The SpringTMS® is a portable, hand-held device that is designed and intended to deliver a brief single pulse of magnetic energy at 0.9 Tesla to the back of the head to induce an electrical current in a portion of the brain called the occipital cortex to stop or lessen the effects of migraine headaches. Since a single pulse of magnetic stimulation is emitted, this method of stimulation is called single pulse transcranial magnetic stimulation or sTMS. The SpringTMS is indicated for the acute treatment and prevention of migraine headache. The device is designed for patient use where treatments are self-administered and can be delivered in a variety of settings including the home or office. The device is intended for prescription use only.

AI/ML Overview

The provided text describes a 510(k) premarket notification for the eNeura Inc. SpringTMS® device. This device is a transcranial magnetic stimulator indicated for the acute and prophylactic treatment of migraine headaches.

Here's an analysis of the acceptance criteria and the study that proves the device meets them:

1. A table of acceptance criteria and the reported device performance

Acceptance Criteria	Reported Device Performance
Primary Effectiveness Endpoint: Mean reduction in headache days over a 28-day period at 12±1 weeks.	FAS: Mean reduction of 2.8 days (from a baseline mean of 9.1 days). Statistically significant (P<0.0001).
Performance Goal (PGMD) for Primary Effectiveness Endpoint: ≥ -0.633 days reduction in migraine headache days. (H0: μT ≥ PGD versus Ha: μT < PGD)	The observed mean reduction of 2.8 days is well below -0.633 days, thus rejecting the null hypothesis and demonstrating a significant reduction.
Primary Safety Endpoint: The proportion of patients experiencing any adverse event in aggregate and by event.	Approximately 29% (62/217) of subjects in the Safety Dataset reported at least one adverse event. No serious adverse events were determined. Common AEs (reported >2%) included headache (2.30%), scalp discomfort (2.30%), tingling (3.23%), lightheadedness (3.69%), discomfort from noise (2.30%), dizziness (2.77%), ringing in ears (3.23%), and worsened headache pain (2.30%).

2. Sample size used for the test set and the data provenance (e.g. country of origin of the data, retrospective or prospective)

Sample Size for Test Set:
- Safety Data Set: 217 subjects (assigned Spring TMS devices).
- Full-Analysis Data Set (FAS): 132 subjects (met protocol requirements based on headache day definition).
- Completed Cases (CC): 117 subjects (finished treatment and completed baseline and Month 3 diaries).
- Per Protocol (PP) Data Set: 95 subjects (complied with protocol instructions regarding device use).
Data Provenance: The study was a prospective, multicenter, observational, clinical study. The country of origin is not explicitly stated in the provided text, but the applicant's address (Sunnyvale, CA, USA) suggests it was conducted in the USA.

3. Number of experts used to establish the ground truth for the test set and the qualifications of those experts (e.g. radiologist with 10 years of experience)

This is a clinical efficacy study for a medical device, not an image-based diagnostic AI. Therefore, there are no "experts" in the typical sense establishing a ground truth from images. The "ground truth" for migraine efficacy is based on patient-reported outcomes via headache diaries and questionnaires, confirmed through established criteria for migraine diagnosis and headache day definitions. The study design (observational, multi-center) implies clinical investigators were involved in patient enrollment and oversight, but their specific qualifications beyond being clinicians involved in migraine care are not detailed.

4. Adjudication method (e.g. 2+1, 3+1, none) for the test set

Adjudication methods like 2+1 or 3+1 are typically used for establishing ground truth in image analysis where multiple readers interpret data. This is not applicable here as the primary "ground truth" for effectiveness is derived from patient self-reporting (headache diaries) and safety is assessed through adverse event reporting, which are intrinsically different from image interpretation. The study was a "prospective, non-randomized, single arm, multi-center observational study," indicating no external adjudication process for reconciling different expert interpretations.

5. If a multi-reader multi-case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance

No, an MRMC comparative effectiveness study was not done. This study evaluates a medical device (Transcranial Magnetic Stimulator) directly, not an AI assisting human readers in interpreting data. Therefore, the concept of "human readers improve with AI vs without AI assistance" is not relevant to this device or study design.

