Purpose:

The purpose of this Funding Opportunity Announcement (FOA) is to encourage small business concerns (SBCs) 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 nonclinical 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 the NIH 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 promote the translation of diagnostic and therapeutic devices to treat pain and catalyze partnerships 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 U44 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, see http://www.fda.gov/downloads/MedicalDevices/DeviceRegulati%20onandGuidance/GuidanceDocuments/UCM279103.pdf2 for details/definition).

The SBIR Phase I will support non-clinical testing toward obtaining of an IDE and IRB approval for an SR study, or to obtain IRB approval for an NSR clinical trial. Fast-track projects will start at the SBIR Phase I and only those SBIR Phase I projects that have met specific criteria (see below) will transition to the subsequent SBIR Phase II after NIH administrative review. The SBIR Phase II will support a small clinical trial and can last up to four years, however, the total project period (including both the SBIR Phase I and Phase II) must not exceed five years. Phase II projects for which only a clinical phase up to four years is proposed can be submitted under this announcement as well. Projects interested in a larger clinical trial or feasibility study may also consider opportunities in the HEAL Clinical Trials Networks.

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 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 , along with the companion FOAs for U18 development, UG3/UH3 phased applications, and UH3 clinical research, 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 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.htm) and a public feedback from a Request for Information issued in the NIH Guide (http://grants.nih.gov/grants/guide/notice-files/NOT-NS-15-032.html).

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 to RFA-EB-18-003, RFA-NS-19-016, RFA-NS-19-018 , or this FOA and are not limited to only working with companies participating in the BRAIN, SPARC, or HEAL PPP. Likewise, companies 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 PPPs, along with associated information, can be found at https://www.braininitiative.nih.gov/resources/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 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 trial, and a device related 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.

Entry Criteria

For entry to the program, projects should have:

• Comprehensive supporting data based on bench, in vitro, and/or in vivo models representative of the intended patient population and indication.
• Identified one or more clinically meaningful device outcome measures based on input from both clinicians and patients, as well as supporting literature.
• A compelling case for successfully obtaining IDE and IRB approvals for a SR clinical trial , or IRB approval for an NSR study prior to starting Phase II activities.
• Applicants to the Fast-Track mechanism are encouraged, but not required, to consult with FDA via a Pre-Submission meeting, study risk designation request, and/or 513(g) submission prior to applying for funding through this grant mechanism. Applicants who do not have sufficiently relevant feedback from the FDA regarding all planned activities prior to application for funding will be expected to do so as the first milestone during the first year of the SBIR Phase I of the award (see https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/NeurologicalDevices/default.htm and https://www.youtube.com/watch?v=u0zPKPLW2mU for helpful resources). Funding will be restricted to a maximum of $100,000 in direct costs until FDA feedback that is consistent with the likely success of the regulatory path to market and overall device development plan outlined in the grant application is received. In the event that FDA feedback is not consistent with the plans in the grant, program staff will evaluate the concerns and change of scope that would be needed and work with the investigators to determine the most appropriate course of action. Project plans and timelines should plan accordingly for these first activities of the award.
• Those applying for the Direct to Phase II mechanism:
  • Completed all non-clinical testing necessary for approval to conduct the clinical trial
  • 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 an in vivo model representative of the intended patient population
  • Overall device development plan, including timeline for interaction with appropriate regulatory bodies and clinical considerations
  • Identification of one or more clinically meaningful device outcome measure(s) based on input from both clinicians and patients
  • FDA IDE and/or IRB approvals are not required at the time of application, however, both the IDE and IRB approvals must be obtained before an award will be made.

SBIR Phase I Scope

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

• are very close to the 'final system' and manufactured using very close to the same manufacturing process as the device to be marketed or studied in a larger clinical trial following the completion of this project; or
• require early feasibility clinical data to inform the final device design or manufacturing processes.

