NEURALIEVE CERENA TRANSCRANIAL MAGNETIC STIMULATOR
Applicant
Eneura Therapeutics
Product Code
OKP · Neurology
Decision Date
Dec 13, 2013
Decision
DENG
Submission Type
Direct
Regulation
21 CFR 882.5808
Device Class
Class 2
Attributes
Therapeutic
Indications for Use
the Cerena Transcranial Magnetic Stimulator, a prescription device under 21 CFR Part 801.109 that is indicated for the acute treatment of pain associated with migraine headache with aura.
Device Story
Portable, hand-held, AC-powered TMS device; delivers brief 0.9 Tesla magnetic pulse to occipital cortex to induce electrical current; intended to stop/lessen migraine pain. Used in home/office by patient. User interface includes two 7-segment LEDs, charging progress LEDs, and two buttons: 'Charge' and 'Treat'. Device requires two independent pulses per treatment; includes 5-minute lockout after second pulse. Provides auditory/vibratory feedback upon pulse delivery. Helps patients manage migraine pain without pharmacological intervention.
Clinical Evidence
Prospective, randomized, double-blind, sham-controlled trial (N=201 enrolled, 113 analyzed). Primary endpoint: proportion of subjects pain-free at 2 hours post-treatment. Results: 37.74% (Cerena) vs 16.67% (sham) (p=0.0181). Secondary endpoint: 33.96% (Cerena) vs 10% (sham) pain-free at 24 hours (p=0.0025). No effectiveness demonstrated for associated symptoms (photophobia, phonophobia, nausea). Adverse events: 9.43% (Cerena) vs 11.67% (sham); no seizures reported.
Technological Characteristics
Transcranial magnetic stimulator; delivers brief, rapidly alternating or pulsed magnetic fields. Requires electromagnetic compatibility, electrical safety, and thermal safety testing. Patient-contacting elements must be biocompatible. Includes software and firmware requiring verification, validation, and hazard analysis. Characterization of magnetic pulse output, magnetic field map, and sound levels required.
Indications for Use
Indicated for acute treatment of pain associated with migraine headache with aura in patients prescribed the device.
Regulatory Classification
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.
Special Controls
*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.
1. Appropriate analysis/testing must demonstrate electromagnetic compatibility (EMC), 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:
a. A summary of the clinical performance testing, including any adverse events and complications.
b. The intended use population in terms of the types of headaches appropriate for use with the device.
c. Information on how to report adverse events and device malfunctions.
d. A diagram or picture depicting the proper placement of the device on the user.
Submission Summary (Full Text)
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### DE NOVO CLASSIFICATION REQUEST FOR CERENA TRANSCRANIAL MAGNETIC STIMULATOR (TMS) DEVICE
#### REGULATORY INFORMATION
FDA identifies this generic type of device as:
Transcranial Magnetic Stimulator for Headache. 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 electric currents for the treatment of headache.
### NEW REGULATION NUMBER: 882.5808
CLASSIFICATION: CLASS II
PRODUCT CODE: OKP
### BACKGROUND
DEVICE NAME: CERENA TRANSCRANIAL MAGNETIC STIMULATOR (TMS) DEVICE
SUBMISSION NUMBER: K130556
DATE OF DE NOVO: MARCH 5, 2013
- CONTACT: ENEURA THERAPEUTICS LLC. 240 NORTH WOLFE ROAD SUNNYVALE, CA 94085
% LARRY GETLIN REGULATORY CONSULTANT 2690 PHEASANT ROAD ORONO, MN 55331
## REQUESTER'S RECOMMENDED CLASSIFICATION: CLASS II
#### INDICATIONS FOR USE
The eNeura Therapeutics® Cerena™ Transcranial Magnetic Stimulator is indicated for the acute treatment of pain associated with migraine headache with aura.
## LIMITATIONS
For prescription use only.
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Patients must not have any metals or conductive materials or metal containing implants in the head, neck, or upper body that are attracted by a magnet.
Patients must not use the device if they have a cardiac pacemaker, deep brain stimulator (DBS), vagus nerve stimulator (VNS), spinal cord stimulator (SCS), or other implanted neurostimulator, implanted cardioverter defibrillator (ICD), or any active implanted medical device.
Patients with implants that are affected by a magnetic field must not use the device.
The device is only intended for use by patients experiencing the onset of pain associated with a migraine headache with aura.