6. If a standalone (i.e. algorithm only without human-in-the loop performance) was done

This refers to a medical device, not an algorithm. The device, SpringTMS®, operates as a standalone therapy administered by the patient for the treatment of migraine. It does not involve an algorithm providing diagnoses or interpretations. The study evaluates the device's performance as a standalone treatment.

7. The type of ground truth used (expert consensus, pathology, outcomes data, etc.)

The ground truth for effectiveness was established primarily through outcomes data, specifically:

Patient-reported headache diaries: Defining "headache days" as ≥4 hours of headache pain which at any time reaches moderate or severe intensity. This is the basis for the primary effectiveness endpoint (mean reduction in headache days).
Patient-reported medication use: For the secondary effectiveness endpoint regarding reduction in medication use.
Patient-reported questionnaires: Like the HIT6 impact questionnaire for another secondary effectiveness endpoint.
Adverse event reporting: For the primary safety endpoint.

8. The sample size for the training set

This study is a clinical trial for a medical device, not a machine learning model. Therefore, there is no "training set" in the context of AI/ML. The provided sample sizes (217 for safety, 132-95 for effectiveness) represent the sizes of the cohorts included in the clinical trial itself.

9. How the ground truth for the training set was established

As there is no training set for an AI/ML model, this question is not applicable. The device's "training" or development would have been based on established scientific principles of transcranial magnetic stimulation and previous research into its effect on migraine. The clinical study described here serves to validate the device's safety and effectiveness in a real-world patient population.

Summary

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Image /page/0/Picture/1 description: The image shows the logo for the U.S. Department of Health & Human Services. The logo features a stylized caduceus symbol, which is often associated with healthcare. The text "DEPARTMENT OF HEALTH & HUMAN SERVICES - USA" is arranged in a circular pattern around the symbol.

Food and Drug Administration 10903 New Hampshire Avenue Document Control Center - WO66-G609 Silver Spring, MD 20993-0002

June 26, 2017

eNeura Inc. c/o Larry W. Getlin Consultant 715 North Pastoria Avenue Sunnyvale, California 94085

Re: K162797

Trade/Device Name: Spring TMS Regulation Number: 21 CFR 882.5808 Regulation Name: Transcranial Magnetic Stimulator For Headache Regulatory Class: Class II Product Code: OKP Dated: October 1, 2016 Received: October 4, 2016

Dear Larry Getlin:

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. 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 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 (reporting of medical devicerelated adverse events) (21 CFR 803); good manufacturing practice requirements as set forth in the quality systems (QS) regulation (21 CFR Part 820); and if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

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If you desire specific advice for your device on our labeling regulation (21 CFR Part 801), please contact the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm. 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

http://www.fda.gov/MedicalDevices/Safety/ReportaProblem/default.htm for the CDRH's Office of Surveillance and Biometrics/Division of Postmarket Surveillance.

You may obtain other general information on your responsibilities under the Act from the Division of Industry and Consumer Education at its toll-free number (800) 638-2041 or (301) 796-7100 or at its Internet address

http://www.fda.gov/MedicalDevices/ResourcesforYou/Industry/default.htm.

Sincerely,

William J. Heetderks -S 2017.06.26 13:17:30 -04'00'

for Carlos L. Peña, PhD, MS Director Division of Neurological and Physical Medicine Devices Office of Device Evaluation Center for Devices and Radiological Health

Enclosure

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Indications for Use Statement

DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration

Indications for Use

510(K) Number (if known)

K162797

Device Name

eNeura, Inc.- SpringTMS®

° Indications for Use (Describe)

The eNeura Inc. SpringTMS® is indicated for the acute and prophylactic treatment of migraine headache.

Type of Use (Select one or both, as applicable) > Prescription Use (Part 21 CFR 801 Subpart D)

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

PLEASE DO NOT WRITE BELOW THIS LINE - CONTINUE ON A SEPARATE PAGE IF NEEDED.

FOR FDA USE ONLY Concurrence of Center for Devices and Radiological Health (CDRH) (Signature)

Form Approved: OMB No. 0910-0120 Expiration Date: January 31, 2017 See PRA Statement below.

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7. Premarket Notification 510(k) Summary

This summary of 510(k) safety and effectiveness information is submitted in accordance with the requirements of SMDA 1990 and 21 CFR 807.92.

510(k) Number: K162797

Applicant Information: 7.1.