Examples of studies that may be proposed during the SBIR Phase I Scope include, but are not limited to:

• Non-Good Laboratory Practice (GLP) animal studies to develop surgical techniques relevant to the device, optimize relevant therapeutic parameters, and refine device design as necessary for subsequent GLP testing or additional clinical trials for regulatory approval.
• Bench-top and animal testing to demonstrate compliance with FDA Recognized Standards.
• GLP compliant large animal model safety and/or testing of an implanted device.
• Activities to become current Good Manufacturing Practice (GMP) compliant.
• Activities to bring the development process under Design and Quality Systems Control,
• Device, software, and firmware design verification and validation activities.
• Development of packaging, connectors, and other accessories necessary for the translation of this technology.
• Regulatory activities, including pre-submission meetings with FDA, IDE submission, or other FDA regulatory submissions (e.g., Humanitarian Use Device (HUD) Designation, Request for Risk Designation, 513(g) submission).
• A limited clinical experience is also allowable during the SBIR Phase I if it is necessary to support the IDE submission for the small clinical trial conducted in the SBIR Phase II. Clinical trials in the SBIR Phase I are out of scope if the planned SBIR Phase II small clinical trial is NSR.

SBIR Phase II Scope

The SBIR Phase II will support a small clinical trial that will lead to either:

• a marketing application;
• 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; or
• 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 proposing solely exempt human subject research;
• 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 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.

SBIR Phase I and Phase II Transition:

An administrative review will be conducted by program staff, with potential input by independent consultants, to decide whether a SBIR Phase I project will transition into the SBIR Phase II based on the

• successful achievement of the defined milestones for the SBIR Phase I of the project;
• likelihood of success in clinical testing;
• competitive landscape;
• program balance;
• availability of funds;
• for significant risk studies, an approved IDE for the clinical trial from the FDA;
• IRB approval(s);
• submission of the final clinical protocol and supporting documents to NIH for administrative review, and notification of approval by NIH;
• feedback on activities involving humans subjects obtained from the Safety and Risk Assessment Committee (SARAC); and
• agreement on updated timeline, milestones and budget for the clinical trial.

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.

IC-Specific Language

NCATS

The National Center for Advancing Translational Sciences (NCATS) will not be accepting any clinical trial(s) under this funding announcement. If your proposed work includes an NIH-defined clinical trial it would be assigned to one of the other NIH Institutes/Centers participating in this funding announcement. Where a clinical trial is contemplated in the proposed work, the NCATS may be amenable to co-funding with one of the other participating ICs. Please contact appropriate program staff if you have any questions.

1. Eligible Applicants

1. Is organized for profit, with a place of business located in the United States, which operates primarily within the United States or which makes a significant contribution to the United States economy through payment of taxes or use of American products, materials or labor;

2. Is in the legal form of an individual proprietorship, partnership, limited liability company, corporation, joint venture, association, trust or cooperative, except that where the form is a joint venture, there must be less than 50 percent participation by foreign business entities in the joint venture;

3. 1. SBIR and STTR. Be a concern which is more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), or any combination of these; OR
   2. SBIR-only. Be a concern which is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these. No single venture capital operating company, hedge fund, or private equity firm may own more than 50% of the concern; OR
   3. SBIR and STTR. Be a joint venture in which each entity to the joint venture must meet the requirements set forth in paragraph 3 (i) or 3 (ii) of this section. A joint venture that includes one or more concerns that meet the requirements of paragraph (ii) of this section must comply with 121.705(b) concerning registration and proposal requirements.
4. Has, including its affiliates, not more than 500 employees.

If the concern is more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these falls under 3 (ii) or 3 (iii) above, see Section IV. Application and Submission Information for additional instructions regarding required application certification.

If an Employee Stock Ownership Plan owns all or part of the concern, each stock trustee and plan member is considered an owner.

If a trust owns all or part of the concern, each trustee and trust beneficiary is considered an owner.

Definitions:

• Hedge fund has the meaning given that term in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The hedge fund must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
• Portfolio company means any company that is owned in whole or part by a venture capital operating company, hedge fund, or private equity firm.
• Private equity firm has the meaning given the term private equity fund in section 13(h)(2) of the Bank Holding Company Act of 1956 (12 U.S.C. 1851(h)(2)). The private equity firm must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.
• Venture capital operating company means an entity described in 121.103(b)(5)(i), (v), or (vi). The venture capital operating company must have a place of business located in the United States and be created or organized in the United States, or under the law of the United States or of any State.

