Keywords

Overview of Conflict of Interest

The term “conflict of interest” relates to any situation in which personal, financial, or professional situations may have influence, or may appear to have a potential for influence on the results of scientific research. Conflicts of interest are prevalent in all levels of academic medicine and every researcher and clinician has personal, professional, and financial drivers which can bias their practice and research. Conflicts of interest are not always obvious and can influence researchers in both conscious and subconscious ways. Most focus has been on financial conflicts of interest within the scientific literature, as it is easier to concretely define and track, although multiple other forms of conflicts of interest exist including personal, professional, and spiritual. This chapter is aimed at discussing the various types of conflict of interest which arise in scientific research, specifically in orthopedic surgical research.

The goal of biomedical research is to improve patient care. However, patients are the key subjects in most scientific research and federal funding of research comes from taxpayer funding sources, and, therefore, public trust in research and institutions is necessary. The loss of public trust, including reductions in funding and research subjects, may be devastating to the institutions producing biomedical research. A case which demonstrates this is the 2005 case of Jesse Gelsinger, which led to the setback of gene therapy for over a decade. Dr. James Wilson, of the University of Pennsylvania, was one of the primary investigators in a study using gene therapy for ornithine transcarbamylase deficiency. Dr. Wilson had a financial relationship with the company which owned the intellectual property of the gene therapy. After receiving gene therapy as part of this study, 18-year-old Jesse Gelsinger developed a severe inflammatory reaction to the gene therapy and died. The resulting investigation revealed that information regarding a series of adverse events in patients and laboratory animals had been kept from the Food and Drug Administration as well as violations in following the strict inclusion criteria for the study and the informed consent process. It was also found that Dr. Wilson was a stakeholder in the company developing the gene therapy. The resulting lawsuits ended in large-sum settlements to the Gelsinger family, and Dr. Wilson was barred from being a principle investigator for a period of time. Beyond that, this case led to the cessation of most gene therapy studies in the USA [1]. The complex financial relationships between physicians, scientists, and industry can lead to bias in research, but when these conflicts negatively affect patients, they put at risk the faith of the public in biomedical research and endanger the ability of researchers to achieve scientific progress.

Biomedical researchers are assumed to be driven by a desire to advance science and improve patient care as well as outcomes. Unfortunately, there are outside motivations which all fall broadly under the category of “conflict of interest.” In fact, 15% of investigators in a 2005 survey revealed that they had changed the design, methods, or results of a manuscript in response to pressure from their funding source [2].

Ethical conduct in biomedical research has become of increasing concern with recent high-profile retractions in the literature due to undisclosed financial conflicts of interest. Orthopedic surgery is one of the medical fields with the strongest ties to industrial partners, but other fields of research are also highly dependent upon medical device and pharmaceutical company sponsorship to investigate and develop new technologies. In 2012, recombinant human bone morphogenic protein-2 (BMP-2) had become popular as an adjunct for use during spinal surgery as it was found to increase rates of fusion. Initial studies showed very high fusion rates (90–100%) when using recombinant human BMP-2 and using it prevented the donor site morbidity and complications of harvesting autograft bone for fusion. In an effort to review how industry sponsorship affected outcome reporting, a 2012 cross-sectional review of studies using recombinant human BMP-2 in spine surgery revealed that complications of using recombinant human BMP-2 were not reported in a single industry-sponsored study, but that all studies which had been performed without industry sponsorship showed complications including malignancy formation, radiculitis, and retrograde ejaculation [3]. This finding does not necessarily indicate that data manipulation occurred, but that industry sponsorship may place pressure on what information gets published in a study, especially in cases where the industry partners are allowed to review the manuscript prior to submission. The role of the industrial partner in manuscript and data preparation should always be made clear as part of the financial disclosure.

Financial relationships between surgeons and industry are beneficial and often necessary for scientific advancement. However, the effects of these relationships on the fidelity of research remain unclear and difficult to quantify. These partnerships between surgeons and industry are not inherently negative. A recent Cochrane review revealed that across medical and surgical specialties, projects which were funded by industry had overall more positive results [4]. The underlying meaning behind this is complicated in that many physician-industry partnerships involve agreements where the industry partner must approve the research manuscript prior to submission, which would help to bury negative findings. Conversely, products or concepts which have made it through initial industry vetting are also more likely to result in positive findings.

Collaborations between industry and physicians also represent the joining of two very different cultures. Industry is largely profit driven and often strives to protect internal documents and methods to prevent competitors from gaining advantage in their niche. Academic scientists, in contrast, are based in a culture of open distribution of ideas and work mostly in nonprofit organizations where the definition of success is very different. This combination of factors can put the interests of industrial partners and scientists or physicians at odds with one another, which is the basis for most financial conflicts of interest.

