The NeuroStar Advanced Therapy System is indicated for the treatment of depressive episodes and for decreasing anxiety symptoms for those who may exhibit comorbid anxiety symptoms in adult patients suffering from Major Depressive Disorder (MDD) and who failed to achieve satisfactory improvement from previous antidepressant medication treatment in the current episode.

Device Description

The NeuroStar Advanced Therapy System is a transcranial magnetic stimulation device. Specifically, it is a computerized, electromechanical medical device that produces and delivers non-invasive magnetic fields to induce electrical currents targeting specific regions of the cerebral cortex. Transcranial magnetic stimulation (TMS) is a non-invasive technique used to apply brief magnetic pulses to the brain. The pulses are administered by passing high currents through an electromagnetic coil placed adjacent to a patient's scalp. The pulses induce an electric field in the underlying brain tissue. When the induced field is above a certain threshold and is directed in an appropriate orientation relative the brain's neuronal pathway, localized axonal depolarizations are produced, thus activating neurons in the targeted brain region.

The NeuroStar System consists of a combination of hardware, disposable, and consumable supplies, which are required for the operation of the system. The basic configuration includes the following components:

Mobile Console
System Software
Treatment Chair
Head Support System
TrakStar PC
TrakStar Software

AI/ML Overview

The NeuroStar Advanced Therapy System is indicated for treating depressive episodes and decreasing anxiety symptoms in adult patients with Major Depressive Disorder (MDD) who have not achieved satisfactory improvement from previous antidepressant medication.

Here's an analysis of the acceptance criteria and supporting studies:

Table of Acceptance Criteria and Reported Device Performance

Acceptance Criteria (Outcome Measures)	Reported NeuroStar Advanced Therapy System Performance
For Depression (Derived from Predicate Device Clearance, not explicitly detailed here for criteria beyond initial clearance)	O'Reardon et al., 2008 & George et al., 2010 (original clearance studies for MDD):
Response Rate (≥ 50% decrease in end score relative to baseline) for HAMD-17 and HAMD-24	Statistically significant improvement (p<0.05) in response rate for both HAMD-17 and HAMD-24 compared to sham.
	TrakStar (unpublished) RWD study (MDD):
Response Rate (≥ 6 point decrease in PHQ-9 score at end of treatment relative to baseline)	58.9% of patients achieved response.
Remission Rate (PHQ-9 < 5 at study endpoint)	30.4% of patients attained remission.
Mean Change in PHQ-9 scores from baseline to endpoint	-10.5 ± 6.7 (p<0.0001).
For Comorbid Anxiety Symptoms (Current Clearance Justification)	O'Reardon et al., 2008, George et al., 2010 (RCTs):
Statistically significant reduction in anxiety symptoms as measured by HAMD – A/S F (a priori defined secondary endpoint) between-group difference in mean change from baseline to 6-week endpoint. (p<0.05)	Statistically significant improvement (p<0.05) in mean change in HAMD – A/S F scores from baseline to 6-week endpoint, in favor of the active treatment group (p=0.023 for O'Reardon; p<0.05 for George et al. stated parenthetically in text, though table only has p<0.05).
Effect size (Cohen's d) for decreasing anxiety symptoms compared to Sham control.	0.36. This compares favorably to predicate device (Brainsway Deep TMS) effect sizes (0.34 and 0.36) for similar indications.
	TrakStar (unpublished) RWD study (Anxiety):
Response Rate (≥ 6 point improvement (reduction) in GAD-7 score at end of treatment relative to baseline)	65.5% of patients met the primary outcome measure for anxiety.
Remission Rate (GAD-7 < 5 at study endpoint)	34.0% of patients attained remission.
Mean Change in GAD-7 scores from baseline to endpoint	-8.0 ± 5.7 (p<0.0001).
Effect size (Hedges g)	-1.4.
	Tuinstra et al., 2022 (Retrospective analysis for Anxiety):
Remission Rate (HAMD AS/F < 7 or GAD-7 < 5)	HAMD AS/F < 7: 87.5%; GAD-7 < 5: 22.6%.
Response Rate (≥ 50% decrease in end score relative to baseline for HAMD AS/F or GAD-7)	HAMD AS/F: 50%; GAD-7: 41.5%.
Clinically Significant Change (final score ≤ 3.2 for HAMD AS/F; mean change from baseline to endpoint ≥ 6 for GAD-7)	HAMD AS/F: 37.5%; GAD-7: 41.5%.
Mean Change in scores from baseline to endpoint (6 weeks) for HAMD AS/F and GAD-7	HAMD AS/F: -3.53, p<0.001; GAD-7: -5.32, p<0.001.
Effect size (Hedges g)	-0.777.

