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.

There are several options available to submit your application through Grants.gov to NIH and Department of Health and Human Services partners. You must use one of these submission options to access the application forms for this opportunity.

1. Use the NIH ASSIST system to prepare, submit and track your application online.
2. Use an institutional system-to-system (S2S) solution to prepare and submit your application to Grants.gov and eRA Commons to track your application. Check with your institutional officials regarding availability.
   
   
3. Use Grants.gov Workspace to prepare and submit your application and eRA Commons to track your application.



Table of Contents
Part 1. Overview Information
Key Dates
Part 2. Full Text of Announcement
Section I. Notice of Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement

Section I. Notice of Funding Opportunity Description

A. Overview

This NOFO supports non-clinical testing to enable IRB approval needed to conduct a small NSR clinical study. Studies addressing neurological diseases and care across the lifespan are highly encouraged. All projects must have two phases: R61 and R33. The R61 phase will support non-clinical testing to obtain IRB approval for an NSR clinical study. All projects will start at the R61 phase. The duration of the R61 phase will depend on the maturity of the project at entry and can range from one to two years. Only those R61 phase projects that have met specific criteria (see below) will transition to the R33 phase after NIH administrative review. The R33 phase will support a small clinical study and can last one to three years, however, the total project period (including both the R61 and R33 phases) must not exceed five years. Projects for which only a clinical phase is proposed are outside of the scope of this funding opportunity.

This NOFO utilizes a R61/R33 Exploratory/Developmental Phased Award mechanism. As such, this NOFO supports milestone-driven projects and involves NIH program staff’s participation in negotiating project and 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.

B. Scope

Projects must focus on a condition that falls within the mission of NINDS. 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 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.

C. Entry criteria

For entry to the program, projects should have:

• Comprehensive supporting data based on bench, in vitro, and/or in vivo models 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 successful IRB approval for an NSR study. All regulatory approvals must be in place prior to the start of the R33 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 may be expected to do so as the first milestone during the first year of the R61 phase of the award. In the event that FDA feedback is not consistent with the plans in the grant, program staff will evaluate the concerns and change of scope that would be needed and work with the investigators to determine the most appropriate course of action. 

D. Phases

R61 phase:
Examples of studies that may be proposed during the R61 phase include, but are not limited to

• Non-Good Laboratory Practice (GLP) animal studies to develop surgical techniques relevant to the device, optimize relevant therapeutic or diagnostic parameters, and refine device design as necessary for subsequent GLP testing or additional clinical studies for regulatory approval.
• Bench-top and animal testing to demonstrate compliance with FDA Recognized Standards.
• Activities to become current Good Manufacturing Practice (GMP) compliant.
• Activities to bring the development process under Design and Quality Systems Control.
• Device, software, and firmware design verification and validation activities.
• Development of packaging, connectors, and other accessories necessary for the translation of this technology.
• Regulatory activities, including pre-submission meetings with FDA or other FDA regulatory submissions (e.g., Humanitarian Device Exemption (HDE), Request for Risk Designation, 513(g) submission).
• A limited Non-Significant Risk (NSR) clinical experience that does not meet the NIH definition of a clinical trial is also allowable during the R61 phase if it is necessary to support the IRB NSR designation for the small clinical study conducted in the R33 phase.

R33 phase:

The R33 phase will support a small Non-Significant Risk (NSR) 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; or
• 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; and
• Initial assessments of device safety are expected, but only in conjunction with obtaining enabling data about device design or function

E. Non-Responsive Activities

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

• Basic research and studies of disease mechanisms.
• Animal model development: all in vivo models must be well established and characterized, and available to the applicant.
• Fundamental basic/applied research projects that employ existing market approved devices for their labeled uses.
• Significant Risk (SR) clinical studies/studies requiring an Investigational Device Exemption (IDE) from the FDA.
• Delayed-onset clinical studies.
• Applications lacking a clinical study protocol synopsis included with the submission.
• Projects focused on technologies for augmentation of healthy individuals.

Applications that are missing parts are deemed to be incomplete and will be withdrawn and not reviewed: 

• Include a Gantt chart 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 Needs Assessment 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.
• Include a Team Management Plan 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.

F. 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 the transition from the R61 phase to the R33 phase 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. 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, 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 milestones in the R61 phase will be evaluated by NIH program staff to recommend a transition to R33 phase. Program staff may involve independent consultants or subject matter experts with relevant expertise. 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.

R61 phase to R33 phase transition:

An administrative review will be conducted by program staff, with potential input by independent consultants, to decide whether a R61 phase project will be transitioned into the R33 phase based on the following:

• Successful achievement of the defined milestones for the R61 phase of the project;
• Likelihood of success in clinical testing;
• Competitive landscape;
• Program balance;
• Availability of funds;
• IRB approval(s) and non-significant risk (NSR) designation;
• 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); and
• Agreement on updated timeline, milestones, and budget for the clinical study

G. 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. 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 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.

H. 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 recipients 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.

