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Global Spine J
Global Spine J
spgsj
GSJ
Global Spine Journal
2192-5682
2192-5690
SAGE Publications Sage CA: Los Angeles, CA

37129370
10.1177_21925682231166379
10.1177/21925682231166379
Original Articles
Association Between Industry Sponsorship of Spine-Related Clinical Trials, Publication Status, and Research Outcomes
https://orcid.org/0000-0002-8894-0608
Munsch Maria A. MD 1
https://orcid.org/0000-0001-7000-9842
Chen Stephen R. MD 1
https://orcid.org/0000-0002-7452-2712
Dalton Jonathan MD 1
Tisherman Robert MD 1
Shaw Jeremy D. MD 1
Lee Joon Y. MD 1
1 Pittsburgh Orthopaedic Spine Research, Division of Spine Surgery, Department of Orthopaedic Surgery, 6595 University of Pittsburgh , Pittsburgh, PA, USA
Maria A. Munsch, MD, Pittsburgh Orthopaedic Spine Research, Division of Spine Surgery, Department of Orthopaedic Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Email: munschma2@upmc.edu
2 5 2023
9 2024
14 7 20392044
© The Author(s) 2023
2023
AO Spine, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses
https://creativecommons.org/licenses/by-nc-nd/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 License (https://creativecommons.org/licenses/by-nc-nd/4.0/) which permits non-commercial use, reproduction and distribution of the work as published without adaptation or alteration, without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).

Study Design

Observational Database Study.

Objectives

Prospective clinical trials in spinal surgery are expensive to conduct, especially when randomized, appropriately powered, and/or multicentered. Industry collaborations generate symbiotic relationships promoting technological advancement; however, they also allow for bias. To the authors’ knowledge, there is no known analysis of correlations between industry sponsorship and publication rates of spine-related clinical trials. This observational work evaluates such potential associations.

Methods

The ClinicalTrials.gov database was queried with terms spine, spinal, spondylosis, spondylolysis, cervical, lumbar, and compression fracture over an 11-year period. Design characteristics and outcomes were recorded from 822 spine surgery-related trials. Trials were stratified based on funding source and intervention class. Groups were compared via two-tailed chi-square test of independence or Fisher’s exact test (α = .05), based on completion status and publication rates of positive vs negative results.

Results

Industry-sponsored spine-related clinical trials were more likely to be terminated than their non-industry-sponsored counterparts (P < .001). Of the trials achieving publication, industry-sponsored trials reported positive results at a higher rate than did trials without industry funding (P = .037). Clinical trials examining devices were more likely to be terminated than those studying other intervention classes (P = .001).

Conclusions

High termination rates and positive result publication rates among industry-sponsored clinical trials in spinal surgery likely reflect industry’s influence on the research community. Such partnership alleviates financial burden and provides accessibility to cutting-edge innovation. It is essential that all parties remain mindful of the significant bias that funding source may impart on study outcome.

spondylosis
spondylitis
cervical, lumbar
typesetterts10
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pmcIntroduction

For approximately four decades, the complex environment surrounding industry-sponsored research in the medical field has garnered both interest and scrutiny. 1 The potential introduction of bias and conflicts of interest offsets the attractive combination of funding and access to cutting-edge technology.2,3 This general trend is of particular relevance in the field of spine surgery, which continues to progress due to the national focus on healthcare reform and the emphasis on evidence-based medicine. 4 A recent study reported that clinical trials of spine devices were substantially more likely to be industry-sponsored, and that those device trials were more likely multi-centered and included significantly more participants. 5 Clinical trials, which are defined as research studies that prospectively evaluate a medical/surgical intervention, are not only of particular importance to the progression of evidence-based medicine, but also create an atmosphere that favors collaboration between industry and surgeons.6,7 This is due to both the high cost and time-consuming nature of implementation of clinical trials, which often create challenges in obtaining and maintaining funding. 8 Although the relationship between industry and clinicians is frequently mutually beneficial and crucial for technological advancement and the progression of medicine and surgery, these ties can potentially breed bias in research publication. 9 This risk has been investigated by several past studies of clinical trials across various medical disciplines, demonstrating a significant association between industry sponsorship and the publication of positive findings; prior work also indicates that industry sponsorship may influence researchers to emphasize conclusions in favor of their products.9-12

