An integrated benefit-risk assessment of cobalt-containing alloys used in medical devices: Implications for regulatory requirements in the European Union.

In 2017, the European Union (EU) Committee for Risk Assessment (RAC) recommended the classification of metallic cobalt (Co) as Category 1B with respect to its carcinogenic and reproductive hazard potential and Category 2 for mutagenicity but did not evaluate the relevance of these classifications for patients exposed to Co-containing alloys (CoCA) used in medical devices. CoCA are inherently different materials from Co metal from a toxicological perspective and thus require a separate assessment. CoCA are biocompatible materials with a unique combination of properties including strength, durability, and a long history of safe use that make them uniquely suited for use in a wide-range of medical devices. Assessments were performed on relevant preclinical and clinical carcinogenicity and reproductive toxicity data for Co and CoCA to meet the requirements under the EU Medical Device Regulation triggered by the ECHA re-classification (adopted in October 2019 under the 14th Adaptation to Technical Progress to CLP) and to address their relevance to patient safety. The objective of this review is to present an integrated overview of these assessments, a benefit-risk assessment and an examination of potential alternative materials. The data support the conclusion that the exposure to CoCA in medical devices via clinically relevant routes does not represent a hazard for carcinogenicity or reproductive toxicity. Additionally, the risk for the adverse effects that are known to occur with elevated Co concentrations (e.g., cardiomyopathy) are very low for CoCA implant devices (infrequent reports often reflecting a unique catastrophic failure event out of millions of patients) and negligible for CoCA non-implant devices (not measurable/no case reports). In conclusion, the favorable benefit-risk profile also in relation to possible alternatives presented herein strongly support continued use of CoCA in medical devices.

A hazard evaluation of the reproductive/developmental toxicity of cobalt in medical devices.

Cobalt (Co) is an essential element with human exposure occurring from the diet, supplement ingestion, occupational sources, and medical devices. The European Chemical Agency (ECHA) recently voted to classify Co metal as a Reproductive Hazard Category 1B; presumed human reproductive toxicant due to adverse testicular effects in male rodents. A weight of evidence evaluation of the preclinical reproductive and developmental toxicity studies and available clinical data was performed to critically evaluate the relevance of this proposed classification for Co in medical devices. Reproductive responses to Co are limited to the male testes and sperm function following high systemic exposure in rodents, only at Co concentrations/doses that result in overt toxicity (i.e., above the maximum tolerable dose (MTD)). The potential mechanisms of Co reproductive/developmental toxicity, including its indirect mode of action in the testes and relevance to humans, are discussed. The available preclinical and clincial evidence suggests that it would be more appropriate to classify Co as a Reproductive Hazard Category 2 compound: suspected human reproductive toxicant and, in the case of Co-containing medical devices, it should not be considered a reproductive hazard.

Carcinogenic hazard assessment of cobalt-containing alloys in medical devices: Review of in vivo studies.

Cobalt (Co) alloys have been used for over seven decades in a wide range of medical devices, including, but not limited to, hip and knee implants, surgical tools, and vascular stents, due to their favorable biocompatibility, durability, and mechanical properties. A recent regulatory hazard classification review by the European Chemicals Agency (ECHA) resulted in the classification of metallic Co as a Class 1B Carcinogen (presumed to have carcinogenic potential for humans), primarily based on inhalation rodent carcinogenicity studies with pure metallic Co. The ECHA review did not specifically consider the carcinogenicity hazard potential of forms or routes of Co that are relevant for medical devices. The purpose of this review is to present a comprehensive assessment of the available in vivo preclinical data on the carcinogenic hazard potential of exposure to Co-containing alloys (CoCA) in medical devices by relevant routes. In vivo data were reviewed from 33 preclinical studies that examined the impact of Co exposure on local and systemic tumor incidence in rats, mice, guinea pigs, and hamsters. Across these studies, there was no significant increase of local or systemic tumors in studies relevant for medical devices. Taken together, the relevant in vivo data led to the conclusion that CoCA in medical devices are not a carcinogenic hazard in available in vivo models. While specific patient and implant factors cannot be fully replicated using in vivo models, the available in vivo preclinical data support that CoCA in medical devices are unlikely a carcinogenic hazard to patients.

Hypertonic Sodium Chloride Preinjectate Increases In Vivo Radiofrequency Ablation Size: Histological and Magnetic Resonance Imaging Findings.

