prodisc L Total Disc Replacement

{0} # SUMMARY OF SAFETY & EFFECTIVENESS DATA (SSED) ## I. GENERAL INFORMATION | Device Generic Name: | Prosthesis, Intervertebral Disc | | --- | --- | | Device Trade Name: | prodisc® L Total Disc Replacement | | Device Product Code: | MJO | | Applicant's Name and Address: | Centinel Spine, LLC 900 Airport Rd, 3B West Chester, PA 19380 USA | | Date(s) of Panel Recommendation: | N/A | | Premarket Approval Application: (PMA Number) | P050010/S020 | | Date of FDA Notice of Approval: | April 10, 2020 | The original PMA (P050010) was approved on August 14, 2006 and is indicated for spinal arthroplasty in skeletally mature patients with degenerative disc disease (DDD) at one level from L3-S1. DDD is defined as discogenic back pain with degeneration of the disc confirmed by patient history and radiographic studies. These DDD patients should have no more than Grade 1 spondylolisthesis at the involved level. Patients receiving the prodisc® L Total Disc Replacement should have failed at least six months of conservative treatment prior to implantation of the prodisc® L Total Disc Replacement. The SSED to support the previously approved one level indication is available on the CDRH website (https://www.accessdata.fda.gov/cdrh_docs/pdf5/P050010B.pdf) and is incorporated by reference here. The current supplement was submitted to expand the indication for the prodisc® L to include use of the device at two (2) contiguous intervertebral level(s). ## II. INDICATIONS FOR USE The prodisc® L ('prodisc® L') Total Disc Replacement is indicated for spinal arthroplasty in skeletally mature patients with degenerative disc disease (DDD) at one or two contiguous intervertebral level(s) from L3-S1. DDD is defined as discogenic back pain with degeneration of the disc confirmed by patient history and radiographic studies. These DDD patients should have no more than Grade 1 spondylolisthesis at the involved level(s). Patients receiving the prodisc® L Total Disc Replacement should have failed at least six months of conservative treatment prior to implantation of the prodisc® L Total Disc Replacement. PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 1 {1} ### III. CONTRAINDICATIONS The prodisc® L Total Disc Replacement should not be implanted in patients with the following conditions: - Active systemic infection or infection localized to the site of implantation - Osteopenia or osteoporosis defined as DEXA bone density measured T-score < -1.0 - Bony lumbar spinal stenosis - Allergy or sensitivity to implant materials (cobalt, chromium, molybdenum, polyethylene, titanium) - Isolated radicular compression syndromes, especially due to disc herniation - Pars defect - Involved vertebral endplate that is dimensionally smaller than 34.5mm in the medial-lateral and/or 27mm in the anterior-posterior directions - Clinically compromised vertebral bodies at the affected level due to current or past trauma - Lytic spondylolisthesis or degenerative spondylolisthesis of grade > 1 ### IV. WARNINGS AND PRECAUTIONS Please refer to the prodisc® L Instructions for Use for warnings and precautions. ### V. DEVICE DESCRIPTION The prodisc® L two-level device that is the subject of this PMA supplement is identical to the currently marketed prodisc® L one-level device (P050010). The prodisc® L is a weight-bearing modular implant consisting of two endplates and one polyethylene inlay. The prodisc® L endplates are manufactured from cobalt-chromium alloy and are available in two sizes (medium and large). The superior endplates are available in three lordotic angles (3°, 6°, 11°) and the inferior endplates are also available in three lordotic angles (0°, 3°, 8°). The surfaces of both inferior and superior endplates are plasma sprayed with commercially pure (CP) titanium. Fixation of the prodisc® L to the vertebral bodies is intended through bony ingrowth, with initial stabilization by a large central keel and two small spikes on the surface of the two endplates. The inlays are manufactured from ultra-high molecular weight polyethylene (UHMWPE), and are available in three heights (10, 12, and 14mm) with anterior-posterior and lateral sizing consistent with the endplate sizing. The Range of Motion (ROM) allowed by the prodisc® L is 13° of flexion, 7° of extension, ±10° of lateral bending, and ±3° of axial rotation, as measured through in vitro testing. The maximum ROM allowed by an assembled prodisc® L device is dependent on the endplate size and inlay height selected. The ROM experienced in flexion, extension, and lateral bending in vivo may be less than the maximum ROM of the implant itself due to anatomical constraints. As the prodisc® L device is constrained with respect to rotational motion, ROM experienced in rotation is entirely dependent on anatomical constraints. PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 2 {2}  Figure 1: prodisc® L device The superior and inferior endplates of prodisc® L are manufactured of Co-28Cr-6Mo (CoCrMo) per ISO 5832-12. The surfaces of both the inferior and superior endplates are plasma sprayed with commercially pure titanium (CpTi) conforming to ISO/DIS 5832-2 (1999) “Implants for surgery”. The fixation of the implant to the vertebral bodies is intended to be achieved through bone ongrowth, with initial stabilization by a keel and two small spikes on the surface of the two endplates. The inlays are manufactured from UHMWPE. For identification of the position of the UHMWPE-inlay under x-ray-control, they include a tantalum x-ray marker per ISO 13782. The inlay snap-locks into the inferior plate and provides the inferior convex bearing surface that articulates with the concave bearing surface of the superior plate. Table 1 and Table 2 describe the available sizes and configurations of the prodisc® L Total Disc Replacement components: Table 1: prodisc® L Endplates | Size | Approximate Dimensions | | Angles (degrees) | | --- | --- | --- | --- | | | Anterior/Posterior width (mm) | Lateral width (mm) | | | Inferior Endplate – Medium | 27 | 34.5 | 0 ° | | Inferior Endplate – Medium | 27 | 34.5 | 3° | | Inferior Endplate – Medium | 27 | 34.5 | 8° | | Inferior Endplate – Large | 30 | 39 | 0 ° | | Inferior Endplate – Large | 30 | 39 | 3° | | Inferior Endplate – Large | 30 | 39 | 8° | | Superior Endplate – Medium | 27 | 34.5 | 3° | | Superior Endplate – Medium | 27 | 34.5 | 6 ° | | Superior Endplate – Medium | 27 | 34.5 | 11 ° | | Superior Endplate – Large | 30 | 39 | 3° | | Superior Endplate – Large | 30 | 39 | 6 ° | | Superior Endplate – Large | 30 | 39 | 11 ° | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 3 {3} **Table 2: prodisc® L Inlays** | Size | Approximate Dimensions | | Height (mm) (Assembled) | | --- | --- | --- | --- | | | Anterior/Posterior width (mm) | Lateral width (mm) | | | PE Inlay – Medium | 26 | 23 | 10 | | PE Inlay – Medium | 26 | 23 | 12 | | PE Inlay – Medium | 26 | 23 | 14 | | PE Inlay – Large | 29 | 25 | 10 | | PE Inlay – Large | 29 | 25 | 12 | | PE Inlay – Large | 29 | 25 | 14 | ## VI. ALTERNATIVE PRACTICES AND PROCEDURES There are several other alternatives for the treatment of DDD at two contiguous intervertebral level(s) from L3-S1. - Nonoperative alternative treatments include, but are not limited to, activity restriction, physical therapy, back exercises, chiropractic care, medication and spinal injections. - Surgical alternatives include, but are not limited to, surgical decompression and/or fusion using various bone grafting techniques or interbody fusion devices, which may or may not be used in conjunction with anterior/anterolateral spinal systems (e.g., plate and screw systems), or posterior spinal systems (e.g., pedicle screw/rod or hook/wire/rod systems). Each alternative 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 prodisc® L Total Disc Replacement has been commercially available in markets outside of the United States since 1990 and is currently available without restrictions on the number of levels implanted. The prodisc® L was approved by the FDA on August 14, 2006 (P050010) for single level implantation. More than 17,900 prodisc® L devices have been sold within the US as of September 2018 (Table 3). **Table 3: prodisc® L Marketing History** | Markets | Units Sold (2004 – 2018) | | --- | --- | | US* | 17,983 | | Outside the US (oUS) | 30,601 | | **Global TOTAL** | **48,584** | * Commercial Distribution within the United States after PMA approval in 2006. The prodisc® L Total Disc Replacement has not been withdrawn from marketing for any reason related to its safety or effectiveness. The prodisc® L Total Disc Replacement is commercially available in the following countries outside of the United States: Argentina Croatia Iran New Zealand South Africa PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 4 {4} | Australia | Czech Republic | Ireland | Norway | South Korea | | --- | --- | --- | --- | --- | | Austria | Denmark | India | Panama | Spain | | Belgium | Ecuador | Israel | Peru | Sweden | | Brazil | Egypt | Italy | Poland | Switzerland | | Bulgaria | Finland | Jamaica | Portugal | Taiwan | | Canada | France | Libya | Romania | Thailand | | Chile | Germany | Luxembourg | Russia | Turkey | | China | Greece | Malaysia | Saudi Arabia | United Arab Emirates | | Columbia | Hong Kong | Mexico | Singapore | United Kingdom | | Costa Rica | Hungary | Netherlands | Slovakia | Venezuela | ## VIII. POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. These adverse effects include: 1) those commonly associated with any surgical procedure; 2) those specifically associated with lumbar spinal surgery using an anterior approach; and, 