The fragility index and reverse fragility index of FDA investigational device exemption trials in spinal fusion surgery: a systematic review.

PURPOSE: FDA investigational device exemption (IDE) studies are considered a gold standard of assessing safety and efficacy of novel devices through RCTs. The fragility index (FI) has emerged as a means to assess robustness of statistically significant study results and inversely, the reverse fragility index (RFI) for non-significant differences. Previous authors have defined results as fragile if loss to follow up is greater than the FI or RFI. The aim of this study was to assess the FI, RFI, and robustness of data supplied by IDE studies in spinal surgery. METHODS: This was a systematic review of the literature. Inclusion criteria included randomized controlled trials with dichotomous outcome measures conducted under IDE guidelines between 2000 and 2023. FI and RFI were calculated through successively changing events to non-events until the outcome changed to non-significance or significance, respectively. The fragility quotient (FQ) and reverse fragility quotient (RFQ) were calculated by dividing the FI and RFI, respectively, by the sample size. RESULTS: Thirty-two studies met inclusion criteria with a total of 40 unique outcome measures; 240 outcomes were analyzed. Twenty-six studies reported 96 statistically significant results. The median FI was 6 (IQR: 3-9.25), and patients lost to follow up was greater than the FI in 99.0% (95/96) of results. The average FQ was 0.027. Thirty studies reported 144 statistically insignificant results and a median RFI of 6 (IQR: 4-8). The average RFQ extrapolated was 0.021, and loss to follow up was greater than the RFI in 98.6% (142/144) of results. CONCLUSIONS: IDE studies in spine surgery are surprisingly fragile given their reputations, large sample sizes, and intent to establish safety in investigational devices. This study found a median FI and RFI of 6. The number of patients lost to follow-up was greater than FIand RFI in 98.8% (237/240) of reported outcomes. FQ and RFQ tell us that changes of two to three patients per hundred can flip the significance of reported outcomes. This is an important reminder of the limitations of RCTs. Analysis of fragility in future studies may help clarify the strength of the relationship between reported data and their conclusions.

Cervical arthroplasty: what does the labeling say?

OBJECTIVE The aim of this paper was to comprehensively review each of the Food and Drug Administration (FDA)-approved labels of 7 total cervical disc replacements, assess the exact methodology in which the trial was conducted, and provide a broad comparison of these devices to allow each surgeon to determine which disc best suits his or her specific treatment goals based on the specific labels and not the studies published. METHODS The FDA-approved labels for each of the 7 artificial discs were obtained from the official FDA website. These labels were meticulously compared with regard to the statistical analysis performed, the safety and efficacy data, and the randomized controlled trial that each artificial disc was involved in to obtain the FDA approval for the product or device. Both single-level and 2-level approvals were examined, and primary and secondary end points were assessed. RESULTS In the single-level group, 4 of the 7 artificial discs-Prestige LP, Prestige ST, Bryan, and Secure-C-showed superiority in overall success. Prestige ST showed superiority in 3 of 4 outcome measures (neurological success, revision surgery, and overall success), while the other aforementioned discs showed superiority in 2 or fewer measures (Prestige LP, neurological and overall success; Bryan, Neck Disability Index [NDI] and overall success; Secure-C, revision surgery and overall success; Pro-Disc C, revision surgery). The PCM and Mobi-C discs demonstrated noninferiority across all outcome measures. In the 2-level group, Prestige LP and Mobi-C demonstrated superiority in 3 outcome measures (NDI, secondary surgery, and overall success) but not neurological success. CONCLUSIONS This paper provides a comprehensive analysis of 7 currently approved and distributed artificial discs in the United States. It compares specific outcome measures of these devices against those following the standard of care, which is anterior cervical discectomy and fusion. This information will provide surgeons the opportunity to easily answer patients' questions and remain knowledgeable when discussing devices with manufacturers.

Prosthesis design and likelihood of achieving physiological range of motion after cervical disc arthroplasty: analysis of range of motion data from 1,173 patients from 7 IDE clinical trials.