Date Prepared:	May 25, 2017
Applicant Name:	eNeura, Inc.
Address:	715 North Pastoria AvenueSunnyvale, CA 94085U.S.A.
Phone:	408-245-6500
FAX:	408-245-6424
Contact Person:	Larry W. Getlin, Regulatory Consultantlwgetlin@gmail.com.
Mobile Number:	(612) 850-8144
Alternative Contact:	Michael A Daniel, Consultantmadaniel@clinregconsult.com
Mobile Number:	(415) 407-0223

7.2. Device Information:

Device Trade Name:	SpringTMS®
Classification Name(s):	Transcranial magnetic stimulator for migraine headache
Product Code/ Regulation:	OKP / 21 CFR§882.5808
Classification:	Class II

7.3. Predicate Device:

SpringTMS®

7.4. Subject Device Description

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7.5. Intended Use / Indications for Use

The eNeura® Spring TMS® is designed and intended to deliver brief duration, pulsed, magnetic fields that are externally directed at spatially discrete regions of the brain to induce electric currents in the brain (Product Code OKP).

The eNeura Inc. SpringTMS® is indicated for the acute and prophylactic treatment of migraine headache.

7.6. Predicate and Subject Device Comparison Chart

Comparison to Predicate and Reference Device:

	Subject Device	Predicate Device	Comparison to predicatedevice
Device Name	SpringTMS	SpringTMS	Same
Manufacturer	eNeura Inc.	eNeura Inc.	Same
510(k) #	Not Assigned	K140094	N/A
RegulationNumber	21 CFR§882.5808	21 CFR§882.5808	Same
Class	Class II	Class II	Same
DeviceClass/Name	Transcranial magneticstimulator	Transcranial magneticstimulator	Same
Product Code	OKP	OKP	Same
Fundamentalscientifictechnology	Portable, hand-held devicethat is designed and intendedto deliver a brief single pulseof magnetic energy at 0.9Tesla to the back of the headto induce an electricalcurrent in a portion of thebrain called the occipitalcortex to stop or lessen theeffects of migraineheadaches.	Portable, hand-held devicethat is designed and intendedto deliver a brief single pulseof magnetic energy at 0.9Tesla to the back of the headto induce an electricalcurrent in a portion of thebrain called the occipitalcortex to stop or lessen theeffects of migraineheadaches.	Same
Intended Use(FromProduct CodeDescription)	Intended to deliverexternally directed, pulsed,magnetic fields to induceelectric currents in spatiallydiscrete regions of the brainsof patients with migraineheadache.	Intended to deliverexternally directed, pulsed,magnetic fields to induceelectric currents in spatiallydiscrete regions of the brainsof patients with migraineheadache.	Same

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	Subject Device	Predicate Device	Comparison to predicate device
Indication for Use	Indications for Use:• The eNeura Inc.SpringTMS® is indicatedfor the acute andprophylactic treatment ofmigraine headache.	Indications for Use:• The acute treatment ofpain associated withmigraine headache withaura.	ADDITIONALINDICATIONS SUPPORTEDBY CLINICAL DATAPROVIDED IN THISSUBMISSION.

Table 7.1. Comparison between subject and predicate devices.

7.7. Testing Completed

In addition to previously completed in vitro and in vivo testing (reference K140094), eNeura completed a prospective, multicenter, observational, clinical study demonstrating device safety and effectiveness in treating and preventing and migraine headaches.