SBCs must also meet the other regulatory requirements found in 13 C.F.R. Part 121. Business concerns, other than investment companies licensed, or state development companies qualifying under the Small Business Investment Act of 1958, 15 U.S.C. 661, et seq., are affiliates of one another when either directly or indirectly, (a) one concern controls or has the power to control the other; or (b) a third-party/parties controls or has the power to control both. Business concerns include, but are not limited to, any individual (sole proprietorship) partnership, corporation, joint venture, association, or cooperative. The SF424 (R&R) SBIR/STTR Application Guide should be referenced for detailed eligibility information.

Small business concerns that are more than 50% owned by multiple venture capital operating companies, hedge funds, private equity firms, or any combination of these are NOT eligible to apply to the NIH STTR program.

Phase I to Phase II Transition Rate Benchmark

In accordance with guidance from the SBA, the HHS SBIR/STTR Program is implementing the Phase I to Phase II Transition Rate benchmark required by the SBIR/STTR Reauthorization Act of 2011. This Transition Rate requirement applies to SBIR and STTR Phase I applicants that have received more than 20 Phase I awards over the past 5 fiscal years, excluding the most recently-completed fiscal year. For these companies, the benchmark establishes a minimum number of Phase II awards the company must have received for a given number of Phase I awards received during the 5-year time period in order to be eligible to apply for a new Phase I award. This requirement does not apply to companies that have received 20 or fewer Phase I awards over the 5 year period.

Companies that do not meet or exceed the benchmark rate will not be eligible to apply for a Phase I Fast-Track, or Direct Phase II (if available) award for a period of one year from the date of the application submission. The Transition Rate is calculated as the total number of SBIR and STTR Phase II awards a company received during the past 5 fiscal years divided by the total number of SBIR and STTR Phase I awards it received during the past 5 fiscal years excluding the most recently-completed year. The benchmark minimum Transition Rate is 0.25.

SBA calculates individual company Phase I to Phase II Transition Rates daily using SBIR and STTR award information across all federal agencies. For those companies that have received more than 20 Phase I awards over the past 5 years, SBA posts the company transition rates on the Company Registry at SBIR.gov. Information on the Phase I to Phase II Transition Rate requirement is available at SBIR.gov.

Applicants to this FOA that may have received more than 20 Phase I awards across all federal SBIR/STTR agencies over the past five (5) years should, prior to application preparation, verify that their company’s Transition Rate on the Company Registry at SBIR.gov meets or exceeds the minimum benchmark rate of 0.25.

Phase II to Phase III Commercialization Benchmark

In accordance with guidance from the SBA, HHS, including NIH, SBIR/STTR Programs are implementing the Phase II to Phase III Commercialization Rate benchmark for Phase I applicants, as required by the SBIR/STTR Reauthorization Act of 2011. The Commercialization Rate Benchmark was published in a Federal Register notice on August 8, 2013 (78 FR 48537).

This requirement applies to companies that have received more than 15 Phase II awards from all agencies over the past 10 years, excluding the two most recently-completed Fiscal Years. Companies that meet this criterion must show an average of at least $100,000 in revenues and/or investments per Phase II award or at least 0.15 (15%) patents per Phase II award resulting from these awards. This requirement does not apply to companies that have received 15 or fewer Phase II awards over the 10 year period, excluding the two most recently-completed Fiscal Years.

Information on the Phase II to Phase III Commercialization Benchmark is available at SBIR.gov.

Applicants to this FOA that may have received more than 15 Phase II awards across all federal SBIR/STTR agencies over the past ten (10) years should, prior to application preparation, verify that their company’s Commercialization Benchmark on the Company Registry at SBIR.gov meets or exceeds the benchmark rate listed above.

Applicants that fail this benchmark will be notified by SBA annually and will not be eligible to apply for New Phase I, Fast-track or Direct Phase II (if applicable) awards for a period of one year.

