The Ouell-FM is a transcutaneous electrical nerve stimulation (TENS) device indicated as an aid for reducing the symptoms of fibromyalgia in adults with high pain sensitivity. The Quell-FM may be used during sleep. The Quell-FM is labeled for use only with compatible NeuroMetrix electrodes.

Device Description

Ouell-FM is a wearable, transcutaneous electrical nerve stimulator designed to stimulate sensory nerves in the upper-calf region. The device utilizes a microprocessor running embedded software and a custom high-voltage Application Specific Integrated Circuit (ASIC) to generate current regulated stimulating pulses with specific characteristics including pulse shape, amplitude, duration, pattern, and frequency. The device utilizes Bluetooth® low energy (BLE) to communicate with a mobile device that allows the user to start and stop therapy, control stimulation intensity, and modify certain operating characteristics. The device is powered by an embedded rechargeable lithium-ion polymer battery that is charged through a USB cable connected to an AC adapter.

The primary components of the device include the Quell-FM device, Band, Electrodes, and Quell-FM mobile app.

A. Quell-FM Device
The Quell-FM device delivers electrical stimulation to the user through a disposable electrode placed on the user's body. The Quell-FM is labeled for use only with compatible NeuroMetrix electrodes (previously cleared in K140586), to which it connects through insulated female medical snap connectors embedded within its housing; no lead-wires are used.
B. Band
A flexible band secures the Quell-FM device and the electrode to the user's leg using a hook and loop material.
C. Electrodes
The Quell-FM device is labeled for use only with compatible NeuroMetrix electrodes (i.e., electrodes cleared under K140586). This use specification, in part, ensures the safe use of the device during sleep because NeuroMetrix electrodes have a known surface area that allows the device to quantitively determine relative skin contact area. Stimulation will be automatically stopped if device detects a decrease in skin-contact area which may lead to unsafe current density to be delivered as would occur during unattended use such as sleeping.
D. Quell-FM Mobile App
Quell-FM is used with a mobile app, running on an iOS or Android mobile device, to which it communicates via Bluetooth. Using the mobile app, the user can start and stop the therapy, control stimulation intensity, and modify certain operating characteristics.

AI/ML Overview

The provided document describes a clinical study to evaluate the effectiveness and safety of the Quell-FM device, a transcutaneous electrical nerve stimulator for fibromyalgia symptoms. Here's a breakdown of the acceptance criteria and the study that proves the device meets those criteria:

Acceptance Criteria and Reported Device Performance

The acceptance criteria for the Quell-FM device are primarily demonstrated through its clinical effectiveness in reducing fibromyalgia symptoms and its safety profile. While explicit "acceptance criteria" in a pass/fail table format aren't directly provided for clinical endpoints (as would be typical for an AI/algorithm-based device), the successful grant of the De Novo request implies that the FDA found the following evidence acceptable for product classification. The "reported device performance" reflects the key findings from the clinical study.

Acceptance Criteria (Implied from De Novo Grant)	Reported Device Performance (Clinical Study Results)
Safety:
- Biocompatibility of patient-contacting components.	- Patient-contacting components (device enclosure, band, electrodes) were found to be biocompatible based on evaluations for cytotoxicity, irritation, and sensitization (per ISO 10993-1:2009), referencing prior clearances (K152954 and K140586).
- Electrical, thermal, and mechanical safety, and electromagnetic compatibility (EMC).	- Tested according to IEC 60601-1-2:2014, IEC 60601-1:2005+A1;C1:2014, IEC 60601-1-11:2015, and IEC 60601-2-10:2012. Results demonstrated the system meets specifications.
- Safe software operation and mitigation of software-related risks.	- Software considered "Moderate" level of concern. All elements of software documentation for this level were provided. Hazard analysis and V&V testing were performed with satisfactory results.
- Wireless coexistence testing.	- Wireless coexistence and communication security testing conducted per FDA guidance (August 14, 2013). Results demonstrated the system meets specifications.
- Lithium-ion battery safety.	- Tested in accordance with IEC 62133-2:2017.
- No serious adverse events; adverse events are minor and resolve with conservative measures.	- No serious adverse events reported. 9 of 12 reported adverse events (rash at site, numbness/tingling, muscle cramping) were definitely or possibly related to TENS use; all were minor and self-limited. Most common was mild rash.
Effectiveness:
- Clinically meaningful reduction in fibromyalgia symptoms, particularly in the indicated population (adults with high pain sensitivity).	- Primary Endpoint (PGIC): Not statistically significant in the ITT population (p=0.279). - However, in the higher pain sensitivity subgroup: Mean PGIC score for active treatment (3.54) was significantly greater than sham (3.14), with a mean difference of 1.25 (95% CI [0.25, 2.24], p=0.015). This difference was considered clinically meaningful. - Secondary Endpoints (ITT population): Active treatment showed significant improvement over sham in FIQR Total Score (p=0.015), BPI Interference (p=0.031), PDQ (p=0.027), and PDI (p=0.044). - Secondary Endpoints (Higher Pain Sensitivity Subgroup): Active treatment showed significant improvement over sham in FIQR Total Score (p=0.031), FIQR Pain Item (p=0.003), BPI Severity (p=0.035), and PDQ (p=0.018). - Responder Analyses: In the higher pain sensitivity subgroup, PGIC responder rate was 28% higher for active (57.8%) vs. sham (30.2%, p=0.025). FIQR responder rate was 30% higher for active (57.5%) vs. sham (28.1%, p=0.019). Pain intensity responder (>30% reduction) was 42% higher for active (59.5%) vs. sham (17.5%, p<0.001).
- Device output parameters meet specifications.	- Electrical stimulation output characterized; system meets specifications.
- Electrode performance meets specifications (electrical, adhesive integrity, shelf life, reusability, current distribution).	- Electrodes passed all testing.
Labeling:
- Labeling consistent with clinical data, covers hazards, and contains required information (IFU, contraindications, warnings, parameters, maintenance, etc.).	- Labeling determined to be sufficient and satisfies 21 CFR § 801.109. Instructions for Use consistent with clinical data and cover all relevant information.

Study Information

This document describes a clinical trial, not directly an AI/algorithm performance study in the typical sense with a "test set" and "ground truth" derived from expert consensus on images. Instead, it's a randomized controlled trial designed to assess clinical efficacy. Therefore, some of the requested points related to AI/algorithm testing (e.g., number of experts for ground truth, MRMC study, standalone performance) are not directly applicable or are interpreted within the context of a clinical trial.

