Required Application Instructions

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. 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

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is a Presidential project aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a new dynamic picture of the brain that, for the first time, shows how individual cells and complex neural circuits interact in both time and space. It is expected that the application of these new tools and technologies will ultimately lead to new ways to treat, cure, and even prevent brain disorders.

NIH is one of several Federal agencies involved in the BRAIN Initiative. Planning for the NIH component of the BRAIN Initiative is guided by the long-term scientific plan, BRAIN 2025: A Scientific Vision, which details seven high-priority research areas and calls for a sustained Federal commitment of $4.5 billion over 12 years. This report can be found at http://braininitiative.nih.gov/. This FOA and other FOAs issued in Fiscal Year 2016 are based on careful consideration by the NIH of the recommendations of the BRAIN 2025 Report, and input from the NIH BRAIN Multi-Council Working Group (http://braininitiative.nih.gov/mcwg.htm).

In addition to its contributions to the federal BRAIN Initiative, the NIH continues to have a substantial annual investment in neuroscience research. The NIH Institutes and Centers contributing to the BRAIN Initiative (listed at http://braininitiative.nih.gov/) provide separate support for neuroscience research through applications received via parent announcements as well as through specific FOAs. Potential applicants to this FOA are strongly encouraged to contact Scientific/Research staff if they have any questions about the best funding opportunity announcement for their research.

This pre-application announcement is related to Section III of the BRAIN 2025 Report, and addresses the goal of developing "a streamlined path for developing, implementing and integrating innovative new technologies for human neuroscience research, through cooperation of clinical and academic research teams and private companies in a pre-competitive space." In particular, the BRAIN 2025 Report specifies that "technologies would include implantable devices with combined recording and stimulation capabilities that both advance clinical diagnostic or therapeutic applications and maximize their scientific research value.

The US Food and Drug Administration typically designates implantable electrodes for stimulating or recording neural activity in humans as Class III devices, meaning that there is significant risk of harm to the patient if they malfunction. For Investigational Device Exemptions (IDEs) to conduct Significant Risk (SR) studies FDA approval requires extensive non-clinical testing, with numerous bench-top, in-vitro and in-vivo tests to ensure patient safety, conducted under Design Controls and potentially incorporating Good Laboratory Practices. Even Institutional Review Board designated Non-Significant Risk studies (NSR) - which therefore do not require an FDA IDE - may require significant non-clinical testing to support the NSR designation (See http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf for more information on NSR and SR studies). As a result, small refinements or modifications to devices or to their proposed use may add significant costs to exploratory clinical research studies.

Because of the costs associated with approvals for new exploratory clinical studies, leveraging devices with existing track records for safety and utility in humans is especially compelling for exploratory clinical studies on critical research issues. This is particularly the case for latest- or next-generation devices that are not yet market-approved, but for which safety and utility data are sufficient to enable new clinical research studies. In addition, market-approved devices often have expanded capabilities for research that aren't accessible for routine therapeutic use because of the potential for accidental misuse outside of a limited and controlled research setting. These "scientific platforms" for existing market-approved devices can only be utilized by working directly with the manufacturer to provide access to the additional research capabilities for a specific study and obtain the necessary regulatory approvals.

This X02 pre-application FOA, along with the companion announcements RFA-NS-16-009 (UG3/UH3 phased award for translational and clinical research) and RFA-NS-16-010 (UH3 award for clinical research), is part of an NIH BRAIN Public-Private Partnership Program (BRAIN PPP), which aims to facilitate partnerships between clinical investigators and manufacturers of latest-generation stimulating and/or recording devices that are FDA-designated as Class III (invasive, posing significant risk of harm), to conduct clinical research in the central nervous system. Through the BRAIN Initiative, NIH is interested in reducing barriers to negotiating such partnerships, and ensuring that new clinical studies leverage manufacturers existing data. Data demonstrating safety and utility of these devices are very costly to obtain and pose a substantial barrier to research progress.