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, may be allowed.

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, SBA Company registry, 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.
• SBA Company Registry See Section IV. Application and Submission Information, SF424(R&R) Other Project Information Component for instructions on how to register and how to attach proof of registration to your application package. Applicants must have a DUNS number to complete this registration. SBA Company registration is NOT required before SAM, Grants.gov or eRA Commons registration.
• 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.

2. Cost Sharing

3. Additional Information on Eligibility

Number of Applications

NIH will not accept similar grant applications with essentially the same research focus from the same applicant organization. This includes derivative or multiple applications that propose to develop a single product, process, or service that, with non-substantive modifications, can be applied to a variety of purposes. Applicants may not simultaneously submit identical/essentially identical applications under both this funding opportunity and any other HHS funding opportunity, including the SBIR and STTR Parent announcements.

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).

A Phase I awardee may submit a Phase II application either before or after expiration of the Phase I budget period, unless the awardee elects to submit a Phase I and Phase II application concurrently under the Fast-Track procedure. To maintain eligibility to seek Phase II or IIB support, a Phase I awardee should submit a Phase II application, and a Phase II awardee should submit a Phase IIB application, within the first six due dates following the expiration of the Phase I or II budget period, respectively.

In Phase II, normally, a minimum of one-half or 50% of the research or analytical effort must be carried out by the small business concern. The total amount of consultant and contractual arrangements to third parties for portions of the scientific and technical effort generally may not exceed 50% of the total Phase II amount requested (direct, F&A/indirect, and fee).

A small business concern may subcontract a portion of its SBIR or STTR award to a Federal laboratory within the limits above. A Federal laboratory, as defined in 15 U.S.C. 3703, means any laboratory, any federally funded research and development center, or any center established under 15 U.S.C. 3705 & 3707 that is owned, leased, or otherwise used by a Federal agency and funded by the Federal Government, whether operated by the Government or by a contractor.

The basis for determining the percentage of work to be performed by each of the cooperative parties in Phase I or Phase II will be the total of the requested costs attributable to each party, unless otherwise described and justified in Consortium/Contractual Arrangements of the PHS 398 Research Plan component of SF424 (R&R) application forms.

Additional details are contained in the SF424 (R&R) SBIR/STTR Application Guide.

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

It is critical that applicants follow the SBIR/STTR (B) Instructions in the SF424 (R&R) SBIR/STTR Application Guide, 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.

Letter of Intent

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

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

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

The letter of intent should be sent to:

Nick Langhals, PhD

National Institute of Neurological Disorders and Stroke (NINDS)

Telephone: 301-496-1779

Fax: 301-480-1080

Email: nick.langhals@nih.gov

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.

The following subsections must be included within the page limit of the Commercialization Plan, in addition to the requirements listed in the SF424 Application Guide:

1. Statement of Need

Applicants must provide a concise "Statement of Need". This statement is expected to provide answers to the questions listed below:

• What is the perceived "Valley of Death" for the product/technology under development?
• To what extent would a possible award under this FOA advance the product or technology far enough to attract sufficient, independent third-party financing and/or strategic partnerships to carry out full commercialization?

2. SBIR/STTR Commercialization History

Applicants should provide an SBIR/STTR Commercialization History that addresses the questions listed below. The following questions should be addressed for all SBIR/STTR awards received from any Federal agency:

• Has the company gone through any name changes within the past five years? If so, then all previous company names should be listed in the application.
• Is the company a subsidiary or a spin-off? If so, then the name of the parent company should be provided.
• What percentage of the company's revenue was derived from SBIR/STTR funding during each of the past 5 years, including both Phase I and Phase II awards? Applicants should report a percentage value for each year individually.
• What is the total number of SBIR/STTR Phase II awards that the company has received from the Federal government? For each award, companies should provide the award number, the award amount, project duration, and the name of the awarding agency.
• What are the total revenues that have been generated to date as a result of the commercialization of the SBIR/STTR projects funded within the past 5 years?

