Neurosurgical Randomized Controlled Trial

Neurosurgical Randomized Controlled Trial

randomized controlled trial (RCT) remains the pinnacle of clinical research design. However, RCTs in neurosurgery, especially those comparing surgery to non-operative treatment, are rare and their relevance and applicability have been questioned.

From 2000 to 2017, PubMed and Embase databases and four trial registries were searched. RCTs were evaluated for study design, funding, adjustments to reported outcome measures, accrual of patients, and academic impact.

Eighty-two neurosurgical RCTs were identified, 40 in spine disorders, 19 neurovascular and neurotrauma, 11 functional neurosurgery, ten peripheral nerve, and two pituitary surgery. Eighty-four RCTs were registered, of which some are ongoing. Trial registration rate differed per subspecialty. Funding was mostly from non-industry institutions (58.5%), but 25.6% of RCTs did not report funding sources. 36.4% of RCTs did not report a difference between surgical and non-operative treatment, 3.7% favored non-operative management. Primary and secondary outcome measures were changed in 13.2% and 34.2% of RCTs respectively and varied by subspecialty. 41.9% of RCTs subtracted ≥ 10% of the anticipated accrual and 12.9% of RCTs added ≥ 10%. 7.3% of registered RCTs were terminated, mostly due to too slow recruitment. Subspecialty, registration, funding, masking, population size, and changing outcome measures were not significantly associated with a reported benefit of surgery. High Jadad scores (≥ 4) were negatively associated with a demonstration of surgical benefit (P < 0.05).

Neurosurgical RCTs comparing surgical to non-operative treatment often find a benefit for surgical treatment. Changes to outcome measurements and anticipated accrual are common and funding sources are not always reported 1).


From January 1961 to June 2016Randomized Controlled Trials (RCTs) with >5 patients assessing any 1 neurosurgical procedure against another procedure, nonsurgical treatment, or no treatment were retrieved from MEDLINEScopus, and Cochrane Library.

The median sample size in the 401 eligible RCTs was 73 patients with a mean patient age of 49.6. Only 111 trials (27.1%) described allocationconcealment, 140 (34.6%) provided power calculations, and 117 (28.9%) were adequately powered. Significant efficacy or trend for efficacy was claimed in 226 reports (56.4%), no difference between the procedures was found in 166 trials (41.4%), and significant harm was reported in 9 trials (2.2%). Trials with a larger sample size were more likely to report randomization mode, specify allocation concealment, and power calculations (all P < .001). Government funding was associated with better specification of power calculations (P = .008) and of allocation concealment (P = .026), while industry funding was associated with reporting significant efficacy (P = .02). Reporting of funding, specification of randomization mode and primary outcomes, and mention of power calculations improved significantly (all, P < .05) over time.

Several aspects of the design and reporting of RCTs on neurosurgical procedures have improved over time. Better powered and accurately reported trials are needed in neurosurgery to deliver evidence based care and achieve optimal outcomes 2).

References

1)

Martin E, Muskens IS, Senders JT, DiRisio AC, Karhade AV, Zaidi HA, Moojen WA, Peul WC, Smith TR, Broekman MLD. Randomized controlled trials comparing surgery to non-operative management in neurosurgery: a systematic review. Acta Neurochir (Wien). 2019 Feb 23. doi: 10.1007/s00701-019-03849-w. [Epub ahead of print] Review. PubMed PMID: 30798479.
2)

Azad TD, Veeravagu A, Mittal V, Esparza R, Johnson E, Ioannidis JPA, Grant GA. Neurosurgical Randomized Controlled Trials-Distance Travelled. Neurosurgery. 2018 May 1;82(5):604-612. doi: 10.1093/neuros/nyx319. PubMed PMID: 28645203.

Conflicts of interest

Conflicts of interest

Definition

The Institute of Medicine (IOM) defines conflict of interest as “circumstances that create a risk that professional judgments or actions regarding a primary interest will be unduly influenced by a secondary interest” 1).


Developmental incentives are fundamental to surgical progress, yet financial and professional incentives inherently create conflicts of interest(COI). Understanding how to manage COI held by neurosurgeons, industryhospitals, and journal editors, without thwarting progress and innovation is critical.