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

• IRB-approved Non Significant-Risk (NSR) clinical research studies
• New Significant Risk (SR) clinical studies requiring amendments to existing Investigational Devices Exemptions (IDEs) from the FDA
• SR clinical studies in which a new IDE would require no or minimal additional non-clinical testing
• SR clinical studies in which a new IDE would require significant additional non-clinical testing, but leverages existing company device data.

Partnership Information

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

There are three sets of agreement documents associated with the program, which are available at the following website (http://braininitiative.nih.gov/BRAIN_PPP/).

• Memoranda of Understanding (MOUs) agreed upon by NIH and device company partners to provide a framework under which the specified proprietary devices and associated support will be provided by these partners to the BRAIN PPP awardees.
• Template Confidential Disclosure Agreements (CDA) to be signed by researchers to initiate detailed discussions that may require knowledge of proprietary company information relevant to the devices and proposed research.
• Template Collaborative Research Agreements (CRA) to be used as common starting points for negotiations of agreements between the device manufacturer, researcher, and research institution.

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

X02 applicants should consider their willingness to agree to the conditions in the appropriate CRA for the selected device prior to submitting a pre-application. Changes to the template CRA terms are permissible, but gross deviations from the template may require extensive time to negotiate, and could preclude timely submission of the subsequent full application. Investigators are strongly encouraged to consult early with their institutional technology transfer or sponsored research office in order to confirm that the terms and conditions of the CDA and CRA for the selected device are at or near acceptable to their institution.

Institutions or businesses that are developing their own devices are welcome to apply to RFA-NS-16-009 or RFA-NS-16-010 without an X02 pre-application, and are not limited to working with companies participating in the BRAIN PPP. Likewise, individuals and institutions that have already established formal collaborations with device manufacturers (that are part of the BRAIN PPP or otherwise) are also allowed to apply without an X02 pre-application.

For applicants submitting an X02 pre-application for a partnership with a manufacturer participating in the BRAIN PPP, a successful application to RFA-NS-16-009 or RFA-NS-16-010 will be contingent on the applicant’s ability to provide the NIH with documentation of company interest in allowing access to the selected device and associated data needed for conducting the proposed non-clinical studies and for filing an investigator-sponsored IDE or IRB NSR study in order to conduct the proposed exploratory clinical research study (e.g., an executed CRA or letter from the partner). Final negotiations need not be completed at the time of submission to RFA-NS-16-009 or RFA-NS-16-010, but an executed CRA will be required before issuance of grant award.

Devices and Support Available for the Program

The list of devices and related support to be offered by different manufacturers can be found at http://braininitiative.nih.gov/BRAIN_PPP/. The non-confidential information available for the devices is expected to be sufficient for applicants to prepare X02 pre-applications in response to this FOA.

The goal of this X02 FOA is to identify clinical research studies that are ready for implementation in selected patient populations, which could capitalize on latest-generation device capabilities to stimulate and record from the human central nervous system enabled through partnerships with the participating manufacturers.

Exploratory clinical research studies may include, but are not limited to:

• Proof-of-concept of device functionality for new therapeutic indications
• Identification of neural signals relevant to potential closed-loop control of device functionality for new therapeutic strategies
• Utilization of device functionality to address fundamental human neuroscience questions
• Studies utilizing device functionality to inform selection of patients likely to respond to therapies of interest

With this program, NIH hopes to spur human research bridging the valley of death that has been a barrier to translating pre-clinical research into therapeutic outcomes. We especially encourage investigators to utilize this framework to test innovative ideas for new therapies, or to address scientific unknowns regarding mechanisms of disease or device action, which will facilitate the creation of solid business cases by industry and venture capital for the larger clinical trials required to take these ideas to market.

