MISHA Knee System

DEN220033 · Moximed, Inc. · QVV · Apr 10, 2023 · Orthopedic

Device Facts

• Record ID: DEN220033
• Device Name: MISHA Knee System
• Applicant: Moximed, Inc.
• Product Code: QVV · Orthopedic
• Decision Date: Apr 10, 2023
• Decision: DENG
• Submission Type: Direct
• Regulation: 21 CFR 888.3610
• Device Class: Class 2
• Attributes: Therapeutic

Intended Use

The MISHA™ Knee System is indicated for patients with medial compartment knee osteoarthritis that have failed to find relief in surgical and/or non-surgical treatment modalities and are still experiencing pain that interferes with activities of daily living and are also unwilling to undergo or ineligible for total knee replacement due to age or absence of advanced osteoarthritis.

Device Story

MISHA™ Knee System is an implantable shock absorber for medial compartment knee osteoarthritis; device implanted outside knee capsule, extending from distal femur to proximal tibia; employs mechanical shock-absorbing system; biomechanically stabilized by plates and screws; reduces loads on intra-articular medial joint surface to improve symptoms; does not span lateral knee; intended for patients failing other treatments; surgical implantation performed by physicians; provides mechanical unloading to alleviate pain and improve function; benefits patients by delaying or avoiding total knee replacement.

Clinical Evidence

Prospective, multicenter study (n=81 MISHA, n=81 HTO control) using propensity score matching. Primary endpoint: Composite Clinical Success (CCS) at 24 months. MISHA success rate 83.5% vs. 57.2% for HTO (p-value not provided, but non-inferiority margin of -0.10 met). Secondary endpoints showed superiority in time to full weight bearing and WOMAC function scores at 3 and 24 months. Safety profile comparable to HTO; no unanticipated adverse device effects.

Technological Characteristics

Medial knee implanted shock absorber; mechanical shock-absorbing system; biomechanically stabilized by plates and screws; implanted outside knee capsule; extends from distal femur to proximal tibia; does not span lateral knee. Requires biocompatibility, sterility, pyrogenicity, and shelf-life validation.

Indications for Use

Indicated for patients with medial compartment knee osteoarthritis who failed surgical/non-surgical treatment, experience pain interfering with daily activities, and are unwilling or ineligible for total knee replacement due to age or lack of advanced osteoarthritis.

Regulatory Classification

Identification

A medial knee implanted shock absorber is a device implanted outside of the knee capsule extending from the distal femur to the proximal tibia. It is intended to reduce loads on the intra-articular medial joint surface to improve symptoms of osteoarthritis. The device employs a shock absorbing mechanical system and is biomechanically stabilized by plates and screws. The device is not intended to span the lateral knee.

Special Controls

In combination with the general controls of the FD&C Act, the medial knee implanted shock absorber is subject to the following special controls:

Submission Summary (Full Text)

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### DE NOVO CLASSIFICATION REQUEST FOR MISHATM KNEE SYSTEM

### REGULATORY INFORMATION

FDA identifies this generic type of device as:

Medial knee implanted shock absorber. A medial knee implanted shock absorber is a device implanted outside of the knee capsule extending from the distal femur to the proximal tibia. It is intended to reduce loads on the intra-articular medial joint surface to improve symptoms of osteoarthritis. The device employs a shock absorbing mechanical system and is biomechanically stabilized by plates and screws. The device is not intended to span the lateral knee.

NEW REGULATION NUMBER: 21 CFR 888.3610

CLASSIFICATION: Class II

PRODUCT CODE: QVV

#### BACKGROUND

DEVICE NAME: MISHATM Knee System

SUBMISSION NUMBER: DEN220033

DATE DE NOVO RECEIVED: July 6, 2022

SPONSOR INFORMATION: Moximed. Inc. 46602 Landing Parkway Fremont, California 94539

#### INDICATIONS FOR USE

The MISHATM Knee System is indicated as follows:

The MISHATM Knee System is indicated for patients with medial compartment knee osteoarthritis that have failed to find relief in surgical and/or non-surgical treatment modalities and are still experiencing pain that interferes with activities of daily living and are also unwilling to undergo or ineligible for total knee replacement due to age or absence of advanced osteoarthritis.

