A. Purpose The purpose of this Funding Opportunity Announcement (FOA) is to encourage investigators to pursue translational activities and small clinical studies to advance the development of therapeutic, and diagnostic devices for disorders that affect the nervous or neuromuscular systems. 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 study. The clinical study is expected to provide information about the device function or final design that cannot be practically obtained through additional non-clinical assessments (e.g., bench top or animal studies) due to the novelty of the device or its intended use. This FOA is a milestone-driven cooperative agreement program and will involve participation of NIH program staff in negotiating the final project plan before award and monitoring of research progress. B. Overview This FOA supports non-clinical testing to enable IRB and/or FDA approval needed to conduct a small clinical study, and the subsequent study itself (e.g., Early Feasibility Study - https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103). All projects will be Fast-Track applications and have two phases. SBIR Phase I will support non-clinical translational device activities to obtain an IDE and IRB approval for an SR clinical study, or to obtain IRB approval for an NSR clinical study. The duration of SBIR Phase I will depend on the maturity of the project at entry. Phase II will support a small clinical study and can last up to three years, however, the total project period (including both phases) must not exceed five years. Projects for which only a clinical phase is proposed are outside of the scope of this funding opportunity. Only those SBIR Phase I projects that have met specific criteria (see below) will be eligible for transition to SBIR Phase II after NIH administrative review. Furthermore, ethical considerations are intrinsic to the responsible conduct of neuroscience research and the translation of neuroscience advances (scientific and technological) into clinical practice. It is expected the immediate next steps following completion of the small clinical study supported under this cooperative agreement will be: a marketing application if only a small clinical study or experience is needed to demonstrate the device is safe and effective. a larger clinical trial that will lead to a marketing application; or device design decisions made based on the information and data collected. As applicants must have comprehensive supporting data, innovation and impact will in part be judged on presenting a credible path towards U.S. regulatory submission/IRB approval at the end of the SBIR Phase I project period, and on the potential to advance the care of patients by addressing an unmet clinical need. This FOA will utilize a Small Business Innovation Research (SBIR) U44 cooperative agreement. As a cooperative agreement, this FOA supports milestone-driven projects and involves NIH program staff’s participation in negotiating project and milestone plan before award, monitoring the research progress, and making go/no-go decisions. The expectations of the program are in line with those of industry regarding the advancement of devices through the developmental and translational pipelines. As such, an inherent rate of attrition is possible within this program. Applicants are strongly advised to contact the Scientific/Research contact listed below prior to submission. C. Scope Projects must focus on a disorder that falls within the mission of NINDS. It is expected that devices within the scope of this program either: are very close to the 'final system' and manufactured using very close to the same manufacturing process as the device to be marketed or studied in a larger clinical trial following the completion of this project; or have received Pre-Submission feedback from the FDA (see https://www.fda.gov/medical-devices/products-and-medical-procedures/neurological-devices and https://www.youtube.com/watch?v=u0zPKPLW2mU for helpful resources); or require early feasibility clinical data to inform the final device design or manufacturing processes; or are already approved, but are being used for a novel indication, target, or patient population. D. Entry criteria: For entry to the program, projects should have: Comprehensive supporting data based on bench, in vitro, and/or in vivo models representative of the intended patient population and indication. Identified one or more clinically meaningful device outcome measures based on input from key stakeholders (e.g., clinicians, patients, and caregivers) as well as supporting literature. A compelling case for a successful IDE submission for an SR study, or IRB approval for an NSR study at the end of SBIR Phase I. All regulatory approvals must be in place prior to the start of the SBIR Phase II. Applicants are encouraged, but not required, to consult with FDA via a Pre-Submission meeting, study risk designation request, and/or 513(g) submission prior to applying for funding through this grant mechanism. Applicants who do not have sufficiently relevant feedback from the FDA regarding all planned activities prior to application for funding will be expected to do so as the first milestone during the first year of SBIR Phase I of the award. 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. Any remaining funds associated with the original award will not be released. E. Phases SBIR Phase I scope: Examples of studies that may be proposed during SBIR Phase I include, but are not limited to: Non-Good Laboratory Practice (GLP) animal studies to develop surgical techniques relevant to the device, optimize relevant therapeutic or diagnostic parameters, and refine device design as necessary for subsequent GLP testing or additional clinical studies for regulatory approval. Bench-top and animal testing to demonstrate compliance with FDA Recognized Standards. 