Proposed studies are anticipated to vary based on the selected devices' stage of clinical development and the strength of the evidence supporting the biological rationale for the proposed therapeutic use or biological study. Some devices may be sufficiently developed to move rapidly to an exploratory clinical study, however others may require non-clinical testing and additional analyses to provide evidence for the necessary study. The applicant's team of investigators should have the appropriate non-clinical models in place, the ability to recruit patients for the specified study, and experience and expertise in implanting devices and conducting clinical trials with the proposed disease population to demonstrate feasibility of expeditiously carrying out the proposed research.

Pre-applications submitted in response to this FOA will be evaluated by outside experts. X02 applicants will receive feedback on the scientific merit, technical feasibility, administration and management plans, and overall potential of the science proposed. Investigators whose X02 pre-applications are identified as being meritorious and relevant to program priorities will be notified of the opportunity to submit a UG3/UH3 or UH3 application under RFA-NS-16-010 or RFA-NS-16-009, respectively, and will be given contact information for the relevant company to collaborate on writing a full-length application. No awards will be made for X02 pre-applications under this FOA.

Although not required, the X02 pre-application process is encouraged for submission to RFA-NS-16-010 or RFA-NS-16-009; applicants should read the appropriate companion FOA for the proposed project prior to submission.

RFA-NS-16-009, UG3/UH3 Phase Innovation Awards Cooperative Agreement

RFA-NS-16-009 uses a UG3/UH3 phased cooperative agreement mechanism to support, for the UG3 phase, non-clinical testing to enable IRB approval and/or a successful IDE submission necessary to conduct a small clinical study, and for the UH3 phase, the subsequent small clinical study (e.g., Early Feasibility Study, see http://www.fda.gov/downloads/MedicalDevices/DeviceRegulati%20onandGuidance/GuidanceDocuments/UCM279103.pdf2 for details/definition). For NSR clinical studies that do not require an IDE, IRB approval is considered sufficient.

RFA-NS-16-009 supports non-clinical testing and clinical studies to answer key questions about the function or final design of a device. It is anticipated that adaptations or refinements required for final device design may require repeating most, if not all, of the non-clinical testing in subsequent studies that are outside the scope of RFA-NS-16-009, on the path to more advanced clinical trials and market approval. The proposed clinical study is expected to provide information that cannot be practically obtained through additional non-clinical assessments (e.g., bench top or animal studies) due to the novelty of the device or its intended use, yet is critical to enable next-generation diagnostic or therapeutic devices. As applicants must have comprehensive supporting data, including proof-of-concept demonstration with a near final prototype in a relevant animal model prior to entry, innovation will in part be judged on presenting a credible path towards an IDE or an NSR clinical study.

Activities that can be supported by RFA-NS-16-009 include, but are not limited to:

• implementation of clinical prototype devices
• design verification and validation activities
• demonstration of non-clinical safety and efficacy
• pursuit of U.S. regulatory approval for clinical study
• a single exploratory clinical research study

RFA-NS-16-010, UH3 Exploratory/Developmental Cooperative Agreement

RFA-NS-16-010 supports projects that address the same goals and criteria as described above for RFA-NS-16-009, but do not require the UG3 non-clinical testing phase to obtain approval for the proposed clinical study, and therefore are ready to submit for approval of an IRB NSR or FDA IDE study in the first year of the award, and proceed directly to the UH3 clinical phase.

Awards made under RFA-NS-16-009 and RFA-NS-16-010 will be milestone-driven and will involve NIH program staff's participation in developing the project plan, monitoring the research progress, and making go/no-go decisions. NIH staff will also provide assistance to academic investigators in familiarizing them with the clinical device development process and the criteria needed to advance therapeutic leads and diagnostics to the clinic. The expectations of the program are in line with those of industry with regard to advancing devices through the translational developmental pipeline. As such, an inherent high rate of attrition is expected within this program.