Test Device	eNeura SpringTMS® Device
Study Design	A prospective, non-randomized, single arm, multi-center observationalstudy designed to evaluate the use of the SpringTMS system inreducing the frequency of headache days against a performance goal.
Number ofPatients	A total of 263 subjects were consented between December 2014 andMarch 2016. 229 of these subjects completed a Baseline Diary and 220were confirmed by the sites to be eligible for participation. There were217 subjects that were assigned Spring TMS devices and these subjectscomprise the Safety Data Set. There were 179 subjects who begantreatment and completed a Month 1 treatment Diary, but 47 of thesesubjects did not meet the definition of a Migraine Headache Day(minimum requirement of at least 4 days with moderate to severeheadache pain for at least 4 hours at baseline). Thus 132 of these subjectscomplied with the protocol requirements based upon headache daydefinition. This was the Full-Analysis Data Set (FAS) described below.There were 117 of these subjects that went on to finish treatment andcompleted both baseline and Month 3 diaries. This was the CompletedCases data set (CC). Of these subjects 95 complied with the protocolinstructions regarding use of the device. This was the per Protocol (PP)data set.
Number of Sites	Seven (7)
Duration of Trial	Each provisionally enrolled subject was followed for 1 month (28±5days) to establish a baseline number of headache days (HD) andconfirm final eligibility and then each confirmed enrolled patient wasfollowed for 3 consecutive months (12±1 weeks) of treatment followedby a final assessment.
Treatment	Patients were instructed to treat daily using the following protocol:
Regimen	1. From the start, treat with 4 Pulses each morning and evening:2 consecutive pulses wait 15 minutes and repeat the 2consecutive pulses.
	2. Additionally, the patient may treat an acute attack with:3 sequential pulses (early) at the onset of migraine painWait 15 minutes, if needed treat with additional 3 pulsesWait 15 minutes, if needed treat with additional 3 pulsesPatients may rescue with acute medication 30 minutes after the firstthree pulses are delivered.
Performance Goal	The originally proposed performance goal for the primary endpoint,representing the mean reduction in headache days for a controlledstudy, assumed an approximate 80% chronic headache population andwas PGMD = -5.3 days.
	This performance goal was amended ahead of un-blinding and thefinal analysis to PGD=-0.633 in order to reflect the actual population of~20% chronic and ~80% episodic enrollment.
PrimaryEffectivenessEndpoint	Mean reduction in headache days over a 28-day period at 12±1 weeks(i.e., weeks 9 through 12 from start of treatment period). The null andalternative hypotheses for this endpoint are:
	H0: $μ$ T ≥ PGMD versus Ha: $μ$ T < PGD
	PGD = - 0.633 days.
	where $μ$ T is the mean reduction in migraine headache days frombaseline at 12±1 weeks in the treated population and PGD is thePerformance Goal.
	Headache day is defined as ≥4 hours of headache pain which at anytime reaches moderate or severe intensity.
SecondaryEffectivenessEndpoints	1. The percentage of subjects who had at least a 50% reduction inheadache days
	2. The reduction from baseline in the days of medications use toacutely treat migraine headaches
	3. The reduction from baseline in the HIT6 impact questionnaire
	4. The reduction from baseline in the days with headache for morethan 4 hours with any pain intensity
	5. Migraine is defined as >4 hours of headache pain which at anytime reached moderate or severe intensity.
Primary SafetyEndpoint	The proportion of patients experiencing any adverse event in aggregateand by event.
Inclusion Criteria	1. Patients 18 to 65 years of age;
	2. Patients able to understand and communicate in English;
	3. Migraine with or without aura;
	4. 4-25 headache days per month (confirmed by 1-month baselinediary, minimum of 5 complete headache-free days/month);
Exclusion Criteria	5. Understand and willing to provide diary and survey data.Subjects will be excluded from participating in this trial if they meet any of the following criteria
	1. Severe co-existing disease having a life expectancy of less than 1 year;
	2. Currently involved in any other investigational clinical trials that have not completed their primary endpoint or that may interfere with the SpringTMS study results;
	3. Mental impairment or other conditions which may not allow the subject to understand the nature, significance and scope of the study and to cooperate with follow-up requirements;
	4. Known drug and/or alcohol addiction or use of illicit substances;
	5. Patients with epilepsy or history of seizure;
	6. Severe active major depression or major psychiatric illness;
	7. Concurrent use of other neurostimulation devices (Cefaly®, TENS, implantable devices);
	8. Use of Botox® within past 4 months;
	9. Extracranial nerve block (e.g. occipital, supraorbital) within past 3 months;
	10. Use of Cefaly for prevention within past month;
	11. Patients with metal containing implants as follows:
	The SpringTMS may not be used in patients who have metals, conductive materials, or metal-containing implants in their head, neck or upper body. Patients with implants that are affected by a magnetic field should not use the SpringTMS. Examples of such implants include:
	● Aneurysm clips or coils● Cochlear implants● Cerebral spinal fluid shunts● Bullets or pellets lodged in the head or upper body● Filters● Electrodes	● Radioactive seeds● Magnetically programmable shunt valves● Stents● Metal plates, screws, staples or sutures in skull, neck, shoulders, arms or hands● Metallic artificial heart valves● Facial tattoos with metallic ink
	Dental implants, fillings, or other dental appliances are okay and are not affected by the device.
	Note: although not explicitly excluded, safety and effectiveness have not been established in pregnant women. Please defer to the judgment of the investigator when considering the eligibility of this population.
Final Enrollment Decision	1. Satisfactory completion of Baseline Patient Diary (~80% or 22 out of 28 days)
Subject Demographics	106 Female / 132 Total (80.3% Female)Age (Range 16-65 years, Mean 42.8 years)

