← Product Code [MJO](/productcode/MJO) · P200022S003

# Simplify Cervical Artificial Disc (P200022S003)

_Nuvasive, Inc. · MJO · Apr 1, 2021 · Orthopedic · APPR_

**Canonical URL:** https://fda-staging.innolitics.com/device/P200022S003

## Device Facts

- **Applicant:** Nuvasive, Inc.
- **Product Code:** [MJO](/productcode/MJO.md)
- **Decision Date:** Apr 1, 2021
- **Decision:** APPR
- **Device Class:** Class 3
- **Review Panel:** Orthopedic
- **Attributes:** Therapeutic

## Indications for Use

Simplify® Cervical Artificial Disc is indicated for use in skeletally mature patients for reconstruction of the disc at one or two contiguous levels from C3-C7 following discectomy for intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain, or myelopathy due to abnormality localized to the disc space and manifested by at least one of the following conditions confirmed by radiographic imaging (e.g., X-rays, computed tomography (CT), magnetic resonance imaging (MRI): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. Patients receiving Simplify® Cervical Artificial Disc should have failed at least six weeks of non-operative treatment or demonstrated progressive signs or symptoms despite non-operative treatment prior to implantation. Simplify® Cervical Artificial Disc is implanted via an open anterior approach.

## Device Story

Cervical artificial intervertebral disc; inserted via open anterior approach; replaces degenerated native disc at one or two contiguous levels (C3-C7). Composed of PEEK endplates with plasma-sprayed titanium coating and mobile ZTA ceramic core. Provides ±12° flexion-extension/lateral bending, unlimited axial rotation, and 1-2 mm translation. Used by surgeons to restore biomechanical function; preserve motion; potentially reduce adjacent segment degeneration. Output is mechanical stabilization of disc space; patient benefits include pain reduction and functional improvement.

## Clinical Evidence

Prospective, non-randomized, multi-center study (IDE #G150206) with historical ACDF control. Primary analysis set: 182 Simplify subjects, 170 PS-matched historical ACDF controls. Primary endpoint: 24-month composite clinical success (NDI improvement ≥15, neurological maintenance/improvement, no implant-associated SAEs, no index-level failure). Results: Simplify superior to ACDF (86.7% vs 77.1% success; 1-sided 95% CI lower bound 0.6%). Secondary endpoints (NDI, pain, SF-36) showed favorable outcomes for Simplify.

## Technological Characteristics

Materials: PEEK endplates, ZTA ceramic core, plasma-sprayed titanium coating (ISO 5832-2, ASTM F1580). Dimensions: 3 footprints, 3 heights (4-6mm), 2 lordosis angles (0°, 5°). Energy source: None (mechanical). Sterilization: ISO 11137. Connectivity: None. MR Conditional (1.5T/3.0T).

## Submission Summary (Full Text)

> This content was OCRed from public FDA records by [Innolitics](https://innolitics.com). If you use, quote, summarize, crawl, or train on this content, cite Innolitics at https://innolitics.com.
>
> Innolitics is a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices, including [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/).

{0}

# SUMMARY OF SAFETY AND EFFECTIVENESS DATA (SSED)

## I. GENERAL INFORMATION

|  Device Generic Name: | Prosthesis, Intervertebral Disc  |
| --- | --- |
|  Device Trade Name: | Simplify® Cervical Artificial Disc  |
|  Device Product Code: | MJO  |
|  Applicant's Name/Address: | Simplify Medical, Inc. 685 North Pastoria Avenue Sunnyvale, CA 94085  |
|  Date of Panel Recommendation: | None  |
|  Premarket Approval Application: (PMA Number) | P200022/S003  |
|  Date of FDA Notice of Approval: | April 1, 2021  |

The original PMA (P200022) was approved on September 18, 2020 and is indicated for use in skeletally mature patients for reconstruction of the disc at one level from C3-C7 following single-level discectomy for intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain, or myelopathy due to a single-level abnormality localized to the level of the disc space and manifested by at least one of the following conditions confirmed by radiographic imaging (e.g., X-rays, computed tomography (CT), magnetic resonance imaging (MRI)): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. Patients receiving Simplify® Cervical Artificial Disc should have failed at least six weeks of non-operative treatment or have the presence of progressive symptoms (e.g., numbness or tingling) prior to implantation. Simplify® Cervical Artificial Disc is implanted via an open anterior approach.

The SSED to support the previously approved one level indication is available on the CDRH website (https://www.accessdata.fda.gov/cdrh_docs/pdf20/P200022B.pdf) and is incorporated by reference here. The current supplement was submitted to expand and modify the indications for use of the Simplify® Cervical Artificial Disc to include use of the device at two (2) contiguous levels.

## II. INDICATIONS FOR USE

Simplify® Cervical Artificial Disc is indicated for use in skeletally mature patients for reconstruction of the disc at one or two contiguous levels from C3-C7 following discectomy for intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain, or myelopathy due to abnormality localized to the disc space and manifested by at least one of the following conditions confirmed by radiographic imaging (e.g., X-rays, computed tomography

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 1 of 88

{1}

(CT), magnetic resonance imaging (MRI): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. Patients receiving Simplify® Cervical Artificial Disc should have failed at least six weeks of non-operative treatment or demonstrated progressive signs or symptoms despite non-operative treatment prior to implantation. Simplify® Cervical Artificial Disc is implanted via an open anterior approach.

### III. CONTRAINDICATIONS

Simplify® Cervical Artificial Disc should not be implanted in patients with the following conditions:

- An active systemic infection or an infection at the operative site.
- Osteoporosis or osteopenia defined as DEXA bone mineral density T-score less than -1.5.
- Known allergy to the implant materials (PEEK, ceramic, titanium).
- Severe facet disease or facet degeneration.
- Bridging osteophytes.
- Marked cervical instability on neutral lateral or flexion/extension radiographs (e.g., radiographic signs of subluxation > 3.0mm or angulation of the disc space more than 11° greater than adjacent segments).
- Significant cervical anatomical deformity at the index levels or clinically compromised cervical vertebral bodies at the index levels due to current or past trauma (e.g., by radiographic appearance of fracture callus, malunion, or nonunion) or disease (e.g., ankylosing spondylitis, rheumatoid arthritis).

### IV. WARNINGS AND PRECAUTIONS

The warnings and precautions can be found in the Simplify® Cervical Artificial Disc Instructions for Use.

### V. DEVICE DESCRIPTION

The Simplify® Cervical Artificial Disc is a cervical artificial intervertebral device that is inserted into the intervertebral disc space at one or two contiguous cervical levels using an anterior approach. It is manufactured from polyetheretherketone (PEEK) endplates and a mobile, zirconia-toughened alumina (ZTA) ceramic core. The PEEK endplates have a plasma-sprayed titanium coating per ISO 5832-2 and ASTM F1580. The articulating surfaces on the endplates have a concave surface

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 2 of 88

{2}

and the core has two convex surfaces. The device is pictured in the figure below (Figure 1 and Figure 2).

![img-0.jpeg](img-0.jpeg)

![img-1.jpeg](img-1.jpeg)

Figure 1: Schematic of Simplify® Cervical Artificial Disc: assembly (left) and mid-sagittal section (right).

For the Simplify® Cervical Artificial Disc family, two core options (i.e., either small or large) are used for all assemblies. The articulating features of superior and inferior endplates are identical and congruent with the appropriate core. Superior and inferior endplates are available in three footprints (Small, Medium, Large), three thicknesses resulting in three device heights (4 mm, 5 mm, 6 mm), and two lordosis angles (0° and 5°), as shown in Figure 3 and Table 1 below. The superior endplates have a retention ring feature. All endplates are titanium coated on the bone interfacing surfaces, with two options available for coating thickness (80 μm or 160 μm). All endplate components, regardless of configuration, have identical manufacturing process flow, including packaging and sterilization.

The Simplify® Cervical Artificial Disc is designed to provide a theoretical maximum of ± 12° in any combination of flexion-extension and lateral bending, unlimited axial rotation, and 1-2 mm translation. These ranges of motion are intended to permit the patient's anatomy to determine actual range of motion without imposing an artificial limit that may be restrictive to the patient's kinematic profile. The maximum range of motion in vivo will be dictated by the patient's anatomical boundaries or the device limits, whichever is smaller.

![img-2.jpeg](img-2.jpeg)

Figure 2: Exploded Schematic of the Simplify® Cervical Artificial Disc

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 3 of 88

{3}

![img-3.jpeg](img-3.jpeg)