BACKGROUND CONTEXT: The functional goals of cervical disc arthroplasty (CDA) are to restore enough range of motion (ROM) to reduce the risk of accelerated adjacent segment degeneration but limit excessive motion to maintain a biomechanically stable index segment. This motion-range is termed the "Physiological mobility range." Clinical studies report postoperative ROM averaged over all study subjects but they do not report what proportion of reconstructed segments yield ROM in the Physiological mobility range following CDA surgery. PURPOSE: To calculate the proportion of reconstructed segments that yield flexion-extension ROM (FE-ROM) in the Physiological mobility range (defined as 5°-16°) by analyzing the 24-month postoperative data reported by clinical trials of various cervical disc prostheses. STUDY DESIGN/SETTING: Analysis of 24-month postoperative FE-ROM data from clinical trials. PATIENT SAMPLE: Data from 1,173 patients from single-level disc replacement clinical trials of 7 cervical disc prostheses. OUTCOME MEASURES: 24-month postoperative index-level FE-ROM. METHODS: The FE-ROM histograms reported in Food and Drug Administration-Investigational Device Exemption (FDA-IDE) submissions and available for this analysis were used to calculate the frequencies of implanted levels with postoperative FE-ROM in the following motion-ranges: Hypomobile (0°-4°), Physiological (5°-16°), and Hypermobile (≥17°). The ROM histograms also allowed calculation of the average ROM of implanted segments in each of the 3 motion-ranges. RESULTS: Only 762 of 1,173 patients (implanted levels) yielded 24-month postCDA FE-ROM in the physiological mobility range (5°-16°). The proportions ranged from 60% to 79% across the 7 disc-prostheses, with an average of 65.0%±6.2%. Three-hundred and two (302) of 1,173 implanted levels yielded ROM in the 0°-4° range. The proportions ranged from 15% to 38% with an average of 25.7%±8.9%. One-hundred and nine (109) of 1,173 implanted levels yielded ROM of ≥17° with a range of 2%-21% and an average proportion of 9.3%±7.9%. The prosthesis with built-in stiffness due to its nucleus-annulus design yielded the highest proportion (103/131, 79%) of implanted segments in the physiological mobility range, compared to the cohort average of 65% (p<.01). Sixty-five of the 350 (18.6%) discs implanted with the 2 mobile-core designs in this cohort yielded ROM≥17° as compared to the cohort average of 9.3% (109/1,173) (p<.05). At 2-year postCDA, the "hypomobile" segments moved on average 2.4±1.2°, those in the "physiological-mobility" group moved 9.4±3.2°, and the hypermobile segments moved 19.6±2.6°. CONCLUSIONS: Prosthesis design significantly influenced the likelihood of achieving FE-ROM in the physiological mobility range, while avoiding hypomobility or hypermobility (p<.01). Postoperative ROM averaged over all study subjects provides incomplete information about the prosthesis performance - it does not tell us how many implanted segments achieve physiological mobility and how many end up with hypomobility or hypermobility. We conclude that the proportion of index levels achieving postCDA motions in the physiological mobility range (5°-16°) is a more useful outcome measure for future clinical trials.

Summary of the FDA virtual public workshop on spinal device clinical review held on September 17, 2021.

The mission of Food and Drug Administration (FDA)'s Center for Devices and Radiological Health is to protect and promote public health. It assures that patients and providers have timely and continued access to safe, effective, and high-quality medical devices and safe radiation-emitting products by providing meaningful and timely information about the products we regulate and the decisions we make. On September 17, 2021, an FDA workshop was held to provide information to stakeholders, including members of the spine community, device manufacturers, regulatory affairs professionals, clinicians, patients, and the general public regarding FDA regulations, guidance and regulatory pathways related to spinal device clinical review. It was not intended to communicate any new policies, processes, or interpretations regarding medical device marketing authorizations. This workshop consisted of individual presentations, group discussions, question and answer sessions, and audience surveys. Information-sharing included discussions related to patient-reported outcomes, clinician-reported outcomes, observer-reported outcomes, and performance outcomes. Discussions involving external subject matter experts covered topics related to spinal device clinical studies including definition of a target population, enrollment criteria, strategies for inclusion of under-represented patient groups, reporting of adverse event and secondary surgical procedures, clinical study endpoints, and clinical outcome assessments. A meeting transcript and webcast workshop link are currently posted on the FDA website. Important related issues and challenges were discussed, and an exciting range of new ideas and concepts were shared which hold promise to advance regulatory science, patient care and future innovation related to spinal devices.

Two-Year Outcomes From a Prospective Multicenter Investigation Device Trial of a Novel Conformal Mesh Interbody Fusion Device.

BACKGROUND: Interbody fusion is a widely utilized and accepted procedure to treat advanced debilitating lumbar degenerative disc disease (DDD). Increasingly, surgeons are seeking interbody devices that are large for stability and grafting purposes but can be inserted with less invasive techniques. To achieve these contrary objectives a novel, conformable mesh interbody fusion device was designed to be placed in the disc space through a small portal and filled with bone graft in situ to a large size. This design can reduce the risk of trauma to surrounding structures while creating a large graft footprint that intimately contours to the patient's own anatomy. The purpose of this Investigational Device Exempt (IDE) trial was to evaluate the perioperative and long-term results of this novel conformable mesh interbody fusion device. METHODS: This investigation is a prospective, multicenter, single-arm, Food and Drug Administration and Institutional Review Board-approved IDE, performance goal trial. A total of 102 adults presenting with DDD at a single level between L2 and S1 and unresponsive to 6 months conservative care had instrumented lumbar interbody fusion. Validated assessment tools include 100 mm visual analog scale for pain, Oswestry Disability Index (ODI) for function, single question survey for patient satisfaction, and computed tomography (CT) scan for fusion. Patients were enrolled across 10 geographically distributed sites. Pain/ODI surveys, physical evaluations, and imaging were performed serially through 24 months. Specifically, CT was performed at 12 and, if not fused, 24 months. Independent radiologists assessed CTs for fusion. An independent committee adjudicated adverse events. Patients with complete data at 24 months were included in the analysis. RESULTS: Ninety-six (96, 94% follow-up rate) patients (57.0 ± 12.0 years, 50.0% female, Body Mass Index 30.6 ± 4.9) reported average decreased low back pain from baseline of 45.0 ± 26.6 at 6 weeks and 51.4 ± 26.2 at 24 months. Right/left leg pain reduced by 28.9 ± 36.7/37.8±32.4 at 6 weeks and 30.5±33.0/40.3 34.6 at 24 months. Mean ODI improved 17.1 ± 18.7 from baseline to 6 weeks and 32.0 ± 18.5 by 24 months. At 24 months, 91.7% of patients rated their procedure as excellent/good. Fusion rates were 97.9% (94/96) at 12 months, and 99% (95/96) at 24 months. Mean operative time, estimated blood loss, and length of stay were 2.6 ± 0.9 hours, 137 ± 217 mL, and 2.3 ± 1.2 days, respectively. No device-related serious adverse events have occurred. CONCLUSIONS: Clinically significant outcomes for pain, function, fusion, and device safety were demonstrated in this population. Substantial clinical improvements occur by 6 weeks postoperative and continue to improve to 24 months. The successful outcomes observed in this trial support use of this novel device in an instrumented lumbar interbody fusion. LEVEL OF EVIDENCE: 3. CLINICAL RELEVANCE: This reports substantiates that the preliminary 1-year findings published earlier for this investigation are confirmed and the fusion rates and that patient improvements reported are sustained through 2 years.