The device should not be used on headaches due to underlying pathology or trauma.
The device should not be used for medication overuse headaches.
The device has not been demonstrated as safe or effective when treating cluster headache or chronic migraine headache.
The device has not been shown to be effective when treating during the aura phase.
The device has not been demonstrated as effective in relieving the associated symptoms of migraine (photophobia, phonophobia, and nausea).
Safety and effectiveness have not been established in pregnant women, children under the age of 18, and adults over the age of 65.
The device should not be used in patients with suspected or diagnosed epilepsy or a personal or family history of seizures.
The recommended daily usage of the device is not to exceed one treatment per 24 hours.
PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
## DEVICE DESCRIPTION
The Neuralieve Cerena Transcranial Magnetic Stimulator (TMS) is a portable, hand-held, ACpowered device that delivers a brief 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 (occipital cortex). This stimulation to the occipital cortex is intended to stop or lessen the effects of migraine headaches (with aura). The device is designed to be used in a home or office setting.
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The device exterior is made of polycarbonate, a plastic routinely used in consumer medical products. Additionally, the device includes an AC/DC power adapter, a separate power cord for a standard 120V wall outlet and an Operator's Manual.
The device has a display on the top surface consisting of two 7- segment LEDs and a row of LEDs that light in sequence to indicate progress when stimulator's capacitors are charging. There is no separate ON-OFF button. When the stimulator is plugged into the power adapter and the power adapter is plugged into a standard wall outlet, the power indicator light turns on and the display lights up. There are two actuation buttons. The button labeled "Charge" is used to begin the capacitor charging process. The button, labeled "Treat," discharges the fully charged capacitors through the coil to generate the single magnetic pulse.
A complete treatment consists of two independent pulses delivered separately. After the patient delivers the first pulse, the device buzzes to alert the user to press the charge button again. The patient has two minutes to press the charge button after delivering the first pulse or the device will deliver an error code. After the device discharges the second pulse, it does not allow the device to charge for 5 minutes. The device cannot be discharged before completing the charging cycle.
When the user successfully presses the "Treat" button as instructed, the device generates a single magnetic field pulse (<1Tesla). The user hears a brief sound when the magnetic pulse occurs. The stimulator also buzzes and vibrates for two seconds to provide additional feedback that a pulse has occurred.
# SUMMARY OF NONCLINICAL/BENCH STUDIES
## BIOCOMPATIBILITY/MATERIALS
The device is intended to only contact intact skin for a limited duration (< 24 hours). The housing of the device is the only patient contacting material and is made from polycarbonate, a plastic routinely used in consumer medical products. In lieu of biocompatibility testing, the sponsor provided a justification that the identical material has a demonstrated long history of safe use in legally marketed devices with the same type and duration of contact.
# SHELF LIFE/STERILITY
This is a non-sterile, reusable device. It is intended only for external use and the user manual includes appropriate cleaning instructions for the external surface of the device. The device does not have a stated shelf life, which based upon the nature of the device components is acceptable.
## ELECTROMAGNETIC COMPATIBILITY AND ELECTRICAL SAFETY
The device was tested for and found to be in compliance with the following standards for electromagnetic compatibility and electrical safety:
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|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--|--|--|
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--|--|--|
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| Standard | Title |
|---------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| IEC 60601-1 | Medical electrical equipment – Part 1: General requirements for<br>safety and essential performance. |
| IEC 60601-1-2 | Medical electrical equipment - Part 1-2: General requirements for<br>basic safety and essential performance - Collateral standard:<br>Electromagnetic compatibility - Requirements and tests |
## SOFTWARE
Software for the device consisted of proprietary software that controls the user interface and energy delivery to the stimulation coil. The software was reviewed, and the provided documentation was found adequate and consistent with a "MODERATE' level of concern as discussed in the FDA document "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, " issued May 11, 2005.
## PERFORMANCE TESTING - BENCH
Device output – Testing was conducted to characterize the device magnetic field output and the magnetic field pulse. The magnetic field was measured to find the contour plots of various field levels along each axis of the device. The magnetic field pulse was also measured and graphed to show the magnetic field over time and the rate of change for the magnetic field over time.
Sound level - Testing was performed to determine the loudness of the sound generated by the device to demonstrate that the device is within the OSHA safety limits for noise exposure.