Timeline for the Program

November 18, 2015	Submission date for X02 pre-applications.
January 2016	Evaluation by outside experts of X02 pre-applications.
February 2016	Notification of opportunity to submit UG3/UH3 or UH3 applications.
April 26, 2016	Submission date for UG3/UH3 and UH3 applications. For applicants submitting an X02 pre-application for a partnership with a manufacturer participating in the BRAIN PPP, submission requires a letter from a participating device manufacturer indicating interest in partnering and providing access to the selected device and associated data.
June 2016	Scientific merit review for UG3/UH3 and UH3 applications.
August 2016	NINDS Advisory Council review of UG3/UH3 and UH3 applications.
September 2016	Earliest possible start date for awarded grants. An executed CRA between the partnering company, researcher(s), and research institution is required for issuance of award.

A technical assistance teleconference will be held for this announcement at a yet unspecified date, and prospective applicants are invited to participate. In order to support the number of participants on the conference call, participants are encouraged to send an email to [email protected] to indicate their interest in participating, and will be notified of registration information as soon as it becomes available. Suggestions for questions to be addressed at this webinar may also be submitted to [email protected]. Answers to the questions will be available on the BRAIN PPP website after the call.

For more information and Frequently Asked Questions about this FOA, see http://braininitiative.nih.gov/BRAIN_PPP/.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made in response to this FOA.

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)

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)
• Eligible Agencies of the Federal Government, including the NIH Intramural Program
• U.S. Territory or Possession

Other

• Independent School Districts
• Public Housing Authorities/Indian Housing Authorities
• Native American Tribal Organizations (other than Federally recognized tribal governments)
• Faith-based or Community-based Organizations
• Regional Organizations

Non-domestic (non-U.S.) Entities (Foreign Institutions) are not eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

• Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
• System for Award Management (SAM) (formerly CCR) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
• eRA Commons - Applicants must have an active DUNS number and SAM registration in order to complete the eRA Commons registration. Organizations can register with the eRA Commons as they are working through their SAM or Grants.gov registration. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
• Grants.gov Applicants must have an active DUNS number and SAM registration in order to complete the Grants.gov registration.

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

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

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

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

For these X02 pre-applications, the PD/PI listed on the X02 pre-application must be the same PD/PI listed on a subsequent UG3/UH3 or UH3 application. For X02 pre-applications proposing multiple PD(s)/PI(s), the contact PD/PI listed on the X02 pre-application must be the same PD/PI listed on a subsequent UG3/UH3 or UH3 application. The contact PD/PI is strongly encouraged to continue the multiple PD(s)/PI(s) leadership identified in the X02 pre-application if notified of the opportunity to submit a UG3/UH3 or UH3 application.

NIH Intramural Research Program (IRP) Investigators are eligible to apply for the X02 FOA. IRP investigators can apply as PD(s)/PI(s), as multiple PD/PIs in conjunction with extramural Investigators (http://grants.nih.gov/grants/multi_pi/index.htm), or as collaborators with extramural academic or biotechnology company investigators, pending the availability of intramural funds to support the project.

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

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

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

• A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
• A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
• An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Applicants must download the SF424 (R&R) application package associated with this funding opportunity using the Apply for Grant Electronically button in this FOA or following the directions provided at Grants.gov.

It is critical that applicants follow the instructions in the SF424 (R&R) Application Guide, including Supplemental Grant Application Instructions except where instructed in this funding opportunity announcement 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.

For information on Application Submission and Receipt, visit Frequently Asked Questions Application Guide, Electronic Submission of Grant Applications.

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:

Stephanie Fertig, MA
National Institute of Neurological Disorders and Stroke
Email: [email protected]

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed, with the following exceptions or additional requirements:

• For this specific FOA, no Specific Aims page will be included.
• For this specific FOA, the Research Strategy section is limited to 6 pages

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

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

Type of submission: Select "Pre-application

Total Federal Funds Requested: Enter "0"

Total Federal and Non-Federal Funds: Enter "0"

Estimated Program Income: Enter "0""

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

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

Are Human Subjects Involved: Answer "No"

Are Vertebrate Animals Used: Answer "No"

Other Attachments: Attach device information for the device selected for use in the project, available at http://[email protected]/BRAIN_PPP

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

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

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

Specific Aims: The Specific Aims section should include Aims delineated for the UG3 stage, if proposed, and UH3 stage:

UG3 (Stage 1): Define the aims of the non-clinical studies, if any are proposed, that support the filing of an IDE for an SR study or to obtain IRB approval for an NSR clinical study.