7.8. Clinical Summary

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	Baseline # of migraine days/month (Range 4-21 days,Mean 9.06 days, Median 9.0 days)
Primary SafetyEndpoint results	Approximately 29% of the 217 subjects included in the Safety Dataset reportedexperiencing at least one adverse event in this study. No subject had events that could bedetermined to be serious adverse events. None of the events required treatment. Adverseevents as described below are the same as those reported in previous studies.
	Adverse Events Reported in the ESPOUSE Study (greater than 2%)
	Adverse Event	x/n (%)	95% LCL,95%UCL	ReportedRelationship toDevice
	Any	62/217(28.57)	22.66, 35.08	19 Not related, 27Possibly, 7 Probably, 5Definitely, 4 NotSpecified
	Headachea	5/217(2.30)	0.75, 5.30	1 Not related, 4Possibly
	Scalp Discomforta	5/217(2.30)	0.75, 5.30	1 Possibly, 4 Probably
	Tinglinga	7/217(3.23)	1.31, 6.53	2 Possibly, 3 Probably,1 Definitely, 1 NotSpecified
	Light Headednessa	8/217(3.69)	1.61, 7.14	1 Not related, 6Possibly, 1 Probably
	Discomfort fromNoisea	5/217(2.30)	0.75, 5.30	Not related, 2 Possibly,2 Definitely
	Dizziness	6/217(2.77)	1.02, 5.92	5 Possibly, 1 Definitely
	Ringing in Ears(Tinnitus)	7/217(3.23)	1.31, 6.53	1 Not Related, 6Possibly
	Worsened HeadachePain	5/217(2.30)	0.75, 5.30	3 Possibly, 2 Notspecified
PrimaryEffectivenessEndpoint results	Primary End Point: Study results showed statistically significantreduction in migraine headache days of 2.8 days (from a baselinemean of 9.1 days) (FAS), P<0.0001; 2.8 days (from a baseline mean of8.9 days) (CC) P<0.0001, and 3.0 days (from a baseline mean of 9.1days) (PP) P<0.0001
ConcomitantMedication Use	Study subjects in the study were neither included nor excluded basedon their use of preventive oral migraine medications at the time ofenrollment in the study

7.9. Summary

Based upon the same intended use, additional indications for use supported by clinical data provided in this premarket notification and the same product design and technical information (supplied in the original submission), the eNeura SpringTMS® has been shown to be substantially equivalent to the cited predicate.

Regulation Number and Section

§ 882.5808 Transcranial magnetic stimulator for headache.

(a)
Identification. A transcranial magnetic stimulator device for headache is a device that delivers brief duration, rapidly alternating, or pulsed, magnetic fields that are externally directed at spatially discrete regions of the brain to induce electrical currents for the treatment of headache.(b)
Classification. Class II (special controls). The special controls for this device are:(1) Appropriate analysis/testing must demonstrate electromagnetic compatibility, electrical safety, and thermal safety.
(2) Appropriate verification, validation, and hazard analysis must be performed on the device software and firmware.
(3) The elements of the device that contact the patient must be assessed to be biocompatible.
(4) Non-clinical testing data must demonstrate that the device performs as intended under anticipated conditions of use. This includes full characterization of the magnetic pulse output and resulting magnetic field map. This also includes characterization of the sound level of the device during use.
(5) Clinical testing must demonstrate that the device is safe and effective for treating headache in the indicated patient population.
(6) The physician and patient labeling must include the following:
(i) A summary of the clinical performance testing, including any adverse events and complications.
(ii) The intended use population in terms of the types of headaches appropriate for use with the device.
(iii) Information on how to report adverse events and device malfunctions.
(iv) A diagram or picture depicting the proper placement of the device on the user.