3) those associated with a total disc replacement device (including the prodisc® L Total Disc Replacement). ### General Surgery Adverse Effects General surgical adverse effects include, but are not limited to: - Anesthetic reaction - Hematoma - Ileus requiring nasogastric tube - Infection (wound, local and/or systemic) - Abscess - Wound dehiscence - Wound necrosis - Edema - Heart and vascular complications - Hypotension - Ischemia - Hemorrhage - Thrombosis including deep vein thrombosis - Embolism including pulmonary embolism - Pulmonary complications - Gastrointestinal and/or genitourinary complications - Seizures - Nerve damage - Vascular damage resulting in catastrophic or fatal bleeding - Paralysis, - Reflex sympathetic dystrophy - Changes to mental status - Complications of pregnancy including miscarriage and congenital defects - Inability to resume activities of daily living - Death ### Anterior Lumbar Surgery Adverse Effects Anterior lumbar surgical adverse effects include, but are not limited to: - Bowel injury or perforation - Epidural hematoma - Hernia - Peritoneal adhesions - Retroperitoneal hematoma - Injury to kidneys or ureters - Nerve damage due to surgical trauma PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 5 {5} - Neurological complications, including bowel and/or bladder dysfunction, impotence, tethering of nerves in scar tissue, muscle weakness or paresthesias - Damage to lymphatic vessels and/or lymphatic fluid exudation - Fracture of vertebral bony structures - Peritonitis - Scarring - Injury to neural structures possibly resulting in neurologic deficits including paralysis or chronic pain - Dural tears or leaks - Surrounding soft tissue damage # Lumbar Total Disc Replacement Adverse Effects Adverse effects specific to lumbar artificial discs, including the prodisc® L, are but may not be limited to: - Expulsion or retropulsion, causing pain, paralysis, vascular or neurological damage - Impingement or damage to neural structures - Need for additional surgery including removal of the prodisc® L - Failure of the device/procedure to improve symptoms and/or function - Wear debris (polyethylene or metal) generation leading to an adverse local tissue reaction that may cause implant loosening or failure - Early or late loosening of the device components - Implant malpositioning which can lead to erosion into adjacent large arteries and veins and cause catastrophic bleeding in the late post-operative period - Implant breakage, disassembly, bending, dislodgement, or migration - Spondylolysis - Spondylolisthesis - Spinal stenosis - Change in lumbar lordosis - Instability of the spine - Facet joint degeneration - Foreign body reaction to the implant including possible tumor formation, autoimmune disease, metallosis, and/or scarring - Bone resorption - Calcification resulting in bridging trabecular bone (heterotopic ossification) and fusion either at the treated level or adjacent levels - Annular ossification - Bending or breakage of prodisc® L instruments including the possibility that fragments may remain in the patient - Sizing issues with device components - Anatomical or technical difficulties placing the device - Loss of disc height - Herniation or degeneration of adjacent discs - Tissue or nerve damage caused by improper positioning or placement of the device or instruments For the specific adverse events that occurred in the prodisc® L clinical study, please see Section X below. # IX. SUMMARY OF NONCLINICAL STUDIES A summary of previously reported nonclinical studies can be found in the SSED for the original PMA and are incorporated by reference here PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 6 {6} (https://www.accessdata.fda.gov/cdrh_docs/pdf5/P050010B.pdf). Additional testing performed to support the two-level indication are provided below (Table 4). - • Wear Mode I (General ROM) - • Wear Mode IV (Impingement) - • Static Axial Compression - • Dynamic Axial Compression - • Static Compression Shear - • Dynamic Compression Shear - • Subluxation - • Subsidence - • Static Inlay Expulsion - • Expulsion - • Magnetic Resonance Safety - • Retrieval Analysis **Table 4: Nonclinical Testing** | Test Description | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Wear Mode I (General ROM) | Evaluate the Mode I wear performance of the prodisc® L total disc replacement. | Specifically, a six-degree-of-freedom spine wear simulator (MTS, Eden Prairie, MN) was used for testing on the smallest and largest prodisc® L constructs. The polyethylene inserts were imaged using a µCT 80 (Scanco Medical AG, Switzerland) at a maximum voxel resolution of 18 µm. The device components were scanned at 0.0 million cycles (MC) and 5.0 MC. A custom Matlab code was written in order to calculate the dimensional changes on each device. ISO 18192-1:2011, ASTM F2423-11 Acceptance Criteria: Less than 30mg/million cycles | The average mass wear rate of the polyethylene insert through 5.0 MC was 5.4 ± 1.3 mg/MC and 4.8 ± 1.1 mg/MC for the large and medium size devices, respectively. | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 7 {7} | Test Description | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Wear Mode IV (Impingement) | The objective of this study was to evaluate the Mode IV wear (impingement) performance of the Centinel Spine prodisc® L total disc replacement. | Through the modeling and sub sequential experimental validation, it was concluded that the large, 11° lordotic angle superior device would be tested using an initial impingement angle of 12°. Overall, the impingement conditions included ± 2° axial rotation, 1200 N static compressive axial load, and 12 ± 2 flexion/extension for both the aligned and 2mm anterior offset test groups. ASTM F3295-18, ISO 14243-2:2009, ISO 18192-1:2011, ISO 181912-3:2017, ASTM F2423-11 Acceptance Criteria: 1. Wear mechanism at the impingement location for the no offset condition will be similar based on the observed wear and damage patterns. 2. The average wear rates demonstrated by this impingement testing for the no offset condition should be found to be less than or equal to the Mode I average wear rates at 1 Mc. The no offset condition should only induce wear in the polyethylene component. If the wear mechanism was found to be similar the wear rate for the UHMWPE is also expected to be comparable. | Under impingement conditions, the rate of mass loss of the polyethylene insert was less than in the Mode I testing condition. The polyethylene demonstrated impingement on the posterior surface. Characteristic of the contact observed on published retrievals, metal-on-metal contact was observed in the 2 mm offset test group. The maximum mass loss experienced by the metal components was converted to maximum volume losses of 0.6 mm³ and 0.5 mm³ for the inferior and superior components, respectively. | | Static Axial Compression | The objective of this test was to characterize the performance of the prodisc® L outside of the US (oUS) Centinel Spine manufactured parts under static axial compression loading | The static axial compression tests were performed in displacement control at a rate of 12 mm/minute. Force and displacement data were recorded using the test system controller software. The ramp waveform was performed until the load cell limit or until gross failure occurred. ASTM F2346-11 Acceptance Criteria: Greater than 1650N | The ultimate load for static compression testing was 24,517.3N±6.2N for the M10 prodisc® L oUS implant constructs, and 24,518.1N±8.5N for the L14 prodisc® L oUS implant constructs. | | Dynamic Axial Compression | The objective of this test was to characterize the performance of the prodisc® L oUS Centinel Spine manufactured parts under dynamic axial compression loading. | A cyclic force with a constant frequency of 5 Hz was applied to each specimen. The forces were maintained with a constant sinusoidal force amplitude control at a constant force ratio (R=min/max) equal to 10. Testing was terminated when the specimen reached the endurance value of 10,000,000 cycles or failure defined as displacement in excess of 1 mm before 500 cycles resulting in permanent deformation of the inlay and/or displacement in excess of 1 mm from the displacement at 500 cycles resulting in permanent deformation of the inlay. ASTM F2346-11 Acceptance Criteria: Greater than 1650N | The axial compression runout loads for both, the M10 and the L14 prodisc® L oUS implant constructs was 4000N, which is greater than the acceptance criteria of 1650N. | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 8 {8} | Test Description | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Static Compression Shear | The objective of this test was to characterize the performance of the prodisc® L oUS Centinel Spine manufactured parts under static compression shear loading. | The specimen was placed within the pockets of the test blocks. These test blocks were placed within the pockets of the custom adapter plates and attached to the rigid superior and inferior 45° fixtures, which were in-line with the actuator. The static shear tests were performed in displacement control at a rate of 12 mm/minute. Force and displacement data were recorded using the test system controller software. The ramp waveform was performed until the load cell limit or until gross failure occurred. ASTM F2346-11 Acceptance Criteria: Greater than 1650N | The ultimate load for static compression-shear testing was 6,758.7N±128.8N for the M10 prodisc® L oUS implant constructs, and 10,467.9±1422.1N for the L14 prodisc® L oUS implant constructs. | | Dynamic Compression Shear | The objective of this test was to characterize the performance of the prodisc® L oUS Centinel Spine manufactured parts under dynamic compression shear loading. | The specimen was placed within the pockets of the test blocks. These test blocks were placed within the pockets of the custom adapter plates and attached to the rigid superior and inferior 45° fixtures, which were in-line with the actuator. A cyclic force with a constant frequency of 5 Hz was applied to each specimen. The forces were maintained with a constant sinusoidal force amplitude control at a constant force ratio (R=min/max) equal to 10. Testing was terminated when the specimen reached the endurance value of 10,000,000 cycles or failure defined as displacement in excess of 2 mm from the displacement at 500 cycles resulting in permanent deformation of the inlay. A 2 mm displacement limit was set after 500 cycles to trigger a test stop and a specimen inspection. Macroscopic checks were performed approximately every 2,000,000 cycles. The failure mode of each specimen and the corresponding cycle count were recorded. Graphical representation of the fatigue data was also generated. ASTM F2346-11 Acceptance Criteria: Greater than 1650N | The dynamic compression-shear runout loads for M10 prodisc® L oUS implant constructs was 1650N, and 3250N for L14 prodisc® L oUS implant constructs. | | Subluxation | The objective of this test was to characterize the prodisc® L oUS device resistance to subluxation. | M10 (N=3), and, L14 (N=3) prodisc® L oUS implant constructs were tested. The expulsion jig setup was positioned such that the loading axis was parallel to the device X-axis and the device positioned such that the X-axis loading was directed in the posterior to anterior direction. Testing was performed at a rate of 6 mm per minute until a significant reduction in force (>20% of measured force), fixture impingement, or until complete subluxation had occurred. Acceptance Criteria: Greater than 230N | The results show that the subluxation force was 275.1±2.5N for the M10 devices and 268.2±4.8N for the L14 devices. | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 9 {9} | Test Description | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Subsidence | The objective of this test was to characterize the prodisc® L oUS implant construct's mechanical strength and durability. | Six (6) prodisc® L oUS implants were inserted into a foam block at a displacement rate control rate of 6mm/minute. Force and displacement data were recorded using the test system controller software. Maximum force was recorded. ASTM F2267-04(2018) Acceptance Criteria: Greater than 3400N | The results show that the subsidence force was 5103N for the M10 implant constructs. | | Static Inlay Expulsion | The objective of this test was to characterize the force required to expulse the PE inlay from the inferior plate. | The inferior plate was machined down such that the point loaded could contact the inlay on the flat, posterior end. A 13.0 mm wide fixture was used to push against the M10 PDL oUS device during the test such that the load was only applied to the inlay. Testing was performed at a rate of 6 mm per minute until a significant reduction in force (>20% of measured force), fixture impingement, or at least 3 mm of displacement. Force and displacement data were recorded at a reasonable rate and saved for analysis to determine the displacement at expulsion strength (mm) and expulsion strength (N). Acceptance Criteria: Greater than 450N | The inlay expulsion force was 961±42N with a displacement of 2.45±0.63mm for the M10 Inlays and Inferior Plates. The inlay expulsion force and was 1,465±49N with a displacement of 1.59±0.10mm for the L14 Inlays and Inferior Plates. | | Expulsion | The objective of this test was to characterize the expulsion force of an assembled implant construct from between simulated vertebral bodies. | The specimen/test block assembly were positioned in the expulsion fixture such that the foam test blocks are rigidly fixed, and a 450 N axial compressive force was applied to the device along the Z-axis. Testing was performed at a rate of 6 mm per minute until a significant reduction in force (>20% of measured force), fixture impingement, or at least 3 mm of displacement. Force and displacement data were recorded at a reasonable rate and saved for analysis to determine the displacement at expulsion strength (mm) and expulsion strength (N). Acceptance Criteria: Greater than 450N | The results show that the expulsion force was 1,125±31N with a displacement of 2.51±0.23mm for the M10 implant constructs. The expulsion force was 1,057±24N with a displacement of 2.43±0.58mm for the L14 implant constructs. | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 10 {10} | Test Description | Purpose | Acceptance Criteria | Results | | --- | --- | --- | --- | | Magnetic Resonance (MR) Safety | The objective of this test was to determine the conditions under which the implant could safely be in an MR environment. | The specimen was tested for magnetically induced displacement force by suspending the specimen from a thin string and placed at a specific location along the Z-axis of a 3.0 T MR scanner. The deflection angle was then calculated. ASMT F2052 The magnetically induced torque was evaluated qualitatively by manually turning the subject device at the isocenter of the 3.0 T magnet. ASTM F2213 The image artifact was measured using FFE and SE sequences in 1.5T and 3.0T MR scanners. ASTM F2119 The implant was placed in a phantom (gel-filled box). Temperature probes were placed on the implant at the locations of highest expected heating. The maximum temperature rise for a 15 minute scan of 2 W/kg was measured. ASTM F2182 | The testing resulted in identifying the following conditions for use in an MR environment. Static Magnetic Field: 1.5 and 3.0 T. Maximum Spatial Gradient: 900 gauss/cm. Maximum MR-system reported SAR of 4 W/kg for 15 minutes. | | Retrieval Analysis | The objective of this test was to evaluate the degradation processes evident in explanted implants. | Three retrieved devices (05103103, 05121601, and 06081002) underwent a Stage II analysis per ASTM F561, which included white light interferometry (WLI). Two of the three retrieved devices (05121601 and 06081002) underwent Micro-CT analysis to look for the presence of subsurface cracking which could be indicative of subsurface oxidation, as well as to calculate dimensional changes due to wear volume loss. Stage III analysis was not conducted and the retrieved devices showed no signs of oxidation (i.e. white-banding, cracking or discoloration), and did not need to be measured. ASTM F561 and ISO 12891-1 | The measured surface roughness of the superior endplate was shown to increase. These findings are consistent with the observed adhesive abrasive damage mode which is common for orthopedic and spine UHMWPE-CoCr bearing surfaces. The roughness values were within the expected range for the observed damage and wear. There was no evidence of subsurface cracking that would be indicative of oxidation and no evidence of gross wear. Micro-CT wear maps were produced, and wear penetration was calculated, which ranged from 0.2 to 0.4 mm in penetration height loss. The penetration values were within the expected range for the observed damage and wear. | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 11 {11} # X. SUMMARY OF CLINICAL STUDIES The applicant performed a clinical study to determine a reasonable assurance of safety and effectiveness of the prodisc® L for patients with contiguous two-level DDD between L3 and S1 who had not previously received fusion surgery at any intervertebral level, and who had failed to improve with conservative treatment for at least 6 months prior to enrollment. Data from this clinical study were the basis of the PMA Supplement approval decision. A summary of the clinical study is presented below. ## A. Study Design Under IDE G010133 (approved in 2001), a multi-center, prospective, randomized, controlled clinical trial in the US was conducted to evaluate the safety and effectiveness of prodisc® L total disc replacement. The control group was treated with circumferential fusion consisting of commercially available femoral ring allograft and posterolateral fusion with autogenous iliac crest bone graft in combination with a pedicle screw-rod system. The IDE study included both one-level and two-level arms. The following pertains to the clinical study results for subjects who were enrolled in the two-level arm of the study. Subjects were treated between January 2002 and June 2004. The database for this PMA Supplement included 255 enrolled subjects who were randomized to either prodisc® L or Fusion. There were 19 investigational sites, of which 16 sites enrolled subjects in the two-level arm. The two-level study was a multicenter, prospective, randomized clinical trial consisting of subjects with contiguous two-level DDD between L3 and S1 who had not previously received fusion surgery at any intervertebral level, and who had failed to improve with conservative treatment for at least 6 months prior to enrollment. Subjects were randomized to receive either the prodisc® L Total Disc Replacement or circumferential fusion according to a 2:1 ratio. The study followed subjects through 60 months follow up, with the primary endpoint assessed with data at 24 months. Inclusion and exclusion criteria were identical to the one level IDE, with the exception of treatment at two levels rather than one level. ### 1. Clinical Inclusion and Exclusion Criteria To be eligible for the