Food and Drug Administration's Perspective on Medical Devices Intended for Weight Loss: A Guide for the Interventional Radiologist.

Medical devices can help patients lose weight. The Food and Drug Administration (FDA) Center for Devices and Radiological Health is responsible for assuring the safety and effectiveness of devices used for weight loss. Interventional radiologists may conduct clinical studies of devices for weight loss, such as embolization beads to stop blood flow to gastric arteries or cryoablation systems to ablate metabolism-linked nerves. The purposes of this paper are (1) to clarify the FDA's role providing regulatory oversight of clinical studies of medical devices; (2) to explain how to engage with the FDA; and (3) to provide information on the design of clinical studies intended to support a weight loss indication. In particular, Investigational Device Exemptions (IDEs) are needed for significant risk studies for new devices, or for off-label use of legally marketed devices. The FDA is available through the Pre-Submission process to assist when determining if a study requires an IDE, and to discuss plans for submitting an IDE. The FDA works with medical device manufacturers and clinical researchers who want to bring novel weight-loss devices to market.

Lumbar disc arthroplasty versus anterior lumbar interbody fusion: 5-year outcomes for patients in the Maverick disc investigational device exemption study.

OBJECTIVE: Despite evidence of its safety and effectiveness, the use of lumbar disc arthroplasty has been slow to expand due in part to concerns about late complications and the risks of revision surgery associated with early devices. More recently, FDA approval of newer devices and improving reimbursements have reversed this trend in the United States. Additional long-term data on lumbar disc arthroplasty are still needed. This study reports the 5-year results of the FDA investigational device exemption clinical trial of the Medtronic Spinal and Biologics' Maverick total disc replacement. METHODS: Patients with single-level degenerative disc disease from L4 to S1 were randomized 2:1 at 31 investigational sites. In the period from April 2003 to August 2004, 405 patients received the investigational device and 172 patients underwent the control procedure of anterior lumbar interbody fusion. Outcome measures included the Oswestry Disability Index (ODI), numeric rating scales (NRSs) for back and leg pain, the SF-36, disc height, interbody motion, heterotopic ossification (investigational device), adverse events (AEs), additional surgeries, and neurological status. Treatment was considered an overall success when all of the following criteria were met: 1) ODI score improvement ≥ 15 points over the preoperative score; 2) maintenance or improvement in neurological status compared with preoperatively; 3) disc height success, that is, no more than a 2-mm reduction in anterior or posterior height; 4) no serious AEs caused by the implant or by the implant and the surgical procedure; and 5) no additional surgery classified as a failure. RESULTS: Compared to that in the control group, improvement in the investigational group was statistically greater according to the ODI and SF-36 Physical Component Summary (PCS) at 1, 2, and 5 years; the NRS for back pain at 1 and 2 years; and the NRS for leg pain at 1 year. The rates of heterotopic ossification increased over time: 1.0% (4/382) at 1 year, 2.6% (9/345) at 2 years, and 5.9% (11/187) at 5 years. Investigational patients had fewer device-related AEs and serious device-related AEs than the control patients at both 2 and 5 years postoperatively. Noninferiority of the composite measure overall success was demonstrated at all follow-up intervals; superiority was demonstrated at 1 and 2 years. CONCLUSIONS: Lumbar disc arthroplasty is a safe and effective treatment for single-level lumbar degenerative disc disease, resulting in improved physical function and reduced pain up to 5 years after surgery.Clinical trial registration no.: NCT00635843 (clinicaltrials.gov).

Radiological and clinical outcomes of 3-level cervical disc arthroplasty.