Sample Size Used for the Test Set and Data Provenance:
- Test Set Sample Size: 119 subjects were randomized: 62 to the active group and 57 to the sham group.
- Data Provenance: The study was a "double-blind, randomized, sham-controlled trial," implying prospective data collection in a clinical setting. The country of origin of the data is not explicitly stated, but the mention of the American College of Rheumatology 2010 diagnostic criteria and the FDA De Novo request suggest the study was conducted in the United States and used patients primarily from that region.
Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
- Context: This question is not directly applicable in the sense of establishing "ground truth" for an AI algorithm's diagnostic performance from expert reads (e.g., radiologist interpreting an image). Instead, the "ground truth" for clinical efficacy in this trial is derived from objective and subjective patient-reported outcomes (PROs) and clinical assessments.
- Expert involvement was in:
  - Diagnosis: Inclusion criteria required a "physician diagnosis of fibromyalgia in the medical record" based on American College of Rheumatology 2010 criteria. The specific number and qualifications of these diagnosing physicians are not detailed in the document but would generally be rheumatologists or pain specialists.
  - Clinical Assessments: Study endpoints relied on standardized questionnaires (e.g., PGIC, FIQR, BPI) and quantitative sensory testing (QST).
  - Adverse Event Assessment: The principal investigator assessed the relatedness of adverse events to TENS use. Qualifications of the principal investigator are not specified but are implied to be a medical professional.
Adjudication Method for the Test Set:
- Context: Adjudication is not applicable in the typical sense of resolving discrepancies between multiple expert readings for image interpretation.
- Clinical Trial Design: The clinical trial used a double-blind, randomized, sham-controlled design. This design inherently controls for bias by blinding both subjects and study coordinators to the treatment allocation. Blinding effectiveness was assessed at the end of the study.
- Statistical Analysis: Missing data for effectiveness measures were handled by single imputation for the primary endpoint and multiple imputation for secondary endpoints. Significance was assessed by two-sample t-tests within an ANCOVA model.
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:
- Not applicable. This study is a clinical trial evaluating the effectiveness of a medical device (TENS) on fibromyalgia symptoms, not an AI algorithm. Therefore, there are no "human readers" or "AI assistance" in this context. The study compares the device (active treatment) directly against a sham device.
If a Standalone (i.e. algorithm only, without human-in-the-loop performance) was done:
- Not applicable. This device is a transcutaneous electrical nerve stimulator, a physical device that delivers electrical stimulation to a patient. It is not an AI algorithm, nor does it operate in a "standalone" algorithmic sense from a diagnostic or interpretative perspective. Its performance is measured by its physiological impact on patients.
The Type of Ground Truth Used:
- Clinical Ground Truth: The ground truth for effectiveness was established through patient-reported outcomes (PROs) and objective measures of fibromyalgia symptoms and their impact, as defined by validated clinical questionnaires and quantitative sensory testing.
  - Primary Endpoint: Patient's Global Impression of Change (PGIC) - a subjective patient assessment.
  - Secondary Endpoints: Fibromyalgia Impact Questionnaire Revised (FIQR), Brief Pain Inventory Short Form (BPI), painDETECT Questionnaire (PDQ), Pain Disability Index (PDI), Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale (PCS) - a mix of subjective patient reports and derived scores.
  - Subgroup Analysis: Quantitative Sensory Testing (QST) at baseline was used to subgroup patients by pain sensitivity. This involved objective measurements of responses to mechanical and cold stimuli.
- Safety Ground Truth: Established through reported adverse events and their assessment by the principal investigator and through compliance with recognized safety standards (biocompatibility, electrical safety, EMC, software V&V).
The Sample Size for the Training Set:
- Not applicable. This was a clinical trial of a medical device, not a machine learning model. Therefore, there was no separate "training set" for an algorithm. The 119 subjects served as the study population for evaluating the device's efficacy and safety.
How the Ground Truth for the Training Set was Established:
- Not applicable. As there was no training set for an AI/algorithm, this question is not relevant to this clinical trial. The "ground truth" for the overall study's clinical endpoints was established as described in point 6.

Summary

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DE NOVO CLASSIFICATION REQUEST FOR QUELL-FIBROMYALGIA (QUELL-FM)

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Transcutaneous electrical nerve stimulator to treat fibromvalgia symptoms. A transcutaneous electrical nerve stimulator to treat fibromyalgia symptoms is a prescription device that transcutaneously stimulates a patient's sensory nerves through electrodes placed on the skin.

NEW REGULATION NUMBER: 21 CFR 882.5888

CLASSIFICATION: Class II

PRODUCT CODE: OSO

BACKGROUND

DEVICE NAME: Quell-Fibromyalgia (Quell-FM)

SUBMISSION NUMBER: DEN210046

DATE OF DE NOVO: October 6, 2021

NeuroMetrix Inc. CONTACT: 4b Gill Street Woburn, MA 01801

INDICATIONS FOR USE

LIMITATIONS

The sale, distribution, and use of the Quell-FM are restricted to prescription use in accordance with 21 CFR 801.109.

Many participants in the clinical study were also taking medication for fibromyalgia and it was difficult to assess the effects of the device compared to medication.

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The device is contraindicated for use by patients who have a cardiac pacemaker, implanted defibrillator, other implanted electronic device, or implanted metal near the device, because this may cause electric shock, burns, electrical interference, or death.

The stimulation electrodes should not be placed across or through the head, directly on the eyes, covering the mouth, on the front of the neck, on the chest or upper back, or crossing the heart.

The device cannot be used while driving, operating machinery, or during any activity in which electrical stimulation can put the patient at risk of injury.

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

DEVICE DESCRIPTION

duration, pattern, and frequency. The device utilizes Bluetooth® low energy (BLE) to communicate with a mobile device that allows the user to start and stop therapy, control stimulation intensity, and modify certain operating characteristics. The device is powered by an embedded rechargeable lithium-ion polymer battery that is charged through a USB cable connected to an AC adapter. An image of the device and its placement on the upper calf is provided in Figure 1.

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Image /page/2/Picture/0 description: The image shows three different images labeled A, B, and C. Image A shows a black device with a blue outline next to a black box with a blue outline. Image B shows a black strap with a blue circle in the middle and a hand placing a white circle on the blue circle. Image C shows a person putting the black strap with the blue circle around their knee.

Figure 1. Ouell-FM device and Band (A). Placement of device in Band and attachment of electrode (B). Placement of Quell-FM on upper calf (C).

The primary components of the device include the Quell-FM device, Band, Electrodes, and Quell-FM mobile app.

A. Quell-FM Device
The Quell-FM device delivers electrical stimulation to the user through a disposable electrode placed on the user's body. The Quell-FM is labeled for use only with compatible NeuroMetrix electrodes (previously cleared in K140586), to which it connects through insulated female medical snap connectors embedded within its housing; no lead-wires are used.
B. Band
A flexible band secures the Quell-FM device and the electrode to the user's leg using a hook and loop material.
C. Electrodes
The Quell-FM device is labeled for use only with compatible NeuroMetrix electrodes (i.e., electrodes cleared under K140586). This use specification, in part, ensures the safe use of the device during sleep because NeuroMetrix electrodes have a known surface area that allows the device to quantitively determine relative skin contact area. Stimulation will be automatically stopped if device detects a decrease in skin-contact area which may lead to unsafe current density to be delivered as would occur during unattended use such as sleeping.
D. Quell-FM Mobile App
Quell-FM is used with a mobile app, running on an iOS or Android mobile device, to which it communicates via Bluetooth. Using the mobile app, the user can start and stop the therapy, control stimulation intensity, and modify certain operating characteristics.