5" LORDOTIC DISC AVAILABLE

Figure 3: Simplify® Cervical Artificial Disc Heights and Sizes

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 4 of 88

{4}

**Table 1: Simplify® Cervical Artificial Disc Part Listing and Size Overview**

|  Disc Sizes | Catalog Number | A/P Width (mm) | Lateral Width (mm) | Height (mm) | Lordosis (°)  |
| --- | --- | --- | --- | --- | --- |
|  **80 Micron Coating**  |   |   |   |   |   |
|  Simplify® Cervical Artificial Disc Size SM, Height 4 | SM-4-T | 12 | 15 | 4 | 0  |
|  Simplify® Cervical Artificial Disc Size SM, Height 4, 5° Lordosis | SM-4L-T | 12 | 15 | 4 | 5  |
|  Simplify® Cervical Artificial Size SM, Height 5 | SM-5-T | 12 | 15 | 5 | 0  |
|  Simplify® Cervical Artificial Disc Size SM, Height 5, 5° Lordosis | SM-5L-T | 12 | 15 | 5 | 5  |
|  Simplify® Cervical Artificial Size SM, Height 6 | SM-6-T | 12 | 15 | 6 | 0  |
|  Simplify® Cervical Artificial Size MD, Height 4 | MD-4-T | 14 | 16 | 4 | 0  |
|  Simplify® Cervical Artificial Size MD, Height 5 | MD-5-T | 14 | 16 | 5 | 0  |
|  Simplify® Cervical Artificial Disc Size MD, Height 5, 5° Lordosis | MD-5L-T | 14 | 16 | 5 | 5  |
|  Simplify® Cervical Artificial Size MD, Height 6 | MD-6-T | 14 | 16 | 6 | 0  |
|  Simplify® Cervical Artificial Disc Size MD, Height 6, 5° Lordosis | MD-6L-T | 14 | 16 | 6 | 5  |
|  Simplify® Cervical Artificial Size LG, Height 5 | LG-5-T | 16 | 18 | 5 | 0  |
|  Simplify® Cervical Artificial Disc Size LG, Height 5, 5° Lordosis | LG-5L-T | 16 | 18 | 5 | 5  |
|  Simplify® Cervical Artificial Disc Size LG, Height 6 | LG-6-T | 16 | 18 | 6 | 0  |
|  Simplify® Cervical Artificial Disc Size LG, Height 6, 5° Lordosis | LG-6L-T | 16 | 18 | 6 | 5  |
|  **160 Micron Coating**  |   |   |   |   |   |
|  Simplify® Cervical Artificial Disc Size SM, Height 4 | SM-4 | 12 | 15 | 4 | 0  |
|  Simplify® Cervical Artificial Disc Size SM, Height 4, 5° Lordosis | SM-4L | 12 | 15 | 4 | 5  |
|  Simplify® Cervical Artificial Disc Size SM, Height 5 | SM-5 | 12 | 15 | 5 | 0  |
|  Simplify® Cervical Artificial Disc Size SM, Height 5, 5° Lordosis | SM-5L | 12 | 15 | 5 | 5  |
|  Simplify® Cervical Artificial Disc Size SM, Height 6 | SM-6 | 12 | 15 | 6 | 0  |
|  Simplify® Cervical Artificial Disc Size MD, Height 4 | MD-4 | 14 | 16 | 4 | 0  |
|  Simplify® Cervical Artificial Disc Size MD, Height 5 | MD-5 | 14 | 16 | 5 | 0  |
|  Simplify® Cervical Artificial Disc Size MD, Height 5, 5° Lordosis | MD-5L | 14 | 16 | 5 | 5  |
|  Simplify® Cervical Artificial Disc Size MD, Height 6 | MD-6 | 14 | 16 | 6 | 0  |
|  Simplify® Cervical Artificial Disc Size MD, Height 6, 5° Lordosis | MD-6L | 14 | 16 | 6 | 5  |
|  Simplify® Cervical Artificial Disc Size LG, Height 5 | LG-5 | 16 | 18 | 5 | 0  |
|  Simplify® Cervical Artificial Disc Size LG, Height 5, 5° Lordosis | LG-5L | 16 | 18 | 5 | 5  |
|  Simplify® Cervical Artificial Disc Size LG, Height 6 | LG-6 | 16 | 18 | 6 | 0  |
|  Simplify® Cervical Artificial Disc Size LG, Height 6, 5° Lordosis | LG-6L | 16 | 18 | 6 | 5  |

## **VI. ALTERNATIVE PRACTICES AND PROCEDURES**

There are several other alternatives for the treatment of symptomatic degeneration of the cervical spine at one or two contiguous levels presenting with arm pain and/or neurological deficit

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 5 of 88

{5}

(intractable radiculopathy), with or without neck pain or myelopathy and radiographic abnormality.

- Nonoperative alternative treatments, which include, but are not limited to, physical therapy, medications, braces, chiropractic care, bed rest, spinal injections, or exercise programs.
- Surgical alternatives, which include, but are not limited to:
  - Surgical decompression alone
  - Surgical decompression using intervertebral cages or bone grafting techniques, with or without supplemental anterior plating
  - Decompression and stabilization with posterior spinal systems (e.g., rods, screws, hooks, wires)
  - Another FDA-approved artificial cervical disc

Each option has advantages and disadvantages. Patients should fully discuss the available alternatives with his or her physician to select the option that best meets their clinical condition, lifestyle and expectations.

## VII. MARKETING HISTORY

The Simplify® Cervical Artificial Disc has been marketed outside of the United States since 2016. The Simplify® Cervical Artificial Disc is currently distributed in the United Kingdom and Germany. The Simplify® Cervical Artificial Disc has been marketed in the US for 1-Level indications since December 2020. The Simplify® Cervical Artificial Disc has not been withdrawn from any distribution/ marketing in any country for safety or effectiveness reasons.

## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH

Below is a list of the potential adverse effects (e.g., complications) identified from the Simplify® Cervical Artificial Disc clinical study results, approved device labeling for other cervical total disc replacement devices, and published scientific literature including: (1) those associated with any general surgical procedure; (2) those associated with anterior cervical spine surgery; and (3) those associated with a cervical artificial disc device, including the Simplify® Cervical Artificial Disc. In addition to the risks listed below, there is also the risk that surgery may not be effective in relieving symptoms or may cause worsening of symptoms. Additional surgery may be required to correct some of the adverse effects.

### General Surgery Risks

General surgical risks are, but may not be limited to:

- Infection/abscess/cyst, localized or systemic
- Blood clots, including pulmonary emboli
- Medication and anesthesia reactions
- Phlebitis
- Pneumonia
- Atelectasis
- Soft tissue damage
- Septicemia
- Hemorrhage possibly requiring a blood transfusion, with possible transfusion reaction

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 6 of 88

{6}

- Myocardial infarction
- Paralysis
- Poor tissue healing
- Cerebrovascular accident (CVA)
- Death

# Anterior Cervical Surgery Risks

Anterior cervical surgical risks are, but may not be limited to:

- Infection/abscess/cyst, localized or systemic
- Injury or damage to the trachea, esophagus, nerves or blood vessels
- Dysphagia
- Hoarseness
- Vocal cord paralysis
- Paresis
- Recurrent laryngeal nerve palsy
- Soft tissue damage
- Spinal cord damage
- Dural tear with cerebrospinal fluid leakage
- Arm weakness or numbness
- Bowel, bladder or sexual dysfunction
- Nerve root injury
- Airway obstruction
- Epidural hematoma or bleeding
- Epidural fibrosis
- Vertebral body fracture
- Dysesthesia or numbness
- Paresthesia
- Unresolved pain
- Surgical intervention at incorrect level
- Need for supplemental fixation
- Spinal instability
- Death

# Cervical Artificial Disc Risks

Risks specific to cervical artificial discs, including the Simplify® Cervical Artificial Disc, are but may not be limited to:

- Infection/abscess/cyst, localized or systemic
- Allergic reaction to the implant materials
- Implant failure
- Device migration
- Device subsidence
- Device fatigue or fracture or breakage
- Device instability
- Separation of device components
- Placement difficulties, device malposition

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 7 of 88

{7}

- Improper device sizing
- Excessive device height loss
- Wear debris
- Disc space collapse
- Material degradation
- Excessive facet loading
- Kyphosis or hyper-extension
- Loss of flexibility
- Asymmetric range of motion
- Vertebral body fracture
- Spinal cord damage,
- Dural tear with cerebrospinal fluid leakage
- Soft tissue damage
- Epidural fibrosis
- Nerve injury, paralysis or weakness that is temporary or permanent
- Injury or damage to the trachea, esophagus, or blood vessels
- Epidural hematoma or bleeding
- Dysesthesia or numbness
- Paresthesia
- Failure to relieve symptoms including unresolved pain
- Additional surgery due to loss of fixation, infection or injury
- Spontaneous fusion due to heterotopic ossification, development of bridging bone or osteophytes
- Periarticular calcification and fusion
- Development of spinal conditions, including but not limited to spinal stenosis, spondylolisthesis, or retrolisthesis
- Removal, revision, reoperation or supplemental fixation of the disc
- Osteolysis, bone loss, or bone resorption
- Death

For the specific adverse events (AEs) that occurred in the Simplify® Cervical Artificial Disc 2-Level clinical study, please see Section X.

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 8 of 88

{8}

## IX. SUMMARY OF NON-CLINICAL STUDIES

A variety of testing was conducted to characterize the performance of the Simplify® Cervical Artificial Disc, as follows:

# Laboratory Studies

- Static Axial Compression
- Dynamic Axial Compression
- Static Compression Shear
- Dynamic Compression Shear
- Static Peripheral Supported Compression
- Dynamic Peripheral Supported Compression
- Subluxation/ Expulsion
- Subsidence
- Wear (Mode 1 Wear)
- Third Body Wear (Mode 3 Wear)
- Impingement (Mode 4 Wear)
- Range of Motion
- Coating Testing

# Additional Studies

- MR Compatibility
- Biocompatibility/ Pyrogenicity /Neurotoxicity
- Device Sterilization
- Shelf Life and Transit Validation

### A. Laboratory Studies

In support of the two-level indications, an additional Two-Level Kinematic Modeling Study was conducted to characterize the range of motion of the Simplify® Cervical Artificial Disc at two contiguous levels. A summary of the conducted testing is presented in the following table (Table 2).

Table 2: Non-Clinical Study Summary

|  Test Name | Purpose | Test Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|  **Static and Dynamic Strength**  |   |   |   |   |
|  **Static and Fatigue under Axial Compression** | Verify static and fatigue performance under simulated physiologic conditions are sufficient to withstand in vivo compressive loads | Six (6) Simplify® Cervical Artificial Disc specimens were tested under static compression in 37°C deionized water at a rate of 25mm/min until failure or ≈10 kN (capacity of load cell) was reached. | Must withstand ≥ 300 N static load without functional failure | Static strength: ≥10 kN Static stiffness: 2317 N/mm (for information only)  |
|   |   |  Three (3) Simplify® Cervical Artificial Disc | Fatigue load (10 x 10⁶ cycles runout) ≥ 150 N | Dynamic strength: Runout Load of 375N Change in disc height: 0.24mm  |

