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 2015 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-Roster.pdf), which held its first meeting on August 25th, 2014 (see http://videocast.nih.gov/summary.asp?file=18555&bhcp=1).

In addition to the National BRAIN Initiative, the NIH continues to have a substantial annual investment in neuroscience research. The Institutes and Centers contributing to the NIH BRAIN Initiative (http://braininitiative.nih.gov/) support those research efforts 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 FOA is related to Section III of the BRAIN 2025 Report, and addresses the goal of developing 'innovative technologies to understand the human brain and treat its disorders'. The NIH recognizes that initial first-in-human studies are a key point in the development of innovative new clinical technologies. The leap from animal studies to humans is large, and initial clinical studies are often necessary to address critical scientific questions about the function of a device in human patients and/or inform a final device design suitable for eventual FDA market approval. Initial demonstrations of novel device function in humans have become increasingly required to encourage the industry and venture capital investment necessary to develop a final safe, reliable, and efficacious device that can be manufactured at scale suitable for regulatory approval, yet at a price point sufficient for sustainable commercial market given insurance reimbursement.

As recommended in the BRAIN 2025 Report this FOA will support pre-clinical testing necessary to enable initial clinical studies of 'implantable devices with recording and/or stimulation capabilities that both advance clinical diagnostic or therapeutic applications and maximize their scientific research value', and a subsequent small clinical study for such devices. Clinical studies supported may consist of acute or short-term procedures that are deemed Non-Significant Risk (NSR) by an Institutional Review Board, or Significant Risk (SR) studies that require an Investigational Device Exemption (IDE) from the FDA, such as chronic implants.

This funding opportunity will utilize a UH2/UH3 cooperative agreement mechanism to support non-clinical testing (formerly pre-clinical testing) to enable IRB approval and/or a successful IDE submission necessary to conduct a small clinical study, and 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. This funding opportunity supports nonclinical testing and clinical studies to answer key questions about the function or final design of a device. This final device design may require most, if not all, of the non-clinical testing on the path to more advanced clinical trials and market approval. The clinical study is expected to provide information that cannot be practically obtained through additional nonclinical 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. Activities that can be supported in this program include 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, and a single small clinical study. 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.

All projects will have two phases, UH2 and UH3. The initial UH2 phase will support nonclinical testing to support to the filing of an IDE for an SR study or to obtain IRB approval for an NSR clinical study. All projects will start at the UH2 phase, but the length of UH2 phase will depend on the maturity of the project at entry. Only those UH2 projects that have met specific criteria (see below) will transition to the second UH3 phase after NIH administrative review. The UH3 phase will support a small clinical study.

An additional companion BRAIN FOA (RFA-NS-15-008) is anticipated to fund projects that are sufficiently developed to move directly to the UH3 clinical studies.

This FOA is milestone-driven and involves 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 in regards to advancing devices through the translational developmental pipeline. As such, an inherent high rate of attrition is expected within this program.

Entry Criteria

For entry to the program, projects should have:

• Comprehensive Supporting Data: Proof-of-concept data of device function are required using a prototype device equivalent to the final device design anticipated for clinical testing, ideally obtained using an in vivo model representative of the intended patient population.
• A compelling case for a successful IDE submission to support the clinical component, or IRB approval for an NSR study, within the period of the award
• Overall device development plan, including timeline for contact and interaction with appropriate regulatory bodies, clinical considerations, and a needs assessment
• Identification of one or more clinically meaningful device outcome measures based on input from both clinicians and patients

UH2 Scope

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

• Non-GLP (Good Laboratory Practice) animal studies to develop surgical techniques relevant to the device, define relevant therapeutic parameters, and refine device design in preparation for subsequent GLP testing for regulatory approval
• In vitro and animal testing to meet FDA recognized ISO/ASTM Standards
• Activities to become GMP (Good Manufacturing Practice) compliant
• Activities to bring the development process under Design and Quality Systems Control
• Device, software, and firmware design verification and validation activities
• GLP compliant large animal model safety and/or testing of an implanted device
• Activities to support submission of an IDE, and submission of an IDE
• UH3 Scope

