The iovera? system is used to destroy tissue during surgical procedures by applying freezing cold. It can also be used to produce lesions in peripheral nervous tissue by the application of cold to the selected site for the blocking of pain. It is also indicated for the relief of pain and symptoms associated with osteoarthritis of the knee for up to 90 days. The iovera" system is not indicated for treatment of central nervous system tissue.

Device Description

The ioveras system is a portable cryogenic surgical device used to destroy tissue and/or produce lesions in nervous tissue creating a nerve block through application of extreme cold to the selected site. The device is based on introduction of a Smart Tip internally cooled by the cryogenic fluid (nitrous oxide, N2O) to a selected area. The Smart Tip is cooled by the Joule-Thomson Effect and/or Latent Heat of Vaporization. The ioveraº system may be used in conjunction with a standard off-the-shelf nerve stimulator device in applications where precise nerve location is desired.

The device is comprised of four main components:

A reusable Handpiece
A Charging Dock
An assortment of single-patient use Smart Tips
A Cartridge (Nitrous Oxide)

The iovera Handpiece is battery powered and provides feedback to the user during device preparation and use. The Handpiece connects to both the Cartridge and to the Smart Tip. The user activates a treatment cycle through a control on the Handpiece, which starts and stops the treatment. The Handpiece also contains LEDs for providing feedback to the user when the device is ready to use. The Charging Dock stores the Handpiece between uses and provides power for charging the battery.

An assortment of Smart Tips is available for the iovera system. All Smart Tip needles are made of stainless steel and have a closed-end that fully contains the cryogen so that it does not enter the target tissue. The Smart Tip is the only patient contacting component of the iovera° system. The user removes the Smart Tip from the sterile packaging and attaches it to the Handpiece.

The ioveras system uses a commercially available nitrous oxide cylinder. The Cartridge is filled with pure N2O.

AI/ML Overview

This document describes the FDA 510(k) clearance for the ioveraº system, a cryogenic surgical device, for an expanded indication related to the relief of pain and symptoms associated with osteoarthritis of the knee.

1. Table of Acceptance Criteria (Primary and Secondary Endpoints) and Reported Device Performance

Acceptance Criteria (Primary/Secondary Endpoints)	Reported Device Performance (ioveraº treatment group vs. Sham control group)
Primary Endpoint
Superiority of ioveraº treatment over sham treatment for reducing pain and symptoms due to osteoarthritis in the knee as assessed by the Total WOMAC scale from baseline to Day 30 (p<0.05)	Met: p = 0.001 ioveraº: -73.311 (LS Mean reduction in WOMAC score) Sham: -42.18 (LS Mean reduction in WOMAC score) (55% improvement vs. 33% improvement)
Secondary Endpoints
Statistically significant superiority of ioveraº treatment over sham treatment for relief of pain and symptoms due to osteoarthritis of the knee on the Total WOMAC scale (pain, stiffness, function) at Day 60 (p<0.05)	Met: Data indicates statistically significant superiority, though specific p-value for Day 60 is not explicitly stated, it's grouped under "Secondary endpoints were also met".
Statistically significant number of patients reported clinically significant pain relief (30% reduction in WOMAC pain score) through 90 days after treatment with the ioveraº system (p<0.05)	Met: Day 30: 74.58% (ioveraº) vs. 44.83% (Sham) Day 60: 76.79% (ioveraº) vs. 56.90% (Sham) Day 90: 80.18% (ioveraº) vs. 54.39% (Sham)

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

Sample Size: 180 subjects were enrolled and analyzed.
- ioveraº system treatment group: 121 subjects
- Sham device control group: 59 subjects
Data Provenance: The study was a multi-center, prospective, randomized, double-blind, sham-treatment controlled trial. The specific country of origin is not explicitly stated in the provided text, but the FDA submission implies a US-based or FDA-regulated study. Being a prospective, randomized, double-blind trial suggests high-quality clinical data.

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

This type of study does not rely on "experts establishing ground truth" in the same way an imaging AI study would. Instead, the "ground truth" for efficacy is established by the participants' self-reported pain and symptom scores using validated instruments (WOMAC scale) and comparison against a sham control. Eligibility criteria included a diagnostic block by a local anesthetic, which would have been assessed by a clinician (likely a physician or pain specialist). The study design (randomized, double-blind, sham-controlled) is a robust method for establishing efficacy.

4. Adjudication Method for the Test Set

Not applicable in the context of this clinical trial for the stated endpoints. The outcome measures are quantitative scores (WOMAC) and percentages of responders, directly recorded from treatment and control groups. Blinding of both the treating investigator and the subject to the study treatment serves as the primary method to prevent bias in assessment.