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 9

{9}

|  Test Name | Purpose | Test Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|   |  | specimens were tested under dynamic compression in 37°C 0.9% saline to 10 x 10⁶ cycles, using a sinusoidal wave form with R=10 at 2 Hz. Testing per ASTM F2346 | Average residual height loss after runout ≤1.5mm | All acceptance criteria were met.  |
|  Static and Fatigue Shear Strength | Verify that the static and fatigue performance are sufficient to withstand anticipated in vivo shear compressive loads | Six (6) Simplify® Cervical Artificial Disc specimens were tested under static compression-shear (27°) in 37°C deionized water at a rate of 25mm/min until failure. Three (3) Simplify® Cervical Artificial Disc specimens were tested under dynamic compression-shear in 37°C 0.9% saline to 10 x 10⁶ cycles, using a sinusoidal wave form with R=10 at 2 Hz. Testing per ASTM F2346 | Must withstand ≥ 20 N static shear without functional failure Fatigue load (10 x10⁶ cycles runout) ≥ 20 N | Static compressive shear strength: 284 N Dynamic compressive shear strength: Runout Load of 123 N All acceptance criteria were met.  |
|  Endplate Strength under Peripheral Support | Characterize the strength of the Simplify® Cervical Artificial Disc under the special case of a peripherally supported endplate | Five (5) Simplify® Cervical Artificial Disc specimens were tested under static compression in 37°C deionized water at a rate of 25mm/min until failure. Custom fixturing left the central 14 mm diameter region unsupported. Seven (7) Simplify® Cervical Artificial Disc specimens were tested under dynamic compression in 37°C 0.9% saline at various loads using a sinusoidal wave form with R=10 at 2 Hz. Runout was considered 2 x 10⁶ cycles, Testing was based on ASTM F2346 | N/A (for characterization purposes) | Ultimate static strength was 1253 N. Linear regression analysis of dynamic tests indicates runout load of ≈388 N. Results compare favorably to static strength requirements.  |
|  **Subluxation/ Expulsion**  |   |   |   |   |
|  Subluxation/ Expulsion | Verify ability of Simplify® Cervical Artificial Disc to resist expulsion | Simplify® Cervical Artificial Discs implanted in Grade 15 polyurethane foam with 100N static axial | Force ≥ 20 N required to cause subluxation or | Resistance to expulsion at 0°: 223 N; at 12°: 193N.  |

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 10

{10}

|  Test Name | Purpose | Test Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|   | and subluxation using simulated physiologic conditions | preload were subjected to 6 mm/min anterior shear. Load was applied to both endplates (expulsion) or one endplate (subluxation) with endplate parallel or in 12° extension. Twenty test specimens, five (5) per test configuration, were tested. | expulsion (defined as movement ≥3 mm) | Resistance to subluxation at 0°: 117N; at 12°: 154 N All acceptance criteria were met.  |
|  **Subsidence**  |   |   |   |   |
|  **Subsidence** | Verify the ability of the Simplify® Cervical Artificial Disc to resist subsidence using simulated physiologic conditions | Five (5) Simplify® Cervical Artificial Disc specimens were compressed between Grade 15 polyurethane foam blocks at a rate 0.1 mm/sec per ASTM F2267. | Subsidence force ≥ 300 N | Subsidence force: 768.0 N. Acceptance criterion was met.  |
|  **Wear**  |   |   |   |   |
|  **Device Wear, Mode I** | Characterize *in vitro* wear properties | Six (6) Simplify® Cervical Artificial Disc test specimens were subjected to 10 x 10⁶ cycles of combined 50-150 N axial load, ±7.5° flexion/extension, ±6° axial rotation, and ±6° lateral bending at 1 Hz per ISO 18192-1 and ASTM F2423 while submerged in bovine serum solution with a protein concentration of 5 g/L. Two (2) test specimens served as load soak controls. | Wear rate ≤ 7 mg/MC (70 mg total) No fracture, functional failure or impingement | Cumulative mass loss: 9.0 mg Average gravimetric wear rate: 0.9 mg/MC (Average volumetric wear rate: 0.7 mm³/MC). No devices demonstrated signs of fracture, functional failure, or impingement. All acceptance criteria were met.  |
|  **Wear, Mode III (Third Body)** | To characterize in vivo wear properties under third-body abrasive wear conditions (Mode III) | A titanium scar was created on both articulating surfaces of the core in Simplify® Cervical Artificial Disc test specimens. Six (6) specimens were then subjected to 5 x 10⁶ cycles of combined 50-150 N axial load, ±7.5° flexion/extension, ±6° axial rotation, and ±6° lateral bending at 1 Hz per ISO 18192-1 and ASTM F2423 while submerged in bovine serum solution with a protein concentration of 5 g/L. Two (2) test specimens | N/A (for characterization purposes) | Average mass wear rate: 2.8 mg/MC No devices demonstrated signs of fracture or functional failure.  |

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 11

{11}

|  Test Name | Purpose | Test Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|   |  | served as load soak controls. |  |   |
|  Wear, Mode IV (Impingement) | Characterize the impingement properties using simulated physiologic conditions (Mode IV wear) | Six (6) Simplify® Cervical Artificial Disc test specimens, three (3) SM and three (3) LG, were subjected to 1 x 10⁶ cycles of combined 150 N axial load, 17-18° extension, and ±6° axial rotation at 1 Hz per ASTM F3295 while submerged in bovine serum solution with a protein concentration of 5 g/L. Two (2) test specimens, oner per size, served as load soak controls. | N/A (for characterization purposes) | Gravimetric wear rates: Size SM: 1.0 mg/MC Size LG: 1.9 mg/MC No devices demonstrated signs of fracture or functional failure.  |
|  **Range of Motion**  |   |   |   |   |
|  Range of Motion | Characterize range of motion of Simplify® Cervical Artificial Disc using finite element techniques. | Finite Element (FE) methods compared range of motion for an intact spine and the same spine with a Simplify® Cervical Artificial Disc implanted at C5/C6 subjected to 100N axial load and various 1.5 Nm moments (flexion, extension, lateral bending, and axial rotation). | N/A (for characterization purposes) | The range of motion for the Simplify® Cervical Artificial Disc is similar to the intact spine model and generally falls within the range of previously published finite element models and cadaver tests.  |
|  Two-Level Kinematic Modeling | Characterize the range of motion for a spine implanted with Simplify® Cervical Artificial Discs at two contiguous levels using finite element techniques. | Finite Element (FE) methods compared range of motion for an intact spine and the same spine with Simplify® Cervical Artificial Discs implanted at C5/C6 and C6/C7 subjected to 100N axial load and various 1.5 Nm moments (flexion, extension, lateral bending, and axial rotation). | N/A (for characterization purposes) | The range of motion for the spine model with two Simplify® Cervical Artificial Discs generally falls within the range of previously published finite element models and cadaver tests.  |
|  **Coating Testing**  |   |   |   |   |
|  Coating Shear Fatigue | Evaluate coating in shear fatigue testing | Six (6) test specimens were subjected to sinusoidal tensile stress of 10 MPa for 10 x 10⁶ cycles per ASTM F1160 | No failure of the coating | None of the test specimens showed any evidence of coating failure. The acceptance criterion was met.  |
|  Coating Static Shear Strength | Evaluate coating in static shear testing | Twenty (20) test specimens were tested per ASTM F1044 | ≥ 20 MPa | 32.04 MPa. The acceptance criterion was met.  |
|  Coating Static Tensile Strength | Evaluate coating in tensile testing | Twenty (20) test specimens were tested per ASTM F1147 | ≥ 22 MPa | 36.2 MPa. The acceptance criterion was met.  |

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 12

{12}

|  Test Name | Purpose | Test Method | Acceptance Criteria | Results  |
| --- | --- | --- | --- | --- |
|  Coating Abrasion | Coating taber abrasion testing | Six (6) test specimens were tested per ASTM F1978 | ≤ 65 mg mass loss after 100 cycles | 49 mg mass loss. The acceptance criterion was met.  |
|  Coating Characterization | Characterize coating morphology | Coating thickness per ASTM F1854, n=60 | 160 ±20 μm | 156.3 μm. Acceptance criterion was met.  |
|   |   |  Roughness Ra per DIN EN ISO 4288 & DIN EN ISO 4287, n=20 | 20 ±5 μm | 19.4 μm. Acceptance criterion was met.  |
|   |   |  Porosity per ASTM F1854, n=59 | 20-40% | 36.54%. Acceptance criterion was met.  |
|   |   |  Visual appearance, n=59 | Uniform | Uniform. Acceptance criterion was met.  |
|  Coated Endplate Characterization | Demonstrate that titanium coating does not degrade or adversely affect the PEEK substrate | Three (3) coated PEEK endplates were characterized per ASTM F2026 using FTIR (chemical composition), DSC (thermal transitions and crystallinity), and GPC (molecular weight and polydispersity), with results compared to those from the original PEEK bar stock used to manufacture the endplates. The PEEK-coating interface was evaluated with optical microscopy for signs of polymer degradation. | N/A (for characterization purposes only) | Coated endplates showed no discernable physiochemical differences from original bar stock and no visual evidence of degradation.  |

### B. Additional Studies

#### Magnetic Resonance (MR) Imaging

The safety and compatibility of the Simplify® Cervical Artificial Disc in the Magnetic Resonance (MR) environment was evaluated. Specifically, it was tested for magnetic field interactions, heating, and artifacts associated with clinically relevant magnetic resonance imaging.

The magnetic field interaction evaluations consisted of displacement and torque assessments. For the assessment of displacement, an induced displacement force test was performed in accordance with ASTM F2052. The evaluation of magnetic torque was performed in accordance with ASTM F2052. The Simplify® Cervical Artificial Disc was tested for MRI-related heating in accordance with ASTM F2182. MR imaging artifacts were assessed in accordance with ASTM F2119.

The results of the assessments demonstrated that the Simplify® Cervical Artificial Disc is MR Conditional. A patient with the Simplify® Cervical Artificial Disc can be scanned safely in an MR system under the following conditions:

- Static magnetic field of 1.5 Tesla (1.5T) or 3.0 Tesla (3.0T).
- Maximum spatial gradient field less than or equal to 5990 Gauss/cm (59.9 T/m).

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 13

{13}

- Maximum whole-body specific absorption rate (SAR) of 2.0 W/kg for 15 minutes of scanning in Normal Operating Mode.
- Transmit/receive body coil.

Under the scan conditions defined, the Simplify® Cervical Artificial Disc is expected to produce a maximum temperature rise of less than 3.0°C after 15 minutes of continuous scanning.

In non-clinical testing per ASTM F2119, the image artifact caused by the Simplify® Cervical Artificial Disc extends approximately 5-mm at 1.5T and 8 mm at 3.0T from Simplify® Cervical Artificial Disc when imaged using a gradient echo pulse sequence.

### Biocompatibility

The Simplify® Cervical Artificial Disc is manufactured from PEEK, zirconia-toughened alumina (ZTA) ceramic, and commercially pure titanium plasma spray (TPS). All implant materials have a long history of successful orthopedic clinical use and well-established biocompatibility. There are no color additives in the Simplify® Cervical Artificial Disc.