3. Intellectual Property (IP) Protection: Applications should include an Intellectual property (IP) strategy. It may be no more than 1 page. Applicants are encouraged to prepare this section of the application in consultation with their institution's technology transfer officials.

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 the applicant proposes using a hit/lead whose IP is not owned by the applicant's institution, as the starting point for optimization, the applicant should address any questions of freedom to operate and IP generation to ensure robust licensing opportunities at project completion.

If patents pertinent to the therapy being developed under this application have been filed, the applicant should indicate the details of filing dates, what type of patents are filed, application status, and associated USPTO links, if applicable.

Applicants should discuss future IP filing plans. For a multiple-PD/PI and/or multiple-institution applications (including those with NIH intramural collaborators), 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. Applicants should clarify how IP will be shared or otherwise managed if multiple PD/PIs and institutions are involved.

Other Attachments:

1. SBIR Application Certification for small business concerns majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms

Applicant small business concerns that are majority-owned by multiple venture capital operating companies, hedge funds, or private equity firms (e.g. majority VCOC-owned) are required to submit a Certification at time of their application submission per the SBIR Policy Directive. Follow the instructions below.

Applicants small business concerns who are more than 50% directly owned and controlled by one or more individuals (who are citizens or permanent resident aliens of the United States), other business concerns (each of which is more than 50% directly owned and controlled by individuals who are citizens or permanent resident aliens of the United States), or any combination of these (i.e. NOT majority VCOC-owned) should NOT fill out this certification and should NOT attach it their application package.

1. Download the VCOC Certification.pdf at the NIH SBIR Forms webpage.

2. Answer the 3 questions and check the certification boxes.

3. The authorized business official must sign the certification.

4. Save the certification using the original file name. The file must be named SBIR Application VCOC Certification.pdf . DO NOT CHANGE OR ALTER THE FILE NAME. Changing the file name may cause delays in the processing of your application.

5. When you are completing the application package, attach this certification as a separate file by clicking "Add Attachments" located to the right of Other Attachments field on the Research and Related Other Project Information form.

In the single Specific Aims attachment, include aims delineated for the non-clinical testing (Phase I) and the clinical trial (Phase II).

• Define the aims of the SBIR Phase I non-clinical development and testing of the device
• Define the aims of the SBIR Phase II clinical trial
• A scientific hypothesis is not required nor expected for work of this nature.

Research Strategy:

The Research Strategy Section should include the following sections:

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 or diagnostic 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).

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.
• 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 trial.

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 the Research Strategy

In this section applicants should elaborate on their device testing strategy to enable the clinical studies. Research plans and milestones for the clinical trial (SBIR Phase II) should be included in the PHS Human Subjects and Clinical Trials Information form.

• SBIR Phase I: Non-clinical activities in SBIR Phase I should include:
  • A project plan compatible with an accelerated timeline to obtain approval to conduct the clinical trial.
  • A clearly stated device testing timeline that includes quantifiable, practical, achievable goals in support of the proposed clinical trial.
  • A description of all non-clinical testing necessary to support the filing of an IDE or to obtain IRB approval for an NSR clinical trial, including the standards to which the testing will comply (e.g., Good Laboratory Practices (GLP), International Organization for Standardization (ISO) 11135, ISO 10993, electromagnetic Compatibility (EMC), International Electrotechnical Commission (IEC), etc.).
  • Plans for contact with and submissions to the appropriate U.S. regulatory bodies (e.g., FDA in the form of pre-submission meetings and IDE submission), if applicable.
  • Plans for all necessary animal studies required by the FDA to support an IDE. Large animal safety studies (e.g., canine, porcine, ovine, etc.) are often required by the FDA and should be considered in this section. Applicants should include a large animal GLP safety study conducted on the full-final device system using the final manufacturing process intended to support the 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 note this in this section and include a communication from the FDA clearly stating this is the case in the form of a response to a Pre-Submission via the "Communication with Regulatory Bodies" PHS Human Subjects and Clinical Trial Information form, Section 4.6a).
  • Anticipated risks in the device testing process, including potential needs for design changes, and mitigations based on initial test results.
  • A description of any independent contractors and their role(s) in the proposed non-clinical study.
  • A description of oversight groups that may be formed and their role(s) in the proposed study.
  • Only minor alterations to the device design necessary to enable the anticipated clinical study.
  • Appropriately timed device design modifications to avoid impacting the validity or schedule for the proposed non-clinical testing.
  • A clear indication that study conceptualization and planning are at a stage sufficient to allow for an assessment of the likelihood of clinical trial success.
  • No clinical dependencies on the development of new and previously untested device elements/concepts that have significant risk of failure.
  • Applicants are strongly encouraged to hold a pre-submission meeting with the FDA to discuss the clinical trial protocol prior to submission of an IDE, as described above. If the stated goal of the clinical trial is to obtain data to support a marketing application, then a clear non-binding indication that the proposed clinical trial protocol is likely sufficient for that purpose must be obtained during this pre-submission meeting.
• SBIR Phase II:
  • 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
  • Justify the outcome metrics for the proposed clinical trial in terms of quantifiable minimum-success criteria necessary to enable this next step.
  • Research plans and milestones for the clinical trial (SBIR Phase II) should be included in the PHS Human Subjects and Clinical Trials Information forms.
• Milestones and Timeline:

Applicants are required to provide detailed project performance and timeline objectives. These milestones will be negotiated prior to issuing the notices of the award.

• • SBIR Phase I Milestones:
    • SBIR Phase I milestones? that focus on those tests that are needed to obtain an FDA IDE or an IRB NSR designation. This may include but is not limited to bio-compatibility testing and large animal studies.
    • For projects proposing non-clinical testing to support an IDE submission for the clinical trial, at a minimum, an FDA pre-submission meeting, with NIH program staff in attendance, is required as a Year 1 milestone. If the need for additional pre-submission meetings is anticipated, they should also include NIH program staff and should be included as milestones. Non-binding FDA feedback during and after this meeting must clearly indicate that the 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 NSR designation, preliminary communications (e.g., letter or other documentation) with the IRB indicating what non-clinical testing will be necessary to support the NSR clinical trial should be included as a Year 1 milestone. The milestone plan should be constructed so that FDA and/or IRB feedback on the testing plan can be incorporated into the design of critical tests prior to their initiation.
    • A project timeline in the form of a Gantt chart that includes all milestones described in the text should be included.
  • SBIR Phase II Milestones:
    • Milestones and timeline related to human subjects and clinical trials related to Phase II should be included in the PHS Human Subjects and Clinical Trials Information form, Section 2.

Letters of support

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

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

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.

Note that Phase I SBIR/STTR Appendix materials are not permitted. Limited items are allowed in the Appendix of other small business applications. The instructions for the Appendix of the Research Plan are described in the SF424 (R&R) Application Guide; any instructions provided here are in addition to the SF424 (R&R) Application Guide Instructions.

When involving NIH-defined human subjects research, clinical research, and/or clinical trials follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

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

Study Record: PHS Human Subjects and Clinical Trials Information

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

Section 2 - Study Population Characteristics

2.7 Study Timeline

SBIR Phase II Milestone Plan

Applicants are required to provide detailed project performance and timeline objectives (note, SBIR Phase I milestones should be included in the Research Strategy section of the application). These milestones will be negotiated prior to issuing the notice of award.

Applicants should 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 should also be included as milestones.

A project timeline in the form of a Gantt chart that includes all milestones described in the text should be included

Examples of appropriate topics covered by SBIR Phase II 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 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.

Section 5 - Other Clinical Trial-related Attachments

5.1 Other Clinical Trial-related Attachments

Long Term Plan for Patients

The Long Term Plan for Patients must not exceed three pages. Applications that exceed this limit will be withdrawn. This attachment should be entitled "Long Term Plan for Patients.pdf", appended with 1, 2, 3, etc., as needed. Applicants must describe a plan for the care of patients at the end of the study and after the study period, if appropriate. These plans may vary from project to project; examples might include 1) explant of indwelling devices once the approved study period is complete, 2) surgical removal of batteries and 'capping' the exposed metals from leads/IS-1 connectors, 3) manufacturer-supported device maintenance for patients responding to therapy, 4) manufacturer support for filing of compassionate use exemptions for device maintenance, etc.

