NUVASIVE PCM CERVICAL DISC SYSTEM

{0} # SUMMARY OF SAFETY AND EFFECTIVENESS DATA ## I. GENERAL INFORMATION | Device Generic Name: | Artificial Cervical Disc | | --- | --- | | Device Trade Name: | PCM® Cervical Disc | | Device Procode: | MJO | | Applicant’s Name and Address: | NuVasive®, Inc. 7475 Lusk Blvd. San Diego, CA 92121 | | Date of Panel Recommendation: | none | | Premarket Approval Application (PMA) Number: | P100012 | | Date of FDA Notice of Approval: | October 26, 2012 | | Expedited: | not applicable | ## II. INDICATIONS FOR USE The PCM Cervical Disc is indicated for use in skeletally mature patients for reconstruction of a degenerated cervical disc at one level from C3-C4 to C6-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 disc space, and manifested by at least one of the following conditions confirmed by radiographic imaging (CT, MRI, X-rays): herniated nucleus pulposus, spondylosis (defined by the presence of osteophytes), and/or visible loss of disc height as compared to adjacent levels. The PCM Cervical Disc is implanted using an anterior approach. Patients should have failed at least 6 weeks of conservative treatment prior to implantation of the PCM Cervical Disc. ## III. CONTRAINDICATIONS The PCM Cervical Disc should not be implanted in patients with the following conditions: - Acute or chronic infections, local or systemic - Osteoporosis (defined as DEXA bone density measured T-Score ≤ -2.5) or osteopenia (defined as DEXA bone density measured T-Score ≤ -1.0) - Congenital stenosis - Allergy or sensitivity to any of the implant materials (cobalt, chromium, molybdenum, titanium, or polyethylene) ## IV. WARNINGS AND PRECAUTIONS The warnings and precautions can be found in the PCM Cervical Disc physician labeling. PMA P100012: FDA Summary of Safety and Effectiveness Page 1 of 61 {1} # V. DEVICE DESCRIPTION The PCM Cervical Disc is a two-piece articulating device that is inserted into the intervertebral disc space at a single cervical level using a standard anterior cervical approach, known as the Smith-Robinson anterior approach. The PCM Cervical Disc is comprised of two cobalt chromium molybdenum (CoCrMo) alloy metal endplates, one cephalad and one caudal, and an ultra-high molecular weight polyethylene (UHMWPE) spacer fixed to the caudal endplate. The articulation consists of a superior concave metallic surface and the inferior polyethylene convex surface. The plates are available in three sizes (small, medium, and large). The dimensions of the endplates are $14 \times 17 \mathrm{~mm}$ (small), $16 \times 17 \mathrm{~mm}$ (medium), and $17 \times 20 \mathrm{~mm}$ (large). The PCM Cervical Disc comes in overall thicknesses of 6.5, 7.2, and $8.0 \mathrm{~mm}$. The contact between the UHMWPE spacer and the cephalad component is ball-and-socket articulation. Refer to Table 1 for a complete listing of part numbers. The bone-contacting surface of each of the endplates has a coating that is comprised of two layers of titanium covered by an electrochemically applied layer of calcium phosphate (TiCaP®). This surface has transverse ridges designed to enhance postoperative bone fixation.  Figure 1: PCM Cervical Disc (PCM-V) The PCM Cervical Disc implant materials consist of the following: - CoCrMo Alloy, according to ISO 5832-12 - UHMWPE, according to ISO 5834-1, ISO 5834-2 / ASTM F648 - Unalloyed Titanium, according to ISO 5832-2 / ASTM F67 - Titanium plasma spray (TPS) and calcium phosphate (CaP) coatings PMA P100012: FDA Summary of Safety and Effectiveness {2} Table 1: PCM Cervical Disc Configurations | Part Number | Description | | --- | --- | | 7680265 | PCM-V Disc, S 6.5 | | 7680272 | PCM-V Disc, S 7.2 | | 7680280 | PCM-V Disc, S 8.0 | | 7680365 | PCM-V Disc, M 6.5 | | 7680372 | PCM-V Disc, M 7.2 | | 7680380 | PCM-V Disc, M 8.0 | | 7680465 | PCM-V Disc, L 6.5 | | 7680472 | PCM-V Disc, L 7.2 | | 7680480 | PCM-V Disc, L 8.0 | VI. ALTERNATIVE PRACTICES AND PROCEDURES Non-operative alternative treatments for intractable radiculopathy or myelopathy due to a single-level abnormality localized to the disc space include, but are not limited to, physical therapy, medications, braces, chiropractic care, bed rest, spinal injections, or exercise programs. In addition, there are alternative surgical techniques which include, but are not limited to, surgical decompression, with or without fusion using various bone grafting techniques (e.g., Cloward bone dowels, Smith Robinson tri-cortical wedges, and keystone grafts) sometimes used in conjunction with anterior spinal systems (e.g., plate and screw systems), posterior spinal systems (e.g., screw/rod, plate systems, posterior wiring systems), cage devices, or other approved cervical discs. Each alternative has its own advantages and disadvantages. A patient should fully discuss these alternatives with his/her physician to select the method that best meets expectations and lifestyle. VII. MARKETING HISTORY The PCM Cervical Disc has been available in markets outside of the United States since 2002. The device has not been withdrawn from the market for any reason relating to the safety and effectiveness of the devices. The countries in which the PCM Cervical Disc is available are as follows: Argentina, Australia, Belgium, Brazil, Canada, China, Finland, Germany, Greece, Italy, Lithuania, Mexico, Netherlands, New Zealand, Norway, Peru, Portugal, South Africa, South Korea, Spain, Sweden, Switzerland, Taiwan, Thailand, Turkey, and the United Kingdom. The device has not been withdrawn from the market for any reason relating to the safety and effectiveness of the devices. PMA P100012: FDA Summary of Safety and Effectiveness Page 3 of 61 {3} # VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Potential risks associated with the use of the PCM Cervical Disc include: 1) those commonly associated with any surgery; 2) those specifically associated with cervical spinal surgery using an anterior approach; and 3) those associated with a spinal implant, as well as those pertaining to the PCM Cervical Disc. However, the causality of these adverse events is not exclusive to these categories. There is also the risk that this surgical procedure will not be effective, and may not relieve or may cause worsening of preoperative symptoms. Some of these effects were observed in the clinical study and are therefore reported in Section X, Summary of Clinical Studies below. - Risks associated with any surgical procedure are those such as: abscess; cellulitis; wound dehiscence; wound necrosis; edema; hematoma; heart and vascular complications; hypertension; thrombosis; ischemia; embolism; thromboembolism; hemorrhage; thrombophlebitis; adverse reactions to anesthesia; pulmonary complications; organ, nerve or muscular damage; gastrointestinal compromise; seizure, convulsion, or changes to mental status; and complications of pregnancy including miscarriage and fetal birth defects; - Risks associated with anterior intervertebral body surgery of the cervical spine include: dysphagia; dysphasia; dysphonia; hoarseness; vocal cord paralysis; laryngeal palsy; sore throat; recurring aspirations; nerve deficits or damage; tracheal, esophageal, or pharyngeal perforation; airway obstruction; external chylorrhea; warmth or tingling in the extremities; damage to the spinal cord, nerve roots, or nerves possibly resulting in paralysis or pain; dural tears or leaking; cerebrospinal fistula; discitis, arachnoiditis, and/or other types of inflammation; loss of disc height; loss of proper curvature, correction, height or reduction of the spine; vertebral slipping; scarring, herniation or degeneration of adjacent discs; surrounding soft tissue damage, spinal stenosis; spondylolysis; otitis media; fistula; vascular damage and/or rupture; seromas or tissue swelling; and headache; - Risks associated with implants in the spine, including the PCM Cervical Disc device, are: early or late loosening of the components; disassembly; bending or breakage of any or all of the components; implant migration; malposition of the implant; loss of purchase; sizing issues with components; anatomical or technical difficulties; implant fracture; bone fracture; skin penetration; irritation, pain, bursitis resulting from pressure on the skin from component parts in patients with inadequate tissue coverage; foreign body reaction to the implants, including possible tumor formation, autoimmune disease, metallosis, and/or scarring; possible tissue reaction; bone resorption; bone formation that may reduce spinal motion or result in a fusion, either at the treated level or at adjacent levels; development of new radiculopathy, myelopathy or pain; tissue or nerve damage caused by improper positioning and placement of implants or instruments; loss of neurological function; decreased strength of extremities; decreased reflexes; cord or nerve root injury; loss of bowel and/or bladder control; and interference with radiographic imaging because of the presence of the implant; - Wound, local and/or systemic infections; - Surgical instrument bending or breakage, as well as the possibility of a fragment of a broken instrument remaining in the patient; - Inability to resume activities of normal daily living; and - Death. PMA P100012: FDA Summary of Safety and Effectiveness Page 4 of 61 {4} # IX. SUMMARY OF PRECLINICAL STUDIES ## A. Biomechanical Tests A series of mechanical tests and animal studies were performed to characterize the properties and function of the PCM Cervical Disc. The IDE study included two different configurations of the PCM Cervical Disc referred to as PCM-Standard and PCM-V, featuring identical sizes, general design configurations, materials, coatings, and articulation. The sponsor introduced the PCM-V to provide another means of immediate fixation of the device