Letter to the Editor: Response to letters regarding Mobi-C cervical artificial disc

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TO THE EDITOR: We appreciate the opportunity to respond to the 2 letters1,7 (Weaver EN Jr: Mobi-C cervical artificial disc. J Neurosurg Spine [epub ahead of print May 22, 2015. DOI: 10.3171/2015.2.SPINE15163]; Bhangoo SS: Smoking status in the ACDF versus 2-level total disc replacement study. J Neurosurg Spine [epub ahead of print May 22, 2015. DOI: 10.3171/2015.1.SPINE141334]) published on our article (Davis RJ, Nunley PD, Kim KD, et al: Two-level total disc replacement with Mobi-C cervical artificial disc versus anterior discectomy and fusion: a prospective, randomized, controlled multicenter clinical trial with 4-year follow-up results. J Neurosurg Spine 22:15–25, January 2015).

Response to Dr. Weaver

The authors on this paper completed personal financial disclosures as required by the journal. It was disclosed that the Sponsor, LDR Spine USA Inc., funded the Investigational Device Exemption (IDE) trial, results of which were reported in this article. Contrary to Dr. Weaver’s assertion, the JNS: Spine reviewers and the Editor-in-Chief did question the authors’ conflicts of interest (COI). In response to the journal inquiry over COI, we added a paragraph to the manuscript, which included analyses of the outcomes from financially interested sites versus sites with no financial interest as defined by FDA regulations. From page 24 of the original article:

All of the authors participated as investigators in the Mobi-C IDE clinical study. To ensure that any potential conflicts of interest have not affected study outcomes, an analysis was completed at each time point to compare the overall success rates of patients between sites with and without financial interest (as defined by FDA regulation 21CFR54). Additionally, this analysis was reported to the FDA as part of the premarket approval package through the 24-month primary endpoint. At 6, 12, 18, 24, 36, and 48 months, this analysis confirmed that financial interest was not indicative of a better (or worse) outcome for either treatment group (p = 0.3132 at 48 months).4

The FDA mandates that a Class III medical device be subjected to a Premarket Approval (PMA) study to establish its safety and effectiveness. The required clinical trial is performed under an IDE study protocol subject to strict FDA regulations for study approval and conduct. The costs for such a clinical trial are tens of millions of dollars, before the device is ever approved for market. Due to the limited funding for spine research available from public entities, including the National Institutes of Health, and the tremendous burden of work associated with performing the trial, it is a rarity for a surgeon or group of surgeons to tackle such an endeavor. This leaves industry sponsors little choice but to fund these studies privately, prompting much debate in the medical community. However, according to a recently published article by Cher and Capobi-anco,2 industry-sponsored studies provide higher levels of evidence than studies with other funding sources. These authors reviewed clinicaltrials.gov for medical device research specifically related to the spine through March 6, 2014. They found 200 spine device trials with 148 being industry funded (74%), 3 federally funded, and 49 funded by academia or other sources. Safety and efficacy was the study purpose for 141 of the 148 industry-funded studies, none (0) of the 3 federally funded studies, and 16 of the 49 other funded studies. Further stratification by types of trials showed that 134 of 200 studies were multicenter studies. Multicenter studies will lead to a higher level of evidence in the findings; of the 134 multicenter studies, 118 were industry funded, 2 were federally funded, and 14 were funded by other sources.

While each of the authors agrees that there is a place for the posterior approach, the control treatment that was selected as the most appropriately matched procedure with the same patient indications and surgical approach as the investigational treatment at study start-up (2005), was anterior cervical discectomy and fusion (ACDF). Therefore, the focus on posterior cervical surgery is outside the scope of this study. It is important to note, however, that each patient reviewed and signed a consent form with their surgeon prior to enrollment in the study. Prior to consent, the surgeon explained all treatment options available to the patient. If a surgeon felt that a patient was better suited for a posterior surgery then that patient would not have been a proper candidate for this study and would not have been offered consent. Patients were selected for the study only after they were determined to qualify based on the entire set of 11 inclusion and 33 exclusion criteria. This was a total of 44 eligibility requirements, not “simply a diagnosis of degenerative disc disease with radiculopathy or myelopathy at 2 contiguous levels from C-3 to C-7.” The original article listed only the most relevant criteria for brevity, but the full lists of inclusion and exclusion criteria are shown in the Summary of Safety and Effectiveness posted on the FDA website.5

Finally, as clinicians and scientists, we welcome the opportunity to participate in a prospective, randomized, multicenter study that compares total disc replacement (TDR) to posterior cervical surgery regardless of the funding entity.

Response to Dr. Bhangoo

Although the ACDF non-union rate reported (14.8%) is higher than most surgeons would report clinically in their own practices, there was a much more rigid set of standards for this IDE study. The predefined criteria for radiographic success for the ACDF group included evidence of bridging bone, < 50% radiolucency lines, and < 2° of angular motion. A failure to achieve all 3 criteria resulted in a radiographic non-union designation. Analysis was conducted by Medical Metrics Inc. (MMI, Houston, Texas), who have performed similar analyses in a number of related IDE studies.