While prior works have widely recognized the collaborative efforts and influences between industry and the medical community with regards to publication status and positive result reporting, there is a paucity of evidence regarding the specific effect of industry on spinal surgery clinical trials. A recent study from the United Kingdom of all spinal surgery research publications from 2010 reported that industry sponsorship is significantly associated with both a lower level of evidence of study, as well as a higher likelihood of reporting favorable outcomes. 13 This work, however, was not focused on clinical trials and only represented a single year of publication data. Additionally, a recent work that did look at clinical trials in the context of spine surgery reported a lower likelihood of publication when associated with industry sponsorship, but did not examine whether or not this correlated with increased reporting of positive results. 14

With this in mind, the primary objective of the current database search is to investigate whether any relationship exists between funding source and completion status of spine-related clinical trials. Secondary objectives were used to evaluate published studies, which included examining any relationships between type of intervention studied and completion status, or between funding sources and whether conclusions support or refute the stated hypotheses. As defined by standard field entries on ClinicalTrials.gov, intervention types include devices, procedures, drugs, biologics, behavioral changes, and “other.” Accordingly, funding sources include industry, the NIH, non-NIH US Federal Government, medical centers/universities, private foundations, and “other.” This study is not intended to judge the merit of industry sponsorship in spine research, but rather to provide data-driven context for analysis of the results of prospective clinical trials.

Materials and Methods

This database review did not directly study human participants, and therefore informed consent and IRB approval were not warranted. The National Institute of Health Clinical Trials Database at ClinicalTrials.gov was queried for titles including the keywords spine OR spinal OR spondylosis OR spondylolysis OR cervical OR lumbar OR compression fracture, between 2008 and 2019. These keywords were chosen with the intention of identifying the greatest number of spine-related studies; in an effort to limit search results to these studies, broader terms such as “stenosis” were not included. Studies with no participating site in the United States and those not pertaining to the spine were excluded. Using information extracted from the Clinical Trials Database as well as PubMed searches, completion and publication status, type of intervention tested, funding source, study design, and reported outcomes were recorded. PubMed queries to determine the publication status of the clinical trials included searches by National Clinical Trial number, title, all listed authors, and a minimum of two keywords or phrases from the study description. On ClinicalTrials.gov, all studies are designated as “completed” or “terminated.” Because many trials reach completion but not publication, a literature search was done to identify all manuscripts resulting from trials designated as “completed.” Those trials that did progress to publication in manuscript form were instead designated as “published.” Conversely, trials that had been published in abstract form only were not categorized as “published.” If multiple publications resulted from the same clinical trial, the publication date of the earliest published manuscript was documented. For each published study, a single reviewer documented the outcome of each study as “positive” or “negative,” depending on whether any conclusion was drawn in support of the primary tested hypothesis. It was also noted whether the study completed tests of statistical significance or published only descriptive statistics and/or qualitative measures.

The trials were stratified based on the following standard fields as logged in ClinicalTrials.gov entries: industry-sponsorship status, other reported funding sources, and type of investigated intervention (“device,” “procedure,” “drug,” “biologic,” “behavioral,” “other,” “multiple,” or “none”). For published studies, all manuscripts were examined for disclosure of additional funding sources. The publication status and outcomes of published studies were then compared between these groups using either two-tailed chi square tests or Fisher exact tests, with α = .05 for all statistical measures.

Results

The ClinicalTrials.gov database returned 3639 studies from the initial search. There were 363 trials excluded for having no study sites in the United States, and 2454 trials were excluded for being unrelated to the spine. Remaining were 822 spine-related clinical trials that were included in this review (Figure 1).Figure 1. Flow chart illustrating application of inclusion and exclusion criteria.

Of the spine-related trials, 331 were at least partially industry-sponsored, and 491 received no industry funding. Industry-sponsored trials were more likely to be terminated and less likely to be published than trials not receiving industry sponsorship (P < .001) (Table 1). Publication status was distributed differently between trials of various funding sources (P = .003) (Table 2). Trials most likely to be published were those receiving no funding and those with funding derived solely from the NIH or from a private foundation. Publication status also varied among type of intervention investigated (P = .001) (Table 3). Trials investigating medical devices were more likely to be terminated than those studying any other type of intervention.Table 1. Publication Status Stratified by Industry Sponsorship Status.