UH3 (Stage 2): Define the aims of the clinical study proposed.

Research Strategy: Within the Research Strategy, provide the following information.

A. Significance

Clinical Impact and Feasibility: The target patient population and intended use should guide the design of the proposed studies.

• Describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed disease indication where appropriate.
• Briefly discuss available alternatives, their limitations, and how the proposed project would provide benefits over existing therapies or diagnostics, regardless of therapeutic class (i.e., agents and devices).
• Identify one or more clinically meaningful device outcome measures based on input from both clinicians and patients.
• Discuss how the proposed project relates to therapy or diagnostic development efforts underway in academia and industry, including both agents and devices.
• Explain the rationale for the minimally acceptable and ideal results. Briefly comment on the feasibility of conducting clinical trials toward these goals (e.g., availability of clinical trial networks).

The projects anticipated in this FOA are expected to have significant unknowns in defining a full regulatory and market path to sustainable commercial dissemination, as the output of the clinical study may be a final device design that will require most, if not all of the non-clinical testing, or to obtain scientific knowledge that is not feasible or practical to conduct in animal models, but is critical to enable next-generation devices. Market size and pricing should only be considered in terms of 'red flags' that are inherently unaddressable in future work, and would completely preclude FDA market approval, reimbursement by the Center for Medicaid Services (CMS) or third party payers, and/or an eventual sustainable market.

B. Supporting Data for Entry

The Supporting Data for Entry section will contain, but is not limited to, comprehensive data and information that validate the feasibility of conducting the proposed clinical study and/or non-clinical testing.

Briefly provide proof-of-concept data necessary to support that the proposed studies are sufficiently advanced to merit accelerated development into an exploratory clinical study, and that the proposed study could not reasonably be conducted in a relevant animal model.

C. Plans for the Research Strategy

In this section applicants should elaborate on their device testing strategy to enable the clinical studies, as well as the research plans for the clinical study.

Study conceptualization and planning must be at a stage sufficient to allow for an assessment of the likelihood of trial success. Description of the clinical study must describe the following:

• The study design and the rationale for this choice.
  • For studies that are intended to inform a final device design, an outline of the plan to inform final device design decisions must be included, with quantifiable, justifiable metrics used to make key decisions
  • For studies that are intended to elucidate fundamental scientific premises that are crucial for determining the basic feasibility of next-generation technologies, studies must be designed to test the relevant significant hypotheses in terms of appropriate quantifiable metrics
• The target population, and why it is an appropriate group to address the hypotheses
• The organization of the study and how the trial will be managed, the role of any internal and external committees (e.g., executive committee, endpoint adjudication committee), and the responsibilities and oversight of any central laboratories/reading centers or resource centers
• Next steps in device development 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:

• Include a letter from an appropriate institutional official, generally a dean or provost, documenting institutional commitment to the project, including provision of resources, space, and available faculty.
• If multiple institutions are involved in an application, a letter should come from each institution.
• Include in the letter confirmation of the institution s willingness to engage in the necessary negotiations with the device company regarding the terms and conditions of the template CDA and CRA for the selected device as a starting point for negotiations.
• Letters of support from relevant device manufacturers are allowed but not required.
• For applications including NIH IRP Investigators, an official letter from the Scientific Director, which indicates approval of the IRP scientist's role as PD/PI or as collaborator in the project, must be included as a letter of support in the submission of the X02 pre-application.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

Generally, Resource Sharing Plans are expected, but they are not applicable for this FOA.