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The device has a single output mode consisting of continuous stimulation at a randomly varying instantaneous frequency centered at 40 Hz (range 30 - 50 Hz), 80 Hz (default, range 60 - 100 Hz) or 160 Hz (range 120 - 200 Hz). The technical specifications are listed in Table 1.

Specification	Value
Configuration	1 stimulator (2-lead)
Waveform (e.g., pulsed monophasic, biphasic)	Biphasic with alternating leading phase, asymmetrical
Shape (e.g., rectangular, spike, rectified sinusoidal)	Rectangular
Regulated current or voltage	current
Maximum Output Voltage (+/- 5%)	50 V @ 500 Ω118 V @ 2000 Ω118 V @ 10000 Ω
Maximum Output Current (+/- 10%)	100 mA @ 500 Ω61 mA @ 2000 Ω12 mA @ 10000 Ω
Duration of primary (depolarizing) phase	100 µs
Pulse Duration	280 µs (does not include 100 µs inter-phase delay)
Pulse Frequency	60-100 Hz (default, randomly varying)30-50 Hz (randomly varying) or120-200 Hz (randomly varying)
Net Charge per pulse (If zero, state method of achieving zero net charge.)	Normally 8 µC @ 500 Ω per pulse;Normally 0 µC per sequential pair of pulses;zero net current
Maximum Phase Charge	18 µC @ 500 Ω18 µC @ 1000 Ω
Maximum Current Density (r.m.s), Calculated for minimum electrode area of 28 cm²	0.54 mA/cm² @ 500 Ω @80 Hz0.76 mA/cm² @ 500 Ω @160 Hz
Maximum Average Current	2.2 mA @ 500 Ω @80 Hz4.5 mA @ 500 Ω @160 Hz
Maximum Average Power Density, Calculated for minimum electrode area of 28 cm²	4.0 mW/cm² @ 500 Ω @80 Hz8.0 mW/cm² @ 500 Ω @160 Hz

			Table 1. Quell-FM Output Parameters
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PROCEDURE DESCRIPTION

Quell-FM delivers therapy automatically as repeating 1-hour sessions with a 1-hour gap between sessions (or 30 minutes sessions and 30 minutes gap), as long as the device is on the body, including overnight. Quell-FM provides continuous stimulation during each session. The stimulation intensity is initially set to a strong but comfortable level through the calibration procedure and can subsequently be manually adjusted by users. The intensity increases slowly during a therapy session (starting after 10 minutes) to compensate for nerve desensitization to

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electrical stimulation (habituation). By default, the intensity increases 0.3% per minute in a stepwise fashion (i.e., increase by 0.3% at one-minute intervals); this is equivalent to a 16% increase over a 60-minute therapy session.

Quell-FM can be used during wakefulness or sleep. Stimulation will stop if the device detects that stimulation cannot be correctly and safely delivered. i.e. "trip condition" (Table 2). The user may halt stimulation at any time using the mobile application or by double tapping the device case. Alternatively, stimulation will stop after the therapy session timer (typically 60minutes) has elapsed. The device has an optional auto-restart timer. If it is enabled then a therapy session will automatically start 1 hour (30-minute option is also available) following the end of the previous session, provided that the user did not manually halt stimulation during the previous therapy session, or a trip condition did not occur.

Trip Condition	Description of TriggeringCriteria	Purpose
No Load	Device not connected to patient	Prevent stimulation with maximum outputvoltage due to open circuit.
Insufficient Charge	Charge delivered duringstimulation below target	Prevent stimulation that may be sub-therapeutic.
Over Load	Charge delivered duringstimulation above target	Prevent stimulation that may be exceedspecification limits.
Electrode Peel	Electrode dislodging from skin	Prevent high current density due to smallelectrode area resulting from unrecognizedelectrode peeling such as during sleeping.
Low Battery	Insufficient battery charge tostart (<10%) or continue (≤5%)stimulating	Prevent therapy from starting or continuing ifbattery charge is low and ensure thatsufficient charge remains for device to operatereliably in standby mode.

Table 2. Quell-FM device trip conditions

SUMMARY OF NONCLINICAL/BENCH STUDIES

BIOCOMPATIBILITY/MATERIALS

Patient contacting components include the Quell-FM device enclosure, the Quell-FM Band, and the electrodes. Per ISO 10993-1:2009 "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process," all three patient contacting components are considered surface devices with intact skin contact with prolonged contact (24 hours to 30 days) contact duration.

The device enclosure and Band are identical to those that are currently marketed by NeuroMetrix for the Quell device cleared under K152954. Additionally, the electrodes

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are identical to the currently marketed NeuroMetrix electrodes cleared under K140586. In K 152954 and K 140586, the patient contacting components for the subject device were found to be biocompatible based on evaluations for cytotoxicity, irritation, and sensitization per ISO 10993-1:2009 "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process."

SHELF LIFE AND STERILITY

The Quell-FM does not have a shelf-life specification. The electrodes have a shelf-life of 3 years based on accelerated and actual age testing.

There are no sterilization requirements for the Quell-FM or its accessories. The user does not sterilize the device before first or repeat uses. The electrodes are for single patient use and should be replaced if the gel does not adhere to the skin. if the gel becomes soiled, if the stimulation becomes uncomfortable, or if the electrode is torn or damaged.

Cleaning and maintenance instructions for the Quell-FM have been provided in the labeling.

ELECTROMAGNETIC COMPATIBILITY AND ELECTRICAL SAFETY

The Quell-FM was tested according to the following FDA-recognized consensus standards:

· IEC 60601-1-2:2014 Ed:4.0 (Equivalent to AAMI/ANSI/IEC 60601-1-2:2014) "Medical Electrical Equipment - Part 1-2: General Requirements for Basic Safety and Essential Performance-Collateral Standard: Electromagnetic disturbances -Requirements and Tests."
IEC 60601-1:2005 Ed:3.0 +A1;C1:2014 "Medical Electrical Equipment; Part 1: . General requirements for basic safety and essential performance." (Equivalent to the FDA recognized consensus standard AAMI/ANSI ES60601-1:2005/(R)2012 and C1:2009/(R)2012 and, A2:2010/(R)2012 "Medical Electrical Equipment; Part 1: General requirements for basic safety and essential performance" (IEC 60601-1:2005, MOD).
. IEC 60601-1-11:2015 Ed:2.0 "Medical electrical equipment Part 1-11: General requirements for basic safety and essential performance collateral standard -Requirements for medical electrical equipment and medical electrical systems used in the home healthcare environment."
· IEC 60601-2-10:2012 Ed:2.0 "Medical electrical equipment Part 2-10: Particular requirements for basic safety and essential performance of nerve and muscle stimulators."