OBJECTIVE: One- and two-level cervical disc arthroplasty (CDA) has been compared to anterior cervical discectomy and fusion (ACDF) in several large-scale, prospective, randomized trials that have demonstrated similar clinical outcomes. However, whether these results would be similar when treating 3-level disc herniation and/or spondylosis has remained unanswered. This study aimed to investigate the differences between 3-level CDA and ACDF. METHODS: A series of 50 patients who underwent 3-level CDA at C3-7 was retrospectively reviewed and compared with another series of 50 patients (age- and sex-matched controls) who underwent ACDF at C3-7. Clinical outcomes were measured using the visual analog scale (VAS) for neck and arm pain, the modified Japanese Orthopaedic Association (mJOA) scale, and the Neck Disability Index (NDI). Radiological outcomes included range of motion (ROM) at the index levels. Every patient was evaluated by CT for the presence of fusion in the ACDF group. Also, complication profiles were investigated. RESULTS: The demographics and levels of distribution in both groups were very similar. During the follow-up period of 24 months, clinical outcomes improved (overall and respectively in each group) for both the CDA and ACDF patients when compared with the patients' preoperative condition. There were essentially few differences between the two groups in terms of neck and arm pain VAS scores, mJOA scores, and NDI scores preoperatively and at 3, 6, 12, and 24 months postoperatively. After the 3-level surgery, the CDA group had an increased mean ROM of approximately 3.4°, at 25.2° ± 8.84°, compared to their preoperative ROM (21.8° ± 7.20°) (p = 0.001), whereas the ACDF group had little mobility (22.8° ± 5.90° before and 1.0° ± 1.28° after surgery; p < 0.001). The mean operative time, estimated blood loss, and complication profiles were similar for both groups. CONCLUSIONS: In this selectively matched retrospective study, clinical outcomes after 3-level CDA and ACDF were similar during the 2-year follow-up period. CDA not only successfully preserved but slightly increased the mobility at the 3 index levels. However, the safety and efficacy of 3-level CDA requires more long-term data for validatation.

Cervical disc arthroplasty: 10-year outcomes of the Prestige LP cervical disc at a single level.

OBJECTIVE: Food and Drug Administration-approved investigational device exemption (IDE) studies have provided level I evidence supporting cervical disc arthroplasty (CDA) as a safe and effective alternative to anterior cervical discectomy and fusion (ACDF). Long-term CDA outcomes continue to be evaluated. Here, the authors present outcomes at 10 years postoperatively for the single-level CDA arm of an IDE study (postapproval study). METHODS: The primary endpoint was overall success, a composite variable composed of five criteria: 1) Neck Disability Index score improvement ≥ 15 points; 2) maintenance or improvement in neurological status; 3) no decline in anterior or posterior functional spinal unit (FSU) height of more than 2 mm compared to 6 weeks postoperatively; 4) no serious adverse event (AE) caused by the implant or the implant and the surgical procedure; and 5) no additional surgery classified as a failure. Additional safety and effectiveness measures included numeric rating scales for neck pain and arm pain, SF-36 quality-of-life physical and mental components, patient satisfaction, range of motion, and AEs. RESULTS: From the reported assessments at 7 years postoperatively to the 10-year postoperative follow-up, the scores for all patient-reported outcomes, rate of overall success (without FSU), and proportion of patients at least maintaining their neurological function remained stable for the CDA group. Nine patients had secondary surgery at the index level, increasing the secondary surgery cumulative rate from 6.6% to 10.3%. In that same time frame, four patients experienced a serious implant or implant/surgical procedure-related AE, for a 10-year cumulative rate of 7.8%. Seven patients had any second surgery at adjacent levels, for a 10-year cumulative rate of 13.8%. Average angular motion at both the index and adjacent levels was well maintained without creating hypermobility. Class IV heterotopic ossification increased from 1.2% at 2 years to 4.6% at 7 years and 9.0% at 10 years. Patient satisfaction was > 90% at 10 years. CONCLUSIONS: CDA remained safe and effective out to 10 years postoperatively, with results comparable to 7-year outcomes and with high patient satisfaction.Clinical trial registration no.: NCT00667459 (clinicaltrials.gov).

Does index level sagittal alignment determine adjacent level disc height loss?

OBJECTIVE: The authors sought to compare the effect of index level sagittal alignment on cephalad radiographic adjacent segment pathology (RASP) in patients undergoing cervical total disc arthroplasty (TDA) or anterior cervical discectomy and fusion (ACDF). METHODS: This was a retrospective study of prospectively collected radiographic data from 79 patients who underwent TDA or ACDF and were enrolled and followed prospectively at two centers in a multicenter FDA investigational device exemption trial of the Bryan cervical disc prosthesis used for arthroplasty. Neutral lateral radiographs were obtained pre- and postoperatively and at 1, 2, 4, and up to 7 years following surgery. The index level Cobb angle was measured both pre- and postoperatively. Cephalad disc degeneration was determined by a previously described measurement of the disc height/anteroposterior (AP) distance ratio. RESULTS: Sixty-eight patients (n = 33 ACDF; n = 35 TDA) had complete radiographs and were included for analysis. Preoperatively, there was no difference in the index level Cobb angle between the ACDF and TDA patients. Postoperatively, the ACDF patients had a larger segment lordosis compared to the TDA patients (p = 0.002). Patients who had a postoperative kyphotic Cobb angle were more likely to have undergone TDA (p = 0.01). A significant decrease in the disc height/AP distance ratio occurred over time (p = 0.035), by an average of 0.01818 at 84 months. However, this decrease was not influenced by preoperative alignment, postoperative alignment, or type of surgery. CONCLUSIONS: In this cohort of patients undergoing TDA and ACDF, the authors found that preoperative and postoperative sagittal alignment have no effect on RASP at follow-up of at least 7 years. They identified time as the only significant factor affecting RASP.