Sample sizes used for the test set and data provenance:
The clinical performance data supporting the expanded indications primarily relies on two Randomized Controlled Trials (RCTs) and supportive real-world data (RWD) and observational studies.
- RCTs (Test Set):
  - O'Reardon et al. (2007/2008): N=301 patients (Active: 155, Sham: 146). Data provenance is from a clinical trial that evaluated the safety and efficacy of the device for MDD.
  - George et al. (2010): N=190 patients (Active: 92, Sham: 98). Data provenance is from a company-independent, NIMH-funded trial.
- Supportive Data (Test Set/Observational):
  - TrakStar (2022) study (unpublished): N=664 patients. This is a large-scale retrospective analysis of real-world data (RWD) derived from the TrakStar registry data, collected from patients across 75 TMS centers in the US over 13 years (since 2008). This is retrospective data.
  - Tuinstra et al. (2022): N=77 patients (57 with clinically significant anxiety symptoms). This is a retrospective analysis of medical records from patients with MDD and comorbid anxiety symptoms, over 3.5 years.
The provenance is primarily retrospective clinical trial data (for the original MDD indication, now leveraged for anxiety) and retrospective real-world data/medical chart reviews for the updated anxiety indication. The country of origin for the studies is not explicitly stated for all, but given the US FDA submission and typical clinical trial conduct for device clearances, it's highly probable to be primarily US-based, especially for the TrakStar registry.
Number of experts used to establish the ground truth for the test set and qualifications of those experts:
The studies described are clinical trials and retrospective analyses of patient outcomes. "Ground truth" in this context refers to the documented clinical status of patients (e.g., diagnosis of MDD, anxiety symptoms, response to treatment, remission). While clinical diagnoses and symptom assessments would typically be performed by qualified clinicians (e.g., psychiatrists, physicians), the specific number of experts involved in establishing the initial diagnoses or ground truth for each patient in the test sets, or their specific years of experience, is not specified in the provided text. The studies utilized standardized psychiatric rating scales (HAMD-17, HAMD-24, HAMD – A/S F, PHQ-9, GAD-7), suggesting these were administered and interpreted by trained personnel.
Adjudication method for the test set:
The provided text does not explicitly detail any adjudication method (e.g., 2+1, 3+1, none) for establishing ground truth or evaluating patient outcomes in the test sets. The RCTs and observational studies would have relied on standard clinical assessment procedures and the reporting of scores from validated psychiatric rating scales.
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, an MRMC comparative effectiveness study was not done. The NeuroStar Advanced Therapy System is a Transcranial Magnetic Stimulation (TMS) device, which is a therapeutic device targeting brain regions for treatment, not an AI-assisted diagnostic tool that requires human readers to interpret images or data. Therefore, the concept of "human readers improve with AI vs without AI assistance" does not apply to this device.
If a standalone (i.e., algorithm only without human-in-the-loop performance) was done:
No, a standalone (algorithm only) performance study was not done. The device is a therapeutic system that is administered by clinicians to patients. Its performance is evaluated through clinical trials and real-world usage in human subjects, not as an isolated algorithm.
The type of ground truth used:
The ground truth used for these studies is clinical outcomes data and expert-evaluated patient status according to standardized psychiatric rating scales.
- Diagnosis of Major Depressive Disorder (MDD), confirmed by clinicians.
- Level of depressive symptoms measured by scales like HAMD-17, HAMD-24, and PHQ-9.
- Level of anxiety symptoms measured by scales like HAMD – A/S F and GAD-7.
- Response to treatment (e.g., ≥50% reduction in symptom scores, or ≥6 point reduction for GAD-7/PHQ-9).
- Remission (e.g., GAD-7 < 5, PHQ-9 < 5, HAMD AS/F < 7).
The sample size for the training set:
The provided information describes clinical studies primarily for validation or performance demonstration of the device for specific indications. It does not mention a "training set" in the context of machine learning model development. The NeuroStar Advanced Therapy System is a physical medical device, not an AI/ML algorithm whose parameters are iteratively "trained" on data. The clinical data presented is for demonstrating safety and effectiveness.
How the ground truth for the training set was established:
As no explicit "training set" in the AI/ML sense is mentioned for this device, this question is not directly applicable. If interpreting "training set" loosely as the cumulative clinical experience and data that informed the device's development or initial indications, the "ground truth" would have been established through a combination of medical understanding of MDD, clinical research, previous clinical trials, and regulatory requirements for therapeutic interventions.

