BRAIN Initiative: Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (U44 Clinical Trial Required)
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BRAIN Initiative: Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (U44 Clinical Trial Required)
The BRAIN Initiative
The Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative is aimed at revolutionizing our understanding of the human brain. By accelerating the development and application of innovative technologies, researchers will be able to produce a new dynamic picture of the brain that, for the first time, will show how individual cells and complex neural circuits interact in both time and space. It is expected that the application of these new tools and technologies will ultimately lead to new ways to treat and prevent brain disorders.
NIH is one of several federal agencies involved in the BRAIN Initiative. Planning for the NIH component of the BRAIN initiative is guided by the long-term scientific plan, "BRAIN 2025: A Scientific Vision," which details seven high-priority research areas and calls for a sustained federal commitment of $4.5 billion over 12 years. This FOA and other recently issued FOAs are based on careful consideration by the NIH of the recommendations of the BRAIN 2025 Report, and input from the NIH BRAIN Multi-Council Working Group. Videocasts of the NIH BRAIN Multi-council Working Group are available at http://www.braininitiative.nih.gov/about/mcwg.htm.
In addition to the National BRAIN initiative, the NIH continues to have a substantial annual investment in neuroscience research. The Institutes and Centers contributing to the NIH BRAIN Initiative (http://braininitiative.nih.gov/) support those research efforts through investigator-initiated applications as well as through specific FOAs. Potential applicants to this FOA are strongly encouraged to contact Scientific/Program staff if they have any questions about the best FOA for their research.
To enable rapid progress in development of new technologies as well as in theory and data analysis, the BRAIN Initiative encourages collaborations between neurobiologists and scientists from statistics, physics, mathematics, engineering, and computer and information sciences; and NIH welcomes applications from investigators in these disciplines.
NIH encourages BRAIN Initiative applications from investigators that are underrepresented in the biomedical, behavioral, or clinical research workforce (see data at http://www.nsf.gov/statistics/showpub.cfm?TopID=2&SubID=27 and the most recent report on Women, Minorities, and Persons with Disabilities in Science and Engineering). Such individuals include those from underrepresented racial and ethnic groups, those with disabilities, and those from disadvantaged backgrounds.
The BRAIN Initiative will require a high level of coordination and sharing between investigators. It is expected that BRAIN Initiative awardees will cooperate and coordinate their activities after awards are made by participating in Program Director/Principal Investigator (PD/PI) meetings and in other activities.
This FOA is related to the recommendations in Section III of the BRAIN 2025 Report, and addresses the goal of developing "innovative technologies to understand the human brain and treat its disorders". Initial first-in-human studies are a key point in the development of innovative new clinical technologies. The leap from animal studies to humans is large, and initial clinical studies are often necessary to address critical scientific questions about the function of a device in human patients and/or inform a final device design suitable for eventual FDA market approval. Initial demonstrations of novel device function in humans have become increasingly required to encourage the industry and venture capital investment necessary to develop a final safe, reliable, and efficacious device that can be manufactured at scale suitable for regulatory approval, yet at a price point sufficient for sustainable commercial market given insurance reimbursement.
As recommended in the BRAIN 2025 Report, this FOA will support non-clinical testing necessary to enable initial clinical studies of "implantable devices with recording and/or stimulation capabilities that both advance clinical diagnostic or therapeutic applications and maximize their scientific research value", and a subsequent small clinical trial for such devices. Clinical studies supported may consist of acute or short-term procedures that are deemed Non-Significant Risk (NSR) by an Institutional Review Board (IRB), or Significant Risk (SR) studies that require an Investigational Device Exemption (IDE) from the FDA, such as chronic implants.
Objectives of this FOA
This FOA seeks to encourage small business concerns (SBCs) to pursue milestone-driven translational and clinical projects for recording and/or stimulating devices to treat central nervous system (CNS) disorders and better understand the human brain.