Phase I trial of caudate deep brain stimulation for treatment-resistant tinnitus.

OBJECTIVE: The objective of this open-label, nonrandomized trial was to evaluate the efficacy and safety of bilateral caudate nucleus deep brain stimulation (DBS) for treatment-resistant tinnitus. METHODS: Six participants underwent DBS electrode implantation. One participant was removed from the study for suicidality unrelated to brain stimulation. Participants underwent a stimulation optimization period that ranged from 5 to 13 months, during which the most promising stimulation parameters for tinnitus reduction for each individual were determined. These individual optimal stimulation parameters were then used during 24 weeks of continuous caudate stimulation to reach the endpoint. The primary outcome for efficacy was the Tinnitus Functional Index (TFI), and executive function (EF) safety was a composite z-score from multiple neuropsychological tests (EF score). The secondary outcome for efficacy was the Tinnitus Handicap Inventory (THI); for neuropsychiatric safety it was the Frontal Systems Behavior Scale (FrSBe), and for hearing safety it was pure tone audiometry at 0.5, 1, 2, 3, 4, and 6 kHz and word recognition score (WRS). Other monitored outcomes included surgery- and device-related adverse events (AEs). Five participants provided full analyzable data sets. Primary and secondary outcomes were based on differences in measurements between baseline and endpoint. RESULTS: The treatment effect size of caudate DBS for tinnitus was assessed by TFI [mean (SE), 23.3 (12.4)] and THI [30.8 (10.4)] scores, both of which were statistically significant (Wilcoxon signed-rank test, 1-tailed; alpha = 0.05). Based on clinically significant treatment response categorical analysis, there were 3 responders determined by TFI (≥ 13-point decrease) and 4 by THI (≥ 20-point decrease) scores. Safety outcomes according to EF score, FrSBe, audiometric thresholds, and WRS showed no significant change with continuous caudate stimulation. Surgery-related and device-related AEs were expected, transient, and reversible. There was only one serious AE, a suicide attempt unrelated to caudate neuromodulation in a participant in whom stimulation was in the off mode for 2 months prior to the event. CONCLUSIONS: Bilateral caudate nucleus neuromodulation by DBS for severe, refractory tinnitus in this phase I trial showed very encouraging results. Primary and secondary outcomes revealed a highly variable treatment effect size and 60%-80% treatment response rate for clinically significant benefit, and no safety concerns. The design of a phase II trial may benefit from targeting refinement for final DBS lead placement to decrease the duration of the stimulation optimization period and to increase treatment effect size uniformity.Clinical trial registration no.: NCT01988688 (clinicaltrials.gov).

Artificial disc replacement versus fusion in patients with cervical degenerative disc disease and radiculopathy: a randomized controlled trial with 5-year outcomes.

In BriefIn this study the authors compare cervical arthroplasty with fusion surgery in a randomized controlled trial using patient-reported outcome measures and MRI after 5 years of follow-up. Because the main purpose of arthroplasties is to prevent adjacent-segment pathology, it is important to investigate if that is actually realized in practice.

Two-level cervical disc arthroplasty versus anterior cervical discectomy and fusion: 10-year outcomes of a prospective, randomized investigational device exemption clinical trial.

OBJECTIVE: The authors assessed the 10-year clinical safety and effectiveness of cervical disc arthroplasty (CDA) to treat degenerative cervical spine disease at 2 adjacent levels compared to anterior cervical discectomy and fusion (ACDF). METHODS: A prospective, randomized, controlled, multicenter FDA-approved clinical trial was conducted comparing the low-profile titanium ceramic composite-based Prestige LP Cervical Disc (n = 209) at two levels with ACDF (n = 188). Ten-year follow-up data from a postapproval study were available on 148 CDA and 118 ACDF patients and are reported here. Clinical and radiographic evaluations were completed preoperatively, intraoperatively, and at regular postoperative follow-up intervals for up to 10 years. The primary endpoint was overall success, a composite variable that included key safety and efficacy considerations. Ten-year follow-up rates were 86.0% for CDA and 84.9% for ACDF. RESULTS: From 2 to 10 years, CDA demonstrated statistical superiority over ACDF for overall success, with rates at 10 years of 80.4% versus 62.2%, respectively (posterior probability of superiority [PPS] = 99.9%). Neck Disability Index (NDI) success was also superior, with rates at 10 years of 88.4% versus 76.5% (PPS = 99.5%), as was neurological success (92.6% vs 86.1%; PPS = 95.6%). Improvements from preoperative results in NDI and neck pain scores were consistently statistically superior for CDA compared to ACDF. All other study effectiveness measures were at least noninferior for CDA compared to ACDF through the 10-year follow-up period, including disc height. Mean angular ranges of motion at treated levels were maintained in the CDA group for up to 10 years. The rates of grade IV heterotopic ossification (HO) at the superior and inferior levels were 8.2% and 10.3%, respectively. The rate of severe HO (grade III or IV) did not increase significantly from 7 years (42.4%) to 10 years (39.0%). The CDA group had fewer serious (grade 3-4) implant-related or implant/surgical procedure-related adverse events (3.8% vs 8.1%; posterior mean 95% Bayesian credible interval [BCI] of the log hazard ratio [LHR] -0.92 [-1.88, -0.01]). The CDA group also had statistically fewer secondary surgical procedures at the index levels (4.7%) than the ACDF group (17.6%) (LHR [95% BCI] -1.39 [-2.15, -0.61]) as well as at adjacent levels (9.0% vs 17.9%). CONCLUSIONS: The Prestige LP Cervical Disc, implanted at two adjacent levels, maintains improved clinical outcomes and segmental motion 10 years after surgery and is a safe and effective alternative to fusion.Clinical trial registration no.: NCT00637156 (clinicaltrials.gov).

