Utilization of Bone-Anchored Annular Defect Closure to Prevent Reherniation Following Lumbar Discectomy: Overcoming Barriers to Clinical Adoption and Market Access.

While achieving premarket approval from the US Food and Drug Administration represents a significant milestone in the development and commercialization of a Class III medical device, the aftermath endeavor of gaining market access can be daunting. This article provides a case study of the Barricaid annular closure device (Barricaid), a reherniation reduction device, which has been demonstrated to decrease the risk of suffering a recurrent lumbar intervertebral disc herniation. Following Food and Drug Administration approval, clinical adoption has been slow due to barriers to market access, including the perception of low-quality clinical evidence, questionable significance of the medical necessity of the procedure, and imaging evidence of increased likelihood of vertebral endplate changes. The aim of this article is to provide appropriate examination, rationale, and rebuttal of these concerns. Weighing the compendium of evidence, we offer a definition of a separate and unique current procedural terminology code to delineate this procedure. Adoption of this code will help to streamline the processing of claims and support the conduct of research, the evaluation of health care utilization, and the development of appropriate medical guidelines.

Nitrilase mediated mild hydrolysis of a carbon-14 nitrile for the radiosynthesis of 4-(7-hydroxycarbamoyl-[1-14 C-heptanoyl]-oxy)-benzoic acid methyl ester, [14 C]-SHP-141: A novel class I/II histone deacetylase (HDAC) inhibitor.

A strategy has been developed for the carbon-14 radiosynthesis of [14 C]-SHP-141, a 4-(7-hydroxycarbamoyl-heptanoyloxy)-benzoic acid methyl ester derivative containing a terminal hydroxamic acid. The synthesis involved four radiochemical transformations. The key step in the radiosynthesis was the conversion of the 7-[14 C]-cyano-heptanoic acid benzyloxyamide [14 C]-4 directly into the carboxylic acid derivative, 7-benzyloxycarbamoyl-[14 C]-heptanoic acid [14 C]-8 using nitrilase-113 biocatalyst. The final step involved deprotection of the benzyloxy group using catalytic hydrogenation to facilitate the release of the hydroxamic acid without cleaving the phenoxy ester. [14 C]-SHP-141 was isolated with a radiochemical purity of 90% and a specific activity of 190 µCi/mg from four radiochemical steps starting from potassium [14 C]-cyanide in a radiochemical yield of 45%.

Cervical fusion for treatment of degenerative conditions: development of appropriate use criteria.

BACKGROUND CONTEXT: High quality evidence is difficult to generate, leaving substantial knowledge gaps in the treatment of spinal conditions. Appropriate use criteria (AUC) are a means of determining appropriate recommendations when high quality evidence is lacking. PURPOSE: Define appropriate use criteria (AUC) of cervical fusion for treatment of degenerative conditions of the cervical spine. STUDY DESIGN/SETTING: Appropriate use criteria for cervical fusion were developed using the RAND/UCLA appropriateness methodology. Following development of clinical guidelines and scenario writing, a one-day workshop was held with a multidisciplinary group of 14 raters, all considered thought leaders in their respective fields, to determine final ratings for cervical fusion appropriateness for various clinical situations. OUTCOME MEASURES: Final rating for cervical fusion recommendation as either "Appropriate," "Uncertain" or "Rarely Appropriate" based on the median final rating among the raters. METHODS: Inclusion criteria for scenarios included patients aged 18 to 80 with degenerative conditions of the cervical spine. Key modifiers were defined and combined to develop a matrix of clinical scenarios. The median score among the raters was used to determine the final rating for each scenario. The final rating was compared between modifier levels. Spearman's rank correlation between each modifier and the final rating was determined. A multivariable ordinal regression model was fit to determine the adjusted odds of an "Appropriate" final rating while adjusting for radiographic diagnosis, number of levels and symptom type. Three decision trees were developed using decision tree classification models and variable importance for each tree was computed. RESULTS: Of the 263 scenarios, 47 (17.9 %) were rated as rarely appropriate, 66 (25%) as uncertain and 150 (57%) were rated as appropriate. Symptom type was the modifier most strongly correlated with the final rating (adjusted ρ2 = 0.58, p<.01). A multivariable ordinal regression adjusting for symptom type, diagnosis, and number of levels and showed high discriminative ability (C statistic = 0.90) and the adjusted odds ratio (aOR) of receiving a final rating of "Appropriate" was highest for myelopathy (aOR, 7.1) and radiculopathy (aOR, 4.8). Three decision tree models showed that symptom type and radiographic diagnosis had the highest variable importance. CONCLUSIONS: Appropriate use criteria for cervical fusion in the setting of cervical degenerative disorders were developed. Symptom type was most strongly correlated with final rating. Myelopathy or radiculopathy were most strongly associated with an "Appropriate" rating, while axial pain without stenosis was most associated with "Rarely Appropriate."