A review of the literature was performed to assess conflicts of interest that affect neurosurgical innovation, and review ways to manage COI of various parties while adhering to ethical standards.

COI are inherent to collaboration and innovation, and are therefore an unavoidable component of neurosurgery. The lack of a clear distinction between clinical practice and innovation, ability to use devices off-label, and unstandardized disclosure requirements create inconsistencies in the way that conflicts of interest are handled. Additionally, lack of requirements to compare innovation to the standard of care and inherent bias that affects study design and interpretation can have profound effects on the medical literature. Conflicts of interest can have both direct and downstream effects on neurosurgical practice, and it is possible to manage them while improving the quality of research and innovation.

Conflicts of interest are inherent to surgical innovation, and can be handled in an ethically sound manner. Neurosurgeons, device companieshospitals, and medical journals can take steps to proactively confront bias and ensure patient autonomy and safety. These steps can preserve public trust and ultimately improve evidence-based neurosurgical practice 2).

Relationships

Financial and nonfinancial relationships between pharmaceutical or medical device industry, physicians, investigators, and academic institutions are common and generally considered essential for development of new technology and advancement in medicine 3) 4).

However, these ties may at the same time create conflicts of interest: a set of circumstances that creates a risk that professional judgments or actions regarding a primary interest will be unduly influenced by a secondary interest 5).

Industry’s interests

The health care industry-manufacturers of drugs, devices, and medical equipment and its associated political and lobbying power, heavily influence strategic directions in clinical research. They may intervene, through experts with disclosed or silenced financial industry ties, in clinical guideline formation and dissemination, and may ultimately affect daily clinical practice.

The industry’s interests are not necessarily aligned with the interests of patients and society and may lead to study participant injury or harm and also reduce the public’s trust and confidence in clinical research.

It is obvious that the growing number of clinical trials conducted in vulnerable countries requires commitment from all stakeholders to ensure adherence to a core of internationally accepted ethical principles that reflect one of the basic ethical premises of the Declaration of Helsinki; that is, that the interests of science and society are not an excuse to conduct clinical trials in vulnerable countries.

Transnational clinical research should be controlled by internationally accredited ethical review boards, and research protocols rejected in one country should not be given permission to proceed elsewhere.

In addition, international human research monitoring agencies should have “…the power to sanction corporations and research groups that fail to respect universal standards”.

While these mechanisms are implemented, the role of major journals publishing the results of RCTs is crucial. This is because, as Smith emphasizes, when results are published in a major journal, the study receives “…the journal’s stamp of approval”, the published results carry a kind of professional approbation, and the paper becomes more attractive to both the readers and media, who may amplify the real value of the results.


A study aimed to determine the prevalence and financial magnitude of potential conflict of interest among editorial board members of five leading spine journals. The editorial boards of: The Spine Journal; Spine; European Spine Journal; Journal of Neurosurgery: Spine; and Journal of Spinal Disorders & Techniques were extracted on January 2013 from the journals’ websites. Disclosure statements were retrieved from the 2013 disclosure index of the North American Spine Society; the program of the 20th International Meeting on Advanced Spine Techniques; the program of the 48th Annual Meeting of the Scoliosis Research Society; the program of the AOSpine global spine congress; the presentations of the 2013 Annual Eurospine meeting; and the disclosure index of the American Academy of Orthopaedic Surgeons. Names of the editorial board members were compared with the individuals who completed a disclosure for one of these indexes. Disclosures were extracted when full names matched. Two hundred and ten (29%) of the 716 identified editorial board members reported a potential conflict of interest and 154 (22%) reported nothing to disclose. The remaining 352 (49%) editorial board members had no disclosure statement listed for one of the indexes. Eighty-nine (42%) of the 210 editorial board members with a potential conflict of interest reported a financial relationship of more than $10,000 during the prior year. This finding confirms that potential conflicts of interest exist in editorial boards which might influence the peer review process and can result in bias. Academia and medical journals in particular should be aware of this and strive to improve transparency of the review process. Janssen et al. emphasize recommendations that contribute to achieving this goal 6).


