate for use in the proposed clinical activities and/or trial(s).
• A clear schematic, drawing, and/or image should be included along with the device description either in the supporting data section or as an optional attachment (see above, Other Attachments- Schematics).
• Applicants should justify the type of stimulation proposed, neural target(s), and patient population.
• Blinding, randomization, power analysis for sample size, and independent replication should be included in the application wherever possible.
• For applications proposing first-in-human studies, preliminary data in humans are not required.

The application should present a credible path towards an IDE. As such, pre-submission feedback from the FDA or preliminary communications with the IRB, if included, should indicate that the proposed regulatory activities will be sufficient to support a successful FDA submission for an IDE by the end of the first phase.

Approach

A. Technology Translation Plan:

Applicants must include an overall plan for device development and translation to outline how the proposed technology will be adopted into clinical practice, based on the work included in the application and beyond. This plan should include:

• A clearly stated device development timeline that includes practical, achievable goals leading up to, during, and beyond the proposed clinical study,
• Evidence of contact with appropriate U.S. regulatory bodies (e.g., FDA in the form of pre-submission meetings and IDE submission), if available, should indicate that the regulatory path to market is reasonable,
• A description of what methods/procedures/approaches used in current clinical practice will change as a result of the adoption of this technology,
• An estimated timeline for when clinical adoption will be feasible, highlighting key benchmarks (e.g., pivotal study, regulatory approval, widespread implementation, clinical adoption),
• A discussion of any additional studies needed and why,
• Key stakeholders and how they will be engaged for each step, and
• A description of any anticipated obstacles that could delay or subvert adoption and potential ways to address/mitigate those obstacles.

B. Detailed Plans for Research Strategy:

In this section applicants should elaborate on their strategy to obtain the regulatory requirements to enable the clinical studies. Research plans and milestones for the clinical trial (UH3 phase) should be included in the PHS Human Subjects and Clinical Trials Information form.

UG3 phase: Non-clinical activities in the UG3 phase should include:

• A project plan compatible with an accelerated timeline to obtain approval to conduct the clinical study.
• A description of all regulatory activities necessary to support the filing of an IDE or to obtain IRB approval for an SR.
• Plans for contact with and submissions to the appropriate U.S. regulatory bodies (e.g., FDA in the form of pre-submission meetings and IDE submission), if applicable.
• A description of oversight groups that may be formed and their role(s) in the proposed study.
• Only minor alterations to the device design necessary to enable the anticipated clinical study.
• A clear indication that study conceptualization and planning are at a stage sufficient to allow for an assessment of the likelihood of clinical study success.
• No clinical dependencies on the development of new and previously untested device elements/concepts that have significant risk of failure.

C. Milestones and Timeline:

Milestones should be associated with clear, quantitative criteria for measuring success and efficacy that can be used for go/no-go decision making.

UG3 Phase:

• Milestones should be included that focus on those activities that are needed to obtain an FDA IDE and to start the clinical trial. This may include pre-submission meetings with FDA, IDE submission, or other FDA regulatory submissions (e.g., Humanitarian Device Exemption (HDE), Request for Risk Designation, 513(g) submission).
• An FDA pre-submission meeting, with NIH program staff in attendance, is required as a Year 1 milestone. If the need for additional pre-submission meetings is anticipated, they should also include NIH program staff and should be included as milestones. Non-binding FDA feedback during and after this meeting must clearly indicate that the clinical study design is acceptable to support a successful FDA submission for an IDE by the end of the non-clinical UG3 phase. The milestone plan should be constructed so that FDA and IRB feedback on the testing plan can be incorporated into the design of critical tests prior to their initiation.

UH3 phase:

• Information related to human subjects and clinical studies that supports the UH3 research strategy (including milestones and timeline) should be included in the PHS Human Subjects and Clinical Trials Information form. Investigators should clearly articulate what the next step will be in technology translation assuming a successful outcome of the clinical study and justify the outcome metrics for the proposed clinical study in terms of quantifiable minimum-success criteria necessary to enable this next step.

Letters of support:

Applicants should include a letter of support from consultants, contractors, and collaborators.

• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing intellectual property associated with this project.
• If research will be performed at more than one institution, include a letter of support from each institution clarifying how intellectual property will be shared or otherwise managed across the institutions.
• If collaborating with a private entity, include a letter of support from that private entity that states whether they are agreeing to provide the device or technology, if there is any limit on the studies that can be performed with that device or technology, limitations on sharing of data, and whether licensing agreements are in place.
• If collaborating with a contract research or manufacturing organization (CRO / CMO), letter of support can summarize results of tests that have been performed but should not contain detailed results of all testing (2 pages max).

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:

Data Management and Sharing (DMS) Plan - Required

• 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.
• If patent protection is being sought, investigators should explain how data will be shared after filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.
• Applicants should anticipate that, if awarded, their project will join a consortium work group, coordinated by the NIH, to identify consensus standards of practice as well as supplemental opportunities to collect and provide data for ancillary studies, and to aggregate and standardize data for dissemination among the wider scientific community. Accordingly, the DMS Plan should include a statement of agreement to join and cooperate with a future collaborative consortium of awardees to maximize data sharing opportunities (including collection, curation, analysis, and sharing) for this unique population of human subjects.
• Consistent with authorities under the 21st Century Cures Act, all applications to BRAIN Initiative NOFOs must include a Data Management and Sharing Plan. The BRAIN Initiative data sharing policy (NOT-MH-19-010) establishes the expectation that this plan should include:
  1. a summary of the data that will be shared;
  2. a description of the standard(s) that will be used to describe the data;
  3. the archive(s) that will house the data; and
  4. the proposed timelines for submitting data to the archive and for sharing data with the research community.
• An updated listing of BRAIN Initiative archives can be found at https://braininitiative.nih.gov/brain-programs/informatics. Currently established archives that may be relevant to this funding opportunity include, but are not limited to: 
  1. Distributed Archives for Neurophysiology Data Integration (DANDI; https://www.dandiarchive.org; R24MH117295) for cellular neurophysiology data;
  2. The Neuroscience Multi-omic Data Archive (NeMO; https://nemoarchive.org/about; R24MH114788) for data from -omics experiments;
  3. The Brain Image Library (BIL; https://www.brainimagelibrary.org; R24MH114793) for confocal microscopy data;
  4. Data Archive for the BRAIN Initiative (DABI; https://dabi.loni.usc.edu; R24MH114796) for data related to human invasive device research;
  5. OpenNeuro (https://openneuro.org; R24MH117179) for magnetic resonance imaging and other neuroimaging data; and
  6. Block and Object Storage Service (BossDB; https://bossdb.org; R24MH114785) for electron microscopy and x-ray microtomography data.

Use of Common Data Elements in NIH-funded Research

NIH encourages the use of common data elements (CDEs) in basic, clinical, and applied research, patient registries, and other human participants research to facilitate broader and more effective use of data and advance research across studies. CDEs are data elements that have been identified and defined for use in multiple data sets across different studies. Investigators are encouraged to consult the NIH CDE Repository and describe in their applications any use they will make of NIH-supported CDEs in their projects, when applicable. Use of CDEs can facilitate data sharing and standardization to improve data quality and enable data integration from multiple studies and sources, including electronic health records. NIH ICs have identified CDEs for many clinical domains (e.g., neurological diseases), types of studies (e.g. genome-wide association studies (GWAS)), types of outcomes (e.g., patient-reported outcomes), and patient registries (e.g., the Global Rare Diseases Patient Registry and Data Repository). NIH has established a "Common Data Element (CDE) Repository Resource Portal" (http://cde.nih.gov/) to assist investigators in identifying NIH-supported CDEs when developing protocols, case report forms, and other instruments for data collection. The Portal provides guidance about and access to NIH-supported CDE initiatives and other tools and resources for the appropriate use of CDEs and data standards in NIH-funded research. NINDS identified CDEs for many clinical neurological/neuromuscular diseases and types of outcomes (e.g., patient-reported outcomes). NINDS provides resources for CDEs (https://www.commondataelements.ninds.nih.gov/#page=Default) to assist investigators in developing protocols, case report forms, and other instruments for data collection. Investigators are encouraged to consult the NINDS CDE website and describe in their applications any use they will make of these CDEs in their projects.

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.

Please see NOT-OD-18-126 for allowable appendix materials.

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.