to help prevent initial migration of the implant. The only differences in design between the PCM-Standard and PCM-V are as follows: - The PCM-V has two rows of small “teeth” (1 mm in height) on the bone-contacting surface of each of the endplates that are angled toward each other in a “V” configuration. - A reduction in the number of ridges along the endplate surface was made to the PCM-V in order to allow space to include the teeth. It should be noted that The PCM-V was allowed to be incorporated into the study based on pullout testing (see Table 2 below) and future sub-group analyses (see Clinical Section below). The sub-group analyses showed that the two device cohorts were poolable. In PMA P100012, the applicant is only seeking marketing approval for the PCM-V. The PCM-Standard device is representative of the PCM-V for all the biomechanical testing except where both devices were tested. ### Table 2: Summary of Preclinical Biomechanical and Animal Testing | BIOMECHANICAL TESTING | | | | | | --- | --- | --- | --- | --- | | Test Name | Purpose | Method | Acceptance Criteria | Results | | Static Axial Compression | To evaluate the static axial compression performance of the PCM device, under worst case conditions. | Five (5) PCM-Standard specimens were tested under static compression in 37°C saline at a rate of 25 mm/min until failure or 2 mm displacement. | Yield load must be greater than the maximum compressive load a cervical vertebral segment can withstand (1.75 kN).^{1} | The average load at 2 mm displacement was 18.7 ± 2.03 kN. These results suggest that the PCM device can withstand axial compression loading that exceeds the anticipated physiologic loads on the cervical spine. | | Dynamic Axial Compression | To evaluate the dynamic axial compression performance of the PCM device, under worst case conditions. | Seven (7) PCM-Standard specimens were tested under dynamic axial compression in 37°C saline to 10 million cycles, using a sinusoidal wave form with R=10 at 1 Hz. | Fatigue load must be greater than the maximum compressive load on a cervical intervertebral disc (155 N).^{2} | Two specimens ran out to 10 million cycles under an 800 N load. These results suggest that the PCM device can withstand dynamic axial compression loading that exceeds the anticipated physiologic loads on the cervical spine. | | Static Compression-Shear | To evaluate the static compression-shear performance | Five (5) PCM-Standard specimens were | Yield load must be greater than the maximum shear load that | The average 2% offset yield load was 1052 ± 72 N, with an average displacement of 1.51 ± 0.18 mm. | PMA P100012: FDA Summary of Safety and Effectiveness Page 5 of 61 {5} PMA P100012: FDA Summary of Safety and Effectiveness Page 6 of 61 | | of the PCM device, under worst case conditions. | tested under static compression in 37°C saline at a rate of 25 mm/min until failure or 2 mm displacement. | a cervical intervertebral disc can receive in a posterior impact situation (270 N).^{3} | These results suggest that the PCM device can withstand compressive loading that exceeds the anticipated physiologic loads on the cervical spine. | | --- | --- | --- | --- | --- | | **Dynamic Compression-Shear** | To evaluate the dynamic compression-shear performance of the PCM device, under worst case conditions. | Seven (7) PCM-Standard specimens were tested under dynamic axial compression in 37°C saline to 10 million cycles, using a sinusoidal wave form with R=10 at 1-1.35 Hz. | Fatigue load must be greater than the maximum shear load that a cervical intervertebral disc can withstand (39 N).^{4} | Two specimens ran out to 10 million cycles under a 350 N load. These results suggest that the PCM device can withstand dynamic compression-shear loading that exceeds the anticipated physiologic loads on the cervical spine. | | **Device Pullout** | To evaluate and compare the device pullout performance of the PCM Standard and PCM-V devices, under worst case conditions. | Eight (8) PCM-Standard and 8 PCM-V specimens were tested for device pullout in ambient air at a rate of 2.5 mm/min. | Maximum load must be greater than the maximum pullout load for of a tri-cortical iliac crest graft (162 N).^{5} | The average maximum load was 257.4 ± 28.5 N for the PCM Standard and 308.1 ± 15.3 N for the PCM-V. These results suggest that the PCM device can withstand device pullout loading that exceeds the anticipated physiologic loads on the cervical spine. | | **Core Expulsion** | To evaluate the core expulsion performance of the PCM device, under worst case conditions. | Five (5) PCM-V specimens were tested for core expulsion in ambient air at a rate of 6 mm/min. | Maximum load must be greater than the maximum shear load that a cervical intervertebral disc can withstand (39 N).^{6} | The average maximum load was 855.6 ± 40.5 N, with an average displacement of 1.75 ± 0.14 mm. These results suggest that the PCM device can withstand core expulsion loading that exceeds the anticipated physiologic loads on the cervical spine. | | **Subluxation** | To evaluate the subluxation performance of the PCM device, under worst case conditions. | Five (5) PCM-V specimens were tested for subluxation in ambient air at a rate of 6 mm/min. | Maximum load must be greater than the maximum shear load that a cervical intervertebral disc can withstand (39 N).^{7} | The average maximum load was 83.2 ± 7.6 N, with an average displacement of 2.19 ± 0.73 mm. These results suggest that the PCM device can withstand subluxation loading that exceeds the anticipated physiologic loads on the cervical spine. | | **Subsidence** | To evaluate the subsidence performance of the PCM device, under worst case conditions. | Five (5) PCM-V specimens were tested for subsidence in ambient air at a rate of 6 mm/min. | Yield load must be greater than the maximum compressive load on a cervical intervertebral disc (155 N).^{8} | The average yield load was 1187.3 ± 13.7 N, with an average displacement of 3.51 ± 0.12 mm. These results suggest that the PCM device can withstand subsidence loading that exceeds the anticipated physiologic loads on the cervical spine. | | **Durability/Wear Testing** | To characterize the wear performance of the small footprint PCM device under Draft ASTM F2423-05 motion. | Five (5) PCM specimens were tested under Draft ASTM F2423-05 conditions (±10° fully reversing lateral bending, ±6° fully reversing axial bending). | This testing was performed to establish the wear characteristics of the small footprint PCM device under Draft ASTM F2423-05 parameters. Implant failure should not occur as a result of the testing. | Average cumulative wear at 10 million cycles was 71.22 ± 17.56 mg. The wear rate was 0.042 mg/million cycles between 3 Mc and 10 Mc. Average wear debris particle sizes determined by low-angle laser light scattering (LALLS) was 2.16 ± 1.19 μm (number basis). No implant failure was observed. | {6} PMA P100012: FDA Summary of Safety and Effectiveness Page 7 of 61 | | | rotation, 100 N axial load) to 10 million cycles (Mc) at 1-1.35 Hz. | | This initial wear testing showed experimental inconsistencies due to (i) fixture degradation, with apparent high wear during the first 3 Mc, and (ii) larger wear particle sizes than expected. See additional wear testing below. | | --- | --- | --- | --- | --- | | **Durability/Wear Testing** | To characterize the wear performance of the small footprint PCM device under worst-case 3-axis cross-shear ISO 18192-1 motion. | Six (6) PCM specimens were tested under ISO 18192-1 cervical conditions to 10 Mc at 1 Hz. | This testing was performed to establish the wear characteristics of the small footprint PCM device under ISO 18192-1 parameters. Implant failure should not occur as a result of the testing. | Average cumulative wear at 10 million cycles was 64.06 ± 2.55 mg and the wear rate was 6.33 mg/million cycles between 1 and 10 Mc. Average central height loss of the inferior component at 10 million cycles was 0.45 ± 0.01 mm. Average wear debris particle sizes determined by SEM were 0.53 ± 0.15 μm and 0.43 ± 0.04 μm, and average aspect ratios were 1.96 ± 0.11 and 2.03 ± 0.12 for the 2 specimens. Particles were smooth globular with some twisted fibrillar at all magnification ranges. No implant failure was observed. | | **Durability/Wear Testing** | To characterize the wear performance of the large footprint PCM device under worst-case 3-axis cross-shear ISO 18192-1 motion. | Six (6) PCM specimens were tested under ISO 18192-1 cervical conditions to 10 Mc at 1 Hz. | This testing was performed to establish the wear characteristics of the large footprint PCM device under ISO 18192-1 parameters. Implant failure should not occur as a result of the testing. | One test device was noted to wear through the polyethylene core to the titanium alloy locking plate at 5 Mc. As a result, the test was terminated at 5 Mc. Average cumulative wear at 5 Mc was 38.2 ± 0.70 mg and the wear rate was 7.37 mg/million cycles between 1 and 5 million cycles. Average central height loss of the inferior component at 5 Mc was 0.19 ± 0.03 mm. Information was presented to support that these test conditions may not be representative of those under which the device would operate in vivo. | | **Durability/Wear Testing** | To characterize the wear performance of the large footprint PCM device using modified ISO 18192-1 motion parameters derived from clinical measurements from the IDE study. | Six (6) PCM specimens were tested under ISO 18192-1 cervical conditions to 5 Mc at 1 Hz. | Wear testing was performed to establish the wear characteristics of the large footprint PCM device under ISO 18192-1 with modified motion parameters derived from IDE study data. Implant failure should not occur as a result of the testing. | Average