#### LIMITATIONS

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The sale, distribution, and use of the MISHA™ Knee System are restricted to prescription use in accordance with 21 CFR 801.109.

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

# DEVICE DESCRIPTION

# Implant Description

The MISHATM Knee System (Figure 1) is a prescription use, extra-capsular knee implant device that is comprised of a tibial base subassembly, femoral base subassembly, absorber subassembly, piston subassembly and locking screws. The tibial base subassembly, femoral base subassembly, piston subassembly and absorber subassembly are provided pre-assembled, and the implant is fixed with locking screws to the medial cortices of the distal femur and proximal tibia to share the loads with the knee joint. The articulating ball-and-sockets allow the implant to accommodate the natural motions of the knee. The implant bases and locking screws are made of titanium alloy and the sockets are CoCrMo alloy. The compressive component of the absorber is made of polycarbonate urethane. The femoral balls, tibial balls, and the internal lining of the absorber are made of carbon-fiber-reinforced polyetheretherketone (CFR-PEEK). The implant comes in two sizes (small and large) and right or left configurations.

Image /page/1/Picture/5 description: The image shows a medical device, possibly a bone fracture fixation device. It consists of two metal end pieces with multiple holes, connected by a central, cylindrical component. The central component appears to be a telescoping rod, possibly with a spring mechanism inside, and is colored yellow.

Figure 1: MISHATM Knee System Implant

# Instrument Description

The instruments for the MISHATM Knee System are used to facilitate targeting, trialing, and fixation of the implant. The instrumentation includes a Fixation Kit, Torque Limiting Driver, and Targeting and Trialing Kits. The Targeting and Trialing kits are intended to support sizing and proper implant selection.

# SUMMARY OF NONCLINICAL/BENCH STUDIES

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## BIOCOMPATIBILITY/MATERIALS

The MISHA™ Knee System is manufactured from the following patient contacting materials:

| Description | Material | Direct<br>Patient<br>Contact | Contact Duration |
|---------------------------------------|------------------------------------------------------------------------------------------------|------------------------------|-------------------|
| Knee System<br>Implant | Cobalt Chromium per ASTM<br>F1537; Ti6Al4V ELI per<br>ASTM F136; CFR-PEEK, 80A<br>PCU; 75D PCU | Yes | Permanent (>30 d) |
| Screws | Ti6Al4V ELI per ASTM F136 | Yes | Permanent (>30 d) |
| Patient-<br>contacting<br>Instruments | Medical Grade Stainless Steel,<br>Polycarbonate, and Silicone | Yes | Limited (≤24 h) |

Table 1: Manufactured Materials of Patient-Contacting Device Components

Biocompatibility evaluation has been completed according to 2020 FDA Guidance, Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process."

For the permanent implant, Table 2 shows the biocompatibility testing performed and the results, which were acceptable for a permanent implant in contact with bone/tissue:

| Test Description | Result |
|----------------------------------------------------------------------------------------------------------------------------------------------|----------------------------|
| Cytotoxicity (per ISO 10993-5 (Biological evaluation<br>of medical devices - Part 5: Tests for in vitro<br>cytotoxicity)) | Non-cytotoxic |
| Irritation (per ISO 10993-10 (Biological evaluation of<br>medical devices - Part 10: Tests for irritation and skin<br>sensitization)) | Non-irritant |
| Sensitization (per ISO 10993-10 (Biological evaluation<br>of medical devices - Part 10: Tests for irritation and<br>skin sensitization)) | Non-sensitizing |
| Implantation Effects (per ISO 10993-6 (Biological<br>evaluation of medical devices - Part 6: Tests for local<br>effects after implantation)) | Null to minimal reactivity |
| Material Mediated Pyrogenicity (per ISO 10993-11<br>(Biological evaluation of medical devices - Part 11:<br>Tests for systemic toxicity)) | Non-pyrogenic |