The radiographic non-union rate for ACDF was 14.8% at 4 years, which is comparable to the 1-level ACDF data from the ProDisc-C trial report of 13.1% at 5 years8 and the Kineflex-C trial report of 18% at 2 years.3 It is noteworthy that these radiographic non-unions at 4 years are identified from radiographs only. The clinical outcomes (as determined by NDI and VAS scores) of ACDF patients with radiographic non-union were similar to those of ACDF patients with successful fusion.

Dr. Bhangoo is correct to identify the study limitation that the inclusion and exclusion criteria in the protocol did not capture smoking status in a manner that allowed for correlation to clinical outcomes. However, 1 pack or less a day was specifically selected to exclude heavy smokers while still allowing for a “real world” population, because approximately 21% of the US population smoked in 2005.6 Dr. Bhangoo brought up some points worthy of consideration. Although the IDE data for smoking in this article were limited, we decided to review our own medical records (not IDE data) to obtain preoperative smoking status for each patient. While it is part of our normal practice to counsel all smoking patients to quit prior to ACDF surgery, we made no assumptions that they actually did and we reported the patient smoking status from their initial assessment. The data retrieved from our 8 investigational sites include 83.6% of the full study cohort (73 ACDF and 203 TDR patients).

Preoperatively, 15.1% (11/73) of ACDF patients and 18.7% (38/203) of TDR patients smoked. ACDF smokers on average smoked 10.3 cigarettes/day and TDR smokers smoked 14.5 cigarettes/day. Comparison of non-union rates for the smokers and non-smokers in the ACDF group for whom 48-month radiographs were available showed that the radiographic non-union rate was significantly higher for patients who smoked (44.4% vs 6.4%, p = 0.0094). When patients who underwent reoperation due to symptomatic non-union are added to the ACDF radiographic non-union rate, patients who smoked had an overall non-union rate of 70%, compared with the non-smokers’ overall non-union rate of 10.6% (p = 0.0003). Clinical outcomes were analyzed between the smoking and non-smoking ACDF patients, including NDI, VAS for neck pain, SF-12 MCS, and SF-12 PCS. For all clinical outcomes there was a statistically significant difference between the 2 groups, with the non-smokers faring better than smokers.

Since this analysis indicated that smoking did impact ACDF fusion and clinical outcomes, we removed all patients who smoked and ran a post hoc comparison of nonsmoking ACDF (n = 62) and non-smoking TDR (n = 165) patients. The ACDF non-smoking group experienced less improvement in NDI, VAS Neck, VAS Arm, SF-12 MCS, and SF-12 PCS than the TDR non-smokers. The IDE study definition of overall success was applied, and 69.8% of the TDR non-smokers met the criteria while only 50.0% of the ACDF non-smokers met the criteria (p = 0.0075).

We thank Dr. Bhangoo and JNS: Spine for this opportunity to respond and to provide post hoc analysis. Over the past 10 years, the spine community has been presented with a growing volume of short- and long-term data from a number of IDE clinical studies. We agree with Dr. Bhangoo that our study is not without limitations, and we look forward to eliciting more details on specific long-term treatment effects, including the effect that smoking may have in this patient population.

References

  • 1

    Bhangoo SS: Smoking status in the ACDF versus 2-level total disc replacement study. J Neurosurg Spine epub ahead of printMay222015. (Letter)

  • 2

    Cher DJCapobianco RA: Spine device clinical trials: design and sponsorship. Spine J 15:113311402015

  • 3

    Coric DNunley PDGuyer RDMusante DCarmody CNGordon CR: Prospective, randomized, multicenter study of cervical arthroplasty: 269 patients from the KineflexIC artificial disc investigational device exemption study with a minimum 2-year follow-up: clinical article. J Neurosurg Spine 15:3483582011. (Erratum in J Neurosurg Spine 16:322 2012)

  • 4

    Davis RJNunley PDKim KDHisey MSJackson RJBae HW: Two-level total disc replacement with Mobi-C cervical artificial disc versus anterior discectomy and fusion: a prospective, randomized, controlled multicenter clinical trial with 4-year follow-up results. J Neurosurg Spine 22:15252015

  • 5

    Food and Drug Administration: Summary of Safety and Effectiveness Data (SSED): Mobi-C Cervical Disc Prosthesis Washington, DCFDA2013. (http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110009b.pdf)Accessed August 28 2015

  • 6

    Jamal AAgaku ITO’Connor EKing BAKenemer JBNeff L: Current cigarette smoking among adults—United States, 2005–2013. MMWR Morb Mortal Wkly Rep 63:110811122014

  • 7

    Weaver EN Jr: Mobi-C cervical artificial disc. J Neurosurg Spine epub ahead of printMay222015. (Letter)

  • 8

    Zigler JEDelamarter RMurrey DSpivak JJanssen M: Pro-Disc-C and anterior cervical discectomy and fusion as surgical treatment for single-level cervical symptomatic degenerative disc disease: five-year results of a Food and Drug Administration study. Spine (Phila Pa 1976) 38:2032092013

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Article Information

INCLUDE WHEN CITING Published online November 13, 2015; DOI: 10.3171/2015.6.SPINE15707.