SOFTWARE

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A failure or latent flaw in the software of the Ouell-FM could indirectly result in minor injury to the patient or operator; therefore, the software of this device is considered to have a "Moderate" level of concern.

The submission contained all the elements of software documentation corresponding to a "Moderate" level of concern, as outlined in the FDA guidance document "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices", issued May 11, 2005 (https://www.fda.gov/media/73065/download). Adequate documentation describing the software, firmware, software specifications, architecture design, software development environment, traceability, revision level history, unresolved anomalies and cybersecurity provides the foundation that the software will operate in a manner as described in the specifications. A hazard analysis was performed to characterize software risks including device malfunction and measurement related errors. The submission included verification and validation (V&V) testing to address the potential hazards with satisfactory result.

ADDITIONAL PERFORMANCE TESTING

The following additional testing was performed:

· Wireless Coexistence Testing

The device hardware communicates with the mobile application through a BLE and it is intended to be used in the home environment. Wireless quality of service, wireless coexistence and communication security testing was conducted per with the FDA Guidance Document "Radio Frequency Wireless Technology in Medical Devices". issued August 14, 2013 (https://www.fda.gov/media/71975/download). Results demonstrated that the system meets specifications.

. Lithium-Ion Battery Testing

The Quell-FM is powered by one rechargeable 3.7V Lithium-Ion battery (500 mAh). The safety of the Quell-FM battery was tested in accordance with 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."

. Electrical Stimulation Output Characterization:

Testing was performed to characterize the stimulation output waveform, the functionality of the Ouell-FM as a system, and the requirements of the output stimulation parameters. Results demonstrated that the system meets specifications.

Electrode Bench Testing: .

The Quell-FM is labeled for use only with compatible NeuroMetrix electrodes that have been FDA cleared under K140586. The NeuroMetrix electrodes have been tested to assess the mechanical measurements, the design of the electrodes (and tolerances), the electrical characteristics (impedance and current distribution) of the electrodes under the expected worst-case conditions of normal operation, and the

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capability to detect a decrease in skin contact area due to electrode peeling. Results demonstrated that the electrodes passed all testing.

SUMMARY OF CLINICAL INFORMATION

a. Overview

The 119-subject clinical study was a double-blind. randomized, sham-controlled trial to evaluate the effectiveness and safety of the Quell-FM by comparing 3-months of at-home treatment with a standard Quell-FM (active) or modified Ouell-FM (sham) in individuals with fibromyalgia. The primary hypothesis was that active treatment would produce greater improvements in pain, somatic symptoms, and functional impairment compared to sham treatment. A second hypothesis was that subjects with higher baseline pain sensitivity by Quantitative Sensory Testing (OST) would exhibit the largest treatment effects.

b. Subject Selection

Inclusion Criteria

. age 21 or older
able to speak and understand English .
own a smartphone that can run the Quell mobile application .
meet American College of Rheumatology 2010 diagnostic criteria for fibromyalgia, . which is defined as chronic widespread pain and somatic symptoms related to fibromyalgia for at least 3-months (Wolfe et al. 2010)
physician diagnosis of fibromyalgia in the medical record .
. average pain intensity > 4 on an 11-point numerical rating scale (NRS).

Exclusion Criteria

. Diagnosis of cancer or any other malignant disease
. Acute osteomyelitis or acute bone disease
. Present or past Diagnostic and Statistical Manual of Mental Disorders (DSM-V) diagnosis of schizophrenia, delusional disorder, psychotic disorder, or dissociative disorder judged to interfere with study participation
· Pregnancy
. Any clinically unstable systemic illness judged to interfere with treatment
A pain condition requiring urgent surgery .
. An active substance use disorder, such as cocaine or IV heroin use (positive on the Mini International Neuropsychiatric Interview: M.I.N.I. v.5.0), that would interfere with study participation
Have an implanted cardiac pacemaker, defibrillator, or other implanted electronic . device

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c. Randomization

Subjects were randomized to an active or sham device with equal allocation. Active and sham devices were physically identical: only differing in whether thev were loaded with standard software or modified software that implemented a sham stimulation protocol. The study coordinators and investigators could not determine whether a device was an active or sham device based on markings or physical characteristics and did not discuss the stimulation experience with subjects. Subjects were told that two types of TENS were being evaluated, a "low intensity" device and a "high intensity" device. Blinding effectiveness for subjects and study coordinators was assessed at the end of the study.

d. Quantitative Sensory Testing

The Quantitative Sensory Testing (QST) procedures used to identify subjects diagnosed with fibromyalgia that had lower vs. higher pain sensitivity included mechanical and cold stimuli. Responses to punctate mechanical stimuli were measured using a standard set of weighted probes. Singular taps were performed on the metacarpophalangeal joint of the middle finger. Mechanical temporal summation was defined as the increase in pain from the first to the tenth stimulus. A pressure algometer was used to measure pain pressure thresholds (PPT) at . the trapezius muscle and thumb joint. Cuff algometry at the calf was used to assess responses to sustained mechanical pressure. Responses to noxious cold were evaluated using a repeated cold pressor task, which involved immersion of the right hand in a circulating water bath maintained at 4°C. Conditioned pain modulation was measured by assessing PPT at the trapezius during the water bath immersions.

e. Intervention

The standard Quell-FM device (active) provided 60-minutes of continuous stimulation during each 1-hour therapy session. The modified Quell-FM device (sham) provided three 2-minute periods of stimulation during each session (at 0. 28, and 58 minutes) for a total of 6-minutes of stimulation. The device placement on the upper calf and usage instructions were identical for the two devices. Subjects were instructed to maintain a strong but comfortable stimulation intensity and to use their device for at least two I-hour therapy sessions each day over the course of the study.

All subjects were asked to continue their pre-study analgesic medications with changes tracked through a weekly interview.

f. Study Endpoints:

Safety:

Adverse events were assessed in weekly phone calls with subjects.

Effectiveness:

The clinical study included one pre-specified primary effectiveness measure and seven prespecified secondary effectiveness measures as shown in Table 3.