I. 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. The NINDS mission is in alignment with the NIH’s overall commitment to ensure that health disparities and minority health research is prioritized across clinical trials and human subject research (NIH UNITE Initiative). 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.

J. Pre-application Consultation

As a milestone-driven R61/R33 Exploratory/Developmental Phased Award mechanism, 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).

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

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

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

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the How to Apply-Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. Failure to complete registrations in advance of  a due date is not a valid reason for a late submission, please reference the NIH Grants Policy Statement Section 2.3.9.2 Electronically Submitted Applications.

• System for Award Management (SAM) – Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code – Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • Unique Entity Identifier (UEI) - A UEI is issued as part of the SAM.gov registration process. The same UEI must be used for all registrations, as well as on the grant application.
• eRA Commons - Once the unique organization identifier is established, organizations can register with eRA Commons in tandem with completing their Grants.gov registration; all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov – Applicants must have an active SAM registration in order to complete the Grants.gov registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account.  PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with their organization to develop an application for support. Individuals from diverse backgrounds, including underrepresented racial and ethnic groups, individuals with disabilities, and women are always encouraged to apply for NIH support. See, Reminder: Notice of NIH's Encouragement of Applications Supporting Individuals from Underrepresented Ethnic and Racial Groups as well as Individuals with Disabilities, NOT-OD-22-019.

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

2. Cost Sharing

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

3. Additional Information on Eligibility

Number of Applications

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time, per NIH Grants Policy Statement Section 2.3.7.4 Submission of Resubmission Application. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NIH Grants Policy Statement 2.3.9.4 Similar, Essentially Identical, or Identical Applications).

Section IV. Application and Submission Information

1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Grants.gov Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Grants.gov Workspace are available in Part 1 of this NOFO. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

Nick Langhals, PhD

Email: [email protected]

Page Limitations

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

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

SF424(R&R) Cover

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

SF424(R&R) Project/Performance Site Locations

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

SF424(R&R) Other Project Information

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

Other Attachments:

Gantt Chart (Required – 1 page max):

Applications that 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 posttrial 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 receiving this care, the anticipated risks and benefits of lacking this care, and the feasibility of facilitating this care. Plans might include, for example:

• Procedure or plans to bring the subjects' condition to pre-intervention baseline levels or minimize unfavorable residual effects.
• 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.

For projects requiring non-clinical testing to support an IRB NSR designation, preliminary communications (e.g., letter or other documentation) with the IRB indicating what non-clinical testing will be necessary to support the NSR clinical study.

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.

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 neurological disorder or disease, even if the device proposed for development could be used for more than one indication. The target patient population and intended use should guide the design of the device and of the proposed clinical activities. Studies seeking to develop technology which addresses neurological diseases and care across the lifespan are highly encouraged.

• 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 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 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.
• 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 (if applicable), 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 a NSR clinical study. As such, pre-submission feedback from the FDA or preliminary communications with the IRB, if included, should indicate that the proposed pre-clinical testing plan is sufficient to support a successful IRB approval for an NSR clinical study by the end of the R61 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 trial.
• Evidence of contact with appropriate U.S. regulatory bodies (e.g., FDA Non-Significant Risk designation), 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 device testing strategy to enable the clinical studies. Research plans and milestones for the clinical study (R33 phase) should be included in the PHS Human Subjects and Clinical Trials Information form.

R61 phase: Non-clinical activities in the R61 phase should include:

• A project plan compatible with an accelerated timeline to obtain approval to conduct the clinical study.
• A clearly stated device testing timeline that includes quantifiable, practical, achievable goals in support of the proposed clinical study.
• A description of all non-clinical testing necessary to support obtaining IRB approval for an NSR clinical study, including the standards to which the testing will comply (e.g., Good Laboratory Practices (GLP), International Organization for Standardization (ISO) 11135, ISO 10993, Electromagnetic Compatibility (EMC), International Electrotechnical Commission (IEC), etc.).
• Plans for contact with and submissions to the appropriate U.S. regulatory bodies (e.g., FDA in the form of pre-submission meetings or Non-Significant Risk designation), if applicable.
• Plans for all necessary benchtop and animal studies required by the FDA to support an NSR study. Biocompatibility and large animal safety studies (e.g., canine, porcine, ovine, etc.) are often required by the FDA and should be considered in this section.
• Applicants should include a large animal GLP safety study conducted on the full-final device system using the final manufacturing process intended to support the market submission.
• If a large animal safety study is not required by the FDA for future market submission, or a test of the full final system using final design and manufacturing processes is not required, applicants should note this in this section and include a communication from the FDA clearly stating this is the case in the form of a response to a Pre-Submission via the “Communication with Regulatory Bodies” attachment (PHS Human Subjects and Clinical Trial Information, Section 4.5.a).
• Anticipated risks in the device testing process, including potential needs for design changes, and mitigations based on initial test results.
• A description of any independent contractors and their role(s) in the proposed non-clinical study.
• 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.
• Appropriately timed device design modifications to avoid impacting the validity or schedule for the proposed non-clinical testing.
• A clear indication that study conceptualization and planning are at a stage sufficient to allow for an assessment of the likelihood of clinical trial 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

R61 Phase to R33 Phase transition:

• Milestones should be included that focus on tests that are needed to obtain an IRB NSR designation. This may include but is not limited to bio-compatibility testing and large animal studies.
• For projects requiring non-clinical testing to support an IRB NSR designation, preliminary communications (e.g., letter or other documentation) with the IRB indicating what non-clinical testing will be necessary to support the NSR clinical trial should be included as a Year 1 milestone. The milestone plan should be constructed so that FDA and/or IRB feedback on the testing plan can be incorporated into the design of critical tests prior to their initiation.

