The ARCEX System is intended to deliver programmed, transcutaneous electrical spinal cord stimulation in conjunction with functional task practice in the clinic to improve hand sensation and strength in individuals between 18 and 75 years old that present with a chronic, non-progressive neurological deficit resulting from an incomplete spinal cord injury (C2-C8 inclusive).

Device Description

The ARCES System is a medical device that delivers transcutaneous programmed. Carrier Frequency-enabled electrical spinal cord stimulation (ARCEN Therapy). The System is intended to be used in conjunction with functional task practice in the clinic to improve hand sensation and strength in individuals with cervical spinal cord injury (SCI). The stimulation is intended to be delivered transcutaneously and the active electrodes are intended to be placed in direct contact with intact skin, in appropriate locations along or near the spine to elicit desired outcomes. The ARCES System is intended to be used in a medical center setting by patients and their rehabilitation professionals. The primary components of the ARCEX System are: ARCEX Stimulator, ARCEX Stimulator Charger, ARCEX Splitter Box, ARCEX Extension Cables, ARCEX Programmer, Programmer Charger, and ARCEX Case. The ARCES System is intended to be used with the FDA-cleared Axelgaard PALS electrodes (K132422).

AI/ML Overview

Here's a summary of the acceptance criteria and the study that proves the ARCEX System meets those criteria, based on the provided text:

Acceptance Criteria and Device Performance for ARCEX System

The acceptance criteria for the ARCEX System are primarily derived from the special controls outlined by the FDA and the demonstrated clinical benefits. The clinical study aimed to demonstrate improvements in hand sensation and strength.

1. Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria Category	Specific Acceptance Criteria	Reported Device Performance and Evidence
Clinical Effectiveness: Hand Sensation Improvement	Demonstrate improvement in hand sensation.	ISNCSCI-UESS: Mean improvement of 2.9 (SD 4.8, 90% CI 1.8, 3.9) in the device use phase (p < 0.001). This met the pre-specified threshold for success and showed a statistically and clinically significant change with adjunctive device use beyond expected rehabilitation alone. GRASSP—Sensibility: Mean improvement of 0.9 (SD 2.4, 90% CI 0.4, 1.4) in the device use phase (p = 0.003). Dermatome Analysis: Trend of greater change in C6-T1 dermatomes for ISNCSCI-UESS, with C6-C8 covering the hand.
Clinical Effectiveness: Hand Strength Improvement	Demonstrate improvement in hand strength.	ISNCSCI-UEMS: Mean improvement of 2.2 (SD 3.2, 90% CI 1.5, 2.8) in the device use phase (p < 0.001). This met the pre-specified threshold for success and showed a statistically and clinically significant change with adjunctive device use beyond expected rehabilitation alone. GRASSP—Strength: Mean improvement of 2.8 (SD 5.4, 90% CI 1.6, 3.9) in the device use phase (p < 0.001). Pinch force: Mean improvement of 4.8 (SD 16.1, 90% CI 1.3, 8.4) in the device use phase (p = 0.002). Grasp force: Mean improvement of 13.7 (SD 27.4, 90% CI 7.8, 19.6) in the device use phase (p < 0.001). Myotome Analysis: Trend of greater improvement in C8 and T1 myotomes for ISNCSCI-UEMS, corresponding with finger flexors and hand intrinsics.
Clinical Effectiveness: Functional Task Practice (Implicit)	Indicated for use in conjunction with functional task practice. Improvements in CUE-T and GRASSP-Prehension demonstrate general upper limb function changes, though their specific attribution to the device vs. rehabilitation alone was questioned.	CUE-T: Mean improvement of 5.3 (SD 5.3, 90% CI 4.2, 6.5) in the device use phase (p < 0.001). GRASSP—Prehension Performance: Mean improvement of 1.6 (SD 2.9, 90% CI 0.9, 2.2) in the device use phase (p < 0.001). While statistically significant, the report notes that the linearity of the plots raises questions about the specific attribution to device vs. continuation of intense rehabilitation alone. However, this still represents improvement in conjunction with the system.
Safety	No serious adverse events related to the device. Device-related non-serious adverse events are manageable and resolve with intervention.	Three non-device related SAEs occurred. 44 ADEs were possibly device-related (musculoskeletal: spasms, stiffness, pain; skin conditions: sweating, redness, irritation, reactions; burning sensation, paresthesias). These resolved by turning off the device or reducing stimulation. The incidence of these events did not exceed what is expected for this patient population.
Non-clinical Performance Testing (Special Control 1)	Characterization of electrical stimulation parameters (waveforms, output modes, amplitudes, duration, frequency, charge). Characterization of impedance monitoring system. Characterization of electrode performance.	Non-clinical performance testing was conducted, conforming to IEC 60601-2-10 2016 Ed. 2.1. The device description provides detailed stimulation parameters (Waveform, Amplitude ranges, Frequencies, Pulse Widths, Ramp-up/Program Durations). The system is intended for use with FDA-cleared Axelgaard PALS electrodes (K132422) which have demonstrated performance. Implicitly, these tests support the intended functioning.
Electromagnetic Compatibility & Electrical Safety (Special Control 2)	Performance data must demonstrate EMC, electrical safety and performance, battery safety, and wireless compatibility.	Testing performed to recognized standards: IEC 60601-1-2:2014/A1:2020 (EMC), IEC/TR 60601-4-2:2016 (EM Immunity), ANSI AAMI HA60601-1-11:2015+AMD1:2021 (Home Healthcare), ANSI/AAMI ES60601-1:2005/A2:2021 (Basic Safety/Performance), IEC 60601-2-10:2016 (Nerve/Muscle Stimulator), IEC 62133-2:2017 (Battery Safety), UN38.3.5 (Battery Transport), EN IEC 55035:2017/A111:2020 (EMC Multimedia).
Software Verification, Validation & Hazard Analysis (Special Control 3)	Software verification, validation, and hazard analysis must be performed.	Device software and cybersecurity documentation was provided per FDA Guidance (June 2023), categorized as Enhanced. Complete verification and validation of all components (software, hardware, firmware, cybersecurity, wireless compatibility, coexistence) were provided.
Biocompatibility (Special Control 4)	Patient-contacting components must be biocompatible.	Electrodes (Axelgaard PALS, K132422) previously cleared and demonstrated biocompatibility. Extension Cables: Biocompatibility testing (cytotoxicity, sensitization, irritation) showed non-cytotoxic, non-sensitizing, non-irritating, and toxicology risk assessment of color additives acceptable. Splitter Box Clip: Biocompatibility testing (cytotoxicity, irritation) showed non-cytotoxic, non-irritating, and toxicology risk assessment of color additives acceptable. All materials listed in Attachment G of FDA Guidance on ISO 10993 with documented safe use; no exclusion criteria applied.
Labeling Requirements (Special Control 5)	Labeling must include: summaries of stimulation parameters; instructions for ADM management; contraindication for active implants/wearable defibrillators; typical sensations; accurate placement instructions; cleaning instructions.	The User Manual meets 21 CFR Part 801.109 for prescription devices. Labeling includes: instructions for software navigation for stimulation setup; applying device, operation, typical sensations; summary of electrical stimulation parameters; cleaning instructions. Contraindications and Warnings/Precautions (including those related to ADM and active implants) are explicitly stated in the provided document, implying their presence in the labeling.

