Mechanical performance of cervical intervertebral body fusion devices: A systematic analysis of data submitted to the Food and Drug Administration

Journal of Biomechanics 54 (2017) 26–32

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Mechanical performance of cervical intervertebral body fusion devices: A systematic analysis of data submitted to the Food and Drug Administration Jonathan H. Peck a,⇑,1, David C. Sing b,c,1, Srinidhi Nagaraja c, Deepa G. Peck d, Jeffrey C. Lotz b, Anton E. Dmitriev c a

U.S. Food and Drug Administration, Center for Devices and Radiological Health, Office of Device Evaluation, Division of Orthopedic Devices, Silver Spring, MD 20993, USA University of California at San Francisco, Department of Orthopedic Surgery, San Francisco, CA 94143, USA c U.S. Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories, Division of Applied Mechanics, Silver Spring, MD 20993, USA d U.S. Food and Drug Administration, Center for Devices and Radiological Health, Office of Surveillance and Biometrics, Division of Postmarket Surveillance, Silver Spring, MD 20993, USA b

a r t i c l e

i n f o

Article history: Accepted 20 January 2017

Keywords: Cervical intervertebral body fusion device Cervical cage Mechanical testing ASTM F2077 ASTM F2267

a b s t r a c t Cervical intervertebral body fusion devices (IBFDs) are utilized to provide stability while fusion occurs in patients with cervical pathology. For a manufacturer to market a new cervical IBFD in the United States, substantial equivalence to a cervical IBFD previously cleared by FDA must be established through the 510(k) regulatory pathway. Mechanical performance data are typically provided as part of the 510(k) process for IBFDs. We reviewed all Traditional 510(k) submissions for cervical IBFDs deemed substantially equivalent and cleared for marketing from 2007 through 2014. To reduce sources of variability in test methods and results, analysis was restricted to cervical IBFD designs without integrated fixation, coatings, or expandable features. Mechanical testing reports were analyzed and results were aggregated for seven commonly performed tests (static and dynamic axial compression, compression-shear, and torsion testing per ASTM F2077, and subsidence testing per ASTM F2267), and percentile distributions of performance measurements were calculated. Eighty-three (83) submissions met the criteria for inclusion in this analysis. The median device yield strength was 10,117 N for static axial compression, 3680 N for static compression-shear, and 8.6 N m for static torsion. Median runout load was 2600 N for dynamic axial compression, 1400 N for dynamic compression-shear, and ±1.5 N m for dynamic torsion. In subsidence testing, median block stiffness (Kp) was 424 N/mm. The mechanical performance data presented here will aid in the development of future cervical IBFDs by providing a means for comparison for design verification purposes. Published by Elsevier Ltd.

1. Introduction Anterior cervical decompression and fusion (ACDF) is a commonly utilized surgical treatment for cervical spine pathologies including radiculopathy or myelopathy, achieving favorable clinical outcomes with minimal surgical risks (Cloward, 1958; Fraser and Härtl, 2007; Gore and Sepic, 1998). ACDF procedures commonly involve implantation of cervical intervertebral body fusion ⇑ Corresponding author at: U.S. Food and Drug Administration, Center for Devices and Radiological Health, 10903 New Hampshire Avenue, Building 66, Room 1418, Silver Spring, MD 20993, USA. E-mail address: [email protected] (J.H. Peck). 1 First two authors contributed equally to this study. http://dx.doi.org/10.1016/j.jbiomech.2017.01.032 0021-9290/Published by Elsevier Ltd.

devices (IBFDs) between adjacent vertebral bodies to maintain or restore disc height while providing stability to allow for the development of a fusion mass (Hacker, 2000; Kulkarni et al., 2007; Niu et al., 2010; Thomé et al., 2004; Vavruch et al., 2002). Cervical IBFDs need to withstand the physiologic loading in the cervical spine while avoiding significant subsidence into the vertebral bodies. Thus, the mechanical strength of cervical IBFDs, as well as the propensity of the device to subside, must be evaluated prior to use in patients. ASTM F2077 Test Methods for Intervertebral Body Fusion Devices contains methods for performing static and dynamic axial compression, compression-shear, and torsion testing on IBFDs. While none of these tests in isolation replicate the complex in vivo loads in the spine, these methods allow for mechanical properties to be compared between devices under the

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Table 1 Components of 510(k) Submissions for IBFDs. Section

