Part 2. Full Text of Announcement

Section I. Funding Opportunity Description

Purpose:

The purpose of this Funding Opportunity Announcement (FOA) is to encourage investigators to pursue translational activities and clinical trials to treat pain with innovative, targeted, and non-addictive diagnostic and/or therapeutic devices that improve patient outcomes and decrease or eliminate the need to prescribe opioids. Activities supported in this program include implementation of clinical prototype devices, non-clinical safety and efficacy testing, design verification and validation activities, obtaining an Investigational Device Exemption (IDE) for a Significant Risk (SR) study or Institutional Review Board (IRB) approval for a Non-Significant Risk (NSR) study, as well as a subsequent small clinical trial (e.g., Early Feasibility Study). The clinical trial is expected to provide information about the device function or final design 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. This is a milestone-driven cooperative agreement program and will involve participation of NIH program staff in the development of the project plan and monitoring of research progress.

Background:

This FOA is part of theNIH’s Helping to End Addiction Long-term (HEAL) Initiative to speed scientific solutions to the national opioid public health crisis.The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at:https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.

Public Law 115-141, the Consolidated Appropriations Act of 2018 (signed March 23, 2018) includes a requirement that grantees from for-profit applicant organizations must provide a 50% match and/or in-kind contribution of all federally awarded dollars under the grant award (direct costs, as well as facilities and administrative costs) for research related to opioid addiction, development of opioid alternatives, pain management and addiction treatment.

Matching Requirement: A grantee from a for-profit organization funded under this funding opportunity announcement must match funds or provide documented in-kind contributions at a rate of not less than 50% of the total-Federally awarded amount, as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018.The applicant will be required to demonstrate that matching funds and/or in-kind contributions are committed or available at the time of, and for the duration of, the award. Applications must identify the source and amount of funds proposed to meet the matching requirement and how the value for in-kind contributions was determined. All matching funds and/or in-kind contributions must be used for the portion of allowable project costs not paid by Federal funds under the grant award. NIH will not be the recipient, nor serve as a pass-through entity, of any such matching funds and/or in-kind contributions required under this announcement. See 45 CFR 75.306 for additional details.

An estimated 20.4% (50 million) Americans suffer from chronic pain and 8% (19.6 million) Americans suffer from high-impact chronic pain. This is a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an overreliance on opioids for chronic pain despite their poor ability to improve function. This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative solutions to develop alternative treatment options for pain are thus critically needed. As part of the mission of the HEAL Initiative, NINDS is working with other NIH Institutes and Centers to encourage the translation of basic research into new non-addictive pain treatments. This program announcement is intended to encourage the translation of diagnostic and therapeutic devices to treat pain and catalyze the development of partnerships between the academic and industrial sectors so that translational research in pain can flourish as a cooperative, iterative process leading to safe, effective, and non-addictive treatments for pain.

This opportunity is part of translational devices to treat pain, a coordinated set of initiatives within HEAL that are intended to support a device-based strategy for new non-addictive pain treatments. Although there are many devices available on the market to treat pain, their efficacy is limited by imprecise targeting resulting from insufficient mechanistic data about the 'device-able' targets, and from lack of closed-loop feedback to modulate the therapy. There is untapped potential to improve patient outcomes through new technologies with enhanced targeting and control. Other initiatives, referenced in the Companion FOAs section above, solicit applications to develop new neuromodulation technologies and to demonstrate the viability of new "device-able" targets. Additional FOAs from the HEAL and BRAIN Initiatives and the SPARC program solicit grant applications to mechanistically research new targets and to demonstrate the viability of these "device-able" targets. Additional FOAs from the HEAL Initiative solicit applications to develop clinical-grade prototypes for new pain treatments, new pre-clinical models for pain, and discovery and validation of new biomarkers of pain.

Objective:

The goal of this Funding Opportunity Announcement (FOA) is to translate innovative, effective, and non-addictive device-based technologies from pre-clinical studies to clinical trials to treat pain in humans. This FOA will support pre-clinical testing and clinical trials to answer key questions about the function or final design of a device. Clinical trials supported are expected to provide information that cannot be practically obtained through additional non-clinical assessments (e.g., bench top or animal studies) and may consist of acute or short-term procedures that are deemed Non-Significant Risk (NSR) by an Institutional Review Board (IRB), or Significant Risk (SR) studies that require an Investigational Device Exemption (IDE) from the U.S. Food and Drug Administration (FDA), such as chronic implants.