Table 2: Implant Biocompatibility Testing Performed

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| Acute/Subacute/Subchronic/Chronic Systemic<br>Toxicity, Genotoxicity and Carcinogenicity (addressed<br>through chemical characterization and toxicological<br>risk assessment per ISO 10993-18 (Biological<br>evaluation of medical devices - Part 18: Chemical<br>characterization of medical device materials within a<br>risk management process)/ISO 10993-17 (Biological<br>evaluation of medical devices - Part 17:<br>Establishment of allowable limits for leachable<br>substances) | Non-systemically<br>toxic/genotoxic/carcinogenic |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------|
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------|

A 26-week combined implantation and systemic toxicity rabbit study was conducted per ISO 10993-11:2017 in combination with assessment of local implantation effects per ISO 10993-6:2016. The test articles did not produce local or systemic toxicological effects.

For the reusable instruments, Table 3 shows the biocompatibility testing performed and the results, which were acceptable for instruments in limited contact with bone/tissue:

| Test Description | Result |
|----------------------------------------------------------------------------------------------------------------------------------------|-----------------|
| Cytotoxicity (per ISO 10993-5 (Biological evaluation<br>of medical devices - Part 5: Tests for in vitro<br>cytotoxicity)) | Non-cytotoxic |
| Irritation (per ISO 10993-10 (Biological evaluation of<br>medical devices - Part 10: Tests for irritation and skin<br>sensitization) ) | Non-irritant |
| Sensitization (ISO 10993-10 (Biological evaluation of<br>medical devices - Part 10: Tests for irritation and skin<br>sensitization)) | Non-sensitizing |
| Acute Systemic Toxicity (per ISO 10993-11<br>(Biological evaluation of medical devices - Part 11:<br>Tests for systemic toxicity)) | Non-toxic |

### Table 3: Instrument Biocompatibility Testing Performed

### STERILITY/PACKAGING AND SHELF-LIFE/PYROGENICITY

### Sterility:

The MISHATM Knee System is a single-use device provided clean and sterile to the user. Gamma Sterilization of the device has been validated to provide a Sterility Assurance Level (SAL) of 10-6 based on the VDMax25 method as recommended by FDA Recognized Consensus Standard series ANSI/AAMI/ISO 11137-1 ("Sterilization of health care products - Radiation - Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices")/-2 ("Sterilization of health care products - Radiation - Part 2: Establishing the sterilization dose").

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# Packaging and Shelf-Life:

The MISHATM Knee System comes in three different packaging configurations. Each configuration includes an inner pouch, an outer pouch, and a protective carton. The material of the packaging is outlined in Table 4. The implants, screws and trials all share the "Small" configuration. The Targeting Kit and Fixation Kits share the "Large" configuration. In addition, the Targeting and Fixation Kits are packaged on a mounting card. The configuration of the Torque Limiting Driver is the same inner and outer pouch as the Targeting and Fixation kit with a protective carton of slightly different dimensions.

## Table 4: Materials of Construction of Packaging System Components

| Inner and Outer Pouches | Protective Cartons | Mounting Cards |
|-------------------------|--------------------|----------------|
| | (b)(4) | |
| | | |
| | | |
| | | |
| | | |
| | | |

Non-clinical performance testing of the implant was used to assess the shelf-life of the device. The testing confirmed a 5-year shelf-life.

# Pyrogenicity:

Bacterial endotoxins testing (BET) was performed to determine whether the MISHATM Knee System met pyrogen limit specifications. All tested devices passed with a reported value of ≤1 EU/device, meeting the recommended endotoxin limits per ANSI/AAMI ST72:2011 ("Bacterial endotoxins - Test methods, routine monitoring, and alternatives to batch testing").