Components

Device description

A device description typically includes information such as indications for use, device sizes and geometries, device materials, and engineering drawings Material characterization can include a description of material properties/leachables/impurities, and a demonstration of the effects of material aging Static and dynamic mechanical testing of worst-case devices is recommended to demonstrate the mechanical performance of the device Animal study data may be included to help evaluate new technological features or the safety of new materials or wear debris Clinical data may be necessary to evaluate new indications for use, new technological features, or devices for which non-clinical data are insufficient to demonstrate substantial equivalence The device should be provided sterile via validated sterilization methods or instructions should be provided to the end user to achieve adequate sterility Biocompatibility of patient contacting materials can be demonstrated with appropriate biocompatibility testing (e.g., per ISO 10993) or a justification that biocompatibility of the material(s) has been previously established Labeling includes appropriate instructions for use (e.g., indications for use, contraindications, warnings/precautions, surgical approach, removal procedures)

Material characterization Mechanical testing Animal testing Clinical testing Sterility Biocompatibility Labeling

The information above is summarized from ‘‘Guidance for Industry and FDA Staff – Class II Special Controls Guidance Document: Intervertebral Body Fusion Devices” available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071408.htm.

predominant loading modes an IBFD is expected to experience in vivo. ASTM F2267 Standard Test Method for Measuring Load Induced Subsidence of Intervertebral Body Fusion Device Under Static Axial Compression contains methods to test the propensity of an IBFD to subside. These standards describe methods that allow spinal device manufacturers to compare the mechanical properties of IBFDs. In the United States, IBFDs are regulated in FDA’s Center for Devices and Radiological Health (CDRH). IBFDs are subject to CDRH’s Pre-Market Notification (510(k)) process, which requires that a new device be deemed ‘‘substantially equivalent” to an FDA-cleared device, based on intended use and technological characteristics (U.S. FDA, 2014). FDA’s guidance document for IBFDs describes the type of information necessary for inclusion in a 510 (k) submission in order to demonstrate substantial equivalence (Table 1) (U.S. FDA, 2007). Comparison of mechanical properties between the new device and a previously FDA-cleared device is an important part of substantial equivalence determinations for IBFDs. The aforementioned FDA guidance recommends that manufacturers conduct static and dynamic axial compression, compression-shear, and torsion testing per ASTM F2077, and subsidence testing per ASTM F2267 on new cervical IBFDs. Standardized mechanical testing is thus an important element in the regulatory process for cervical IBFDs. However, publicly available mechanical performance data for cervical IBFDs are scarce. The objective of this study was to increase transparency in the FDA review process by presenting aggregated cervical IBFD mechanical testing results accumulated in 510(k) submissions. In addition, we evaluated the clinical failure modes (adverse events) for cervical IBFDs in FDA’s Medical Device Reporting (MDR) database to ensure there were no significant performance issues being reported for the devices whose mechanical test data were aggregated in this study. The data presented provides the spinal device community with a range of mechanical performance values that can be used as a means for comparison in the design verification process of new cervical IBFDs.

2. Methods Mechanical testing data and device dimensions were retrospectively collected from Traditional2 510(k) submissions for cervical IBFDs cleared by FDA from 2007 through 2014. Only single-piece cervical IBFDs without integrated fixation, unique materials (i.e., materials other than metals or poly-ether-ether-ketone (PEEK)), expandable features, or coatings were included in this analysis. IBFDs with these 2 Traditional 510(k)s are typically submitted when marketing clearance is sought for new devices, and are differentiated from Special 510(k)s which are typically submitted for modifications to previously cleared devices.

more complex or unique features were excluded as they contribute additional variability to test methods and failure modes that can confound the aggregation of results. Of the 145 Traditional 510(k) submissions for cervical IBFDs initially screened, 62 (42.8%) submissions were excluded leaving 83 submissions from 74 different manufacturers for analysis (Fig. 1). Multiple device sizes were often tested in a single 510 (k) submission resulting in a total of 127 different devices tested. In total, within the 83 submissions, 360 mechanical tests (each test performed on 5 or more specimens), conducted at 22 different laboratories (12 independent laboratories and 10 in-house laboratories), met the criteria for inclusion in this analysis. General device design information was collected from each submission including device material, shape (box-shape, D-shape, or other), and range of dimensions (width, depth, height, and lordosis angle). Dimensions were recorded as shown in Fig. 2. The dimensions of the specific device being tested were also collected.