The UH3 phase will support a small clinical study to answer key questions about the function or final design of a device. 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 trials and eventual market approval
• Basic proof-of-concept testing in human patients
• Studies of the key physiological variables that may impact the function of the device in humans
• Initial assessments of device safety are expected, but only in conjunction with obtaining enabling data about device design or function

Out of Scope Activities for this FOA

The following are out of scope for this program:

• Basic research and studies of disease mechanisms
• Animal model development: All in vivo models must have been previously established and characterized
• Rehabilitation strategies
• Imaging technologies
• Definitive clinical trials of therapeutic devices, such as a traditional Feasibility study and/or Pivotal Trial (see http://www.fda.gov/downloads/MedicalDevices/DeviceRegulati%20onandGuidance/GuidanceDocuments/UCM279103.pdf2 for the definition of an Early Feasibility Study, Feasibility Study and Pivotal Trial)
• Efforts to develop neurotechnology for fundamental study of the central nervous system
• Fundamental basic/applied research projects that employ existing market approved devices for their labeled uses are outside the scope of this FOA but may be within scope of future BRAIN FOAs
• Projects focused on augmentation of neural function in healthy individuals
• Technologies intended for implant outside of the central nervous system

As a cooperative agreement, implementation will involve the participation of NIH program staff in the planning and execution of the projects. Applicants are strongly encouraged to consult with NIH Scientific/Research staff when planning an application. Early contact provides an opportunity for NIH scientific/research staff to provide guidance on program scope, goals, and appropriate yearly milestones with metric driven criteria that can be verified by NIH staff for sufficiency. Applicants should contact NIH Scientific/Research staff as early as possible before a due date.

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 not eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are not 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.

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).

In addition, the NIH will not accept a resubmission (A1) application that is submitted later than 37 months after submission of the new (A0) application that it follows. The NIH will accept submission:

• To an RFA of an application that was submitted previously as an investigator-initiated application but not paid;
• Of an investigator-initiated application that was originally submitted to an RFA but not paid; or
• Of an application with a changed grant activity code.

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.

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed

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.

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

All instructions in the SF424 (R&R) Application Guide must be followed. Please note the following additional instructions:

Other Attachments: Applicants are required to include the following four items: Needs Assessment, Intellectual Property Strategy, Team Management Plan, and Clinical Protocol Synopsis. These four items must be uploaded as separate attachments in pdf format with filenames that correspond to the individual items (Needs Assessment, Intellectual Property Strategy, Team Management Plan, and Clinical Protocol Synopsis). Applications lacking these required items will be deemed incomplete and will not be reviewed.

Needs Assessment: Applications should include a needs assessment that is no more than six pages. 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.

The needs assessment should:

• Provide strong, systematic evidence for the most efficient and effective route to addressing an unmet need
• 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
• Identify any human factors incorporated into the proposed research that optimize human interaction, productivity, and understanding while using the technology.

Intellectual Property Strategy: Applications should include an Intellectual property (IP) strategy that is no more than one page. Applications that exceed this limit will be withdrawn. This attachment should be entitled "IP_Strategy.pdf" and will be reflected in the final image. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials, if applicable.

Applicants should describe the IP landscape surrounding their therapeutic device or diagnostic. Applicants should describe 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 of freedom to operate that are consistent with achieving the goals of the program. Applicants should include a letter (see Letters of Support) from the entity who owns the IP indicating whether they will provide the device or technology, if there are any limits on the studies that can be performed with that device or technology, and 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 or diagnostic being developed under this application have been filed, the applicant 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 discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe 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.