# MAGNETIC RESONANCE (MR) COMPATIBILITY

To support MR conditional labeling for the MISHATM Knee System, the following MR testing was conducted to evaluate device safety and compatibility:

- Magnetically Induced Displacement Force per ASTM F2052-15. "Standard Test . Method for Measurement of Magnetically Induced Displacement Force on Medical Devices in the Magnetic Resonance Environment";
- Magnetically Induced Torque per ASTM F2213-11, "Standard Test Method for . Measurement of Magnetically Induced Torque on Medical Devices in the Magnetic Resonance Environment";
- . Radiofrequency Induced Heating per ASTM F2182-11a, "Standard Test Method for Measurement of Radio Frequency Induced Heating Near Passive Implants During Magnetic Resonance Imaging"; and

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- Imaging Artifacts per ASTM F2119-07 (Reapproved 2013), "Standard Test Method . for Evaluation of MR Image Artifacts from Passive Implants"
In magnetic field interaction tests, the MISHA™ Knee System implant showed a translation deflection angle of piral the maximum spatial gradient was (D)(4) (bx) and no torque. In image artifact testing, the maximum image artifact was measured for both spin echo and gradient echo pulse sequences in a 3.0 T MR scanner, and the maximum artifact size caused by the device extends approximately 37 mm from the implant when imaged with a gradient echo pulse sequence. In MRI-related heating testing, test results and in vivo modeling show that, the maximum temperature rise after 60 minutes continuous exposure is less than 6°C under the condition of the whole-body specific absorption rate (SAR) at 2 W/kg.

### PERFORMANCE TESTING - BENCH

A summary of non-clinical mechanical performance evaluations is provided in Table 5:

| Test | Purpose | Method | Performance<br>Criteria | Results |
|--------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------|--------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Absorber Unloading<br>Capacity | Demonstrate the<br>minimum<br>compressive<br>resistance force<br>produced by the<br>absorber at its<br>implanted length. | (b)(4) | Demonstrate the<br>minimum<br>compressive<br>resistance force<br>produced by the<br>absorber at its<br>implanted length is ≥<br>15 lbs. | All specimens<br>exceeded the<br>performance criteria. |
| Durability, Wear,<br>and Corrosion<br>Resistance | Demonstrate the<br>implant functionality,<br>wear rate and<br>corrosion resistance in<br>a simulated in vivo<br>environment. | | Demonstrate the mean<br>polymeric and<br>metallic wear rate are<br>$≤$ 6.1 and $≤$ 0.004<br>$mm³$ per one million<br>cycles, respectively.<br>Demonstrate implant<br>materials (including | The mean polymeric<br>wear rate was 0.248<br>$mm³$ per one million<br>cycles.<br>The mean metallic<br>wear rate was 0.004<br>$mm³$ per one million<br>cycles. |
| Test | Purpose | Method | Performance<br>Criteria | Results |
| | | (b)(4) | (markings) are<br>corrosion resistant in<br>simulated in vivo<br>environments.<br>Demonstrate the<br>implant functionality<br>can be maintained for<br>$\ge$ 10 million<br>simulated gait cycles<br>at its implanted<br>length.<br>Functionality is<br>defined as: (1)<br>fixation of the bases<br>on the bones is<br>maintained, (2) the<br>device carries load<br>during low knee<br>flexion angles<br>representative of the<br>stance phase of gait,<br>and (3) device<br>components remain<br>contiguous and<br>mobile relative to one<br>another throughout<br>knee motion. | There was no<br>evidence of corrosion<br>after immersion in the<br>simulated in vivo<br>environment.<br>All test articles<br>remained functional<br>throughout testing<br>(10.3 million cycles). |
| Static Strength | Demonstrate the<br>implant will not<br>fracture or break<br>when subjected to<br>clinically relevant<br>loads. | | Demonstrate the<br>implant will not<br>fracture or break<br>when subjected to a<br>static compressive<br>load up to 60 lbs. | All articles survived a<br>static compressive<br>load of 65 lbs.<br>without any signs of<br>permanent<br>deformation or<br>damage of the<br>structural<br>components. |