2. Sample Size Used for the Test Set and Data Provenance

Sample Size:
- Enrolled: 65 participants
- Completed Study (Test Set): 60 participants
Data Provenance: Prospective, non-randomized, within-subject controlled clinical trial. Data collected from fourteen (14) investigational sites, five (5) of which were located outside of the United States (Canada, the Netherlands, and Scotland).

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The study was a clinical investigation assessing patient outcomes (strength, sensation, function) using standardized clinical assessment scales (ISNCSCI-UEMS, GRASSP, Pinch/Grasp force, CUE-T, ISNCSCI-UESS, PGIC). These assessments are often performed by trained clinicians (e.g., neurologists, physical therapists, occupational therapists) specializing in spinal cord injury.

The text does not explicitly state the "number of experts" used to establish the ground truth for the test set in the sense of independent adjudication for each case, nor does it detail their specific qualifications (e.g., "radiologist with 10 years of experience"). However, the assessments themselves constitute the "ground truth" for the study's endpoints, and these are inherently administered and interpreted by qualified clinical personnel at the investigational sites. The study was published in "Nat Med," indicating peer review and a robust methodology, which assumes qualified professionals administered the tests.

4. Adjudication Method for the Test Set

The text does not describe an explicit "adjudication method" in the sense of multiple independent readers reviewing cases. Instead, the study relied on standardized clinical assessment scales administered by trained personnel. The "ground truth" for the effectiveness endpoints (strength, sensation, function) was the scores obtained from these validated instruments. The study design was a within-subject control, where each participant served as their own control (rehabilitation-only phase vs. rehabilitation + ARCEX phase).

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs without AI Assistance

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not performed. This device is a transcutaneous electrical stimulator, not an AI-assisted diagnostic or interpretative tool that would involve "human readers" interpreting images or data with and without AI assistance. The study assessed the device's direct therapeutic effect on patients.

6. If a Standalone (i.e. algorithm only without human-in-the-loop performance) Was Done

This question is not directly applicable to the ARCEX System, as it is a therapeutic device that works in conjunction with a human professional (rehabilitation professional) in a clinic setting. The device delivers programmed electrical stimulation, but its performance is measured by the patient's physiological and functional response, not by an algorithm's classification accuracy. The "without human-in-the-loop" concept doesn't fit a physical therapeutic device like this. However, the software component underwent standalone verification and validation to ensure it performed as intended in controlling the stimulator.

