BRAIN Initiative: Next-Generation Invasive Devices for Recording and Modulation in the Human Central Nervous System (U44)

The Brain Research through Advancing Innovative Neurotechnologies (BRAIN®) Initiative is a Presidential project 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, shows 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, cure, and even 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 report can be found at http://braininitiative.nih.gov/.  This FOA and other FOAs issued in Fiscal Year 2016 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 (http://braininitiative.nih.gov/mcwg.htm). 

In addition to its contributions to the Federal BRAIN Initiative, NIH continues to have a substantial annual investment in neuroscience research.  The Institutes and Centers contributing to the NIH BRAIN Initiative (listed at http://braininitiative.nih.gov/) provide separate support for neuroscience research through applications received via parent announcements as well as through specific FOAs.  Potential applicants to this FOA are strongly encouraged to contact Scientific/Research staff if they have any questions about the best funding opportunity announcement for their research.

This Funding Opportunity Announcement (FOA) is related to 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 study 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. 

The purpose of this FOA is to encourage small business concerns (SBCs) to pursue translational and clinical studies for recording and/or stimulating devices to treat nervous system 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 study, and the subsequent small clinical study (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 study 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 study, and a single small clinical study.  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 study.

All projects will have two phases, Phase I and Phase II, using the Fast-track mechanism.  The initial Phase I will support non-clinical testing toward filing of an IDE for an SR study or obtaining IRB approval for an NSR clinical study.  All projects will start at Phase I, and the length of Phase I will depend on the maturity of the project at entry.  Only those Phase I projects that have met specific criteria (see below) will transition to the subsequent Phase II after NIH administrative review.  The Phase II will support a small clinical study. 

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. 

For this funding opportunity announcement phase I clinical testing, studies or trials refer to the common phases of a clinical trial. U44 Phase I and II refer to the project phases of the SBIR program.

Entry Criteria

For entry to the program, projects should have:

• Comprehensive Supporting Data: Proof-of-concept data of device function are required 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
• A compelling case for a successful IDE submission to support the clinical component, or IRB approval for an NSR study, within the period of the award
• Overall device development plan, including timeline for contact and interaction with appropriate regulatory bodies, clinical considerations, and a needs assessment
• Identification of one or more clinically meaningful device outcome measures based on input from both clinicians and patients

U44 Phase I Scope

Examples of studies that can be proposed during the non-clinical Phase I include, but are not limited to:

• Non-GLP (Good Laboratory Practice) 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 and animal testing to meet FDA recognized ISO/ASTM Standards
• Activities to become GMP (Good Manufacturing Practice) compliant
• Activities to bring the development process under Design and Quality Systems Control
• Device, software, and firmware design verification and validation activities
• GLP compliant large animal model safety and/or testing of an implanted device
• Activities to support submission of an IDE

U44 Phase II Scope

Phase II will support a small clinical study to answer key questions about the function or final design of a device.  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 have been previously established and characterized
• Rehabilitation strategies
• Imaging technologies
• Definitive clinical trials of therapeutic devices, such as a traditional Feasibility study and/or Pivotal Trial (see http://www.fda.gov/downloads/MedicalDevices/DeviceRegulati%20onandGuidance/GuidanceDocuments/UCM279103.pdf2 for the definition of an Early Feasibility Study, Feasibility Study and Pivotal Trial) 
• Efforts to develop neurotechnology for fundamental study of the CNS
• Fundamental basic/applied research projects that employ existing market-approved devices for their labeled uses are outside the scope of this FOA but may be within scope of future BRAIN FOAs
• Projects focused on augmentation of neural function in healthy individuals
• 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. 

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 the receipt date.    

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