# SUMMARY OF CLINICAL INFORMATION
One clinical trial was performed with the device to demonstrate the safety and effectiveness of the device for the treatment of migraine headache with aura.
## Design
The study was a prospective, randomized, double blind, multi-center, sham-controlled trial. The sham device used provided a similar auditory and vibratory output to mimic the treatment device.
The study consisted of a one month, lead-in phase to establish the subjects' baseline frequency and severity of migraine followed by a randomized, double-blind treatment phase consisting of three treatments or three months, whichever happened first. Subjects were required to have at least one aura episode during the lead-in phase to enter the migraine treatment phase.
Subjects were instructed to treat their migraine headache during the aura phase and to record their pain severity, severity of associated migraine symptoms (photophobia, phonophobia, nausea), presence of vomiting, and use of rescue medications at the time of treatment as well as at 1, 2, 24, and 48 hours after treatment.
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## Population
The study population was limited to subjects aged 18 to 65 years who had an International Classification of Headache Disorders, 2nd edition (ICHD-II) diagnosis of migraine with aura, at least one migraine with aura episode during the one month lead-in phase, and an average of one to eight migraine episodes per month.
Subjects were required to have a history of an aura preceding more than 30% of their headaches but were not required to have aura during every migraine episode. Headache severity must have been moderate or severe for approximately 90% of migraine attacks. Key exclusion criteria included subjects with an aura that lasted more than 60 minutes, headaches due to underlying pathology or trauma, and overuse of medication for headaches.
## Results
A total of 201 subjects were enrolled in the study at a 1:1 ratio (102 used Cerena, 99 used the sham control). A total of 164 subjects (82 in each group) recorded at least one treatment of a migraine attack with aura using the device (or sham). A total of 113 subjects (53 with Cerena, 60 with Sham) recorded at least one treatment of a migraine when there was pain of any severity (pain score of 1-3 ) at the time of the treatment. Pain was measured on a scale of 0-3 with 0 representing no pain and 3 representing severe pain. These 113 subjects were used to evaluate the primary and secondary effectiveness end points.
With a post-hoc analysis of these 113 subjects, the primary endpoint (proportion of subjects who were free of pain 2 hours after treatment) analysis demonstrated a statistically significant 21.07% difference in favor of the device over the sham device (37.74% for Cerena and 16.67% for sham. p=0.0181).
The secondary endpoints were evaluated, and the data demonstrated non-inferiority of the Cerena device to sham for the proportion of subjects free of photophobia, meaning that the device does not worsen these associated symptoms. The data did not demonstrate non-inferiority for the proportion of subjects free of nausea and phonophobia.
The data also supported device effectiveness in the proportion of subjects who were pain free after 24 hours (33.96% for Cerena and 10% for sham, p=0.0025).
The study was not designed to necessarily demonstrate effectiveness on successive treatments because subjects did not need to treat more than one migraine when they did not experience more than one in the 3-month trial period.
## Adverse Events
There were 7 AEs in 5 subjects (9.43%) of the Cerena group and 11 reported in 7 subjects (11.67%) of the sham group. Events possibly related to the use of the device include dizziness (N=2). Other reported events included sinusitis, aphasia, and vertigo (N=1 each). No seizures were reported.
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# LABELING
The Cerena physician and patient manuals are consistent with the clinical data and cover all the hazards and other clinically relevant information that may impact use of the device. The labeling is sufficient and satisfies the requirements of 21 CFR § 801.109 Prescription devices.
## RISKS TO HEALTH
The table below identifies the risks to health that may be associated with use of transcranial magnetic stimulator devices for headache and the measures necessary to mitigate these risks.
| Identified Risk | Mitigation Method |
|------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------|
| Failure to identify correct population | Clinical testing<br>Labeling |
| Ineffective treatment | Clinical testing<br>Non-Clinical Testing<br>Software Verification, Validation, and<br>Hazard Analysis<br>Labeling |
| Risk of seizure | Clinical Testing<br>Non-Clinical Testing<br>Labeling |
| Scalp discomfort, scalp burn, dizziness,<br>nausea, or other adverse effects | Clinical testing<br>Non-Clinical Testing<br>Thermal Safety<br>Software Verification, Validation, and<br>Hazard Analysis<br>Labeling |
| Adverse tissue reaction | Biocompatibility<br>Labeling |
| Electrical shock, burn | Electrical Equipment Safety<br>Thermal Safety<br>Labeling |
| Interference with other electrical<br>equipment | Electromagnetic Compatibility<br>Labeling |
| Noise Irritation and Hearing Loss | Non-Clinical Testing<br>Labeling |
## SPECIAL CONTROLS:
- 1. Appropriate analysis/testing must demonstrate electromagnetic compatibility (EMC), electrical safety, and thermal safety.