Overview:

Cooperative Agreements

This FOA utilizes a UH3 cooperative agreement mechanism to support non-clinical testing to enable IRB and/or an IDE approval necessary to conduct a small clinical trial, and the subsequent small clinical trial (e.g., Early Feasibility Study, seehttp://www.fda.gov/downloads/MedicalDevices/DeviceRegulati%20onandGuidance/GuidanceDocuments/UCM279103.pdf2for details/definition).

As a cooperative agreement, this FOA supports milestone-driven projects and involves NIH program staff's participation in developing the final project plan, monitoring the research progress, and making go/no-go decisions. NIH staff will also assist academic investigators in familiarizing themselves 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 regarding the advancement of devices through the translational developmental pipeline. As such, an inherent rate of attrition is expected within this program.

Public Private Partnership Programs

This FOA for UH3 awards, along with the companion FOAs for U18 development, UG3/UH3 phased applicationss, and U44 SBIR applications , will leverage Public-Private Partnership Programs (PPPs) initiated through the NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the Office of Strategic Coordination The Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) Program, and the HEAL Initiative, which aim to facilitate partnerships between clinical investigators and manufacturers of latest-generation stimulating and/or recording devices to conduct clinical research for the treatment of pain. Through these initiatives, the NIH is interested in reducing barriers to negotiating such partnerships and ensuring that new clinical trials 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 trials requiring amendments to existing Investigational Devices Exemptions (IDEs) from the FDA
• SR clinical trials in which a new IDE would require no or minimal additional non-clinical testing
• SR clinical trials in which a new IDE would require significant additional non-clinical testing, but leverages existing company device data.

The central feature of the BRAIN and SPARC PPPs is a set of template research agreements for collaborations between researchers, research institutions, and device manufacturers. These template agreements were generated with substantial input from industry partners, clinical researchers, the FDA and representatives from institutional tech-transfer and contracts offices, and refined from input at a workshop held on June 3-4, 2015, (video of the workshop is publicly archived at (http://braininitiative.nih.gov/meetings/June-2015-PPP.html)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).

There are three sets of agreement documents associated with the program, which are available at the following websites http://braininitiative.nih.gov/BRAIN_PPP/ and https://commonfund.nih.gov/sparc/newmarkets.

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 HEAL 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 utilizing latest-generation devices for early-stage clinical research. The intent of the template agreements is to create 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.

Institutions or businesses that are developing their own devices are welcome to apply tothis FOA or any of the companion opportunities and are not limited to only working with companies participating in the BRAIN, SPARC, or HEAL PPP. Likewise, individuals and institutions that have already established formal collaborations with device manufacturers (that are part of either PPP or otherwise) are also allowed to apply.

For applications proposing a collaboration with an industry partner, a successful application will be contingent on the applicant's ability to provide the NIH with documentation of company interest in allowing access to the selected device and associated data needed for conducting the proposed non-clinical trials 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, but an executed CRA will be required before issuance of grant award.

A list of devices being offered as part of the BRAIN and SPARC PPPs, along with associated information, can be found at http://braininitiative.nih.gov/BRAIN_PPP/, https://commonfund.nih.gov/sparc/newmarkets,and https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative/public-private-partnership.

Scope

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 a clinical trial, and conduct of a small clinical trial. The development and testing of both diagnostic and therapeutic devices of electrical, chemical, optical, sonic, or other relevant modalities that interface either invasively or non-invasively are within scope of this FOA. Therapeutic devices should address a specific, clinically meaningful purpose related to the treatment of pain. Relevant diagnostic devices should be novel tools used to characterize or identify the nature or cause of a medical condition. Existing diagnostic devices for which there is little to no development needed and the diagnosis serves as an endpoint and/or biomarker might also consider RFA-NS-18-041 or RFA-NS-18-046; Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain and Analytical and/or Clinical Validation of a Candidate Biomarker for Pain, respectively.

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 trial.