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

Not applicable. This is a clinical trial evaluating a medical device (cryogenic surgical system) for pain relief, not an AI software evaluating medical images. Therefore, the concept of "human readers improving with AI" does not apply.

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

Not applicable. The ioveraº system is a physical device used by a clinician, not an algorithm. Its performance is determined by its physiological effect (tissue destruction/nerve lesioning) and resulting clinical outcomes. This study evaluates the device in use by humans.

7. The Type of Ground Truth Used

The ground truth for the efficacy endpoints was based on patient-reported outcomes (PROs) using the validated Total WOMAC (Western Ontario and McMaster Universities Arthritis Index) scale, specifically measuring changes from baseline in pain, stiffness, and physical function. The diagnostic block of the infrapatellar branch of the saphenous nerve with a local anesthetic served as a pre-screening "ground truth" to confirm a subject was a candidate for treatment before randomization.

8. The Sample Size for the Training Set

Not applicable. This is a clinical trial for a medical device and does not involve an AI algorithm with a training set.

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

Not applicable, as there is no training set for an AI algorithm in this context.

Summary

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

March 24, 2017

Myoscience, Inc. Tracey Henry General Manager 46400 Fremont Blvd Fremont, California 94538

Re: K161835

Trade/Device Name: ioveraº System Regulation Number: 21 CFR 882.4250 Regulation Name: Cryogenic Surgical Device Regulatory Class: Class II Product Code: GXH Dated: February 17, 2017 Received: February 23, 2017

Dear Ms. Henry:

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 yours,

Michael J. Hoffmann -S

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

510(k) Number (if known) K161835

Device Name ioveraº system

Indications for Use (Describe)

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)

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Section 5: 510(k) Summary

Device Information:

Category	Comments
Sponsor / Submitter:	Myoscience, Inc46400 Fremont BlvdFremont, CA 94538Ph: 510.933.1500Fax: 410.933.1501
Correspondent ContactInformation:	Tracey HenryGeneral Manager, Myoscience, IncTelephone: 510.933.1510Email: thenry@myoscience.com
Device Common Name:	Cryogenic surgical device
Device Classification & Code:	Class II, GXH
Device Classification Name:	Cryosurgical unit and accessories (21 CFR 882.4250)
Device Trade Name:	iovera° system

a. Predicate Device Information:

510(k) Number	Product	Sponsor
K142866	iovera o system	Myoscience, Inc

b. Date Summary Prepared

15 February 2017

c. Description of Device

Device Design

The device is comprised of four main components:

1. A reusable Handpiece
1. A Charging Dock
1. An assortment of single-patient use Smart Tips
1. A Cartridge (Nitrous Oxide)

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The ioveras system uses a commercially available nitrous oxide cylinder. The Cartridge is filled with pure N2O.

Device Functionality/Scientific Concepts

The device functionality is based on the user introducing the Smart Tip to the selected treatment area; unwanted tissue or the target nervous tissue. The user then initiates the flow of cryogen by pressing the on/off button. Liquid cryogen flows from the Handpiece into the closed-end Smart Tip. The Smart Tip is cooled by the Joule-Thomson Effect and/or Latent Heat of Vaporization; as the liquid cryogen expands into a gas, the temperature drops around the external surface of the Smart Tip causing the surrounding tissue to freeze. The treatment is completed after a preprogrammed amount of time at which time the user can safely remove the Smart Tip.

d. Indications for Use

The iovera system is used to destroy tissue during surgical procedures by applying freezing cold. It can also be used to produce lesions in peripheral nervous tissue by the application of cold to the selected site for the blocking of pain. It is also indicated for the relief of pain and symptoms associated with osteoarthritis of the knee for up to 90 days. The iovera system is not indicated for treatment of central nervous system tissue.

The Indications for Use statement for the subject device has been expanded to include "for the relief of pain and symptoms associated with osteoarthritis of the knee." This additional wording adds specificity to the already cleared indication. Clinical data demonstrate that this specific use does not affect the safety or effectiveness of the iovera system when used as labeled. There were no new questions of safety or effectiveness raised.

e. Comparison of Technological Characteristics with the Predicate Device

There are no differences in technological characteristics, as summarized below, and therefore no new or different questions of safety and effectiveness for the subject device are raised.