2.1. Mechanical testing per ASTM F2077 Static and dynamic axial compression, compression-shear, and torsion test results were submitted to FDA per the methods described in ASTM F2077. Briefly, in each of these tests, devices are fixtured into a load frame and a static or dynamic axial compression load, compression-shear load, or torque is applied. Static tests are run until device failure, device-fixture interface failure, or test machine limits are reached. Dynamic tests are run until device failure occurs or the device reaches 5 million cycles without failure. ASTM F2077 offers the option to perform compression-shear testing at a sagittal inclination of either 45° or 27°. The vast majority of manufacturers that performed compression-shear testing utilized the 45° test setup; therefore, results were excluded from this analysis if testing was not performed at 45°. Torsion tests were excluded from this analysis if testing was not performed using a 100 N axial preload, and dynamic torsion tests were excluded if fully reversed loads were not used as specified in ASTM F2077. For each static test, the mean and standard deviation were collected for stiffness, yield load/torque, and ultimate load/torque. The failure mode was also documented for each test based on the manufacturer’s description and photographs of failed devices provided in the test reports. Yield values were only included in this analysis if yield behavior was observed on the load vs. displacement plot, and the yield load was calculated as specified in ASTM F2077. Likewise, ultimate load values were only included in this analysis if ultimate behavior was observed on the load vs. displacement plot. Fig. 3 shows generic examples of three common scenarios for load vs. displacement plots observed in test reports. It is important to note that characterizations of yield and ultimate behavior were made strictly based on load vs. displacement plots and not the behavior of the specimen itself. For example, certain devices in the cohort clearly experienced plastic deformation during testing, but did not exhibit yield behavior on the load vs. displacement plot. Therefore, yield load was not included in the results for such devices as no yield load could be calculated. For each dynamic test, the following information was collected as reported by the manufacturers: cyclic load or torque at which the device did not exhibit any failures prior to reaching 5 million cycles (i.e., the runout load), number of specimens that achieved the runout load, and the lowest failure load at which a specimen failed prior to reaching 5 million cycles. ASTM F2077 provides two definitions of specimen failure: (1) functional failure – permanent deformation rendering the IBFD unable to resist force, and (2) mechanical failure – onset of a new material defect (e.g., crack initiation). For the purposes of 510(k) submissions, FDA defines IBFD failure as the presence of functional or mechanical failure. Precision of the runout load was calculated by dividing the lowest failure load by the runout load. Fatigue test results were excluded if the manufacturer did not present

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J.H. Peck et al. / Journal of Biomechanics 54 (2017) 26–32

Traditional 510(k) submissions screened for eligibility (n = 145)

Excluded (n = 62) Submission contained no cervical IBFD mechanical test data (e.g., modification to labeling) (n = 34) Integrated fixation (n = 18) Coated, expandable, or uncommon material (n = 10)

Submissions meeting criteria for inclusion in analysis (n = 83)

Different devices tested (n=127)

Static axial compression ASTM F2077 (n=89)

Dynamic axial compression ASTM F2077 (n=51)

Static compression-shear ASTM F2077 (n=36)

Dynamic compression-shear ASTM F2077 (n=15)

Static torsion ASTM F2077 (n=65)

Dynamic torsion ASTM F2077 (n=34)

Subsidence ASTM F2267 (n=70)

Fig. 1. Flowchart showing reasons for submission exclusions and sample size for each test meeting criteria for inclusion.

A

Cranial

B

Ant. Width

Ant.

Caudal

Depth

Height

Post.

Post.

Fig. 2. Dimensions recorded for cervical IBFDs. (A) Isometric view showing inserter hole location on anterior wall. (B) Transverse plane view also referred to as footprint view.

at least two devices that achieved runout at a given load and did not achieve a precision of less than or equal to 1.5 (i.e., lowest failure load had to be less than or equal to 150% of the highest established runout load), to ensure that the runout load being reported was sufficiently representative of the actual fatigue strength of the device.

of the foam block as it deforms under the loads applied. A higher stiffness measurement is generally expected to represent that a device is more resistant to subsidence into a vertebral body.

2.2. Subsidence testing per ASTM F2267

To maintain confidentiality, all data presented here are aggregated and de-identified, and the lowest 5% and highest 5% of results from each data range are not presented. With regard to device design, dimensional range data were aggregated and the 5th percentile of the minimum dimension offered and the 95th percentile of the maximum dimension offered were calculated. Data for each mechanical performance parameter (static testing: stiffness, yield, and ultimate strength; dynamic testing: runout load; subsidence testing: block stiffness [Kp]) were aggregated and the 5th, 25th, 50th, 75th, and 95th percentile were calculated.