7. The Type of Ground Truth Used

The ground truth used in the clinical study was based on standardized clinical assessment scores reflecting objective physiological and functional changes in patients. These included:

International Standards for Neurological Classification of Spinal Cord Injury - Upper Extremity Motor Score (ISNCSCI-UEMS) for strength.
International Standards for Neurological Classification of Spinal Cord Injury - Upper Extremity Sensory Score (ISNCSCI-UESS) for sensation.
Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP) subscales for strength, prehension performance, and sensibility.
Pinch and grasp forces for strength.
Capabilities of Upper Extremity Test (CUE-T) for upper limb function.
Patient Global Impression of Change (PGIC) as a patient-reported outcome.

8. The Sample Size for the Training Set

The provided text describes a single clinical investigation which served as the pivotal study for the de novo submission. It does not mention a separate "training set" as would be typical for machine learning model development. The 60 participants who completed the study are the entirety of the clinical data presented for evaluating the device's safety and effectiveness.

If "training set" refers to the prior data or knowledge informing device development or clinical trial design, the text does not quantify this. It mentions the "rehabilitation-only phase" (Month 0 to Month 2) which served as a within-subject control period, essentially helping to establish a baseline and the expected rate of improvement without the device, before the device was introduced.

9. How the Ground Truth for the Training Set Was Established

As noted above, there isn't a "training set" in the machine learning sense explicitly described. For the purposes of the clinical trial's within-subject control design, the "ground truth" for the rehabilitation-only phase (Month 0 to Month 2) was established by the same standardized clinical assessment scores administered by trained clinical personnel, just as it was for the device-use phase. This allowed for a comparison of improvement rates within the same individuals.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR ARCEX SYSTEM

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Transcutaneous electrical spine stimulator to improve skeletal muscle strength and sensation. A transcutaneous electrical spine stimulator to improve skeletal muscle strength and sensation is a device that can be programmed to apply an electrical current via electrodes on a patient's skin over the spine to improve muscle strength and sensation after neurological deficit.

NEW REGULATION NUMBER: 21 CFR 890.5851

CLASSIFICATION: Class II

PRODUCT CODE: SDO

BACKGROUND

DEVICE NAME: ARCEX System

SUBMISSION NUMBER: DEN240014

DATE DE NOVO RECEIVED: March 28, 2024

SPONSOR INFORMATION:

Onward Medical Inc. 50 Milk Street Boston, Massachusetts 02109

INDICATIONS FOR USE

The ARCEX System is indicated as follows:

The ARCES System is intended to deliver programmed, transcutaneous electrical spinal cord stimulation in conjunction with functional task practice in the clinic to improve hand sensation and strength in individuals between 18 and 75 years old that present with a chronic, non-progressive neurological deficit resulting from an incomplete spinal cord injury (C2-C8 inclusive).

LIMITATIONS

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The sale, distribution, and use of the ARCESS System are restricted to prescription use in accordance with 21 CFR 801.109.

In FDA's evaluation of the benefits of the ARCEX device, the following observations were noted:

Probable benefits of the ARCEA therapy were observed only in conjunction with intensive . outpatient rehabilitation.
. Due to the nature of the single-arm, within-subject control, open-label study design, it is unclear which improvements in outcome measures were the result of device use or ongoing intensive rehabilitation effects. (Refer to Summary of Clinical Information for more details)
. There are no demonstrated functional benefits associated with the device. This includes no demonstration of neurological recovery as defined by change in neurological level of injury as per America Spinal Injury Association (ASIA) exam, or ASIA Impairment Scale (AIS) grade.
. Durability testing of benefits has not been completed: persistence of benefits beyond adjunctive device use with rehabilitation are currently unknown.

Contraindications

. The ARCEX System is contraindicated for patients with active implantable devices or wearable defibrillators.

Warnings and Precautions

The long-term effects of chronic electrical stimulation are unknown.
. Operation in close proximity (e.g. 1 m) to shortwave or microwave therapy medical electrical equipment may produce instability in the Stimulator output.
. Safety of use during pregnancy has not been established.
Caution should be used for patients with suspected or diagnosed heart problems. .
. Caution should be used for patients with suspected or diagnosed epilepsy.

Risks:

. Autonomic dysreflexia may be triggered by electrical stimulation. The chances of experiencing autonomic dysreflexia can be reduced by following these precautions:
. Ensure patient has emptied their bladder and bowels before starting a session with the ARCEX System.
Do not use ARCEX System if there is an ongoing bladder infection or fever. ●
. Electrical stimulation may lead to musculoskeletal spasms, stiffness, and pain. If this occurs, consider adapting the stimulation parameters (e.g. reduce amplitude) or if symptoms persist, pause the therapy session. For more details on how to adjust stimulation parameters, refer to Labeling (Instructions for Use).
. Electrical stimulation may lead to skin irritation, sweating and redness. If this occurs, move the electrode(s) to a new location.
Electrical stimulation may lead to a temporary increase in heart rate. If this persists, adapt . the stimulation parameters (e.g. reduce amplitude) or if symptoms persist, pause the

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therapy session. For more details on how to adjust stimulation parameters, refer to Labeling (Instructions for Use).