For entry to the program, projects should have:

• Comprehensive supporting data showing proof-of-concept of device function using a prototype device equivalent to the final device design anticipated for clinical testing, ideally obtained using anin vivomodel representative of the intended patient population
• Completed all non-clinical testing necessary for approval to conduct the clinical trial
• A compelling case for a successful IDE submission to support the clinical component, or IRB approval for an NSR study, within the first year 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 measure(s) based on input from both clinicians and patients

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

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

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

• Optimization of the device design with respect to the human functional anatomy
• Identification of the most simple, reliable, and cost-effective device configuration for more advanced clinical 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

The following activities are non-responsive to this FOA, and will not be reviewed:

• animal model development: all in vivo models must be well established and characterized, and available to the applicant;
• efforts to develop neurotechnology for study of the fundamental function or physiology;
• projects solely proposing exempt human subject research;
• non-clinical testing necessary to support regulatory approval;
• delayed-onset studies; and
• projects focused on augmentation of neural function in healthy individuals;

Milestones

Because device development is inherently high-risk, attrition is anticipated as projects move through the process. To help mitigate this risk, applications must propose one or more milestones associated with each of the research plan's objectives, in each year of the project. Milestones are goals that measure success and/or efficacy that can be used for go/no-go decision-making for the project and should have quantitative success criteria and the rationale for that criteria associated with them (see Section IV.2 for details). Quantitative criteria should be robust and consistent with the state-of-the-art in the field. ?Details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured) should be included for each milestone. Each milestone must have a timeline, and be incorporated into the overall project timeline, which should also be reflected in a Gantt chart.

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

NIH encourages increasing the rigor and reproducibility of observed results.In some cases, conducting additional critical experiments will be important for NIH to have confidence in making a funding decision.Therefore, program staff may suggest modification or additional experimentsthat 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.

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.NIH recognizes that the degree to which Design Controls and Quality Systems processes are required by the FDA may vary substantially depending on the specific device.Investigators are encouraged to discuss these issues with the FDA and regulatory consultants prior to submitting an application so the extent to which these processes are required is clearly defined and verifiable in the application. Applicants should consider the Quality System requirements at the IDE stage (i.e., design controls) when preparing their device development activities. Applicants should consider Guidelines and Policies for Monitoring Clinical Research in the formation of a plan for data and safety monitoring as required by the appropriate IC.

Intellectual Property (IP)

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

Pre-Submission Consultation

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.

Section II. Award Information

Section III. Eligibility Information

1. Eligible Applicants

Higher Education Institutions

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

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

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

Nonprofits Other Than Institutions of Higher Education

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

For-Profit Organizations

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

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
• U.S. Territory or Possession

• 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

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.

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.

2. Cost Sharing

For grantees from a for-profit organization, this FOA does require cost sharing, as defined in the NIH Grants Policy Statement. More information on cost matching requirements is in Section IV.2 R&R or Modular Budget

3. Additional Information on Eligibility

Number of Applications

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)

Section IV. Application and Submission Information

1. Requesting an Application Package

Buttons to access the online ASSIST system or to download application forms are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

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

Letter of Intent

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

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

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

The letter of intent should be sent to:

N ick Langhals, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Fax: 301-480-1080
Email: [email protected]

Needs Assessment: Applications must include a needs assessment that is no more than three pages. Applications that exceed this limit will be withdrawn. This attachment should be entitled "Needs Assessment.pdf". The needs assessment should establish performance requirements with clear, quantifiable metrics and identify significant issues faced by stakeholders (patients, clinicians, caregivers, customers), which is a key step in the design control process and will be evaluated for adequacy.

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; and identify any human factors incorporated into the proposed research that optimize human interaction, productivity, and understanding while using the technology.

Intellectual Property (IP) Strategy: Applications are expected to include an IP strategy that is no more than three pages. Applications that exceed this limit will be withdrawn. This attachment should be entitled "IP Strategy.pdf" which 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.

A goal of this program initiative is to advance research towards the development of products that will benefit the public. Accordingly, applicants should describe the IP landscape surrounding their therapeutic or diagnostic device. This should include any known constraints that could impede the development of their therapeutic device or diagnostic (e.g., certain restrictions under transfer or sharing agreements, applicants' previous or present IP filings and publications, similar technologies that are under patent and/or on the market, etc.) and how these issues could be addressed as appropriate and consistent with achieving the goals of the program. If the applicant proposes using a device or technology whose IP is not owned by the applicant's institution, either an investigational therapeutic or diagnostic, FDA-approved therapeutic or diagnostic, or other licensed product, the applicant should address any questions that may constrain or impede its ability to operate and move the technology forward consistent with achieving the goals of the program. Applicants should include a letter (see Letters of Support) from the entity that owns the IP indicating whether the entity will provide the device or technology, if there are any limits on the studies that can be performed with that device or technology, and agreement about public disclosure of results (including negative results), and whether there is an agreement already in place.