Team Management Plan: The team management plan should not exceed one page. Applications that exceed this limit will be withdrawn. NIH strongly encourages applicants to form multidisciplinary teams that consist of non-clinical and clinical scientists, disease experts, regulatory experts, statisticians, experts in manufacture under Quality Systems and Design Controls, and other relevant academic/industry experts. This multidisciplinary team should be able to define the overall device development plan to ensure gaps that need to be filled can clearly be defined and addressed during this funding period, to design the details of the plans and experiments, and to execute the research strategy. 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. Applicants should clarify how IP will be shared or otherwise managed if multiple PIs and institutions are involved, as appropriate and consistent with achieving the goals of the program. 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 should establish a Scientific Steering Group that consists of representatives from each of the partnering organizations and meets regularly to discuss project status, problems, and directions. Those individuals identified in the team management plan, who together would have the intellectual and leadership responsibilities, would likely be members of the Scientific Steering Group. Technology transfer officials from the participating organizations are also encouraged to be members of the Scientific Steering Group. Plans for enhancing the abilities and opportunities for investigators to work across disciplinary boundaries should also be included.

Clinical Protocol Synopsis: The clinical protocol synopsis should not exceed six pages (applications that exceed this limit will be withdrawn), and must include the following information:

• A list of participant eligibility criteria
• Participant recruitment and retention plans, including a discussion of the availability of participants for the proposed study and the ability of enrollment sites to recruit and retain the proposed number of participants meeting the eligibility criteria, including women and minority participants. Data supporting recruitment and retention estimates must be provided. Evidence should be provided that relevant stakeholders (e.g., potential participants, referring and treating physicians, patient groups) have sufficient equipoise, consider the question to be important and the study acceptable. This evidence may be supported by letters from stakeholders (e.g., professional organizations or patient groups).
• A description of all assessments including clinical, laboratory, physiological, behavioral, patient-centered, or other outcomes addressing the primary and secondary research questions. Use of patient reported outcomes, including those available through PROMIS and Neuro-QoL as well as other data collection approaches (e.g., telephone, mobile devices, or web-based systems) should be considered.
• Discussion of the potential biases in the study and how they will be addressed
• Statistical Methods: Discussion of sample size and power calculations, study outcome measures, plans for interim and final analyses, methods of bias control, and methods for handling missing data. Examples of the critical elements of a well-designed study are summarized on the NINDS website http://www.ninds.nih.gov/funding/transparency_in_reporting_guidance.pdf.
• Data Management and Quality Control: Details of efficient data management and methods for monitoring quality, methods for monitoring the quality and consistency of intervention administration, and methods for ensuring participant confidentiality. Applicants are expected to incorporate data elements from the NINDS Common Data Elements (CDE) Project in their data collection forms (see http://www.commondataelements.ninds.nih.gov )
• Discussion of the challenges expected in implementing the trial and how these might be overcome
• Data and Safety Monitoring Plan: The clinical protocol should also include a Data and Safety Monitoring (DSM) Plan that is commensurate with the risk level of the proposed clinical trial (see http://grants.nih.gov/grants/guide/notice-files/not98-084.html). For exploratory clinical trials it generally will be acceptable for the data and safety monitoring to be conducted by an investigator-appointed Study Monitoring Committee (SMC), an Independent Medical Monitor (IMM), or, for single-site trials involving low risk, the Program Director/Principal Investigator and his/her IRB. However, NIH may decide to establish an independent Data and Safety Monitoring Board (DSMB) depending on the score and risk of the trial. Applicants should refer to NIH’s policy on data and safety monitoring (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-038.html) as well as the NINDS Guidelines for Data and Safety Monitoring (http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm).

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: Budgeting for consultants with expertise in the Design Control process and/or regulatory submission is permissible.

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: Include Aims delineated for the non-clinical testing and the Clinical Study.

1. Define the aims of the UH2 non-clinical development of the device

2. Define the aims of the UH3 clinical study

Research Strategy: The Research Strategy attachment should include the following sections:

A. Significance: Clinical Impact and Feasibility

B. Supporting Data for Entry

C. Detailed Plans for Research Strategy (Including Milestones and Timelines)

A. Significance

Clinical Impact and Feasibility: The target patient population and intended use should guide the design of the device and the non-clinical 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 is intended to either 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 should contain, but is not limited to, comprehensive data and information that validate the feasibility of conducting studies to address the specific aims. When presenting results, sufficient information must be available about study design, execution, analysis, and interpretation. PD(s)/PI(s) should explain the choice of models or assays, primary, secondary and exploratory endpoints and how they are clinically relevant.