Traditional peer-review processes used by journal editors to aid in deciding which papers are worth publishing is not capable of filtering some of the more sophisticated techniques of covered marketing and conflicts of interest. The incorporation of ethicists in the peer review process would likely help to raise red flags and to properly consider the routine statement that the study was accepted by the “human review board” of some prestigious university. By rejecting suspicious ethical studies, editors may not be able to help make the world a fairer place, but they will help in building a healthier scientific community and sending a clear message, to both scientists and the industry, that it is unacceptable to exploit and potentially harm a few people for the sake of many 7).

Surgeon-industry

Surgeon-industry conflict of interest (COI) has become a source of considerable interest. Professional medical societiesindustry, and policy makers have attempted to regulate potential COI without consideration for public opinion.

The objective of a study was to report on the opinions of individuals representing the general public regarding surgeon-industry consulting relationships.

Survey was administered using a “spine Web site,” and opinions are collected on surgeon-industry consulting and regulation. Associations among responses to similar questions were assessed to ensure validity and subgroup analysis performed for respondent age, sex, education, insurance, employment, and patient status.

Six hundred ten of 642 surveys had complete data. The sample population comprised more females and was older and more educated than the American population. About 80% of respondents felt it was ethical and either beneficial or of no influence to the quality of health care if surgeons were consultants for surgical device companies. Most felt disclosure of an industry relationship was important and paying surgeons royalties for devices, other than those they directly implant, would not affect quality of care. Respondents support multidisciplinary surgeon-industry COI regulation and trust doctors and their professional societies to head this effort.

Despite the known potential negative impact of surgeon-industry COI on patient care, this study revealed that this does not seem to be reflected in the opinion of the general public. The respondents felt that disclosure is deemed one of the most important means of self-regulation and COI management, which is in agreement with current trends of most spine societies and journals that are increasing the stringency of disclosure policies 8).

Editorial board members of medical journals

Conflicts of interest arising from ties between pharmaceutical industry and physicians are common and may bias research. The extent to which these ties exist among editorial board members of medical journals is not known.

A study aims to determine the prevalence and financial magnitude of potential conflicts of interest among editorial board members of five leading spine journals. The editorial boards of: The Spine Journal; Spine; European Spine Journal; Journal of Neurosurgery: Spine; and Journal of Spinal Disorders & Techniques were extracted on January 2013 from the journals’ websites. Disclosure statements were retrieved from the 2013 disclosure index of the North American Spine Society; the program of the 20th International Meeting on Advanced Spine Techniques; the program of the 48th Annual Meeting of the Scoliosis Research Society; the program of the AOSpine global spine congress; the presentations of the 2013 Annual Eurospine meeting; and the disclosure index of the American Academy of Orthopaedic Surgeons. Names of the editorial board members were compared with the individuals who completed a disclosure for one of these indexes. Disclosures were extracted when full names matched. Two hundred and ten (29%) of the 716 identified editorial board members reported a potential conflict of interest and 154 (22%) reported nothing to disclose. The remaining 352 (49%) editorial board members had no disclosure statement listed for one of the indexes. Eighty-nine (42%) of the 210 editorial board members with a potential conflict of interest reported a financial relationship of more than $10,000 during the prior year. This finding confirms that potential conflicts of interest exist in editorial boards which might influence the peer review process and can result in bias. Academia and medical journals in particular should be aware of this and strive to improve transparency of the review process. Janssen et al. emphasize recommendations that contribute to achieving this goal 9).

Physician fully employed by industry

We would not allow a physician fully employed by industry to make a scientific presentation or publish an article for a peer-reviewed journal related to his or her company’s device or drug, yet we know from previously released orthopedic surgeon related data that many physician lecturers and writers are receiving yearly “consulting fees” and “royalty arrangements” that greatly exceed what is paid to physicians employed by device manufacturers—many above $1 million/year 10) 11) 12).

If publicly reporting these numbers places some in an uncomfortable position, so be it. This information is critical in the analysis of the clarity, sanctity, and scientific integrity of information and data presented. Collaboration has been valuable, but full transparency is critical to open, unbiased scientific dialogue and exchange.