Summary

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July 14, 2022

Neuronetics, Inc Robin Fatzinger Director, Regulatory Affairs 3222 Phoenixville Pike Malvern, Pennsylvania 19355

Re: K220127

Trade/Device Name: NeuroStar TMS Therapy System, NeuroStar Advanced Therapy System, NeuroStar, NeuroStar Advanced Therapy for Mental Health Regulation Number: 21 CFR 882.5805 Regulation Name: Repetitive Transcranial Magnetic Stimulation System Regulatory Class: Class II Product Code: OBP Dated: June 11, 2022 Received: June 14, 2022

Dear Robin Fatzinger :

We have reviewed your Section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database located at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal

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statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR 803) for devices or postmarketing safety reporting (21 CFR 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about medical devices and radiation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic. See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Pamela Scott Assistant Director DHT5B: Division of Neuromodulation and Physical Medicine Devices OHT5: Office of Neurological and Physical Medicine Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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Indications for Use

510(k) Number (if known) K220127

Device Name

NeuroStar TMS Therapy System, NeuroStar Advanced Therapy System, NeuroStar Advanced Therapy for Mental Health

Indications for Use (Describe)

Type of Use (Select one or both, as applicable)
☒ Prescription Use (Part 21 CFR 201 Subpart D)
☐ Over-The-Counter Use (21 CFR 201 Subpart G)

Prescription Use (Part 21 CFR 801 Subpart D)

__ Over-The-Counter Use (21 CFR 801 Subpart C)

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510(k) Number:	K220127
Date Prepared:	14 July 2022
Applicant:	Neuronetics, Inc.3222 Phoenixville PikeMalvern, PA 19355
Primary Contact:	Robin Fatzinger, RACSr. Director, Regulatory AffairsPhone: 610-981-4027Email: robin.fatzinger@neurostar.com
Secondary Contact:	Cory AndersonVP, Clinical Affairs & Product DevelopmentPhone: 610-981-4104Email: cory.anderson@neurostar.com
Device Trade Names:	NeuroStar, NeuroStar TMS Therapy System, NeuroStar Advanced TherapySystem, NeuroStar Advanced Therapy for Mental Health
Device Common Name:	Transcranial Magnetic Stimulator
Classification:	21 CFR 882.5805
Product Code:	ОВР
Predicate Devices:	Primary Predicate: Brainsway Deep Transcranial Magnetic Stimulation(K210201)Predicate: NeuroStar Advanced Therapy System (K201158, K161519,K160703, K133408, K130233, K083538)

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Device Description

Mobile Console
System Software
Treatment Chair
Head Support System
TrakStar PC
TrakStar Software

Indications for Use:

The indications for use for the subject device (NeuroStar Advanced Therapy System) is identical to that of the Primary Predicate Device.

Technological Characteristics and Substantial Equivalence:

NeuroStar TMS Therapy system has previously obtained FDA clearance for treatment of major depressive disorder in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode (K061053, K083538, K130233, K133408, K160703, K161519, K201158).

The subject device is substantially equivalent to the primary predicate device that was cleared under K210201. Neuronetics has implemented minor labeling changes to update the indications for use and clinical summaries. None of these changes alter the technical specifications for the subject device. Consistent with the primary predicate and predicate devices, the NeuroStar Advanced Therapy System enables non-invasive activation of brain regions.