Proof-of-concept data of device function are required prior to submission. These data must be obtained using a prototype device close to the final device design anticipated for clinical testing, ideally tested in an in vivo animal model representative of the intended patient population. Consequently, the supporting data for entry should include a description of the device with sufficient detail for reviewers to assess if the device used to obtain proof-of-concept data is representative of the final device design proposed for accelerated non-clinical testing to enable the proposed clinical studies.

As applicants must have comprehensive supporting data - including proof-of-concept demonstration with a near final prototype - prior to entry, innovation will in part be judged on presenting a credible path towards an IDE or an NSR clinical study.

C. Detailed Plans for the Research Strategy (Including Milestones and Timelines for each phase)

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.

The overall plan for device testing should include:

• A clearly stated device testing timeline that includes practical, achievable goals in support of the proposed clinical study.
• Evidence of contact with appropriate U.S. regulatory bodies (e.g., FDA in the form of Pre-submission meetings and IDE submission)
• Anticipated risks in the device testing process, including potential needs for design changes, and mitigations based on initial test results
• Clinical considerations including, but not limited to, the tools and process for device insertion and method for evaluating the functional integrity of the device. This plan will often involve collaboration between the investigators, clinical researchers, and may include the participation of private-sector companies and/or voluntary agencies.
• UH2 Phase

The initial UH2 phase should detail nonclinical testing necessary to support to the filing of an IDE or to obtain IRB approval for an NSR clinical study. Consequently, alterations to the device design made within the project period should only consist of minor changes necessary to enable the anticipated clinical study, and timed appropriately to avoid impacting the validity or schedule for the proposed non-clinical testing. Given the accelerated timeline to obtain approval to conduct the clinical study, applications are discouraged from having critical dependencies on the development of new and previously untested device elements/concepts that have significant risk of failure.

Applicants should describe milestones to be used for measuring success in achieving each of the research plan’s objectives. One or more milestones should be used for each objective. 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 for the quantitative criteria. Quantitative criteria should be robust and consistent with the state-of-the-art in the field. Most of the time the quantitative criteria for success in the milestones will also be used for making go/no-go decisions and this should be specified. Specify the timeline for each milestone. There should be at least one milestone proposed for completion at the end of each year. Applicants are encouraged to read examples of milestones (found on the CREATE Devices website; http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-Devices.htm).

The UH2 milestones should focus on those tests that are needed to obtain an FDA IDE or an IRB NSR designation. Large animal safety studies are often required by the FDA to support an IDE. 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 IDE. If a large animal safety study is not required by the FDA for an IDE, or a test of the full final system using final 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.

For projects proposing non-clinical (formerly pre-clinical) testing to support an IDE submission for the clinical study, an FDA Pre-Submission meeting with NIH staff in attendance is required as a year 1 milestone. Non-binding feedback during this meeting must clearly indicate that the proposed non-clinical testing plan is sufficient to support a successful FDA submission for an IDE by the end of the non-clinical phase. For projects requiring non-clinical testing to support an IRB Non-Significant Risk (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 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.

UH3 Phase

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 for the UH3 phase must include:

• A description of the study design and the rationale for this choice.
  • For studies that are intended to inform a final device design, a 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
• A description of the target population, and why it is an appropriate group to address the hypotheses
• Descriptions of 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
• A timeline and milestones for completion of key stages of the trial, especially participant accrual and yearly minimum success criteria for ongoing evaluations of device safety and efficacy

Investigators should clearly articulate what the next step will be 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.

Applicants are strongly encouraged to conduct a Pre-Submission meeting with the FDA to discuss the clinical study protocol as an end of year milestone prior to the anticipated transition to the UH3 phase, with NIH Staff in attendance. If the stated goal of the Early Feasibility Study is to obtain data to support a 510(k) or 510(k) De Novo submission, then a clear indication that the proposed protocol is likely sufficient for that purpose must be obtained during this Pre-Submission meeting.