It is normal for electrical stimulation to cause some discomfort, paresthesia, or neuralgia. ● This sensation may become familiar as the patient uses the ARCEX System.

PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

DEVICE DESCRIPTION

The stimulation is intended to be delivered transcutaneously and the active electrodes are intended to be placed in direct contact with intact skin, in appropriate locations along or near the spine to elicit desired outcomes. The ARCES System is intended to be used in a medical center setting by patients and their rehabilitation professionals.

Image /page/2/Figure/6 description: The image shows the ARCEX system, which includes a programmer, stimulator, and splitter box. The programmer is a tablet-like device with the word "Welcome" displayed on the screen. The stimulator is a white device with a power button and two other buttons. The splitter box is connected to the stimulator and has four ports labeled 1, 2, 3, and 4 on one side and A, B, C, and D on the other side. The system is connected to a person's body with electrodes placed on the neck and abdomen.

Figure 1: Schematic representation of ARCEX System

The primary components of the ARCEX System are:

ARCEX Stimulator .
De Novo Summary (DEN240014)

The Stimulator is an internally powered device equipped with a rechargeable battery. It generates and delivers electrical stimulation to the Electrodes based on commands received from the ARCEX Programmer.

ARCEX Stimulator Charger ● The Stimulator Charger is a wired charger used to recharge the Stimulator battery.

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. ARCEX Splitter Box
The Splitter Box is used to connect and transmit current from the Stimulator to the Electrodes (via the Extension Cables).
ARCEX Extension Cables ●
The Extension Cables are used to connect the Splitter Box to the Electrodes. Two different Extension cable lengths are provided: short Extension Cables (50 cm/19.7 inches long) long Extension Cables (100 cm/39.4 inches long)
ARCEX Programmer ●
The Programmer is an off-the-shelf tablet with the ARCEX PRO app pre-installed and can be used by the Rehabilitation Professional, to exchange data with the Stimulator.
Programmer Charger The Programmer Charger (Tablet Charger) is used to recharge the Tablet battery.
ARCEX Case ●

The Case is intended for transportation and storage, in between use, of the ARCEA System.

The ARCES System is intended to be used with the FDA-cleared Axelgaard PALS electrodes (K132422).

Stimulation Parameters:

Electrical stimulation parameters generated by the ARCEX System are summarized in the table below:

Parameter	Values
Waveform	Monophasic or Biphasic
Monophasic Stimulation PulseAmplitude range	0 mA – 100 mAFor load impedance range from 150 Ohms to 500Ohms
Monophasic Balance PulseAmplitude range	0 mA – 12.5 mANote: the amplitude is configured automatically forcharge balancing.
Biphasic Stimulation PulseAmplitude range	0 mA – 250 mAFor load impedance range from 150 Ohms to 500Ohms

Table 1: Stimulation Parameters

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Intra-burst Pulse RepetitionFrequency	10000 Hz or 20000 Hz
Intra-burst Pulse Width	50 us or 100 us
Carrier Frequency	5000 Hz or 10000 Hz
Frequency	0.2 Hz – 100 Hz
Pulse (Burst) Width	0.1 ms – 5 ms
Ramp-up Duration	2 s – 60 s
Program Duration	1 min – 180 min

SUMMARY OF NONCLINICAL/BENCH STUDIES

BIOCOMPATIBILITY/MATERIALS

The patient contacting materials are:

Table 15: Patient contacting part - description and duration

Part	Description of contact	Cumulative duration
Electrodes	Direct contact with intact skin for the duration of therapy (1 hour per session)	Long term contact
Extension Cable	Direct contact with intact skin for the duration of therapy (1 hour per session)	Long term contact
Splitter clip	Box Clipped to patients' clothes (clothes, pocket, collar, etc.), can be in direct contact with intact skin if clipped on collar	Prolonged contact

Overall biocompatibility evaluation:

Parts are in direct contact with intact skin only.

All the materials in Table 15: Patient contacting part - description and duration and mentioned in section 17.2.2 are listed in Section B in the Attachment G of the FDA Guidance on the use of ISO 10993, and are known to have a documented history of safe use.

None of the exclusion criteria listed in Section C of Annex G apply. ●
In the framework of a least burdensome approach, no further testing was deemed necessary per ISO 10993-1, and the ARCER System was determined to not raise a significant biological risk.