Appendix: Do not use the Appendix to circumvent page limits. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Planned Enrollment Reports as described in the SF424 (R&R) Application Guide.

When conducting clinical research, follow all instructions for completing Cumulative Inclusion Enrollment Report as described in the SF424 (R&R) Application Guide.

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

See Part I. Section III.1 for information regarding the requirements for obtaining a Dun and Bradstreet Universal Numbering System (DUNS) Number and for completing and maintaining an active System for Award Management (SAM) registration. Part I. Overview Information contains information about Key Dates. 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.

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. If a Changed/Corrected application is submitted after the deadline, the application will be considered late.

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

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

This initiative is not subject to intergovernmental review.

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

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Guidelines for Applicants Experiencing System Issues.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review, NIH. Applications that are incomplete or non-compliant will not be reviewed.

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 FOA. 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.

Applicants are required to follow the instructions for post-submission materials, as described in NOT-OD-13-030.

Only the review criteria described below will be considered in the review process. As part of the NIH mission, all applications submitted to the NIH in support of biomedical and behavioral research are evaluated for scientific and technical merit through the NIH peer review system.

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

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

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

What is the potential clinical significance in the context of existing diagnostics, treatments and therapeutics development efforts (both devices and agents) underway in academia and industry? Will the proposed study remove key knowledge barriers/define unknown risks critical for developing a full business case for the therapeutic or diagnostic device?

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

Team Management: Has an interdisciplinary team been assembled, and have experts in clinical development been included in the conception, design, and proposed implementation of the project? Evaluate the adequacy of the level of expertise and experience of the investigative team for the clinical components of the project. Are there any concerns about the investigative group’s ability to move the device forward into a study in humans?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Are there ongoing or completed clinical studies using similar devices and/or targets for this patient population? How would this clinical study be novel?

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed?

Is sufficient evidence presented to support the scientific rationale for the proposed clinical study? Do results from preliminary studies support the feasibility of conducting the proposed specific non-clinical testing and clinical study?

For studies in which a scientific hypothesis is being tested that is critically enabling to a potential therapeutic device, is the study designed so that data confirming the null hypothesis would still maximize value to the scientific community? Are the assessments and outcome measures described adequate for the study proposed?

Does the application clearly articulate what the next step in device development will be assuming a successful outcome of the clinical study? Does the proposed study as outlined provide data sufficient to move to this next step in device development?

Is the target population appropriate for the clinical study of the proposed device? Are the inclusion/exclusion criteria, clearly justified and explained in the application? Does the application document the following?

• Availability of the requisite eligible subject pool in proposed clinical center(s)
• Plans for recruitment outreach and, as appropriate, follow-up procedures to ensure collection of data at stated intervals
• Adequate retention plans and practices

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

Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Is there evidence of institutional commitment to the project? Is there institutional confirmation that the terms and conditions of the CDA and CRA are acceptable to the technology transfer or sponsored research office (for example, through the letter documenting the Institution's willingness to enter into the necessary agreements with the company partner)?

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.

Not Applicable

Not Applicable

Not Applicable

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

Not Applicable

Not Applicable

Not Applicable

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.

Not Applicable

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

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

Not Applicable

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:

• 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.
• Will receive a written critique.

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.

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

Not Applicable

Not Applicable

Cooperative Agreement Terms and Conditions of Award

Not Applicable

Not Applicable

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

eRA Commons Help Desk (Questions regarding eRA Commons registration, submitting and tracking an application, documenting system problems that threaten submission by the due date, post submission issues)
Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

Grants.gov Customer Support (Questions regarding Grants.gov registration and submission, downloading forms and application packages)
Contact CenterTelephone: 800-518-4726
Web ticketing system: https://grants-portal.psc.gov/ContactUs.aspx
Email: [email protected]

GrantsInfo (Questions regarding application instructions and process, finding NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-710-0267

Stephanie Fertig, MBA
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]

Tijuanna Decoster, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: [email protected]

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

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