Quality and Compliance Requirements: The use of the Design Control and Quality Systems processes (http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm070627.htm) to the degree specified by the FDA is required. Intermediate steps in the Design Control process (e.g., design reviews, design verification, design validation, and design transfer activities) where appropriate, and IDE submission should be represented in the annual milestones.

Protection of Human Subjects: NIH’s policy requiring education on the protection of human research participants must be followed for all key personnel (see http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html).

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

• If applying from an academic institution, include a letter of support from the technology transfer official who will be managing IP associated with this project.
• If research will be performed at more than one institution, include a letter of support from each institution clarifying how IP will be shared or otherwise managed across the institutions as appropriate and consistent with achieving the goals of the program.
• If collaborating with a private entity, state if they are agreeing to provide the device (or technology), whether there are any limits on the studies that can be performed with that device (or technology) or limitations on sharing of data, and whether licensing agreements are in place

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:

• All applications submitted for the January 25, 2015 due date or after are expected to comply with the NIH Genomic Data Sharing Policy as detailed in NOT-OD-14-111, as applicable.
• Investigators are expected to include a brief one-paragraph description of how the final research data will be shared or why data-sharing is not possible. If patent protection is being sought, investigators should explain how data will be shared after patent protection is secured..

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.

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 and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive 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.

For this particular announcement, note the following:

The market size for the proposed therapeutic device should not be considered in assessing the significance of a project. NIH is supportive of research for both rare and high incidence disorders that fall under the mission of NIH.

As applicants must have comprehensive supporting data - including proof-of-concept demonstration with a near final prototype - prior to entry, innovation will in part be judged on presenting a credible path towards an IDE or an NSR clinical study.

The UH2/UH3 phased Exploratory/Developmental Cooperative Agreement grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or from investigator-generated data. Accordingly, reviewers will focus their evaluation on the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding. Reviewers will assign a single impact score for the entire application, which includes both the UH2 and UH3 phases.

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?

Overall Device Development Plan:

Is the overall plan for device development reasonable? Is the needs assessment adequate and complete? Does the needs assessment incorporate input from all relevant stakeholders (patients, clinicians, caregivers)? Are there clear metric driven design criteria developed with input from stakeholders? Have PDs)/PI(s) identified one or more clinically meaningful device outcome measures based on input from both clinicians and patients?

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 non-clinical development and 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 both non-clinical and clinical components of the project. Are there any concerns about the investigative group’s ability to move the device forward into a trial 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?

How significant an advantage does the proposed device offer over all existing approaches, as well as those known to be in development? If the proposed therapeutic or diagnostic device is aiming to improve over early generations that may or may not have been marketed, are the potential advantages truly transformative?

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?

Entry Criteria:

What is the robustness of the unpublished and published data used in support of the application?

Were the data obtained using a prototype equivalent to the device proposed for non-clinical testing in an in vivo animal model representative of the intended patient population? If not obtained in a representative animal model, did the applicant provide adequate justification for the model used?

Do results from preliminary studies support the feasibility of conducting the proposed specific aims?

Plans for the Specific Aims:

Will the implementation of the overarching plan lead to the development and testing of the proposed device?

Are the proposed experiments designed using rigorous methodological approaches?

For studies including non-clinical testing to enable an IDE, is a large animal safety study performed utilizing GLP proposed or is there clear communication from the FDA denoting that a large animal GLP safety study will not be necessary?

Will the project reach an IDE for a significant risk study or IRB approval for a non-significant risk (NSR) study at end of the non-clinical testing phase?

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?

Is the study design complete and adequately described and justified in terms of the goals and any challenges expected? Does the proposed clinical testing include clear quantitative metrics that will be used to inform design decisions for the final device?

Does the study fit with the overall device development plan? Does the application clearly articulate what the next step in device development will be assuming a successful outcome of the clinical study? Is the clinical study appropriately designed to inform this next step?

Is the target population appropriate for the clinical study of the proposed device? Are the inclusion/exclusion criteria, sample size, and power calculations clearly justified and explained in the application?

