HEAL Initiative: Translational Devices to Treat Pain (U44 Clinical Trial Optional)

Purpose:

The purpose of this Funding Opportunity Announcement (FOA) is to encourage small business concerns (SBCs) to pursue translational activities and clinical trials to treat pain with innovative, targeted, and non-addictive diagnostic and/or therapeutic devices that improve patient outcomes and decrease or eliminate the need to prescribe opioids. 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 trial (e.g., Early Feasibility Study). The clinical trial is expected to provide information about the device function or final design that cannot be practically obtained through additional nonclinical assessments (e.g., bench top or animal studies) due to the novelty of the device or its intended use. This is a milestone-driven cooperative agreement program and will involve participation of NIH program staff in the development of the project plan and monitoring of research progress.

Background:

This FOA is part of the NIH Helping to End Addiction Long-term (HEAL) Initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative will bolster research across NIH to (1) improve treatment for opioid misuse and addiction and (2) enhance pain management. More information about the HEAL Initiative is available at:  https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative.

Public Law 115-141, the Consolidated Appropriations Act of 2018 (signed March 23, 2018) includes a requirement that grantees from for-profit applicant organizations must provide a 50% match and/or in-kind contribution of all federally awarded dollars under the grant award (direct costs, as well as facilities and administrative costs) for research related to opioid addiction, development of opioid alternatives, pain management and addiction treatment.

Matching Requirement: A grantee from a for-profit organization funded under this funding opportunity announcement must match funds or provide documented in-kind contributions at a rate of not less than 50% of the total-Federally awarded amount, as stipulated by Public Law 115-141, the Consolidated Appropriations Act of 2018.The applicant will be required to demonstrate that matching funds and/or in-kind contributions are committed or available at the time of, and for the duration of, the award. Applications must identify the source and amount of funds proposed to meet the matching requirement and how the value for in-kind contributions was determined. All matching funds and/or in-kind contributions must be used for the portion of allowable project costs not paid by Federal funds under the grant award.  NIH will not be the recipient, nor serve as a pass-through entity, of any such matching funds and/or in-kind contributions required under this announcement.  See 45 CFR 75.306 for additional details.

 

An estimated 20.4% (50 million) Americans suffer from chronic pain and 8% (19.6 million) Americans suffer from high-impact chronic pain. This is a highly debilitating medical condition that is complex and lacks effective treatments. In recent decades, there has been an overreliance on opioids for chronic pain despite their poor ability to improve function. This contributed to a significant and alarming epidemic of opioid overdose deaths and addictions. Innovative solutions to develop alternative treatment options for pain are thus critically needed. As part of the mission of the HEAL Initiative, NINDS is working with other NIH Institutes and Centers to encourage the translation of basic research into new non-addictive pain treatments. This program announcement is intended to promote the translation of diagnostic and therapeutic devices to treat pain and catalyze partnerships so that translational research in pain can flourish as a cooperative, iterative process leading to safe, effective, and non-addictive treatments for pain.

This opportunity is part of translational devices to treat pain, a coordinated set of initiatives within HEAL that are intended to support a device-based strategy for new non-addictive pain treatments. Although there are many devices available on the market to treat pain, their efficacy is limited by imprecise targeting resulting from insufficient mechanistic data about the 'device-able' targets, and from lack of closed-loop feedback to modulate the therapy. There is untapped potential to improve patient outcomes through new technologies with enhanced targeting and control. Other initiatives, referenced in the Companion FOAs section above, solicit applications to develop new neuromodulation technologies and to demonstrate the viability of new "device-able" targets. Additional FOAs from the HEAL and BRAIN Initiatives and the SPARC program solicit grant applications to mechanistically research new targets and to demonstrate the viability of these "device-able" targets. Additional FOAs from the HEAL Initiative solicit applications to develop clinical-grade prototypes for new pain treatments, new pre-clinical models for pain, and discovery and validation of new biomarkers of pain.

Objective:

The goal of this Funding Opportunity Announcement (FOA) is to translate innovative, effective, and non-addictive device-based technologies from pre-clinical studies to clinical trials to treat pain in humans. This FOA will support pre-clinical testing and clinical trials to answer key questions about the function or final design of a device.  Clinical trials supported are expected to provide information that cannot be practically obtained through additional non-clinical assessments (e.g., bench top or animal studies) and 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 U.S. Food and Drug Administration (FDA), such as chronic implants.

Overview:

Cooperative Agreements

This FOA utilizes a U44 cooperative agreement mechanism to support non-clinical testing to enable IRB and/or an IDE approval 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).