Subsidence testing, as described in ASTM F2267, is intended to characterize the propensity of an IBFD to subside into the vertebral body endplates. Subsidence testing involves placing the IBFD between two blocks of grade 15 polyurethane foam (intended to replicate compression properties of trabecular bone) and applying a compressive load. Per ASTM F2267, the relative propensity of a device to subside is quantified by a stiffness measurement, Kp (N/mm), which represents the stiffness

2.3. Mechanical testing data analysis

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Force or Torque (N or Nm)

J.H. Peck et al. / Journal of Biomechanics 54 (2017) 26–32

3. Results

A Ultimate

Force or Torque (N or Nm)

Displacement (mm or deg)

B Yield

No Ultimate Behavior

Displacement (mm or deg) Force or Torque (N or Nm)

3.1. Device design

Yield Table 2 shows the dimensional range offerings in the submissions for width (11–20 mm), depth (10–16 mm), height (4–14 mm), and lordosis angle (0–7 degrees). By material type, 90.4% were PEEK, and 9.6% were metallic. For device shape, 81.9% were box-shaped, 14.5% were D-shaped, and 3.6% had other single-piece designs. The smallest footprint device (i.e., smallest width  smallest depth), from the range of sizes in a single submission, was chosen by the manufacturer for testing greater than 87% of the time for each of the tests. The tallest device was chosen for testing approximately 50% of the time for static and dynamic axial compression and subsidence testing, approximately 75% of the time for static and dynamic compression-shear, and approximately 70% of the time for static and dynamic torsion. For device offerings with a range of lordosis angles, the maximum lordosis angle was selected approximately 50% of the time for static and dynamic axial compression, static and dynamic torsion, and subsidence testing. The largest lordosis angle was chosen approximately 64% of the time for static and dynamic compression-shear testing.

C 3.2. Mechanical test results

No Yield or Ultimate Behavior Displacement (mm or deg)

Fig. 3. (A) Load-displacement curve with both yield and ultimate behavior. (B) Load-displacement curve with yield behavior but no ultimate behavior. (C) Loaddisplacement curve with neither yield nor ultimate behavior.

The median and interquartile range were calculated for the coefficient of variation for each static performance result. Coefficient of variation for a given test is the standard deviation normalized to the mean; this parameter allows for intralaboratory variability to be collated and compared across laboratories despite the large data ranges. The most common failure modes for each test were determined based on the manufacturer’s description of the failure mode which was corroborated using the photographic documentation provided. A Student’s t-test was used to determine if there were significant differences (p  0.05) between PEEK and metallic devices for each mechanical performance parameter (static testing: stiffness, yield, and ultimate strength; dynamic testing: runout load; subsidence testing: block stiffness [Kp]). Additionally, a Student’s ttest was used to determine if there were significant differences (p  0.05) in device height between devices that experienced or did not experience yield or ultimate behavior during static testing.

Table 3 lists the range of results for each test parameter. It is important to note that the ranges of yield and ultimate strengths reported in Table 3 represent a subset of devices for which the behavior was observed in load vs. displacement plots, and not for the entire cohort. The most common failure mode for all static tests was plastic deformation of the device. Static axial compression usually resulted in buckling of the portion of the device not shielded by the fixture blocks. Static compression-shear usually resulted in plastic deformation of the device in the direction shear force was applied. Static torsion loading most commonly resulted in indentations from the fixture blocks and often did not result in significant permanent torsional deformation of the exposed portion of the device. Several manufacturers noted slippage of the device from the test blocks during static compression-shear and static torsion testing. Dynamic axial compression failure modes typically involved cracks propagating from features such as surgical instrument insertion holes, side windows, or device endplates. In certain instances, cracks propagated to the point of complete device fracture into two or more pieces. Dynamic compression-shear failures