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), eRA Commons, and Grants.gov

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and time. 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) SBIR/STTR 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) SBIR/STTR 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.

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 (SAM). Additional information may be found in the SF424 (R&R) SBIR/STTR Application Guide.

See more tips for avoiding common errors.

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.

1. Criteria

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.

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 and provide some economic benefit to the applicant company, 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 U44 Cooperative Agreement 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. Reviewers will assign a single impact score for the entire application, which includes both SBIR Phase I and II.

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? Does the proposed project have commercial potential to lead to a marketable product, process or service? (In the case of Phase II, Fast-Track, and Phase II Competing Renewals, does the Commercialization Plan demonstrate a high probability of commercialization?)

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 by the end of SBIR Phase I? 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?

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 preclinical, 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?
• I?f 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? For a Phase I application, are there clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

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?
• If applicable, does the proposed device sufficiently incorporate the ability to synchronize relevant peripheral, ambulatory behavioral data signals with neural recordings?

Detailed Plans for Research Strategy:

• Will the implementation of the overarching plan lead to the development and testing of the proposed therapeutic device?
• Is a large animal safety study performed utilizing GLP proposed or is there a clear reason that a large animal study will not be necessary to support an IDE (e.g., communication from the FDA)?
• Will the project reach an IDE or IRB approval for a non-significant risk (NSR) study at end of SBIR Phase I?

If Applicable - Long Term Plan for Patients (PHS Human subjects and Clinical Trials Information, Section 5.1):

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

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?

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 arrangement?

For this particular announcement, note the following:

• Is there sufficient regulatory expertise on the team to facilitate regulatory consultations and approvals?
• Is the environment at the applicant institution or the subcontracting organization sufficient to support any proposed GMP and GLP activities?

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?

Phase II Applications

For Phase II Applications, how well did the applicant demonstrate progress toward meeting the Phase I objectives, demonstrating feasibility, and providing a solid foundation for the proposed Phase II activity?

Phase I/Phase II Fast-Track Applications

For Phase I/Phase II Fast-Track Applications, reviewers will consider the following:

1. Does the Phase I application specify clear, appropriate, measurable goals (milestones) that should be achieved prior to initiating Phase II?

2. To what extent was the applicant able to obtain letters of interest, additional funding commitments, and/or resources from the private sector or non-SBIR/STTR funding sources that would enhance the likelihood for commercialization?

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.

Phase IIB Competing 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.

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.

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 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 committee 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.

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 Institute of Neurological Disorders and Stroke Advisory 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.

3. Anticipated Announcement and Award Dates

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

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).

Special award condition specific to this FOA: A grantee from a for-profit organization funded under this 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. See 45 CFR 75.306 for additional details. Matching funds must be non-Federal funds set aside for this project and are available from the source(s) identified in the application, as committed to by the recipient. Cost matching will be evaluated by the awarding office to ensure that this requirement is being met. Compliance with the matching requirement must be verified on an annual basis and must be documented in the annual and final FFR.

2. Administrative and National Policy Requirements

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.

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.

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.

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.

T he 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

NIH requires that SBIR/STTR grantees submit the following reports within 120 days of the end of the grant budget period unless the grantee is under an extension. 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 Research Performance Progress Report (F-RPPR; requirements have recently changed - please see the NOT-OD-17-085),
• Invention statement and certification (HHS 568), 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.

Annual Invention Utilization Reports and SBIR.gov reporting are also required . Quarterly reports are due to the Payment Management System 30 days following the end of each calendar quarter.

Failure to submit timely final reports may affect future funding to the organization or awards with the same PD/PI.

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.