DISCLOSURES LDR contributed to the design and conduct of the study and also provided assistance with analysis of data. Dr. Davis has served as a consultant for LDR, has received clinical or research support for this study from LDR, and has received support for statistical analysis and for study/writing or editorial assistance on this paper from LDR. Dr. Bae is a patent holder for LDR Spine, has invested in a private fund that holds equity in LDR Spine among other medical companies, has received research support from LDR Spine, has served as a consultant for LDR Spine, and receives royalties for products from NuVasive, Stryker, and Zimmer Spine. Dr. Hisey serves as a consultant for LDR Spine, Zimmer Spine, DePuy/Synthes Spine, and Baxano Surgical and is a patent holder for LDR Spine and Zimmer Spine. Dr. Kim is a patent holder for LDR; is a consultant for LDR, Globus, and Stryker; owns stock in Molecular Matrix, Inc; is a consultant for FzioMed; and has a speaking/teaching arrangement with Precision Spine, LDR, and Globus. Dr. Nunley has direct stock ownership in Amedica, Paradigm Spine, and Spineology; has received support of non-study-related clinical or research effort from the Cervical Spine Research Society, K2M, Biomet Spine, Axiomed, Medtronic, Nutech, NuVasive, Spinal Motion, and Vertiflex; has received study related research support from LDR; is a patent holder for K2M and LDR Spine (specifically for the ROI-A anterior lumbar interbody fusion cage); is a consultant for Nutech, Amedica, K2M, and LDR; and has received royalties from, performed speaking and teaching arrangements for, and served on the scientific advisory board of Osprey Biomedical and K2M. Dr. Hoffman has direct stock ownership in, and serves as a consultant to, LDR and Nanovis. Dr. Gaede received clinical or research support for this study from LDR. Dr. Danielson and Dr. Gordon have received clinical or research support for this study from LDR and are patent holders with LDR (specifically for the ROI-A anterior lumbar interbody fusion cage). Dr. Jackson is a consultant for LDR Spine and has received clinical or research support for this study from LDR. Dr. Stone did not receive research support from LDR for this paper but has received institutional support for the clinical trial and other related research. Dr. Rami has received clinical or research support for this study from LDR.

Dr. Rami has replaced Dr. Davis as the principal investigator on the Mobi-C study at the Greater Baltimore Neurosurgery Center and was involved in formulating this response to the letters by Drs. Weaver and Bhangoo. He is thus included in the authorship despite not having been an author of the original article.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1

    Bhangoo SS: Smoking status in the ACDF versus 2-level total disc replacement study. J Neurosurg Spine epub ahead of printMay222015. (Letter)

  • 2

    Cher DJCapobianco RA: Spine device clinical trials: design and sponsorship. Spine J 15:113311402015

  • 3

    Coric DNunley PDGuyer RDMusante DCarmody CNGordon CR: Prospective, randomized, multicenter study of cervical arthroplasty: 269 patients from the KineflexIC artificial disc investigational device exemption study with a minimum 2-year follow-up: clinical article. J Neurosurg Spine 15:3483582011. (Erratum in J Neurosurg Spine 16:322 2012)

  • 4

    Davis RJNunley PDKim KDHisey MSJackson RJBae HW: Two-level total disc replacement with Mobi-C cervical artificial disc versus anterior discectomy and fusion: a prospective, randomized, controlled multicenter clinical trial with 4-year follow-up results. J Neurosurg Spine 22:15252015

  • 5

    Food and Drug Administration: Summary of Safety and Effectiveness Data (SSED): Mobi-C Cervical Disc Prosthesis Washington, DCFDA2013. (http://www.accessdata.fda.gov/cdrh_docs/pdf11/P110009b.pdf)Accessed August 28 2015

  • 6

    Jamal AAgaku ITO’Connor EKing BAKenemer JBNeff L: Current cigarette smoking among adults—United States, 2005–2013. MMWR Morb Mortal Wkly Rep 63:110811122014

  • 7

    Weaver EN Jr: Mobi-C cervical artificial disc. J Neurosurg Spine epub ahead of printMay222015. (Letter)

  • 8

    Zigler JEDelamarter RMurrey DSpivak JJanssen M: Pro-Disc-C and anterior cervical discectomy and fusion as surgical treatment for single-level cervical symptomatic degenerative disc disease: five-year results of a Food and Drug Administration study. Spine (Phila Pa 1976) 38:2032092013

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