Table 3. Pre-specified primary and secondary effectiveness measures

Effectiveness Measures	Description
Primary
Patient's Global Impressionof Change (PGIC)	Overall belief about the effectiveness of treatment. This study included twoPGIC measures per Hurst and Bolton, a 7-point categorical verbal scale(PGIC-VRS) and an 11-point numerical rating scale (PGIC-NRS). TheVRS ranged from (1) "no change or condition has gotten worse" to (7) "agreat deal better and a considerable improvement that has made all thedifference." The use of PGIC-VRS was prespecified in the protocol andincluded in the statistical analyses.
Secondary
Fibromyalgia ImpactQuestionnaire Revised(FIQR)	Fibromyalgia specific instrument for assessment of disease impact andhealth-related quality-of-life (QoL). It is comprised of 21 individual itemseach rated on an 11-point NRS. The FIQR Total Score ranges from 0 to100, with higher scores indicating more fibromyalgia related impairment.FIQR is composed of three subscales: function, overall impact andsymptoms. The symptom subscale includes a pain intensity assessment(FIQR pain item) that may be analyzed separately and was used in theresponder analyses.
Brief Pain Inventory ShortForm (BPI)	Assessment of pain severity and interference rated on an 11-point NRS.BPI Severity is the average of 4 pain intensity items. Pain Interference isthe average of 7 function items. BPI Severity and BPI Interference wereanalyzed as distinct effectiveness measures.
painDETECT Questionnaire(PDQ)	Assessment of the presence and severity of neuropathic pain. ThepainDETECT questionnaire is composed of 7 pain-quality items and 2items for pain-course and pain-radiation. Recent studies have shown thatthe 7-item painDETECT questionnaire has better discrimination forneuropathic pain compared to the full 9-item instrument and was thereforeused in this study. The 7-item score ranges from 0 to 35, with higher scoresindicating greater neuropathic pain.
Pain Disability Index (PDI)	Assessment of pain related disability. Score ranges from 0 to 70, withhigher scores indicating greater pain related disability.
Hospital Anxiety andDepression Scale (HADS)	Assesses the severity of anxious and depressive symptoms. Score rangesfrom 0 to 42, with higher scores indicating greater severity of anxiety anddepression. HADS is composed of two subscales: anxiety and depression.
Pain Catastrophizing Scale(PCS)	Assessment of pain rumination, magnification, and helplessness. Scoreranges from 0 to 52, with higher scores indicating greater catastrophicthinking.

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g. Statistical Analysis

The primary analysis of treatment effects was conducted in the intention-to-treat (ITT) population, which included all 119 randomized subjects.

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One pre-specified subgroup analysis was carried out in the ITT population. The study protocol predicted that subjects with higher pain sensitivity based on OST measures would demonstrate the greatest treatment effects. Subjects were classified as having lower or higher pain sensitivity by their baseline OST data. Principal component analysis was applied to the correlation matrix of the baseline OST data to identify the prominent pain patterns in the study population. The first principal component accounted for 40% of the total variance. The component had negative loadings for mechanical pain thresholds, positive loadings for pain responses to punctate stimuli and cold stimuli, and a positive loading for temporal summation, and could therefore be interpreted as a composite index of pain sensitivity. Subjects were classified as lower (< median) or higher (> median) pain sensitivity using this principal component. This yielded a lower pain sensitivity subgroup with 59 subjects and a higher pain sensitivity subgroup with 60 subjects.

The 3-month least-squares (LS) mean PGIC scores were compared between the active and sham treatment groups, controlling for baseline pain severity (BPI average pain item), tenderness (dichotomized FIOR tenderness item) and body mass index (BMI) with an ANCOVA model. Missing scores were filled in using single imputation. Significance was assessed by the two-sample t-test with a Type I error rate of 0.05 (two-sided). The subgroup analysis was conducted to test for heterogeneity in the treatment response based on pain. sensitivity. Between and within subgroup treatment effects were assessed with the primary ANCOVA model that included a treatment by subgroup interaction.

The baseline to 3-month LS mean change scores for the secondary effectiveness measures were compared between the active and sham treatment groups. controlling for baseline value, pain severity, tenderness and BMI with an ANCOVA model. Missing data were filled in using multiple imputation. Significance was assessed by the two-sample t-test with a Type I error rate of 0.05 (two-sided).

Responder analyses for PGIC, FIOR Total Score and pain intensity (FIOR pain item) were conducted to inform the clinical meaningfulness of treatment effects. Responder rates were compared between treatment groups using logistic regression, controlling for baseline pain severity, tenderness and BMI. P-values were not assessed against a significance threshold because the study was not specifically powered for responder analyses.

h. Results

Of the 170 individuals screened for the study, 119 met the inclusion/exclusion criteria and were randomized to an active (62) or a sham (57) device for 3-months. Among these subjects, 19 (10 active, 9 sham) withdrew: 16 (7 active, 9 sham) were lost to follow-up and 3 (3 active. 0 sham) withdrew but completed the 3-month assessments. The remaining 100 subjects completed 3-months of treatment, however 4 (1 active, 3 sham) did not return the 3month assessments via mail following implementation of COVID-19 restrictions on inperson clinic visits.

Analgesic Use

At the baseline, half of the subjects (010 %) were taking over-the-counter analgesics 11/6 were prescribed neuroleptics. 100 were prescribed an antidepressant and PM 1% were taking an opioid, including tramadol. At the baseline, 11 % and 1 1 % of the participants in the sham and active treatment groups use pain medication. There was no discernable change

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in analgesic use over the course of the study and there were no significant differences between the treatment groups for any week.

Device Use

Table 4 displays key characteristics of the distributions for Therapy Hours and Wear Time (Hours) for subjects randomized to receive the active device or sham device. One therapy hour (also called therapy session) equals 1 hour of electrical stimulation. Wear Time represents the total amount of time the device is on the patient's skin and is approximated as (2x Therapy Hours - 1 hour) rounded down to the nearest hour.

	Sham Arm (n=59)	Active Arm (n=60)	All Subjects (N=119)
Therapy Hours*
Median	3.9	3.8	3.8
75th Percentile	5.4	5.8	5.6
95th Percentile	8.4	8.4	8.4
Wear Time (Hours)*
Median	6	6	6
75th Percentile	9	10	10
95th Percentile	15	15	15

Table 4. Distribution of daily therapy hours for subjects randomized to the active device or sham device

*One therapy hour (also called therapy session) represents 1-hour of electrical stimulation.

Wear time represents the total amount of time the device is on the patient's skin and is approximated as (2 x Therapy Hours - 1 hour) rounded down to the nearest hour.

Blinding Assessment

Blinding was assessed as each subject completed the study by asking the coordinators and subjects to identify whether a low intensity or high intensity Quell-FM device was used. The coordinator identified the correct treatment in 54.7% (95% CI [45.2, 64.2]) of the 103 subjects that completed the study (n=100) or withdrew but provided the 3-month assessment (n=3). The treatment was correctly identified 63.8% (95% CI [51.4. 76.21) of the time for the active device and 43.8% (95% CI [29.7%, 57.8%]) of the time for the sham device.

Of the 99 subjects that completed the 3-month assessment, 86 answered the blinding question which was included in the satisfaction questionnaire. Among the 13 that did not answer this question, 3 did not complete any part of the satisfaction questionnaire. In the subjects that answered the blinding question. 50.0% (95% CI [39.4. 60.6]) identified the correct treatment. Subjects in the active group correctly identified their treatment 17.4% (95% CI [6.4. 28.3]) of the time and subjects in the sham group correctly identified their treatment 87.5% (95% CI

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[77.3, 97.7]) of the time. Among all subjects, 84.9% (95% CI [77.3, 92.5]) believed they received a low intensity device.