Table 5: Summary of Non-clinical Mechanical Performance Evaluations

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# SUMMARY OF CLINICAL INFORMATION

Study Design

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The sponsor conducted a prospective, multicenter clinical study comparing the Calypso Knee System (rebranded for this De Novo request) to the cohort of subjects treated with High Tibial Osteotomy (HTO) from a non-randomized trial ("GOAL" study-historical data from the Atlas IDE study). The Calypso Clinical Study was submitted to demonstrate the system's safety and effectiveness. Propensity Score (PS) methodology was employed to account for potential selection bias in the non-randomized comparison of the two groups and resulting in a PS Analysis set of 81 Calypso subjects and 81 Control (HTO) subjects in data through 24 months post-treatment. Clinical and radiographic follow-up visits occurred at 6 weeks, 3, 6, 12, 18 (N/A for HTO), and 24 months post-treatment. The Control (HTO) group completed follow-up visit at 24-months and the Calypso Knee group will continue to be followed through 5 years post-treatment.

### Subject Demographics

The study population included male or female subjects aged 25 to 65 years for the Calypso Knee group and 25 to 80 years for the Control (HTO) group, with a diagnosis of medial knee osteoarthritis and knee pain with an overall Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score ≥ 40 (scale 0-100), who have failed to improve after at least six months of conservative medical treatment.

A total of eighty-one (81) Calypso subjects and ninety-two (92) Control (HTO) subjects were enrolled. After PS matching, eight-one (81) Control (HTO) subjects were included in the study analysis. Table 6 presents a summary of the baseline characteristics for the Calypso Knee group and Control (HTO) group:

| Measure | Calypso | Control<br>(HTO) |
|-----------------------------------------------------------|------------------|------------------|
| N | 81 | 81 |
| Age, years | $51.2 \pm 7.71$ | $52.5 \pm 7.58$ |
| BMI, kg/m² | $28.4 \pm 3.44$ | $29.3 \pm 4.36$ |
| Duration (months) of OA<br>symptoms | $52.8 \pm 54.33$ | $35.3 \pm 50.69$ |
| KL Grade | $2.5 \pm 0.88$ | $2.8 \pm 0.98$ |
| WOMAC Pain | $60.4 \pm 12.37$ | $52.9 \pm 13.10$ |
| WOMAC Function | $59.9 \pm 15.93$ | $48.4 \pm 13.78$ |
| Debridement | 14.8% | 13.6% |
| Microfracture | 7.41% | 11.1% |
| Sex = Male % | 60.49% | 65.43% |
| Failed non-operative treatment<br>at/before Month 6 = Yes | 100% | 100% |
| Tourniquet Used | 82.7% | 75.3% |
| White | 98.8% | 100% |
| Non-Hispanic | 96.3% | 98% |

Table 6: Patient Baseline Characteristics

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The age and BMI of the Calypso Knee group and Control (HTO) group are similar. The percentage of male subjects for the Calypso Knee group was about 5% lower compared to the Control (HTO) group and on average the Calypso Knee group had OA symptoms for 17.5 months longer compared to the Control (HTO) group. Despite the difference of the duration of osteoarthritis (OA) symptoms, the Kellgren and Lawrence (KL) Grade was similar for both groups. The baseline characteristics for the Calypso Knee and Control (HTO) group are comparable.

