TRL 7 (pain) and 510(k)
Injectrode Technology has reached Technology Readiness Level Seven (TRL 7). This is based on the extensive benchtop and preclinical work done to ensure a V&V data package for the upcoming 510(k) submission and to enable cGMP manufacturing in Cleveland, OH with US suppliers under ISO 13485 and the subsequent successful Lumbar Injectrode Feasibility Evaluation (LIFE) clinical study that gathered human clinical data in the lower back and provided mechanism of action data for future pain treatments.
Injectrode reaches TRL 7 for Back Pain Therapy
Technology Readiness Levels (TRL) represent a scale initially defined by NASA and later implemented by the US DOD, DARPA, BARDA, NIH and other Federal Agencies to assess the maturity level of a particular technology from concept to market introduction / deployment. There are nine technology readiness levels with TRL 1 being the lowest (“initial concept”) and TRL 9 the highest (“ready for deployment” or “FDA approval achieved, ready to market”). At each stage, the technology is evaluated against the parameter requirements defining each technology level and is then assigned a TRL rating based on the development progress. The TRL scale is described in detail at the end of this page.
Injectrode technology at TRL 7 for lower back pain treatment
The Neuronoff US clinical Lumbar Injectrode Feasibility Evaluation (LIFE) study (NCT06206356) conducted in Dayton, OH, USA demonstrated that the Injectrode can be placed and removed minimally invasively and that the activation of lumbar erector spinal and multifidus muscles can be achieved using only transcutaneous stimulation under 30 V. Participants described voltages below 30 V applied to the outside of the body as comfortable, if they felt them. Contraction of targeted muscle groups was documented by ultrasound, participant feedback and physician palpation. Unilateral and bilateral placement of the Injectrodes was performed under local anesthesia only (no requirement for e.g. OTC pain follow-up). Activation thresholds for activation on day of explant (<30 days) were comparable to thresholds measured during placement up to ~25 days earlier. A detailed publication describing the LIFE study is expected soon. Due to the absence of percutaneous wires, study participants reported forgetting about the presence of the implanted device. Aesthetic aspects of interest were confirmed when the formerly placed Injectrodes had left no or only minimal indication of the former needle puncture, necessitating fluoroscopy for confirmation of Injectrode location on the day of explant.
Video Set 1: Highlighting LIFE study overview, virtually invisible and minimally invasive nature of Injectrode. More details here.
USAMRMC Equivalent TRL Descriptions
Following the definition of TRL-7 as defined by the "USAMRMC Equivalent TRL Descriptions" (ref [1, 2]), a fully functional Injectrode model system was utilized and applied to the operational model (clinical study), following chronic multi-month large preclinical model studies as a representational model to stimulate spinal peripheral nerves in the human lower back and evoke strong contraction of erector spinae and multifidus muscles (figure 1). With the successful completion of chronic large animal preclinical models for long-term safety and efficacy, followed by the successful completion of the Lumbar Injectrode Feasibility Evaluation (LIFE) study (NCT06206356), the Neuronoff Injectrode system was successfully trialed clinically for safety and effectiveness as a future pain therapy.
With clinical safety and effectiveness trials (preclinical and clinical) completed, and clinical user validation study work initiated, TRL 7 has been reached. The final product design has been validated, and final prototype and/or initial commercial scale devices are being produced. Data have been collected, presented, and discussed with FDA/CDRH to support continued device development. Components of the PNS Injectrode F1 System were design-frozen to allow component tests, component drawings, design history file, design review, and master device record updated and verified. Production technology has been demonstrated through production-scale cGMP plant qualification (ISO 13485). Clinical safety and neuro-stimulation effectiveness have been verified, along with easy deployment and removal of implanted components.
Figure 1: USAMRMC Equivalent TRL 6 (left) and TRL 7 (right) descriptions and decision criteria explained. Ref [1, 2].