Safety Endpoint

A total of 12 (5 active, 7 sham) adverse events were reported. They included rash at the site of the device, numbness and tingling, and muscle cramping. Six (3 active, 3 sham) were determined to be related to TENS use, 3 (1 active, 2 sham) were deemed possibly related to TENS use, and 3 (1 active. 2 sham) were judged to be unrelated to TENS use by the principal investigator. The 9 events that were definitely or possibly related to TENS use were minor and self-limited. The most common occurrence was a rash under the Quell- FM electrodes. Ten subjects averaged more than 8 therapy hours (i.e., about 15 wear hours) per day (Table 4). Among these ten subjects, one experienced skin irritation that resolved after 1-week of not wearing their device. These ten subjects did not report any other adverse events. Skin irritation is a known minor risk of TENS use that generally resolves with conservative measures.

Primary Effectiveness Outcome

The difference in the LS mean PGIC scores between active (3.54, SE 0.25) and sham (3.14, SE 0.26) treatment at 3-months was not significant in the ITT population (mean difference 0.40, 95% C1 [-0.33, 1.13], p=0.279) (Figure 2), In the pre-specified subgroup analysis, the interaction between treatment and baseline pain sensitivity was significant (p=0.020), which indicated that baseline pain sensitivity moderated the relationship between treatment and PGIC at 3-months. In the higher pain sensitivity subgroup. PGIC was significantly greater for active treatment compared to sham treatment (mean difference 1.25, 95% CI [0.25, 2.24]. p=0.015). The difference between active treatment and sham treatment in subjects with lower pain sensitivity was not significant (mean difference -0.45, 95% CI [-1.48. 0.58], p=0.393),

Image /page/12/Figure/5 description: The image is a bar graph comparing PGIC scores at 3 months for sham and active treatments across different populations. The x-axis represents the ITT population, lower pain sensitivity, and higher pain sensitivity. The y-axis represents the PGIC score at 3 months, ranging from 0 to 5. For the ITT population, the sham group has a score of 3.14 (n=57) and the active group has a score of 3.54 (n=62).

Figure 1. Comparison of PGIC in ITT population and in pain sensitivity subgroups

Secondary Effectiveness Endpoints

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Table 5 shows the 3-month LS mean change scores for the pre-specified secondary effectiveness measures in the ITT population. Negative values indicate improvement. All seven effectiveness measures showed significant within-group (i.e., baseline to 3-months) improvements for active treatment compared to 4 of 7 for sham treatment. The within-group improvements for active treatment were numerically greater than sham treatment for all measures except PCS. The treatment group differences were significant in the FIQR Total Score (-8.58, 95% CI [-15.44, -1.72], p=0.015), BPI Interference (-0.86, 95% CI [-1.64. -0.08], p=0.031), PDQ (-2.21. 95% CI [-3.90, -0.15], p=0.027) and PDI (-4.90, 95% CI [-9.65, -0.14], p=0.044).

Measure	N	Mean	SE	Diff	Treatment Comparison(Active - Sham)95% CI	p-value
	FIQR Total Score
Sham	57	-5.07‡	2.53
Active	62	-13.65‡	2.23	-8.58	-15.44, -1.72	0.015
FIQR Pain Item*
Sham	57	-1.01‡	0.26
Active	62	-1.72‡	0.24	-0.71	-1.44, 0.02	0.055
BPI Severity
Sham	57	-0.80‡	0.23
Active	62	-1.28‡	0.22	-0.48	-1.13, 0.17	0.144
BPI Interference
Sham	57	-0.95‡	0.28
Active	62	-1.81‡	0.26	-0.86	-1.64, -0.08	0.031
PDQ
Sham	57	0.13	0.71
Active	62	-2.08‡	0.65	-2.21	-3.90, -0.15	0.027
PDI
Sham	57	-2.40	1.76
Active	62	-7.30‡	1.54	-4.90	-9.65, -0.14	0.044
HADS
Sham	57	-0.88	0.71
Active	62	-2.42‡	0.66	-1.54	-3.52, 0.43	0.124
PCS
Sham	57	-4.37‡	1.25
Active	62	3.66‡	1.16	0.70	-2.73, 4.14	0.684

Table 5. LS mean changes in secondary effectiveness measures from baseline to 3months for the ITT population.

sample t-test.

Table 6 shows the 3-month LS mean change scores for the secondary effectiveness measures in the subgroup with high pain sensitivity. Negative values indicate improvement. Six of 7 effectiveness measures showed significant within-group (i.e., baseline to 3-months) improvements for active treatment compared to 1 of 7 for sham treatment. The within-group improvements for active treatment were numerically greater than sham treatment for all measures. The treatment group differences were significant for FIQR Total Score ( (0(4) p=0.031). FIOR Pain Item ( 0014) 95% CI 95% CI | 同(写) (DX4) p=0.003).

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BPI Severity	(b)(4) 95% CI	(b)(4) p=0.035) and PDQ	(b)(6) 95% CI
p=0.018).

					Treatment Comparison(Active - Sham)
Measure	N	Mean	SE	Diff	95% CI	p-value
FIQR Total Score
Sham	30	-2.66	3.96
Active	30	-13.97‡	3.24	-11.31	-21.55, -1.07	0.031
FIQR Pain Item*
Sham	30	-0.69	0.38
Active	30	-2.25‡	0.36	-1.57	-2.59, -0.54	0.003
BPI Severity
Sham	30	-0.31	0.34
Active	30	-1.30‡	0.31	-0.99	-1.90, -0.07	0.035
BPI Interference
Sham	30	-0.78	0.40
Active	30	-1.86‡	0.37	-1.09	-2.18, 0.00	0.051
PDQ
Sham	30	0.68	1.00
Active	30	-2.68†	0.95	-3.35	-6.13, -0.58	0.018
PDI
Sham	30	-0.99	2.62
Active	30	-7.35†	2.26	-6.37	-13.16, 0.43	0.066
HADS
Sham	30	-0.90	1.01
Active	30	-1.90	0.97	-0.99	-3.74, 1.75	0.474
PCS
Sham	30	-3.78†	1.76

Table 6. LS mean changes in secondary effectiveness measures from baseline to 3-months in the subgroup with high pain sensitivity

Table 7 shows 3-month LS mean change scores of the 21 items comprising the FIQR Total Score in the ITT population. FIOR is a comprehensive health related Quality of Life (OoL) assessment specifically designed for fibromyalgia. It captures pain, somatic symptoms, activities of daily living and overall disease impact. The purpose of this post-hoc analysis is to determine if active treatment broadly improves fibromyalgia symptoms or disproportionally impacts certain symptoms. For active treatment, 19 of 21 symptoms exhibited a significant improvement from baseline to 3-months compared to 5 of 21 for sham treatment. Similarly, 16 of 21 symptoms decreased by at least 1 point compared to 2 of 21 for sham treatment. The active group exhibited significantly better improvement than sham for 9 of the 21 symptoms.