Is there adequate consultation with patients and other stakeholders in study design?

Are the assessments and outcome measures described adequate for the study proposed?

Are the timelines and milestones for completion of key stages of the trial (e.g., participant accrual) realistic and inclusive of necessary steps?

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?

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.

Milestones:

Are milestones robust and associated with clear, quantitative criteria for success that allow go/no-go decisions? If milestones are not to be used for go/no-go decisions, are they justifiable?

Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without unnecessary steps? Are there additional key experiments that need milestones that could be incorporated into the study design? For projects proposing significant non-clinical testing to enable an IDE, is a Pre-Submission meeting with the FDA to obtain feedback on the proposed testing plan included as a Year 1 milestone?

Plans for Patient Recruitment/Retention:

Does the application document the following?

• Availability of the requisite eligible subject pool in proposed clinical center(s);
• Status of evidence showing whether or not clinically important sex/gender and race/ethnicity differences in the intervention effect are to be expected (see Inclusion of Women and Minorities in Clinical Research below);
• Sites and plans appropriate for the inclusion of minorities and women;
• Plans for recruitment outreach and, as appropriate, follow-up procedures to ensure collection of data at stated intervals; and
• Adequate retention plans and practices?

For research that involves human subjects but does not involve one of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the six categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of children to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following five points: 1) proposed use of the animals, and species, strains, ages, sex, and numbers to be used; 2) justifications for the use of animals and for the appropriateness of the species and numbers proposed; 3) adequacy of veterinary care; 4) procedures for limiting discomfort, distress, pain and injury to that which is unavoidable in the conduct of scientifically sound research including the use of analgesic, anesthetic, and tranquilizing drugs and/or comfortable restraining devices; and 5) methods of euthanasia and reason for selection if not consistent with the AVMA Guidelines on Euthanasia. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

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.

Intellectual Property (IP) Strategy

Are potential issues regarding the IP landscape for the device being developed and the freedom to operate addressed? Do the IP Strategy attachment and related letters of support address potentially concerns? Are there any known constraints that could impede the development of the therapeutic or diagnostic device? Are IP filing plans described? If multiple institutions are involved, is IP sharing addressed as appropriate?

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.

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

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

As part of the scientific peer review, all applications:

• 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.

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

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Neurological Disorders and Stroke Council. The following will be considered in making funding decisions:

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

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.

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.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the grantee’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. 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, Grantees, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Progress towards achievement of the final set of milestones will be evaluated by NIH program staff. NIH program staff may consult as necessary with independent consultants with relevant expertise. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NIH portfolio balance and program priorities, competitive landscape, and availability of funds.

UH2/UH3 Transition

An administrative review will be conducted by NIH program staff with potential input by NIH independent consultants to decide which projects will be transitioned into the clinical study based on the following:

• Successful achievement of the defined milestones for the non-clinical testing period of the project
• Likelihood of success in clinical testing
• Submission of the IDE for the clinical study with documentation of approval or conditional approval of the IDE from the FDA to start the human study or IRB approval for an NSR study
• IRB Approval
• Submission of the final clinical protocol and supporting documents to NIH for administrative review, and notification of approval by NIH
• Agreement on updated timeline, milestones and budget for the clinical study

Because device testing to enable regulatory approval is an inherently high-risk process, it is anticipated that there will be significant attrition as projects move through the process. Prior to funding an application, NIH program staff will contact the applicant to discuss the proposed milestones and any changes suggested by the NIH review panel or NIH program staff. A final set of NIH approved milestones will be specified in the Notice of Award.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Parts 74 and 92 (Part 92 is applicable when State and local Governments are eligible to apply), and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the UH2/UH3 cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with the awardees for the project as a whole, although specific tasks and activities may be shared among the awardees and the NIH as defined below.