study, subjects were required to meet all inclusion criteria and none of the exclusion criteria, which are presented below in Table 5. PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 12 {12} Table 5: Study Inclusion/Exclusion Criteria | Inclusion Criteria | Exclusion Criteria | | --- | --- | | - Degenerative Disc Disease (DDD) in two adjacent vertebral levels between L3 and S1. Diagnosis of DDD required, back and/or leg (radicular) pain; and radiographic confirmation of any of the following by CT, MRI, discography, plain film, myelography and/or flexion/extension films: - Instability (≥ 3mm translation or ≥ 5° angulation); - Decreased disc height > 2mm; - Scarring/thickening of annulus fibrosis; - Herniated nucleus pulposus; or - Vacuum phenomenon. - Age between 18 and 60 years. - Failed at least six months of conservative treatment. - Oswestry Low Back Pain Disability Questionnaire (Oswestry Disability Index, ODI) score of at least 20/50 (40%) (Interpreted as moderate/severe disability). - Psychosocially, mentally and physically able to fully comply with this protocol including adhering to follow-up schedule and requirements and filling out of forms. - Signed informed consent. | - No more than 2 vertebral levels may have DDD and all diseased levels must be treated - Subjects with involved vertebral endplates dimensionally smaller than 34.5 mm in the medial-lateral and/or 27 mm in the anterior-posterior directions - Known allergy to titanium, polyethylene, cobalt, chromium or molybdenum - Prior fusion surgery at any vertebral level (limited to prior lumbar fusion surgery) - Clinically compromised vertebral bodies at the affected level(s) due to current or past trauma - Radiographic confirmation of facet joint disease or degeneration - Lytic spondylolisthesis or spinal stenosis - Degenerative spondylolisthesis of grade > 1 - Back or leg pain of unknown etiology - Osteoporosis: A screening questionnaire for osteoporosis, SCORE (Simple - Calculated Osteoporosis Risk Estimation), used to screen subjects who require a DEXA bone mineral density measurement. If DEXA was required, exclusion was 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) - Morbid obesity defined as a body mass index > 40 or a weight more than 100 lbs. over ideal body weight - Pregnant or interested in becoming pregnant in the next 3 years. - Active infection - systemic or local - Taking medications or any drug known to potentially interfere with bone/soft tissue healing (e.g., steroids) - Rheumatoid arthritis or other autoimmune disease - Systemic disease including AIDS, HIV, Hepatitis - Active malignancy: A subject with a history of any invasive malignancy (except non-melanoma skin cancer), unless he/she had been treated with curative intent and there had been no clinical signs or symptoms of the malignancy for at least 5 years. | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 13 {13} ## 2. Follow-Up Schedule Table 6: Follow-up Schedule | Visit | Background Data & Medical History | Physical & Neurological Exam | DEXA | Confirm DDD | A/P & Lateral Films | Flexion Extension and Lateral Bending Films | Subject Self-Assessment | | --- | --- | --- | --- | --- | --- | --- | --- | | Enrollment / Pre-operative | X | X | A | B | X | X | C | | Post-op/ Prior to Discharge | | | | | D | | | | 6 wk. (+/- 2 wk.) | | X | | | X | F | E | | 3 mo. (+/- 2 wk.) | | X | | | X | F | E | | 6 mo. (+/- 1 mo) | | X | | | X | X | E | | 12 mo. (+/- 2 mo.) | | X | | | X | X | E | | 18 mo. (+/- 2 mo) | | X | | | X | X | E | | 24 months (+/- 2 mo.) | | X | | | X | X | E | | Annually thereafter (+/- 2 mo.) | | X | | | X | X | E | A. DEXA bone mineral density was recorded when dictated by osteoporosis screening (SCORE). B. In accordance with the definition of DDD, disc pathology was confirmed by MRI, CT, discography, plain film, myelography and/or flexion/extension films. All clinical imaging used in the confirmation of DDD must have been taken at this visit or within the last 6 months. C. Subject completed self-assessment tools: pain (VAS); Oswestry Questionnaire (ODI); and SF-36. D. A/P and lateral films were taken early post-op and/or prior to hospital discharge. E. Subject completed self-assessment tools: pain (VAS); satisfaction (VAS); Oswestry Questionnaire (ODI); and SF-36. F. Flexion-extension films and lateral bending films were taken at this visit for prodisc® L recipients and were taken for fusion subjects whenever possible and clinically advisable (i.e., at the surgeon's clinical discretion). ## 3. Clinical Endpoints The protocol specified that the primary endpoints were based on the Month 24 visit, with the exception of re-operations that were cumulative from index surgery through Month 24 post-operative. Treatment success was defined in the protocol using a composite endpoint for safety and effectiveness as follows: An individual subject's prodisc® L implantation was considered successful, if and only if, all of the following criteria were met: | ODI: | Improvement of 15% at 24 months compared to the baseline value | | --- | --- | | Re-operation: | No re-operation required to remove or modify the prodisc® L implant (investigational group) or to modify the fusion site or correct a complication with an implant (control group) | | Short Form (SF-36) | Improvement compared to Baseline (24-month score-Baseline score > 0) | | Neurologic status: | Neurologic status improved or maintained in motor, sensory, reflex, and straight leg-raise tests | | Radiographic success: | - No radiographic evidence of device migration or subsidence (>3mm) | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 14 {14} - No extensive radiolucency along the implant/bone interface (< 25% of interface's length for each endplate) - ROM at the implanted level was maintained or improved from the pre-operative baseline* - No loss of disc height (> 3 mm) - No evidence of bony fusion in investigational group *ROM at the implanted level maintained or improved if the flexion/extension ROM at 24 months was maintained from baseline measurement (with ± 3° measurement error applied) The margin for establishing non-inferiority was 12.5%. A control subject's fusion surgery was considered successful, if and only if all of the following criteria were met: | ODI: | Improvement of 15% over the baseline value | | --- | --- | | Re-operation: | No re-operation required to modify the fusion site or correct a complication with an implant | | Short Form (SF-36) | Improvement compared to baseline | | Neurologic status: | Neurologic status improved or maintained in motor, sensory, reflex, and straight leg-raise tests | | Radiographic success: | - Strong evidence of fusion including > 50% trabecular bridging or bone mass maturation and increased or maintained bone density at the interbody fusion site; - No motion (defined as translation >3 mm and angulation >5° on flexion-extension films); - No visible gaps in the fusion mass; - No loss of disc height (> 3mm); - No migration and subsidence of implants (> 3mm) - No implant loosening (no halos/radiolucencies around the implant). | The protocol considered the study a success if at 24 months the overall success rate of the investigational group was not inferior to that of the overall success rate of the control group; and the device related complication rate (including subsequent surgical interventions and PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 15 {15} neurological complications) of the investigational group was not inferior to that of the control group. The margin for establishing non-inferiority was stated in the protocol as 12.5%. As part of its review of the PMA Supplement for two-level implantation for prodisc® L, FDA requested analysis of a revised endpoint. This FDA-requested endpoint was similar to the protocol-defined endpoint described above but utilized a 15-point improvement in ODI as well as the radiographic success defined below. The FDA-requested endpoints required a margin for establishing non-inferiority of 10%. In addition, in part due to the lack of validated values for “ideal” ROM in the lumbar spine, a correlation between ROM and clinical success had not been demonstrated at the time of this PMA Supplement. As a result, an assessment of the FDA-requested overall success without the range of motion component was also utilized. The results from these FDA-requested endpoints (with and without ROM) are the ones presented in this document. The FDA-requested primary endpoints include: | ODI: | Improvement of ≥ 15 points at 24 months compared to baseline | | --- | --- | | Re-operation: | No re-operation required to remove or modify the prodisc® L implant (investigational group) or to modify the fusion site or correct a complication with an implant (control group) | | Short Form (SF-36) | Improvement compared to Baseline (24-month score-Baseline score > 0) | | Neurologic status: | Improved or maintained in motor, sensory, reflex, and straight leg-raise tests | | Radiographic success: | a. No radiographic evidence of device migration or subsidence (>3mm) b. No extensive radiolucency along the implant/bone interface or implant loosening (< 25% of interface length at each endplate for implant group, and no halos or radiolucencies around the implant in the control group) c. No loss of disc height (> 3 mm) d. No evidence of bony fusion in investigational group; strong evidence of fusion in control (>50% trabecular bridging bone or bone mass maturation and increased or maintained bone density at the interbody fusion site) with no visible gaps in the fusion mass e. ROM at implanted level maintained or improved