This FOA utilizes a cooperative agreement mechanism to support non-clinical testing to enable IRB approval and/or a successful IDE submission 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). This funding opportunity supports non-clinical testing and clinical studies to answer key questions about the function or final design of a device. This final device design may require most, if not all, of the non-clinical testing on the path to more advanced clinical trials and market approval. The clinical trial is expected to provide information 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, yet is critical to enable next-generation diagnostic or therapeutic devices. Activities that can be supported in this program include testing 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 single small clinical trial. 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.
All projects must have two phases, SBIR Phase I and Phase II, using the Fast-track mechanism. The initial SBIR Phase I will support non-clinical testing toward filing of an IDE for an SR study or obtaining IRB approval for an NSR clinical trial. All projects will start at SBIR Phase I, and the length 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 transition to the subsequent SBIR Phase II after NIH administrative review. The SBIR Phase II will support a small clinical trial.
Proposed next generation devices are strongly encouraged to incorporate the ability to synchronize peripheral, ambulatory behavioral data signals. These signals must be synchronized in real time, but analysis may be done in an online or offline manner. Data does not have to be stored on board by the device but may be streamed out, as long as it does not interfere significantly with the naturalistic behavior (i.e., a participant must not be required to carry around a large personal computer with them for synchronization to occur). Behavioral signals may be those captured by a phone (GPS, keyboard usage, accelerometer, etc.), a smartwatch, or related peripheral behavioral capture device.
This FOA is milestone-driven and involves NIH program staff's participation in developing the project plan, monitoring the research progress, and making go/no-go decisions. NIH staff will also provide assistance to academic investigators in familiarizing them with the clinical device development process and the criteria needed to advance therapeutic leads and diagnostics to the clinic. The expectations of the program are in line with those of industry in regards to advancing devices through the translational developmental pipeline. As such, an inherent high rate of attrition is expected within this program.
Projects must focus on a single disorder that falls within the mission of one of the participating institutes of the BRAIN Initiative.
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.
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.
- Identification of 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 can be proposed during the SBIR Phase I include, but are not limited to:
- Non-Good Laboratory Practice (GLP) animal studies to develop surgical techniques relevant to the device, define relevant therapeutic parameters, and refine device design in preparation for subsequent GLP testing for regulatory approval.
- In vitro/bench-top and animal testing to meet 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 activities related to synchronization naturalistic behavioral data with neural recordings.
- 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 studies that can be proposed during the clinical phase include, but are not limited to:
- Optimization of the device design with respect to the human functional anatomy
- Identification of the most simple, reliable, and cost effective device configuration for more advanced clinical trials and eventual market approval
- Basic proof-of-concept testing in human patients
- Studies of the key physiological variables that may impact the function of the device in humans
- Initial assessments of device safety are expected, but only in conjunction with obtaining enabling data about device design or function
The following activities are non-responsive to this FOA, and will not be reviewed:
- 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 rehabilitation strategies;
- development of imaging technologies;
- efforts to develop neurotechnology to study the fundamental function or physiology of the CNS;
- fundamental basic/applied research projects that employ existing market-approved devices for their labeled uses;
- delayed onset studies;
- projects focused on augmentation of neural function in healthy individuals; and
- technologies exclusively intended for implant outside of the CNS that do not treat CNS disorders or provide knowledge about CNS function (this includes dorsal root ganglion, peripheral, or cranial nerve modulation for the treatment of peripheral nervous system disorders).
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).
Projects should include quantitative milestones and go/no-go decision points. Applicants must describe milestones to be used for measuring success in achieving each of the research plan's objectives. One or more milestones should be used for each objective. Details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured) should be included for each milestone. Applicants are expected to include 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. Each milestone must have a timeline, and be incorporated into the overall project timeline, which should also be reflected in a Gantt chart. There should be at least one milestone proposed for completion at the end of each year.
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 suggest modification or additional experiments 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.
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 or 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.
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.
See Section VIII. Other Information for award authorities and regulations.