If patents pertinent to the therapeutic or diagnostic device being developed under this application have been filed, the applicants should indicate the details of filing dates, what types of patents are filed, application status, and associated United States Patent Office (USPTO) links, if applicable.

Applicants should also discuss future IP filing plans. For a multiple-PD/PI, multiple-institution application, applicants should describe how IP will be shared or otherwise managed, and the infrastructure of each institution for bringing the technologies to practical application and for coordinating these efforts (e.g., licensing, managing IP) among the institutions in the Team Management Plan.

Communications with the IRB: For projects proposing an NSR clinical trial, either IRB NSR designation, or preliminary communications (e.g., letter or other documentation) with the IRB indicating likelihood to support the NSR clinical trial should be included with a description of how the feedback will be incorporated. This attachment should be entitled "IRB_Communications.pdf" which will be reflected in the final image?.

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

Specific Aims:

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

• Define the aims of the clinical study.
• A scientific hypothesis is not required nor expected for work of this nature.

Research Strategy:

The single Research Strategy attachment should include the following subsections:

Significance

Clinical Impact and Feasibility

The target patient population and intended use should guide the design of the device and of the pre-clinical studies.

• Describe the current state of knowledge of the etiology, clinical characteristics, and current and projected prevalence of the proposed disease indication.
• Briefly discuss available treatments, their limitations, and how the proposed project would address an unmet clinical need or provide a benefit over existing therapies, regardless of therapeutic class (i.e. agents and devices).
• Identify one or more clinically robust and meaningful device outcome measures based on input from both clinicians and patients, and supporting literature.
• Discuss how the proposed project would affect clinical practice and how it relates to therapy development efforts underway in academia and industry, including both agents and devices.
• ?Explain the rationale for the minimally acceptable and ideal results.

Supporting Data for Entry

• Include 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.
• Prior to entry, all projects must have completed all non-clinical testing necessary to obtain an Investigational Device Exemption (IDE) for a Significant Risk (SR) clinical trial or obtained Institutional Review Board (IRB) approval for a Non-Significant Risk (NSR) clinical trial. Approval is not required at the time of application. In addition, projects must obtain the necessary approval to conduct the clinical trial prior to entry or within the first year of the award.

Approach

Overall Device Development Plan?

Applicants must include an overall plan for device development. This plan should include:

• A clearly stated device development timeline that includes practical, achievable goals leading up to, during, and beyond the proposed clinical trial.
• Discussion of how feedback from appropriate U.S. regulatory bodies (e.g., FDA in the form of pre-submission meetings and IDE submission) has been incorporated into the development plan, if available.
• 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.

Detailed Plans for Research Strategy

• Elaborate on the device testing strategy to enable the clinical studies.
• Investigators should clearly articulate what the next step will be in device development assuming a successful outcome of the clinical trial
• J?ustify the outcome metrics for the proposed clinical trial in terms of quantifialbe minimum-success criteria necessary to enable the next step.
• Research plans and milestones for the clinical trial should be included in the PHS Human Subjects and Clinical Trials Information forms.

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.

For-profit applicants must include a letter(s) of support confirming that the required secured cost matching (cash; in-kind commitments such as salary, consultant costs, equipment) is available and confirm that the essential personnel have the authority within the organization to allocate resources.

The following modifications also apply:

• All applications, regardless of the amount of direct costs requested for any one year, should address a Data Sharing Plan.
• 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 filing for patent protection to allow for both further research and the development of commercial products to advance forward, consistent with achieving the goals of the program.
• Applicants should anticipate that, if awarded, their project will join a consortium work group, coordinated by the NIH, to identify consensus standards of practice as well as supplemental opportunities to collect and provide data for ancillary studies, and to aggregate and standardize data for dissemination among the wider scientific community. Accordingly, the Data Sharing Plan should include a statement of intention to join and cooperate with a future collaborative consortium of awardees to maximize data sharing opportunities (including collection, curation, analysis and sharing) for this unique population of human subjects.