Section 2 - Study Population Characteristics

2.5 Recruitment and Retention Plan

Applicants should include adequate scientific justification for inclusion/exclusion criteria. Exclusion criteria should avoid discrimination against particular groups.

2.7 Study Timeline

Attachment: UH3 Milestone Plan: Applicants are required to provide detailed project performance and timeline objectives (note, UG3 milestones should be included in the Research Strategy section of the application). These milestones will be negotiated prior to issuing the notice of award. Applications that lack a Milestone Plan are considered incomplete / non-responsive and will not be peer reviewed.

• Applicants should include a timeline and quantitative milestones for completion of key stages of the study, especially participant recruitment, enrollment, and retention through the planned follow-up periods.
• Yearly minimum success criteria for ongoing evaluations of device safety and efficacy that define clear go/no-go points should also be included as milestones.
• Applicants are strongly encouraged to hold a pre-submission meeting with the FDA to discuss the clinical study protocol prior to submission of an IDE, as described above. If the stated goal of the small clinical study is to obtain data to support a marketing application, then a clear non-binding indication that the proposed clinical study protocol is likely sufficient for that purpose must be obtained during this pre-submission meeting.
• A patient engagement timeline should be included as either text or graphical depiction. This timeline should include major activities performed by or with patients as part of the study (i.e., patient enrollment, implants, assessments, data collection, etc.).

For a list of example milestones see Milestones for Translational Device Cooperative Agreements. 

Section 3 - Protection and Monitoring Plans

3.1 Protection of Human Subjects

In addition to the standard components, this section should include a Neuroethics section.  Ethical considerations are intrinsic to the responsible conduct of neuroscience research and the translation of neuroscience advances (scientific and technological) into clinical practice. The NIH BRAIN Initiative emphasizes proactive, ongoing assessment of the neuroethical implications of the development and application of BRAIN-funded tools and neurotechnologies. Applicants are required to describe the ethical considerations related to:

• the design and conduct of the proposed study (e.g., for trials in which research is ancillary to a clinical procedure, therapeutic misconception may be a concern, or for trials without a prospect of benefit to participants, the appropriateness of the risks of the study may require consideration) and
• the potential (long-term) implications of the proposed study (e.g., the potential psychosocial or legal implications for patients of developing predictive biomarkers for pre-symptomatic individuals).

Where relevant, applicants should describe how these ethical considerations are addressed in the study design and monitoring plan addressing the guiding principles below (see Neuroethics Guiding Principles for the NIH BRAIN Initiative for additional considerations).

• Make assessing safety paramount.
• Anticipate special issues related to capacity, autonomy, and agency.
• Protect the privacy and confidentiality of neural data.
• Attend to possible malign uses of neuroscience tools and neurotechnologies.
• Move neuroscience tools and neurotechnologies into medical or nonmedical uses with caution.
• Identify and address specific concerns of the public about the brain.
• Encourage public education and dialogue.
• Behave justly and share the benefits of neuroscience research and resulting technologies.
• In addition to the general guidelines (see https://grants.nih.gov/grants/how-to-apply-application-guide/forms-h/general/g.500-phs-human-subjects-and-clinical-trials-information.htm#3) include an adequate description and justification of safety risks to participants that includes risks incurred during the trial and for device removal. This description should incorporate how risks will be mitigated.
• Describe any plan to address cybersecurity and confidentiality of participants’ personal data (if applicable).

3.3 Data Safety and Monitoring Plan

Attachment: DSMP: Applicants must submit a data safety and monitoring plan and should consider Guidelines and Policies for Monitoring Clinical Research in the formation of the plan as required by the appropriate IC. Applicants should:

• Describe plans to incorporate an independent committee to evaluate data safety and monitor patient safety, including what expertise will be included (https://www.ninds.nih.gov/current-research/research-funded-ninds/clinical-research/ninds-guidelines-monitoring-clinical-trials).