## Primary Endpoint

The primary endpoint is a Composite Clinical Success (CCS) demonstrating noninferiority of the Calypso Knee System to HTO data from the GOAL study at 24 months post-treatment. A subject is considered a success at 24 months if all of the following components were met at 24 months:

- . Clinically significant improvement of at least 20% from baseline on the WOMAC pain questions in the Knee Injury and Osteoarthritis Outcome Score (KOOS) Knee questionnaire with a change of ≥ 10 points
- . Clinically significant improvement of at least 20% from baseline on the WOMAC function questions in the KOOS Knee questionnaire with a change of ≥ 10 points
- . Freedom from the following device-related serious adverse events. or "Safety Endpoint Event" (SEE):
- · Deep infection requiring surgical intervention (Both arms)
- Damage to adjacent neurovascular or ligament structures necessitating o reconstruction (Both arms)
- o Non-union (HTO only)
- Maintenance of implant integrity as evaluated by radiographic assessment .

In addition to the four components, the protocol noted that a subject would also be a failure if a conversion to arthroplasty occurs through 24-months.

The sponsor conducted analysis of the primary endpoint with multiple imputation based on average treatment effect in the treated (ATT) for Month 24 clinical composite score. Using multiple imputation to account for missing data, the success rate was 83.5% for the Calvpso Knee group and 57.2% for the Control (HTO) group. Study success is based on a priori selected non-inferiority margin (δ) of -0.10. The success rate of the Calypso Knee group led the Control (HTO) group by 26.3% and the primary endpoint at 24 months was achieved in this study. Results are presented in Table 7 for all study subjects.

| | Calypso | | | Control | | |
|-------------------------------------------------|---------|----|--------|---------|----|--------|
| Outcome | N | n | % | N | n | % |
| Enrolled | 81 | 81 | 100.0% | 81 | 81 | 100.0% |
| No Endpoint Subsequent Surgical<br>Intervention | 81 | 80 | 98.8% | 81 | 80 | 98.8% |

| Table 7: Primary Endpoint Success at Month 24 Post-Treatment | | | |
|--------------------------------------------------------------|--|--|--|
| | | | |

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| | Calypso | | | Control | | |
|---------------------------------------|---------|------|-------|---------|------|-------|
| Outcome | N | n | % | N | n | % |
| WOMAC Pain endpoint responder | 72 | 69 | 95.8% | 58 | 51 | 87.9% |
| WOMAC Function endpoint<br>responder | 72 | 66 | 91.7% | 64 | 52 | 81.3% |
| No Safety Endpoint Event (CEC) | 81 | 77 | 95.1% | 81 | 76 | 93.8% |
| No Endpoint Implant Integrity Failure | 81 | 80 | 98.8% | 81 | 80 | 98.8% |
| Crude Observed | 74 | 62 | 83.8% | 63 | 41 | 65.1% |
| Completers | 74 | 62 | 83.8% | 63 | 34.3 | 54.4% |
| Multiple Imputation (MI) | 81 | 67.6 | 83.5% | 81 | 46.4 | 57.2% |

A tipping point analysis was conducted to analyze the sensitivity of missing data. Compared to the multiple imputation model, the tipping analysis does not require the same statistical assumptions as it analyzes every possible combination of the missing data. The results from the tipping analysis indicate that the non-inferiority study conclusion is robust and not impacted by the missing data.

## Secondary Endpoints

The sponsor assessed the following five secondary endpoints to evaluate the superiority of the Calypso Knee System to the Control (HTO):