Injectrode platform beyond chronic pain
The Injectrode platform is designed to enable easier and faster access for neuromodulation treatments wherever a drug-injection based intervention is utilized today. The time required to place an Injectrode under fluoroscorpic or ultrasound guidance is comparable to the time needed to guide a needle to e.g. a nerve target with the intent to inject a drug using the same visualizaton modalities. This means that the time-on-table for the future patient is similar, as is the time spent in the surgical suite / ASC OR room. Needle based interventions are significantly faster than therapies requiring surgical access, greatly aiding clinic logistics and optimal clinician time utilization.
Figure 2: A) Fluoroscopic AP view showing bilateral Injectrode placement in the lower back. B) Placement site on day 25, demonstrating virtually invisible placement site after healing.
Injectrode at TRL 5 for neuromodulation therapies outside of pain
In collaboration with various academic labs, Neuronoff has gathered acute and chronic large animal data for medical applications beyond chronic pain. These include Injectrodes placed on PNS nerves to modulate neurogenic and overactive bladder applications; on sacral nerves to modulate neurogenic and overactive bladder applications, Injectrodes placed on cranial nerves for neuromodulation of hypertension symptoms and heart failure. Upcoming work will study the effects of vagal stimulation and modulation of autonomic activity for chronic pain and other use cases. NIH and DOD grant applications have been submitted for clinical stage neurogenic and overactive bladder use cases, as well as targeted tissue growth and repair. Additional grant applications are in process.
Video 4: What if there was a simpler way to try out neuromodulation, similar to how we try drugs to treat a condition today? Only the Injectrode is implanted (fully, nothing sticking out).
Video 5: How to power the Injectrode: connecting the Programmer with External Pulse Generator (EPG).
Video 6: Customizing the waveforms for the specific use case.
Call for proposals: Joint Therapy Development
Neuronoff’s preclinical and clinical database is growing. We are interested in partnering with experienced institutions for joint development of therapies for chronic conditions.
If you would like to discuss the development of a neuromodulation intervention requiring shallow or deep tissue access, please contact manfred@neuronoff.com.
Next: 510(k) and TRL 9 for Injectrode system
Work is underway to submit the first 510(k) application for the use of the PNS Injectrode F1 system for the treatment of chronic pain in the peripheral nervous system (PNS; excluding craniofacial placement locations) by the early 2025.
Verification and Validation (V&V) Reports included in the 510(k) package are:
System Safety Testing
Usability Testing (clinician, technician, and patient user)
MRI Testing (1.5 and 3 T)
Functionality Testing
EtO Sterilization
System Integration
Cleaning in Mfg
Electrochemistry Testing
Electrical compatibility and safety, Wireless coexistence (60601 Compliance)
Clinical data
Biocompatibility Testing (implanted and external components)
External Pulse Generator (EPG) Benchtop Testing
EPG and implanted component supply chain documentation
Simulation
Software/Firmware Verification and Validation
Cybersecurity
Chronic Large Model Preclinical Safety Study
Packaging, Handling, Shelf Life
In parallel, a clinical study is being designed for reimbursement coverage with CMS and private insurance providers. The clinical data are anticipated to provide further support for TRL-7. Communication with the FDA is ongoing. All required benchtop, preclinical and clinical documentation is being prepared as per expectation for the 510(k) application.
TRL 8 will be reached with the submission of the 510(k) package to the US regulatory body, targeted for early 2025. Typical 510(k) review takes approximately 90 days. TRL 9 will be officially achieved with the first US regulatory approval, enabling market introduction in the United States, Switzerland and other jurisdictions accepting US FDA approval.
Note that a product/therapy development can "jump" TRL based on the parameters required for each level. For platform technologies, it's possible to leverage data gathered for another clinical application if the regulatory body agrees with the cross-functional applicability, potentially jumping to TRL 5 or 6 for subsequent clinical indications. Any clinical use case beyond chronic pain is expected to be a new label and will likely utilize the US FDA de novo submission pathway, a time and cost-efficient strategy to bring novel, lower risk therapies to market. These de novo FDA submissions are anticipated to leverage the pre- and post-market data from the initial PNS pain 510(k) indication.