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

• The PD(s)/PI(s) will have primary responsibility for defining objectives and approaches, and for planning, conducting, analyzing, interpreting, drawing conclusions on their studies, publishing and sharing the results.
• Awardees are responsible for developing and proposing rigorous milestones that will be achieved during the project period.
• Awardees will retain custody of and have all rights to the data and technology developed under these awards, subject to Government rights of access consistent with current DHHS, PHS, and NIH policies.
• Awardees are responsible for pursuing patent protection.
• Awardees are responsible for providing progress reports with completeness that include experimental design with rigor, including assumptions for the design of the experiments, the results of the investigations, interpretations of the results, and for concluding whether milestones have been met or not. In cases when NIH program staff request raw data, awardees agree to provide the data.
• Awardees agree to participate at least once a year in progress meetings (teleconferences) that are organized by NIH staff.
• Regarding meetings and interactions with regulatory agencies, awardees agree to communicate meeting dates and agenda to the NIH program staff and invite their participation. Note, the FDA does allow NIH program staff to participate in Pre-Submission discussions.
• Awardees agree to communicate study reports from Contract Research Organizations (CROs), meeting minutes (and associated data packages if applicable), letters and other forms of communications with FDA, Recombinant DNA Advisory Committee, and other authorities, and to provide IND/IDE# and registration numbers in clinical trial.gov, if applicable.
• Awardees are responsible for providing regulatory and clinical documents that are required for administrative review.
• Awardees must verify that the clinical trial is performed in accord with Good Clinical Practices (GCP) and in accord with NINDS Guidelines for Data and Safety Monitoring in Clinical Trials: http://www.ninds.nih.gov/research/clinical_research/policies/data_safety_monitoring.htm, and must provide data and regular updates to NIH.

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

• Each project will have the support of one or more Project Scientists from NIH program staff who are assigned an administrative role for the nervous system disorders being studied and have expertise in the implementation of translational research.
• The NIH Project Scientists will have substantial scientific/programmatic involvement during the conduct of this activity, through technical assistance, advice, and coordination above and beyond normal program stewardship for grants.
• NIH Project Scientist(s) provides input on the milestones and makes decisions regarding their finalization.
• NIH Project Scientist(s) will be responsible for assessing the progress of the project towards the specified milestones, and for recommending if further funds should be released to the project.
• NIH Project Scientist(s), in consultation with the PIs, may add critical experiments that need to be conducted prior to or during the award as an additional milestone(s). In most cases, these studies will be supported by additional funds from NIH.
• NIH Project Scientist(s) participates in meetings together with PIs with regulatory agencies related to the funded project.
• An important part of the program is the coordination of research efforts across different funding mechanisms and research capabilities, and the coordination among efforts aimed at different nervous system disorders. NIH Project Scientists will have the primary responsibility for this overall coordination.
• Additionally, an NIH Program Officer will be responsible for the normal scientific and programmatic stewardship of the award and will be named in the award notice.
• NIH leadership will make decisions on project continuation based on program staff recommendations, programmatic prioritizations and budget considerations. NIH program staff may consult as necessary with independent consultants with relevant expertise. If justified, future year milestones may be revised based on data and information obtained during the previous year. If, based on the progress report, a funded project does not meet the milestones, funding for the project may be discontinued. In addition to milestones, the decision regarding continued funding will also be based on the overall robustness of the entire data package that adequately allows an interpretation of the results (regardless if they have been captured in the milestones), overall progress, NIH portfolio balance and program priorities, competitive landscape, and availability of funds.

Areas of Joint Responsibility include:

Clarifying and negotiating the milestones and timelines

Dispute Resolution:

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NIH may be brought to Dispute Resolution. A Dispute Resolution Panel composed of three members will be convened. It will have three members: a designee for the investigators chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of disagreement, the first member may be chosen by the individual awardee. This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16. Final decisions made by NIH regarding a discontinuation are not appealable

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final progress report, 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.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at www.fsrs.gov on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

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)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)
Finding Help Online: http://grants.nih.gov/support/index.html
Email: [email protected]

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)
Telephone: 301-710-0267
Email: [email protected]

Kip Ludwig, PhD
National Institute of Neurological Disorders and Stroke (NINDS))
Telephone: 301-496-1447
Email: [email protected]

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

Tijuanna DeCoster, PhD
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 Parts 74 and 92.