R33 phase:

• Information related to human subjects and clinical studies that supports the R33 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 letters 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 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.

Use of Common Data Elements in NIH-funded Research

NINDS 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.

The NIH notices referenced below provide additional NIH guidance that should be considered in developing a strong data management and sharing plan. The list is instructive but not comprehensive.

• Elements of an NIH Data Management and Sharing Plan (NOT-OD-21-014)
• Applicants are encouraged to ensure that data collected by the study conform to Findable, Accessible, Interoperable, and Reusable (FAIR) principles.
• NIH has provided guidance around selecting a repository for data generated by NIH-supported research and has developed desirable characteristics for all data repositories (NOT-OD-21-016).
• NIH encourages human-subject studies to incorporate the measures from the Core and Specialty collections, which are now available in the PhenX Toolkit (www.phenxtoolkit.org) (for example, see NOT-DA-12-008, NOT-MH-15-009)
• Data should be organized according to a standard model that is widely accepted within the field. An example for the clinical research studies would be the OMOP Common Data Model, which has also been successfully adapted for use with observational (including survey) studies more generally. In addition, the HL7 FHIR (Fast Healthcare Interoperability Resources) standard (NOT-OD-19-122) may facilitate the flow of data with electronic health record (EHR)-based datasets, tools, and applications.
• NIH encourages clinical research programs and researchers to adopt and use the standardized set of data classes, data elements, and associated vocabulary standards specified in the United States Core Data for Interoperability (USCDI) standards, as they are applicable (NOT-OD-20-146). Use of the USCDI can complement the FHIR standard and enable researchers to leverage structured EHR data for research and enable discovery. 

Recipients  conducting research that includes collection of genomic data should incorporate requirements under the NIH Genomic Data Sharing Policy (NOT-OD-14-124, NOT-OD-15-086).

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. 

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.  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: Regardless of whether the proposed study is a clinical trial or not, 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. In addition to standard guidelines, 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/Funding/Apply-Funding/Application-Support-Library/NINDS-Guidelines-Data-and-Safety-Monitoring).

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 max including summary). This material should only be submitted in section 4.5.a of the application or as post-submission material.
• Large animal safety studies are often required by the FDA to support a market submission. Applicants should include a large animal GLP safety study conducted on the full-final device system using the final manufacturing process intended to support their market submission. If a large animal safety study is not required by the FDA, or a test of the full final system using final design and manufacturing processes is not required, applicants should include a communication from the FDA clearly stating this is the case in the form of a response to a Pre-Submission. If these studies are proposed, but ultimately not needed, program staff will work with the investigators to remove the relevant milestones and associated costs of these activities from the award.

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 trials are not responsive and will not be accepted.

PHS Assignment Request Form

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

Foreign Organizations

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

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

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

4. Submission Dates and Times

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

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

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the How to Apply- Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

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.

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.

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

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

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

Send written disclosures to the NIH Chief Grants Management Officer listed on the Notice of Award for the IC that funded the award and to the HHS Office of Inspector Grant Self Disclosure Program at [email protected].

Post Submission Materials

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

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.
• For projects requiring non-clinical testing to support an IRB NSR designation, preliminary communications (e.g., letter or other documentation) with the IRB indicating what non-clinical testing will be necessary to support the IRB NSR determination

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
• 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 R61/R33 Exploratory/Developmental Phased 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, for Non-Significant Risk (NSR) studies, assess whether the preliminary communications with the IRB indicate that the proposed pre-clinical testing plan is sufficient to support the NSR clinical study.

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

• 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 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 plans and timeline indicate a likelihood of reaching  IRB approval for a non-significant risk (NSR) study at the end of the R61 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., successfully obtaining IRB approval for a NSR clinical study. 

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 of 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 attachment Intellectual Property (IP) strategy:

• 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. 

Not Applicable

Consistent with the 2023 NIH Policy for Data Management and Sharing, when data management and sharing is applicable to the award, recipients will be required to adhere to the Data Management and Sharing requirements as outlined in the NIH Grants Policy Statement. Upon the approval of a Data Management and Sharing Plan, it is required for recipients to implement the plan as described.

4. Reporting

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

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

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

Nick Langhals, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email: [email protected]

Chief, Scientific Review Branch
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9223
Email: [email protected]

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

Section VIII. Other Information

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

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