Publication Status	
Funding Source	Published	Completed (not published)	Terminated	Total	
Industry	120/331 (36.3%)	130/331 (39.3%)	81/331 (24.5%)	331	
No industry	241/491 (49.1%)	192/491 (39.1%)	58/491 (11.8%)	491	
Total	361/822 (43.9%)	322/822 (39.2%)	139/822 (16.9%)	822	
Two-tailed chi square test: P < .001	

Table 2. Publication Status Stratified by Funding Source.

Publication Status	
Funding Source	Published	Completed (not published)	Terminated	Total	
Industry	102/271 (37.6%)	103/271 (38.0%)	66/271 (24.4%)	271	
NIH	28/32 (87.5%)	3/32 (9.4%)	1/32 (3.1%)	32	
Non-NIH federal	37/331 (11.1%)	26/331 (7.9%)	0/331 (.0%)	63	
Medical center or university	50/202 (24.8%)	110/202 (54.5%)	42/202 (20.8%)	202	
Private foundation	32/39 (82.1%)	7/39 (18.0%)	0/39 (.0%)	39	
Multiple	78/174 (44.8%)	68/174 (39.1%)	28/174 (16.1%)	174	
Other	2/8 (25.0%)	4/8 (50.0%)	2/8 (25.0%)	8	
None	32/33 (97.0%)	1/33 (3.0%)	0/33 (.0%)	33	
Total	361/822 (43.9%)	322/822 (39.2%)	139/822 (16.9%)	822	
Two-tailed Fisher exact test: P = .003	

Table 3. Publication Status Stratified by Type of Intervention Investigated.

Publication Status	
Intervention	Published	Completed (not published)	Terminated	Total	
Device	84/221 (38.0%)	85/221 (38.4%)	52/221 (23.5%)	221	
Procedure	90/187 (48.1%)	71/187 (38.0%)	26/187 (13.9%)	187	
Drug	81/169 (47.9%)	56/169 (33.1%)	32/169 (18.9%)	169	
Biologic	15/37 (40.5%)	15/37 (40.5%)	7/37 (18.9%)	37	
Behavioral	51/97 (52.6%)	38/97 (39.2%)	8/97 (8.2%)	97	
Multiple	22/48 (45.8%)	17/48 (35.4%)	9/48 (18.8%)	48	
Other (not included in statistical analysis)	0/2 (.0%)	2/2 (100.0%)	0/2 (.0%)	2	
None	18/61 (29.5%)	38/61 (62.3%)	5/61 (8.2%)	61	
Total	361/822 (43.9%)	322 (39.2%)	139 (16.9%)	822	
Two-tailed Fisher exact test: P = .001	

Publication of a manuscript was achieved by 361 spine-related clinical trials. Of clinical trials achieving publication, the proportion of published trials reporting positive outcomes clearly correlated with industry sponsorship. Trials that were even partially industry-sponsored were more likely to publish positive results and less likely to publish negative results than non-industry sponsored trials (P = .037) (Table 4). Upon consideration of funding source between trials that were not industry-sponsored, however, there was no difference in outcomes of published results between groups (P = .082) (Table 5).Table 4. Outcome of Published Studies Stratified by Industry Sponsorship Status.

Study Outcome	
Funding Source	Positive	Negative	Total	
Industry	105/120 (87.5%)	15/120 (12.5%)	120	
No industry	189/241 (78.4%)	52/241 (21.6%)	241	
Total	294/361 (81.4%)	67/361 (18.6%)	361	
Two-tailed chi square test: P = .037	

Table 5. Outcome of Published Studies Stratified by Funding Source.