- . Time to full weight bearing
- Percent change from baseline to 3-months on the WOMAC pain in the KOOS . Knee Survey
- Percent change from baseline to 3-months on the WOMAC function in the KOOS . Knee Survey
- Percent change from baseline to 24-months on the WOMAC pain in the KOOS . Knee Survey
- Percent change from baseline to 24-months on the WOMAC function in the . KOOS Knee Survey

| Outcome | N | Calypso | | N | Control | |
|------------------------------------------------------|----|---------|-------|----|---------|-------|
| | | Mean | SD | | Mean | SD |
| Time (days) to Full Weight Bearing | 81 | 13.4 | 10.12 | 77 | 58.0 | 39.91 |
| WOMAC Pain % Change from<br>Baseline at Month 3 | 81 | -55.5% | 29.3% | 72 | -33.4% | 35.8% |
| WOMAC Pain % Change from<br>Baseline at Month 24 | 72 | -76.0% | 28.2% | 58 | -72.5% | 33.0% |
| WOMAC Function % Change from<br>Baseline at Month 3 | 81 | -52.2% | 32.0% | 75 | -24.3% | 37.0% |
| WOMAC Function % Change from<br>Baseline at Month 24 | 72 | -73.9% | 29.6% | 64 | -67.1% | 35.8% |

The results for the secondary endpoint are outlined in Table 8 below:

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The results from the study supported superiority of the Calypso Knee group compared to the Control (HTO) group in four of the five secondary endpoints. The one endpoint that the data did not support superiority for the Calypso Knee group was the WOMAC Pain % change from Baseline at Month 24.

## Safety Analysis

There were no Unanticipated Adverse Device Effects as determined by the independent medical monitor for both the Calypso Knee group and Control (HTO) group. All deviceand procedure-related serious adverse events (SAEs) were considered expected complications. There were 11 removals (11/81. 13.58%) and 3 reoperations (3/81, 3.70%) for the Calypso Knee group and 61 removals (61/81, 75.31%), 1 revision (1/81, 1.23%), and 7 reoperations (7/81, 8.64%) for the Control (HTO) group. Note that the HTO plate can be electively removed after completing bone consolidation.

SAEs for the Calypso Knee group included 4 deep incisional surgical site infection (4/81, 4.94%) and 4 due to pain (4/81, 4.94%). Additional SAEs include nerve injury to a nerve resulting in motor or sensory symptoms, scar formation, discomfort, and cellulitis.

## Pediatric Extrapolation

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

# LABELING

The labeling consists of the following: device description, indications for use, instructions for use including surgical steps (e.g., device selection and placement), principles of device operation, identification of device materials, contraindications, warnings, precautions, a list of potential adverse effects, and summary of the clinical data. Furthermore, the sterile packaging includes a shelf-life for the device. The labeling meets the requirements of 21 CFR 801.109 for prescription devices.

# TRAINING

The surgical technique program consisted of slides that walk the surgeon through each step of the procedure to implant the MISHATM Knee System. The surgical technique training also provides insight on proper patient selection, surgical procedures, selection of appropriate implant size, instrumentation for implantation, indications for use of the device, contraindications, warnings, and precautions. A trained representative may be present to support surgical procedures.

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# RISKS TO HEALTH

The table below identifies the risks to health that may be associated with use of the medial knee implanted shock absorber and the measures necessary to mitigate these risks.

| Risks to Health | Mitigation Measures |
|---------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------|
| Implant failure to improve<br>osteoarthritis symptoms, including<br>pain and discomfort | Clinical data<br>Non-clinical performance testing<br>Training |
| Pain and discomfort due to implant | Clinical data<br>Training |
| Loss of implant integrity leading to<br>loss of fixation and reoperation | Clinical data<br>Non-clinical performance testing |
| Ligament or nerve injury resulting in<br>motor and/or sensory damage | Clinical data<br>Training |
| Scar formation | Clinical data<br>Training |
| Infection | Sterilization validation<br>Reprocessing validation<br>Shelf-life testing<br>Pyrogenicity testing<br>Labeling |
| Adverse tissue reaction due to<br>Device materials Fretting and corrosion Wear particulates | Biocompatibility evaluation<br>Non-clinical performance testing |

## SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the medial knee implanted shock absorber is subject to the following special controls:

- Clinical data must demonstrate that the device performs as intended under anticipated (1) conditions of use and include the following:
- Evaluation of improvement of knee function and reduction of osteoarthritis (i) symptoms, including pain and function; and
- (ii) Evaluation of relevant adverse events.
- (2) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use and include the following:
- (i) Evaluation of the mechanical function and durability of the implant (including evaluation of absorber unloading capacity, fretting and corrosion, static strength, wear analysis, and fatigue testing); and
- (ii) Evaluation of worst-case device range of motion.