3.5 Overall Structure of Study Team

Attachment: Team Management Plan (Required – 2 pages max): Applications that exceed this limit or do not include this attachment will be withdrawn. NIH strongly encourages applicants to form multidisciplinary teams that consist of non-clinical and clinical scientists, disease experts, regulatory experts, bioethics specialists, experts in manufacturing under Quality Systems and Design Controls, and other relevant academic, clinical, and/or industry experts. This team should have the expertise to clearly define gaps to be addressed during this funding period, to develop the details of the project plans and experiments, and to successfully execute the research strategy and clinical study. An organizational structure that clearly defines the team structure and relationships among the various components must be described in the team management plan and illustrated in an organizational chart. This plan should also describe the governance and organizational structure of the leadership team and the research project, including communication plans, processes for making decisions on scientific direction, intellectual property, and procedures for resolving conflicts. For publications, policies to address the ordering and recognition of authors, and decisions about what material to publish, consistent with the interests of commercial partners (where applicable), should be presented.

The team management plan must establish and name a Scientific Steering Group (SSG) that consists of senior and/or key team members and meets regularly to discuss project status, problems, and directions. In cases of partnering organizations/institutions, the SSG should include representatives from each organization/institution. Those individuals identified in the team management plan, who together would have the intellectual and leadership responsibilities, would likely be members of the SSG. Technology transfer officials from the participating organizations are also encouraged to be members of the SSG. Plans for enhancing the abilities and opportunities for investigators to work across disciplinary boundaries should also be included.

Section 4 - Protocol Synopsis

4.5 Will the study use an FDA-regulated intervention?
4.5.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status:
Attachment: FDA Communications:

• Applicants should include a summary (1-page max) of interactions with the FDA supported by attached FDA letters or correspondence (10 pages maximum including summary). This material should only be submitted in section 4.5.a of the application or as post-submission material.

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.

Delayed onset studies are not responsive and will not be accepted.

PHS Assignment Request Form

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), 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.

Applications Involving the NIH Intramural Research Program

The requests by NIH Intramural Scientists will be limited to the incremental costs required for participation. As such, these requests will not include any salary and related fringe benefits for career, career conditional or other Federal employees (civilian or uniformed service) with permanent appointments under existing position ceilings or any costs related to administrative or facilities support (equivalent to Facilities and Administrative or F&A costs). These costs may include salary for staff to be specifically hired under a temporary appointment for the project, consultant costs, equipment, supplies, travel, and other items typically listed under Other Expenses. Applicants should indicate the number of person-months devoted to the project, even if no funds are requested for salary and fringe benefits.

If selected, appropriate funding will be provided by the NIH Intramural Program. NIH intramural scientists will participate in this program as PDs/PIs in accord with the Terms and Conditions provided in this NOFO. Intellectual property will be managed in accord with established policy of the NIH in compliance with Executive Order 10096, as amended, 45 CFR Part 7; patent rights for inventions developed in NIH facilities are NIH property unless NIH waives its rights.

Should an extramural application include the collaboration with an intramural scientist, no funds for the support of the intramural scientist may be requested in the application. The intramural scientist may submit a separate request for intramural funding as described above.

Intramural Scientist may not serve as PD/PI on extramural awards.

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.

Applications must include a PEDP submitted as Other Project Information as an attachment. Applications that fail to include a PEDP will be considered incomplete and will be administratively withdrawn before review.

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.

Post Submission Materials

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

IRB Communications (Optional – 5 pages max):

• Submissions that exceed this limit will not be accepted.
• This attachment should be entitled “IRB Communications.pdf”.
• Applicants should submit relevant approval letters and associated attachments.

FDA Communications (Optional - 10 pages max including summary):

Applicants should include a summary (1-page max) of interactions with the FDA, supported by the following associated and attached documentation:

• approved minutes from all pre-submission meetings,
• notice of IDE approval and any associated attachments,
• notification of risk determination,
• breakthrough device designation,
• 513(g) letter (if applicable),
• communications on official FDA letterhead,
• email communications with substantive information regarding the device, review, or outcome.

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:

• The market size for the proposed types of therapeutic or diagnostic devices through this request for applications may be considered small compared to other markets. Provided these smaller markets are sustainable, applications should not be penalized for their comparatively smaller market. NIH is supportive of research for both rare and high incidence disorders that fall under the mission of NIH.
• The UG3/UH3 Cooperative Agreement grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or from investigator-generated data. Accordingly, the evaluation will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding.
• 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 scored 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. As part of the overall impact score, reviewers should consider and indicate how the plan to enhance diverse perspectives affects the scientific merit of the project.