Management of degenerative spondylolisthesis: development of appropriate use criteria.

BACKGROUND CONTEXT: Outcomes of treatment in care of patients with spinal disorders are directly related to patient selection and treatment indications. However, for many disorders, there is absence of consensus for precise indications. With the increasing emphasis on quality and value in spine care, it is essential that treatment recommendations and decisions are optimized. PURPOSE: The purpose of the North American Spine Society Appropriate Use Criteria was to determine the appropriate (ie reasonable) multidisciplinary treatment recommendations for patients with degenerative spondylolisthesis across a spectrum of more common clinical scenarios. STUDY DESIGN: A Modified Delphi process was used. METHODS: The methodology was based on the Appropriate Use Criteria development process established by the Research AND Development Corporation. The topic of degenerative spondylolisthesis was selected by the committee, key modifiers determined, and consensus reached on standard definitions. A literature search and evidence analysis were completed by one work group simultaneously as scenarios were written, reviewed, and finalized by another work group. A separate multidisciplinary rating group was assembled. Based on the literature, provider experience, and group discussion, each scenario was scored on a nine-point scale on two separate occasions, once without discussion and then a second time following discussion based on the initial responses. The median rating for each scenario was then used to determine if indications were rarely appropriate (1 - 3), uncertain (4-6), or appropriate (7-9). Consensus was not mandatory. RESULTS: There were 131 discrete scenarios. These addressed questions on bone grafting, imaging, mechanical instability, radiculopathy with or without neurological deficits, obesity, and yellow flags consisting of psychosocial and medical comorbidities. For most of these, appropriateness was established for physical therapy, injections, and various forms of surgical intervention. The diagnosis of spondylolisthesis should be determined by an upright x-ray. Scenarios pertaining to bone grafting suggested that patients should quit smoking prior to surgery, and that use of BMP should be reserved for patients who had risk factors for non-union. Across all clinical scenarios, physical therapy (PT) had an adjusted mean of 7.66, epidural steroid injections 5.76, and surgery 4.52. Physical therapy was appropriate in most scenarios, and most appropriate in patients with back pain and no neurological deficits. Epidural steroid injections were most appropriate in patients with radiculopathy. Surgery was generally more appropriate for patients with neurological deficits, higher disability scores, and dynamic spondylolisthesis. Mechanical back pain and presence of yellow flags tended to be less appropriate, and obesity in general had relatively little influence on decision making. Decompression alone was more strongly considered in the presence of static versus dynamic spondylolisthesis. On average, posterior fusion with or without interbody fusion was similarly appropriate, and generally more appropriate than stand-alone interbody fusion which was in turn more appropriate than interspinous spacers. CONCLUSIONS: Multidisciplinary appropriate treatment criteria were generated based on the Research AND Development methodology. While there were consistent and significant differences between surgeons and non-surgeons, these differences were generally very small. This document provides comprehensive evidence-based recommendations for evaluation and treatment of degenerative spondylolisthesis. The document in its entirety will be found on the North American Spine Society website (https://www.spine.org/Research-Clinical-Care/Quality-Improvement/Appropriate-Use-Criteria).