Table 2 Cervical IBFD characteristics. Number of submissions

2.4. MDR database analysis The FDA MDR database was queried for adverse events related to single-piece cervical IBFDs using two different searches. Both queried for reports submitted to FDA prior to August 8, 2015 and employed product codes – three letter codes created by FDA to define the generic category of a device. The first search utilized the product code ODP (defined as ‘‘Intervertebral Fusion Device with Bone Graft, Cervical”). MDRs are occasionally submitted with incorrect product codes. Therefore, a second search utilizing all remaining IBFD product codes (MAX – ‘‘Intervertebral Fusion Device with Bone Graft, Lumbar”, OVD – ‘‘Intervertebral Fusion Device with Integrated Fixation, Lumbar”, and OVE – ‘‘Intervertebral Fusion Device with Integrated Fixation, Cervical”) was conducted. The results were cross-referenced with the device names for which mechanical testing results were collected to ensure all MDRs related to single-piece cervical IBFDs were captured. The resulting MDRs were combined; duplicates, reports for unrelated devices, and MDRs related to supplemental fixation (i.e., screws, plates) were removed. The remaining MDRs were reviewed individually.

IBFD dimensions Width (mm) Depth (mm) Height (mm) Lordosis (deg)

a b

83 5th Percentilea 11 10 4 0

95th Percentileb 20 16 14 7

IBFD shape Box D-Shape Other

N (%) 68 (81.9) 12 (14.5) 3 (3.6)

Material PEEK Metallic

N (%) 75 (90.4) 8 (9.6)

5th percentile of minimum dimension submitted. 95th percentile of maximum dimension submitted.

5760 2450 ±3.0

791

3500 1875 ±2.0

522

0.048 [0.032, 0.081]

– – –

[0.018, [0.010, [0.010, [0.025, [0.014, [0.015, [0.028, [0.019, [0.020, 19,203 15,256 32,863 10,538 6685 11,001 4.7 18.8 25.3 13,300 12,131 14,728 6140 5265 6868 1.9 12.0 13.8

0.039 0.023 0.015 0.053 0.029 0.026 0.045 0.034 0.029

95th Percentile 75th Percentile

424 324 Kp, Block stiffness (N/mm)

70

257

2600 1400 ±1.5 2000 1000 ±1.5 Runout load (N) Runout load (N) Runout torque (N m)

Subsidence (ASTM F2267)

Axial compression Compression – shear Torsion Dynamic (ASTM F2077)

Torsion

Compression – shear

51 15 34

1500 679 ±1.0

10,108 10,117 10,800 4347 3680 4626 1.0 8.6 9.9 7984 8379 8935 2927 2447 2861 0.7 6.1 7.6 5097 5450 6236 1492 1464 1515 0.3 3.1 3.3

50th Percentile 25th Percentile 5th Percentile

89 70 19 36 35 27 65 60 57

N Test parameter

Stiffness (N/mm) Yield strength (N) Ultimate strength (N) Stiffness (N/mm) Yield strength (N) Ultimate strength (N) Torsional stiffness (N m/degree) Yield moment (N m) Ultimate moment (N m) Axial compression

Test

often involved crack propagation similar to that observed during dynamic axial compression testing, as well as plastic deformation of the device at the test block interface. Dynamic torsion specimens often experienced cracks or fractures propagating from a point of contact with the test block (e.g., fracture of the corner of the device). The failure mode during subsidence testing consisted of the device sinking into the polyurethane foam test block, with no structural failures of the cervical IBFDs reported. Metallic IBFDs had significantly higher static axial compression stiffness compared to PEEK IBFDs (22,448 ± 12,075 N/mm vs. 10,300 ± 3417 N/mm, p = 0.025). Statistically significant differences were not detected between PEEK and metallic devices for any other mechanical performance parameter (p  0.14). Devices that exhibited axial compression yield behavior were significantly taller than devices that did not (9.8 ± 3.4 mm vs. 6.3 ± 2.9 mm, p  0.01). Similarly, devices that exhibited axial compression ultimate behavior were significantly taller than devices that did not (12 ± 2.7 mm vs. 8.1 ± 3.3 mm, p  0.01). There was no statistical difference in device height detected between devices that did and did not exhibit yield or ultimate behavior in static compression-shear or torsion testing.

3.3. Postmarket MDR database analysis

Static (ASTM F2077)

Table 3 Mechanical testing results.

0.058] 0.046] 0.047] 0.087] 0.070] 0.063] 0.105] 0.063] 0.050]

J.H. Peck et al. / Journal of Biomechanics 54 (2017) 26–32

Coefficient of variation (median [IQR])

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A total of 81 MDRs were identified for single-piece cervical IBFDs. The ten most reported events associated with these MDRs are tabulated in Table 4. The most frequently reported events were fracture of the IBFD during insertion, instrument failure, and surgical revision. Due to potential underreporting of adverse events and the lack of information on the total number of implantations, rates of events cannot be determined. However, the MDRs can be used to establish a qualitative view of the adverse event profile for a device type.