Expanded Patient Access to Investigational New Devices: Review of Emergency and Nonemergency Expanded Use, Custom, and 3D-Printed Devices.

U.S. Food and Drug Administration (FDA) approval of Class III medical devices can take from 3 to 7 years. Although this is shorter than times for drug approvals, patients with serious or life-threatening diseases and disorders may not have time to wait for device approval to access needed treatments. The FDA has a number of pathways, similar to drug approval processes, for expanded use of unapproved medical devices in patients for whom no reasonable alternative therapy is available. Additionally, the FDA regulates the manufacture and use of "custom" medical devices-those made for use by 1 specific patient. With the advent of 3-dimensional printing and bioprinting, new rules are evolving to address concerns that lines may be blurred between "custom" treatments and unregulated human experimentation.

Prospective, randomized multicenter study of cervical arthroplasty versus anterior cervical discectomy and fusion: 5-year results with a metal-on-metal artificial disc.

OBJECTIVE Seven cervical total disc replacement (TDR) devices have received FDA approval since 2006. These devices represent a heterogeneous assortment of implants made from various biomaterials with different biomechanical properties. The majority of these devices are composed of metallic endplates with a polymer core. In this prospective, randomized multicenter study, the authors evaluate the safety and efficacy of a metal-on-metal (MoM) TDR (Kineflex|C) versus anterior cervical discectomy and fusion (ACDF) in the treatment of single-level spondylosis with radiculopathy through a long-term (5-year) follow-up. METHODS An FDA-regulated investigational device exemption (IDE) pivotal trial was conducted at 21 centers across the United States. Standard validated outcome measures including the Neck Disability Index (NDI) and visual analog scale (VAS) for assessing pain were used. Patients were randomized to undergo TDR using the Kineflex|C cervical artificial disc or anterior cervical fusion using structural allograft and an anterior plate. Patients were evaluated preoperatively and at 6 weeks and 3, 6, 12, 24, 36, 48, and 60 months after surgery. Serum ion analysis was performed on a subset of patients randomized to receive the MoM TDR. RESULTS A total of 269 patients were enrolled and randomly assigned to undergo either TDR (136 patients) or ACDF (133 patients). There were no significant differences between the TDR and ACDF groups in terms of operative time, blood loss, or length of hospital stay. In both groups, the mean NDI scores improved significantly by 6 weeks after surgery and remained significantly improved throughout the 60-month follow-up (both p < 0.01). Similarly, VAS pain scores improved significantly by 6 weeks and remained significantly improved through the 60-month follow-up (both p < 0.01). There were no significant changes in outcomes between the 24- and 60-month follow-ups in either group. Range of motion in the TDR group decreased at 3 months but was significantly greater than the preoperative mean value at the 12- and 24-month follow-ups and remained significantly improved through the 60-month period. There were no significant differences between the 2 groups in terms of reoperation/revision surgery or device-/surgery-related adverse events. The serum ion analysis revealed cobalt and chromium levels significantly lower than the levels that merit monitoring. CONCLUSIONS Cervical TDR with an MoM device is safe and efficacious at the 5-year follow-up. These results from a prospective randomized study support that Kineflex|C TDR as a viable alternative to ACDF in appropriately selected patients with cervical radiculopathy. Clinical trial registration no.: NCT00374413 (clinicaltrials.gov).

Artificial disc replacement versus fusion in patients with cervical degenerative disc disease with radiculopathy: 5-year outcomes from the National Swedish Spine Register.

OBJECTIVE: The long-term efficacy of artificial disc replacement (ADR) surgery compared with fusion after decompression for the treatment of cervical degenerative disc disease and radiculopathy has not previously been investigated in a population-based setting. METHODS: All patients with cervical degenerative disc disease and radiculopathy who were in the national Swedish Spine Registry (Swespine) beginning in January 1, 2006, were eligible for the study. Follow-up information was obtained up to November 15, 2017. The authors compared, using propensity score matching, patients treated with anterior decompression and insertion of an ADR with patients who underwent anterior decompression combined with fusion surgery. The primary outcome was the Neck Disability Index (NDI), a patient-reported function score ranging from 0% to 100%, with higher scores indicating greater disability and a minimum clinically important difference of > 15%. RESULTS: A total of 3998 patients (2018:1980 women/men) met the inclusion criteria, of whom 204 had undergone arthroplasty and 3794 had undergone fusion. After propensity score matching, 185 patients with a mean age of 49.7 years remained in each group. Scores on the NDI were approximately halved in both groups after 5 years, but without a significant mean difference in NDI (3.0%; 95% CI -8.4 to 2.4; p = 0.28) between the groups. There were no differences between the groups in EuroQol-5 Dimensions or in pain scores for the neck and arm. CONCLUSIONS: In patients with cervical degenerative disc disease and radiculopathy, decompression plus ADR surgery did not result in a clinically important difference in outcomes after 5 years, compared with decompression and fusion surgery.