Guideline summary review: an evidence-based clinical guideline for the diagnosis and treatment of low back pain.

BACKGROUND CONTEXT: The North American Spine Society's (NASS) Evidence Based Clinical Guideline for the Diagnosis and Treatment of Low Back Pain features evidence-based recommendations for diagnosing and treating adult patients with nonspecific low back pain. The guideline is intended to reflect contemporary treatment concepts for nonspecific low back pain as reflected in the highest quality clinical literature available on this subject as of February 2016. PURPOSE: The purpose of the guideline is to provide an evidence-based educational tool to assist spine specialists when making clinical decisions for adult patients with nonspecific low back pain. This article provides a brief summary of the evidence-based guideline recommendations for diagnosing and treating patients with this condition. STUDY DESIGN: This is a guideline summary review. METHODS: This guideline is the product of the Low Back Pain Work Group of NASS' Evidence-Based Clinical Guideline Development Committee. The methods used to develop this guideline are detailed in the complete guideline and technical report available on the NASS website. In brief, a multidisciplinary work group of spine care specialists convened to identify clinical questions to address in the guideline. The literature search strategy was developed in consultation with medical librarians. Upon completion of the systematic literature search, evidence relevant to the clinical questions posed in the guideline was reviewed. Work group members utilized NASS evidentiary table templates to summarize study conclusions, identify study strengths and weaknesses, and assign levels of evidence. Work group members participated in webcasts and in-person recommendation meetings to update and formulate evidence-based recommendations and incorporate expert opinion when necessary. The draft guideline was submitted to an internal and external peer review process and ultimately approved by the NASS Board of Directors. RESULTS: Eighty-two clinical questions were addressed, and the answers are summarized in this article. The respective recommendations were graded according to the levels of evidence of the supporting literature. CONCLUSIONS: The evidence-based clinical guideline has been created using techniques of evidence-based medicine and best available evidence to aid practitioners in the diagnosis and treatment of adult patients with nonspecific low back pain. The entire guideline document, including the evidentiary tables, literature search parameters, literature attrition flowchart, suggestions for future research, and all of the references, is available electronically on the NASS website at https://www.spine.org/ResearchClinicalCare/QualityImprovement/ClinicalGuidelines.aspx.

Closing the Treatment Gap for Lumbar Disc Herniation Patients with Large Annular Defects: A Systematic Review of Techniques and Outcomes in this High-risk Population.

Lumbar disc herniation (LDH) is one of the most common spinal pathologies and can be associated with debilitating pain and neurological dysfunction. Discectomy is the primary surgical intervention for LDH and is typically successful. Yet, some patients experience recurrent LDH (RLDH) after discectomy, which is associated with worse clinical outcomes and greater socioeconomic burden. Large defects in the annulus fibrosis are a significant risk factor for RLDH and present a critical treatment challenge. It is essential to identify reliable and cost-effective treatments for this at-risk population. A systematic review of the PubMed and Embase databases was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify studies describing the treatment of LDH patients with large annular defects. The incidence of large annular defects, measurement technique, RLDH rate, and reoperation rate were compiled and stratified by surgical technique. The risk of bias was scored for each study and for the identification of RLDH and reoperation. Study heterogeneity and pooled estimates were calculated from the included articles. Fifteen unique studies describing 2,768 subjects were included. The pooled incidence of patients with a large annular defect was 44%. The pooled incidence of RLDH and reoperation following conventional limited discectomy in this population was 10.6% and 6.0%, respectively. A more aggressive technique, subtotal discectomy, tended to have lower rates of RLDH (5.8%) and reoperation (3.8%). However, patients treated with subtotal discectomy reported greater back and leg pain associated with disc degeneration. The quality of evidence was low for subtotal discectomy as an alternative to limited discectomy. Each report had a high risk of bias and treatments were never randomized. A recent randomized controlled trial with 550 subjects examined an annular closure device (ACD) and observed significant reductions in RLDH and reoperation rates (>50% reduction). Based on the available evidence, current discectomy techniques are inadequate for patients with large annular defects, leaving a treatment gap for this high-risk population. Currently, the strongest evidence indicates that augmenting limited discectomy with an ACD can reduce RLDH and revision rates in patients with large annular defects, with a low risk of device complications.