Biocompatibility testing was performed on the Simplify® Cervical Artificial Disc in its final sterilized state in accordance with ISO 10993-1, ISO 10993-12, ISO 10993-17, and ISO 10993-18, for the level of contact duration of a permanent implant contacting tissue and bone. The battery of biocompatibility tests conducted included: Cytotoxicity (ISO 10993-5), Pyrogenicity (ISO 10993-11), Bacterial Endotoxin Evaluation (ANSI/AAMI ST72, USP<85>, USP<161>), Neurotoxicity Assessment (ASTM F2423, ISO 18192-1, ASTM WK33006), and Biological Risk Assessment (ISO 10993-1, -12, -17, -18). All test results met the acceptance criteria demonstrating biocompatibility in line with the requirements of ISO 10993-1.

### Sterilization Validation

Full sterilization validation has been conducted for the Simplify® Cervical Artificial Disc implants per ISO 11137. Full sterilization validation has been conducted for the Simplify® Cervical Artificial Disc Instruments per ANSI/AAMI ST79, AAMI TIR12, and ISO 17665-1.

### Shelf Life and Transit Validation

Shelf life and transit validation studies, including assessments of packaging seal integrity and real-time aging testing, were conducted to demonstrate that the device packaging can maintain a sterile barrier over a 4-year shelf life.

### X. SUMMARY OF PRIMARY CLINICAL STUDY

The applicant performed a clinical study to establish a reasonable assurance of safety and effectiveness of replacement of the degenerated native disc with the Simplify® Cervical Artificial Disc in skeletally mature patients for reconstruction of the disc at two contiguous levels from C3-C7 following discectomy for intractable radiculopathy (arm pain and/or a neurological deficit) with or without neck pain, or myelopathy due to abnormality localized to the disc space and manifested by at least one of the following conditions confirmed by radiographic imaging (e.g., X-rays, computed tomography (CT), magnetic resonance imaging (MRI)): herniated nucleus pulposus or spondylosis (defined by the presence of osteophytes). The study was performed in the United States under IDE #G150206 with additional control anterior cervical discectomy and fusion

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 14

{14}

(ACDF) data from a separate IDE study performed in the United States. A summary of the clinical study is presented below.

### A. Study Design

Subjects in the Simplify® Cervical Artificial Disc two-level pivotal study (“Simplify® Cervical Artificial Disc IDE study”) were treated between April 2017 and November 2018. The database for this PMA reflects data collected through October 2020 and included 182 Simplify® Cervical Artificial Disc subjects (200 including training subjects) at 18 sites and 188 historical ACDF control subjects treated at 30 sites. Control subjects were treated between June 2006 and November 2007.

The prospective, non-randomized, historically controlled, multi-center study was performed in the United States under IDE #G150206 combined with historical control ACDF data from a previous multi-center, prospective, randomized concurrently-controlled cervical disc IDE study performed in the United States. The previous study incorporated a similar study design, indications for use, study entry criteria, study endpoints, and data collected. The two studies were not identical, and differences were identified in some categories and are discussed below. A Clinical Events Committee (CEC) adjudicated all historical AEs, secondary surgeries, neurological data, and protocol deviations to ensure consistency with the Simplify® Cervical Artificial Disc study.

A statistical plan utilizing propensity score (PS) modeling was developed to incorporate the historical control and to match the baseline covariates to the Simplify® Cervical Artificial Disc group. The resultant PS Selected study cohort used for the primary analysis population thus included all investigational Simplify® Cervical Artificial Disc subjects (excluding training subjects) and historical control subjects (excluding trimmed subjects) and is termed the “Primary Analysis Set.”

#### 1. Clinical Inclusion and Exclusion Criteria

To be eligible for the Simplify® Cervical Artificial Disc IDE study, subjects had to be eligible for a fusion procedure using the anterior approach and meet all of the inclusion criteria and none of the exclusion criteria (Table 3):

**Table 3: Study Inclusion/Exclusion Criteria**

|  Study Inclusion Criteria | Study Exclusion Criteria  |
| --- | --- |
|  - Has cervical degenerative disc disease at two (2) adjacent cervical levels (from C3- C7) requiring surgical treatment and involving intractable radiculopathy, myelopathy, or both; - Has a herniated disc and/or osteophyte formation at each level to be treated that is producing symptomatic nerve root and/or spinal cord compression. The condition is documented by patient history (e.g., neck pain with arm pain, functional deficit and/or neurological deficit), and the requirement for surgical treatment is evidenced by radiographic studies (e.g., CT, MRI, x-rays, etc.); - Has been unresponsive to non-operative treatment for at least six weeks or has the presence of progressive symptoms or signs of nerve root/spinal | - Has a cervical spinal condition other than symptomatic cervical DDD requiring surgical treatment at the involved levels; - Has documented or diagnosed cervical instability relative to adjacent segments at either level, defined by dynamic (flexion/extension) radiographs showing:     - Sagittal plane translation >3.5 mm, or     - Sagittal plane angulation >20°; - Has more than two cervical levels requiring surgical treatment; - Has a fused level (or artificial disc replacement) adjacent to the levels to be treated; - Has severe pathology of the facet joints of the involved vertebral bodies;  |

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 15

{15}

|  Study Inclusion Criteria | Study Exclusion Criteria  |
| --- | --- |
|  cord compression in the face of continued non-operative management; • Has no previous surgical intervention at the involved levels or any subsequent planned/staged surgical procedure at the involved or adjacent level(s); • Must be at least 18 years of age and be skeletally mature at the time of surgery; • Has a pre-operative Neck Disability Index (NDI) ≥30; • Has a pre-operative neck pain score ≥8 based on the pre-operative Neck and Arm Pain Questionnaire; • If a female of childbearing potential, patient is non-pregnant,^{1} non-nursing, and agrees not to become pregnant during the study period; • Is willing to comply with the study plan and sign the Patient Informed Consent Form. | • Has had previous surgical intervention at either one or both of the involved levels or at adjacent levels; • Axial neck pain only (no radicular or myelopathy symptoms); • Has been previously diagnosed with osteopenia or osteomalacia; • Has any of the following that may be associated with a diagnosis of osteoporosis (if “Yes” to any of the below risk factors, a DEXA Scan will be required to determine eligibility): ○ Postmenopausal non-black female over 60 years of age who weighs less than 140 pounds; ○ Postmenopausal female who has sustained a non-traumatic hip, spine, or wrist fracture; ○ Male over the age of 70; ○ Male over the age of 60 who has sustained a non-traumatic hip or spine fracture. ○ If the level of bone mineral density is a T score of -1.5 or lower (i.e., -1.6, -1.7, etc.), then the patient is excluded from the study • Has presence of spinal metastases; • Has overt or active bacterial infection, either local or systemic; • Has insulin-dependent diabetes; • Has chronic or acute renal failure or prior history of renal disease; • Known PEEK, ceramic, titanium allergy; • Is mentally incompetent (if questionable, obtain psychiatric consult); • Is a prisoner; • Is pregnant^{1}; • Is currently an alcohol and/or drug abuser or currently undergoing treatment for alcohol and/or drug abuse; • Is involved with current or pending litigation regarding a spinal condition; • Has received drugs that may interfere with bone metabolism within two weeks prior to the planned date of spinal surgery (e.g., steroids or methotrexate), excluding routine perioperative anti-inflammatory drugs; • Has a history of an endocrine or metabolic disorder known to affect osteogenesis (e.g., Paget’s Disease, renal osteodystrophy, Ehlers-Danlos Syndrome, or osteogenesis imperfecta); • Has a condition that requires post-operative medications that interfere with the stability of the implant, such as steroids. (This does not include low-dose aspirin for prophylactic anticoagulation and routine perioperative anti-inflammatory drugs); • Has received treatment with an investigational therapy within 28 days prior to implantation  |

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 16

{16}

|  Study Inclusion Criteria | Study Exclusion Criteria  |
| --- | --- |
|   | surgery or such treatment is planned during the 16 weeks following implantation. NOTE: If a patient did not meet the entry criteria during the initial enrollment, the patient was not re-evaluated for entry into the study at a later time.  |

¹ Pregnancy during participation in this study should also be discouraged, since pregnancy may prohibit exposure to X-rays during necessary follow-up timeframes.

## 2. Control

Control subjects received ACDF. The historical control was collected from the control arm of a previously completed multi-center, prospective, randomized non-inferiority clinical trial. Comparison of the data collected from the Simplify® Cervical Artificial Disc Pivotal IDE study and historical ACDF control demonstrated that the cohorts were comparable, though not identical.

- A detailed comparison of the indications and inclusion/exclusion criteria of the historical ACDF cohort and the Simplify® Cervical Artificial Disc IDE study protocol was conducted to determine if the historical data were adequate to serve as comparator and support a PMA Supplement application. The protocol and case report forms were reviewed and discussed with FDA. It was determined that the historical study was similar to the IDE study in its Indications for Use and Inclusion/Exclusion criteria.
- The historical study collected the parameters used to calculate overall success, success of the individual components of the composite primary endpoint, secondary endpoints, and safety assessments per the defined assessments in the Simplify® Cervical Artificial Disc IDE study protocol.

A PS method was used to address selection bias in the observational study design when pooling data from the historical control and actively enrolled Simplify® Cervical Artificial Disc group. The objective of the observational design was to select from the candidate pool of historical controls those subjects whose baseline covariate distribution was approximately the same as Simplify® Cervical Artificial Disc subjects within PS subclasses. The final Primary Analysis set included all 182 Simplify® Cervical Artificial Disc subjects (200 including training subjects) and 170 of 188 historical control subjects. Rigorous statistical criteria and graphical analyses demonstrated that within PS subclasses, Simplify® Cervical Artificial Disc subjects and PS-selected historical controls had approximately the same multivariate baseline covariate distribution.