The components of, and mechanisms of operation for, the subject device are identical to the

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previously cleared predicate device, NeuroStar Advanced Therapy System (K061053, K083538, K130233, K133408, K160703, K161519, K201158). The performance characteristics, including the Electrical and Magnetic Field Distribution testing are the same as the previously cleared NeuroStar Advanced Therapy System. The subject device has the following similarities to the primary predicate (Brainsway Deep TMS; K210201) and predicate NeuroStar Advanced Therapy System:

Principles of operation
Design for delivery of Transcranial Magnetic Stimulation (TMS)
Materials

The stimulation parameters (frequency, train duration, interval, number of trains, number of pulses, and total duration of treatment) of the subject device are different from those of the primary predicate. Substantial equivalence between the subject device and the primary predicate device was established based on clinical performance data.

The proposed changes for the NeuroStar Advanced Therapy System are limited to labeling updates, specifically to include the treatment of adult patients with MDD who failed to achieve satisfactory improvement from previous antidepressant medication treatment in the current episode and may exhibit comorbid anxiety symptoms. The proposed changes are supported by information submitted in this premarket notification and with the following rationale:

The subject device is substantially equivalent to the FDA-cleared Brainsway Deep TMS (K210201).
The predicate device, NeuroStar Advanced Therapy System, was previously cleared by the FDA under DEN060153/K061053, K083538, K130233 and K133408, K160703, K161519, and K201158.
. The subject device changes remain limited to labeling revisions, in support of the reference to treatment of adult patients with MDD who failed to achieve satisfactory improvement from previous antidepressant medication treatment in the current episode and may exhibit comorbid anxiety symptoms. No other changes are made to the device or product labeling.

Supportive clinical data has been provided to support the substantial equivalence of the subject NeuroStar Advanced Therapy System in terms of safety and effectiveness for the expanded indications for use. Therefore, the NeuroStar TMS Therapy System with the proposed changes to the product labeling is substantially equivalent to the primary predicate and predicate devices.

Non-Clinical Testing:

The subject device has been tested in accordance with IEC60601 Edition 3.1 and verified to comply with the specified permissible sound pressure levels and permissible thresholds for exposure defined by the Occupational Safety and Health Administration (OSHA).

These tests provide evidence that the NeuroStar Advanced Therapy system does not pose any risk for potential hearing reduction or loss in either patients or operators.

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Performance Standards:

The NeuroStar Advanced Therapy System has been tested and conforms with the following standards:

. ISO 13485:2016
IEC60601-1
IEC60601-1-2

Additionally, the contents of this 510(k) complies with the FDA Guidance Document: "Class II Special Controls Guidance Document: Repetitive Transcranial Magnetic Stimulation (rTMS) Systems - Guidance for Industry and Food and Drug Administration Staff". The non-clinical performance testing of the components of NeuroStar Advanced Therapy System was conducted as required according to the standards listed above. All system components have been previously cleared by the FDA.

Clinical Performance Data:

Clinical performance data was provided to support the safety and effectiveness of the NeuroStar Advanced Therapy System device for decreasing anxiety symptoms for those who may exhibit comorbid anxiety symptoms in adult patients suffering from Major Depressive Disorder (MDD), as described in the Indications for Use statement. The clinical performance data was based on 2 Randomized Controlled Trials (RCTs) (George et al. (2010), O'Reardon et al. (2007)) in a total of 491patients and on supportive data from a total of 874 patients in one open-label study and four observational studies (retrospective medical chart review), including a large-scale analysis of real-world data (RWD).

The 2007 O'Reardon study was designed to evaluate the safety and efficacy of the NeuroStar Advanced Therapy System for the treatment of adult patients with major depressive disorder (MDD) (N=301) who failed to receive benefit from 1 to 4 prior antidepressant medications verified by the ATHF. The 2010 study by George et al. was a company-independent, NIMH-funded trial designed to evaluate the safety and efficacy of TMS in adult patients (N=190) with moderate to severe MDD who failed to receive benefit from 1 to 4 prior antidepressant medications verified by the ATHF (George, et al, 2010). Clinical data from these two randomized sham-controlled trials were originally used to establish the safety and efficacy effectiveness of NeuroStar Advanced Therapy for the treatment of adult patients with MDD (DEN060153/K061053) and as such, patient demographics and depression outcomes are presented in detail in earlier sections.