Is cervical disc arthroplasty good for congenital cervical stenosis?

OBJECTIVE Cervical disc arthroplasty (CDA) has been demonstrated to be as safe and effective as anterior cervical discectomy and fusion (ACDF) in the management of 1- and 2-level degenerative disc disease (DDD). However, there has been a lack of data to address the fundamental discrepancy between the two surgeries (CDA vs ACDF), and preservation versus elimination of motion, in the management of cervical myelopathy associated with congenital cervical stenosis (CCS). Although younger patients tend to benefit more from motion preservation, it is uncertain if CCS caused by multilevel DDD can be treated safely with CDA. METHODS Consecutive patients who underwent 3-level anterior cervical discectomy were retrospectively reviewed. Inclusion criteria were age less than 50 years, CCS (Pavlov ratio ≤ 0.82), symptomatic myelopathy correlated with DDD, and stenosis limited to 3 levels of the subaxial cervical (C3-7) spine. Exclusion criteria were ossification of the posterior longitudinal ligament, previous posterior decompression surgery (e.g., laminoplasty or laminectomy), osteoporosis, previous trauma, or other rheumatic diseases that might have caused the cervical myelopathy. All these patients who underwent 3-level discectomy were divided into 2 groups according to the strategies of management: preservation or elimination of motion (the hybrid-CDA group and the ACDF group). The hybrid-CDA group underwent 2-level CDA plus 1-level ACDF, whereas the ACDF group underwent 3-level ACDF. Clinical assessment was measured by the visual analog scales (VAS) for neck and arm pain, Japanese Orthopaedic Association (JOA) scores, and Nurick grades. Radiographic outcomes were measured using dynamic radiographs for evaluation of range of motion (ROM). RESULTS Thirty-seven patients, with a mean (± SD) age of 44.57 ± 5.10 years, were included in the final analysis. There was a male predominance in this series (78.4%, 29 male patients), and the mean follow-up duration was 2.37 ± 1.60 years. There were 20 patients in the hybrid-CDA group, and 17 in the ACDF group. Both groups demonstrated similar clinical improvement at 2 years' follow-up. These patients with 3-level stenosis experienced significant improvement after either type of surgery (hybrid-CDA and ACDF). There were no significant differences between the 2 groups at each of the follow-up visits postoperatively. The preoperative ROM over the operated subaxial levels was similar between both groups (21.9° vs 21.67°; p = 0.94). Postoperatively, the hybrid-CDA group had significantly greater ROM (10.65° vs 2.19°; p < 0.001) than the ACDF group. Complications, adverse events, and reoperations in both groups were similarly low. CONCLUSIONS Hybrid-CDA yielded similar clinical improvement to 3-level ACDF in patients with myelopathy caused by CCS. In this relatively young group of patients, hybrid-CDA demonstrated significantly more ROM than 3-level ACDF without adjacent-segment disease (ASD) at 2 years' follow-up. Therefore, hybrid-CDA appears to be an acceptable option in the management of CCS. The strategy of motion preservation yielded similar improvements of cervical myelopathy to motion elimination (i.e., ACDF) in patients with CCS, while the theoretical benefit of reducing ASD required further validation.

Cervical disc arthroplasty with the Prestige LP disc versus anterior cervical discectomy and fusion, at 2 levels: results of a prospective, multicenter randomized controlled clinical trial at 24 months.