Technological Characteristics
Predicate Device (K142866)	Subject Device
Cryogenic device	Same
Nitrous oxide coolant, pressurized cylinder	Same
Reusable handpiece, battery powered	Same
Single use tip for subdermal cooling, EO sterilized	Same
Charging dock	Same
Sensors, monitor nitrous oxide deliver and rate of cooling	Same
Smart Tip Needle Length: 6 – 55mm (0.2 – 2.2 in) Size: Ø.31 – .72mm (25 – 30 gauge) Patient contacting materials:Closed sharp cutting and blunt tip Stainless Steel needle	Same

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f. Performance Data

The following performance data were provided in support of the substantial equivalence determination.

Bench Testing	No bench testing was necessary for the expanded indications for use.
PreclinicalTestingSubmitted:	No preclinical testing was deemed necessary for the expanded indications foruse.
Clinical TestingSubmitted:	Clinical testing demonstrating the safety and effectiveness of the iovera°system for the relief of pain and symptoms associated with osteoarthritisof the knee was submitted.
	Study Design:This was a multi-center, prospective, randomized, double-blind, sham-treatment controlled trial. The treating Investigator and Subject were blindedto study treatment. Each Subject was followed a minimum of 120 days post-treatment. Eligible subjects were diagnosed with Grade II or III osteoarthritisof the knee (Kellgren-Lawrence classification grading scale) and washed outof all pain medication. A local anesthetic was used to create a diagnosticblock of the infrapatellar branch of the saphenous nerve, as assessed by a50% decrease in VAS pain upon standing from a seated position or walkingup stairs, to confirm that the subject was a candidate for treatment.
	121 subjects were treated with the iovera system and 59 subjects weretreated with a sham device, with ages ranging from 36 to 75 years. Datafrom all 180 subjects enrolled were collected and analyzed. The primaryendpoint (superiority of the iovera° treatment over sham treatment forreducing pain and symptoms due to osteoarthritis in the knee as assessed bythe Total WOMAC scale from baseline to Day 30) was met, p=0.001.Subjects treated with the iovera° system reported substantially more pain andsymptom relief as subjects treated with the sham device (55% improvementversus 33% improvement).
	Secondary endpoints were also met, including statistically significantsuperiority of iovera° treatment over sham treatment for relief of pain andsymptoms due to osteoarthritis of the knee on the Total WOMAC scale(pain, stiffness, function) at Day 60 and a statistically significant number ofpatients reported clinically significant pain relief (30% reduction inWOMAC pain score) through 90 days after treatment with the iovera°system.

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		IoveratreatmentgroupN=121	Shamcontrolgroup(n=59)
Reduction in pain andsymptoms on Total WOMACscale 30 days post-treatment		-73.311	-42.18
Percentage of patientsreporting 30% improvementin pain and symptoms onTotal WOMAC scale post-treatment	30 days	74.58%	44.83%
	60 days	76.79%	56.90%
	90 days	80.18%	54.39%

1 LS Means and p-value were obtained by fitting an ANCOVA model with treatment as factor and WOMAC baseline score as a covariate.

There were no serious device-related or procedure-related adverse events. All device-related adverse events were as anticipated per the device labeling. A summary of adverse reactions, including site-specific reactions and/or known effects from cryoanalgesia (e.g., bruising, swelling, redness) which lasted longer than 30 days follows.

Adverse reactions	Iovera	Sham
	N=121	N=59
Numbness	18 (14.8%)	1 (1.7%)
Tenderness upon palpation	14 (11.6%)	8 (13.6%)
Local pain	8 (6.6%)	4 (6.8%)
Altered sensation/ localized dysethesia	3 (2.5%)	2 (3.4%)
Tingling	3 (2.5%)	1 (1.7%)
Swelling	3 (2.5%)	3 (5.1%)
Bruising	3 (2.5%)	2 (3.4%)
Itching	2 (1.6%)	0
Vasovagal response	1 (0.8%)	0
Knee pain	1 (0.8%)	2 (3.4%)
Redness/inflammation	1 (0.8%)	1 (1.7%)
Pain, aggravated	0	1 (1.7%)

g. Conclusion

Use of the already cleared ioveraº system in the Clinical Study described herein has shown that the device can be used safely and effectively, within its intended use, to provide relief for pain and symptoms associated with osteoarthritis of the knee. Substantial equivalence to the predicate device has been established, therefore, as there was no change to the intended use or the technological characteristics of the device, and data from the Clinical Study demonstrate safety and efficacy; the primary and secondary endpoints were met and there were no new questions of safety or effectiveness.

Regulation Number and Section

§ 882.4250 Cryogenic surgical device.

(a)
Identification. A cryogenic surgical device is a device used to destroy nervous tissue or produce lesions in nervous tissue by the application of extreme cold to the selected site.(b)
Classification. Class II (performance standards).