For the 2007 O'Reardon study and the 2010 George study, the effect sizes were identical, 0.36 (Cohen's d), representing a low effect size for decreasing anxiety symptoms in this patient population when compared to Sham control. These effect sizes compare favorably to the effect size reported in two of the three RCTs (Levkovitz et al. (2015) – 0.34 and Kaster et al. (2018) – 0.36) which formed the basis for clearance of Brainsway Deep TMS™ System (K210201), the primary predicate device, for the indications for use in section referenced above.

In both RCT studies, the effectiveness of NeuroStar Advanced Therapy for the treatment of comorbid anxiety symptoms in adult patients with MDD and comorbid anxiety symptoms was assessed using the Hamilton-D anxiety/somatization factor (HAMD – A/S F) Scale. The HAMD – A/S F Scale is a validated scale comprising six anxiety-specific items from the HAMD-17 or the HAMD-24. In O'Reardon et al. (2007), evaluation of change on the HAMD – A/S F was an a priori defined secondary endpoint. In both trials, the

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between-group difference in the mean change in HAMD – A/S F scores from baseline to the 6-week endpoint evaluation was statistically significant (p<0.05) in favor of the active treatment group.

Additional clinical evidence intended to support the safety and efficacy effectiveness of The NeuroStar Advanced Therapy System administered to the left dorsolateral prefrontal cortex (DFLPFC), as per the standard NeuroStar treatment protocol for MDD, in patients with MDD and comorbid anxiety symptoms included data from the following studies:

1. A retrospective analysis of medical records from 57 adult patients with major depressive disorder (MDD) and comorbid anxiety symptoms who received rTMS treatment with The NeuroStar Advanced Therapy System demonstrated a clinically significant reduction in anxiety symptoms over a 6-week period, as measured by the HAMD-21 – A/S F or Generalized Anxiety Disorder-7 (GAD-7) score. (Tunistra et al. (2022)).
1. A large-scale retrospective analysis of real-world data (RWD) derived from the TrakStar registry data of 664 patients who received the standard NeuroStar treatment protocol for MDD over a span of 13 years, beginning in 2008. This RWD was collected from patients across 75 TMS centers in the US. These 664 patient records were analyzed to determine the difference in measures of depression (PHQ-9 scores) and anxiety (GAD-7 scores) over a pre-post TMS treatment interval of 6 weeks. (TrakStar (2022) study).

Patients included in this RWD study had a primary diagnosis of MDD, had received at least 20 treatments with NeuroStar Advanced Therapy to the left dorsolateral prefrontal cortex (DLPFC); were required to exhibit baseline moderate or greater depression, defined as a score on the Physician Health Questionnaire-9 (PHQ-9) ≥ 10, and baseline moderate or greater anxiety symptoms, defined as a score on the Generalized Anxiety Disorder-7 (GAD-7) ≥ 10. The average patient age was 47.4 ± 13.9 years, and 67.9% were female.

A total of 65.5% of patients met the primary outcome measure for anxiety which was the proportion of subjects who achieved a 6+ point improvement (reduction) in the GAD-7 score at end of treatment relative to baseline. The mean change in GAD-7 scores from baseline to endpoint was -8.0 ± 5.7 (p<0.0001), and 34.0% of patients attained remission, with remission of anxiety symptoms defined as a score on the GAD-7 < 5 at study endpoint. These statistically significant and clinically meaningful improvements in anxiety symptoms were accompanied by comparable changes in depression scores on the PHQ-9.

The TrakStar registry did not account for medication or other treatment change for MDD or symptoms of anxiety that may have occurred during the treatment phase.