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- 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:
- a. A summary of the clinical performance testing, including any adverse events and complications.
- b. The intended use population in terms of the types of headaches appropriate for use with the device.
- c. Information on how to report adverse events and device malfunctions.
- d. A diagram or picture depicting the proper placement of the device on the user.
## BENEFIT/RISK DETERMINATION
The risks of the device are based on data collected in the clinical studies described above. No serious device-related adverse events were reported in the clinical performance data. The majority of adverse events were minor and all resolved on their own shortly after discontinuation of device use. Based on this information, the risk associated with this device is considered low.
The probable benefits of the device are also based on data collected in clinical study of subjects with migraine with aura described above. A post-hoc analysis of the subgroup of subjects with any pain at the time of treatment was performed. The analysis demonstrated effectiveness in treating pain associated with migraine headaches both at the 2 and 24 hours after treatment. However, the study did not demonstrate effectiveness on treating the associated symptoms of migraine (photophobia, phonophobia, nausea).
Additional factors to be considered in determining probable risks and benefits for the device include: (1) There are no legally marketed devices available for patients with migraine. There are approved drug treatments, but these have known adverse effects that are more common and more severe than those seen in the Cerena trials. (2) Long-term safety and effectiveness data for the Cerena are not available. The clinical data are limited to 3 months in duration and limited to evaluation of the first treated migraine.
Given the available information, the data support that the probable benefits outweigh the probable risks for the Cerena device for treating migraine pain. The device risks can be mitigated by the use of general and the identified special controls.
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# CONCLUSION
The de novo for the Cerena TMS device is granted and the device is classified under the following:
Device Type: Transcranial magnetic stimulator device for headache Regulation: 21 CFR 882.5808 Class: Class II Product Code: OKP
Two short videos show you everything — or skip straight to the written tutorial if you'd rather read. You can reopen this any time from the Tutorial button in the top bar.
Part 1 — Search, results, and everyday workflows 16 min
Part 2 — Embeddings: the galaxy map 3 min
1. Search: exact and fuzzy
Type a phrase like "coronary artery calcification" into the search box. You get two kinds of results. Exact results match the literal phrase — prefix searches work ("coronary artery calcificati") but suffix searches do not. Fuzzy results match on the meaning and intent of your phrase rather than the exact words, and are sorted by relevance score. Hover over the Exact or Fuzzy badge on any row to see exactly why it matched.
Use the checkboxes above the results to narrow: SaMD keeps only software-only devices, AI / ML keeps only devices with AI.
Exact vs. fuzzy search: what's the difference?
Exact matches on the literal phrase (prefix search works, suffix does not). Fuzzy matches on the meaning and intent of the phrase rather than the exact words. Hover over the badge on any row to see why it matched.
You search "coronary artery calcification" and want only software devices with AI. What two filters do you apply?
Narrow by SaMD (software-only devices), then narrow by AI/ML (devices with AI).
2. The results table
Scroll right in the results table. The intended use is extracted for you — no need to open the PDF. The device story gives a high-level snapshot of what the device does and how it's used. The AI Performance sub-table shows each output name, acceptance criteria, observed values, and development/test dataset descriptions — the same format Innolitics uses for regulatory strategy outputs, and the fastest high-level fingerprint of an AI device. It is AI-generated but has been very reliable in practice.
Where do you find a device's intended use without opening the PDF?
Scroll right in the search results table. The intended use column is extracted for you; no need to dig into the 510(k) summary PDF.
What does the AI Performance sub-table show, and why is it useful?
Output name, acceptance criteria, observed values, development dataset description, and test dataset description. It's the same format we use for regulatory strategy output and Fast 510(k) input, and the fastest high-level fingerprint of an AI device. AI-generated but reliable in practice.
3. Judging fuzzy relevance
Fuzzy results trail off in relevance as you scroll. Use three signals to decide how far down to go: the fuzzy badge explanations, the intended use column, and whether your target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, you're past the relevant zone. A top hit with a low score (~0.4) and a stretched explanation is a hint the closest predicates are far away — the project may be headed for De Novo. Note the fuzzy search is a pattern match: it doesn't handle negation ("not") well, and hardware devices can appear — filter by SaMD/AI ML to cut them.