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.7 Study Timeline

UH3 Milestone Plan

• Applicants are required to provide detailed project performance and timeline objectives. These milestones will be negotiated prior to issuing the notice of award.
• Applicants must include a timeline and quantitative milestones for completion of key stages of the trial, especially participant recruitment, enrollment, and retention through the planned follow-up periods.
• Yearly minimum success criteria for ongoing evaluations of device safety and efficacy that define clear go/no-go points must also be included as milestones.
• A project timeline in the form of a Gantt chart that includes all milestones described in the text must be included

Examples of appropriate topics covered by UH3 Milestones include:

• Finalization of clinical protocol (with program agreement, if applicable);
• Registration of clinical trial in ClinicalTrials.gov;
• Completion of regulatory approvals;
• Enrollment of the first subject;
• Enrollment and randomization, if applicable of the projected study population, including women, minorities and children (as appropriate);
• Completion of data collection time period;
• Completion of primary endpoint and secondary endpoint data analyses;
• Completion of final study report;
• Reporting of results in ClinicalTrials.gov;
• Other protocol-specific performance milestones and timeline; these milestones will be negotiated prior to issuing the award, if appropriate.

Section 3 - Protection and Monitoring Plans

3.5 Overall structure of the Study Team

Team Management Plan

The team management plan must not exceed two pages. 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, experts in manufacturing under Quality Systems and Design Controls, and other relevant academic/industry experts. This multi-disciplinary 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. For publications, policies to address the ordering and recognition of authors, and decisions about what material to publish, consistent with the interests of commercial partners (where applicable), should be presented.

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

Section 4 - Protocol Synopsis
4.6 Will the study use an FDA-regulated intervention?
4.6.a. If yes, describe the availability of Investigational Product (IP) and Investigational New Drug (IND)/Investigational Device Exemption (IDE) status:
Communications with FDA:

• Applicants should include minutes from all pre-submission meetings, notice of IDE, risk determination, email communications, and other relevant documentation. This material should only be submitted in section 4.6.a of the application or as post-submission material.
• 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 design and manufacturing processes is not required, applicants should include a communication from the FDA clearly stating this is the case in the form of a response to a Pre-Submission. If these studies are

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

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

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

4. Submission Dates and Times

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

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

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.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

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

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

7. Other Submission Requirements and Information

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. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile 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.

In addition to the items described in the policy, letters and documentation of communications with regulatory bodies, including the FDA or IRB, may be submitted as post-submission materials (NIH post-submission deadline applies).

Communications with the IRB.

• For projects requiring non-clinical testing to support an IRB NSR designation, preliminary communications (e.g., letter or other documentation) with the IRB indicating what non-clinical testing will be necessary to support the NSR clinical trial should be included with a description of how the feedback will be incorporated. This document must not exceed 5 pages.

Communications with FDA

• Applicants should include minutes from all pre-submission meetings, notice of IDE, risk determination, email communications, and other relevant documentation. This material should only be submitted in section 4.6.a of the application or as post-submission material.
• 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 design and manufacturing processes is not required, applicants should include a communication from the FDA clearly stating this is the case in the form of a response to a Pre-Submission. If these studies are proposed, but ultimately not needed, program staff will work with the investigators to remove the relevant milestones and associated costs of these activities from the award. This document must not exceed 30 pages.

Section V. Application Review Information

1. Criteria

Only the review criteria described below will be considered in the review process. Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

In addition, for applications involving clinical trials:

A proposed Clinical Trial application may include study design, methods, and intervention that are not by themselves innovative but address important questions or unmet needs. Additionally, the results of the clinical trial may indicate that further clinical development of the intervention is unwarranted or lead to new avenues of scientific investigation.

For this particular announcement, note the following:

The market size for the proposed types of therapeutic or diagnostic devices through this request for applications may be considered small compared to other markets. Provided these smaller markets are sustainable, applications should not be penalized for their comparatively smaller market. NIH is supportive of research for both rare and high incidence disorders that fall under the mission of NIH.

The UH3 Cooperative Agreement grant supports investigation of novel scientific ideas or new interventions, model systems, tools, or technologies that have the potential for significant impact on biomedical or behavioral and social sciences research. Appropriate justification for the proposed work can be provided through literature citations, data from other sources, or from investigator-generated data. Accordingly, the evaluation will emphasize the conceptual framework, the level of innovation, and the potential to significantly advance our knowledge or understanding.