OBJECTIVE The authors compared the efficacy and safety of arthroplasty using the Prestige LP cervical disc with those of anterior cervical discectomy and fusion (ACDF) for the treatment of degenerative disc disease (DDD) at 2 adjacent levels. METHODS Patients from 30 investigational sites were randomized to 1 of 2 groups: investigational patients (209) underwent arthroplasty using a Prestige LP artificial disc, and control patients (188) underwent ACDF with a cortical ring allograft and anterior cervical plate. Patients were evaluated preoperatively, intraoperatively, and at 1.5, 3, 6, 12, and 24 months postoperatively. Efficacy and safety outcomes were measured according to the Neck Disability Index (NDI), Numeric Rating Scales for neck and arm pain, 36-Item Short-Form Health Survey (SF-36), gait abnormality, disc height, range of motion (investigational) or fusion (control), adverse events (AEs), additional surgeries, and neurological status. Treatment was considered an overall success when all 4 of the following criteria were met: 1) NDI score improvement of ≥ 15 points over the preoperative score, 2) maintenance or improvement in neurological status compared with preoperatively, 3) no serious AE caused by the implant or by the implant and surgical procedure, and 4) no additional surgery (supplemental fixation, revision, or nonelective implant removal). Independent statisticians performed Bayesian statistical analyses. RESULTS The 24-month rates of overall success were 81.4% for the investigational group and 69.4% for the control group. The posterior mean for overall success in the investigational group exceeded that in the control group by 0.112 (95% highest posterior density interval = 0.023 to 0.201) with a posterior probability of 1 for noninferiority and 0.993 for superiority, demonstrating the superiority of the investigational group for overall success. Noninferiority of the investigational group was demonstrated for all individual components of overall success and individual effectiveness end points, except for the SF-36 Mental Component Summary. The investigational group was superior to the control group for NDI success. The proportion of patients experiencing any AE was 93.3% (195/209) in the investigational group and 92.0% (173/188) in the control group, which were not statistically different. The rate of patients who reported any serious AE (Grade 3 or 4) was significantly higher in the control group (90 [47.9%] of 188) than in the investigational group (72 [34.4%] of 209) with a posterior probability of superiority of 0.996. Radiographic success was achieved in 51.0% (100/196) of the investigational patients (maintenance of motion without evidence of bridging bone) and 82.1% (119/145) of the control patients (fusion). At 24 months, heterotopic ossification was identified in 27.8% (55/198) of the superior levels and 36.4% (72/198) of the inferior levels of investigational patients. CONCLUSIONS Arthroplasty with the Prestige LP cervical disc is as effective and safe as ACDF for the treatment of cervical DDD at 2 contiguous levels and is an alternative treatment for intractable radiculopathy or myelopathy at 2 adjacent levels. Clinical trial registration no.: NCT00637156 ( clinicaltrials.gov ).

Subsequent surgery rates after cervical total disc replacement using a Mobi-C Cervical Disc Prosthesis versus anterior cervical discectomy and fusion: a prospective randomized clinical trial with 5-year follow-up.

OBJECTIVE Cervical total disc replacement (TDR) has been shown in a number of prospective clinical studies to be a viable treatment alternative to anterior cervical discectomy and fusion (ACDF) for the treatment of symptomatic degenerative disc disease. In addition to preserving motion, evidence suggests that cervical TDR may result in a lower incidence of subsequent surgical intervention than treatment with fusion. The goal of this study was to evaluate subsequent surgery rates up to 5 years in patients treated with TDR or ACDF at 1 or 2 contiguous levels between C-3 and C-7. METHODS This was a prospective, multicenter, randomized, unblinded clinical trial. Patients with symptomatic degenerative disc disease were enrolled to receive 1- or 2-level treatment with either TDR as the investigational device or ACDF as the control treatment. There were 260 patients in the 1-level study (179 TDR and 81 ACDF patients) and 339 patients in the 2-level study (234 TDR and 105 ACDF patients). RESULTS At 5 years, the occurrence of subsequent surgical intervention was significantly higher among ACDF patients for 1-level (TDR, 4.5% [8/179]; ACDF, 17.3% [14/81]; p = 0.0012) and 2-level (TDR, 7.3% [17/234]; ACDF, 21.0% [22/105], p = 0.0007) treatment. The TDR group demonstrated significantly fewer index- and adjacent-level subsequent surgeries in both the 1- and 2-level cohorts. CONCLUSIONS Five-year results showed treatment with cervical TDR to result in a significantly lower rate of subsequent surgical intervention than treatment with ACDF for both 1 and 2 levels of treatment. Clinical trial registration no.: NCT00389597 ( clinicaltrials.gov ).

Five-year clinical results of cervical total disc replacement compared with anterior discectomy and fusion for treatment of 2-level symptomatic degenerative disc disease: a prospective, randomized, controlled, multicenter investigational device exemption clinical trial.

OBJECTIVE The purpose of this study was to report the outcome of a study of 2-level cervical total disc replacement (Mobi-C) versus anterior cervical discectomy and fusion (ACDF). Although the long-term outcome of single-level disc replacement has been extensively described, there have not been previous reports of the 5-year outcome of 2-level cervical disc replacement. METHODS This study reports the 5-year results of a prospective, randomized US FDA investigational device exemption (IDE) study conducted at 24 centers in patients with 2-level, contiguous, cervical spondylosis. Clinical outcomes at up to 60 months were evaluated, including validated outcome measures, incidence of reoperation, and adverse events. The complete study data and methodology were critically reviewed by 3 independent surgeon authors without affiliation with the IDE study or financial or institutional bias toward the study sponsor. RESULTS A total of 225 patients received the Mobi-C cervical total disc replacement device and 105 patients received ACDF. The Mobi-C and ACDF follow-up rates were 90.7% and 86.7%, respectively (p = 0.39), at 60 months. There was significant improvement in all outcome scores relative to baseline at all time points. The Mobi-C patients had significantly more improvement than ACDF patients in terms of Neck Disability Index score, SF-12 Physical Component Summary, and overall satisfaction with treatment at 60 months. The reoperation rate was significantly lower with Mobi-C (4%) versus ACDF (16%). There were no significant differences in the adverse event rate between groups. CONCLUSIONS Both cervical total disc replacement and ACDF significantly improved general and disease-specific measures compared with baseline. However, there was significantly greater improvement in general and disease-specific outcome measures and a lower rate of reoperation in the 2-level disc replacement patients versus ACDF control patients. Clinical trial registration no. NCT00389597 ( clinicaltrials.gov ).