### 3. Follow-up Schedule

All subjects were evaluated pre-operatively, at treatment/discharge (prior to the subject being discharged from the hospital) and post-operatively at 6 weeks (±2 weeks), 3 months (±2 weeks), 6 months (±1 month), 1 year (±2 months), 2 years (±2 months), 3 years (±2 months) and annually thereafter (±3 months). The following parameters (Table 4) were measured throughout the study:

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 17

{17}

**Table 4: Simplify® Cervical Artificial Disc IDE Study Assessment Schedule**

|  Timepoint | Pre-op | Tx/ Discharge | 6W | 3M | 6M | 12M | 24M | Post 24M  |
| --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  Informed Consent | X |  |  |  |  |  |  |   |
|  DDD assessment (MRI, CT or X-ray) | X |  |  |  |  |  |  |   |
|  Medical History & Physical Examination | X |  |  |  |  |  |  |   |
|  DXA | X |  |  |  |  |  |  |   |
|  AP & Lateral X-rays | X | X | X | X | X | X | X | X  |
|  Flexion & Extension X-rays | X |  | X | X | X | X | X | X  |
|  Lateral bending X-rays | X |  |  |  | X | X | X | X  |
|  MRI (or CT at Pre-op only); Investigational group only at 24M | X |  |  |  |  |  | X |   |
|  Radiographic Core Lab Assessments | X | X | X | X | X | X | X | X  |
|  Pre-operative Patient Survey | X |  |  |  |  |  |  |   |
|  Dysphagia Handicap Index | X |  | X | X | X | X | X | X  |
|  NDI | X |  | X | X | X | X | X | X  |
|  SF-36 Health Survey | X |  |  |  | X | X | X | X  |
|  Neck and Arm Pain Questionnaires | X |  | X | X | X | X | X | X  |
|  Foraminal Compression Test | X |  | X | X | X | X | X | X  |
|  Physician Perception of Results |  |  | X | X | X | X | X | X  |
|  Neurologic Exam | X | X | X | X | X | X | X | X  |
|  Gait Assessment | X |  | X | X | X | X | X | X  |
|  Medications | X |  | X | X | X | X | X | X  |
|  Work Status | X |  | X | X | X | X | X | X  |
|  Treatment Assessments |  | X |  |  |  |  |  |   |
|  Post-operative Subject Survey |  |  | X | X | X | X | X | X  |
|  Health Economic Data |  |  | As available  |   |   |   |   |   |
|  AE Assessment | N/A |  | As needed  |   |   |   |   |   |
|  Study Completion/ Termination | N/A | N/A | As needed  |   |   |   |   |   |

PMA P200022: FDA Summary of Safety and Effectiveness Data

Page 18

{18}

#### 4. Clinical Endpoints

The effectiveness of the Simplify® Cervical Artificial Disc was assessed using a composite endpoint, as described below. Effectiveness was evaluated by assessing improvement in the Neck Disability Index (NDI), neck and arm pain questionnaires, and health-related quality of life using the short-form questionnaire (SF-36), work status, as well as patient satisfaction of the Simplify® Cervical Artificial Disc group compared to the historical ACDF control group. Similar criteria were used to measure success in both groups.

The safety of the Simplify® Cervical Artificial Disc was assessed by comparison to the historical ACDF control group with respect to the nature and frequency of AEs (overall and in terms of severity and relationship to the implant), subsequent index level surgical procedures and maintenance or improvement in neurological status.

# Primary Endpoints

The study hypothesis for the Simplify® Cervical Artificial Disc IDE Study was that the Month 24 (i.e., 24 months post-operatively) composite clinical success (CCS) rate of the two-level Simplify® Cervical Artificial Disc would be no worse than conventional two-level ACDF when success is evaluated at Month 24 in patients with intractable radiculopathy (arm pain and/or a neurological deficit) with neck pain or myelopathy due to abnormalities localized to the levels of the two contiguous disc spaces at two contiguous levels from C3 to C7 that is unresponsive to conservative management or have presence of progressive signs or symptoms of nerve root/spinal cord compression.

Individual success for both the investigational and control groups was defined as:

- Neck Disability Index (NDI) score improvement of at least 15 points (out of 100) as compared to baseline at Month 24;
- Maintenance or improvement in neurological status at Month 24¹;
- No serious adverse event (SAE) classified as implant associated or implant/surgical procedure associated within 24 months of index procedure; and
- No additional surgical procedure classified as a “failure” within 24 months of index procedure.

Device failure was defined as breakage, migration, or mechanical failure of the components.

Overall success was determined based on data collected during the initial 24 months of follow-up. Each element of the neurological study exam was evaluated for maintenance or improvement.

All secondary index surgeries were classified as failures.

¹ Maintenance or improvement in neurological status was based on motor, sensory, and myelopathic gait assessments.

PMA P200022: FDA Summary of Safety and Effectiveness Data

Page 19

{19}

Per the FDA Guidance for the Preparation of IDEs for Spinal Systems, the following definitions applied:

- Reoperation - any surgical procedure at the index level(s) that *does not involve* modification, addition or removal of any components of the device and is not considered a removal, revision, or supplemental fixation.
- Revision – any procedure in the post-operative or follow-up period that adjusts or in any way modifies either one or both of the original implant configurations (e.g., adjusting the position of the original configuration, removal with replacement with same type of study implant).
- Removal – a procedure that removes one or more components of the original implant configuration without replacement with the same type of trial implant.
- Supplemental fixation – a procedure at the index level(s) in which additional spinal devices not approved as part of the protocol are placed.
- Other – any additional surgical procedure not classified as a removal, revision, supplemental fixation, or reoperation.

# Secondary Endpoints

Secondary endpoints, measured in both groups (except as noted), included:

- Clinically significant improvement in one or more radicular symptoms or myelopathy at each post-operative timepoint compared to baseline for the investigational two-level Simplify® Cervical Artificial Disc group and the two-level historical ACDF control group. The data collected reflected the number of patients who improved (numbers were stratified to reflect clinical improvement), who remain unchanged, and who deteriorated at each study timepoint. These endpoints were graded and defined as follows:
  - Pain questionnaires were used to evaluate each of the following pain locations:
    - Neck pain
    - Arm pain
    - Left arm pain (investigational group only);
    - Right arm pain (investigational group only);
  - Motor status - A change of one or more grade levels in muscle strength was regarded as clinically significant.
  - Sensory status - Sensation was graded as normal or abnormal (diminished or absent). Any changes from abnormal to normal or absent to diminished were regarded as clinically significant improvement.²
- Time to recovery (earliest time at which a minimum 15-point (out of 100) NDI improvement is reached).
- Disc height at each post-operative timepoint compared to baseline (6 weeks). Both levels had to be a disc height success to claim success for overall disc height. Disc height success

² Hacker et al., supra note 7, at 2648; Aids to the Investigation of Peripheral Nerve Injuries (UK Medical Research Council, War Memorandum No. 7 (2d ed. Rev. 1943).

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 20

{20}

for each level is based on either the anterior or posterior measurements meet the following criterions:

o Post-operative Height – 6 Week Post-operative Height ≥-2 mm
• Adjacent level deterioration at 24 months compared to baseline for the investigational group.
• Displacement or migration of the device for the investigational group; only a change of >3 mm was considered significant due to the margin of error in radiographic determination of displacement distances.
• Return to work status post-operatively.
• Patient satisfaction and perceived effect at each applicable post-operative timepoint. Success for each of the three satisfaction questions) was defined as either a “Definitely True” or “Mostly True” response. Success for the perceived effect question was defined as either a “Completely Recovered,” “Much Improved,” or “Slightly Improved” response.
• Health Survey (SF-36) at each applicable post-operative timepoint compared to baseline. Success was expressed in terms of the PCS (physical component summary) and MCS (mental component summary) scores and was defined as a maintenance or improvement in status post-operatively as compared to the pre-operative condition. To be classified as a success for each component summary, the following criteria must be met:

PCSPostop - PCSPreop ≥0

MCSPostop - MCSPreop ≥0

• Dysphagia Handicap Index (DHI scale) at each applicable post-operative timepoint compared to baseline for the investigational group.
• Facet deterioration at 24 months compared to baseline for the investigational group.
• Adjacent Level Motion (Stability) was compared at each applicable post-operative timepoint to baseline.
• Results at each applicable post-operative timepoint were categorized by the physician’s perception of the subject’s condition (excellent, good, fair, or poor).
• Gait assessment at each applicable timepoint compared to baseline. This was based on Nurick’s classification. Success was defined as maintenance or improvement in the post-operative status as compared to the pre-operative condition:

Pre-operative Score – Post-operative Score ≥0

# 5. Clinical Events Committees (CEC)

A CEC was utilized for the Simplify® Cervical Artificial Disc IDE study, including the historical ACDF control population, to mitigate reporting bias of safety-related events. The CEC was comprised of two (2) independent spine surgeons and one (1) independent radiologist, and a CEC charter was used to define the role of the CEC. The committee was responsible for classification or adjudication of AEs (i.e., AE code, relationship to implant/procedure, seriousness, severity, and unanticipated adverse device effects), secondary surgical intervention (SSI) (i.e., classification of revision, removal, reoperation, supplemental fixation or other), protocol deviations (i.e.,

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 21

{21}

classification as Major or Minor), and neurological success criterion (classification of neurologic status at Month 24 as compared to baseline).

### **B. Accountability of PMA Cohort**

One-hundred eighty-two (182) subjects were enrolled in the Simplify® Cervical Artificial Disc population. An additional 18 Simplify® Cervical Artificial Disc subjects were training subjects for total 200 investigational subjects. The historical ACDF control population included 188 subjects.

The 370 available subjects (182 Simplify® Cervical Artificial Disc (excluding training subjects) and 188 historical ACDF control) were assessed via the PS sub-classification sequential model-building process. After applying a sequential heuristic for PS modeling, all 182 randomized Simplify® Cervical Artificial Disc and 170 historical ACDF control subjects were retained in the final PS designed sample.$^{3}$ Inclusion into a PS subclass is the observational study analogue to randomized treatment allocation. When accounting for the PS design, there was excellent balance across all considered baseline covariates. For subjects at Month 24, the follow-up rates for expected due subjects was 97% for Simplify® Cervical Artificial Disc subjects and 84% for the PS Selected historical ACDF control subjects. With regards to CCS evaluable follow up, there were 173 Simplify® Cervical Artificial Disc subjects and 145 historical ACDF control subjects at 24 months, resulting in an overall follow-up rate of 95.1% (173/182) and 85.3% (145/170) for the Simplify® Cervical Artificial Disc and historical ACDF control subjects, respectively.

The subject accountability for Month 12 and Month 24 clinical evaluations is presented in **Table 5** and **Figure 4**.

$^{3}$ Maislin G and Rubin DB. Design of Non-Randomized Medical Device Trials Based on Sub-Classification Using Propensity Score Quintiles, Topic Contributed Session on Medical Devices. Proceedings of the Joint Statistical Meetings 2010, pg 2182-2196.