Objectivity is an essential part of research integrity and is fundamental for public trust in biomedical research. Despite the large sums of money paid to surgeons in consulting roles, the public trust in surgeons remains high and surveys have shown that public disclosure of conflicts of interest is strongly supported by patients [5]. Conflicts of interest are present in all aspects of biomedical science, but understanding the impacts of internal and external conflicts of interest on research methods, subjects, and presentations can lead to more transparency in research and improve the quality and safety of research. Appropriate disclosure of potential conflicts of interest allows for appropriate measures to be taken to mitigate bias in professional settings as well as can lead to appropriate further scrutiny in cases of research where strong industrial bias may be present. Conflicts of interest imply the potential for bias, but not necessarily the likelihood that any action was taken based upon the conflict.

Fact Box

  • Conflict of interest encompasses personal, financial, and professional influences on scientific research outcomes.

  • Biomedical research, aimed at improving patient care, relies on public trust and can be jeopardized by conflicts of interest.

  • Financial ties between researchers and industry partners may lead to biased reporting of study outcomes.

  • Collaborations between industry and academia bring together differing cultures and priorities, potentially leading to conflicts of interest.

  • Objectivity and transparency are crucial in biomedical research to maintain public trust and ensure research integrity.

Financial Conflict of Interest

Biomedical research requires significant financial investments from government and private industries in order to promote advancement in medical science and technology. These financial interactions between both government and private funding sources represent a potential conflict of interest from the pressure which financial incentives can have on the need to produce results. Subsequently, these incentives may consciously or subconsciously affect the results. Biomedical researchers who perform and distribute science in a completely unbiased manner is the ideal, but financial constraints on research and the need for industrial partners make this more difficult. It is generally accepted that if financial relationships are present between a researcher and an industrial sponsor, that the compensation for the efforts is proportionate to the work done so as not to unduly influence or place pressure on the results. Paid consultancies are commonplace and represent a deeper conflict of interest as the researcher may have both financial and intellectual conflicts of interest in the work. Financial conflicts of interest are often under increased scrutiny compared with other types of conflicts as they may be viewed as being more likely to influence scientific publications.

In orthopedic surgery, there is an inherent reliance upon medical devices to provide care for patients. As such, there are strong ties between medical device manufacturers and orthopedic research which provide benefits to both parties. Biomedical research is a costly endeavor which can be supported by private industrial partners looking to advance their own product as well as the field of orthopedics. From the perspective of the biomedical device manufacturers, development of products without access to patients for testing or the expertise of surgeons using the products can lead to early product failure. This two-way street means that the interactions between physicians and industrial partners can advance the field of orthopedics, but also provides a potential for strong financial conflicts of interest.

Within the USA, there have been regulations placed at the federal level which require the public disclosure of all payments received by qualifying physicians. These payments are publicly viewable via the Center for Medicare and Medicaid Services (CMS) Open Payments Database. This serves as an example of government-driven efforts to make interactions between physicians and industry which represent a conflict of interest viewable by the public to increase accountability. A similar database, to our knowledge, does not exist in other countries.

Disclosure of the financial support provided to researchers when publishing is crucial to maintain the appearance of objectivity in research and maintain the trust between readers, publishers, and researchers. Research into the financial relationships between industrial partners and surgeons publishing in orthopedic journals reveals that there are significant discrepancies between the financial payments. This has been investigated in subspeciality journals including foot and ankle [6], spine [7], trauma [8], hand [9], and sports medicine [10]. Additionally, there have been comparisons between the Open Payments Database and the disclosures of financial relationships for individuals presenting at the American Academy of Orthopedic Surgery which reveal large discrepancies. The discrepancies between payments received and disclosed are significantly higher in first and middle authors, as well as in authors who received less total compensation. This indicates a need to increase the education about the importance of accurate financial disclosure in young physician scientists as these likely represent the bulk of first and middle authors [11].

The differences between disclosed financial relationships and the financial interactions between specific physicians and industry are likely unintentional, but there have been high-profile instances of research misconduct relating to physician-industry relationships which have led to severe consequences for the researchers involved.

Research integrity and misconduct are the most common reasons for article retraction in the scientific literature [12], but it is ambiguous where merely missing a conflict of interest during submission should be grounds for a scientific retraction.