Table 7. LS mean changes in symptoms of fibromyalgia from baseline to 3-months in the ITT population

FIQR Item (11-point NRS)	Sham	Active	Treatment Comparison(Active - Sham)Difference	p-value
Pain	-1.01 (0.26)‡	-1.72 (0.24)‡	-0.71 (0.36)	0.055

107149

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Sleep	-0.55 (0.42)	-1.56 (0.37)‡	-1.01 (0.58)	0.080
Fatigue	-0.06 (0.35)	-1.23 (0.31)‡	-1.17 (0.48)	0.016
Sensitivity	-1.12 (0.41)†	-1.06 (0.38)†	0.06 (0.57)	0.917
Tenderness	-0.21 (0.36)	-0.64 (0.30)†	-0.43 (0.48)	0.373
Stiffness	-0.60 (0.32)	-1.24 (0.29)‡	-0.64 (0.44)	0.150
Balance	-0.35 (0.34)	-1.32 (0.30)‡	-0.97 (0.46)	0.039
Anxiety	-0.56 (0.37)	-0.41 (0.31)	0.14 (0.49)	0.77
Depression	-0.16 (0.37)	-0.69 (0.31)†	-0.53 (0.50)	0.294
Memory	-0.71 (0.36)†	-0.85 (0.31)†	-0.13 (0.48)	0.785
Goals disrupted by fibromyalgia	-0.72 (0.40)	-1.89 (0.33)‡	-1.16 (0.53)	0.03
Overwhelmed by symptoms	-0.86 (0.39)†	-2.23 (0.34)‡	-1.37 (0.52)	0.010
Ability to walk	-0.76 (0.37)†	-1.22 (0.35)†	-0.46 (0.52)	0.379
Ability to climb stairs	-0.08 (0.35)	-1.05 (0.33)†	-0.98 (0.49)	0.050
Ability to clean floors	-0.37 (0.43)	-1.32 (0.39)†	-0.96 (0.59)	0.108
Ability to shop for groceries	-0.11 (0.38)	-1.15 (0.34)†	-1.05 (0.52)	0.049
Ability to prepare meal	-0.42 (0.36)	-1.29 (0.31)‡	-0.87 (0.48)	0.072
Ability to comb hair	-0.21 (0.31)	-0.51 (0.29)	-0.30 (0.43)	0.484
Ability to change bed sheets	-0.23 (0.37)	-1.37 (0.32)‡	-1.14 (0.50)	0.025
Ability to carry bag of groceries	-0.31 (0.37)	-1.43 (0.33)‡	-1.12 (0.50)	0.029
Ability to sit for 45 minutes	-0.31 (0.39)	-1.62 (0.36)†	-1.31 (0.54)	0.016

Responder Analyses

A PGIC responder was defined as a subject with a score ≥ 5 at 3-months, which corresponds to moderately better symptoms, functional abilities and overall health. Forty-three percent (43%) of active treatment subjects in the ITT population and 58% in the higher pain sensitivity subgroup were PGIC responders (Table 8). The difference in the responder rate between active and sham treatment was 28% (p=0.025) in the higher pain sensitivity subgroup.

Population	Sham % (SE)	Active % (SE)	Diff (95% CI)	p-value
ITT (N=119)	34.6 (6.3)	42.4 (6.3)	7.8 (-9.9, 25.5)	0.389
Subgroup Analysis (N=119)
Higher Pain Sensitivity (n=60)	30.2 (8.4)	57.8 (9.2)	27.7 (3.5, 51.8)	0.025
Lower Pain Sensitivity (n=59)	39.1 (9.7)	28.2 (8.0)	-10.9 (-35.5, 13.7)	0.385

	Table 8. PGIC responder analysis.

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A FIOR responder was defined as a subject that exhibited ≥ 15% reduction in their FIQR Total Score from baseline to 3-months. This threshold corresponds to the minimal clinically important difference. Fifty-seven percent (57%) of active treatment subjects in the ITT population and 58% in the higher pain sensitivity subgroup were FIQR responders (Table 9). The difference in the responder rate between active and sham treatment was 23% in the ITT population (p=0.014) and 30% (p=0.019) in the higher pain sensitivity subgroup.

Population	Sham % (SE)	Active % (SE)	Diff (95% CI)	p-value
ITT (N=119)	34.0 (6.4)	56.9 (6.5)	22.9 (4.7, 41.0)	0.014
Subgroup Analysis (N=119)
Higher Pain Sensitivity (n=60)	28.1 (8.7)	57.5 (9.2)	29.5 (4.8, 54.1)	0.019
Lower Pain Sensitivity (n=59)	40.3 (9.7)	55.8 (9.0)	15.5 (-10.4, 41.5)	0.240

	Table 9. FIQR Total Score responder analysis.
--	-----------------------------------------------	--	--	--

A pain intensity responder was defined as a subject that exhibited a > 30% or > 50% reduction in their pain rating (FIOR pain item) from baseline to 3-months. The 30% cutoff represents moderate improvement in pain and the > 50% cutoff represents a substantial improvement in pain. Table 10 shows the pain intensity responder rates. Forty-six percent (46%) of active treatment subjects in the ITT population and 60% in the higher pain sensitivity subgroup were responders at the > 30% level or moderate improvement. Substantial improvement (≥ 50% reduction) was exhibited by 27% of subjects in the ITT population and 43% in the higher pain sensitivity subgroup. The moderate improvement responder rate was 17% greater for active treatment compared to sham (p=0.074). In the higher pain sensitivity subgroup, active treatment was greater than sham by 42% (p=0.001). A similar pattern was observed for substantial improvement responder rates.

			Table 10. Pain intensity responder analysis.
--	--	--	----------------------------------------------	--

Population	Sham % (SE)	Active % (SE)	Diff (95% CI)	p-value
≥ 30% Reduction in pain intensity from baseline to 3-months (moderate improvement)
ITT (N=119)	29.3 (6.2)	45.8 (6.7)	16.5 (-1.6, 34.6)	0.074
Subgroup Analysis (N=119)
Higher Pain Sensitivity (n=60)	17.5 (7.6)	59.5 (9.6)	41.9 (18.6, 65.3)	<0.001
Lower Pain Sensitivity (n=59)	40.3 (10.0)	33.1 (8.6)	-7.3 (-33.1, 18.6)	0.582

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≥ 50% Reduction in pain intensity from baseline to 3-months (substantial improvement)
ITT (N=119)	12.5 (4.4)	27.3 (6.0)	14.8 (0.03, 29.4)	0.04
Subgroup Analysis (N=119)
Higher Pain Sensitivity (n=60)	8.7 (5.6)	43.1 (9.8)	34.4 (12.8, 56.1)	0.00
Lower Pain Sensitivity (n=59)	15.3 (6.7)	14.9 (6.5)	-0.4 (-18.7, 17.9)	0.96

Pediatric Extrapolation

In this De Novo request, existing clinical data were not leveraged to support the use of the device in a pediatric patient population.