Synthesis of carbon-14-labelled peptides.

Carbon-14 (14 C)-labelled active pharmaceutical ingredients (APIs) and investigational medicinal products (IMPs) are required for phase 0/I to phase III mass balance and micro-dosing clinical trials. In some cases, this may involve the synthesis of 14 C-labelled peptides, and the analysis can be performed by accelerated mass spectrometry (AMS). The 14 C-peptide is typically prepared by the solid-phase peptide synthesis (SPPS) approach using custom-made glassware for the key coupling steps. Further modification of the purified 14 C-peptide can then be performed.

The Global Spine Care Initiative: classification system for spine-related concerns.

PURPOSE: The purpose of this report is to describe the development of a classification system that would apply to anyone with a spine-related concern and that can be used in an evidence-based spine care pathway. METHODS: Existing classification systems for spinal disorders were assembled. A seed document was developed through round-table discussions followed by a modified Delphi process. International and interprofessional clinicians and scientists with expertise in spine-related conditions were invited to participate. RESULTS: Thirty-six experts from 15 countries participated. After the second round, there was 95% agreement of the proposed classification system. The six major classifications included: no or minimal symptoms (class 0); mild symptoms (i.e., neck or back pain) but no interference with activities (class I); moderate or severe symptoms with interference of activities (class II); spine-related neurological signs or symptoms (class III); severe bony spine deformity, trauma or pathology (class IV); and spine-related symptoms or destructive lesions associated with systemic pathology (class V). Subclasses for each major class included chronicity and severity when different interventions were anticipated or recommended. CONCLUSIONS: An international and interprofessional group developed a comprehensive classification system for all potential presentations of people who may seek care or advice at a spine care program. This classification can be used in the development of a spine care pathway, in clinical practice, and for research purposes. This classification needs to be tested for validity, reliability, and consistency among clinicians from different specialties and in different communities and cultures. These slides can be retrieved under Electronic Supplementary Material.

The Global Spine Care Initiative: care pathway for people with spine-related concerns.

PURPOSE: The purpose of this report is to describe the development of an evidence-based care pathway that can be implemented globally. METHODS: The Global Spine Care Initiative (GSCI) care pathway development team extracted interventions recommended for the management of spinal disorders from six GSCI articles that synthesized the available evidence from guidelines and relevant literature. Sixty-eight international and interprofessional clinicians and scientists with expertise in spine-related conditions were invited to participate. An iterative consensus process was used. RESULTS: After three rounds of review, 46 experts from 16 countries reached consensus for the care pathway that includes five decision steps: awareness, initial triage, provider assessment, interventions (e.g., non-invasive treatment; invasive treatment; psychological and social intervention; prevention and public health; specialty care and interprofessional management), and outcomes. The care pathway can be used to guide the management of patients with any spine-related concern (e.g., back and neck pain, deformity, spinal injury, neurological conditions, pathology, spinal diseases). The pathway is simple and can be incorporated into educational tools, decision-making trees, and electronic medical records. CONCLUSION: A care pathway for the management of individuals presenting with spine-related concerns includes evidence-based recommendations to guide health care providers in the management of common spinal disorders. The proposed pathway is person-centered and evidence-based. The acceptability and utility of this care pathway will need to be evaluated in various communities, especially in low- and middle-income countries, with different cultural background and resources. These slides can be retrieved under Electronic Supplementary Material.

Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 1: introduction and methodology.