Conflicts of interest exist not only at the individual level, but also at the institutional level. Agreements exists between industry partners and academic institutions which allow for research to be conducted on new products or concepts. These agreements may also include stipulations that the research data and publication must be approved by the industrial partner before release to the public. This creates a complex interaction where data may be suppressed or even filtered if it does not align with the desires of the industrial partner. In the USA, tax-exempt status for academic institutions is prohibited from generating “unrelated business income.” Therefore, agreements with companies which limit the ability of nonprofit organizations, which include more academic medical centers and institutions, from publishing results may lead to tax-exemption issues as the research can be considered commercial product development [13]. Institutions are not left without the ability to profit from scientific work. The 1980 Small Business Patent Procedure Act, also known at the Bayh-Dole Act, allowed for institutions and small businesses to patent technologies and findings which had been funded by federal research monies [14]. The possibility of developing and profiting from a technology represents a conflict of interest, and any patents related to a specific research study should be included in the disclosure. Institution-level conflicts of interest can place pressure on individuals to publish or not publish certain studies and should be disclosed appropriately. This disclosure should include details of the agreement between the company and the institution. Institutional relationships with industry are also more difficult to directly track in national databases, such as the CMS Open Payments Database because the researchers and authors involved in a study may not be listed in the institutional disclosure.

It is important to recognize that there are more subtle forms of financial conflicts which include payments in the form of educational seminars, sponsorship, dinners, and conference events. These are often sponsored by industry for trainees and early-career surgeons to give them educational opportunities which they might not be able to afford otherwise. Surveys of surgeons have demonstrated that there is a belief that these educational opportunities sponsored by industry do not negatively bias practice or patient care, and may actually improve patient care by giving trainees hands-on experiences [15]. It has been shown that surgeons are more likely to choose products from vendors which have provided direct financial support or education [16]. To the authors’ knowledge, there is no study linking industry-sponsored education to implant or vendor selection in the field of orthopedic surgery, but this issue has been studied in internal medicine, psychiatry, and other fields where multiple studies have shown that industry-sponsored educational events, including low-cost lunches, can influence prescribing practices for as little as $20 [17].

Fact Box

  • Financial investments from both government and private sectors in biomedical research pose potential conflicts of interest due to the influence of financial incentives on research outcomes.

  • Collaborations between medical device manufacturers and orthopedic researchers can lead to advancements in the field but also raise concerns about financial conflicts of interest.

  • Public disclosure of payments received by physicians is mandated in the USA to increase transparency and accountability in physician-industry interactions.

  • Discrepancies between disclosed financial relationships and actual payments received highlight the importance of accurate financial disclosure in research publications.

  • Institutional conflicts of interest can arise from agreements between industry partners and academic institutions, potentially influencing research data and publication approvals.

  • Subtle forms of financial conflicts, such as industry-sponsored educational events, may impact physician decision-making and should be subject to scrutiny and disclosure.

Personal and Professional Conflict of Interest or Bias in Research

Beyond overt financial conflicts of interest which can be more easily quantified, there are a myriad of nonfinancial conflicts of interest which can bias research methodology, results, and reporting. This includes, but is not limited to, positive publication bias and belief in the concept of the study or confirmation bias.

Positive result or publication bias is the underlying idea that studies with negative results are less likely to be submitted and accepted for publication. Underreporting of negative results can influence meta-analyses and cause them to falsely conclude differences with an intervention [18]. Additionally, the lack of negative result publications may lead to unnecessary duplication of research which is a waste of resources as well as a potential risk for human study subjects. Publication of negative results in a well-performed study should be encouraged in all cases, but studies with positive results are often prioritized by researchers, editors, and funding sources, including industry partners who may attempt to prevent publication of negative results. The US Clinical Trials Database is one source where negative and positive raw data is published for all studies enrolled in the database, but often these studies do not reach publication in widely distributed journals. The most effective method for prevention of positive publication bias is to attempt public dissemination of all positive and negative results in well-performed and well-designed studies.

Confirmation bias occurs when an individual or group uses only the data or sources which are in accordance with the initial hypothesis and expected result of the study. This bias has also been called “belief in the concept” bias, as inherently researchers are biased to believe that their hypothesis at the outset of a study is correct. The ideal of a “null hypothesis” when starting a research study is an idealistic notion which is often not employed by researchers during the design and analysis phase but is the most effective method for prevention of confirmation bias. Confirmation bias has been found to occur widely in clinical and research settings [19], including high-profile cases. An example is the meta-analysis of cholesterol-lowering statin drugs where an initial expert analysis by the prior president of the National Lipid Association, Dr. Peter Toth, discounted studies which did not confirm his hypothesis and he wrongly concluded that statins reduced all-cause mortality in elderly patients [20]. Dr. Toth authored over 200 publications in the field of cardiology and lipids, served on the board for the American Society of Preventive Cardiology, and was the vice president of the American Board of Clinical Lipidology. His analysis became widely cited and received coverage in the lay press as well. On further analysis of the level 1 available literature, other researchers found that he had excluded studies which would lead to the conclusion that there was no benefit to all-cause mortality [21]. His findings were discredited, but no formal action was taken against Dr. Toth. This example shows how personal biases can be propagated and may negatively impact both research findings and patient care.