LABELING

The labeling is sufficient and satisfies the requirements of 21 CFR § 801.109 Prescription devices.

The Instructions for Use are consistent with the clinical data and cover all the hazards and other clinically relevant information that may impact use of the Quell-FM device. It contains the Indications for Use, contraindications, warnings, precautions, device description, instructions for use and typical sensations experienced during treatment, a summary of the electrical stimulation output and device technical parameters, instructions on care and cleaning of the device, summary of clinical data, information related to electromagnetic compatibility and wireless specifications, device storage, disposal information, and symbols and markings.

RISKS TO HEALTH

Table 11 below identifies the risks to health that may be associated with use of the transcutaneous electrical nerve stimulator to treat fibromyalgia symptoms and the measures necessary to mitigate these risks.

Identified Risks to Health	Mitigation Measures
Adverse tissue reaction	Biocompatibility evaluation
Skin discomfort, burns, electricalshock, or pain at stimulation site	Electromagnetic compatibility testingElectrical, mechanical, and thermal safety testingNon-clinical performance testingSoftware verification, validation, and hazard analysisLabeling
Device failure due to interferencewith other devices	Electromagnetic compatibility (EMC) testingSoftware verification, validation, and hazard analysis

	Table 11. Identified Risks to Health and Mitigation Measures

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	Labeling
Delayed or ineffective treatmentdue to user error	Labeling

SPECIAL CONTROLS

In combination with the general controls of the FD&C Act. the transcutaneous electrical nerve stimulator to treat fibromyalgia symptoms 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. This testing must include:
- a) Characterization of the electrical stimulation parameters, including the following: waveforms; output modes; maximum output voltage and maximum output current (at 500Ω, 2kΩ, and 10kΩ loads); pulse duration; frequency; net charge per pulse; maximum phase charge, maximum current density, maximum average current, and maximum average power density (at 500Ω):
- b) Characterization of the impedance monitoring system; and
- c) Characterization of electrode performance, including the electrical performance, adhesive integrity, shelf life, reusability, and current distribution of the electrode surface area.
1. The patient-contacting components of the device must be demonstrated to be biocompatible.
1. Performance testing must demonstrate electrical, thermal, and mechanical safety along with electromagnetic compatibility (EMC) of the device in the intended use environment.
1. Software verification, validation, and hazard analysis must be performed.
1. Labeling must include the following:
- a) Recommended treatment regimes, including but not limited to, frequency and duration of use, application site(s), and typical sensations experienced during treatment;
- b) A shelf life for the electrode and reuse information:
- c) Summaries of the electrical stimulation parameters and device technical parameters (including any wireless specifications); and
- d) Instructions on how to correctly use and maintain the device, including all userinterface components.

BENEFIT/RISK DETERMINATION

The risks of the Quell-FM device were established with data collected in nonclinical studies (e.g., biocompatibility, electrical safety, EMC, and software testing) as well as data collected in the clinical trial described above and are generally well understood. Specifically,

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a. The results of the nonclinical testing demonstrated that the Ouell-FM performed as per specifications and the results did not raise concerns regarding risks to the patients.
b. There were no serious adverse events reported in the study. Nine adverse events reported in the clinical trial were judged to be definitely or possibly related to the use of Quell-FM, all of which were minor and self-limited. The most common adverse event experienced when using the Quell-FM device to treat the symptoms of fibromyalgia was a mild rash at the site of electrode placement, a known side-effect of TENS devices that typically resolves quickly with conservative measures. Should any adverse reactions or discomfort occur, the user can reduce or halt the stimulation at any time using the mobile application or double tapping the device.
c. The provided IFU and labeling (i.e., description of clinical study results) will guide physicians towards prescribing Quell-FM to treat the patient population demonstrated to be most responsive to the therapy.
d. Any patient diagnosed with fibromyalgia that does not experience improvement with the Ouell-FM can stop treatment without negative physiological effects (e.g., withdrawal symptoms).

The probable benefits of the device are based on data collected in the clinical study. Although many participants in the clinical study were also taking medication for fibromvalgia and it was difficult to assess the effects of the device compared to medication, there are several clinically meaningful benefits for using the Quell-FM as an aid for reducing the symptoms of fibromyalgia in adults, especially in those with high pain sensitivity. Specifically,

Primary endpoint: Although the trial did not meet its primary effectiveness endpoint of a a. significant treatment group difference in the 3-month mean PGIC scores, it is important to note that the difference of 0.4 points in the ITT analysis was similar to that observed in trials of FDA approved drugs widely used for management of fibromyalgia. Therefore, Quell-FM treatment of fibromyalgia patients exhibited comparable benefits when compared to FDAapproved drug therapies for fibromyalgia, with none of the side effects that are intolerable for some patients such as nausea, dizziness, and somnolence. Moreover, in subjects with higher baseline pain sensitivity, the mean PGIC score for those receiving active treatment was 1.2points greater than those receiving sham treatment. This difference was statistically significant (p=0.015) and clinically meaningful. These results are also consistent with the pain intensity responder analysis, which demonstrated a larger group difference in responder rates in the higher pain sensitivity subgroup compared to the entire ITT population.
b. Secondary endpoints: The active treatment was favored in the following secondary endpoints.
- i. Statistically and clinically meaningful improvement in health-related quality of life compared to sham as measured by the FIOR instrument.
- ii. Improvement in multiple effectiveness measures over three months that include pain severity (including neuropathic symptoms), pain interference with function, pain related disability and psychological impairment. The improvement in neuropathic symptoms (PDQ), pain interference with function (BPI-SF Interference), and pain . related disability (PDI) were significant compared to sham.
- ii. Pressure pain threshold at the trapezius was significantly increased compared to sham.

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indicating a reduction in hyperalgesia.

Thus, Quell-FM provides clinically meaningful relief from fibromyalgia symptoms.

Patient Perspectives

Patient perspectives considered for the Quell-FM included patient reported outcomes (PROs) that assess patients' impression about the treatment effectiveness and disease impact, including the primary effectiveness outcome PGIC, secondary effectiveness outcome FIOR, and pain outcomes.

Benefit/Risk Conclusion

In conclusion, given the available information above, the data support that the probable benefits outweigh the probable risks for the Ouell-FM device for the following indications for use statement:

The Quell-FM is a transcutaneous electrical nerve stimulation (TENS) device indicated as an aid for reducing the symptoms of fibromyalgia in adults with high pain sensitivity. The Quell-FM may be used during sleep. The Quell-FM is labeled for use only with compatible NeuroMetrix electrodes.

The Quell-FM 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 Quell-FM is granted and the device is classified under the following:

Product Code: OSO Device Type: Transcutaneous electrical nerve stimulator to treat fibromyalgia symptoms Class: II Regulation: 21 CFR 882.5888

REFERENCE

Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). May 2010:62(5):600-10.

Regulation Number and Section

N/A