Background: Understanding the TRL scale
Technology Readiness Levels (TRL) provide a common set of definitions for determining the development status of a therapy or technology from initial concept (TRL 1) to successful deployment / market introduction (TRL 9). The TRL criteria allow a research and development program to be classified by its degree of maturity, from basic research about the mechanisms of a disease to the evaluation of a candidate therapy / technology using animal models and clinical studies. Government agencies such as NASA, DARPA, and BARDA utilize TRL numbers to better assess progress, program risks, and expected timelines until operational readiness.
Milestone Definitions & Decision Criteria
As stated in MTEC's "TRL Definitions" [2], "The DoD has incorporated the concept of TRLs in DoD 5000.2-R2 for major acquisition programs. Although the definitions, descriptions, and references to TRLs are almost always in engineering terms, the TRL concept is applicable to any technology. DoD 5000.2-R does not define the TRL that must be achieved as an exit or entrance criterion for life cycle transition points. Rather, a TRL is one of the many variables that a Milestone Decision Authority (MDA) must consider in the milestone decision process; it does not drive the decision. Biomedical TRL descriptions provide a systematic way for the science and technology (S&T) community to assess and communicate to the MDA the level of maturity of a particular technology or combination of technologies as it relates to the particular category and the maturity necessary for successful product development."
TRL 1: Basic principle observed and reported
A technology at TRL 1 is at the earliest stage of capturing an idea. The underlying basic principles for function have been studied and practical applications can be applied to those initial findings. In simplified terms: Lowest level of technology readiness. Scientific research begins to be translated into applied research and development. Examples might include paper studies of a technology's basic properties. [figure 3; 1, 2, 3, 4]
Figure 3: TRL 1 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
TRL 2: Technology concept and/or application defined
A technology at TRL 2 has a first defined concept including a written description, advantages over the state of the art, an understanding of its mechanism of action, and a project plan for future research and development work. TRL 2 technology may still be very speculative, as there is little to no experimental proof of concept. In simplified terms: Invention begins. Once basic principles are observed, practical applications can be invented. Applications are speculative and there may be no proof or detailed analysis to support the assumptions. Examples are limited to analytic studies. [figure 4; 1, 2, 3, 4]
Figure 4: TRL 2 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
TRL 3: Analytical and experimental critical function and/or characteristic proof-of-concept in hand
When active research and design begin, a technology is elevated to TRL 3. Both analytical and laboratory studies are generally required at this level to see if a technology is viable and ready to proceed further through the development process. Often during TRL 3, a proof-of-concept model is constructed. In simplified terms, active research and development is initiated. This includes analytical studies and laboratory studies to physically validate analytical predictions of separate elements of the technology. Examples include components that are not yet integrated or representative. [figure 5; 1, 2, 3, 4]
Figure 5: TRL 3 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
TRL 4: Component and/or breadboard validation in laboratory environment
Once the proof-of-concept technology is ready, the technology advances to TRL 4. During TRL 4, multiple component pieces are tested alone and jointly within the system. In simplified terms, basic technological components are integrated to establish that they will work together. This is relatively "low fidelity" compared to the eventual system. Examples include integration of "ad hoc" hardware in the laboratory. [figure 6; 1, 2, 3, 4]
Figure 6: TRL 4 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
TRL 5: Component and/or breadboard validation in a relevant environment.
TRL 5 is a continuation of TRL 4, but a technology at level 5 is identified as a breadboard technology and must undergo more rigorous testing than TRL 4 level technology. Simulations should be run in environments that are as close to realistic as possible. Once the testing of TRL 5 is complete, a technology may advance to TRL 6. In simplified terms, fidelity of breadboard technology increases significantly. The basic technological components are integrated with reasonably realistic supporting elements so they can be tested in a simulated environment. Examples include "high fidelity" laboratory integration of components. [figure 7; 1, 2, 3, 4]
Figure 7: TRL 5 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
TRL 6: System/subsystem model or prototype demonstration in a relevant environment.