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- (3) The patient-contacting components of the device must be demonstrated to be biocompatible.
- Performance data must support the sterility and pyrogenicity of the device components (4) intended to be sterile.
- (5) Performance data must validate the reprocessing instructions for the reusable components of the device.
- (6) Performance data must support the shelf life of the device by demonstrating continued sterility, package integrity, and device functionality over the identified shelf-life.
- (7) A training program must be included so that upon completion of the training program, the user can safely and successfully implant the device.
- (8) Labeling must include the following:
- Validated methods and instructions for reprocessing of any reusable components; (i) and
- (ii) A shelf-life.

# BENEFIT-RISK DETERMINATION

## BENEFITS:

- 1) The clinical study demonstrates the MISHATM Knee System leads to clinically meaningful improvements in knee function and symptoms (e.g., reduction in pain) that are maintained over time to at least 24 months;
- 2) Performance has been demonstrated to be non-inferior to High Tibial Osteotomy (HTO);
- 3) The MISHATM Knee System secondary endpoint results (Return to Full Wait Bearing, Improved WOMAC Pain and Function Scores from baseline at 3 months, Improved WOMAC Function Scores from baseline at 24 months) support clinically meaningful, patient-valued benefits at a magnitude similar to, or numerically greater than, those observed with the Control HTO:
- 4) The MISHATM Knee System does not require any bone cutting and maintains the natural joint surface compared to the Control HTO;
- 5) Preserves the knee joint for future surgeries compared to the Control HTO.

# RISKS:

- 1) Adverse events of the index knee including pain, discomfort, unanticipated adverse device effects, subsequent surgical interventions, loosening and migration, and revision, including revision due to device wear, screw back out, or device failure;
- 2) Adverse tissue reactions due to device materials, fretting and corrosion, and wear particulates:
- 3) Infection:
- 4) Loss of implant integrity;
- 5) Ligament or nerve injury.

Based on the totality of the evidence, the MISHATM Knee System demonstrated a reasonable assurance of safety and effectiveness for the device for its intended use/indications for use. While there is a low degree of uncertainty in this finding due to the missing data from the control group in the clinical study and removal rate for the MISHA™ Knee System, the risks are not greater than HTO. To address the concerns of the longer-term safety and benefits of the MISHATM Knee System, the sponsor will be conducting a five (5) year 522 Postmarket

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Surveillance Study. In addition, the MISHA™ Knee System demonstrated improvement on the WOMAC pain and function scores over the course of the clinical study. In conclusion, the benefits of using the MISHATM Knee System for its intended use/indications for use outweigh the probable risks to health.

## Patient Perspectives

Patient perspectives considered for the Misha Knee System during the review include:

- WOMAC Pain and Function Scores .
- KSS Satisfaction Scores .

### Benefit/Risk Conclusion

In conclusion, given the available information above, for the following indication statement:

"The MISHA™ Knee System is indicated for patients with medial compartment knee osteoarthritis that have failed to find relief in surgical and/or non-surgical treatment modalities and are still experiencing pain that interferes with activities of daily living and are also unwilling to undergo or ineligible for total knee replacement due to age or absence of advanced osteoarthritis."

The probable benefits outweigh the probable risks for the MISHATM Knee System. The device provides benefits, and the risks can be mitigated by the general controls and the identified special controls.

## CONCLUSION

The De Novo request for the MISHATM Knee System is granted and the device is classified as follows:

Product Code: OVV Device Type: Medial knee implanted shock absorber Regulation Number: 21 CFR 888.3610 Class: II