from pre-operative baseline in investigational group and no motion on flexion/extension films (defined as < 3mm translation and < 5° angulation) in the control group | The margin for establishing non-inferiority was 10%. Secondary endpoints are expected to further define the safety and effectiveness of prodisc® L Total Disc Replacement for the implantation at two adjacent vertebral levels. Secondary endpoints included: PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 16 {16} - • Back and Leg Pain as assessed using the Visual Analog Scale (VAS) - • Health-Related Quality of Life (SF-36) - • Subject Satisfaction as assessed using the Visual Analog Scale (VAS) - • Subject Satisfaction as assessed by the question: 'Would you have the surgery again?' - • Pain management medication (medication use) - • Peri- and intra-operative data (operative time, blood loss, hospital stay length) - • Return to Work - • Physical Labor - • Adverse Events - • Adjacent level analysis (surgical interventions at the adjacent level, non-surgical AEs, and radiographic analysis) ### *Clinical Events Committee (CEC)* A Clinical Events Committee (CEC) was convened after completion of the study to review and adjudicate adverse event determinations. The CEC consisted of two independent spine surgeons. The CEC members had no financial interest with the sponsor and had prior experience implanting and treating patients with lumbar total disc replacement devices. The CEC reviewed all adverse events. For each AE, the CEC indicated either agreement or disagreement with the original designations that were made by the investigator (for implant relatedness, surgery relatedness, and severity) or sponsor (for severe/life-threatening status and AE category). The CEC adjudicated all adverse events such that unanimous agreement was required for all decisions to agree or disagree/revise a prior designation. The CEC-adjudicated AE designations were used as a basis for the results reported in the safety section of this document. ### **B. Accountability of PMA Cohort** Detailed pre-operative demographic information was collected for all subjects entering the study. Subjects who met all inclusion/exclusion criteria were asked to enroll in the study. Subjects who agreed to participate in the study then signed the informed consent forms prior to being randomized. After the subject signed the informed consent form, the surgeon notified the sponsor to obtain the subject's treatment assignment. In this study, the first prodisc® L two-level implantation occurred on January 10, 2002. Enrollment in the randomized cohort closed on June 23, 2004. This study required a 24 Month follow-up period. The analysis populations for this study are defined below. A schematic showing subject flow for these analysis populations at Month 24 is included as Figure 2. PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 17 {17}  *One prodisc® L subject was surgically enrolled in the investigational arm without the use of the randomization sequence. This subject was excluded from the ITT cohort and this accounting tree but was included in the safety analysis of the treated subjects, for n=165 prodisc® L subjects in the safety analysis. Figure 2: Subject Accounting Tree The Intent to Treat (ITT) population included every subject randomized according to randomized treatment assignment. The Treated population included all subjects who were enrolled and treated. There were 236 subjects in the Treated population (n=72, Fusion; n= 164, prodisc® L). The demographic and safety analyses utilized the Treated population, with the addition of one prodisc® L subject who was surgically enrolled in the investigational arm without the use of the randomization sequence (n=72, Fusion; n= 165, prodisc® L). This single subject was excluded from the ITT population due to not being formally randomized. According to the ICH Guidelines for Statistical Principles for Clinical Trials (E9), the use of an intent-to-treat population in equivalence or non-inferiority trials is generally not conservative. Therefore, the study hypothesis (i.e., overall success) was evaluated using the Per Protocol population. The Per Protocol population included all subjects who were enrolled and treated on protocol and excludes Major Protocol Violators (MPVs). There were 229 subjects (n=68, Fusion and 161 prodisc® L) in the Per Protocol population. PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 18 {18} Subjects were followed to Month 60. Definitions are provided below for each of the categories contained in the Subject Accountability Table (Table 7). The database was closed June 29, 2012 and locked on November 20, 2012. **Table 7: Subject Accounting and Follow-up Compliance Table for Outcomes** | | Month 24 | | | | Month 60 | | | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | prodisc® L | | Fusion | | prodisc® L | | Fusion | | | | n | % | n | % | n | % | n | % | | **ITT Cohort** | **173** | **--** | **82** | **--** | **173** | **--** | **82** | **--** | | *Not Treated* | 9 | -- | 10 | -- | 9 | -- | 10 | -- | | *Major Protocol Violations* | 3 | -- | 4 | -- | 3 | -- | 4 | -- | | **Per Protocol Cohort** | **161** | **--** | **68** | **--** | **161** | **--** | **68** | **--** | | *Deaths* | 2 | -- | 0 | -- | 2 | -- | 1 | -- | | *Not Yet Overdue/Not Yet Due* | 0 | -- | 0 | -- | 0 | -- | 0 | -- | | **Expected Due** | **159** | **--** | **68** | **--** | **159** | **--** | **67*** | **--** | | **Overall Success Evaluation** | | | | | | | | | | • Overall Success Evaluation (FDA requested) | 143 | 89.9% | 60 | 88.2% | 127 | 79.9% | 57 | 83.8% | | • Overall Success Evaluation (FDA requested, no ROM) | 143 | 89.9% | 60 | 88.2% | 126 | 79.2% | 57 | 83.8% | | **Clinical Evaluation** | | | | | | | | | | • Neurological Evaluation | 142 | 89.3% | 61 | 89.7% | 125 | 78.6% | 53 | 79.1% | | • Oswestry Disability Index Evaluation | 143 | 89.9% | 61 | 89.7% | 125 | 78.6% | 53 | 79.1% | | • SF-36 Evaluation | 142 | 89.3% | 58 | 85.3% | 123 | 77.4% | 52 | 77.6% | | • VAS Low Back and Leg Pain Evaluation | 142 | 89.3% | 61 | 89.7% | 124 | 78.0% | 53 | 79.1% | | **Radiographic Evaluation** | | | | | | | | | | • Range of Motion Evaluation | 131 | 82.4% | 60 | 88.2% | 118 | 74.2% | 51 | 76.1% | | • Bridging Bone Evaluation | 141 | 88.7% | 60 | 88.2% | 120 | 75.5% | 51 | 76.1% | | • Disc Height Evaluation | 135 | 84.9% | 57 | 83.8% | 119 | 74.8% | 51 | 76.1% | | • Migration Evaluation | 141 | 88.7% | 60 | 88.2% | 120 | 75.5% | 51 | 76.1% | | • Radiolucency Evaluation | 141 | 88.7% | 60 | 88.2% | 120 | 75.5% | 51 | 76.1% | | • Subsidence Evaluation | 141 | 88.7% | 60 | 88.2% | 120 | 75.5% | 51 | 76.1% | \*One Fusion subject died in the Month 60 timeframe, but previously had a surgical intervention. As such, this subject was included in the expected due for overall success measurements, but not for clinical and radiographic evaluation. ### **C. Study Population Demographics and Baseline Parameters** Detailed preoperative demographic information was collected for all subjects entering the study. The demographics of the study population are typical for a total-disc replacement study performed in the US. Pre-operative data for Fusion, and prodisc® L subjects in the treated population are presented in Table 8, including: age, gender, race, smoking status, height, weight, body mass index (BMI), Oswestry score, percentage pain in the back versus leg, and duration of pain in the back/leg. The mean age demographic profile for the treated subjects (Fusion and prodisc® L) was 41.8 years of age. The demographic profiles of the Fusion and prodisc® L subjects for all categories were not statistically different. PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 19 {19} **Table 8: Pre-Operative Demographic Profile for Fusion and prodisc® L** | | prodisc® L n = 164 | Fusion n = 72 | p- value* | | --- | --- | --- | --- | | **Age at Surgery (Years)** | | | **0.955** | | Mean (STD) | 41.8 (7.75) | 41.8 (7.81) | | | Range | 22 - 60 | 22 - 58 | | | **Age Group** | | | **0.889** | | <= 42 Years | 86 (52.4%) | 37 (51.4%) | | | > 42 Years | 78 (47.6%) | 35 (48.6%) | | | Total | 164 (100%) | 72 (100%) | | | **Gender** | | | **0.671** | | Female | 70 (42.7%) | 33 (45.8%) | | | Male | 94 (57.3%) | 39 (54.2%) | | | Total | 164 (100%) | 72 (100%) | | | **Race** | | | **0.387** | | Caucasian | 144 (87.8%) | 66 (91.7%) | | | African American | 2 (1.2%) | 2 (2.8%) | | | Hispanic | 13 (7.9%) | 3 (4.2%) | | | Asian | 1 (0.6%) | 1 (1.4%) | | | Other | 4 (2.4%) | 0 (0.0%) | | | Total | 164 (100%) | 72 (100%) | | | **Smoking Status** | | | **0.208** | | Never | 85 (52.1%) | 29 (40.3%) | | | Former | 31 (19.0%) | 21 (29.2%) | | | Current | 47 (28.9%) | 22 (30.6%) | | | Total | 163 (100%) | 72 (100%) | | | **Height (in)** | | | **0.952** | | Mean (STD) | 68.30 (4.20) | 68.3 (3.71) | | | Range | 58 - 78 | 60 - 80 | | | **Weight (lbs.)