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Study	Device(s)	Study Design	Population	Sample size	OutcomeMeasure(s)	StudyResults
O'Reardonet al., 2008	NeuroStar	• RCT• Left-sideddorsolateralprefrontal cortex(DLPFC) rTMSTherapy perstandard NeuroStartreatment protocol	• Mean age (years):- Active: 47.9 ± 11.0- Sham: 48.7 ± 10.6• Females:- Active: 55.5%- Sham: 48.7%• Primary diagnosis ofMDD.	301:- Active:155- Sham: 146	• HAMD-24• HAMD-17• HAMD AS/F (apriori definedsecondaryendpoint)	Comparison between active and sham TMS groups in thechange from baseline to endpoint (6 weeks):Response Rate: ≥ 50% decrease in end score relative to baseline(6 weeks):HAMD17:p<0.05HAMD-24:p<0.05Mean Change in Scores from Baseline toEndpoint: HAMD-17: p<0.01HAMD-24: p<0.05HAMD-17-AS/F: p<0.05 (p=0.023)Effect size (Cohen's d): 0.36
	NeuroStar	• RCT• Left-sideddorsolateralprefrontal cortex(DLPFC) rTMSTherapy perstandard NeuroStartreatment protocol	• Mean age (years):- Active: 47.7 ± 10.6- Sham: 46.5 ± 12.3• Females:- Active: 63%- Sham: 51%• Primary diagnosis ofMDD.	190:- Active:92- Sham: 98	• HAMD-24• HAMD AS/F	Comparison between active and sham TMS groups in thechange from baseline to endpoint (6 weeks):Response Rate: ≥ 50% decrease in end score relative to baseline(6 weeks):HAMD-24: p<0.01Remission:HAMD-24 < 10: p<0.05Mean Change in Scores from Baseline toEndpoint (6 weeks): HAMD-17-AS/F:p<0.05:- Active: -1.3; = Sham: -0.4Effect size (Cohen's d): 0.36
TrakStar(unpublished)	NeuroStar	• Retrospectivechart review &analysis of RWDsince 2008.• Left-sided DLPFCrTMS Therapy perstandardNeuroStartreatmentprotocol.	• Adults 22-70 years;mean age of$47.4\pm13.9$ years.• 67.9% female• Primary diagnosis ofMDD.• Baseline score on theGAD-7 ≥ 10	664	• GAD-7• PHQ-9	Response Rate: ≥ 6 point decrease in end score relativeto baseline (6 weeks): PHQ-9: 58.9%GAD-7: 65.5%Remission:PHQ-9: < 5: 30.4%GAD-7 < 5: 34.0%Mean Change in Scores from Baseline toEndpoint (6 weeks): PHQ-9: $-10.5 \pm 6.7$ ,p<0.0001GAD-7: $-8.0 \pm 5.7$ : p<0.0001Effect size (Hedges g): -1.4
Tuinstra, etal. 2022	NeuroStar	• Retrospectivechart review andanalysis of RWDover 3.5 years.• Left-sideddorsolateralprefrontal cortex(DLPFC) rTMSTherapy perstandard NeuroStartreatment protocol	• Adults 18-77 years;mean age of$45.3\pm16.7$ years.• 61% female• Primary diagnosis ofTreatment ResistantDepressions (TRD).• 52% had at least onediagnosis of acomorbid anxietydisorder	7757 hadclinicallysignificantanxietysymptoms	• HAMD-17AnxietySomatizationFactor (AS/F)Subscale• GAD-7• PHQ-9	Remission:HAMD AS/F < 7: 87.5%GAD-7 < 5: 22.6%Response Rate: ≥ 50% decrease in end score relative to baseline(6 weeks):HAMD AS/F: 50%GAD-7: 41.5%Clinically Significant Change:HAMD AS/F: final score ≤ 3.2: 37.5%GAD-7: mean change from baseline to endpoint ≥ 6: 41.5%Mean Change in Scores from Baseline to Endpoint(6 weeks): HAMD AS/F: -3.53, p<0.001GAD-7: -5.32: p<0.001Effect size (Hedges g): -0.777

Table 1: Study Design and Outcomes from NeuroStar RCTs, TrakStar Data and Supportive Literature

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Table 2: Substantial Equivalence Comparison