Electrodes:

Description: In normal use of the ARCEX System, the primary patient contacting components are the Electrodes, affixed to the patient's intact skin. The ARCEX System is labeled for use only with compatible Electrodes:

o Round active Electrodes

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o Rectangular return Electrodes
Both Electrode types are manufactured by Axelgaard and have been previously cleared by FDA (K132422) for the same nature of body contact and contact duration.

Biocompatibility evaluation: These Electrodes have demonstrated biocompatibility based on evaluations per ISO 10993-1 "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process." Their use with the ARCEX System does not impact biocompatibility and no new assessment of these cleared devices are required.

Extension cable:

. Description: Extension Cables are connected to the Electrodes (active and return), and the Splitter Box. Up to 8 Extensions Cables can be used in a therapy session, depending on the number of Electrodes set by the Rehabilitation professional. Sections of the cable and the cable plugs connected to the Electrodes are in direct contact with patient skin. for the duration of the therapy. The Extension Cable body is silicone based, and extension cable plugs are made of polyamide.
. Biocompatibility evaluation:

Biocompatibility testing of the Extension Cables, including cytotoxicity, sensitization, and irritation was provided. The testing followed the appropriate standards, and the results support the Extension Cables are non-cytotoxic, non-sensitizing, and non-irritating.

This testing was viewed as supplementary information since adequate information per Attachment G for the Extension Cables was provided.

(1) Toxicology risk assessment of color additives: Color additive information was provided. The color additives in the extension cable and plug were titanium dioxide and carbon black. The color additive information for the Extension Cable (body and white housing of plugs) and the toxicological risk assessment of the color additives was provided and found to be acceptable.

Splitter Box:

Description: Splitter Box is connected directly to the Stimulator and to the Extension Cables. It is intended to be clipped to the patient's clothes by means of the Splitter Box Clip (indicated by an arrow on Figure 5), including a clipping to the collar. Splitter Box Clip is coated with Polyurethane (Cardinal Polyurethane Coating 6700-BK21129) on a Polycarbonate enclosure.
Biocompatibility evaluation: ●

Additionally, the sponsor submitted biocompatibility testing of the Splitter Box Clip, including cytotoxicity, and irritation, followed the appropriate standards, and the results support the Splitter Box Clip is non-cytotoxic and non-irritating. We note that it is unclear if the test article is representative of the final device, and there was no sensitization testing;

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however, this testing was viewed as supplementary information since there was adequate information per Attachment G for the Splitter Box Clip. Toxicology risk assessment of color additives: Color additive information was provided. The color additives in the splitter box were titanium dioxide, carbon black, yellow iron oxide and red iron oxide. The color additive information for the Splitter Box Clip and the toxicological risk assessment of the color additives was provided and found to be acceptable.

SHELF LIFE/STERILITY

Sterility:

The ARCES system is non-sterile. It is meant for multiple uses with different patients when used in the hospital environment. The Off-The-Shelf (OTS) electrodes are nonsterile and are intended for multiple uses for a single patient. They are intended to be replaced when their adhesive no longer fully adheres to the skin.

Shelf-Life:

The ARCEX system does not have a shelf-life. The device is non-invasive, externally used, and comprised entirely of electronic components and medical grade plastics. The composition of the device, including the rechargeable battery, does not predispose it towards deterioration and diminution of its safety and effectiveness when stored under conditions specified in device labeling. As such the device is not adversely affected by aging and has no shelf-life specifications. The expiry date of the Electrodes (previously cleared under K132422) is 3 years and is specified on the Electrode's packaging. The Electrodes are replaceable and information on how to obtain new electrodes is included in the user manual.

ELECTROMAGNETIC CAPABILITY & ELECTROMAGNETIC SAFETY

Testing was performed to conform to the following FDA recognized standards:

Electromagnetic compatibility (EMC):

IEC 60601-1-2:2014/A1:2020 Medical electrical equipment Part 1-2: General . requirements for basic safety and essential performance - Collateral Standard: Electromagnetic disturbances - Requirements and tests
IEC/TR 60601-4-2 Edition 1.0 2016-05 Medical electrical equipment Part 4- 2: ● Guidance and interpretation - Electromagnetic immunity: performance of medical electrical equipment and medical electrical systems
ANSI AAMI HA60601-1-11:2015+AMD1:2021 Medical Electrical Equipment --. Part 1-11: General requirements for basic safety and essential performance --Collateral Standard: Requirements for medical electrical equipment and medical electrical equipment and medical electrical systems used in the home healthcare environment

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Electrical, thermal, and mechanical safety:

ANSI/AAMI ES60601-1:2005/A2:2021Medical electrical equipment General . requirements for basic safety and essential performance
. ANSI AAMI HA60601-1-11:2015+AMD1:2021 Medical Electrical Equipment --Part 1-11: General requirements for basic safety and essential performance --Collateral Standard: Requirements for medical electrical equipment and medical electrical equipment and medical electrical systems used in the home healthcare environment
. IEC 60601-2-10 2016 - Ed. 2.1 Medical electrical equipment - Part 2-10: Particular requirements for the basic safety and essential performance of nerve and muscle stimulator