BACKGROUND AND OBJECTIVES: Emphasis has been placed on methods to enlarge monopolar radiofrequency (RF) lesion size for pain management. Ex vivo research has suggested that fluid modulation may be an effective method to enlarge lesion zone. To date, these findings have not been confirmed in vivo. The purpose of this study was to determine the effect of hypertonic saline on in vivo lesion size through both histological and magnetic resonance imaging (MRI) analysis. A secondary purpose was to validate in vivo characterization of RF lesions using contrast-enhanced MRI. METHODS: Monopolar RF was performed in an in vivo porcine model in 3 groups: (1) without fluid preinjection, (2) with preinjection of 1% lidocaine, or (3) with preinjection of 1% lidocaine and 8% sodium chloride. Following lesioning, MRI processing with gadolinium-enhanced, T1-weighted imaging and histological analysis was performed. RESULTS: The addition of 8% sodium chloride significantly increased the size of RF lesion in comparison to the addition of 1% lidocaine alone and to the absence of fluid injection, as assessed by histological and MRI analysis. Three distinct histological lesion zones were identified. In comparison to the no-fluid group, the addition of hypertonic saline significantly altered the shape and histological composition of the lesion. There was a significant correlation of lesion volume as assessed by MRI and by histology measurements. Peak power and total energy delivery also correlated with lesion size. CONCLUSIONS: This study validates the ability of hypertonic saline to increase in vivo RF lesion size. With further refinement, MRI may be a viable method to assess RF lesion size.

Sustained analgesic effect of clonidine co-polymer depot in a porcine incisional pain model.

BACKGROUND: Previous research suggests that the α2 adrenergic agonist clonidine, a centrally acting analgesic and antihypertensive, may also have direct effects on peripheral pain generators. However, aqueous injections are limited by rapid systemic absorption leading to off target effects and a brief analgesic duration of action. PURPOSE: The aim of this study was to examine the efficacy of a sustained-release clonidine depot, placed in the wound bed, in a pig incisional pain model. METHODS: The depot was a 15 mm ×5 mm ×0.3 mm poly(lactide-co-caprolactone) polymer film containing 3% (w/w) clonidine HCl (MDT3). Fifty-two young adult mix Landrace pigs (9-11 kg) were divided into seven groups. All subjects received a 6 cm, full-thickness, linear incision into the left lateral flank. Group 1 served as a Sham control group (Sham, n=8). Group 2 received three placebo strips (PBO, n=8), placed end-to-end in the subcutaneous wound bed before wound closure. Group 3 received one MDT3 and two PBO (n=8), Group 4 received two MDT3 and one PBO (n=8), and Group 5 received three MDT3 (n=8). Positive control groups received peri-incisional injections of bupivacaine solution (Group 6, 30 mg/day bupivacaine, n=8) or clonidine solution (Group 7, 225 µg/day, n=4). RESULTS: The surgical procedure was associated with significant peri-incisional tactile allodynia. There was a dose-dependent effect of MDT3 in partially reversing the peri-incisional tactile allodynia, with maximum pain relief relative to Sham at 72 hours. Daily injections of bupivacaine (30 mg), but not clonidine (up to 225 µg), completely reversed allodynia within 48 hours. There was a statistically significant correlation between the dose of MDT3 and cumulative withdrawal threshold from 4 hours through the conclusion of the study on day 7. CONCLUSION: These data suggest that a sustained-release clonidine depot may be a viable nonopioid, nonamide anesthetic therapy for the treatment of acute postsurgical nociceptive sensitization.

Tissue distribution of clonidine following intraforaminal implantation of biodegradable pellets: potential alternative to epidural steroid for radiculopathy.

BACKGROUND: Epidural steroid injections have shown efficacy in short-term pain relief, but often require repeated injections in order to provide continued pain relief. It has been suggested that a continuous, locally administered dose of an anti-inflammatory compound may provide sustained pain relief at doses lower than those needed with injections. OBJECTIVE: To evaluate the distribution of clonidine after transforaminal placement of a biodegradable drug delivery depot system. STUDY DESIGN: A preclinical animal study. METHODS: A biodegradable polymer drug depot designed to provide sustained delivery of clonidine was placed in or near a single lumbar neural foramen in 12 farm pigs. Clonidine tissue concentrations were measured at the implant site and at incremental distances from the implant over a time period of 12 weeks. Plasma clonidine levels were measured at 4 hours postimplantation on days 1, 2, 3, 5, and 7, and then weekly until the termination of the study. RESULTS: Clonidine was detectable up to 6 cm away from the drug depot. The highest concentrations of clonidine were present within the targeted spinal nerve; the concentration decreased with increasing distance from the depot. Clonidine was undetectable in plasma from all animals at all time points. LIMITATIONS: While clonidine was detected up to 6 cm from the drug depot, it is unknown if the drug concentration has clinical relevance. CONCLUSIONS: The results indicate that a biodegradable depot designed to be placed in a specific location to provide local sustained release of an anti-inflammatory and analgesic drug may be a feasible new approach to treat radicular pain associated with intervertebral disc pathology and other spinal conditions.

Differences between neurosurgeons and orthopedic surgeons in classifying cervical dislocation injuries and making assessment and treatment decisions: a multicenter reliability study.