Fusion procedures are an accepted and successful management strategy to alleviate pain and/or neurological symptoms associated with degenerative disease of the lumbar spine. In 2005, the first version of the "Guidelines for the performance of fusion procedures for degenerative disease of the lumbar spine" was published in the Journal of Neurosurgery: Spine. In an effort to incorporate evidence obtained since the original publication of these guidelines, an expert panel of neurosurgical and orthopedic spine specialists was convened in 2009. Topics reviewed were essentially identical to the original publication. Selected manuscripts from the first iteration of these guidelines as well as relevant publications between 2005 through 2011 were reviewed. Several modifications to the methodology of guideline development were adopted for the current update. In contrast to the 2005 guidelines, a 5-tiered level of evidence strategy was employed, primarily allowing a distinction between lower levels of evidence. The qualitative descriptors (standards/guidelines/options) used in the 2005 recommendations were abandoned and replaced with grades to reflect the strength of medical evidence supporting the recommendation. Recommendations that conflicted with the original publication, if present, were highlighted at the beginning of each chapter. As with the original guideline publication, the intent of this update is to provide a foundation from which an appropriate treatment strategy can be formulated.

Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 2: assessment of functional outcome following lumbar fusion.

Assessment of functional patient-reported outcome following lumbar spinal fusion continues to be essential for comparing the effectiveness of different treatments for patients presenting with degenerative disease of the lumbar spine. When assessing functional outcome in patients being treated with lumbar spinal fusion, a reliable, valid, and responsive outcomes instrument such as the Oswestry Disability Index should be used. The SF-36 and the SF-12 have emerged as dominant measures of general health-related quality of life. Research has established the minimum clinically important difference for major functional outcomes measures, and this should be considered when assessing clinical outcome. The results of recent studies suggest that a patient's pretreatment psychological state is a major independent variable that affects the ability to detect change in functional outcome.

Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 3: assessment of economic outcome.

A comprehensive economic analysis generally involves the calculation of indirect and direct health costs from a societal perspective as opposed to simply reporting costs from a hospital or payer perspective. Hospital charges for a surgical procedure must be converted to cost data when performing a cost-effectiveness analysis. Once cost data has been calculated, quality-adjusted life year data from a surgical treatment are calculated by using a preference-based health-related quality-of-life instrument such as the EQ-5D. A recent cost-utility analysis from a single study has demonstrated the long-term (over an 8-year time period) benefits of circumferential fusions over stand-alone posterolateral fusions. In addition, economic analysis from a single study has found that lumbar fusion for selected patients with low-back pain can be recommended from an economic perspective. Recent economic analysis, from a single study, finds that femoral ring allograft might be more cost-effective compared with a specific titanium cage when performing an anterior lumbar interbody fusion plus posterolateral fusion.

Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 4: radiographic assessment of fusion status.

The ability to identify a successful arthrodesis is an essential element in the management of patients undergoing lumbar fusion procedures. The hypothetical gold standard of intraoperative exploration to identify, under direct observation, a solid arthrodesis is an impractical alternative. Therefore, radiographic assessment remains the most viable instrument to evaluate for a successful arthrodesis. Static radiographs, particularly in the presence of instrumentation, are not recommended. In the absence of spinal instrumentation, lack of motion on flexion-extension radiographs is highly suggestive of a successful fusion; however, motion observed at the treated levels does not necessarily predict pseudarthrosis. The degree of motion on dynamic views that would distinguish between a successful arthrodesis and pseudarthrosis has not been clearly defined. Computed tomography with fine-cut axial images and multiplanar views is recommended and appears to be the most sensitive for assessing fusion following instrumented posterolateral and anterior lumbar interbody fusions. For suspected symptomatic pseudarthrosis, a combination of techniques including static and dynamic radiographs as well as CT images is recommended as an option. Lack of facet fusion is considered to be more suggestive of a pseudarthrosis compared with absence of bridging posterolateral bone. Studies exploring additional noninvasive modalities of fusion assessment have demonstrated either poor potential, such as with (99m)Tc bone scans, or provide insufficient information to formulate a definitive recommendation.

Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 5: correlation between radiographic outcome and function.

In an effort to diminish pain or progressive instability, due to either the pathological process or as a result of surgical decompression, one of the primary goals of a fusion procedure is to achieve a solid arthrodesis. Assuming that pain and disability result from lost mechanical integrity of the spine, the objective of a fusion across an unstable segment is to eliminate pathological motion and improve clinical outcome. However, conclusive evidence of this correlation, between successful fusion and clinical outcome, remains elusive, and thus the necessity of documenting successful arthrodesis through radiographic analysis remains debatable. Although a definitive cause and effect relationship has not been demonstrated, there is moderate evidence that demonstrates a positive association between radiographic presence of fusion and improved clinical outcome. Due to this growing body of literature, it is recommended that strategies intended to enhance the potential for radiographic fusion are considered when performing a lumbar arthrodesis for degenerative spine disease.

Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 6: discography for patient selection.

Identifying the etiology of pain for patients suffering from chronic low-back pain remains problematic. Noninvasive imaging modalities, used in isolation, have not consistently provided sufficient evidence to support performance of a lumbar fusion. Provocative testing has been used as an adjunct in this assessment, either alone or in combination with other modalities, to enhance the diagnostic capabilities when evaluating patients with low-back pain. There have been a limited number of studies investigating this topic since the publication of the original guidelines. Based primarily on retrospective studies, discography, as a stand-alone test, is not recommended to formulate treatment strategies for patients with low-back pain. A single randomized cohort study demonstrated an improved potential of discoblock over discography as a predictor of success following lumbar fusion. It is therefore recommended that discoblock be considered as a diagnostic option. There is a possibility, based on a matched cohort study, that an association exists between progression of degenerative disc disease and the performance of a provocative discogram. It is therefore recommended that patients be counseled regarding this potential development prior to undergoing discography.

Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 8: lumbar fusion for disc herniation and radiculopathy.

Patients suffering from a lumbar herniated disc will typically present with signs and symptoms consistent with radiculopathy. They may also have low-back pain, however, and the source of this pain is less certain, as it may be from the degenerative process that led to the herniation. The surgical alternative of choice remains a lumbar discectomy, but fusions have been performed for both primary and recurrent disc herniations. In the original guidelines, the inclusion of a fusion for routine discectomies was not recommended. This recommendation continues to be supported by more recent evidence. Based on low-level evidence, the incorporation of a lumbar fusion may be considered an option when a herniation is associated with evidence of spinal instability, chronic low-back pain, and/or severe degenerative changes, or if the patient participates in heavy manual labor. For recurrent disc herniations, there is low-level evidence to support the inclusion of lumbar fusion for patients with evidence of instability or chronic low-back pain.

Guideline update for the performance of fusion procedures for degenerative disease of the lumbar spine. Part 7: lumbar fusion for intractable low-back pain without stenosis or spondylolisthesis.

Establishing an appropriate treatment strategy for patients presenting with low-back pain, in the absence of stenosis or spondylolisthesis, remains a controversial subject. Inherent to this situation is often an inability to adequately identify the source of low-back pain to justify various treatment recommendations, such as lumbar fusion. The current evidence does not identify a single best treatment alternative for these patients. Based on a number of prospective, randomized trials, comparable outcomes, for patients presenting with 1- or 2-level degenerative disc disease, have been demonstrated following either lumbar fusion or a comprehensive rehabilitation program with a cognitive element. Limited access to such comprehensive rehabilitative programs may prove problematic when pursuing this alternative. For patients whose pain is refractory to conservative care, lumbar fusion is recommended. Limitations of these studies preclude the ability to present the most robust recommendation in support of lumbar fusion. A number of lesser-quality studies, primarily case series, also support the use of lumbar fusion in this patient population.