Translational Neural Devices (U44 Clinical Trial Required)

A. Overview

This Funding Opportunity Announcement (FOA) seeks to encourage the translation of research discoveries into new treatments for disorders that affect the nervous system by supporting milestone-driven projects for the development, testing, and demonstration of therapeutic and diagnostic devices.

This funding opportunity will utilize a Small Business Innovation Research (SBIR) U44 cooperative agreement to support the translation of devices on the verge of clinical trial. The translational device activities, including translational bench/in vitro, and small and large animal studies to support regulatory approval of a small clinical trial, are expected to lead to submission of an Investigational Device Exemption (IDE) to the U.S. Food and Drug Administration (FDA) or Institutional Review Board (IRB) application for a Non-Significant Risk (NSR) study. This cooperative agreement will also support the subsequent small clinical trial (e.g., Early Feasibility Study - https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279103, small clinical trial or experience to support a marketing application, or small clinical trial to inform final device design). It is expected the immediate next steps following completion of the small clinical trial supported under this cooperative agreement will be:

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

All projects will be Fast-Track applications and have two phases. SBIR Phase I will support translational device activities leading to submission of an IDE to the FDA, or an IRB application for an NSR study. The duration of SBIR Phase I will depend on the maturity of the project at entry. 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. SBIR Phase II will support a small clinical trial, as described above.

The SBIR U44 cooperative agreement mechanism is milestone-driven and involves significant input from NIH program staff regarding project and milestone planning, monitoring of research progress, and go/no-go decision-making. NIH staff may also provide assistance to academic investigators in familiarizing them with the device development process and the criteria needed to advance therapeutic and diagnostic leads to the clinic. The expectations of the program are in line with those of industry in regards to advancing devices through the developmental pipeline. As such, an inherent risk of attrition is possible within this program.

Applicants are strongly advised to contact the Scientific/Research contact listed below prior to submission.

B. Scope

Projects must focus on a single disorder that falls within the mission of one of the participating institutes.

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.

It is also expected that devices within the scope of this program have either received Pre-Submission feedback from the FDA or will conduct a Pre-Submission to the FDA early in the first year of SBIR Phase I (see https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/NeurologicalDevices/default.htm and https://www.youtube.com/watch?v=u0zPKPLW2mU for helpful resources). Project plans and timelines should plan accordingly for these first activities of the award.

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 a successful IDE submission, or IRB approval for an NSR study at the end of SBIR Phase I.
• 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.

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 Use Device (HUD) Designation, 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 trial conducted in SBIR Phase II. Clinical studies in SBIR Phase I are out of scope if the planned SBIR Phase II small clinical trial is NSR.

SBIR Phase II scope:

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

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

Examples of non-responsive activities to this FOA include:

• 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;
• development of imaging technologies;
• 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 studies that do not have a clinical trial protocol included with the submission; and
• projects focused on neural prosthetic technologies for augmentation of healthy individuals.

C. Milestones

Because device development is an inherently high-risk 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 can be used for go/no-go decision-making for the project, and should have quantitative criteria associated with them (see Section IV.2 for details).

Applications should include quantitative milestones and go/no-go decision points. Projects must include milestones to be used for measuring success in achieving each of the research plan’s objectives. One or more milestones should be used for each objective. For each milestone provide details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured). Specify the quantitative criteria for measuring success and the rationale for the quantitative criteria. Quantitative criteria should be robust and consistent with the state-of-the-art in the field. Most of the time the quantitative criteria for success in the milestones will also be used for making go/no-go decisions and this should be specified. Specify the timeline for each milestone. There should be at least one milestone proposed for completion at the end of each year. A Gantt chart is also required. Applicants are encouraged to read examples of milestones (https://www.ninds.nih.gov/Funding/Apply-Funding/Application-Support-Library/Neural-Prosthetics-Milestones).

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. Program staff may involve independent consultants with relevant expertise. If justified, future milestones may be revised based on data and information obtained during the previous project period. If, based on the progress report, a funded project does not meet the milestones, funding for the project 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 add 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 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

• 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, submission of an IDE for the clinical trial with 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 Safety and Risk Assessment Committee (SARAC); and
• agreement on updated timeline, milestones and budget for the clinical trial.

D. 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.

E. 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.

F. Pre-application Consultation

As a U44 cooperative agreement, NIH program staff will be involved 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 Scientific/Research staff to provide further guidance on program scope, goals, and developing appropriate milestones. Applicants should contact Scientific/Research staff at least 12 weeks before a receipt date. 

G. 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 (R01).

See Section VIII. Other Information for award authorities and regulations.