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:

Evaluate the following regarding Supporting Data for Entry in the application:

• For a novel device, assess if the proof-of-concept data on device function is obtained using a prototype device that is close to the final device design.
• Evaluate if the device and device capabilities are clearly described with sufficient detail, and whether the device appears appropriate for use in the proposed clinical study.
• If included, assess whether the FDA Pre-Submission (formerly pre-IDE) feedback indicates that the proposed regulatory activities are sufficient to support a successful FDA submission for an IDE by the end of the UG3 phase.

Evaluate the following based on information provided in attachment Needs Assessment in the application:

• In the context of device development, assess whether the needs assessment incorporates input from all relevant stakeholders (patients, clinicians, caregivers) regarding the device performance requirement(s) for the clinical issue to be addressed.
• In the context of device development, evaluate if the beneficiaries of the proposed research were described and whether their needs were identified.

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:

Evaluate the following based on information provided regarding Overall Technology Translation Plan in the application:

• Evaluate whether the regulatory plan is reasonable in terms of regulatory path to market as well as FDA data requirements to meet the appropriate regulatory standard (e.g., reasonable assurance of safety and effectiveness for PMA submissions, substantial equivalence for 510(k) submissions).
• Evaluate whether the estimated timeline for clinical adoption indicates feasible key translation benchmarks for adoption into clinical practice.
• Assess if the plan addresses whether and how key stakeholders will be engaged at each step.

Evaluate the following based on information provided regarding Detailed Plans for Research Strategy in the application:

• Assess whether the implementation of the overarching plan leads to the development and testing of the proposed therapeutic device.
• Evaluate whether the proposed project plan and timeline indicate a likelihood of reaching an IDE at end of the UG3 phase.
• Evaluate whether the neuroethical concerns of the proposed study design have been adequately addressed.

Evaluate the following based on information provided in attachment Long-term Patient Care Plan in the application:

• Assess if the applicant has anticipated the key long-term care needs that patients may have, related to trial participation.
• Evaluate whether the plan for care of patients at the end of the study is reasonable. For example, evaluate if the plan addresses whether patients are likely to have other ways to access this care, the anticipated risks and benefits of receiving this care, the anticipated risks and benefits of lacking this care, and the feasibility of facilitating this care can be considered in this determination.
• If applicable, evaluate how the plan addresses financial liability for injury, device removal, device revision, and management of in-dwelling devices either during or after the study.

Evaluate the following based on information provided regarding Milestone Plan in the application:

• Evaluate whether the Gantt chart provides sufficient detail of the projected timeline with key project tasks and whether these details demonstrate feasible and well-justified plans for completion of the study.
• Evaluate whether milestones are timely and robust and associated with clear, quantitative criteria for efficacy and success that allow go/no-go decisions.
• Evaluate whether the timelines proposed for achieving the milestones are realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps.
• Evaluate whether milestones are included that reflect the planned regulatory requirements of the project, e.g., FDA pre-submission meeting(s), submission for an IDE.

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:

Evaluate the following based on information provided in attachment Team Management Plan in the application:

• Evaluate whether the team’s governance and organizational structure is appropriate for the support of the research project.
• Evaluate the Scientific Steering Group (SSG). Assess whether the members are appropriate and whether an interdisciplinary team been assembled. 

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.

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.

Specific to this NOFO:

Evaluate the following based on information provided in Intellectual Property (IP) strategy attachment:

• Evaluate whether potential issues regarding the IP landscape for the device being developed and means for addressing any IP hurdles/barriers are addressed and whether the IP Strategy attachment and related letters of support address potential concerns.
• Assess if there are any known constraints that could impede the development of the device.
• Evaluate whether IP filing plans are well described and appropriate.
• If multiple institutions/companies are involved, evaluate whether IP sharing is adequately addressed.

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.

Appeals of initial peer review will not be accepted for applications submitted in response to this NOFO.

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 submitted in response to this NOFO. 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, consistent with applicable law.

• Scientific and technical merit of the proposed project, including the PEDP, as determined by scientific peer review.
• Availability of funds.
• Relevance of the proposed project to program priorities.