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 22

{22}

**Table 5: Subject Accounting Summary (Primary Analysis Population)**

|   | Month 12 |   | Month 24  |   |
| --- | --- | --- | --- | --- |
|   |  I | C | I | C  |
|  **Accounting**  |   |   |   |   |
|  (1) Theoretical follow-up | 182 | 170 | 181 | 170  |
|  (2) Cumulative Death | 0 | 0 | 2 | 1  |
|  (3a) Intra-Op Deviations | 1 | 4 | 1 | 4  |
|  (3b) Cumulative SSI Failures | 2 | 11 | 4 | 14  |
|  (4) Not Yet Overdue | 0 | 0 | 0 | 0  |
|  (5) Deaths+SSI failures+Intra-Op Deviations among theoretically due | 3 | 15 | 7 | 19  |
|  (6) Expected Due [(6)=(1)-(4)-(5)] | 179 | 155 | 174 | 151  |
|  (7) SSI failures+Intra-Op Deviations among theoretically due | 3 | 15 | 5 | 18  |
|  (8) Expected due+SSI failures+Intra-Op Deviations among theoretically Due [(8)=(6)+(7)] | 182 | 170 | 179 | 169  |
|  **All Evaluated Accounting (Actual^{B}) Among Expected Due Procedures**  |   |   |   |   |
|  (9) Procedures with any clinical data in interval† | 177 | 136 | 168 | 127  |
|  (10) Visit Compliance (%) | 99% | 88% | 97% | 84%  |
|  (11) Change in NDI | 177 | 136 | 168 | 127  |
|  (12) Neuro evaluations | 177 | 136 | 166 | 127  |
|  (13) Composite Clinical Success (CCS) |  |  | 168 | 127  |
|  (14) Actual^{B} % Follow-up for CCS |  |  | 97% | 84%  |
|  **Within Window Accounting (Actual^{A}) Among Expected Due Procedures**  |   |   |   |   |
|  (15) Procedures with any clinical data in interval† | 173 | 129 | 158 | 109  |
|  (16) Visit Compliance (%) | 97% | 83% | 91% | 72%  |
|  (17) Change in NDI | 173 | 129 | 158 | 109  |
|  (18) Neuro evaluations | 173 | 129 | 157 | 109  |
|  (19) Composite Clinical Success (CCS) |  |  | 158 | 109  |
|  (20) Actual^{A} % Follow-up for CCS |  |  | 91% | 72%  |
|  **Composite Study Success**  |   |   |   |   |
|  (21) Composite Clinical Success (CCS) |  |  | 173 | 145  |
|  (22) % Follow-up for CCS |  |  | 95.1% | 85.3%  |
|  † Defined as Change in NDI or available Neuro motor status. Source: Tables Follow-up Compliance.sas; Analyzed: 09NOV2020  |   |   |   |   |

Actual$^{A}$: Patients with complete data for each endpoint, within window.

Actual$^{B}$: Patients with any follow-up data reviewed or evaluated by investigator (“all evaluated” accounting).

**(1) Theoretical follow-up:** The theoretical follow-up is the number of devices at two levels that would have been examined if all patients returned on the exact anniversary of their respective initial surgery dates. The date of database closure for these analyses was November 3, 2020. All subjects were theoretically due for Month 12 and Month 24 follow-up at the date of database closure, with the exception of one subject that was theoretically due on November 12, 2020 and missed the Month 24 visit.

**(2) Cumulative deaths:** Cumulative deaths up to the date of the exact anniversary defining the current interval. Deaths occurring after the exact anniversary are recorded in the next interval.

**(3a) Intra-Op Deviations:** Subjects who were to be treated with Simplify® Cervical Artificial Disc but converted to alternate treatment intra-operatively. Intra-operative deviation subjects are

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 23

{23}

considered a treatment failure in the CCS primary endpoint calculation and censored at day 0 for SSI and device survivorship. In the Simplify® Cervical Artificial Disc population, there was one subject who was enrolled to be treated with Simplify® Cervical Artificial Disc, but at time of surgery, the surgeon identified a large flowing osteophyte at one level that prevented adequate placement of a TDR as too much bone had to be removed. The surgeon proceeded with a fusion at that level and a commercially available TDR at the other level. In the control study, four subjects received a different fusion device. In one case, the patient was very small in stature and the control plate was too wide; in the other three cases, the investigators deviated from the protocol requirements. Since these intra-op deviations do not meet the definition of an SSI, they are accounted for separately. These five subjects were recorded as intra-operative deviations and are accounted for in Figure 4.

(3b) Cumulative SSI Failures: Failures are defined as any result that removes the patient from further evaluation of effectiveness, that is, these Failures are "terminal failures". As per FDA Guidance (2004), failure includes SSIs categorized as reoperations, revisions, removals, or supplemental fixation. It also includes other severe AEs or other parameters that would define the device as ineffective or unsafe from that point on. Failures are counted up to the date of the exact anniversary defining the current interval. Terminal failures occurring after the exact anniversary are recorded in the next interval. Terminal failures on this row do not include radiographic failure since radiographic failure does not remove a subject from the study. It also does not include clinical failures determined on the basis of clinical scores such NDI, Neck and Arm Pain Questionnaire, or deteriorating neurological status because these types of failure do not remove the patient from further follow-up. Although the cumulative number of failures is recorded on this row, only failures among devices that are theoretically due for that interval are subtracted from theoretically due to determine the number expected due for clinical indices.

(4) Not Yet Overdue: Includes subjects whose surgical anniversary has occurred; however, clinical data has not yet been collected (i.e., NDI or Neck and Arm Pain Questionnaire is currently unavailable) but the subject is still in the protocol specified follow-up window. Such subjects may not yet be observed and so follow-up compliance estimates account for this by removing such subjects from the denominator as well as from the numerator when determining compliance ratios. There are no subjects Not Yet Overdue for Month 24 at the time of this database lock.

(5) Deaths + SSI Failures + Intra-Op Deviations among theoretically due: This row records the sum of deaths, SSI Failures, and Intra-Op Deviations among those theoretically due for follow-up according to the exact anniversary of the scheduled follow-up visit. Only deaths, SSI Failures, and Intra-Op Deviations among procedures that are theoretically due for that interval are subtracted from theoretically due to determine the number expected due for clinical index evaluation.

(6) Expected Due for clinic visit: This row is the number of subjects expected for a given time interval. These include the theoretical number of subjects who are due to be evaluated, less the number of subjects who died or who were considered failures by that time interval and less the subjects in the "Not yet overdue" category. Expected = Theoretical - [Deaths + Failures + Not yet overdue] where the counts of the numbers of Deaths, Failures, and Not yet overdue are determined from among the theoretically due subjects. At the time of database lock, no subjects are Not Yet Overdue. This row serves as denominator for evaluation % follow-up for clinical indices (e.g., NDI). The Expected row includes subjects lost to follow-up, and major protocol violations are included in the expected group for all timepoints.

(7) SSI Failures + Intra-Op Deviations among theoretical due: SSI failures and intra-op deviations among theoretically due is the count of theoretically due Failures that need to be "added back" to the number of expected due to serve as the correct denominator for CCS counts when determining CCS follow-up compliance.

(8) Expected due + SSI Failures + Intra-Op Deviations among theoretical due: Expected due plus theoretical due Failures is computed by adding expected due in row (6) to the number of cumulative Failures among theoretically due devices in row (7). This row serves as the

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 24

{24}

denominator for composite clinical success (CCS) outcomes since CCS status is known for subjects with a Failure as defined in row (3).

(9) and (15) Procedures with any clinical data in interval: These rows indicate the number of subjects with any clinical data that report a change in NDI or neurological status for all evaluated subjects among expected due subjects (9) and for all subjects that are within window among expected due subjects (15).
(10) and (16) Visit Compliance (%): These rows indicate the percentage of subjects compliant with the specified visit scheduled for all evaluated subjects among expected due subjects (10) and for all subjects that are within window among expected due subjects (16).
(11) and (17) Change in NDI: These rows indicate the number of subjects reporting a change in NDI for all evaluated subjects among expected due procedures (11) and for all subjects that are within window among expected due procedures (17).
(12) and (18) Neuro evaluations: These rows indicate the number of subjects reporting a change in neurological status for all evaluated subjects among expected due procedures (12) and for all subjects that are within window among expected due procedures (18).
(13) and (19) Composite Clinical Success: These rows indicate the number of subjects meeting clinical composite success for all evaluated subjects among expected due procedures (13) and for all subjects that are within window among expected due procedures (19).
(14) and (20) Actual Follow-up for CCS: These rows indicate the percentage of subjects with follow-up data available used to evaluate CCS for all evaluated subjects among expected due procedures (14) and for all subjects that are within window among expected due procedures (20).
(21) and (22) Composite Clinical Success (CCS): These rows indicate the number (21) and percentage (22) of subjects with observed data available to evaluate CCS among all PS Selected subjects in the Primary Analysis group.

Figure 4: Subject Accountability Tree

![img-4.jpeg](img-4.jpeg)

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 25

{25}

### C. Study Population Demographics and Baseline Parameters

After adjusting for PS subclass, demographic data showed that the treatment groups were well-balanced and no statistically significant differences were noted in the demographic characteristics and categorical values. The mean baseline pre-operative assessments for NDI, Neck and Arm Pain Questionnaire, SF-36 and baseline radiographic parameters were also similar between treatment groups. There was no significant difference between groups for all clinical baseline parameters (Table 6 through Table 9).