cumulative wear at 5 Mc was 16.0 ± 0.87 mg. The steady-state wear rate was 2.86 mg/million cycles between 2 and 5 million cycles. Average central height loss of the inferior component at 5 Mc was 0.096 ± 0.008 mm. No implant failure was observed. | {7} | PRECLINICAL ANIMAL TESTING | | | | | | --- | --- | --- | --- | --- | | The PCM device was implanted into the cervical spine of goats to evaluate the short-term biological and mechanical responses to the device in vivo. There was no evidence of mechanical loosening and there were no adverse reactions to the device. Particulate wear debris animal testing was performed to characterize the biological response to the device. Rabbits were implanted with acute doses of CoCr particles and UHMWPE particles directly on the dura. There was no evidence of acute histopathological response to the materials. | | | | | | Test Name | Purpose | Method | Acceptance Criteria | Results | | Caprine Study | To characterize the biological and biomechanical response to the device. | Goats were implanted with the PCM device at C3-C4. Six and 12 month time-points were evaluated for histology, immunocytochemistry, and range of motion. | Animal implantation testing was performed to further establish the biological response to the device. An adverse biological response should not be present. | No animals displayed evidence of implant loosening or inflammatory reactions from particulate wear debris. Histologic evidence of osseous integration at the implant-bone interface was observed, and segmental motion was preserved between 6 and 12 months. These results suggest that the PCM device does not elicit an adverse biological response or restrict motion with time. | | Wear Debris Particulate Animal Test | To characterize the biological response to wear debris from the device. | Rabbits were implanted with acute doses of CoCr particles or UHMWPE particles placed directly on the dura. Animals were sacrificed at 3 and 6 months. | Wear debris particulate animal testing was performed to establish the biological response to the device. An adverse biological response should not be present. | At both post-operative time periods, there was no evidence of an acute neural or systemic histopathological response to the materials included in this study. These results suggest that the PCM device does not elicit an adverse biological response. | ## Additional Discussion of Wear Testing Four wear tests were completed as described in Table 2. Results from the initial 10 million cycle (Mc) test per ASTM F2423-05 were inconsistent. This test was repeated to 10 MC under cross-shear (ISO 18192-1) motions using the same small footprint (14 × 17 mm), shortest height (6.5 mm) device size in order to clarify the initial results. On completion of the test, a new worst case device size for wear testing was established and an additional ISO test was performed on the large footprint device size (17 × 20 mm) with smallest thickness (6.5 mm) which was continued to 5 MC. The recommended range of motion (ROM) and subsequent cross-shear created under ISO 18192-1 may not be consistent with the in vivo kinematics of a large bearing radius, semi-constrained TDR device, such as PCM, for both the small and large footprint devices. In order to develop a more clinically relevant wear test, ISO motion parameters were modified by incorporating actual motions derived from the IDE study. Motion parameters were based on: - ISO 18192-1: - “the aim of the wear test method is to simulate average loading conditions rather than the extreme”, and - “daily living activities are assumed to cover a certain percentage of the maximum range of motion with single events of higher loads and motions.” - Full active flexion-extension and lateral bending ROM for the PCM large footprint device at 2 years were independently assessed by a core radiographic laboratory. The 95th PMA P100012: FDA Summary of Safety and Effectiveness Page 8 of 61 {8} percentile motions were used to provide a robust estimation of the population (the 95th percentile was also greater than 2 standard deviations from the mean). - Literature analysis revealed that most activities of daily living (ADL) utilized 10-20% of the full active ROM. To be conservative, 50% of the full ROM was adopted. Axial rotation motion was based on worst-case (highest cross-shear) coupled motion reported by White and Panjabi¹ of 2° of coupled axial rotation for every 3° of lateral bending. - The motion parameters are provided in Table 3. Other wear testing parameters were as defined by ISO 18192-1. Table 3: Clinically-Derived Motions for Wear Testing Based on ADLs of 50% of Full Active ROM (95th Percentile) | Motion | ADL ROM (50% of Full Active ROM) (degrees) | | --- | --- | | Flexion-Extension | 6.5° (±3.25°) | | Lateral Bending | 3.5° (±1.75°) | | Axial Rotation | 2.3° (±1.17°) | ## B. Biocompatibility The PCM Cervical Disc is composed of the following materials: cobalt chromium molybdenum (CoCrMo) endplates per ISO 5832-12; an ultra-high molecular weight polyethylene (UHMWPE) core per ISO 5834-1, ISO 5834-2 and ASTM F648; Titanium locking plate per ISO 5832-2 and ASTM F67; and titanium plasma spray (TPS) and calcium phosphate (CaP) coatings. Biocompatibility testing was performed on the PCM Cervical Disc in their final sterilized state. Testing was conducted according to the requirements of ISO 10993-1, for the level and contact duration of a permanent implant contacting tissue and bone. The battery of biocompatibility tests conducted include: Cytotoxicity - MEM Elution (ISO 10993-5), Sensitization (ISO 10993-10), Intracutaneous Reactivity Test (Irritation) (ISO 10993-10), Acute Systemic Toxicity (ISO 10993-11), Genotoxicity - Ames Test (ISO 10993-3), and Genotoxicity - Chromosomal Aberration (ISO 10993-3). All test results met acceptance criteria demonstrating biocompatibility in line with the requirements of ISO 10993-1. ## C. Sterilization and Shelf Life A full sterilization validation has been conducted in accordance with 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. In order to validate the distribution and shelf-life of the PCM Cervical Disc, a distribution simulation and accelerated aging test has been conducted to support a five-year shelf life for the product. PMA P100012: FDA Summary of Safety and Effectiveness Page 9 of 61 {9} # X. SUMMARY OF CLINICAL STUDIES Clinical data were collected in the United States under IDE G040081 to evaluate the safety and effectiveness of the PCM Cervical Disc. Data from this clinical study were the basis for the PMA approval decision. A summary of the pivotal clinical study is presented below. ## A. Study Design and Objective A prospective, multicenter, two-arm, randomized, concurrently controlled, non-inferiority clinical trial to compare the safety and effectiveness of the PCM Cervical Disc with anterior cervical discectomy and fusion (ACDF) with allograft and plate in treating patients with a degenerated cervical disc at one level from C3-C4 to C7-T1. Clinical surgeries were performed during a period from January 19, 2005, to December 5, 2007. A total of 494 patients were enrolled at 24 investigational sites and 479 were treated in the clinical trial. Each investigational site was allowed to enroll a maximum of four patients in order for the investigators to become familiar with the implantation procedure for the PCM Cervical Disc. Overall, 289 patients were treated with the PCM Cervical Disc (75 Training, 214 PCM) and 190 were treated with ACDF. Note, 1 Training PCM patient and 4 randomized PCM patients were intraoperatively switched to receive ACDF due to surgical reasons. The control group received a standard ACDF using the Synthes CSLP or DePuy Spine Slim-Loc System anterior cervical plate and structural allograft. Among the 289 investigational patients treated in the IDE study, 198 received the PCM Standard device and 91 received the PCM-V device. The Sponsor was able to justify the poolability of the PCM Standard and PCM-V devices (see Poolability Analysis discussion). The various analyses were carried out on this subset cohort in addition to analyses on the all enrolled cohort. In PMA P100012, the applicant is only seeking marketing approval for the PCM-V. The results and conclusions presented below represent updated data collected through September 2011. Patients were evaluated preoperatively, intraoperatively, immediately postoperatively and then at 6 Weeks, 3 Months, 6 Months, 12 Months and 24 Months, and annually thereafter. The recommended postoperative care included a physical therapy program for non-impact exercises and active range of motion exercises. Patients were instructed to avoid repetitive cervical flexion and extension bending and lateral bending and rotation for 6 weeks following surgery. All adverse events (implant-related or not) were monitored over the course of the trial and radiographic assessments were performed by an independent core laboratory. For the PMA, all adverse events were independently adjudicated (for adverse event code, severity and relationship to the device and/or procedure) by a Clinical Events Committee comprised of three board-certified spine surgeons. The clinical trial used a non-inferiority study design, with a non-inferiority margin (delta) of 12.5%, to compare the overall success rate at 24 months postoperative between the PCM and ACDF groups. The primary overall success endpoint is a composite of several subcomponents, each of which must be a success in order for a patient to be deemed an overall success. Additional analyses were performed using a non-inferiority margin of 10% as requested by the Food and Drug Administration (FDA). PMA P100012: FDA Summary of Safety and Effectiveness Page 10 of 61 {10} PMA P100012: FDA Summary of Safety and