Significance

Does the project address an important problem or a critical barrier to progress in the field? Is there a strong scientific premise for the project? 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?

For this particular announcement, note the following:

Supporting Data for Entry:

• If included, does the FDA Pre-Submission (formerly pre-IDE) feedback indicate that the proposed pre-clinical testing plan is sufficient to support a successful FDA submission for an IDE? Or for Non-Significant Risk (NSR) studies, do the preliminary communications with the IRB indicate that the proposed pre-clinical testing plan is sufficient to support the NSR clinical trial?

Needs Assessment:

• Is the needs assessment adequate and complete?
• Does the needs assessment incorporate input from all relevant stakeholders (patients, clinicians, caregivers)?

In addition, for applications involving clinical trials

Are the scientific rationale and need for a clinical trial to test the proposed hypothesis or intervention well supported by preliminary data, clinical and/or preclinical studies, or information in the literature or knowledge of biological mechanisms? For trials focusing on clinical or public health endpoints, is this clinical trial necessary for testing the safety, efficacy or effectiveness of an intervention that could lead to a change in clinical practice, community behaviors or health care policy? For trials focusing on mechanistic, behavioral, physiological, biochemical, or other biomedical endpoints, is this trial needed to advance scientific understanding?

Investigator(s)

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those 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?

For this particular announcement, note the following:

Team Management Plan (PHS Human Subjects and Clinical Trials Information, Section 3.5):

• Has an interdisciplinary team been assembled, and have experts in pre-clinical development and clinical development been appropriately 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 pre-clinical, regulatory, 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?
• Has a Scientific Steering Group (SSG) been described and are the members appropriate?

In addition, for applications involving clinical trials

With regard to the proposed leadership for the project, do the PD/PI(s) and key personnel have the expertise, experience, and ability to organize, manage and implement the proposed clinical trial and meet milestones and timelines? Do they have appropriate expertise in study coordination, data management and statistics? For a multicenter trial, is the organizational structure appropriate and does the application identify a core of potential center investigators and staffing for a coordinating center?

Innovation

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?

For this particular announcement, note the following:

• How significant of an advantage does the proposed device offer over all existing approaches as well as those in development for the same indication regardless of therapeutic or diagnostic classes, including drugs, biologics, as well as competing device technologies?
• If the proposed device is designed to improve over early generations that may or may not have been marketed, are the potential advantages truly significant? Are those changes likely to succeed where the predecessor did not?

In addition, for applications involving clinical trials

Does the design/research plan include innovative elements, as appropriate, that enhance its sensitivity, potential for information or potential to advance scientific knowledge or clinical practice?

Approach

Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? 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? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

In addition, for applications involving clinical trials

Does the application adequately address the following, if applicable

Study Design

Is the study design justified and appropriate to address primary and secondary outcome variable(s)/endpoints that will be clear, informative and relevant to the hypothesis being tested? Is the scientific rationale/premise of the study based on previously well-designed preclinical and/or clinical research? Given the methods used to assign participants and deliver interventions, is the study design adequately powered to answer the research question(s), test the proposed hypothesis/hypotheses, and provide interpretable results? Is the trial appropriately designed to conduct the research efficiently? Are the study populations (size, gender, age, demographic group), proposed intervention arms/dose, and duration of the trial, appropriate and well justified?

Are potential ethical issues adequately addressed? Is the process for obtaining informed consent or assent appropriate? Is the eligible population available? Are the plans for recruitment outreach, enrollment, retention, handling dropouts, missed visits, and losses to follow-up appropriate to ensure robust data collection? Are the planned recruitment timelines feasible and is the plan to monitor accrual adequate? Has the need for randomization (or not), masking (if appropriate), controls, and inclusion/exclusion criteria been addressed? Are differences addressed, if applicable, in the intervention effect due to sex/gender and race/ethnicity?

Are the plans to standardize, assure quality of, and monitor adherence to, the trial protocol and data collection or distribution guidelines appropriate? Is there a plan to obtain required study agent(s)? Does the application propose to use existing available resources, as applicable?

Data Management and Statistical Analysis

Are planned analyses and statistical approach appropriate for the proposed study design and methods used to assign participants and deliver interventions? Are the procedures for data management and quality control of data adequate at clinical site(s) or at center laboratories, as applicable? Have the methods for standardization of procedures for data management to assess the effect of the intervention and quality control been addressed? Is there a plan to complete data analysis within the proposed period of the award?