Table 6: Summary of Demographic and Baseline Continuous Variables (Clinical) (Primary Analysis Population)

|   | Simplify Disc |   |   |   |   |   | ACDF |   |   |   |   |   | Group Difference*  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | p | Δ | LB | UB  |
|  All  |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Age (years) | 182 | 49.25 | 9.39 | 49.17 | 25.14 | 71.54 | 170 | 47.45 | 7.89 | 48.00 | 25.00 | 69.00 | 0.943 | -0.07 | -2.10 | 1.95  |
|  BMI (kg/m²) | 182 | 29.30 | 6.04 | 28.81 | 19.00 | 56.88 | 170 | 28.44 | 4.97 | 28.06 | 17.97 | 43.40 | 0.990 | 0.01 | -1.31 | 1.33  |
|  Height (inches) | 182 | 67.32 | 3.95 | 67.00 | 57.00 | 76.00 | 170 | 67.61 | 4.01 | 67.00 | 60.00 | 78.00 | 0.753 | -0.15 | -1.11 | 0.80  |
|  Weight (lbs) | 182 | 188.97 | 41.11 | 185.00 | 98.00 | 311.00 | 170 | 185.21 | 37.37 | 185.00 | 106.00 | 300.00 | 0.828 | -1.03 | -10.41 | 8.34  |
|  Male  |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Age (years) | 87 | 51.01 | 10.08 | 50.52 | 29.49 | 71.54 | 81 | 48.12 | 7.84 | 49.00 | 29.00 | 66.00 | 0.683 | 0.66 | -2.50 | 3.81  |
|  BMI (kg/m²) | 87 | 29.15 | 4.98 | 28.24 | 20.36 | 45.61 | 81 | 28.59 | 4.35 | 28.69 | 17.97 | 39.58 | 0.605 | 0.44 | -1.23 | 2.11  |
|  Height (inches) | 87 | 70.51 | 2.61 | 71.00 | 63.00 | 76.00 | 81 | 70.83 | 2.63 | 71.00 | 64.00 | 78.00 | 0.847 | 0.09 | -0.84 | 1.02  |
|  Weight (lbs) | 87 | 206.03 | 35.83 | 200.00 | 130.00 | 300.00 | 81 | 203.96 | 32.99 | 200.00 | 140.00 | 300.00 | 0.599 | 3.28 | -9.02 | 15.58  |
|  Female  |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Age (years) | 95 | 47.63 | 8.44 | 48.01 | 25.14 | 68.79 | 89 | 46.84 | 7.93 | 47.00 | 25.00 | 69.00 | 0.834 | -0.28 | -2.91 | 2.35  |
|  BMI (kg/m²) | 95 | 29.43 | 6.90 | 29.26 | 19.00 | 56.88 | 89 | 28.30 | 5.50 | 27.25 | 18.48 | 43.40 | 0.857 | -0.18 | -2.20 | 1.83  |
|  Height (inches) | 95 | 64.41 | 2.43 | 64.00 | 57.00 | 72.00 | 89 | 64.67 | 2.51 | 65.00 | 60.00 | 70.00 | 0.755 | -0.13 | -0.95 | 0.69  |
|  Weight (lbs) | 95 | 173.34 | 39.53 | 172.00 | 98.00 | 311.00 | 89 | 168.13 | 32.77 | 165.00 | 106.00 | 260.00 | 0.722 | -2.13 | -13.92 | 9.66  |
|  Clinical Scores  |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |
|  Neck Disability Index | 182 | 58.65 | 14.31 | 58.00 | 30.00 | 88.00 | 170 | 53.65 | 14.52 | 54.00 | 30.00 | 92.00 | 0.699 | 0.64 | -2.61 | 3.89  |
|  Neck Pain | 173 | 16.91 | 2.54 | 17.00 | 8.00 | 20.00 | 170 | 16.33 | 2.63 | 17.00 | 8.00 | 20.00 | 0.610 | 0.16 | -0.45 | 0.76  |
|  Neck Pain Frequency | 173 | 8.97 | 1.46 | 10.00 | 3.00 | 10.00 | 170 | 8.68 | 1.57 | 9.00 | 3.00 | 10.00 | 0.768 | 0.05 | -0.31 | 0.41  |
|  Neck Pain Intensity | 173 | 7.95 | 1.60 | 8.00 | 2.00 | 10.00 | 170 | 7.65 | 1.74 | 8.00 | 2.00 | 10.00 | 0.608 | 0.10 | -0.29 | 0.50  |
|  Arm Pain | 173 | 15.68 | 3.48 | 16.00 | 2.00 | 20.00 | 170 | 14.66 | 3.92 | 15.00 | 0.00 | 20.00 | 0.718 | 0.16 | -0.71 | 1.02  |
|  Arm Pain Frequency | 173 | 8.16 | 1.96 | 9.00 | 1.00 | 10.00 | 170 | 7.69 | 2.27 | 8.00 | 0.00 | 10.00 | 0.865 | 0.04 | -0.45 | 0.54  |
|  Arm Pain Intensity | 173 | 7.51 | 1.83 | 8.00 | 1.00 | 10.00 | 170 | 6.98 | 2.19 | 7.00 | 0.00 | 10.00 | 0.632 | 0.12 | -0.36 | 0.59  |
|  SF36 PCS | 173 | 31.41 | 7.65 | 30.76 | 11.28 | 58.90 | 170 | 32.97 | 7.13 | 33.15 | 14.00 | 52.43 | 0.916 | -0.09 | -1.84 | 1.65  |
|  SF36 MCS | 173 | 41.22 | 12.31 | 41.01 | 10.41 | 72.13 | 170 | 43.15 | 12.29 | 44.70 | 14.54 | 66.67 | 0.186 | -2.00 | -4.97 | 0.97  |

*Device group mean differences and 95% CI adjusting for propensity score (PS) subclass using two-way analysis of variance.
Source: Tables Baseline Demo.sas; Analyzed: 25AUG2020

Table 7: Summary of Baseline Categorical Variables (Primary Analysis Population)

|   | Simplify Disc |   |   | ACDF |   |   | Group Difference*  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  N | n | % | N | n | % | p | Δ | LB | UB  |
|  Any Narcotic (weak or strong) | 173 | 56 | 32.4% | 170 | 69 | 40.6% | 0.193 | -7.7% | -18.6% | 3.2%  |
|  Neurological Sensory Deficit | 179 | 84 | 46.9% | 170 | 61 | 35.9% | 0.675 | 2.6% | -8.8% | 14.0%  |
|  Neurological Motor Deficit | 182 | 59 | 32.4% | 170 | 75 | 44.1% | 0.727 | 2.1% | -9.2% | 13.4%  |
|  Work Status = Employed | 173 | 112 | 64.7% | 170 | 103 | 60.6% | 0.588 | 3.2% | -7.8% | 14.2%  |

*Device group differences and 95% CI adjusting for propensity score (PS) subclass using two-way generalized linear model.
Source: Tables Baseline additional.sas; Analyzed: 18FEB2021

** Narcotic data presented is within the past 8 hours of preop visit.

Table 8 summarizes the available race and ethnicity data. Please note, complete race and ethnicity data were not collected in the historical fusion arm.

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 26

{26}

**Table 8: Summary of Baseline Categorical Variables – Race and Ethnicity (Primary Analysis Population)**

|   | Simplify Disc |   |   | ACDF |   |   | p*  |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |  N | n | % | N | n | %  |   |
|  **Race** |  |  |  |  |  |  | 0.931  |
|  Caucasian | 182 | 170 | 93.4% | 170 | 157 | 92.4% |   |
|  Black |   | 6 | 3.3% |   | 6 | 3.5%  |   |
|  Asian |   | 1 | 0.6% |   | 3 | 1.8%  |   |
|  Hispanic |   |  |  |   | 3 | 1.8%  |   |
|  Other |  | 5 | 2.8% |  | 1 | 0.6% |   |
|  **Ethnicity** |  |  |  |  |  |  |   |
|  Hispanic or Latino | 182 | 5 | 2.7% |  |  |  |   |
|  Not Hispanic or Latino |   | 177 | 97.3% |  |  |  |   |
|  *p-value adjusted for PS subclass using two-way analysis of variance with race dichotomized as Caucasian vs. Non-Caucasian. Source: Tables Baseline Demo.sas; Analyzed: 27OCT2020  |   |   |   |   |   |   |   |

The radiographic findings used to qualify a subject for enrollment are provided with post-hoc nominal measures of significance in **Table 9**.

**Table 9: Summary of Baseline Variables – Radiographic Data (Primary Analysis Population)**

|   |  | Simplify Disc |   |   | ACDF  |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   |   |  N | n | % | N | n | %  |
|  Superior Level | Herniated Disc | 182 | 161 | 88.5% | 170 | 142 | 83.5%  |
|   |  Osteophyte Formation | 182 | 113 | 62.1% | 170 | 121 | 71.2%  |
|  Inferior Level | Herniated Disc | 182 | 158 | 86.8% | 170 | 143 | 84.1%  |
|   |  Osteophyte Formation | 182 | 115 | 63.2% | 170 | 113 | 66.5%  |
|  Source: Radiographic Inclusion.sas; Analyzed 26OCT2020  |   |   |   |   |   |   |   |

**Table 10** provides a summary of the operative variables of operative time, blood loss, and length of hospital stay.

**Table 10: Summary of Operative Continuous Variables (Primary Analysis Population)**

|   | Simplify Disc |   |   |   |   |   | ACDF |   |   |   |   |   | Group Difference*  |   |   |   |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|   |  N | Mean | SD | Med | Min | Max | N | Mean | SD | Med | Min | Max | p | Δ | LB | UB  |
|  Operative Time (minutes) | 182 | 100.62 | 26.84 | 98.50 | 48.00 | 180.00 | 170 | 100.02 | 44.44 | 93.50 | 39.00 | 296.00 | 0.868 | 0.73 | -7.92 | 9.38  |
|  Blood loss (cc) | 182 | 44.66 | 44.36 | 25.00 | 0.00 | 300.00 | 170 | 56.29 | 46.99 | 50.00 | 0.00 | 250.00 | 0.169 | -7.62 | -18.49 | 3.26  |
|  Length of hospital stay | 182 | 0.59 | 0.77 | 1.00 | 0.00 | 7.00 | 170 | 1.31 | 0.95 | 1.00 | 0.00 | 8.00 | <.001 | -0.80 | -1.01 | -0.60  |
|  *Device group mean differences and 95% CI adjusting for propensity score (PS) subclass using two-way analysis of variance. Source: Tables Intra-op details.sas; Analyzed: 19FEB2021  |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |   |

The mean, standard deviations from the mean, median, minimum, and maximum values are presented for each variable. There were no significant differences between groups in operative time or blood loss. A statistically significant difference was seen between the two groups for length of hospital stay favoring the investigational group (p<0.001); however, this difference in length of hospital stay is likely attributable to the fact that a majority of the investigational group procedures were performed at out-patient sites. Due to the differences in surgical sites between the

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 27

{27}

investigational group and historical ACDF control arm, no clinical meaningful benefit can be derived from the length of hospital stay.

**Table 11** through **Table 13** provides a summary of additional intraoperative surgical variables for subjects treated in the study for both the investigational and ACDF control groups, where applicable. Variables summarized include operative level, status of the posterior ligament, and device size used.