Effectiveness Page 11 of 61 # B. Study Population The target population was comprised of patients with degenerated cervical discs and neurological symptoms at one level from C3 to T1. The study participants must have met the following inclusion/exclusion criteria: ## Inclusion Criteria To have qualified for enrollment in this study, patients must have met *all* of the inclusion criteria as follows: - Age 18-65 years; - Diagnosis of radiculopathy or myelopathy of the cervical spine, with either radiculopathy symptoms – pain, paresthesias, or paralysis in a specific nerve root distribution C4, C5, C6, C7, or C8, including at least one of the following: arm/shoulder pain (at least 30 mm on 100 mm VAS scale); decreased muscle strength of at least one level on the 0-5 scale; abnormal sensation, including hyperesthesia or hypoesthesia; and/or abnormal reflexes; or myelopathy symptoms including positive Romberg evaluation, abnormal heel/toe walk, pathologic hyperreflexia or clonus in lower extremity, positive Babinski, or positive Hoffman’s; - Symptomatic at only one level from C3-C4 to C7-T1; - Radiographically determined pathology at level to be treated correlating to primary symptoms, including at least one of the following: - Decreased disc height compared to adjacent levels on radiographic film, CT, or MRI; - Degenerative spondylosis on CT or MRI; - Disc herniation on CT or MRI. - Neck Disability Index (NDI) score ≥30% (15/50); - Unresponsive to non-operative treatment for six weeks, or has the presence of progressive symptoms or signs of nerve root/spinal cord compression in the face of conservative treatment; - Appropriate for treatment using an anterior surgical approach, including having no more than one previous anterior surgical approach to the cervical spine; - Ability and willingness to comply with follow-up regimen; and - Written informed consent given by patient or patient's legally authorized representative. ## Exclusion Criteria To have qualified for enrollment in this study, patients must have met *none* of the exclusion criteria as follows: - Infection at the site of surgery; - History of, or anticipated treatment for, active systemic infection, including HIV infection or hepatitis C; - Prior attempted or completed cervical spine surgery, except (1) laminoforaminotomy, which includes removal of disc material necessary to perform a nerve root decompression, with less than one-third facetectomy at any level, or (2) a successful single-level anterior cervical fusion; - More than one immobile vertebral level between C1-T1 from any cause, including but not limited to congenital abnormalities, osteoarthritic “spontaneous” fusions, and prior cervical spinal fusions; {11} - Previous trauma to the C3-T1 levels resulting in significant bony or disco-ligamentous cervical spine injury; - Axial neck pain in the absence of other symptoms of radiculopathy or myelopathy justifying the need for surgical intervention; - Radiographic confirmation of severe facet joint disease or degeneration. - Osteoporosis: A screening questionnaire for osteoporosis, SCORE (Simple Calculated Osteoporosis Risk Estimation), will be used to screen patients to determine those patients who require a DEXA bone mineral density measurement. If DEXA is required, exclusion will be defined as a DEXA bone density measured T score ≤ -2.5 (The World Health Organization definition of osteoporosis); - Paget’s disease, osteomalacia, or any other metabolic bone disease (excluding osteoporosis which is addressed above); - Severe diabetes mellitus requiring daily insulin management; - Active malignancy: a history of any invasive malignancy (except non-melanoma skin cancer), unless the patient has been treated with curative intent and there have been no clinical signs or symptoms of the malignancy for at least 5 years; - Tumor as source of symptoms; - Symptomatic degenerative disc disease or significant cervical spondylosis at two or more levels; - Marked cervical instability on resting lateral or flexion/extension radiographs demonstrated by: - Translation &gt; 3.5 mm and/or; - &gt; 11° angular difference to that of either adjacent level; - Known or suspected allergy to cobalt, chromium, molybdenum, titanium, or polyethylene; - Severe myelopathy to the extent that the patient is wheelchair bound; - Congenital canal stenosis resulting in a canal diameter of &lt; 10 mm, as measured by CT or MRI; - Kyphotic segmental angulation of greater than 11° at treatment or adjacent levels; - Arachnoiditis; - Pregnant (verified in patients of childbearing potential by a negative urine pregnancy test when preadmission testing is obtained), or interested in becoming pregnant during the duration of the study; - Autoimmune disorders that impact the musculoskeletal system (e.g., lupus, rheumatoid arthritis; ankylosing spondylitis); - Congenital bony and/or spinal cord abnormalities that affect spinal stability; - Spinal axis disease (thoracic or lumbar) to the extent that surgical consideration is likely anticipated within 6 months after the randomized cervical procedure; - Other degenerative joint disease (e.g. shoulder, hip, knee) to the extent that surgical consideration is likely anticipated within 6 months after the randomized cervical procedure; - Previous spine surgery within the 6 months preceding the randomized cervical procedure; - Diseases or conditions that would preclude accurate clinical evaluation (e.g. neuromuscular disorders); - Medications that could interfere with fusion or other bone/soft tissue healing (e.g. anticipated continued use of systemic steroid medication postoperatively); - Currently experiencing acute episode of major mental illness (psychosis, major affective disorder, or schizophrenia), or manifesting physical symptoms without a diagnosable medical condition to account for the symptoms, which may indicate symptoms of psychological rather than physical origin; PMA P100012: FDA Summary of Safety and Effectiveness Page 12 of 61 {12} - Current or recent history of substance abuse (drug or alcohol); - Morbid obesity, defined as body mass index (BMI) &gt; 40 or more than 100 lbs. over ideal body weight; - Currently using, or planning to use, bone growth stimulators in the cervical spine; - Use of any other investigational drug or medical device within the last 30 days prior to surgery - Currently a prisoner; or - Currently pursuing personal litigation (defined as litigation that will likely influence the patient’s ability or willingness to accurately report their treatment outcomes) related to the neck or cervical spine injury; however, involvement in worker’s compensation related litigation is not a required exclusion. ## C. Sample Size Determination This clinical study was based on a non-inferiority hypothesis that the primary overall success rate of the investigational PCM group was statistically non-inferior to the ACDF control group’s rate. Based on Blackwelder’s method⁹ and assuming an overall success rate of 70% for both the PCM and ACDF groups, a 1.3:1 randomization ratio, a 12.5% non-inferiority margin (delta), a type I error of 5% (one-sided), and 80% power, the necessary sample size was determined to be 340 patients (192 PCM patients and 148 ACDF patients). Accounting for up to a 15% drop-out rate, loss to follow-up and small differences based on site-stratified randomization, the total sample size was upward adjusted to 416 patients (226 PCM patients and 190 ACDF patients). This sample size did not include the additional training patients. Analyses were conducted to adequately justify the poolability of the randomized PCM-V (N=81) and PCM Standard (N=133) sub-groups. ## D. Study Evaluations The protocol required each patient to remain in the study for 24 months postoperatively. In addition, all patients were required to return for annual follow-up visits until the last enrolled patient reached the 24 Months follow-up. The visit schedule and evaluations are summarized in Table 4. All radiographic endpoints were evaluated independently at a core laboratory by a board certified independent radiologist. Table 4: Evaluation Summary and Visit Schedule | Evaluations | Preoperative (within 30 days prior to surgery) | Follow-Up Visit Windows | | | | | | | --- | --- | --- | --- | --- | --- | --- | --- | | | | Post-Operative (7-21 days) | 6 Weeks (± 2 wks) | 3 Months (± 2 wks) | 6 Months (± 2 wks) | 12 Months (± 2 wks) | 24 Months and Other Annual (± 2 wks) | | Eligibility | x | | | | | | | | Demographics | x | | | | | | | | Medical History | x | | | | | | | | Medications | x | x | x | x | x | x | x | | Neurological Assessment | x | x | x | x | x | x | x | | Radiographic Evaluation | x | x | x | x | x | x | x | | Neck Disability Index | x | | x | x | x | x | x | | Pain VAS | x | | x | x | x | x | x | | Dysphagia VAS | x | | x | x | x | x | x | PMA P100012: FDA Summary of Safety and Effectiveness Page 13 of 61 {13} | Bazaz Dysphagia | x | | x | x | x | x | x | | --- | --- | --- | --- | --- | --- | --- | --- | | Nurick's Assessment | x | | x | x | x | x | x | | Odom’s Criteria | x | | x | x | x | x | x | | SF-36 | x | | x | x | x | x | x | | Employment Status | x | | x | x | x | x | x | | Patient Satisfaction | | | | | | x | x | | Adverse Events/ Surgical Intervention | x | x | x | x | x | x | x | ## E. Study Endpoints The safety of the PCM was assessed by comparing the nature and frequency of adverse events (overall and in terms of severity and relationship to the device and/or procedure) and secondary surgical procedures as well as maintenance or improvement in neurological status to the ACDF control group. The effectiveness of the PCM was assessed by evaluating improvement in the Neck Disability Index (NDI), neck and arm pain based on a Visual Analog Scale (VAS), and quality of life