How do you judge how far down fuzzy search results to go?
Use the relevancy signals: the fuzzy badge explanations, the intended use column, and whether the target output (e.g., Cobb angle) still appears in the AI Performance sub-table. Once it stops appearing, results are trailing off in relevancy.
4. Device detail page: chat and citations
Click a device name to open its detail page: device facts on the left, a chat window on the right. Ask something like "Describe the training data". The answer carries little citation bubbles — click one to jump to the highlighted passage in the source PDF, so you can verify every AI answer against the document. There's also a Download PDF button for sharing.
How do you verify an AI chat answer on the device detail page?
Click the citation bubbles to jump to the relevant highlight in the source document.
Reading rule for every project: how many summaries do you read in full?
At least the three most relevant 510(k) or De Novo summaries, in full. After that, use targeted chat questions to confirm your memory quickly. The tool supports this professional habit — it doesn't replace it.
5. Side-by-side comparison
Select multiple rows in the results table (aim for under ~10), then open the PDF Viewer tab. Ask one question — it goes to all selected devices in parallel, each with citations. This is the fastest way to compare and contrast devices: training data, PCCP scope, how they handled adding new scanners, and so on.
What does the side-by-side PDF viewer mode do?
Select multiple devices, open the PDF viewer tab, and ask one question (e.g., "Describe the training data"). It queries all selected devices simultaneously with citations, so you can compare and contrast quickly.
6. Collections
With rows selected, go to the Collections tab and create a labeled collection (e.g., "Cobb Angle Project"). Reload that selection any time — before a client call, pull up the collection and ask questions across all of its devices at once.
How do you save a set of selected devices for later use?
Select the rows, go to the Collections tab, and create a labeled collection (e.g., "Cobb Angle Project"). You can reload the selection anytime and carry it into the PDF viewer and other tabs that support selections.
7. Product codes and the regulations tree
Click a product code in the results to jump to it in the regulations tree — identification text, sibling product codes, and devices you can open in a PDF viewer on the right. Click a regulation number to see its identification, special controls, and related product codes. You can also search by product code or regulation number at the top of the tree. Always read the special controls if any exist for your device — it broadens your search and sharpens pre-kickoff research.
What can you do from the regulations tree view?
Browse product codes and regulation numbers, read the identification text and special controls, browse sibling product codes, open device PDFs on the right, and search by product code or regulation number at the top of the tree.
8. Chart view
Click Show Chart and segment by regulation number (or product code) to see which regulations dominate your result set. Clicking a regulation takes you into the regulations tree. Great for spotting that most matches are, say, hardware laparoscopic devices — a cue to go back and filter.
How do you see which regulations dominate a search result set?
Click "Show Chart" and segment by Regulation Number. Clicking a regulation takes you to the regulations tree.
9. The predicate graph
Open the Predicates tab for a family-tree view of predicate relationships. Click a node to trace its parents and children; selections from search carry over pre-selected. Commonly predicated devices are worth reading — a lot of people predicated them for a reason. The visual lineage is also handy on client calls, e.g. to show how a predicate family evolved and justify why your predicate still holds.
In the predicate graph, why are commonly predicated devices worth reading?
A lot of people predicated them for a reason. Clicking a node traces parents and children, and selections from search carry over pre-selected.
10. Embeddings: the galaxy map
The Embeddings tab plots every matching document in a 2-D "galaxy map" where semantically similar devices cluster together. Hover or click clusters to explore, and let AI label the clusters for you. Embeddings beat product codes for grouping: two devices can carry different product codes (LLZ vs. QIH) yet do the same thing — the embedding captures the meaning of the intended use and device story. This is also exactly how retrieval-augmented generation (RAG) works under the hood, and it makes a great visual on client calls.
Try it yourself
Head to the search page and work through a few of these AI/ML fuzzy searches to build intuition: perivascular fat on CT · aortic valve calcification opportunistic screening on noncontrast CT · breast cancer prediction on digital pathology slides · autism detection · gestational age prediction · a hearing aid that can also detect a pulse · foundation model based analysis of ECG · large language models · penetration test. Watch how the relevance scores, intended use, and AI Performance tables tell you when results stop being meaningful.