Battery safety:

. IEC 62133-2:2017 - Secondary cells and batteries containing alkaline or other non-acid electrolytes - Safety requirements for portable sealed secondary lithium cells, and for batteries made from them, for use in portable applications - Part 2: Lithium systems
UN38.3.5 United Nations Recommendations on the Transport of Dangerous . Goods Manual of Tests and Criteria PARTIII, section 38.3 (ST/SG/AC.10/11/Rev.6/Amend.1).
EN IEC 55035:2017/A111:2020 Electromagnetic compatibility of multimedia . equipment - Immunity requirements

MAGNETIC RESONANCE (MR) COMPATIBILITY

The ARCES device is not an implant and is not intended to be used with the MR environment (Computed Tomography (CT) system, operating room table, etc.) and therefore MR compatibility was not evaluated and not needed.

SOFTWARE & CYBERSECURITY

The device software and cybersecurity documentation was provided according to FDA Guidance document, "Content of Premarket Submissions for Device Software Functions," issued June, 2023. The software level of documentation was determined to be Enhanced. Complete verification and validation of all components of the device, including software, hardware, firmware, cybersecurity, wireless compatibility and coexistence were provided.

PERFORMANCE TESTING - BENCH

Testing was performed to conform to the following FDA recognized standards:

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IEC 60601-2-10 2016 Ed. 2.1 Medical electrical equipment Part 2-10: . Particular requirements for the basic safety and essential performance of nerve and muscle stimulator

SUMMARY OF CLINICAL INFORMATION

One clinical investigation was performed to evaluate the safety and effectiveness of the ARCEX system. The results are published in Moritz et al. 2024 (Moritz, C., Field-Fote, E.C., Tefertiller, C. et al. Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial. Nat Med 30, 1276-1283 (2024). https://doi.org/10.1038/s41591-024-02940-9).

The study was a prospective, non-randomized, within-subject controlled trial performed at fourteen (14) investigational sites, five (5) of which were located outside of the United States, in Canada, the Netherlands, and Scotland. The study enrolled adults (at least 22 years of age) who had experienced a C2-C8 incomplete spinal cord injury (SCI) at least 12 months prior and had upper limb weakness and not paralysis as evidenced by screening assessments.

The goal of the study was to assess whether adjunctive use of the transcutaneous spinal cord stimulator (ARCEX system) would improve upper limb strength and sensation when used adjunctively with intensive outpatient rehabilitation in individuals with chronic incomplete cervical SCI. Sixty-five participants were enrolled and ultimately 60 completed the study. The study was carried out in two phases. In Phase 1, each participant completed 2 months of intensive outpatient rehabilitation, consisting of 60-minute sessions with 12-20 sessions a month. They completed functional assessments at baseline, after the first month, and after the second month. They also completed the standard Box and Blocks test at each rehabilitation session. Those who completed the study completed at least 24 sessions over the rehabilitation-only phase, with a mean of 25 sessions. Participants then went onto Phase 2, during which they completed another 2 months of the same intensive outpatient rehabilitation schedule with the addition of transcutaneous spinal cord stimulation via the ARCES system. Monthly assessments during Phase 2 were completed with stimulation turned off. Those who completed the study completed at least 24 sessions over the rehabilitation-only phase, with a mean of 25 sessions.

All study participants underwent the same monthly assessments. These consisted of:

The International Standards for Neurological Classification of Spinal Cord Injury - Upper Extremity Motor Score (ISNCSCI-UEMS) to assess change in upper limb strength

The Graded Redefined Assessment of Strength, Sensibility, and Prehension (GRASSP)-- Strength. Prehension Performance, and Sensibility subscales to assess change in upper limb strength, function, and sensation
-Pinch and grasp forces to assess change in pinch and grasp strength
Capabilities of Upper Extremity Test (CUE-T) to assess change in upper limb function -
-The International Standards for Neurological Classification of Spinal Cord Injury - Upper Extremity Sensory Score (ISNCSCI-UESS) to assess change in upper limb sensation

From baseline to 2 months (end of rehabilitation-only phase), participants (N=60) demonstrated a mean improvement in the measures as follows:

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Measure	Mean	Standard Deviation	90% Confidence Interval	P-value
ISNCSCI-UEMS	0.2	2.9	-0.5, 0.8	0.292
GRASSP—Strength	3.6	6.6	2.2, 5.1	<0.001
GRASSP—PrehensionPerformance	1.3	3.7	0.5, 2.1	0.004
Pinch force	2.6	16.7	-1.16, 6.32	0.35
Grasp force	10.5	28.3	4.4, 16.6	0.003
CUE-T	5.8	6.5	4.3, 7.2	<0.001
ISNCSCI-UESS	-0.2	5.9	-1.5, 1.0	0.620
GRASSP—Sensibility	0.0	1.8	-0.4, 0.4	0.313