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 Device Exemption (HED), Request for Risk Designation, 513(g) submission). A limited clinical experience is also allowable during SBIR Phase I if it is necessary to support the IDE submission for the small clinical study conducted in SBIR Phase II. Clinical studies in SBIR Phase I are out of scope if the planned SBIR Phase II small clinical study is NSR. SBIR Phase II scope: SBIR Phase II will support a small clinical study that will lead to either: A marketing application if only a small clinical trial or experience is needed to demonstrate the device is safe and effective, or A larger clinical trial that will lead to a marketing application; or A larger clinical study that will lead to a marketing application; or Use of the clinical experience to inform device design decisions Examples of studies that may be proposed during SBIR Phase II include, but are not limited to: Optimization of the device design with respect to the human functional anatomy. Identification of the most simple, reliable, and cost-effective device configuration for more. advanced clinical studies and eventual market approval. Basic proof-of-concept testing in human patients. Studies of the key physiological variables that may impact the function of the device in humans. Initial assessments of device safety are expected, but only in conjunction with obtaining enabling data about device design or function F. Non-Responsive Activities: Applications that include the following activities will be considered non-responsive and will be withdrawn and not reviewed: Basic research and studies of disease mechanisms; Animal model development: all in vivo models must be well established and characterized, and available to the applicant; Efforts to develop neurotechnology for fundamental study of the nervous system; Fundamental basic/applied research projects that employ existing market approved devices for their labeled uses are outside the scope of the present FOA; Delayed onset clinical studies Proposals lacking a clinical study protocol included with the submission Projects focused on technologies for augmentation of healthy individuals Applications that do not include all required attachments (e.g., Gantt Chart, Long-term care plan) Applications that do not include a neuroethics section as part of the human subjects protection attachment. G. Milestones Because device development is an inherently risky process, it is anticipated that there may be attrition as projects move through the process. Applications must propose one or more milestones associated with each objective in each year of the project. Milestones are goals that measure success and efficacy that will be used for go/no-go decision-making for the project and should have quantitative success criteria associated with them (see below for details). For each milestone, provide details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured). Specify the quantitative criteria for measuring success and the rationale used to develop and justify the quantitative criteria identified. Quantitative criteria should be robust and consistent with the state-of-the-art in the field. Applicants are encouraged to read examples of milestones (https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/Devices-Milestones). NIH program staff will contact the applicant to discuss, negotiate the proposed milestones and any changes suggested prior to funding the application. The final agreed upon and approved milestones will be specified in the Notice of Award (NoA). Progress towards achievement of the final set of milestones will be evaluated yearly by NIH program staff. Program staff may involve independent consultants or subject matter experts with relevant expertise. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project 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. SBIR Phase I to 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 be transitioned into SBIR Phase II based on the following: Successful achievement of the defined milestones for SBIR Phase I of the project; Likelihood of success in clinical testing; Competitive landscape; Program balance; Availability of funds; For significant risk studies, documentation of final or conditional approval of the IDE 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 NINDS Safety and Risk Assessment Committee (SARAC); and Agreement on updated timeline, milestones and budget for the clinical study. H. Quality and Compliance Requirements The use of the Design Control and Quality Systems processes (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/design-control-guidance-medical-device-manufacturers) to the degree specified by the FDA is required. Intermediate steps in the Design Control process (e.g., design reviews, design verification, design validation, and design transfer activities) where appropriate, 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. I. 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. J. Pre-application Consultation As an U44 cooperative agreement, NIH program staff will be involved in the negotiation and execution of the projects. Applicants are strongly encouraged to consult with NIH program staff when planning an application. Early contact provides an opportunity for staff to provide further guidance on program scope, goals, and developing appropriate milestones. When possible, applicants should contact program staff at least 12 weeks before a receipt date. K. Institute Statements of Interest The National Institute for Neurological Disorders and Stroke (NINDS) will support translational device applications relevant to its mission (https://www.ninds.nih.gov/About-NINDS/Who-We-Are) under this FOA. Applications for NINDS proposing pre-translational, pre-clinical, investigative research projects on deliberative optimization and development of devices for impacts in neurology and neuroscience should apply through the Bioengineering Research Grants (R01s: see PAR-19-158 and PAR-19-159). Applicants are expected to incorporate data elements from the NINDS Common Data Elements (CDE) Project in their data collection forms when appropriate (see https://www.commondataelements.ninds.nih.gov).