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NINDS CREATE Devices: Translational and Clinical Studies on the Path to 510(k) (U44)

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Agency: Department of Health and Human Services
Program/Year: SBIR / 2014
Solicitation Number: PAR-14-296
Release Date: July 28, 2014
Open Date: September 21, 2014
Close Date: May 7, 2017 (closing in 964 days)
001: Funding Opportunity Description
Description:

A. Overview

This FOA is part of a suite of complementary programs to encourage the translation of research discoveries into new treatments for neurological disorders and stroke (http://www.ninds.nih.gov/funding/areas/translational_research/index.htm) that fall under the NINDS mission. The NINDS Cooperative Research to Enable and Advance Translational Enterprises for Devices (CREATE Devices, http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-Devices.htm) supports milestone-driven projects for the development, testing, and demonstration of therapeutic devices to treat neurological disorders that fall under the NINDS mission.

This funding opportunity will utilize a fast-track U44 cooperative agreement mechanism to support pre-clinical testing to enable an Investigational Device Exemption (IDE) submission or IRB approval for a Non-Significant Risk (NSR) study and the subsequent clinical study. This funding opportunity supports pre-clinical and small clinical studies where the immediate next steps upon completion will be a 510(k)/510(k) De Novo submission or a larger clinical trial that will lead directly to a 510(k)/510(k) De Novo submission. It is expected that changes to the system design informed by the Early Feasibility Study will be minor and not require additional animal testing. Activities that can be supported in this program include implementation of clinical prototype devices, design verification and validation activities, demonstration of preclinical safety and efficacy, pursuit of U.S. regulatory approval for clinical study, and small clinical studies. As applicants must have comprehensive supporting data, innovation will in part be judged on presenting a credible path towards U.S. regulatory submission at the end of the Phase I project period.

The CREATE Devices program for small businesses consists of three Small Business Innovative Research (SBIR) FOAs focused on different device development tracks and applicants should apply to the appropriate track for their technology. Applicants should apply to only one track per project. Projects to enable clinical studies where the immediate next step upon completion of the study is a subsequent full Feasibility Study and a Pivotal trial to support Pre-Market Approval (PMA) or Humanitarian Device Exemption (HDE) are not within scope of this FOA.  Such projects - where changes to the system design informed by the Early Feasibility Study will be minor and not require additional animal testing - should instead apply to the 'Translational and Early Feasibility Studies on the Path to Pre-Market Approval (PMA) or Humanitarian Device Exemption (HDE) FOA (PAR-14-299). Projects to enable Investigational Device Exemption (IDE) submission, where the early clinical studies would inform a final device design that would have to go through most - if not all - of the bench-top and preclinical animal testing on the path to clinical trial and market approval, are not within the scope of this program announcement.  These projects should apply to the Translational and Clinical Studies to Inform Final Device Design FOA (PAR-14-300).

All projects will have two phases, Phase I and Phase II. The initial Phase I will support preclinical development toward filing of an IDE or obtaining IRB approval for an NSR study. All projects will start at the Phase I but the length of the 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 be eligible for transition to the Phase II after NIH administrative review. The Phase II will support a small clinical study. NINDS recognizes the funding in terms of lengths of award and amount is only sufficient to support small clinical studies leading to 510(k) or 510(k) De Novo submission. 

The U44 cooperative agreement mechanism is milestone-driven and involves NINDS program staff's participation in developing the project plan, monitoring research progress, and appropriate go/no-go decision-making. NINDS staff will also provide assistance to academic investigators in familiarizing them with the therapeutic device development process and the criteria needed to advance therapeutic leads to the clinic.  The expectations of the program are in line with those of industry in regards to advancing therapeutic devices through the developmental pipeline.  As such, an inherent high rate of attrition is expected within this program.  

Applicants are strongly advised to read through the CREATE FOA Frequently Asked Questions (FAQs) and examples at the website (http://www.ninds.nih.gov/funding/areas/translational_research/CREATE-FAQ.htm). 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.

B. Scope

Projects must focus on a single disorder that falls within the mission of NINDS.

Devices within the scope of this program are expected to be very close to the 'final system' and manufactured using very close to the same manufacturing process for any subsequent clinical studies and eventual market manufacture. If a subsequent larger clinical study is required for market approval, it is expected that any changes to the manufacturing process or the final system design informed by this small clinical study will be minor, and will not require additional pre-clinical data or clinical data prior to conducting the larger clinical study.   

Entry Criteria

For entry to the program, projects should have:

  • Comprehensive Supporting Data: Ideally, preliminary proof-of-concept data would be obtained using an in vivo model representative of the intended patient population.
  • A compelling case for a successful IDE submission by the end of the Phase I or IRB approval for a Non-Significant Risk (NSR) study at the end of the Phase I.
  • Overall device development plan, including when contact with the appropriate regulatory bodies is planned, clinical considerations, and a needs assessment.
  • Identified one or more clinically meaningful device outcome measures based on input from both clinicians and patients
  • Proposed technology directly on the path to U.S. regulatory approval. The next step should be a 510(k)/510(k) De Novo submission or a larger clinical trial leading directly to a 510(k)/510(k) De Novo submission. Changes to the device and study design after the clinical study will be minor and will not require additional animal testing. 
  • Non-binding FDA Pre-Submission (formerly pre-IDE) feedback clearly denoting that the proposed pre-clinical testing plan is sufficient to support a successful FDA submission for an IDE by the end of the Phase I. For Non-Significant Risk (NSR) studies, preliminary communications (e.g. letter or other documentation) with the IRB indicating what pre-clinical testing will be necessary to support the NSR clinical study is sufficient.
  • If the end-goal of the U44 Phase II is a 510(k) or 510(k) De Novo submission, pre-Submission feedback from the FDA (formerly pre-IDE) indicating that the outlined clinical protocol if successful is likely to lead to a successful 510(k) or 510(k) De Novo submission.
  • If the end-goal of the U44 Phase II is a small clinical study to inform criteria for a subsequent larger clinical study to support a 510(k) submission, clear metrics for success must be defined.       