using the short-form 36 questionnaire (SF-36) as well as patient satisfaction compared to the ACDF control group. In addition, several radiographic endpoints were considered in evaluating both safety and effectiveness, including range of motion, disc height, device displacement or migration, radiolucency, spinal fusion status, and heterotopic ossification. ## Primary Endpoint – Overall Success The primary endpoint of the study was individual patient overall success, a composite endpoint determined at 24 Months postoperative and defined as: - Improvement of at least 20% on the Neck Disability Index (NDI) compared to baseline; - No device failures requiring revision, reoperation, or removal; and - Absence of major complications. For the purpose of determining individual patient success, a major complication was defined as any of the following that are related to the PCM or ACDF device system or device component: - Documented permanent neurologic damage or permanent nerve root injury related to the surgically treated level, defined as: - Decrease in one or more grades of motor strength or muscle atrophy, - New onset of reflex sympathetic dystrophy, - Persistent new onset of pathologic reflexes (Babinski, Hoffman, clonus, Romberg) present at 24 Months, or - Progression of paresthesia or anaesthesia in a specific cervical nerve root distribution; - Vessel injury, bleeding, or hematoma requiring surgical intervention; - Deep infection requiring surgical intervention (irrigation / debridement) or intravenous antibiotics; - Spontaneous fusion of the treatment site (PCM patients only); or - Failure of fusion of the treated level (ACDF patients only), defined as &gt;2° of segmental movement on lateral flexion/extension x-rays and radiolucent lines at &gt;50% of the graft-vertebra interfaces. PMA P100012: FDA Summary of Safety and Effectiveness Page 14 of 61 {14} # Secondary Endpoints Secondary endpoints included: - Time to recovery, defined as time to first achieve at least 20% improvement on NDI, sustained over all subsequent follow-up visits, as well as the following assessments at 24 Months compared to baseline - Neck Pain VAS - Arm Pain VAS - Neurological status - Spinal stability - Disc height - Quality of Life, SF-36 - Dysphagia VAS - Bazaz dysphagia index - Patient satisfaction - Nurick’s myelopathy assessment - Displacement or migration of the device, graft or plate - Radiolucency at the metal bone interface for the PCM - Heterotopic ossification - Adjacent segment degeneration - Range of motion in flexion/extension at the operated level # Other Endpoints Other endpoints included: - Duration of hospitalization - Blood loss - Operative time # Safety Assessment Information on all adverse events was collected during the course of the study. # F. Accountability of PMA Cohort The patient accountability data are summarized in Table 5, where training cases are referred to as the Training (TRN) group, the randomized investigational patients are referred to as the PCM group, and the randomized ACDF control patients are referred to as the ACDF group. The follow-up rates are calculated from a maximum Per Protocol population of 75 Training, 211 PCM, and 184 ACDF patients. The patients evaluable for the primary composite overall success endpoint at 24 Months were 74.7%, 89.6% and 82.1% for the Training group, PCM group, and ACDF group, respectively. PMA P100012: FDA Summary of Safety and Effectiveness Page 15 of 61 {15} Table 5: Patient Accountability | | 12 Months (±2 Months) | | | 24 Months (-3 Months, +6 Months) | | | 36 Months (±6 Months) | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | TRN | PCM | ACDF | TRN | PCM | ACDF | TRN | PCM | ACDF | | Enrolled/ITT | 78 | 224 | 192 | 78 | 224 | 192 | 78 | 224 | 192 | | Not Treated | 2 | 6 | 7 | 2 | 6 | 7 | 2 | 6 | 7 | | Treated (MITT) | 76 | 218 | 185 | 76 | 218 | 185 | 76 | 218 | 185 | | Treated (Safety) | 75 | 214 | 190 | 75 | 214 | 190 | 75 | 214 | 190 | | Deaths | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | | Eligible Deviations | 1 | 6 | 1 | 1 | 6 | 1 | 1 | 6 | 1 | | Not Yet Overdue | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | | Per Protocol (Maximum) | 75 | 211 | 184 | 75 | 211 | 184 | 75 | 211 | 184 | | Per Protocol (In Window) | 66 | 202 | 162 | 56 | 189 | 153 | 46 | 180 | 141 | | Primary Endpoint (Protocol Defined)* | 65 | 198 | 156 | 56 | 189 | 151 | 51 | 182 | 136 | | % Follow-up, Primary Endpoint (Protocol Defined)# | 86.7% | 93.8% | 84.8% | 74.7% | 89.6% | 82.1% | 68.0% | 86.3% | 73.9% | ITT = Intent-to-Treat; MITT = Modified Intent-to-Treat. * Number of patients evaluable for the primary composite overall success endpoint as defined in the protocol. # % Follow-up, Primary Endpoint = Primary Endpoint (Protocol Defined) / Per Protocol (Maximum). The following flow diagram in Figure 2 illustrates the origins of the analysis populations: Enrolled, Intent-to-Treat (ITT), Modified Intent-to-Treat (MITT), Per Protocol, Per Protocol In Window, and Safety. The analysis populations are defined as follows: - Enrolled population includes any patient who gave Informed Consent and was enrolled. Analysis by group the patient was enrolled to. - Intent-to-Treat (ITT) population includes any patient who was enrolled (Training) or randomized (PCM, ACDF). Analysis by group the patient was enrolled (Training) or randomized (PCM, ACDF) to. - Modified Intent-to-Treat (MITT) population includes any patient who was treated. Analysis by group the patient was enrolled (Training) or randomized (PCM, ACDF) to. - Per Protocol population includes any patient who was treated with the device they were randomized to, met the eligibility criteria, and had no major protocol violations. Analysis by group the patient was enrolled (Training) or randomized (PCM, ACDF) to. - Per Protocol In Window population includes any patients who was treated with the device they were enrolled/randomized to, met the eligibility criteria, had no major protocol violations, and had a 24 Months visit within the visit window (i.e., 21 to 30 months). Analysis by group the patient was enrolled (Training) or randomized (PCM, ACDF) to. - Safety population includes any patient who was treated. Analysis by group the patient was actually treated with (i.e., as-treated). The Safety population is the basis of the safety analyses. Patient Demographics, Baseline Characteristics, and Surgical Characteristics were analyzed using both the MITT and Per Protocol In Window population. PMA P100012: FDA Summary of Safety and Effectiveness Page 16 of 61 {16} The principal analysis of the primary endpoint was based on the Per Protocol population, with a visit window at 24 Months of -3 months to +6 months (e.g., 21 to 30 months). All primary endpoint statistical comparisons are made between the randomized PCM and ACDF groups. Analysis of the secondary endpoints was generally based on the Per Protocol In Window population, with statistical comparisons being made between the randomized group. The primary and select secondary endpoints were also analyzed using ITT and MITT population. Sensitivity analyses were performed to assess the effect of covariates on the primary endpoint analysis. In addition, various imputation scenarios (e.g., Worst-Case) were performed to assess the potential effect of missing data on the primary endpoint analysis. Sub-group analyses were conducted to justify the poolability of the randomized PCM-V (N=81) and PCM Standard (N=133) cohorts.  Figure 2: Patient Accountability Flowchart PMA P100012: FDA Summary of Safety and Effectiveness Page 17 of 61 {17} The data accounting for the protocol-required 24 Months clinical and radiographic assessments are tabulated in Table 6. Table 6: Patient Data Accounting at 24 Months | | Training | PCM | ACDF | | --- | --- | --- | --- | | Enrolled/ITT | 78 | 224 | 192 | | Treated (MITT) | 76 | 218 | 185 | | Treated (Safety; As-Treated) | 75 | 214 | 190 | | Eligible Deviations | 1 | 6 | 1 | | Deaths | 0 | 1 | 0 | | Per Protocol (Maximum) | 75 | 211 | 184 | | Per Protocol (In Window) | 56 | 189 | 153 | | Clinical Assessments, n (%)* | | | | | Neck Disability Index (NDI) | 55 (73.3%) | 187 (88.6%) | 151 (82.1%) | | VAS Neck and Arm Pain | 55 (73.3%) | 187 (88.6%) | 150 (81.5%) | | SF-36 | 54 (72.0%) | 187 (88.6%) | 151 (82.1%) | | Patient Satisfaction | 53 (70.7%) | 182 (86.3%) | 146 (79.3%) | | Dysphagia | 52 (69.3%) | 187 (88.6%) | 149 (81.0%) | | Neurological Exam | 54 (72.0%) | 188 (89.1%) | 153 (83.2%) | | Radiographic Assessments, n (%)* | | | | | Normal Disc Height | 51 (68.0%) | 182 (86.3%) | 140 (76.1%) | | Maintenance of Disc Height | 50 (66.7%) | 177 (83.9%) | 135 (73.4%) | | Radiolucency | 51 (68.0%) | 182 (86.3%) | 152 (82.6%) | | Migration | 51 (68.0%) | 182 (86.3%) | 152 (82.6%) | | ROM | 53 (70.7%) | 182 (86.3%) | 151 (82.1%) | | Dynamic Canal Stenosis | 51 (68.0%) | 182 (86.3%) | 144 (78.3%) | | Spine Stability | 53 (70.7%) | 182 (86.3%) | 149 (81.0%) | | Hypermobility | 52 (69.3%) | 181 (85.8%) | 149 (81.0%) | | Heterotopic Ossification | 51 (68.0%) | 182 (86.3%) | NA | | Adjacent Segment Degeneration | 41 (54.7%) | 147 (69.7%) | 119 (64.7%) | ITT = Intent-to-Treat.; MITT = Modified Intent-to-Treat. * Percentage are based on the Per Protocol (Maximum) patient population. PMA P100012: FDA Summary of Safety and Effectiveness Page 18 of 61 {18} # G. Patient Demographics and Baseline Parameters The demographics of the study population are typical for a cervical artificial disc study conducted in the US. Demographic data and preoperative evaluations for all patients enrolled and treated in the study are included in Table 7 and Table 8. Table 7: Patient Demographics and Baseline Characteristics (Modified Intent-to-Treat Population) | | Training (N=76) | PCM (N=218) | ACDF (N=185) | P-Value* | | --- | --- | --- | --- | --- | | Age, mean (SD) years | 42.2 (8.2) | 45.3 (9.0) | 43.7 (8.3) | 0.059 (b) | | Female, no. (%) | 29 (38.2%) | 105 (48.2%) | 89 (48.1%) | 0.991 (a) | | Race, no. (%) | | | | | | Caucasian | 70 (92.1%) | 202 (92.7%) | 170 (91.9%) | 0.145 (a) | | Black | 2 (2.6%) | 10 (4.6%) | 7 (3.8%) | | | Asian | 0 (0.0%) | 0 (0.0%) | 5 (2.7%) | | | Hispanic | 3 (3.9%) | 3 (1.4%) | 2 (1.1%) | | | Other | 1 (1.3%) | 3 (1.4%) | 1 (0.5%) | | | Height, mean (SD) inches | 68.3 (4.4) | 67.4 (4.2) | 67.3 (3.8) | 0.737 (b) | | Weight, mean (SD) pounds | 186.0 (40.2) | 182.9 (39.9) | 177.1 (38.8) | 0.143 (b) | | BMI, mean (SD) kg/m² | 28.0 (4.9) | 28.2 (4.6) | 27.3 (4.8) | 0.079 (b) | | Current Tobacco Use, no. (%) | 39 (51.3%) | 113 (51.8%) | 90 (48.6%) | 0.524 (a) | | History Nonoperative Care, no. (%) | | | | | | Medication Used | 73 (96.1%) | 210 (96.3%) | 181 (97.8%) | 0.558 (c) | | Injections | 34 (44.7%) | 117 (53.7%) | 80 (43.2%) | 0.045 (c) | | Physical Therapy | 54 (71.1%) | 157 (72.0%) | 126 (68.1%) | 0.444 (c) | | Brace | 5 (6.6%) | 24 (11.0%) | 25 (13.5%) | 0.449 (c) | | Chiropractic | 24 (31.6%) | 66 (30.3%) | 75 (40.5%) | 0.036 (c) | | Other | 20 (26.3%) | 33 (15.1%) | 39 (21.1%) | 0.151 (c) | | History Prior Surgery, no. (%) | | | | | | Lamino-foraminotomy without Facetectomy | 2 (2.6%) | 1 (0.5%) | 3 (1.6%) | 0.337 (c) | | Lamino-foraminotomy with Facetectomy | 0 (0.0%) | 1 (0.5%) | 4 (2.2%) | 0.184 (c) | | Fusion | 14 (18.4%) | 29 (13.3%) | 20 (10.8%) | 0.541 (c) | | Neurological Symptoms, no. (%) | | | | | | Radiculopathy and Myelopathy | 11 (14.5%) | 33 (15.1%) | 45 (24.3%) | 0.023 (c) | | Radiculopathy Only | 65 (85.5%) | 184 (84.4%) | 140 (75.7%) | | | Myelopathy Only | 0 (0.0%) | 1 (0.4%) | 0 (0.0%) | | | Radiographic Findings, no. (%) | | | | | | Herniated Nucleus Pulposus | 66 (86.8%) | 176 (80.7%) | 155 (83.8%) | 0.437 (c) | | Spondylosis | 11 (14.5%) | 41 (18.8%) | 28 (15.1%) | 0.355 (c) | | Loss of Disc Height | 16 (21.1%) | 39 (17.9%) | 53 (28.6%) | 0.012 (c) | Note: Percentages are based on total number of patients for each treatment group. * Comparing PCM and ACDF (two-sided): (a) Chi-squared test; (b) t-test; (c) Fisher's exact test. P-values are not adjusted for multiplicity. They are included to help clinical interpretation, without defining statistical significance. PMA P100012: FDA Summary of Safety and Effectiveness Page 19 of 61 {19} Preoperative clinical and radiographic endpoints, including Neck Disability Index (NDI) scores, Visual Analog Scale (VAS) Neck Pain, VAS Arm Pain (left, right, worst arm), SF-36 (Physical Component Score [PCS] and Mental Component Score [MCS]), neurological status, and index level range of motion (ROM) and translation, are shown in Table 8. Based on the baseline evaluations, it was concluded that the randomization was successful and the PCM and ACDF groups were similar and well balanced. Table 8: Baseline Evaluation of Clinical Endpoints (Per Protocol 24 Months In Window Population) | Endpoint | Training (N=56) | PCM (N=189) | ACDF (N=153) | P-Value | | --- | --- | --- | --- | --- | | Neck Disability Index (NDI) | 51.2 (13.8) | 55.8 (14.5) | 54.7 (14.0) | 0.470 (a) | | VAS Neck Pain, mm | 66.8 (24.5) | 68.4 (22.3) | 73.5 (18.6) | 0.076 (a) | | VAS Right Arm Pain, mm | 49.3 (34.3) | 47.9 (33.7) | 50.6 (33.4) | 0.625 (a) | | VAS Left Arm Pain, mm | 43.0 (36.7) | 51.2 (33.9) | 50.0 (32.6) | 0.679 (a) | | VAS Worst Arm Pain, mm | 74.9 (17.3) | 73.4 (19.4) | 74.4 (18.2) | 0.791 (a) | | SF-36 PCS | 36.3 (6.3) | 34.4 (6.8) | 34.6 (6.3) | 0.681 (b) | | SF-36 MCS | 43.0 (12.7) | 43.3 (12.3) | 41.9 (11.4) | 0.303 (b) | | Neurological Status, no. (%) | | | | | | Motor (normal) | 18 (32.1%) | 63 (33.3%) | 57 (37.3%) | 0.495 (c) | | Sensory (normal) | 24 (42.9%) | 87 (46.0%) | 68 (44.4%) | 0.827 (c) | | Reflexes (normal) | 49 (87.5%) | 167 (88.4%) | 124 (81.0%) | 0.068 (c) | | Range of Motion, degrees | 7.9 (4.5) | 7.9 (4.7) | 7.8 (4.4) | 0.910 (b) | | Translation, mm | 0.8 (0.5) | 0.9 (0.6) | 0.9 (0.7) | 0.470 (b) | Note: Continuous variables are reported as means and standard deviations. * Comparing PCM and ACDF (two-sided): (a) Mann-Whitney-Wilcoxon rank sum test; (b) t-test; (c) Fisher's exact test. P-values are not adjusted for multiplicity. They are included to help clinical interpretation, without defining statistical significance. ## H. Surgical and Hospitalization Parameters Typical operative characteristics including surgical time, blood loss, and length of hospital stay are reported in Table 9. There were differences between the groups in mean surgical time, at 100.8 minutes (SD 42.0) in the PCM group, compared to 85.7 (SD 40.5) minutes in the control group. The average 15.1 minute difference may be explained by differences in disc space preparation surgical technique associated with the surgeons learning a new procedure. The mean surgical time of the Training group alone was 127.6 minutes (SD 47.5). The amount of blood loss was comparable between groups with 65.6 mL for PCM and 58.6 mL for ACDF. The average length of hospital stay was shorter in the PCM group at 1.2 days (range 0-3) compared to the ACDF group at 1.4 days (range 0-6). Similar and comparable results were obtained when the analysis was performed on the Per Protocol In Window population. PMA P100012: FDA Summary of Safety and Effectiveness Page 20 of 61 {20} Table 9: Surgical Data (Modified Intent-to-Treat Population) | | Training (N=76) | PCM (N=218) | ACDF (N=185) | | --- | --- | --- | --- | | Treated Level, no. (%) | | | | | C3-C4 | 1 (1.3%) | 0 (0.0)% | 8 (4.3%) | | C4-C5 | 5 (6.6%) | 31 (14.2%) | 17 (9.2%) | | C5-C6 | 33 (43.4%) | 109 (50.0%) | 98 (53.0%) | | C6-C7 | 35 (46.1%) | 76 (34.9%) | 62 (33.5%) | | C7-T1 | 2 (2.6%) | 2 (0.9%) | 0 (0.0%) | | Surgery Time, mean (SD) min | 126.7 (45.6) | 100.8 (42.0) | 85.7 (40.5) | | Blood Loss, mean (SD) mL | 82.5 (58.5) | 65.6 (48.3) | 58.6 (46.1) | | Hospitalization, mean (SD) days | 1.3 (0.6) | 1.2 (0.6) | 1.4 (0.7) | In the PCM group, a conventional discectomy was performed to remove the disc and accomplish neural decompression, and the disc space was then prepared to receive the PCM implant. The depth and width of the disc space were measured, and PCM trial sizers were used to maximize endplate coverage and select the appropriate implant footprint. This was verified radiographically. In the clinical study, the Small PCM was implanted in 18.7% of patients, Medium PCM in 46.3%, and Large PCM in 35.0%. The selected PCM heights were 6.5 mm in 76.8%, 7.2 mm in 6.2%, and 8.0 mm in 17.0% of patients. The PCM Standard was used in 68.6% of cases and the PCM-V was used in 31.4%. Table 10: PCM Implants Used (Safety Population; N=289) | Height | Small (14mm × 17mm) | Medium (16mm × 17mm) | Large (17mm × 20mm) | | --- | --- | --- | --- | | Standard (n=198), no. (%) | | | | | 6.5 mm | 26 (9.0%) | 77 (26.6%) | 48 (16.7%) | | 8.0 mm | 6 (2.1%) | 15 (5.2%) | 26 (9.0%) | | V-Teeth (n=91), no. (%) | | | | | 6.5 mm | 22 (7.6%) | 33 (11.4%) | 16 (5.5%) | | 7.2 mm | 0 (0.0%) | 7 (2.4%) | 11 (3.8%) | | 8.0 mm | 0 (0.0%) | 2 (0.7%) | 0 (0.0%) | Note: Percentages (%) are based on PCM Safety population (combined Training and PCM). ## I. Safety and Effectiveness Results ### 1) Safety Results The safety of the investigational treatment was assessed based on the Safety (as-treated) population of 479 patients (75 Training, 214 PCM, and 190 ACDF). One Training patient and 4 PCM patients were intraoperatively switched to the ACDF procedure. In the following safety analyses, they are classified in the ACDF group. As of September 2011, the average follow-up time for the Training, PCM, and ACDF groups were 5.7 years, 5.1 years, and 4.9 years, respectively. All Adverse Events (AEs) were classified as Serious Adverse Events (SAEs), Subsequent Secondary Surgical Interventions (SSSIs), or Unanticipated Adverse Device Effects (UADE), according to the protocol definitions. A Clinical Events Committee (CEC) was utilized during the course of the PCM study to provide an expert assessment of study safety data. Details pertaining to the adverse event categories are provided in Section XVI. PMA P100012: FDA Summary of Safety and Effectiveness Page 21 of 61 {21} # a) Adverse Events The definitions for the adverse event categories are provided below: | Category | Definition | | --- | --- | | Implant Related Events - Related or possibly related to the implant | | | Adjacent Level Disease | Onset of degeneration or spinal disease at a level adjacent to the implant. | | Implant Displacement/Loosening | Migration or loosening of the implant. | | Malpositioned Implant | Improper placement of the implant. | | Neck/Arm Pain | Pain in the neck and/or arm. | | Non-union | Failure of the vertebral bodies to fuse at the treated level. | | Other | Other events not defined, includes implant related headaches and implant noise. | | Radiolucency | Transparency of the bony structures surrounding the implant. | | Spinal Event | Degeneration or disease of the spine, including bone growth and stenosis. | | Subsidence | Events associated with implant subsidence into the vertebral bone. | | Trauma | Damage inflicted on the body as the direct or indirect result of an external force. | | Surgery Related Events - Related or possibly related to the surgical procedure | | | Dysphagia/Dysphonia | Difficulty swallowing or speaking. | | Gastrointestinal | Ailments relating to or affecting the stomach or intestines. | | Incision Site | Events associated with the surgical incision site. | | Infection | Ailments associated with an infectious agent. | | Neck/Arm Pain | Events primarily associated with reports of neck and/or arm pain. | | Neurologic | Conditions related to or potentially related to the neurological system. | | Other | Events or unknown