** | | | **0.819** | | Mean (STD) | 180.36 (39.42) | 180.9 (35.88) | | | Range | 98 - 285 | 111 - 285 | | | **Body Mass Index (Kg/m^{2})** | | | **0.915** | | Mean (STD) | 27.07 (4.52) | 27.1 (4.05) | | | Range | 17.96 - 38.92 | 19.2 - 37.4 | | | **Oswestry Disability Index** | | | **0.845** | | Mean (STD) | 64.70 (11.42) | 64.8 (9.54) | | | Range | 40.0 – 98.0 | 44.0 – 82.0 | | | **Percent Pain in the Back versus Leg** | | | **0.094** | | 100%/0% | 50 (30.5%) | 21 (30.0%) | | | 75%/25% | 95 (57.9%) | 36 (51.4%) | | | 50%/50% | 19 (11.6%) | 13 (18.6%) | | | 25%/75% | 0 (0.0%) | 0 (0.0%) | | | 0%/100% | 0 (0.0%) | 0 (0.0%) | | | Total | 164 (100%) | 70 (1%) | | | **Duration of Pain in the Back/Leg** | | | **0.530** | | < 6 Months | 1 (0.6%) | 0 (0.0%) | | | 6 Months To 1 Year | 16 (9.8%) | 4 (5.6%) | | | > 1 Year | 147 (89.6%) | 68 (94.4%) | | | Total | 164 (100%) | 72 (100%) | | \*Continuous and ordinal variables were analyzed by a two-sided Wilcoxon rank sum test, and categorical variables were analyzed using a two-sided Fisher's exact test to compare Fusion and prodisc® L. PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 20 {20} Table 9 summarizes the available pre-operative data related to the radiographic inclusion criteria for the treated population. **Table 9: Radiographic Findings Reported at the Pre-Operative Visit** | | prodisc® L | | Fusion | | | --- | --- | --- | --- | --- | | | Cranial | Caudal | Cranial | Caudal | | Satisfied inclusion criteria for DDD | 164/164 (100%) | 164/164 (100%) | 72/ 72 (100%) | 72/ 72 (100%) | | Exclusion Criteria: ≤ Grade I | 0/164 (0.0%) | 0/164 (0.0%) | 0/ 72 (0.0%) | 0/ 72 (0.0%) | | **Additional pre-operative radiographic findings:** | | | | | | Scarring/thickening of annulus fibrosis | 59/158 (37.3%) | 61/156 (39.1%) | 19/ 64 (29.7%) | 21/ 64 (32.8%) | | Herniated nucleus pulposus | 47/158 (29.7%) | 56/156 (35.9%) | 22/ 64 (34.4%) | 25/ 65 (38.5%) | | Vacuum phenomenon | 18/159 (11.3%) | 38/158 (24.1%) | 4/ 64 (6.3%) | 12/ 64 (18.8%) | | Grade I spondylolisthesis | 0/158 (0.0%) | 0/157 (0.0%) | 0/ 64 (0.0%) | 0/ 65 (0.0%) | | ≥5° angulation (flexion-extension) | 76/159 (47.8%) | 78/155 (50.3%) | 39/ 68 (57.4%) | 41/ 67 (61.2%) | Information regarding pre-operative medical treatment in the treated population is presented in Table 10. **Table 10: Pre-Operative Treatment for Fusion and prodisc® L** | | prodisc® L n = 164 | Fusion n = 72 | | --- | --- | --- | | **Prior Treatment* (Other Than Medication)** | | | | Injection | 126 (76.8%) | 52 (72.2%) | | Physical Therapy | 135 (82.3%) | 61 (84.7%) | | Corset/Brace | 68 (41.5%) | 28 (38.9%) | | Chiropractic | 59 (36.0%) | 28 (38.9%) | | Other | 34 (20.7%) | 12 (16.7%) | | **Prior Surgical Treatment*** | | | | None | 96 (58.5%) | 43 (59.7%) | | Any Prior Surgery | 68 (41.5%) | 30 (41.1%) | | Discectomy | 31 (18.9%) | 13 (18.1%) | | IDET** | 16 (9.8%) | 7 (9.7%) | | Laminectomy | 31 (18.9%) | 9 (12.5%) | | Laminotomy | 4 (2.4%) | 2 (2.8%) | | Other | 12 (7.3%) | 8 (11.1%) | * Subjects may be included in more than one category. Number of subjects treated was used as the denominator to compute all percentages. ** Intradiscal Electrothermoplasty Selected intra-operative and discharge results for subjects in the treated population are presented in Table 11. Table 12 summarizes the distribution of device component sizes utilized in the study for prodisc® L subjects in the treated population. PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 21 {21} The mean intra-operative time was significantly shorter in the prodisc® L group compared to the Fusion group (p < 0.001). The estimated blood loss was significantly less in the prodisc® L group compared to the Fusion group (p < 0.001). The length of hospital stay was also significantly shorter in the prodisc® L group compared to the Fusion group (p < 0.001). There were 14 subjects with intra-operative blood loss >1500 mL (6 Fusion [8.3%] and 8 prodisc® L [4.9%]). The incidence rate between Fusion and prodisc® L was not significant (p = 0.3719). Table 11: Intra-operative and Discharge Summary Statistics | | prodisc® L (n = 164) | Fusion (n = 72) | p-value* | | --- | --- | --- | --- | | Levels Treated | | | 0.460 | | L3-L5 | 13 (7.9%) | 7 (9.7%) | | | L4-S1 | 150 (91.5%) | 64 (88.9%) | | | Other (1- or 3-level) | 1 (0.6%) | 1 (1.4%) | | | Intra-Operative Time (Minutes) | | | <0.001 | | N | 164 | 72 | | | Mean (STD) | 159.3 (72.64) | 272.8 (81.68) | | | Range | 66 – 430 | 86 - 515 | | | Estimated Blood Loss (cc) | | | <0.001 | | N | 161 | 72 | | | Mean (STD) | 398.7 (452.82) | 549.3 (466.63) | | | Range | 0 – 3000 | 0 - 2000 | | | Intra-Operative Antibiotics | | | 0.863 | | Yes | 130 (79.3%) | 56 (77.8%) | | | No | 34 (20.7%) | 16 (22.2%) | | | Total | 164 (100%) | 72 (100%) | | | DVT Prophylaxis** | | | N/A | | None | 0 (0.0%) | 0 (0.0%) | | | TED Hose | 147 (89.6%) | 65 (90.3%) | | | SCD | 81 (49.4%) | 38 (52.8%) | | | Other | 6 (3.7%) | 4 (5.6%) | | | Length of Hospital Stay (days) | | | <0.001 | | N | 164 | 72 | | | Mean (STD) | 3.8 (1.53) | 5.0 (1.93) | | | Range | 1 – 10 | 2 - 14 | | | *Continuous and ordinal variables were analyzed by a Wilcoxon rank sum test, and categorical variables were analyzed using Fisher's exact test to compare Fusion to prodisc® L. ** Subjects may be included in more than one category. Number of subjects treated used as the denominator to compute all percentages. | | | | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 22 {22} **Table 12: Distribution of prodisc® L Sizes** | Size | Angle | Polyethylene Height | prodisc® L | | --- | --- | --- | --- | | Medium | 6 degrees | 10 mm | 159 (49.1%) | | | | 12 mm | 24 (7.4%) | | | | 14 mm | 1 (0.3%) | | | 11 degrees | 10 mm | 44 (13.6%) | | | | 12 mm | 6 (1.9%) | | | | 14 mm | 1 (0.3%) | | Large | 6 degrees | 10 mm | 51 (15.7%) | | | | 12 mm | 19 (5.9%) | | | | 14 mm | 2 (0.6%) | | | 11 degrees | 10 mm | 11 (3.4%) | | | | 12 mm | 6 (1.9%) | | | | 14 mm | 0 (0.0%) | | **Total number of devices** | | | **326 (100%)** | ## **D. Safety and Effectiveness Results** ### **1. Safety Results** The safety analysis cohort (Figure 2) consisted of all subjects randomized and treated plus one prodisc® L subject who received the treatment without randomization (n=72, Fusion; n= 165, prodisc® L). All adverse events available up to 5-years follow-up were reported. The key safety findings and adverse events are reported in Tables 13 to 25. **Table 13: Comparisons of Summary Adverse Event Rates between prodisc® L and Fusion Groups** | | prodisc® L (n=165) | | | Fusion (n=72) | | | Dif | Exact | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Events | Subjs | %* | Events | Subjs | %* | %* | p^{1} | | **Any adverse event** | **1058** | **153** | **92.7%** | **536** | **70** | **97.2%** | **-4.5%** | **0.238** | | **Any device or surgery-related adverse event** | **265** | **99** | **60.0%** | **162** | **49** | **68.1%** | **-8.1%** | **0.248** | | Device-related adverse event | 2 | 2 | 1.2% | 2 | 2 | 2.8% | -1.6% | 0.587 | | Surgery-related adverse event | 264 | 98 | 59.4% | 161 | 48 | 66.7% | -7.3% | 0.312 | | **Any severe or life-threatening adverse event** | **65** | **41** | **24.8%** | **42** | **26** | **36.1%** | **-11.3%** | **0.086** | | **Any device or surgery-related severe or life-threatening adverse event** | **16** | **13** | **7.9%** | **21** | **16** | **22.2%** | **-14.3%** | **0.004** | | Device-related severe or life-threatening adverse event | 1 | 1 | 0.6% | 0 | 0 | 0.0% | 0.6% | 1.000 | | Surgery-related severe or life-threatening adverse event | 15 | 12 | 7.3% | 21 | 16 | 22.2% | -14.9% | 0.002 | | **Deaths** | **2** | **2** | **1.2%** | **1** | **1** | **1.4%** | **-0.2%** | **1.000** | *Percentage of subjects experiencing specific event without regard to length of follow-up. $^{1}$Two-sided Fisher's Exact test. As seen in Table 13, there was not a statistically significant difference in the total adverse event rate between the prodisc® L and Fusion groups. However, compared to the Fusion subjects, the prodisc® L subjects exhibited a lower overall rate of any severe or life-threatening adverse events (24.8 vs. 36.1%) and any device or surgery related severe or life-threatening adverse events (7.9 vs. 22.2%). It should be noted that the only device-related severe or life-threatening adverse PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 23 {23} event occurred in the prodisc® L group. These lower adverse event rates were statistically significant. This statistically significant difference was attributed to the nature of the therapeutic interventions in each cohort. A more detailed description of the adverse event categorizations utilized in this study are described in Table 14. **Table 14: Adverse Event Categories** | CATEGORY | DEFINITION | | --- | --- | | **PAIN – BACK AND LOWER EXTREMITY** | | | pain – back | pain (including ache, stiffness, strain, sensitivity or throbbing) limited to the back and pelvis. | | pain - back and lower extremities | pain (including ache, stiffness, strain, sensitivity or throbbing) involving the back and lower extremities; excluding cases with burning sensation. | | pain - back and lower extremities with burning | pain (including ache, stiffness, strain, sensitivity or throbbing) involving the back and lower extremities combined with tingling / burning in the lower leg. | | pain - back and lower extremities with numbness at index level | pain (including ache, stiffness, strain, sensitivity or throbbing) involving the back and lower extremities combined with numbness or tingling within the distribution of nerves at the index level. | | pain - back and other | pain (including ache, stiffness, strain, sensitivity or throbbing) of the back combined with pain in another area of the body (e.g., neck, chest and pelvis). | | pain - groin area | pain limited to the groin area | | pain - lower extremities | pain (including ache, stiffness, strain, sensitivity or throbbing) involving the lower extremities. | | pain - lower extremities with numbness at index level | pain (including ache, stiffness, strain, sensitivity or throbbing) involving the lower extremities combined with numbness or tingling within the distribution of nerves at the index level. | | **NEUROLOGICAL** | | | motor deficit in index level | any condition relating to a motor deficit at the spinal