**Table 11: Summary of Index Level**

|   | Simplify Disc |   | ACDF  |   |
| --- | --- | --- | --- | --- |
|   |  n | % | n | %  |
|  C3/4-C4/5 | 5 | 3% | 2 | 1%  |
|  C4/5-C5/6 | 44 | 24% | 40 | 24%  |
|  C5/6-C6/7 | 133 | 73% | 128 | 75%  |
|  Source: Tables Intra-op details.sas; Analyzed: 25AUG2020  |   |   |   |   |

**Table 12: Summary of Posterior Ligament Cut (Simplify Subjects Only)**

|   | Superior |   | Inferior  |   |
| --- | --- | --- | --- | --- |
|   |  n | % | n | %  |
|  No | 2 | 1% | 2 | 1%  |
|  Yes | 180 | 99% | 180 | 99%  |
|  Source: Tables Intra-op details.sas; Analyzed: 25AUG2020  |   |   |   |   |

**Table 13: Summary of Device Size (Simplify Subjects Only)**

|   | Superior |   | Inferior  |   |
| --- | --- | --- | --- | --- |
|   |  n | % | n | %  |
|  SM-4 | 35 | 19% | 23 | 13%  |
|  SM-5S | 4 | 2% | 4 | 2%  |
|  SM-6S | 1 | 1% | 1 | 1%  |
|  MD-4 | 71 | 39% | 65 | 36%  |
|  MD-5 | 11 | 6% | 12 | 7%  |
|  MD-5L | 14 | 8% | 20 | 11%  |
|  MD-6 | 1 | 1% | 1 | 1%  |
|  LG-5 | 20 | 10% | 15 | 9%  |
|  LG-5L | 19 | 10% | 33 | 18%  |
|  LG-6 | 3 | 2% | 6 | 3%  |
|  LG-6L | 2 | 1% | 1 | 1%  |
|  Source: Tables Intra-op details.sas; Analyzed: 23OCT2020  |   |   |   |   |

\*S indicates small core if small and large core options were available; L indicates lordotic

As shown in **Table 11**, the majority of subjects in both groups were treated at C5/C6 and C6/C7 levels. Additionally, as shown in **Table 12**, a majority of subjects in the investigational group also

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 28

{28}

had their posterior longitudinal ligament cut. **Table 13** summarizes the device size used for the investigational subjects. The smallest device height, 4mm height, accounted for 54% of the devices implanted in Simplify® Cervical Artificial Disc subjects.

#### **D. Safety and Effectiveness Results**

**Please note: There are potential differences in AE data reporting and collection between historical ACDF and prospective Simplify® Cervical Artificial Disc study arms, which may account for group differences in the AE rates exhibited between the Simplify® Cervical Artificial Disc and ACDF cohorts.**

##### **1. Safety Results**

**Table 14** presents a summary of AE rates between the Simplify® Cervical Artificial Disc cohort and the historical ACDF control cohort. It is important to note that implant associated events were determined to only have potential for causal relationship to implant, and vice versa for procedure associated events. Implant/procedure associated events were used in cases where it was undetermined if the event was implant or procedure associated, or it was determined it was both. Lastly, treatment associated is the sum of all implant associated, procedure associated, and implant / procedure associated events. Overall, the Simplify® Cervical Artificial Disc cohort experienced a numerically lower number of AEs (250 events in 121 subjects) than the historical ACDF control group (574 events in 155 subjects).

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 29

{29}

**Table 14: Comparisons of Summary AE Rates between Simplify® Cervical Artificial Disc and ACDF Groups (Primary Analysis Set through Day 790)**

|   | Simplify Disc (N= 182) |   |   | ACDF (N= 170)  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Events | Subjs | %^{1} | Events | Subjs | %^{1}  |
|  **Adverse Events**  |   |   |   |   |   |   |
|  All | 250 | 121 | 66.5% | 574 | 155 | 91.2%  |
|  Treatment Associated | 32 | 28 | 15.4% | 91 | 61 | 35.9%  |
|  Implant Associated | 8 | 7 | 3.8% | 6 | 6 | 3.5%  |
|  Procedure Associated | 18 | 16 | 8.8% | 62 | 40 | 23.5%  |
|  Implant/Procedure Associated | 6 | 6 | 3.3% | 23 | 22 | 12.9%  |
|  **Serious Adverse Events**  |   |   |   |   |   |   |
|  All | 41 | 32 | 17.6% | 85 | 62 | 36.5%  |
|  Treatment Associated | 8 | 8 | 4.4% | 26 | 22 | 12.9%  |
|  Implant Associated | 2 | 2 | 1.1% | 1 | 1 | 0.6%  |
|  Procedure Associated | 2 | 2 | 1.1% | 14 | 13 | 7.6%  |
|  Implant/Procedure Associated | 4 | 4 | 2.2% | 11 | 11 | 6.5%  |
|  **AE by Severity**  |   |   |   |   |   |   |
|  Mild | 47 | 39 | 21.4% | 157 | 90 | 52.9%  |
|  Moderate | 159 | 87 | 47.8% | 336 | 134 | 78.8%  |
|  Severe | 38 | 30 | 16.5% | 76 | 52 | 30.6%  |
|  Life Threatening | 6 | 6 | 3.3% | 5 | 5 | 2.9%  |
|  **SAE by Severity**  |   |   |   |   |   |   |
|  Mild | 0 | 0 | 0.0% | 2 | 2 | 1.2%  |
|  Moderate | 4 | 4 | 2.2% | 15 | 14 | 8.2%  |
|  Severe | 31 | 24 | 13.2% | 63 | 47 | 27.6%  |
|  Life Threatening | 6 | 6 | 3.3% | 5 | 5 | 2.9%  |
|  **Death**  |   |   |   |   |   |   |
|  All | 2 | 2 | 1.1% | 1 | 1 | 0.6%  |
|  Percentage of subjects experiencing specific event; Source: Tables Safety - AE Summary.sas; Analyzed: 17DEC2020  |   |   |   |   |   |   |

Counts and percentages of subjects with specific AEs are presented in **Table 15** and counts of AEs by timecourse are presented in **Table 16**. The most commonly occurring events reported to have occurred in the Simplify® Cervical Artificial Disc cohort include cervical radiculopathy (14.3% - 26/182), lumbar radiculopathy (13.7% - 25/182), and pain with no narcotic given (12.6% - 23/182). In the historical ACDF control cohort, the most commonly reported AEs include accidental trauma (22.9% - 39/170), cervical radiculopathy (20% - 34/170), and pain with no narcotic given (20% - 34/170).

PMA P200022/S003: FDA Summary of Safety and Effectiveness Data

Page 30

{30}

**Table 15: Counts and Percentages of Subjects with Specific AEs (Primary Analysis Set through Day 790)**

|   | Simplify Disc (N= 182) |   |   | ACDF (N= 170)  |   |   |
| --- | --- | --- | --- | --- | --- | --- |
|   |  Events | Subs | % | Events | Subs | %  |
|  All Events | 250 | 121 | 66.5% | 574 | 155 | 91.2%  |
|  Soft tissue damage | 4 | 3 | 1.6% | 2 | 1 | 0.6%  |
|  Death | 2 | 2 | 1.1% | 1 | 1 | 0.6%  |
|  Infection localized to cervical surgical site | 2 | 2 | 1.1% | 3 | 3 | 1.8%  |
|  Hoarseness | 3 | 3 | 1.6% | 1 | 1 | 0.6%  |
|  Embolism | 1 | 1 | 0.5% | 1 | 1 | 0.6%  |
|  Dental Pain | 2 | 2 | 1.1% | 3 | 3 | 1.8%  |
|  Thoracic Radiculopathy | 1 | 1 | 0.5% | 2 | 2 | 1.2%  |
|  Drug allergy (administered) | 2 | 2 | 1.1% | 2 | 2 | 1.2%  |
|  Cardiac Event | 2 | 2 | 1.1% | 3 | 3 | 1.8%  |
|  Dysphonia | 1 | 1 | 0.5% | 2 | 2 | 1.2%  |
|  Compressive Neuropathy | 12 | 12 | 6.6% | 18 | 18 | 10.6%  |
|  Lumbar Radiculopathy | 26 | 25 | 13.7% | 30 | 29 | 17.1%  |
|  Cancer | 1 | 1 | 0.5% | 3 | 3 | 1.8%  |
|  Psychological Illness | 1 | 1 | 0.5% | 9 | 8 | 4.7%  |
|  Hypertension | 3 | 3 | 1.6% | 5 | 5 | 2.9%  |
|  Infection (all other infections-NOT at cervical surgical site) | 19 | 15 | 8.2% | 22 | 19 | 11.2%  |
|  Difficulty with urination | 2 | 2 | 1.1% | 6 | 5 | 2.9%  |
|  Nonunion/pseudoarthrosis | 1 | 1 | 0.5% | 12 | 12 | 7.1%  |
|  Other | 8 | 8 | 4.4% | 15 | 14 | 8.2%  |
|  Dermatitis/Skin allergy | 2 | 2 | 1.1% | 10 | 10 | 5.9%  |
|  Cervical Radiculopathy | 30 | 26 | 14.3% | 39 | 34 | 20.0%  |
|  Pain (narcotic given) | 6 | 6 | 3.3% | 14 | 13 | 7.6%  |
|  Spasm | 3 | 3 | 1.6% | 13 | 11 | 6.5%  |
|  Gastrointestinal complications including ileus, nausea and vomiting | 7 | 7 | 3.8% | 22 | 17 | 10.0%  |
|  Headache | 9 | 9 | 4.9% | 24 | 23 | 13.5%  |
|  Development of DDD at adjacent levels | 1 | 1 | 0.5% | 10 | 10 | 5.9%  |
|  Inflammation | 23 | 21 | 11.5% | 35 | 31 | 18.2%  |
|  Numbness - increased from pre-op or prior visit | 4 | 4 | 2.2% | 14 | 14 | 8.2%  |
|  Dysphagia | 7 |…

---

**Source:** [https://fda-staging.innolitics.com/device/P200022S003](https://fda-staging.innolitics.com/device/P200022S003)

**Published by [Innolitics](https://innolitics.com)** — a medical-device software consultancy. We help companies design, build, and clear FDA-regulated software and AI/ML devices. If you're preparing [a PMA](https://innolitics.com/services/regulatory/), [a 510(k)](https://innolitics.com/services/510ks/), [a SaMD](https://innolitics.com/services/end-to-end-samd/), [an AI/ML medical device](https://innolitics.com/services/medical-imaging-ai-development/), or [an FDA regulatory strategy](https://innolitics.com/services/regulatory/), [get in touch](https://innolitics.com/contact).

**Cite:** Innolitics at https://innolitics.com