During the device use phase, in conjunction with ongoing rehabilitation (from Month 2 to Month 4), participants (N=60) demonstrated a mean improvement in the measures as follows:

Measure	Mean	StandardDeviation	90% ConfidenceInterval	P-value
ISNCSCI-UEMS	2.2	3.2	1.5, 2.8	<0.001
GRASSP—Strength	2.8	5.4	1.6, 3.9	<0.001
GRASSP—PrehensionPerformance	1.6	2.9	0.9, 2.2	<0.001
Pinch force	4.8	16.1	1.3, 8.4	0.002
Grasp force	13.7	27.4	7.8, 19.6	<0.001
CUE-T	5.3	5.3	4.2, 6.5	<0.001
ISNCSCI-UESS	2.9	4.8	1.8, 3.9	<0.001
GRASSP—Sensibility	0.9	2.4	0.4, 1.4	0.003

The following graph was published in Moritz, C., Field-Fote, E.C., Tefertiller, C. et al. Noninvasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial. Nat Med 30, 1276-1283 (2024). https://doi.org/10.1038/s41591-024-02940-9.

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Image /page/10/Figure/0 description: The image contains nine line graphs comparing the effects of rehabilitation alone versus rehabilitation with ARCEX therapy on various metrics. Each graph plots delta metric score against timepoint (baseline, 1, 2, 3, and 4 months). The metrics include ISNCSCI-UEMS, grasp force, pinch force, ISNCSCI sensory score, ISNCSCI-UESS, GRASSP-Sensibility, CUE-T total score, GRASSP-Prehension, and GRASSP-Strength. Statistical significance (NS, **, ***) is indicated above the lines for each therapy period.

This graph summarizes changes in the various outcome measures in the rehabilitation-only and ARCES therapy phases of the clinical trial. Due to the nature of the single-arm, open-label study design, in several outcome measures it is difficult to differentiate the effects of ongoing rehabilitation from that of the ARCEX System. This uncertainty is highlighted in the two functional measures (CUE-T total score and GRASSP-Prehension) in the middle and left panels of the bottom row. Despite the statistical significance between month-4 and month-2, the linearity of the plots raises the question if improvement in CUE-T and GRASSP-Prehension are due to continuation of intense rehabilitation alone or are attributable to adjunctive device use. This is reinforced when considering the mean change during rehabilitation only versus device

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use in conjunction with rehabilitation for these two measures (5.8 and 5.3 for the CUE-T and 1.3 and 1.6 for GRASSP-Prehension as shown in the tables above). When considering the potential for ongoing rehabilitation effect during Phase II for strength measures, the ISNCSCI-UEMS, ISCNSCI-UESS, and Grasp force demonstrate a statistically and clinically significant change with adjunctive device use beyond that which might be expected with rehabilitation alone. The change during this second phase also meets the pre-specified threshold for success for the measures.

When analyzing the change in ISCNSCI-UESS based on dermatome, there is a trend of greater change in C6-T1 dermatomes, with C6-C8 dermatomes covering the hand. When analyzing the ISCNSCI-UEMS results, there was a trend of greater improvement in C8 and T1 myotomes, corresponding with finger flexors and hand intrinsics.

Over the course of the study, three participants experienced non-device related serious adverse events (constipation, urinary tract infection, and cystoliths). There were a total of 238 nonserious adverse events, the two most common being urinary tract infections or urinary/renal disorders and musculoskeletal and connective tissue disorders, such as spasms, stiffness, pain. sweating, skin redness, or irritation. The majority of these adverse events were mild or moderate in severity and the incidence of these events did not exceed beyond what is expected for these patients to experience in daily life.

Forty-four adverse events were thought to be possibly related to the device and thirty-seven were thought to be related to study procedure. The most common device-related adverse events were musculoskeletal, such as spasms, stiffness, and pain. The second most common adverse events were skin conditions, including sweating and redness, irritation, or reactions at the active electrode site. Other adverse events included burning sensation and paresthesias in the extremities. These events resolved with turning off the device or reducing stimulation. The most common procedure-related adverse event was musculoskeletal in nature, such spasms, stiffness, and pain.

Pediatric Extrapolation

The ARCHA System is indicated for patients aged 18 years and older. For medical devices, the FD&C Act defines patients before their 22nd birthday as pediatric patients. In this De Novo request, complete data from patients between 22-74 (mean age 46.5) years were used to support the use of the device in adult patients. It was appropriate to indicate the device for individuals 18 and older because patients aged 18 to 21 years do not carry additional differences or risks relative to the patient population studied, incidence of spinal cord injury and upper limb weakness is present in the transitional adolescent population (pediatric sub-population) of 18-21 years of age, and this device has a likely benefit for this group.