Other professional conflicts of interest are widespread in academia. There is significant pressure to publish from both universities and industry sponsors which represents a conflict of interest and the pressure to publish can affect one’s employment and advancement. Publications in academia are often required for career advancement and obtaining funding for further research. The pressure to publish can lead to rushed results, data analysis, and even alterations to data, especially in early- and mid-career researchers [2]. Understanding that these pressures can affect the quality of research is key in mitigating the effects of professional pressure in the research setting.

Listing all potential conflicts of interest is beyond the scope of this chapter, but employment, religion, and social factors can all lead to subconscious biases in research and introspection can reveal many of these biases and help to counteract them. Nonfinancial conflicts of interest are not necessarily required to be reported, but the more aware researchers are of the potential influences on their decisions during the design, implementation, and reporting phrases of research, the more easily these outside influences can be avoided. Recognition, acknowledgment, and proactive resolution of these conflicts will improve the integrity and ultimately the quality of published research.

Fact Box

  • Positive publication bias, where studies with positive results are more likely to be published, can skew meta-analyses and lead to unnecessary duplication of research.

  • Confirmation bias, also known as “belief in the concept” bias, occurs when researchers selectively use data that supports their initial hypothesis, potentially leading to flawed conclusions.

  • Professional conflicts of interest in academia, such as pressure to publish for career advancement and funding, can result in rushed or altered research outcomes, particularly among early- and mid-career researchers.

  • Awareness and introspection regarding nonfinancial conflicts of interest, such as employment, religion, and social factors, can help researchers recognize and mitigate subconscious biases during the research process, improving the integrity and quality of published research.

Reporting of Conflicts of Interest

Publishing of scientific literature has focused on self-reporting of financial, personal, and professional conflicts of interests. Scientific publishers have relied on self-reporting systems which are used almost universally. There have been conflict reporting standards suggested by the International Committee of Medical Journal Editors [22], but their utilization varies throughout biomedical journals and this is reliant upon an author’s understanding of what constitutes a conflict of interest. Multiple studies have shown large discrepancies between reported financial conflicts of interest and publicly disclosed financial ties between researchers and industrial sponsors [6, 7].

An example of one program which aims to prevent discrepancies when submitting research is the conflict-of-interest reporting system developed by The American Academy of Orthopedic Surgery (AAOS). AAOS developed an electronic disclosure program in 2007 and has established a comprehensive conflict-of-interest disclosure form which is mandatory for individuals involved in editorial or organization activities, as well as members submitting to the annual meeting or publishing in the Journal of the American Academy of Orthopedic Surgery. This model for centralization of conflicts of interest helps to streamline the conflict-of-interest reporting process and can prevent errors of omission. This system has been shown to have a large number of discrepancies when compared to the CMS Open Payments Database and other publicly available information [23, 24], and could be improved upon to further streamline the process of disclosure and increase disclosure accuracy.

Failure to disclose financial or personal conflicts of interest, even those that may not influence the results of scientific works overtly or occur intentionally, represents a breach of the trust between the public, scientific publishers, and researchers. There is a growing need for a more systematic approach to nonfinancial and financial conflict of interest to ensure that published work is as free of bias as possible [25]. In cases where human subjects have been injured or other controversies have occurred, including research being overturned by further investigations, there may be an assumption that the conflicts of interest which were not disclosed led to deficiencies in study design or reporting.

Almost all US academic institutions require internal disclosure of financial and personal relationships which might constitute a conflict of interest due to federal regulations requiring this internal monitoring for grant funding. These comprehensive internal disclosures may also benefit from cross-referencing with publicly available databases, which could be further used to streamline reporting during publication. To our knowledge, this has not been implemented on a large scale at either academic institutions or in medical journals, both of which rely on self-reporting of all conflicts.

Fact Box

  • Scientific publishers predominantly rely on self-reporting systems for disclosing financial, personal, and professional conflicts of interest, leading to discrepancies between reported conflicts and publicly disclosed financial ties.

  • Programs like the conflict-of-interest reporting system by AAOS aim to streamline conflict-of-interest reporting but may still have significant discrepancies compared to publicly available databases, highlighting the need for improved accuracy and transparency.

  • There is a growing need for a systematic approach to both financial and nonfinancial conflicts of interest to ensure published work is free of bias, with potential benefits from cross-referencing internal disclosures with publicly available databases to enhance accuracy and streamline reporting.

Conclusions

Conflicts of interest arise when there are divergent interests in various stakeholders surrounding biomedical research. There is wide variation in the accuracy of self-reported financial disclosures in orthopedics which places public trust in orthopedic research at risk.