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?

For this particular announcement, note the following:

Overall device development plan:

• Is the overall plan for device development reasonable, including the plan after conclusion of the proposed trial?
• Are there clear metric driven design criteria developed with input from stakeholders? Is the regulatory plan reasonable in terms of regulatory path to market as well as FDA data requirements to meet the appropriate regulatory standard (e.g., reasonable assurance of safety and effectiveness for PMA submissions, substantial equivalence for 510(k) submissions?

Detailed Plans for Research Strategy:

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

Long Term Plan for Patients (PHS Human Subjects and Clinical Trials Information, Section 5.1):

• Is a plan for care of patients at the end of the study reasonable?
• If appropriate, is care for patients beyond the study period described?

Environment

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?

For this particular announcement, note the following:

• Is there sufficient regulatory expertise on the team to facilitate regulatory consultations and approvals?

In addition, for applications involving clinical trials

If proposed, are the administrative, data coordinating, enrollment and laboratory/testing centers, appropriate for the trial proposed?

Does the application adequately address the capability and ability to conduct the trial at the proposed site(s) or centers? Are the plans to add or drop enrollment centers, as needed, appropriate?

If international site(s) is/are proposed, does the application adequately address the complexity of executing the clinical trial?

If multi-sites/centers, is there evidence of the ability of the individual site or center to: (1) enroll the proposed numbers; (2) adhere to the protocol; (3) collect and transmit data in an accurate and timely fashion; and, (4) operate within the proposed organizational structure?

Study Timeline

Specific to applications involving clinical trials:

• Is the study timeline described in detail, taking into account start-up activities, the anticipated rate of enrollment, and planned follow-up assessment?
• Is the projected timeline feasible and well justified?
• Does the project incorporate efficiencies and utilize existing resources (e.g., CTSAs, practice-based research networks, electronic medical records, administrative database, or patient registries) to increase the efficiency of participant enrollment and data collection, as appropriate?
• Are potential challenges and corresponding solutions discussed (e.g., strategies that can be implemented in the event of enrollment shortfalls)?

Milestone Plan

• Are milestones timely and robust and associated with clear, quantitative criteria for efficacy and success that allow go/no-go decisions?
• Are the timelines proposed for achieving the milestones realistic and inclusive of necessary steps, but also efficient without adding unnecessary steps?
• Are there additional key experiments that need to have milestones?
• Does the provided Gantt chart demonstrate a reasonable timeline for the project plan?

Protections for Human Subjects

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.

Inclusion of Women, Minorities, and Children

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.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.

Biohazards

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.

Resubmissions

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

Renewals

Not Applicable

Revisions

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

Intellectual Property (IP) strategy:

• Are potential issues regarding the IP landscape for the device being developed and means for addressing any IP hurdles/barriers addressed?
• Do the IP Strategy attachment and related letters of support address potential concerns?
• Are there any known constraints that could impede the development of the device?
• Are IP filing plans described and appropriate?

Applications from Foreign Organizations

Not Applicable

Select Agent Research

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).

Resource Sharing Plans

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 Data Sharing Plan (GDS).

Authentication of Key Biological and/or Chemical Resources:

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

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.
Specific to this FOA:
How likely is it that the plans for cost matching will be adequate?

2. Review and Selection Process

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

• 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.

• 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.

3. Anticipated Announcement and Award Dates

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

Section VI. Award Administration Information

1. Award Notices

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.

Individual awards are based on the application submitted to, and as approved by, the NIH and are subject to the IC-specific terms and conditions identified in the NoA.

ClinicalTrials.gov: If an award provides for one or more clinical trials. By law (Title VIII, Section 801 of Public Law 110-85), the "responsible party" must register and submit results information for certain applicable clinical trials on the ClinicalTrials.gov Protocol Registration and Results System Information Website (https://register.clinicaltrials.gov). NIH expects registration of all trials whether required under the law or not. For more information, see http://grants.nih.gov/ClinicalTrials_fdaaa/

Institutional Review Board or Independent Ethics Committee Approval: Grantee institutions must ensure that the application as well as all protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols. Data and Safety Monitoring Requirements: The NIH policy for data and safety monitoring requires oversight and monitoring of all NIH-conducted or -supported human biomedical and behavioral intervention studies (clinical trials) to ensure the safety of participants and the validity and integrity of the data. Further information concerning these requirements is found at http://grants.nih.gov/grants/policy/hs/data_safety.htm and in the application instructions (SF424 (R&R) and PHS 398).