4. Discussion The present study is the first comprehensive analysis of mechanical testing data for FDA-cleared cervical IBFDs. These mechanical tests are important tools for spinal device manufacturers for design verification and regulatory purposes. Graham and Estes discuss the two typical sources for acceptance criteria for standardized mechanical tests: (1) test results of a comparable device, and (2) expected physiologic loads (Graham and Estes, 2009). They state that comparing test results between devices is often more straight forward than attempting to derive acceptance criteria from biomechanical literature. In fact, ASTM F2077 states that forces applied during mechanical testing may not be representative of the complex in vivo loads, and encourages the user to compare test results between devices. Due to the paucity of publicly available mechanical performance data on cervical IBFDs, the current data provide spinal device designers with valuable information that can be used for comparative purposes to aid in the development of future devices. Our findings (Table 3) indicate a large range in the mechanical properties of FDA-cleared cervical IBFDs, which is largely due to differences in device material and geometry. As expected, we found that static axial compression stiffness was significantly higher for metallic devices as compared to PEEK devices. Although we did not detect significant differences for any other mechanical test parameter based on device material, differences in device material certainly contribute to the large ranges in mechanical properties presented in Table 3. While not captured in our analysis, geometric features (e.g., side windows, wall thickness) also impact the mechanical performance for single-piece cervical IBFDs.

J.H. Peck et al. / Journal of Biomechanics 54 (2017) 26–32 Table 4 Top clinical failure modes (MDR Postmarket Surveillance).

a

Adverse event

Counta

Fracture during insertion Instrument issue Revision Migration Pain Fracture of device Hematoma Allergic reaction Labeling issue Nonunion

32 12 12 10 5 4 3 2 2 2

A single MDR may be associated with more than one adverse event type.

Determining fatigue strength is important when characterizing the long term durability of IBFDs. However, approximately 47% of fatigue tests screened were excluded because adequate precision was not established (i.e., the lowest failure load was greater than 150% of the highest runout load level) and/or at least two devices were not tested out to 5 million cycles at the highest runout load level. Fatigue failure is dependent on many factors and runout of one or two samples may not guarantee that replicates will also reach 5 million cycles at that fatigue load without failure. Therefore, dynamic testing can be improved through testing of more devices at the highest runout level to establish a runout load with more confidence. Additionally, the fatigue behavior of devices can be better characterized by achieving adequate precision. The current recommendation in ASTM F2077 is that maximum runout force should not deviate more than 10% of the static ultimate strength of the IBFD. However, ultimate behavior was not established in many static tests (e.g., only 19 of 89 static axial compression tests resulted in calculable ultimate strengths). Therefore, we were required to define a new criterion (i.e., lowest failure load must be less than or equal to 150% of established runout load) for this study based on what we believed represented minimally acceptable precision for runout loads of cervical IBFDs. The selection of the worst-case device size for mechanical testing is an important decision to ensure that the mechanical integrity of all other implant sizes in a 510(k) submission will have the same or better mechanical performance than the size tested. Logically, the smallest footprint (width  depth) was used at least 87% of the time in each of the seven tests, because the smallest footprint device often has the lowest cross-sectional area and structural strength. Unlike the selection of device footprint, selection of device height for testing is often not as straight forward. For static and dynamic axial compression tests, manufacturers selected the tallest device for testing about 50% of the time. Our study found that devices that exhibited static axial compression yield and ultimate behavior were significantly taller than the devices that did not exhibit these behaviors on load vs. displacement plots. Shorter devices may deform in a way that allows them to continue to bear increasing load even though permanent deformation has occurred. Therefore, testing the tallest device for a given footprint in static axial compression appears to provide a better chance of obtaining calculable yield and ultimate loads. While significant differences in device height were not detected based on yield and ultimate behavior for compression-shear and torsion testing, utilizing the tallest device for these two tests allows for the use of deeper test pockets; this may reduce the influence of device slippage from the fixture blocks on the mechanical property measurements. In some instances, testing both the shortest and tallest device may be appropriate if a clear worst case cannot be determined. Analysis of MDRs for single-piece cervical IBFDs showed low numbers of reported adverse events related to the post-operative structural integrity of the devices. Many of the reported MDRs