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: GrantsInfo@nih.gov (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: support@grants.gov

SBA Company Registry (Questions regarding required registration at the SBA Company Registry and for technical questions or issues)
Website to Email: http://sbir.gov/feedback?type=reg

ick Langhals, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email:nick.langhals@nih.gov

Emily Caporello, Ph.D.
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-1779
Email:Emily.caporello@nih.gov

Danilo Tagle, Ph.D
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-594-8064
Email: danilo.tagle@nih.gov

Wen G. Chen, MMSc, PhD
National Center for Complementary and Integrative Health (NCCIH)
Telephone: 301-451-3989
Email: chenw@mail.nih.gov

Diane St. Germain
National Cancer Institute (NCI)
Telephone: 240-276-7082
Email: dstgermain@mail.nih.gov

Houmam Araj
National Eye Institute (NEI)
301-451-2020
regunathans@mail.nih.gov

Soundar Regunathan, Ph.D.
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Phone: 301-443-1192
Email: regunathans@mail.nih.gov

Charles H. Washabaugh, Ph.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Telephone: 301-594-5050
Email: Charles.Washabaugh@nih.gov

Michael B. Wolfson
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301-451-4778
Email: Michael.Wolfson@nih.gov

Kevin Walton
National Institute on Drug Abuse (NIDA)
Telephone: 301-827-5980
Email: kevin.walton@nih.gov

Yolanda F. Vallejo, PhD
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301.827.4655
E-mail:yolanda.vallejo@nih.gov

Teresa L.Z. Jones, MD
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-435-2996
Email: teresa.jones@nih.gov

David McMullen, M.D.
National Institute of Mental Health (NIMH)
Telephone: 301-451-0180
Email: david.mcmullen@nih.gov

Augie Diana, Ph.D.
National Institute of Nursing Research (NINR)
Telephone: (301) 402-6423
Email: dianaa@mail.nih.gov

Tijuanna E. DeCoster, PhD
National Institute of Neurological Disorders and Stroke (NINDS)
Telephone: 301-496-9231
Email: decostert@mail.nih.gov

Esther Young
National Center for Advancing Translational Sciences (NCATS)
Telephone: 301-402-7183
Email: esther.young@nih.gov

Shelley Carow
National Center for Complementary and Integrative Health (NCCIH)
carows@mail.nih.gov
301.594.3788

Amy Bartosch
National Cancer Institute (NCI)
Telephone: 240-276-6912
Email:bartoschar@mail.nih.gov

Karen Robinson Smith
National Eye Institute (NEI)
Telephone: 301-451-2020
Email: Karen.Robinson.Smith@nei.nih.gov

Judy Fox
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Telephone: 301-443-4704
Email: jfox@mail.nih.gov

Katie Ellis
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Telephone: 301-451-4791
Email:kellis@mail.nih.gov

Erik Edgerton
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Tel:(301) 594-7760
Email: edgertont@mail.nih.gov

Bryan S. Clark, MBA
Eunice Kennedy ShriverNational Institute of Child Health and Human Development (NICHD)
Telephone: 301-402-0915
Email:clarkb1@mail.nih.gov

Pam Fleming
National Institute on Drug Abuse (NIDA)
Telephone: 301-480-1159
Email:pfleming@nida.nih.gov

Diana Rutberg, MBA
National Institute of Dental and Craniofacial Research (NIDCR)
Telephone: 301-594-4798
Email: rutbergd@mail.nih.gov

Christina Coriz
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Telephone: 301-594-8848
Email:corizc@niddk.nih.gov

Rebecca Claycamp
National Institute of Mental Health (NIMH)
Telephone: 301-443-2811
E-mail:rclaycam@mail.nih.gov

Kelli Oster
National Institute of Nursing Research (NINR)
Telephone: 301-594-2177
Email:osterk@mail.nih.gov

The SBIR Program is mandated by the Small Business Innovation Development Act of 1982 (P.L. 97-219), reauthorizing legislation (P.L. 99-443) P.L. 102-564, P.L. 112-81 (SBIR/STTR Reauthorization Act of 2011), and as reauthorized and extended under P.L. 114-328, Section 1834. The basic design of the NIH SBIR Program is in accordance with the Small Business Administration (SBA) SBIR Policy Directive.