Variability exists in the management of cervical spinal injuries. The goal of this study was to assess the effect of training specialty (orthopedic surgery vs neurosurgery) on management of cervical dislocations. Twenty-nine spine surgeons reviewed 10 cases of cervical dislocation injuries. For each of the 10 cases, the surgeons evaluated 3 clinical scenarios, which included a neurologically intact patient, a patient with an incomplete spinal cord injury (SCI), and a patient with complete SCI. Surgeons determined whether a unilateral or bilateral facet dislocation was present and whether pretreatment magnetic resonance imaging (MRI) or immediate closed reduction was indicated. Management decisions were re-assessed after review of MRIs. While spine surgeons may agree on what they see on MRI and how they classify certain cervical injuries irrespective of training, significant differences of opinion continue to exist regarding the therapeutic implications of this information, specifically, whether to order a pretreatment MRI and how to manage the injury.

Mean subaxial space available for the cord index as a novel method of measuring cervical spine geometry to predict the chronic stinger syndrome in American football players.

OBJECT: The chronic stinger syndrome is a distinct entity from acute stingers and has been shown to have its own pathophysiology that, unlike acute stingers, may reflect long-standing geometrical changes of the subaxial spinal canal and chronic irritation/degeneration of the exiting nerve root complex. There is no method available, however, to accurately predict these symptoms in athletes. The mean subaxial cervical space available for the cord (MSCSAC) is a novel alternative to the Torg ratio for predicting neurological symptoms caused by cervical spondylosis in elite athletes. It is the goal of this study to determine critical values for this measurement index and to retrospectively correlate those values to neurological symptoms. METHODS: Magnetic resonance images obtained in 103 male athletes participating in the 2005 and 2006 National Football League Scouting Combine and a control group of 42 age-matched male nonathletes were retrospectively reviewed. The Torg ratio and SAC values were calculated in triplicate at each cervical level from C3-6 by using lateral radiographs and midsagittal T2-weighted MR images of the cervical spine, respectively. These values were then averaged for each individual to produce mean subaxial cervical Torg ratio (MSCTR) and MSCSAC values. Receiver operating characteristic curves were constructed for each measurement technique and were compared based on their respective area under the curves (AUCs). RESULTS: The MSCSAC difference between athletes with and without chronic stingers was statistically significant (p < 0.01). The difference between athletes with and without chronic stingers compared with controls was also statistically significant (p < 0.001 and p < 0.001, respectively). The AUC for the MSCSAC was 0.813, which was significantly greater than the AUC for both the MSCTR (p = 0.0475) and the individual Torg ratio (p = 0.0277). The MSCTR had the second largest AUC (0.676) and the conventional method of measuring individual Torg ratio values produced the lowest AUC (0.661). It was found that using the MSCSAC with a critical value of 5.0 mm produced a sensitivity of 80% and a negative likelihood ratio of 0.23 for predicting chronic stingers. Lowering the cutoff value to 4.3 mm for the MSCSAC resulted in a possible confirmatory test with a specificity of 96% and a positive likelihood ratio of 13.25. CONCLUSIONS: A critical value of 5.0 mm for the MSCSAC provides the clinician with a screening test for chronic stingers and anything < 4.3 mm adds additional confidence as a confirmatory test. These results are approximately 20% more accurate than the classic Torg ratio based on our AUC analysis. It was found that measuring the spinal geometry throughout the length of the subaxial cervical spine produced a more reliable method by which to predict neurological symptoms than the traditional approach of measuring individual levels. This shows that the underlying pathogenesis of the chronic stinger syndrome is best characterized as a process that involves the entire subaxial region uniformly.

Intrarater and interrater reliability and validity in the assessment of the mechanism of injury and integrity of the posterior ligamentous complex: a novel injury severity scoring system for thoracolumbar injuries. Invited submission from the Joint Section Meeting On Disorders of the Spine and Peripheral Nerves, March 2005.

OBJECT: A new classification and treatment algorithm for thoracolumbar injuries was recently introduced by Vaccaro and colleagues in 2005. A thoracolumbar injury severity scale (TLISS) was proposed for grading and guiding treatment for these injuries. The scale is based on the following: 1) the mechanism of injury; 2) the integrity of the posterior ligamentous complex (PLC); and 3) the patient's neurological status. The reliability and validity of assessing injury mechanism and the integrity of the PLC was assessed. METHODS: Forty-eight spine surgeons, consisting of neurosurgeons and orthopedic surgeons, reviewed 56 clinical thoracolumbar injury case histories. Each was classified and scored to determine treatment recommendations according to a novel classification system. After 3 months the case histories were reordered and the physicians repeated the exercise. Validity of this classification was good among reviewers; the vast majority (> 90%) agreed with the system's treatment recommendations. Surgeons were unclear as to a cogent description of PLC disruption and fracture mechanism. CONCLUSIONS: The TLISS demonstrated acceptable reliability in terms of intra- and interobserver agreement on the algorithm's treatment recommendations. Replacing injury mechanism with a description of injury morphology and better definition of PLC injury will improve inter- and intraobserver reliability of this injury classification system.