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were intraoperative, such as fracture of the device during insertion or instrument related issues. Currently, there are no standard methods to assess the integrity of IBFDs against impaction forces that occur during insertion. Therefore, additional research and attention should be devoted to this type of failure during device development and evaluation. Regardless, the relatively low volume of reports for post-operative device failure supports the notion that the previously cleared single-piece cervical IBFDs, that were the subject of this analysis, generally have sufficient strength to endure in vivo cervical spine loads. One important limitation of this study was the exclusion of more complex cervical IBFD designs (e.g., IBFDs with integrated fixation or expandable features) in order to reduce variability in test methods and failure modes. If mechanical test results of more complex cervical IBFDs are compared to the data in the present analysis, differences in test methods (e.g., use of integrated fixation features during testing) and failure modes (e.g., collapse of expandable features, failure of integrated fixation screws) should be taken into account. In addition, despite narrowing our analysis to singlepiece cervical IBFDs, we observed variations in testing methodology (e.g., rigidity of test fixtures, test block pocket depth). A recent interlaboratory study (ILS) published in ASTM F2077, involving 13 laboratories testing identical IBFDs per ASTM F2077 test methods, revealed the potential for interlaboratory variability in measured mechanical properties of IBFDs (results published in Section 11 of ASTM F2077). Based on the ASTM ILS, it is important to note that deviations from the ASTM F2077 standard may inflate measured mechanical properties of a device and invalidate comparisons to the data presented here. In summary, this study established a range of mechanical properties of FDA-cleared single-piece cervical IBFDs. The current data can assist the spine community by improving the overall understanding of the mechanical performance of devices in this category. Future efforts could leverage this methodology to establish comparative mechanical testing values for other common spinal implant types, such as lumbar IBFDs, anterior plates, or pedicle screw systems. Conflict of interest The authors of this manuscript have no conflicts of interest to report. Acknowledgements This publication was made possible by Grant Number U01FD004979 from the FDA, which supports the UCSF-Stanford Center of Excellence in Regulatory Sciences. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the HHS or FDA. The authors would like to thank Vivek Palepu for his assistance with figures, and Katherine Kavlock, Melissa Hall, Caroline Rhim, Ronald Jean, and Mark Melkerson for their help with review. References Cloward, R.B., 1958. The anterior approach for removal of ruptured cervical disks⁄. J. Neurosurgery 15, 602–617. Fraser, J.F., Härtl, R., 2007. Anterior approaches to fusion of the cervical spine: a metaanalysis of fusion rates. J. Neurosurgery: Spine 6, 298–303. Gore, D.R., Sepic, S.B., 1998. Anterior Discectomy and Fusion for Painful Cervical Disc Disease: A Report of 50 Patients with an Average Follow-up of 21 Years. Spine 23, pp. 2047–2051. Graham, J., Estes, B.T., 2009. What standards can (and can’t) tell us about a spinal device. SAS J. 3, 178–183. Hacker, R.J., 2000. A randomized prospective study of an anterior cervical interbody fusion device with a minimum of 2 years of follow-up results. J. Neurosurgery: Spine 93, 222–226.

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Kulkarni, A.G., Hee, H.T., Wong, H.K., 2007. Solis cage (PEEK) for anterior cervical fusion: preliminary radiological results with emphasis on fusion and subsidence. Spine J. 7, 205–209. Niu, C.-C., Liao, J.-C., Chen, W.-J., Chen, L.-H., 2010. Outcomes of interbody fusion cages used in 1 and 2-levels anterior cervical discectomy and fusion: titanium cages versus polyetheretherketone (PEEK) cages. J. Spinal Disorders Tech. 23, 310–316. Thomé, C., Krauss, J.K., Zevgaridis, D., 2004. A prospective clinical comparison of rectangular titanium cages and iliac crest autografts in anterior cervical discectomy and fusion. Neurosurgical Rev. 27, 34–41.

U.S. Food and Drug Administration, 2007. FDA Guidance for Industry and FDA Staff – Class II Special Controls Guidance Document: Intervertebral Body Fusion Device. U.S. Food and Drug Administration, 2014. The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] – Guidance for Industry and Food and Drug Administration Staff. Vavruch, L., Hedlund, R., Javid, D., Leszniewski, W., Shalabi, A., 2002. A prospective randomized comparison between the Cloward procedure and a carbon fiber cage in the cervical spine: a clinical and radiologic study. Spine 27, 1694–1701.