etiology or that cannot be readily classified into other criteria | | Respiratory | Ailments or symptoms associated with respiration or the respiratory system. | | Spinal Event | Events or conditions associated with the spine. | | Urogenital | Conditions relating to or affecting the organs or functions of excretion and reproduction. | | Vertebral Fracture | Fractures of the vertebra. | | Systemic Events - Unrelated to the device or surgical procedure | | | Cardiac Events | Any condition primarily associated with the heart and/or vascular system. | | Dysphagia/Dysphonia | Difficulty swallowing or speaking. | | Gastrointestinal | Ailments relating to or affecting the stomach or intestines. | | Infection | Ailments associated with an infectious agent. | | Mental Disorder | Ailments or disorders of a psychiatric nature or origin. | | Musculoskeletal Trauma | Conditions pertaining to the muscles and skeleton, such as fracture, ligament tear, arthritis of any kind, and degenerative conditions, excluding muscle spasms and events related to spinal degenerative conditions | | Musculoskeletal/Adjacent Level Disease | Conditions pertaining to the muscles and skeleton associated with Adjacent Level Disease of the spine | | Musculoskeletal/Back/Leg Pain | Conditions pertaining to the muscles and skeleton primarily associated with reports of back and/or leg pain. | | Musculoskeletal/Neck/Arm Pain | Conditions pertaining to the muscles and skeleton primarily associated with reports of neck and/or arm pain. | | Musculoskeletal/Other | Conditions pertaining to the muscles and skeleton of unknown etiology or that cannot be readily be classified in another category. | | Musculoskeletal/Spinal Event | Conditions pertaining to the muscles and skeleton primarily associated with the spine. | | Neurologic | Conditions related to or potentially related to the neurological system. | | Other | Events or unknown etiology or that cannot be readily classified into other criteria. | | Other Trauma | Traumatic events associated with symptoms not identified in any other category. | | Respiratory | Ailments or symptoms associated with respiration or the respiratory system. | | Urogenital | Conditions relating to or affecting the organs or functions of excretion and reproduction. | PMA P100012: FDA Summary of Safety and Effectiveness Page 22 of 61 {22} A summary of all adverse events is shown in Table 11. There were a total of 226 AEs in the Training group, 507 AEs in the PCM group, and 484 AEs in the ACDF group. Table 11: Summary of Adverse Events (Safety Population) | Category | Counts | Training (N=75) | PCM (N=214) | ACDF (N=190) | P-Value | | --- | --- | --- | --- | --- | --- | | All Adverse Events (AEs) | Patients (%) | 59 (79%) | 180 (84%) | 163 (86%) | 0.678 | | | Events (E/pt) | 226 (3.0) | 507 (2.4) | 484 (2.6) | | | Implant-Related AEs | Patients (%) | 26 (35%) | 29 (14%) | 44 (23%) | 0.014 | | | Events (E/pt) | 35 (0.5) | 33 (0.2) | 54 (0.3) | | | Surgery-Related AEs | Patients (%) | 23 (31%) | 59 (28%) | 67 (35%) | 0.107 | | | Events (E/pt) | 35 (0.5) | 79 (0.4) | 97 (0.5) | | | Serious Adverse Events (SAEs) | Patients (%) | 23 (31%) | 68 (32%) | 57 (30%) | 0.747 | | | Events (E/pt) | 51 (0.7) | 95 (0.4) | 86 (0.5) | | | AEs within 48 Hours of Surgery | Patients (%) | 12 (16%) | 31 (14%) | 26 (14%) | 0.887 | | | Events | 15 (0.2) | 32 (0.2) | 35 (0.2) | | | Device Failures (Revision, Reoperation, Removal, or Supplemental Fixation) | Patients (%) | 9 (12%) | 16 (7%) | 14 (7%) | 1.000 | | | Events (E/pt) | 11 (0.1) | 16 (0.1) | 14 (0.1) | | Note: 1. Adverse Events (AEs) based on cumulative AE database as of September 2011. 2. Percentages and events/patients are based on total number of patients for each treatment group. * Comparing PCM and ACDF based on Fisher's exact test (two-sided). P-values are not adjusted for multiplicity. They are included to help clinical interpretation, without defining statistical significance. Table 12 lists the adverse events by category for the All PCM group (Training and PCM) and the ACDF group. PMA P100012: FDA Summary of Safety and Effectiveness 30 Page 23 of 61 {23} Page 24 of 61 PMA P1 :2: FDA Summary of Safety and Effectiveness Table 12: All Adverse Events (Safety Population) | Adverse Event | Intraop (0 - 2 Days) | | Periop (>2 Days -6 Wks.) | | Short Term (>6 Wks. - 12 Mon.) | | Long Term (>12 - 24 Mon.) | | Longer Term (>24 Mon.) | | All PCM (N=289) | | ACDF (N=190) | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | All PCM | ACDF | All PCM | ACDF | All PCM | ACDF | All PCM | ACDF | All PCM | ACDF | Pts (%) | Events (E/Pt) | Pts (%) | Events (E/Pt) | | All Adverse Events | 47 | 35 | 78 | 40 | 182 | 120 | 179 | 138 | 247 | 151 | 239 (82.7%) | 733 (2.54) | 163 (85.8%) | 484 (2.55) | | Implant Related - Adjacent Level Disease | 0 | 0 | 0 | 0 | 4 | 5 | 2 | 17 | 3 | 7 | 9 (3.1%) | 9 (0.03) | 27 (14.2%) | 29 (0.15) | | Implant Related - Implant Displacement/Loosening | 0 | 0 | 2 | 0 | 8 | 1 | 6 | 0 | 6 | 0 | 22 (7.6%) | 22 (0.08) | 1 (0.5%) | 1 (0.01) | | Implant Related - Malpositioned Implant | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 1 (0.3%) | 1 (<0.01) | 0 (0.0%) | 0 (0.00) | | Implant Related - Neck/Arm Pain | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 (0.0%) | 0 (0.00) | 1 (0.5%) | 1 (0.01) | | Implant Related - Non-union | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 8 | 0 | 2 | 0 (0.0%) | 0 (0.00) | 11 (5.8%) | 12 (0.06) | | Implant Related - Other | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 (0.3%) | 1 (<0.01) | 1 (0.5%) | 1 (0.01) | | Implant Related - Radiolucency | 0 | 0 | 0 | 0 | 5 | 0 | 4 | 2 | 0 | 1 | 9 (3.1%) | 9 (0.03) | 3 (1.6%) | 3 (0.02) | | Implant Related - Spinal Event | 1 | 0 | 1 | 0 | 3 | 0 | 9 | 2 | 7 | 2 | 20 (6.9%) | 21 (0.07) | 4 (2.1%) | 4 (0.02) | | Implant Related - Subsidence | 0 | 0 | 1 | 1 | 1 | 1 | 0 | 0 | 1 | 0 | 3 (1.0%) | 3 (0.01) | 2 (1.1%) | 2 (0.01) | | Implant Related - Trauma | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 2 (0.7%) | 2 (0.01) | 1 (0.5%) | 1 (0.01) | | Surgery Related - Dysphagia/Dysphonia | 5 | 10 | 8 | 1 | 5 | 8 | 3 | 3 | 3 | 6 | 22 (7.6%) | 24 (0.08) | 23 (12.1%) | 28 (0.15) | | Surgery Related - Gastrointestinal | 2 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 (1.0%) | 3 (0.01) | 2 (1.1%) | 2 (0.01) | | Surgery Related - Incision Site | 4 | 0 | 7 | 3 | 3 | 0 | 1 | 1 | 0 | 0 | 14 (4.8%) | 15 (0.05) | 4 (2.1%) | 4 (0.02) | | Surgery Related - Infection | 0 | 0 | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.3%) | 1 (<0.01) | 1 (0.5%) | 1 (0.01) | | Surgery Related - Neck/Arm Pain | 5 | 4 | 11 | 5 | 18 | 14 | 8 | 9 | 5 | 3 | 37 (12.8%) | 47 (0.16) | 32 (16.8%) | 35 (0.18) | | Surgery Related - Neurologic | 2 | 3 | 2 | 2 | 2 | 1 | 6 | 3 | 3 | 1 | 14 (4.8%) | 15 (0.05) | 10 (5.3%) | 10 (0.05) | | Surgery Related - Other | 5 | 3 | 0 | 2 | 0 | 2 | 0 | 0 | 0 | 0 | 5 (1.7%) | 5 (0.02) | 7 (3.7%) | 7 (0.04) | | Surgery Related - Respiratory | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.3%) | 1 (<0.01) | 0 (0.0%) | 0 (0.00) | {24} Page 25 of 61 Note: Adverse Events (AEs) based on cumulative AE database as of September 2011. | Adverse Event | Intraop (0 - 2 Days) | | Periop (>2 Days - 6 Wks.) | | Heart Term (>6 Wks. - 12 Mon.) | | Long Term (>12 - 24 Mon.) | | Longer Term (>24 Mon.) | | All PCM (N=289) | | CDF (N=190) | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | All PCM | ACDF | All PCM | ACDF | All PCM | ACDF | All PCM | ACDF | All PCM | ACDF | Pts (%) | Events (E/Pt) | Pts (%) | Events (E/Pt) | | Surgery Related - Spinal Event | 0 | 1 | 0 | 0 | 1 | 1 | 0 | 4 | 1 | 2 | 2 (0.7%) | 2 (0.01) | 8 (4.2%) | 8 (0.04) | | Surgery Related - Urogenital | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 (0.0%) | 0 (0.00) | 2 (1.1%) | 2 (0.01) | | Surgery Related - Vertebral Fracture | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 (0.3%) | 1 (<0.01) | 0 (0.0%) | 0 (0.00) | | Systemic - Cardiac Events | 3 | 2 | 1 | 1 | 2 | 1 | 3 | 2 | 4 | 0 | 12 (4.2%) | 13 (0.04) | 6 (3.2%) | 6 (0.03) | | Systemic - Dysphagia/Dysphonia | 0 | 0 | 0 | 0 | 2 | 0 | 1 | 4 | 1 | 0 | 3 (1.0%) | 4 (0.01) | 4 (2.1%) | 4 (0.02) | | Systemic - Gastrointestinal | 2 | 0 | 2 | 1 | 6 | 2 | 5 | 1 | 3 | 2 | 14 (4.8%) | 18 (0.06) | 6 (3.2%) | 6 (0.03) | | Systemic - Infection | 0 | 2 | 2 | 2 | 1 | 0 | 4 | 2 | 15 | 8 | 19 (6.6%) | 22 (0.08) | 12 (6.3%) | 14 (0.07) | | Systemic - Mental Disorder | 0 | 1 | 0 | 0 | 1 | 0 | 1 | 2 | 2 | 1 | 4 (1.4%) | 4 (0.01) | 4 (2.1%) | 4 (0.02) | | Systemic - Musculoskeletal Trauma | 1 | 0 | 4 | 2 | 15 | 16 | 20 | 12 | 35 | 16 | 59 (20.4%) | 75 (0.26) | 32 (16.8%) | 46 (0.24) | | Systemic - Musculoskeletal/Adjacent Level Disease | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 2 (0.7%) | 2 (0.01) | 1 (0.5%) | 1 (0.01) | | Systemic - Musculoskeletal/Back/Leg Pain | 0 | 0 | 1 | 1 | 20 | 7 | 16 | 10 | 25 | 16 | 47 (16.3%) | 62 (0.21) | 33 (17.4%) | 34 (0.18) | | Systemic - Musculoskeletal/Neck/Arm Pain | 1 | 0 | 13 | 9 | 54 | 36 | 35 | 15 | 41 | 36 | 114 (39.4%) | 144 (0.50) | 68 (35.8%) | 96 (0.51) | | Systemic - Musculoskeletal/Other | 1 | 1 | 4 | 0 | 6 | 4 | 15 | 5 | 23 | 8 | 37 (12.8%) | 49 (0.17) | 17 (8.9%) | 18 (0.09) | | Systemic - Musculoskeletal/Spinal Event | 0 | 0 | 1 | 1 | 3 | 4 | 12 | 6 | 21 | 14 | 36 (12.5%) | 37 (0.13) | 22 (11.6%) | 25 (0.13) | | Systemic - Neurologic | 2 | 0 | 4 | 2 | 6 | 9 | 6 | 11 | 7 | 9 | 23 (8.0%) | 25 (0.09) | 27 (14.2%) | 31 (0.16) | | Systemic - Other | 7 | 3 | 5 | 4 | 14 | 3 | 15 | 13 | 31 | 12 | 57 (19.7%) | 72 (0.25) | 26 (13.7%) | 35 (0.18) | | Systemic - Other Trauma | 3 | 0 | 3 | 1 | 1 | 0 | 1 | 1 | 1 | 0 | 9 (3.1%) | 9 (0.03) | 2 (1.1%) | 2 (0.01) | | Systemic - Respiratory | 0 | 0 | 2 | 0 | 0 | 0 | 3 | 1 | 1 | 1 | 4 (1.4%) | 6 (0.02) | 2 (1.1%) | 2 (0.01) | | Systemic - Urogenital | 1 | 1 | 2 | 0 | 0 | 1 | 1 | 4 | 5 | 3 | 7 (2.4%) | 9 (0.03) | 8 (4.2%) | 9 (0.05) | PMA P100012: FDA Summary of Safety and Effectiveness {25} The cumulative number and incidence rates for each adverse event category were compared between the PCM and ACDF groups in *Table 13* which also reports unadjusted p-values (two-sided). As a result of multiplicity, caution should be used when making statistical inferences regarding difference in incidence rates. Adverse events that occurred in greater than 5% of the patients in the PCM group included Implant-Related Spinal Event (5.1%), Surgery-Related Dysphagia/Dysphonia (6.5%), Surgery-Related Incision Site (5.6%), Surgery-Related Neck/Arm Pain (9.8%), Surgery-Related Neurologic (5.6%), Systemic Gastrointestinal (5.6%), Systemic Infection (7.0%), Musculoskeletal Trauma (19.6%), Musculoskeletal Back/Leg Pain (16.8%), Musculoskeletal Other (13.6%), Musculoskeletal Spinal Event (15.0%), Musculoskeletal Neurologic (5.6%), and Systemic Other (19.6%). Adverse events that occurred in greater than 5% of the patients in the ACDF group included Implant-Related Adjacent Level Disease (14.2%), Implant-Related Non-Union (5.8%), Surgery-Related Dysphagia/Dysphonia (12.1%), Surgery-Related Neck Arm Pain (16.8%), Surgery-Related Neurologic (5.3%), Systemic Infection (6.3%), Musculoskeletal Trauma (16.8%), Musculoskeletal Back/Leg Pain (17.4%), Musculoskeletal Neck/Arm Pain (35.8%), Musculoskeletal Other (8.9%), Musculoskeletal Spinal Event (11.6%), Musculoskeletal Neurologic (14.2%), and Systemic Other (13.7%). PMA P100012: FDA Summary of Safety and Effectiveness Page 26 of 61 {26} Table 13: Comparison of Adverse Events (Safety Population) | Adverse Event | Patients Experiencing Adverse Events (%) | | P-Value* | | --- | --- | --- | --- | | | PCM (N=214) | ACDF (N=190) | | | All Adverse Event | 180 (84.1%) | 163 (85.8%) | 0.678 | | Implant Related - Adjacent Level Disease | 5 (2.3%) | 27 (14.2%) | < 0.001 | | Implant Related - Implant Displacement/Loosening | 10 (4.7%) | 1 (0.5%) | 0.012 | | Implant Related - Neck/Arm Pain | 0 (0.0%) | 1 (0.5%) | 0.470 | | Implant Related - Non-union | 0 (0.0%) | 11 (5.8%) | < 0.001 | | Implant Related - Other | 1 (0.5%) | 1 (0.5%) | 1.000 | | Implant Related - Radiolucency | 3 (1.4%) | 3 (1.6%) | 1.000 | | Implant Related - Spinal Event | 11 (5.1%) | 4 (2.1%) | 0.121 | | Implant Related - Subsidence | 1 (0.5%) | 2 (1.1%) | 0.603 | | Implant Related - Trauma | 1 (0.5%) | 1 (0.5%) | 1.000 | | Surgery Related - Dysphagia/Dysphonia | 14 (6.5%) | 23 (12.1%) | 0.059 | | Surgery Related - Gastrointestinal | 2 (0.9%) | 2 (1.1%) | 1.000 | | Surgery Related - Incision Site | 12 (5.6%) | 4 (2.1%) | 0.079 | | Surgery Related - Infection | 1 (0.5%) | 1 (0.5%) | 1.000 | | Surgery Related - Neck/Arm Pain | 21 (9.8%) | 32 (16.8%) | 0.040 | | Surgery Related - Neurologic | 12 (5.6%) | 10 (5.3%) | 1.000 | | Surgery Related - Other | 4 (1.9%) | 7 (3.7%) | 0.361 | | Surgery Related - Respiratory | 1 (0.5%) | 0 (0.0%) | 1.000 | | Surgery Related - Spinal Event | 2 (0.9%) | 8 (4.2%) | 0.511 | | Surgery Related - Urogenital | 0 (0.0%) | 2 (1.1%) | 0.221 | | Surgery Related - Vertebral Fracture | 1 (0.5%) | 0 (0.0%) | 1.000 | | Systemic - Cardiac Events | 7 (3.3%) | 6 (3.2%) | 1.000 | | Systemic - Dysphagia/Dysphonia | 2 (0.9%) | 4 (2.1%) | 0.426 | | Systemic - Gastrointestinal | 12 (5.6%) | 6 (3.2%) | 0.334 | | Systemic - Infection | 15 (7.0%) | 12 (6.3%) | 0.844 | | Systemic - Mental Disorder | 2 (0.9%) | 4 (2.1%) | 0.426 | | Systemic - Musculoskeletal Trauma | 42 (19.6%) | 32 (16.8%) | 0.520 | | Systemic - Musculoskeletal/Adjacent Level Disease | 2 (0.9%) | 1 (0.5%) | 1.000 | | Systemic - Musculoskeletal/Back/Leg Pain | 36 (16.8%) | 33 (17.4%) | 0.895 | | Systemic - Musculoskeletal/Neck/Arm Pain | 87 (40.7%) | 68 (35.8%) | 0.356 | | Systemic - Musculoskeletal/Other | 29 (13.6%) | 17 (8.9%) | 0.160 | | Systemic - Musculoskeletal/Spinal Event | 32 (15.0%) | 22 (11.6%) | 0.380 | | Systemic - Neurologic | 12 (5.6%) | 27 (14.2%) | 0.004 | | Systemic - Other | 42 (19.6%) | 26 (13.7%) | 0.143 | | Systemic - Other Trauma | 6 (2.8%) | 2 (1.1%) | 0.291 | | Systemic - Respiratory | 3 (1.4%) | 2 (1.1%) | 1.000 | | Systemic - Urogenital | 2 (0.9%) | 8 (4.2%) | 0.051 | Note: Adverse Events (AEs) based on cumulative AE database as of September 2011. * Comparing PCM and ACDF based on Fisher's exact test (two-sided). P-values are not adjusted for multiplicity. They are included to help clinical interpretation, without defining statistical significance. PMA P100012: FDA Summary of Safety and Effectiveness Page 27 of 61 {27} Implant-related adverse events are shown in Table 14. Implant-related AEs with an incidence rate greater than 5% were spinal events (5.1%) in the PCM group, and adjacent level disease (14.2%) and non-union (5.8%) in the ACDF group. In addition, implant displacement/loosening occurred at a rate of 4.7% in the PCM group. Table 14: Implant-Related Adverse Events (Safety Population) | Adverse Event | Intraop (0 - 2 Days) | | Periop (>2 Days - 6 Wks.) | | Short Term (>6 Wks. - 12 Mon.) | | Long Term (>12 - 24Mon.) | | Longer Term (>24 Mon.) | | PCM (N=214) | ACDF (N=190) | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | PCM | ACDF | PCM | ACDF | PCM | ACDF | PCM | ACDF | PCM | ACDF | Patients (%) | Patients (%) | | Implant Related - Adjacent Level Disease | 0 | 0 | 0 | 0 | 2 | 5 | 2 | 17 | 1 | 7 | 5 (2.3%) | 27 (14.2%) | | Implant Related - Implant Displacement/Loosening | 0 | 0 | 1 | 0 | 3 | 1 | 1 | 0 | 5 | 0 | 10 (4.7%) | 1 (0.5%) | | Implant Related - Neck/Arm Pain | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 (0.0%) | 1 (0.5%) | | Implant Related - Non-union | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 8 | 0 | 2 | 0 (0.0%) | 11 (5.8%) | | Implant Related - Other | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 (0.5%) | 1 (0.5%) | | Implant Related - Radiolucency | 0 | 0 | 0 | 0 | 3 | 0 | 0 | 2 | 0 | 1 | 3 (1.4%) | 3 (1.6%) | | Implant Related - Spinal Event | 1 | 0 | 0 | 0 | 0 | 0 | 6 | 2 | 5 | 2 | 11 (5.1%) | 4 (2.1%) | | Implant Related - Subsidence | 0 | 0 | 1 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 1 (0.5%) | 2 (1.1%) | | Implant Related - Trauma | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 1 (0.5%) | 1 (0.5%) | Note: Adverse Events (AEs) based on cumulative AE database as of September 2011. PMA PI 12: FDA Summary of Safety and Effectiveness {28} As shown in Table 15, there were 27.6% of patients who experienced surgery-related AEs in the PCM group and 36.8% in the ACDF group. Surgery-related AEs that occurred at an incidence rate greater than 5% were: neck/arm pain (9.8%), dysphagia/dysphonia events (6.5%), neurologic (5.6%), incision site (5.6%) in the PCM group; and neck/arm pain (16.8%), dysphagia/dysphonia (12.1%), neurologic (5.3%) in the ACDF group. Table 15: Surgery-Related Adverse Events (Safety Population) | Adverse Event | PCM (N=214) | | ACDF (N=190) | | | --- | --- | --- | --- | --- | | | Patients (%) | Events (E/Pt) | Patients (%) | Events (E/Pt) | | Surgery-Related Adverse Event | 59 (27.6%) | 79 (0.37) | 70 (36.8%) | 97 (0.51) | | Surgery Related - Dysphagia/Dysphonia | 14 (6.5%) | 15 (0.07) | 23 (12.1%) | 28 (0.15) | | Surgery Related - Gastrointestinal | 2 (0.9%) | 2 (0.01) | 2 (1.1%) | 2 (0.01) | | Surgery Related - Incision Site | 12 (5.6%) | 13 (0.06) | 4 (2.1%) | 4 (0.02) | | Surgery Related - Infection | 1 (0.5%) | 1 (<0.01) | 1 (0.5%) | 1 (0.01) | | Surgery Related - Neck/Arm Pain | 21 (9.8%) | 27 (0.13) | 32 (16.8%) | 35 (0.18) | | Surgery Related - Neurologic | 12 (5.6%) | 13 (0.06) | 10 (5.3%) | 10 (0.05) | | Surgery Related - Other | 4 (1.9%) | 4 (0.02) | 7 (3.7%) | 7 (0.04) | | Surgery Related - Respiratory | 1 (0.5%) | 1 (<0.01) | 0 (0.0%) | 0 (0.00) | | Surgery Related - Spinal Event | 2 (0.9%) | 2 (0.01) | 8 (4.2%) | 8 (0.04) | | Surgery Related - Urogenital | 0 (0.0%) | 0 (0.00) | 2 (1.1%) | 2 (0.01) | | Surgery Related - Vertebral Fracture | 1 (0.5%) | 1 (<0.01) | 0 (0.0%) | 0 (0.00) | Note: Adverse Events (AEs) based on cumulative AE database as of September 2011. The cumulative totals of adverse events related to pain are tabulated in Table 16. Over 62% of patients reported at least one AE related to pain in patients with more than one pain AE and in the total number of pain AEs. There were no significant differences between groups except for the "Other" category which included fibromyalgia, myofascial pain syndrome, jaw pain, kidney stones, corneal abrasion, and other miscellaneous non-spine related reports of pain. Table 16: Summary of Pain Adverse Events (Safety Population) | Category | TRN (N=75) | PCM (N=214) | ACDF (N=190) | P-Value* | | --- | --- | --- | --- | --- | | Patients with ≥1 Pain AE | 47 (62.7%) | 132 (61.7%) | 120 (63.2%) | 0.837 (a) | | Total Number of Pain AEs (AEs/Patient) | 104 (1.39) | 264 (1.23) | 232 (1.22) | 0.909 (b) | | Pain AEs by Location (AEs/Patient) | | | | | | Neck Only | 26 (0.35) | 64 (0.30) | 56 (0.29) | 0.937 (b) | | Arm Only | 29 (0.39) | 64 (0.30) | 68 (0.36) | 0.303 (b) | | Neck and Arm | 14 (0.19) | 35 (0.16) | 42 (0.22) | 0.188 (b) | | Headache | 5 (0.07) | 12 (0.06) | 9 (0.05) | 0.702 (b) | | Back and/or Lower Extremity | 21 (0.28) | 69 (0.32) | 52 (0.27) | 0.372 (b) | | Other | 9 (0.12) | 20 (0.09) | 5 (0.03) | 0.011 (b) | Note: Adverse Events (AEs) based on cumulative AE database as of September 2011. * Comparing PCM and ACDF (two-sided): (a) Fisher's exact test; (b) Chi-squared test (rate ratio). P-values are not adjusted for multiplicity. They are included to help clinical interpretation, without defining statistical significance. PMA P100012: FDA Summary of Safety and Effectiveness Page 29 of 61 {29} The number and relative frequency of…