Investigational New Drug or Investigational Device Exemption Requirements: Consistent with federal regulations, clinical research projects involving the use of investigational therapeutics, vaccines, or other medical interventions (including licensed products and devices for a purpose other than that for which they were licensed) in humans under a research protocol must be performed under a Food and Drug Administration (FDA) investigational new drug (IND) or investigational device exemption (IDE).

2. Administrative and National Policy Requirements

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights law. This means that recipients of HHS funds must ensure equal access to their programs without regard to a person’s race, color, national origin, disability, age and, in some circumstances, sex and religion. This includes ensuring your programs are accessible to persons with limited English proficiency. HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA. HHS provides general guidance to recipients of FFA on meeting their legal obligation to take reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. Please see http://www.hhs.gov/ocr/civilrights/resources/laws/revisedlep.html. The HHS Office for Civil Rights also provides guidance on complying with civil rights laws enforced by HHS. Please see http://www.hhs.gov/ocr/civilrights/understanding/section1557/index.html; and http://www.hhs.gov/ocr/civilrights/understanding/index.html. Recipients of FFA also have specific legal obligations for serving qualified individuals with disabilities. Please see http://www.hhs.gov/ocr/civilrights/understanding/disability/index.html. Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at http://www.hhs.gov/ocr/office/about/rgn-hqaddresses.html or call 1-800-368-1019 or TDD 1-800-537-7697. Also note it is an HHS Departmental goal to ensure access to quality, culturally competent care, including long-term services and supports, for vulnerable populations. For further guidance on providing culturally and linguistically appropriate services, recipients should review the National Standards for Culturally and Linguistically Appropriate Services in Health and Health Care at http://minorityhealth.hhs.gov/omh/browse.aspx?lvl=2&lvlid=53.

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 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this program will be the cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the 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:

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

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

• 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 disorder(s) 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 suggest modification or additional experiments 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:

3. Reporting

A final Research Performance Progress Report (F-RPPR), invention statement, and the expenditure data portion of the Federal Financial Report, including Federal and non-Federal share for cost matching, 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.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

Finding Help Online: http://grants.nih.gov/support/ (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application processes and NIH grant resources)
Email: [email protected] (preferred method of contact)
Telephone: 301-945-7573

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

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

Danilo Tagle, Ph.D
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-8064
Email: [email protected]

Wen G. Chen, MMSc, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-451-3989
Email: [email protected]

Diane St. Germain
National Cancer Institute (NCI)
Telephone: 240-276-7082
Email: [email protected]

Houmam Araj
National Eye Institute (NEI)
Phone: 301-451-2020
Email: [email protected]

Soundar Regunathan, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: 301-443-1192
Email: [email protected]

Charles H. Washabaugh, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5050
Email: [email protected]

Michael B. Wolfson
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301-451-4778
Email: [email protected]

Kevin Walton
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-5980
Email: [email protected]

Yolanda F. Vallejo, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301.827.4655
E-mail: [email protected]

Teresa L.Z. Jones, MD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-435-2996
Email: [email protected]

David McMullen, M.D.
National Institute of Mental Health (NIMH)
Telephone: 301-451-0180
Email: [email protected]

Augie Diana, Ph.D.
National Institute of Nursing Research (NINR)
Telephone: (301) 402-6423
Email: [email protected]

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

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

Ki-Cha Flash
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-435-0846
Email: [email protected]

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301.594.3788
Email: [email protected]

Amy Bartosch
National Cancer Institute (NCI)
Telephone: 240-276-6912
Email: [email protected]

Karen Robinson Smith
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: [email protected]

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: [email protected]

Katie Ellis
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301-451-4791
Email: [email protected]

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Tel:(301) 594-7760
Email: [email protected]

Bryan S. Clark, MBA
Eunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-0915
Email: [email protected]

Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-1159
Email: [email protected]

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: [email protected]

Christina Coriz
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8848
Email: [email protected]

Rebecca Claycamp
National Institute of Mental Health (NIMH)
Telephone: 301-443-2811
E-mail: [email protected]

Kelli Oster
National Institute of Nursing Research (NINR)
Telephone: 301-594-2177
Email: [email protected]

Section VIII. Other Information