U44 Phase I Scope

Examples of studies that can be proposed during the 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
  • Bench-top 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
  • Regulatory affairs
  • GLP compliant large animal model safety and/or testing of an implanted device
  • IDE submission

U44 Phase II Scope

Phase II will support a small clinical study that will lead to either a 510(k)/510(k) De Novo submission or a larger clinical trial leading directly to a 510(k)/510(k) De Novo submission. It should be noted that clinical studies are only supported for projects where the preclinical activities are conducted under this funding mechanism.

  • Examples of Activities Inappropriate for this FOA: Basic research and studies of disease mechanisms
  • Animal model development: All in vivo models must have been established and characterized in the applicants or collaborators laboratory.
  • Development of diagnostics, or diagnostic devices.
  • Rehabilitation strategies.
  • Imaging technologies.
  • Definitive clinical trials of therapeutic devices, such as a full Feasibility study and/or Pivotal Trial
  • Applications without pre-clinical testing or activities Applicants proposing clinical trials or biomarker studies that fall outside of the scope of this FOA may wish to consider applying to the NINDS NeuroNEXT clinical trials program (http://www.ninds.nih.gov/news_and_events/proceedings/20101217-NEXT.htm), the NINDS Exploratory Clinical Trials program (http://grants.nih.gov/grants/guide/pa-files/PAR-13-281.html), or to the NIH StrokeNet program for stroke indications (http://www.ninds.nih.gov/research/clinical_research/NINDS_stroke_trials_network.htm.
  • Pre-clinical studies to enable IDE submission, where the early clinical studies would inform a final study design that would require additional pre-clinical testing.
  • Pre-clinical studies to enable IDE submission, where the immediate next steps upon completion of an Early Feasibility Study will be a full Feasibility Study and a Pivotal Trial in support of a PMA (Pre-Market Approval) or HDE (Humanitarian Device Exemption), instead of directly leading to a 510(k) submission
  • 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 but may be within scope of the Bioengineering Research Grants and Partnerships program announcements (see http://www.ninds.nih.gov/research/bioengineering/).
  • 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 will be significant attrition as projects move through the device development process. Applications must propose one or more milestones associated with each Specific Aim. Milestones are goals that are quantifiable for measuring success 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).

Prior to funding an application, NINDS program staff will contact the applicant to discuss the proposed milestones and any changes suggested by the NINDS review panel or NINDS program staff.  A final set of NINDS approved milestones will be specified in the Notice of Award.

Progress towards achievement of the final set of milestones will be evaluated by NINDS program staff.  NINDS program staff may consult as necessary with 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 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, NINDS portfolio balance and program priorities, competitive landscape, and availability of funds.

NINDS encourages increasing the robustness and reproducibility of observed results.  In some cases, conducting additional critical experiments will be important for NINDS to have confidence in making a funding decision.  Therefore, NINDS 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 from NINDS.

Phase I/Phase II Transition

An administrative review will be conducted by NINDS program staff, with potential input by NINDS independent consultants to decide on which of the Phase I projects will be transitioned into the Phase II based on the following:

  • Successful achievement of the defined milestones for the Phase I of the project
  • Likelihood of success in clinical testing
  • Competitive landscape
  • Program balance
  • Availability of funds
  • Submission of the IDE for the clinical study with documentation of final or conditional approval of the IDE from the FDA to start the human study or Institutional Review Board (IRB) approval for a Non-Significant Risk (NSR) study
  • IRB Approval
  • Submission of the final clinical protocol and supporting documents to NINDS for administrative review, and notification of approval by NINDS
  • Agreement on updated timeline, milestones and budget for the clinical study

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.  NINDS 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 are clearly defined and verifiable in the application.  Applicants should consider Guidelines and Policies for Monitoring Clinical Research in the formation of a plan for data and safety monitoring: http://www.ninds.nih.gov/research/clinical_research/policies/dsm.htm.

E. Intellectual Property (IP)

Since the ultimate goal of the CREATE program is to bring new therapeutic 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 is expected to work closely with technology transfer officials at his or her 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 NINDS Scientific/Research staff to get further guidance.

F. Pre-application Consultation

As a U44 cooperative agreement, implementation will involve the participation of NINDS program staff in the planning and execution of the projects.  Applicants are strongly encouraged to consult with NINDS Scientific/Research staff when planning an application. Early contact provides an opportunity for NINDS Scientific/Research staff to provide further guidance on program scope, goals, and developing appropriate milestones. Applicants should contact NINDS Scientific/Research staff at least 12 weeks before a receipt date.