Publication Status	
Funding Source	Positive	Negative	Total	
Industry	91/102 (89.2%)	11/102 (10.7%)	102	
NIH	23/28 (82.1%)	5/28 (17.8%)	28	
Non-NIH federal	30/37 (81.0%)	7/37 (18.9%)	37	
Medical center or university	34/50 (68.0%)	16/50 (32.0%)	50	
Private foundation	23/32 (71.9%)	9/32 (28.1%)	32	
Multiple	65/78 (83.3%)	13/78 (16.7%)	78	
Other	2/2 (100.0%)	0/2 (100.0%)	2	
None	26/32 (81.3%)	6/32 (18.8%)	32	
Total	294/361 (81.4%)	67/361 (18.6%)	361	
Two-tailed Fisher exact test: P = .082	

Discussion

Prospective clinical trials are essential to the advancement of spine surgery, especially with the advent of healthcare reform and an ever-increasing demand for evidence-based medicine to support the value of various medical and surgical interventions. 4 Disorders of the spine are increasingly associated with substantial disability, decreased productivity, and diminished health-related quality of life, with spine-related medical expenditures escalating significantly over the past two decades. 15 Thus, it is imperative to continue to pursue high quality clinical and surgical advancements via spine research. Prospective clinical trials generally constitute a lengthy, costly process; partnering with industry not only offsets these factors but also establishes a direct pipeline for new technologies to reach clinicians and patients. Therefore, prospective clinical trials remain an attractive target for industry sponsorships, which creates the risk of significant industry-centric bias.

In 2014, Amiri et al considered industry sponsorship of spine-related research studies of various levels of evidence published in five major medical and surgical journals over the course of a single year (2010), which demonstrated a significant association between industry funding and reporting of favorable outcomes in published manuscripts. 13 This work did not focus on prospective clinical trials and represents only a single year of publication. Ohnmeiss in 2015 reported on the fate of spine-related clinical trials, revealing a 38.9% publication rate across all spine-related clinical trials and noted a significant association between funding source and publication rate, with industry sponsorship being associated with decreased rate of publication. 14 However, there was no focus on the potential influence that funding source may have on the reporting and publication of positive or negative results. This current query expands on these important prior works13,14 by incorporating prospective clinical trials from an 11-year period and publications across all PubMed-indexed journals. Most notably, this effort considers trends not only among published studies, but also examines those that were terminated or completed yet unpublished, while remaining indexed on the Clinical Trials database.

Overall, clinical trials that obtained at least partial industry-sponsorship were less likely to be published and more likely to be terminated than their non-industry funded counterparts. Of those industry-sponsored trials that did achieve publication, an overwhelming majority published results in favor of their studied intervention. The influences leading to this outcome are likely multifactorial. These findings likely reflect some degree of positive results bias. However, may also indicate the rigorous review and refinement that companies impart upon their medical devices. If a single company develops a product and subsequently funds a clinical trial testing it, that company finds itself in a unique position to receive immediate feedback concerning the product’s performance. When shortcomings are found, the company then has the opportunity to pull the product and its related trials, implement improvements, and conduct a new trial. This ability to improve devices soon after their introduction to the spinal surgery community likely contributes to the higher termination rates and publication of positive findings among industry-sponsored clinical trials, as well as the higher termination rates among trials investigating medical devices.

While termination of clinical trials does present industry and surgeons alike with the ability to focus on implementation of the most cutting-edge, effective devices, it remains a controversial practice. Factors such as futility or ethical concerns can dictate the termination of clinical trials, but those that are terminated for other reasons can make it more difficult for subsequent trials on similar topics to obtain funding. 16 In addition, including data from a previously terminated trial in the literature can lead to overestimation of treatment effects, potentially prompting investigators to draw false conclusions. 16 Finally, discoveries that lead to termination of trials could hide important conclusions from the global research community. This potential source of waste may fuel the financial burden associated with the execution of high-quality clinical trials.

As with any study, this review does have associated limitations. Published studies that are not PubMed indexed have not been identified in this review. In addition, the inclusion of funding sources was limited to those disclosed within the Clinical Trials database and within any subsequent publications, and there may have been additional funding sources that were not disclosed. Furthermore, “completion” or “termination” status was not defined or assessed by any author, but rather was defined by the designated status of each study as assigned within the Clinical Trials database.