	Subject DeviceK220127	Primary Predicate DeviceK210201
Specification	NeuroStar Advanced Therapy System	Brainsway Deep TMS System	Justification of Differences
Indications for use	The NeuroStar Advanced Therapy System isindicated for the treatment of depressive episodesand for decreasing anxiety symptoms for thosewho may exhibit comorbid anxiety symptoms inadult patients suffering from Major DepressiveDisorder (MDD) and who failed to achievesatisfactory improvement from previousantidepressant medication treatment in thecurrent episode.	The Brainsway Deep TMS™ System is indicated forthe treatment of depressive episodes and forexhibit comorbid anxiety symptoms in adultpatients suffering from Major Depressive Disorder(MDD) and who failed to achieve satisfactoryimprovement from previous antidepressantmedication treatment in the current episode.	No Difference
Intended Use	Major Depressive Disorder (MDD) and comorbidanxiety symptoms	Major Depressive Disorder (MDD) and comorbidanxiety symptoms	No Difference
Anatomical Sites	Left dorsolateral prefrontal cortex	Left dorsolateral prefrontal cortex	No Difference
Target Population	Adult Patients	Adult Patients	No Difference
Clinical Setting	Inpatient and outpatient settings includingphysician's offices and clinics, hospitals, andgeneral medical/surgical hospitals	Inpatient and outpatient settings includingphysician's offices and clinics, hospitals, andgeneral medical/surgical hospitals	No Difference
Treatment Schedule	5 daily sessions per week for 6 weeks plus 6 tapersessions over 3 weeks (36 total sessions)	5 daily sessions for 4 weeks; bi-weekly sessions for12 Weeks (optional maintenance treatments)	The difference in treatmentschedule between the subject andpredicate devices is dependent onthe device treatment protocol;differences do not raise differencesin safety or effectiveness based onclinical data. Clinical evidence forthe subject device has been includedand demonstrated safety andeffectiveness for the intended use.

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	Treatment parameters		Treatment parameters
	Magnetic Field Intensity	120%	Magnetic Field Intensity	120%	No Difference
Energy Delivered andPerformance	Repetition Rate	10 Hz	Repetition Rate	20 Hz	While the frequency is differentbetween the subject and predicatedevices, they are appropriate andwithin safe limits based on the trainduration and intensity for each asindicated in Table 2 in Section 4 ofthe Special Controls Guidance.Clinical evidence for the subjectdevice has been included anddemonstrated safety andeffectiveness for the intended use.
	Train Duration	4 sec	Train Duration	2 sec	While the train duration is differentbetween the subject and predicatedevices, they are appropriate andwithin safe limits based on thefrequency and intensity for each asindicated in Table 2 in Section 4 ofthe Special Controls Guidance.Clinical evidence for the subjectdevice has been included anddemonstrated safety andeffectiveness for the intended use.
	Inter-Train-Interval	11-26 secs	Inter-Train-Interval	20 secs	The difference between the inter-train-intervals is appropriate foreach device design and treatmentprotocol. These differences do notraise different questions of safetyor effectiveness based on non-clinical and clinical testing.Clinical evidence for the subjectdevice has been included anddemonstrated safety andeffectiveness for the intended use.
	Number of Trains	75	Number of Trains	55	The difference between thenumber of trains is appropriate for
					each device design and treatment.protocol. This difference does notraise different questions of safety oreffectiveness based on non-clinicaland clinical testing. Clinicalevidence for the subject device hasbeen included and demonstratedsafety and effectiveness for theintended use.
	Number of Pulses	3000	Number of Pulses	1980	The difference between the numberof pulses is appropriate for eachdevice design and treatment protocol.This difference does not raisedifferent questions of safety oreffectiveness based on non-clinicaland clinical testing. Clinical evidencefor the subject device has beenincluded and demonstrated safety andeffectiveness for the intended use.
	Treatment Duration	18.75 min	Treatment Duration	20.2 min	The difference between thetreatment duration is appropriatefor each device design andtreatment protocol. This differencedoes not raise different questions ofsafety or effectiveness based onnon- clinical and clinical testing.Clinical evidence for the subjectdevice has been included anddemonstratedsafety and effectiveness for theintended use.
	Treatment area of brain to be stimulated:Left Dorsolateral Prefrontal Cortex		Treatment area of brain to be stimulated:Left Dorsolateral Prefrontal Cortex		No Difference
	Output Stimulation ParametersAvailable Stimulation Intensity in terms of StandardMotor Threshold (SMT) units		Output Stimulation Parameters:Available Stimulation Intensity in terms of StandardMotor Threshold (SMT) units		The differences between the SMTranges are dependent on the devicedesign and treatment