A TRL 6 technology has a fully functional prototype or representational model. Clinical trials are conducted to demonstrate safety of candidate Class III medical devices in a small number of humans under carefully controlled and monitored clinical conditions. Component tests, component drawings, design history file, design review, and any master device record are updated and verified. Production technology is demonstrated through production-scale cGMP plant qualification. For 510(k), component tests, component drawings, design history file, design review, and any master device record are updated and verified. Manufacturing facility is ready for cGMP inspection. In simplified terms, a representative model or prototype system, which is well beyond that of TRL 5, is tested in a relevant environment. This represents a major step up in a technology's demonstrated readiness. Examples include testing a prototype in a high-fidelity laboratory environment or in a simulated operational environment. [figure 8; 1, 2, 3, 4]
Figure 8: TRL 6 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
TRL 7: System prototype demonstration in an operational environment.
TRL 7 technology requires that the working model or prototype be demonstrated in an operational environment (e.g. in the clinic able to treat a condition, in the OR, in space). Final design tested in clinical environment to treat the condition of interest and gather data required for FDA submission. In simplified terms, the prototype is near, or at, planned operational system. Represents a major step up from TRL 6, requiring demonstration of an actual system prototype in an operational environment such as an aircraft, vehicle, or space. Examples include testing the prototype in a test bed aircraft. [figure 9; 1, 2, 3, 4]
Figure 9: TRL7 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
TRL 8: Actual system completed and “flight qualified” through test and demonstration.
TRL 8 technology has been tested and “flight qualified” and it’s ready for implementation into an already existing technology or technology system. FDA 510(k) application submitted. Once FDA approves 510(k) application, move to the next and final TRL. In simplified terms, the technology has been proven to work in its final form and under expected conditions. In almost all cases, this TRL represents the end of true system development. Examples include developmental test and evaluation of the system in its intended operational system to determine if it meets design specifications. Package for FDA submission ready to be submitted. [figure 10; 1, 2, 3, 4]
Figure 10: TRL 9 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
TRL 9: Actual system “flight proven” through successful mission operations.
Once a technology has been “flight proven” during a successful mission, it can be called TRL 9. In simplified terms, actual application of the technology in its final form and under mission conditions, such as those encountered in operational test and evaluation. Examples include using the system under operational mission conditions. FDA approval in hand and marketing of the therapy may commence. [figure 11; 1, 2, 3, 4]
Figure 11: TRL 9 based on NASA/DOD 5000.2-R for Pharmaceutical, Medical Devices, and Informatics. [2]
A different perspective on TRL provided by NASA:
Technology Readiness Levels as a set of nine graded definitions/descriptions of stages of technology maturity were originated by the National Aeronautics and Space Administration (NASA) and adapted by the Department of Defense (DOD) for use in its acquisition system. Below is a summarized definition of TRL levels 1-9 from NASA’s point of view. Similar to medical devices, safety and efficacy must be proven in different stages before the actual system is allowed to perform missions. Source: [3, 5]
References
[1] DOTE: “Defense Acquisition Guidebook”; Page 848, 849 of 1248 & others; 2013-09-16; https://www.dote.osd.mil/Portals/97/docs/TEMPGuide/DefenseAcquisitionGuidebook.pdf
[2] MTEC: “TRL Definitions”; https://mtec-sc.org/wp-content/uploads/2016/12/TRL-definitions.pdf
[3] NASA: “Technology Readiness Levels”; 2023-09-27; https://www.nasa.gov/directorates/somd/space-communications-navigation-program/technology-readiness-levels/
[4]: U.S. Government Accountability Office (GAO): “GAO Technology Readiness Assessment Guide”; GAO-20-48G; 2023-06; https://www.gao.gov/assets/gao-23-106059.pdf
[5] AcqNotes: “Technology Readiness Level (TRL) – Overview”; 2024-05-02; https://acqnotes.com/acqnote/tasks/technology-readiness-level