Conclusion

Industry sponsorship of spinal surgery-related clinical trials unequivocally correlates with higher termination rates, as well as greater likelihood to publish positive results. The various influences that may guide this trend include positive results bias and conflicts of interest, as well as pre-publication feedback and development. Further exploration is needed to further examine the motivations behind trial termination and arrested publication of industry-sponsored clinical trials in spinal surgery. However, the findings outlined in this study magnify the unique environment posed by industry sponsorships; prior to embarking on an industry-sponsored prospective clinical trial, spinal surgeons should carefully weigh both their positive and negative implications on the spinal research community.

ORCID iDs

Maria A. Munsch https://orcid.org/0000-0002-8894-0608

Stephen R. Chen https://orcid.org/0000-0001-7000-9842

Jonathan Dalton https://orcid.org/0000-0002-7452-2712

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
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References

1 Relman AS . The new medical-industrial complex. N Engl J Med. 1980;303 :963-970. doi:10.1056/NEJM198010233031703 7412851
2 [Anonymous] . Conflicts of interest in medical center/industry research relationships. Council on Scientific Affairs and Council on Ethical and Judicial Affairs. JAMA. 1990;263 :2790-2793.2332923
3 Blumenthal D Gluck M Louis KS Wise D . Industrial support of university research in biotechnology. Science. 1986;231 :242-246. doi:10.1126/science.3941897 3941897
4 Allen RT Rihn JA Glassman SD Currier B Albert TJ Phillips FM . An evidence-based approach to spine surgery. Am J Med Qual. 2009;24 :15s-24s. doi:10.1177/1062860609348743 19890181
5 Cher DJ Capobianco RA . Spine device clinical trials: design and sponsorship. Spine J. 2015;15 :1133-1140. doi:10.1016/j.spinee.2015.01.027 25637470
6 Hilibrand AS Spindler K O'Keefe RJ . Demonstrating the value of orthopaedic surgery through multicenter trials: AOA critical issues. J Bone Joint Surg Am. 2015;97 :e35. doi:10.2106/JBJS.N.00159 25834087
7 Sprague S Tornetta P 3rd Slobogean GP , et al. Are large clinical trials in orthopaedic trauma justified? BMC Musculoskelet Disord. 2018;19 :124. doi:10.1186/s12891-018-2029-3 29678204
8 Emanuel EJ Schnipper LE Kamin DY Levinson J Lichter AS . The costs of conducting clinical research. J Clin Oncol. 2003;21 :4145-4150. doi:10.1200/jco.2003.08.156 14559889
9 Bekelman JE Li Y Gross CP . Scope and impact of financial conflicts of interest in biomedical research: a systematic review. JAMA. 2003;289 :454-465. doi:10.1001/jama.289.4.454 12533125
10 Kjaergard LL Als-Nielsen B . Association between competing interests and authors' conclusions: epidemiological study of randomised clinical trials published in the BMJ. BMJ. 2002;325 :249. doi:10.1136/bmj.325.7358.249 12153921
11 Als-Nielsen B Chen W Gluud C Kjaergard LL . Association of funding and conclusions in randomized drug trials: a reflection of treatment effect or adverse events? JAMA. 2003;290 :921-928. doi:10.1001/jama.290.7.921 12928469
12 Bhandari M Busse JW Jackowski D , et al. Association between industry funding and statistically significant pro-industry findings in medical and surgical randomized trials. CMAJ (Can Med Assoc J). 2004;170 :477-480.14970094
13 Amiri AR Kanesalingam K Cro S Casey ATH . Does source of funding and conflict of interest influence the outcome and quality of spinal research? Spine J. 2014;14 :308-314. doi:10.1016/j.spinee.2013.10.047 24231776
14 Ohnmeiss DD . The fate of prospective spine studies registered on www.ClinicalTrials.gov. Spine J. 2015;15 :487-491. doi:10.1016/j.spinee.2014.10.008. www.ClinicalTrials.gov 25315132
15 Martin BI Deyo RA Mirza SK , et al. Expenditures and health status among adults with back and neck problems. JAMA. 2008;299 :656-664. doi:10.1001/jama.299.6.656 18270354
16 Briel M Bassler D Wang AT Guyatt GH Montori VM . The dangers of stopping a trial too early. J Bone Joint Surg Am. 2012;94 (suppl 1 ):56-60. doi:10.2106/JBJS.K.01412 22810449