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	Range: .22 - 2.08Waveform: Biphasic	Range: 0.6-1.4Waveform: Biphasic	protocols. Each range is within thetherapeutic stimulation range of thedevice. The difference does notraise new issues of safety oreffectiveness since the maximum(100%) output level is unchangedfrom the previously clearedNeuronetics predicate device.Clinical evidence for the subjectdevice has been included anddemonstrated safety andeffectiveness for the intended use.
Design	The system consists of:1. Mobile console2. System software with GUI3. Treatment chair4. Head support system5. Coil positioning system6. Same Coil for both MT and treatment7. Coil fixture8. Data management system	The system consists of:1. Mobile console2. System software with GUI3. Treatment chair4. Head support system5. Coil positioning system6. Same Coil for both MT and treatment7. Coil fixture8. Data management system	No Difference

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Image /page/14/Picture/0 description: The image shows a logo with the letters "NS" in bold, purple font. Above the letters is a stylized star shape, also in purple, with three figures incorporated into the design. The figures appear to be reaching upwards, contributing to the star's overall shape. The logo has a clean and modern look.

Coil	Biphasic Figure 8 Coil with Ferromagnetic Core	Biphasic H-Coil with Air Core	Both coils rely on transcranialmagnetic stimulation by means ofrepetitive pulse trains atpredetermined frequency. Bothcoils use the same mechanism ofaction (electromechanicalinstrument that produces anddelivers brief duration, pulsedmagnetic fields to induce electricalcurrents in localized regions of theprefrontal cortex). Differences indesign do not raise differentquestions of safety or effectivenessas demonstrated by the clinicalevidence presented within the510(k). Clinical evidence for thesubject device has been includedand demonstrated safety andeffectiveness for the intended use.
Cooling	Air cooled.Used for both MT determination and treatment	Liquid cooledUsed for both MT determination and treatment	The H-Coil uses liquid cooling tomaintain safe operatingtemperatures. The iron core figure-8 coil uses air cooling to maintainsafe operating temperatures. Bothmethods of cooling are sufficient forthe specific design. The differencesdo not raise different questions ofsafety or effectiveness asdemonstrated by the non-clinicaland clinical testing provided withinthe 510(k). Clinical evidence for thesubject device has been includedand demonstrated safety andeffectiveness for the intended use.
Quality & Risk Standards	Company complies with ISO 13485:2016 and ISO14971	Company complies with ISO 13485:2016 and ISO14971	No Difference
Electrical Safety &ElectromagneticCompatibility	Complies with IEC60601-1 and IEC60601-1-2	Complies with IEC60601-1 v. 3.1, and IEC60601-1-2	No Difference

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Image /page/15/Picture/1 description: The image shows a logo with the letters "NS" in a bold, purple font. The letters are stylized and slightly overlapping. Above the letters, there is a star-like shape formed by three abstract figures that appear to be people with their arms raised. The overall design is simple and modern, with a focus on the letters and the star-like symbol.

Conclusion:

The NeuroStar Advanced Therapy System has the same intended use and indications, principles of operation, and similar technological characteristics as the primary predicate device and the previously cleared predicate device. The differences noted in the technical characteristics do not raise different questions of safety or effectiveness. Clinical performance data demonstrates that the subject device is safe and effective for its intended use. Thus, the NeuroStar Advanced Therapy System is substantially equivalent to the primary predicate and predicate devices.

Regulation Number and Section

§ 882.5805 Repetitive transcranial magnetic stimulation system.

(a)
Identification. A repetitive transcranial magnetic stimulation system is an external device that delivers transcranial repetitive pulsed magnetic fields of sufficient magnitude to induce neural action potentials in the prefrontal cortex to treat the symptoms of major depressive disorder without inducing seizure in patients who have failed at least one antidepressant medication and are currently not on any antidepressant therapy.(b)
Classification. Class II (special controls). The special control is FDA's “Class II Special Controls Guidance Document: Repetitive Transcranial Magnetic Stimulation System.” See § 882.1(e) for the availability of this guidance document.