The SBIR Phase I will support non-clinical testing toward obtaining of an IDE and IRB approval for an SR study, or to obtain IRB approval for an NSR clinical trial. Fast-track projects will start at the SBIR Phase I and 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 and can last up to four years, however, the total project period (including both the SBIR Phase I and Phase II) must not exceed five years.  Phase II projects for which only a clinical phase up to four years is proposed can be submitted under this announcement as well. Projects interested in a larger clinical trial or feasibility study may also consider opportunities in the HEAL Clinical Trials Networks.

As a cooperative agreement, this FOA supports milestone-driven projects and involves NIH program staff's participation in developing the final project plan, monitoring the research progress, and making go/no-go decisions. NIH staff will also assist investigators in familiarizing themselves 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 regarding the advancement of devices through the translational developmental pipeline.  As such, an inherent rate of attrition is expected within this program.

Public Private Partnership Programs

This FOA , along with the companion FOAs for U18 development, UG3/UH3 phased applications, and UH3 clinical research, will leverage Public-Private Partnership Programs (PPPs) initiated through the NIH Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, the Office of Strategic Coordination – The Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) Program, and the HEAL Initiative which aim to facilitate partnerships between clinical investigators and manufacturers of latest-generation stimulating and/or recording devices to conduct clinical research for the treatment of pain.  Through these initiatives, the NIH is interested in reducing barriers to negotiating such partnerships and ensuring that new clinical trials leverage manufacturers' existing data. Data demonstrating safety and utility of these devices are very costly to obtain and pose a substantial barrier to research progress. Types of research NIH plans to support with these partnerships include:

• IRB-approved Non-Significant Risk (NSR) clinical research studies
• New Significant Risk (SR) clinical trials requiring amendments to existing Investigational Devices Exemptions (IDEs) from the FDA 
• SR clinical trials in which a new IDE would require no or minimal additional non-clinical testing
• SR clinical trials in which a new IDE would require significant additional non-clinical testing, but leverages existing company device data.

The central feature of the PPPs is a set of template research agreements for collaborations between researchers, research institutions, and device manufacturers.  These template agreements were generated with substantial input from industry partners, clinical researchers, the FDA and representatives from institutional tech-transfer and contracts offices, and refined from input at a workshop held on June 3-4, 2015, (video of the workshop is publicly archived at http://braininitiative.nih.gov/meetings/June-2015-PPP.htm) and a public feedback from a Request for Information issued in the NIH Guide (http://grants.nih.gov/grants/guide/notice-files/NOT-NS-15-032.html).

There are three sets of agreement documents associated with the program, which are available at the following websites http://braininitiative.nih.gov/BRAIN_PPP/and https://commonfund.nih.gov/sparc/newmarkets. 

Memoranda of Understanding (MOUs) agreed upon by NIH and device company partners to provide a framework under which the specified proprietary devices and associated support will be provided by these partners to HEAL awardees. 

Template Confidential Disclosure Agreements (CDA) to be signed by researchers to initiate detailed discussions that may require knowledge of proprietary company information relevant to the devices and proposed research.

Template Collaborative Research Agreements (CRA) to be used as common starting points for negotiations of agreements between the device manufacturer, researcher, and research institution. 

These template agreements have been developed to streamline interactions among the parties and expedite the formation of partnerships to conduct exploratory clinical research utilizing latest-generation devices for early-stage clinical research. The intent of the template agreements is to create a reasonable starting point for negotiations.  The NIH recognizes that specific terms and clauses may need to be altered for specific projects by consensus agreement of the two parties.   

Institutions or businesses that are developing their own devices are welcome to apply to RFA-EB-18-003, RFA-NS-19-016, RFA-NS-19-018 , or this FOA and are not limited to only working with companies participating in the BRAIN, SPARC, or HEAL PPP.  Likewise, companies that have already established formal collaborations with device manufacturers (that are part of either PPP or otherwise) are also allowed to apply.   

For applications proposing a collaboration with an industry partner, a successful application will be contingent on the applicant's ability to provide the NIH with documentation of company interest in allowing access to the selected device and associated data needed for conducting the proposed non-clinical trials and for filing an investigator-sponsored IDE or IRB NSR study in order to conduct the proposed exploratory clinical research study (e.g., an executed CRA or letter from the partner).  Final negotiations need not be completed at the time of submission, but an executed CRA will be required before issuance of grant award.