References

1)

IOM (Institute of Medicine) Conflict of interest in medical research, education, and practice. Washington, DC: National Academies Press; 2009.
2)

DiRisio AC, Muskens IS, Cote DJ, Babu M, Gormley WB, Smith TR, Moojen WA, Broekman ML. Oversight and Ethical Regulation of Conflicts of Interest in Neurosurgery in the United States. Neurosurgery. 2019 Feb 1;84(2):305-312. doi: 10.1093/neuros/nyy227. PubMed PMID: 29850841.
3)

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.
4)

Garfin SR. Spine surgeons: spine industry. Eur Spine J. 2008; 17: 785–790.
5)

Steering Committee on Science and Creationism: National Academy of Sciences (1999) Science and Creationism: A View from the National Academy of Sciences, Second Edition The National Academies Press;
6) , 9)

Janssen SJ, Bredenoord AL, Dhert W, de Kleuver M, Oner FC, Verlaan JJ. Potential Conflicts of Interest of Editorial Board Members from Five Leading Spine Journals. PLoS One. 2015 Jun 4;10(6):e0127362. doi: 10.1371/journal.pone.0127362. eCollection 2015. PubMed PMID: 26042410.
7)

Sahuquillo J, Biestro A. Is intracranial pressure monitoring still required in the management of severe traumatic brain injury? Ethical and methodological considerations on conducting clinical research in poor and low-income countries. Surg Neurol Int. 2014 Jun 5;5:86. doi: 10.4103/2152-7806.133993. eCollection 2014. PubMed PMID: 25024886; PubMed Central PMCID: PMC4093744.
8)

DiPaola CP, Dea N, Noonan VK, Bailey CS, Dvorak MF, Fisher CG. Surgeon-industry conflict of interest: survey of North Americans’ opinions regarding surgeons consulting with industry. Spine J. 2014 Apr;14(4):584-91. doi: 10.1016/j.spinee.2013.06.028. Epub 2013 Aug 22. PubMed PMID: 23973098.
10)

Feder BJ. New focus of inquiry into bribes: doctors. New York Times. 2008 Mar 22; Available at: http://www.nytimes.com/2008/03/22/business/22device.html. Accessed December 30, 2010.
11)

Burns G. Partnerships between surgeons, implant makers raise ethical concerns. Chicago Tribune. 2008 Oct 26;
12)

Carryerou J, McGinty T. Top spine surgeons reap royalties, Medicare bounty. Wall Street Journal. 2010 Dec 20;:A1. Available at: http://online.wsj.com/article/SB10001424-052748703395204576024023361023138.html. Accessed December 30, 2010.

A review invalidates thousands of studies of the brain

A computer failure and bad widespread practices call into question 15 years of research

Functional MRI (fMRI) is 25 years old, yet surprisingly its most common statistical methods have not been validated using real data. Eklund et al. , used resting-state fMRI data from 499 healthy controls to conduct 3 million task group analyses. Using this null data with different experimental designs, they estimate the incidence of significant results. In theory, they should find 5% false positives (for a significance threshold of 5%), but instead they found that the most common software packages for fMRI analysis (SPM, FSL, AFNI) can result in false-positive rates of up to 70%. These results question the validity of some 40,000 fMRI studies and may have a large impact on the interpretation of neuroimaging results.


The most widely used task functional magnetic resonance imaging (fMRI) analyses use parametric statistical methods that depend on a variety of assumptions. In this work, we use real resting-state data and a total of 3 million random task group analyses to compute empirical familywise error rates for the fMRI software packages SPM, FSL, and AFNI, as well as a nonparametric permutation method. For a nominal familywise error rate of 5%, the parametric statistical methods are shown to be conservative for voxelwise inference and invalid for clusterwise inference. Our results suggest that the principal cause of the invalid cluster inferences is spatial autocorrelation functions that do not follow the assumed Gaussian shape. By comparison, the nonparametric permutation test is found to produce nominal results for voxelwise as well as clusterwise inference. These findings speak to the need of validating the statistical methods being used in the field of neuroimaging.

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