LABELING

The labeling (User Manual) meets the requirements of 21 CFR Part 801.109 for prescription devices.

The labeling includes instructions explaining how users can navigate the software application to set-up different stimulation programs. Instructions for use includes information on applying the

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device to the patient, how the device operates, and the typical sensations experienced during treatment.

The labeling also includes a summary of the ARCES System electrical stimulation parameters and outlines the cleaning for clinical use.

RISKS TO HEALTH

The table below identifies the risks to health that mav be associated with use of the transcutaneous electrical spine stimulator to improve skeletal muscle strength and sensation and the measures necessary to mitigate these risks.

Risks to Health	Mitigation Measures
Ineffective treatment from insufficientstimulation due to device failure,interference with other devices, or usererror, leading to worsening condition	Non-clinical performance testingSoftware verification, validation, and hazard analysisLabeling
Adverse tissue reaction	Biocompatibility evaluationLabeling
Overstimulation due to device failure,interference with other devices, or usererror, leading to skin discomfort,burns, electrical shock, pain atstimulation site, muscle spasms andstiffness	Non-clinical performance testingElectromagnetic compatibility (EMC) testingElectrical, thermal, and mechanical safety testingSoftware verification, validation, and hazard analysisLabeling

SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the transcutaneous electrical spine stimulator to improve skeletal muscle strength and sensation is subject to the following special controls:

(1) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following performance characteristics must be evaluated:
- (i) Characterization of the electrical stimulation parameters, including the following: waveforms; output modes; maximum output voltage and maximum output current; pulse duration; frequency; net charge per pulse; maximum phase charge, maximum current density, maximum average current, and maximum average power density:
- Characterization of the impedance monitoring system; and (ii)
- Characterization of electrode performance, including the electrical performance, (iii) adhesive integrity, shelf life, reusability, and current distribution of the electrode surface area.
(2) Performance data must demonstrate the electromagnetic compatibility, electrical safety and performance, battery safety, and wireless compatibility of the device.
Software verification, validation and hazard analysis must be performed. (3)

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(4) The patient-contacting components of the device must be demonstrated to be biocompatible.
(ર) Labeling must include:
- Summaries of electrical stimulation parameters; (i)
- Instructions for user management of the device in the event of adverse effects; (ii)
- A contraindication for patients with active implantable devices or wearable (iii) defibrillators:
- (iv) Information on the typical sensations experienced during treatment;
- Instructions for accurate placement of the device on the patient; and (v)
- Cleaning instructions. (vi)

BENEFIT-RISK DETERMINATION

The risks of the device are based on data collected in a clinical study described above. Adverse events such as pain, spasms, muscle stiffness, skin irritation, reaction at the electrode site, dysesthesias, and paresthesias occurred during the study. Known risks for skin contacting devices include issues of biocompatibility and issues due to electrodes peeling off and/or stimulation being concentrated in an unintended way due to lack of proper adherence of the electrodes, leading to injuries such as burns, especially in patients with impaired sensation. With devices of this type, malfunction due to electromagnetic interference or software faults can also pose risks such as thermal injury or inability to treat due to device failure. None of the above are serious and all can be resolved quickly and easily by discontinuing use or adjusting the device.

The probable benefits of the device are also based on data collected in the clinical study as described above. Improvements include improved ISNCSCI-UEMS, ISCNCSCI-UESS, and grasp force which were demonstrated to be both statistically sigmificant and clinically meaningful in the hand.

Sources of uncertainty in the benefits included the potential ongoing rehabilitation effect when device use was added, a single arm open label study design that does not account for potential bias, and a lack of follow up time after rehabilitation and device use to establish durability of treatment effect. In addition, there is insufficient literature to support the threshold for clinically significant change in the reported outcome measures in patients with chronic incomplete SCI, however a justification for the pre-selected thresholds was provided for this study.

Patient Perspectives

A statistically significant change in the Patient Global Impression of Change (PGIC) measure was observed only during the combined device use and rehabilitation phase of the study. The PGIC measure is a patient reported measure of perceived change on a Likert scale from 1 (very much improved) to 7 (very much worse) (https://eprovide.mapi-trust.org/instruments/patientglobal-impressions-scale-change-improvement-severity). However the mean change was -0.6, the clinical significance of which is unclear.

Benefit/Risk Conclusion

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In conclusion, given the available information above, for the following indication statement:

the probable benefits outweigh the probable risks for the ARCES System. The device provides benefits and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

The De Novo request for the ARCEX System is granted and the device is classified as follows:

Product Code: SDO Device Type: Transcutaneous electrical spine stimulator to improve skeletal muscle strength and sensation Regulation Number: 21 CFR 890.5851 Class: II

Regulation Number and Section

N/A