Please note that reviewers will not consider race, ethnicity, age, or gender of a researcher, award participant, or trainee, even in part, in providing critiques, scores, or funding recommendations. NIH will not consider such factors in making its funding decisions.

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 for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
• Developing and proposing rigorous milestones that will be achieved during the project period.
• 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.
• Pursuing patent protection, as appropriate and consistent with the terms and conditions of the award and goals of the program.
• Providing progress reports with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not. In cases when NIH program staff request raw data, recipients agree to provide the data.
• Participate in progress meetings (virtual) at least twice a year that are organized with NIH staff.
• Communicating regulatory meeting dates and agenda to the NIH program staff and invite their participation.
• Communicating study reports from CROs, meeting minutes (and associated data packages if applicable), letters and other forms of communications with FDA, Recombinant DNA Advisory Committee (RAC), and other authorities, and to provide IDE/IND and registration numbers in clinical trial.gov, if applicable.
• Providing regulatory and clinical documents that are required for administrative review.
• Verifying that the clinical study is performed in accordance with Good Clinical Practices (GCP) and all IC specific guidelines for data and safety monitoring in clinical trials (e.g. NINDS Guidelines for Data and Safety Monitoring in Clinical Trials: http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm, and must provide data and regular updates to NIH

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

• The Project Coordinator will have substantial programmatic involvement during conduct of this activity, through technical assistance, advice, and coordination above and beyond the levels required normally for program stewardship of grants, as described below.
• Each project will have the support of one or more Subject Matter Expert(s) from NIH program staff who are consulted based on their expertise in the disorder(s) being studied and / or the implementation of the proposed translational research. The responsibility of the SME is to advise the Program Official on project approvals.
• NIH program staff provide input on the milestones and make recommendations regarding their finalization.
• NIH program staff will be responsible for assessing the progress of the project towards the specified milestones, and for recommending if further funds should be released to the project.
• NIH program staff, in consultation with the PIs, 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 participate in meetings together with PIs with regulatory agencies related to the funded project.
• NIH program staff may consult as necessary with independent consultants or specialists with relevant expertise, assuming confidentiality agreements are in place to mitigate conflicts and protect intellectual property.
• An NIH Program Director may be assigned to an award with the primary responsibility for the overall coordination of research efforts across different funding mechanisms and research activities.
• In rare, well-justified occasions, 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.
• In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NIH portfolio balance and program priorities, competitive landscape, and availability of funds.
• The Program Officer will  be responsible for normal programmatic stewardship and be listed on the NoA.  However, the Associate Division Director overseeing this program will make final decisions on project continuation based on program staff recommendations, programmatic prioritization, and budget considerations. This second level of approval is designed to mitigate any potential perceived bias in the administration of the cooperative agreement.
• If there is a disagreement between program staff and the Associate Division Director, they will collaborate with the other Associate Division Directors for resolution of the disagreement with program officials. If disagreements remain, concerns may be escalated to the Director of the Institute for final decision.

Areas of Joint Responsibility include:

None; all responsibilities are divided between recipients and NIH staff as described above.

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. Final decisions made by NIH regarding a discontinuation are not appealable.

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.

Additionally, in accordance with the Notice of Data Sharing Policy for the BRAIN Initiative (NOT-MH-19-010), recipients of BRAIN Initiative awards will be required to share the data they collect using the BRAIN Initiative informatics infrastructure (both data archives and relevant data standards), consistent with authorities under the 21st Century Cures Act and these awards authorized under that Act. Recipients will be expected to coordinate with Program Staff to select appropriate BRAIN Initiative data archives and to submit data to the selected archives every 6 months of the award period. Submitting data to an archive is distinct from sharing that data with the research community. Submitted data will be held in a private enclave until the data are shared with the research community. After the data have been submitted to the appropriate data archive, it will be shared with the research community when papers using the data have been published or at the end of the award period, whichever occurs sooner.

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.

• Awardees will provide updates at least annually on implementation of the PEDP.

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: 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

Megan Frankowski, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: NINDS-Devices@nih.gov

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: nindsreview.nih.gov@mail.nih.gov

Chief Grants Management Officer
National Institute of Neurological Disorders and Stroke (NINDS)
Email: ChiefGrantsManagementOfficer@ninds.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 42 CFR Part 52 and 2 CFR Part 200.