A list of devices being offered as part of the PPPs, along with associated information, can be found at https://www.braininitiative.nih.gov/resources/BRAIN_PPP/, https://commonfund.nih.gov/sparc/newmarkets, and https://www.nih.gov/research-training/medical-research-initiatives/heal-initiative/public-private-partnership.?

Scope:

Activities supported in this program include implementation 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 device related clinical trial. The development and testing of both diagnostic and therapeutic devices of electrical, chemical, optical, sonic, or other relevant modalities that interface either invasively or non-invasively are within scope of this FOA. Therapeutic devices should address a specific, clinically meaningful purpose related to the treatment of pain. Relevant diagnostic devices should be novel tools used to characterize or identify the nature or cause of a medical condition. Existing diagnostic devices for which there is little to no development needed and the diagnosis serves as an endpoint and/or biomarker might also consider RFA-NS-18-041 or RFA-NS-18-046; Discovery of Biomarkers, Biomarker Signatures, and Endpoints for Pain and Analytical and/or Clinical Validation of a Candidate Biomarker for Pain, respectively.

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.

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 successfully obtaining IDE and IRB approvals for a SR clinical trial , or IRB approval for an NSR study prior to starting Phase II activities.
• Applicants to the Fast-Track mechanism 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 the SBIR Phase I of the award (see https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/NeurologicalDevices/default.htm and https://www.youtube.com/watch?v=u0zPKPLW2mU for helpful resources). 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. Project plans and timelines should plan accordingly for these first activities of the award.
• Those applying for the Direct to Phase II mechanism:
  • Completed all non-clinical testing necessary for approval to conduct the clinical trial
  • Comprehensive supporting data showing proof-of-concept of device function 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
  • Overall device development plan, including timeline for interaction with appropriate regulatory bodies and clinical considerations
  • Identification of one or more clinically meaningful device outcome measure(s) based on input from both clinicians and patients
  • FDA IDE and/or IRB approvals are not required at the time of application, however, both the IDE and IRB approvals must be obtained before an award will be made.

SBIR Phase I Scope

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.

Examples of studies that may be proposed during the SBIR Phase I Scope include, but are not limited to:

• Non-Good Laboratory Practice (GLP) animal studies to develop surgical techniques relevant to the device, optimize relevant therapeutic parameters, and refine device design as necessary for subsequent GLP testing or additional clinical trials 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 the SBIR Phase I if it is necessary to support the IDE submission for the small clinical trial conducted in the SBIR Phase II. Clinical trials in the SBIR Phase I are out of scope if the planned SBIR Phase II small clinical trial is NSR.

SBIR Phase II Scope

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

• a marketing application;
• 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; or
• 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:

• animal model development: all in vivo models must be well established and characterized, and available to the applicant;
• efforts to develop neurotechnology for study of the fundamental function or physiology;
• projects proposing solely exempt human subject research;
• delayed-onset studies; and
• projects focused on augmentation of neural function in healthy individuals.

Milestones

Because device development is inherently high-risk, attrition is anticipated as projects move through the process. To help mitigate this risk, applications must propose one or more milestones associated with each of the research plan's objectives, in each year of the project. Milestones are goals that measure success and/or efficacy that can be used for go/no-go decision-making for the project and should have quantitative success criteria and the rationale for that criteria associated with them (see Section IV.2 for details). Quantitative criteria should be robust and consistent with the state-of-the-art in the field. ?Details on methods, assumptions, experimental designs, and data analysis plans (if the results are quantitatively measured) should be included for each milestone. Each milestone must have a timeline, and be incorporated into the overall project timeline, which should also be reflected in a Gantt chart.

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 on a yearly basis. Program staff may involve independent consultants with relevant expertise. If, based on the progress report, a funded project does not meet the yearly 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 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 and 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 transition into the SBIR Phase II based on the

• successful achievement of the defined milestones for the SBIR Phase I of the project;
• likelihood of success in clinical testing;
• competitive landscape;
• program balance;
• availability of funds;
• for significant risk studies, an approved IDE for the clinical trial 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 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.

Pre-Submission Consultation

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 a due date.

IC-Specific Language

NCATS

The National Center for Advancing Translational Sciences (NCATS) will not be accepting any clinical trial(s) under this funding announcement. If your proposed work includes an NIH-defined clinical trial it would be assigned to one of the other NIH Institutes/Centers participating in this funding announcement.  Where a clinical trial is contemplated in the proposed work, the NCATS may be amenable to co-funding with one of the other participating ICs.  Please contact appropriate program staff if you have any questions.

 

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