level of the index treatment. | | nerve root injury | a condition with symptoms of nerve root injury. | | numbness index level related | numbness or tingling within the distribution of nerves at the index level. | | numbness peripheral nerve or non-index level related | numbness or tingling outside the distribution of nerves at the index level. | | reflex change | a change in reflex. | | retrograde ejaculation | retrograde ejaculation | | **DEGENERATIVE DISEASE PROGRESSION** | | | degenerative disease progression, non-lumbar | new signs or symptoms of spinal degeneration outside the lumbar spine | | degenerative disease progression, other lumbar | new signs or symptoms of spinal degeneration of the lumbar spine, excluding herniated nucleus pulposus. | | herniated nucleus pulposus | a herniation of the nucleus pulposus intervertebral disc, distant from the index level. | | herniated nucleus pulposus, adjacent level | a herniation of the nucleus pulposus intervertebral disc, adjacent to the index level. | | **ADDITIONAL SURGERY INDEX LEVEL** | | | migration requiring surgery | post-op radiographs indicate that the implant may have changed positions in a direction parallel to the vertebral endplate and this led to further surgery. | | surgery - index level (other) | a surgical procedure at the same level of the lumbar spine as the index procedure performed subsequent to the index procedure which did not involve removal or modification of the implant or implantation of additional instrumentation. | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 24 {24} | CATEGORY | DEFINITION | | --- | --- | | surgery - index level (revision) | a surgical procedure at the same level of the lumbar spine as the index procedure performed subsequent to the index procedure which involved modification of the implant or removal of any part of the implant (with or without replacement). | | surgery - index level (supplemental fixation) | a surgical procedure at the same level of the lumbar spine as the index procedure performed subsequent to the index procedure which involved implantation of additional instrumentation at the index level. | | **INCISION SITE RELATED** | | | infection - superficial wound with incision site | an infection near the surface of the surgical incision. | | pain | | | pain - incision site | pain limited to the area of the surgical incision(s) including the graft site. | | wound issues, other | a condition pertaining to the surgical or other wound that did not involve infection. | | **INFECTION, NOT INDEX LEVEL RELATED** | | | infection - other non-wound related | an infection in an area other than the surgical incision (except urinary tract infections) | | infection - uti | an infection in the urinary system. | | pulmonary infection | an infection of the pulmonary system or symptoms consistent with a pulmonary infection (e.g., bronchitis) | | **MUSCULOSKELETAL SPASMS** | | | musculoskeletal spasms - back | a condition involving sudden contraction of muscles limited to the back or pelvis. | | musculoskeletal spasms - back and leg | a condition involving sudden contraction of muscles involving both the back and lower extremities. | | musculoskeletal spasms - leg | a condition involving sudden contraction of muscles limited to the legs. | | non-specific musculoskeletal spasms | a condition involving sudden contraction of muscles without identification of specific muscles or regions affected. | | **DERMATOLOGICAL OR DRUG ALLERGY** | | | dermatological | any condition pertaining to the skin other than drug allergies or surgical wound site. | | dermatological drug allergy | any condition pertaining to the skin associated with drug allergies. | | drug allergy | any condition associated with abnormal immune system reaction to a medication (other than dermatological drug allergies) | | pruritus | itching or rash | | **VASCULAR INJURY** | | | clinically significant blood loss (>1500 cc) | blood loss > 1500 cc without corresponding notation of physical injury to a blood vessel | | vessel damage/bleeding, major | physical injury to a blood vessel resulting in blood loss > 1500 cc. | | vessel damage/bleeding, minor | physical injury to a blood vessel resulting in blood loss up to 1500 cc. | | **OTHER** | | | anemia | a decrease in red blood cell count evidenced by diagnosis, lab test results, or treatment with a blood transfusion. | | burning or dysesthetic pain | dysesthesia in the back, or lower extremities or surgical site. | | cardiovascular | any condition of the heart and/or blood vessels (excluding the blood vessels that supply the brain). | | death | termination of life. | | dizziness | a condition described as feeling faint, lightheaded or unsteady. | | dural tear | a tear of the dura with or without evidence of spinal fluid leakage | | edema | swelling of tissues. | | fatigue | a feeling of tiredness. | | fever | diagnosis of fever or elevated temperature. | | fracture (non-vertebral) | a break in the continuity of the bone (excluding the spinal vertebra). | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 25 {25} | CATEGORY | DEFINITION | | --- | --- | | gastrointestinal | any condition pertaining to the stomach and intestines. | | genitourinary | any condition pertaining to the reproductive or urinary systems (except infections of the urinary system). | | headache | pain in various parts of the head. | | hernia | a hernia in the abdominal region. | | incontinence | involuntary leakage of urine or fecal matter. | | insomnia | a sleep disorder in which there is an inability to fall asleep or to remain asleep as long as desired. | | migration not requiring surgery | post-op radiographs indicate that the implant may have changed positions in a direction parallel to the vertebral endplate; however, this did not lead to further surgery. | | narcotics use | a diagnosis or other report indicating drug dependency or addiction. | | other | an adverse event not associated with any other term. | | other musculoskeletal | any condition pertaining to the muscles or skeleton excluding those under more specific terms | | pain other (not back/hip/leg) | pain not associated with any other term. | | psychological | any psychological condition | | radiolucency - graft | radiographic appearance of radiolucency without clinical symptoms. | | respiratory | a condition pertaining to the respiratory system; excluding pulmonary infections | | subsidence not requiring surgery | post-op radiographs indicate that the implant may have subsided into the vertebral endplate; however, this did not lead to further surgery. | | surgery - adjacent level | a surgical procedure on the lumbar spine at a different level of the spine than the index procedure and performed subsequent to the index procedure. | | surgery - other | a surgical procedure that did not involve treatment of degenerative disc disease of the lumbar spine, this includes spinal and non-spinal surgeries | | thrombosis | a condition involving symptoms of thrombosis | | thrombosis (dvt leg) | a condition involving a diagnosis of deep vein thrombosis | | vertebral fracture | a break in the continuity of the bone of the spinal vertebra. | Table 15 presents the incidence of adverse events, the number of events, and the events reported per subject in both prodisc® L (n=153 total adverse events, n=165 subjects) and Fusion (n=70 total adverse events, n=72 subjects) groups. The rates of adverse events are summarized by category and subcategory. Table 15: Counts and Percentages of Subjects with Specific Adverse Event Categories | All Adverse Events | prodisc® L | | | Fusion | | | Dif | Exact | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Events | Subjs | %* | Events | Subjs | %* | %* | p¹ | | ALL | 1058 | 153 | 92.7% | 536 | 70 | 97.2% | -4.5% | 0.238 | | PAIN - BACK AND LOWER EXTREMITY | 288 | 121 | 73.3% | 148 | 63 | 87.5% | -14.2% | 0.017 | | pain - back | 97 | 67 | 40.6% | 55 | 42 | 58.3% | -17.7% | 0.016 | | pain - back and lower extremities | 63 | 46 | 27.9% | 27 | 23 | 31.9% | -4.1% | 0.537 | | pain - back and lower extremities with burning | 3 | 3 | 1.8% | 2 | 1 | 1.4% | 0.4% | 1.000 | | pain - back and lower extremities with numbness at index level | 9 | 8 | 4.8% | 3 | 3 | 4.2% | 0.7% | 1.000 | | pain - back and other | 15 | 15 | 9.1% | 5 | 5 | 6.9% | 2.1% | 0.800 | | pain - groin area | 7 | 7 | 4.2% | 3 | 2 | 2.8% | 1.5% | 0.726 | | pain - lower extremities | 83 | 61 | 37.0% | 43 | 30 | 41.7% | -4.7% | 0.562 | | pain - lower extremities and incision site | 1 | 1 | 0.6% | 1 | 1 | 1.4% | -0.8% | 0.516 | | pain - lower extremities with numbness at index level | 10 | 8 | 4.8% | 9 | 6 | 8.3% | -3.5% | 0.369 | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 26 {26} | All Adverse Events | prodisc^{®} L | | | Fusion | | | Dif | Exact | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Events | Subjs | %* | Events | Subjs | %* | %* | p^{1} | | **NEUROLOGICAL EVENTS** | **58** | **39** | **23.6%** | **28** | **19** | **26.4%** | **-2.8%** | **0.743** | | motor deficit in index level | 5 | 5 | 3.0% | 1 | 1 | 1.4% | 1.6% | 0.670 | | neurological | 5 | 4 | 2.4% | 2 | 2 | 2.8% | -0.4% | 1.000 | | numbness index level related | 5 | 5 | 3.0% | 4 | 3 | 4.2% | -1.1% | 0.702 | | numbness peripheral nerve or non-index level related | 43 | 31 | 18.8% | 20 | 15 | 20.8% | -2.0% | 0.723 | | reflex change | 0 | 0 | 0.0% | 1 | 1 | 1.4% | -1.4% | 0.304 | | **DEGENERATIVE DISEASE PROGRESSION** | **15** | **12** | **7.3%** | **9** | **8** | **11.1%** | **-3.8%** | **0.322** | | degenerative disease progression, non-lumbar | 7 | 7 | 4.2% | 1 | 1 | 1.4% | 2.9% | 0.441 | | degenerative disease progression, other lumbar | 7 | 6 | 3.6% | 8 | 7 | 9.7% | -6.1% | 0.069 | | herniated nucleus pulposus | 1 | 1 | 0.6% | 0 | 0 | 0.0% | 0.6% | 1.000 | | **ADDITIONAL SURGERY INDEX LEVEL** | **5** | **5** | **3.0%** | **14** | **12** | **16.7%** | **-13.6%** | **<.001** | | migration requiring surgery | 1 | 1 | 0.6% | 0 | 0 | 0.0% | 0.6% | 1.000 | | surgery - index level (other) | 3 | 3 | 1.8% | 0 | 0 | 0.0% | 1.8% | 0.555 | | surgery - index level (revision) | 0 | 0 | 0.0% | 14 | 12 | 16.7% | -16.7% | <.001 | | surgery - index level (supplemental fixation) | 1 | 1 | 0.6% | 0 | 0 | 0.0% | 0.6% | 1.000 | | **INCISION SITE RELATED** | **42** | **36** | **21.8%** | **23** | **20** | **27.8%** | **-6.0%** | **0.324** | | infection - superficial wound with incision site pain | 6 | 6 | 3.6% | 6 | 6 | 8.3% | -4.7% | 0.194 | | pain - incision site | 19 | 19 | 11.5% | 9 | 8 | 11.1% | 0.4% | 1.000 | | wound issues, other | 17 | 15 | 9.1% | 8 | 7 | 9.7% | -0.6% | 1.000 | | **INFECTION, NOT INDEX LEVEL RELATED** | **20** | **15** | **9.1%** | **7** | **7** | **9.7%** | **-0.6%** | **1.000** | | infection - other non-wound related | 14 | 13 | 7.9% | 4 | 4 | 5.6% | 2.3% | 0.597 | | infection - uti | 4 | 4 | 2.4% | 2 | 2 | 2.8% | -0.4% | 1.000 | | pulmonary infection | 2 | 2 | 1.2% | 1 | 1 | 1.4% | -0.2% | 1.000 | | **MUSCULOSKELETAL SPASMS** | **49** | **34** | **20.6%** | **15** | **12** | **16.7%** | **3.9%** | **0.593** | | musculoskeletal spasms - back | 24 | 21 | 12.7% | 9 | 9 | 12.5% | 0.2% | 1.000 | | musculoskeletal spasms - back and leg | 5 | 5 | 3.0% | 1 | 1 | 1.4% | 1.6% | 0.670 | | musculoskeletal spasms - leg | 10 | 9 | 5.5% | 3 | 3 | 4.2% | 1.3% | 1.000 | | non-specific musculoskeletal spasms | 10 | 8 | 4.8% | 2 | 2 | 2.8% | 2.1% | 0.728 | | **DERMATOLOGICAL OR DRUG ALLERGY** | **20** | **16** | **9.7%** | **16** | **11** | **15.3%** | **-5.6%** | **0.266** | | dermatological | 8 | 5 | 3.0% | 8 | 6 | 8.3% | -5.3% | 0.094 | | drug allergy/reaction | 2 | 2 | 1.2% | 3 | 3 | 4.2% | -3.0% | 0.166 | | pruritus | 10 | 10 | 6.1% | 5 | 4 | 5.6% | 0.5% | 1.000 | | **VASCULAR INJURY** | **10** | **10** | **6.1%** | **7** | **7** | **9.7%** | **-3.7%** | **0.411** | | clinically significant blood loss (>1500 cc) | 6 | 6 | 3.6% | 6 | 6 | 8.3% | -4.7% | 0.194 | | vessel damage/bleeding, major | 2 | 2 | 1.2% | 1 | 1 | 1.4% | -0.2% | 1.000 | | vessel damage/bleeding, minor | 2 | 2 | 1.2% | 0 | 0 | 0.0% | 1.2% | 1.000 | | **OTHER** | **551** | **135** | **81.8%** | **270** | **58** | **80.6%** | **1.3%** | **0.857** | | anemia | 11 | 11 | 6.7% | 15 | 11 | 15.3% | -8.6% | 0.050 | | bowel perforation | 1 | 1 | 0.6% | 0 | 0 | 0.0% | 0.6% | 1.000 | | burning or dysesthetic pain | 10 | 10 | 6.1% | 3 | 2 | 2.8% | 3.3% | 0.355 | | cardiovascular | 20 | 17 | 10.3% | 11 | 7 | 9.7% | 0.6% | 1.000 | | death | 2 | 2 | 1.2% | 1 | 1 | 1.4% | -0.2% | 1.000 | | dizziness | 7 | 7 | 4.2% | 4 | 4 | 5.6% | -1.3% | 0.739 | | dural tear | 1 | 1 | 0.6% | 3 | 3 | 4.2% | -3.6% | 0.085 | | edema | 15 | 12 | 7.3% | 8 | 8 | 11.1% | -3.8% | 0.322 | | fatigue | 1 | 1 | 0.6% | 2 | 2 | 2.8% | -2.2% | 0.220 | | fever | 32 | 31 | 18.8% | 15 | 13 | 18.1% | 0.7% | 1.000 | | fracture (non-vertebral) | 6 | 6 | 3.6% | 3 | 3 | 4.2% | -0.5% | 1.000 | | gastrointestinal | 98 | 67 | 40.6% | 52 | 29 | 40.3% | 0.3% | 1.000 | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 27 {27} | All Adverse Events | prodisc^{®} L | | | Fusion | | | Dif | Exact | | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | Events | Subjs | %* | Events | Subjs | %* | %* | p^{1} | | genitourinary | 28 | 25 | 15.2% | 12 | 10 | 13.9% | 1.3% | 1.000 | | headache | 22 | 18 | 10.9% | 12 | 10 | 13.9% | -3.0% | 0.517 | | hernia | 1 | 1 | 0.6% | 0 | 0 | 0.0% | 0.6% | 1.000 | | incontinence | 5 | 5 | 3.0% | 1 | 1 | 1.4% | 1.6% | 0.670 | | insomnia | 23 | 22 | 13.3% | 12 | 10 | 13.9% | -0.6% | 1.000 | | migration not requiring surgery | 1 | 1 | 0.6% | 0 | 0 | 0.0% | 0.6% | 1.000 | | narcotics use | 8 | 8 | 4.8% | 0 | 0 | 0.0% | 4.8% | 0.110 | | neoplasm | 1 | 1 | 0.6% | 1 | 1 | 1.4% | -0.8% | 0.516 | | other | 38 | 28 | 17.0% | 19 | 13 | 18.1% | -1.1% | 0.853 | | other musculoskeletal | 24 | 20 | 12.1% | 11 | 11 | 15.3% | -3.2% | 0.533 | | pain other (not back/hip/leg) | 40 | 34 | 20.6% | 25 | 17 | 23.6% | -3.0% | 0.610 | | pseudoarthrosis | 0 | 0 | 0.0% | 4 | 4 | 5.6% | -5.6% | 0.008 | | psychological | 41 | 32 | 19.4% | 17 | 12 | 16.7% | 2.7% | 0.718 | | respiratory | 25 | 24 | 14.5% | 8 | 8 | 11.1% | 3.4% | 0.541 | | spinal stenosis | 1 | 1 | 0.6% | 1 | 1 | 1.4% | -0.8% | 0.516 | | subsidence not requiring surgery | 9 | 8 | 4.8% | 1 | 1 | 1.4% | 3.5% | 0.283 | | surgery - adjacent level | 3 | 3 | 1.8% | 4 | 4 | 5.6% | -3.7% | 0.204 | | surgery - other | 73 | 47 | 28.5% | 21 | 16 | 22.2% | 6.3% | 0.342 | | thrombosis (dvt leg) | 3 | 2 | 1.2% | 2 | 2 | 2.8% | -1.6% | 0.587 | | vertebral fracture | 1 | 1 | 0.6% | 1 | 1 | 1.4% | -0.8% | 0.516 | *Percentage of subjects experiencing specific event without regard to length of follow-up. $^{1}$Two-sided Fisher's Exact test. Table 16 depicts a time course of all adverse events by category. In some cases, the available information did not allow for determination of the AE start date and therefore the time course for these events was unknown; these events are included in the Missing column. **Table 16: Counts of Specific Adverse Events by Time of Occurrence** | All Adverse Events - Timecourse | Missing | | 0-2 days | | 2-42 days | | 42-210 days | | 210-730 days | | 730-1095 days | | 1095-1460 days | | >1460 days | | Total | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C | | **ALL** | **4** | **7** | **301** | **142** | **136** | **85** | **190** | **76** | **231** | **121** | **72** | **39** | **59** | **33** | **63** | **33** | **1056** | **536** | | **PAIN - BACK AND LOWER EXTREMITY** | **0** | **3** | **26** | **10** | **32** | **17** | **74** | **39** | **92** | **43** | **21** | **12** | **19** | **14** | **24** | **10** | **288** | **148** | | pain - back | 0 | 2 | 6 | 5 | 5 | 0 | 25 | 15 | 42 | 16 | 6 | 6 | 7 | 7 | 6 | 4 | 97 | 55 | | pain - back and lower extremities | 0 | 0 | 5 | 1 | 7 | 3 | 16 | 6 | 20 | 10 | 4 | 1 | 7 | 4 | 4 | 2 | 63 | 27 | | pain - back and lower extremities with burning | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 3 | 2 | | pain - back and lower extremities with numbness at index level | 0 | 0 | 0 | 0 | 1 | 0 | 3 | 1 | 2 | 1 | 2 | 1 | 0 | 0 | 1 | 0 | 9 | 3 | | pain - back and other | 0 | 0 | 10 | 4 | 0 | 0 | 0 | 0 | 4 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 15 | 5 | | pain - groin area | 0 | 0 | 2 | 0 | 3 | 1 | 1 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 7 | 3 | | pain - lower extremities | 0 | 1 | 2 | 0 | 15 | 9 | 26 | 13 | 20 | 13 | 8 | 2 | 2 | 2 | 10 | 3 | 83 | 43 | | pain - lower extremities and incision site | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | | pain - lower extremities with numbness at index level | 0 | 0 | 1 | 0 | 1 | 4 | 0 | 3 | 3 | 1 | 1 | 0 | 2 | 1 | 2 | 0 | 10 | 9 | PMA P050010/S020: FDA Summary of Safety and Effectiveness Data Page 28 {28} | All Adverse Events - Timecourse | Missing | | 0-2 days | | 2-42 days | | 42-210 days | | 210-730 days | | 730-1095 days | | 1095-1460 days | | >1460 days | | Total | | | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | | | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C | I | C | | **NEUROLOGICAL EVENTS** | **0** | **0** | **6** | **5** | **8** | **2** | **17** | **2** | **22** | **14** | **3** | **1** | **0** | **1** | **1** | **3** | **57** | **28** | | motor deficit in index level | 0 | 0 | 1 | 0 | 0 | 0 | 1 | 0 | 2 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 4 | 1 | | neurological | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 0 | 5 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 5 | 2 | | numbness index level related | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 1 | 2 | 2 | 1 | 0 | 0 | 0 | 0 | 1 | 5 | 4 | | numbness peripheral nerve or non-index level related | 0 | 0 | 5 | 4 | 8 | 1 | 14 | 1 | 13 | 10 | 2 | 1 | 0 | 1 | 1 | 2 | 43 | 20 | | reflex change | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | | **DEGENERATIVE DISEASE PROGRESSION** | **0** | **0** | **0** | **0** | **0** | **0** | **1** | **1** | **5** | **5** | **2** | **1** | **3** | **0** | **4** | **2** | **15** | **9** | | degenerative disease progression, non-lumbar | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 2 | 0 | 1 | 0 | 1 | 0 | 2 | 0 | 7 | 1 | | degenerative disease progression, other lumbar | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 2 | 5 | 1 | 1 | 2 | 0 | 2 | 2 | 7 | 8 | | herniated nucleus pulposus | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | | **ADDITIONAL SURGERY INDEX LEVEL** | **0** | **0** | **0** | **0** | **2** | **0** | **1** | **0** | **1** | **7** | **0** | **3** | **0** | **2** | **1** | **2** | **5** | **14** | | migration requiring surgery | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | | surgery - index level (other) | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 3 | 0 | | surgery - index level (revision) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 7 | 0 | 3 | 0 | 2 | 0 | 2 | 0 | 14 | | surgery - index level (supplemental fixation) | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 1 | 0 | | **INCISION SITE RELATED** | **0** | **0** | **15** | **6** | **16** | **12** | **8** | **2** | **2** | **3** | **1** | **0** | **0** | **0** | **0** | **0** | **42** | **23** | | infection - superficial wound with incision site pain | 0 | 0 | 2 | 0 | 2 | 5 | 2 | 0 | 0 | 1 | 0 | 0…