Conflicts of interest and the clinical investigator
Tuesday, August 1, 2017
A conflict of interest (COI) can erode the judgment of clinical research professionals, leading to questions about their professionalism and integrity. Every professional has a COI. It could be an interest in a promotion, a financial collaboration, or a need to gain more research funding or be published in a medical journal. The May 2, 2017, issue of the Journal of the American Medical Association (JAMA) looked at the issue of COI; one topic addressed biomedical researchers and the difference between financial and nonfinancial possible biases.
The reasonable person standard
The term “conflict of interest” generally means “a financial interest that relates to the issue at hand,” says Harvey V. Fineberg, president of the Gordon and Betty Moore Foundation in Palo Alto, California. His article, “Conflict of interest: Why does it matter?” is part of the JAMA package. “More specifically, a conflict of interest can be discerned by using a reasonable person standard; i.e., a conflict of interest exists when a reasonable person would interpret the financial circumstances pertaining to a situation as potentially sufficient to influence the judgment of the physician in question.”1 Physicians employed by pharmaceutical companies may say their scientific or clinical judgment could not be influenced by any money they received or financial interest they have been given. But they miss the point, Fineberg says. “If a reasonable person would perceive that the financial circumstances could potentially influence their judgment, a failure to acknowledge and respond to the conflict of interest threatens to erode the trust that undergirds the value of professional judgment and expertise.”
Bias from a “preformed judgment” can stem from sources other than financial interests, he continues. “Friendships, institutional associations, previous study and reflection, knowledge of a field, and life experience can all produce a predisposition to accept, reject, or interpret evidence in a particular way.” The aim of COI policies is to expose “the sources of influence that stem from financial interests and to reduce the likelihood they will intrude into professional judgments.”
The presence of a COI is also subjective—based on the judgment of a reasonable person—and situational, that is, “dependent on the specific financial circumstances and relationship to the specific role of the person involved,” Fineberg says. The standards for evaluating this COI also may be bound by time and place, which means it may have a different meaning if it occurred at a different time or place. “In practical terms, policy about conflict of interest should be specific to the role, and clear about the financial thresholds and time frames that count, explicit about interests of individuals related to the person in question, and describe specific remedies, such as disclosure or exclusion. The policies should be public, readily understood, and applied evenhandedly. The basis for any exceptions should be spelled out. The aim, throughout, is to preserve and protect public trust in the independence and objectivity of physicians involved in the exercise in question.”
Financial vs. nonfinancial interests
Discussion of bias in research often centers around a statistical definition, such as “a systematic error or deviation from the truth in results or inferences,” says Lisa Bero, professor of the Charles Perkins Centre, Faculty of Pharmacy, University of Sydney in Australia. But a study can be biased in the way the questions are asked, how the study is conducted, and if and in what form the study is published. Therefore, researchers should acknowledge that a study can have methodological rigor and still be considered biased, she says.
In her JAMA article “Addressing bias and conflict of interest among biomedical researchers,” Bero makes a distinction between nonfinancial interests—such as personal beliefs, academic competition, and theoretical approach—and financial COI. “Treating nonfinancial interests in the same way as conflicts of interest ignores the reality that research is not value free and is conducted in a social context. Thus, the nonfinancial interests of researchers should and do affect their research.”2 Financial COIs create differences between investigators, she argues, since not all choose to participate in activities such as advisory boards and consulting. However, all researchers have nonfinancial interests. “[D]esires for academic advancement, intellectual commitment, and a personal interest in the topics of their research are presumably shared among all researchers as part of their professional role.”
Although several researchers in a study may have some financial ties to the same pharmaceutical company, few share the same nonfinancial interests that could bias their research in a unified direction, Bero continues. “Thus, these characteristics are intrinsic to the individuals and who they are as scientists and are not secondary interests that influence the primary interest of conducting and reporting unbiased research.”
Handling nonfinancial interests the same way as financial COI, through disclosure, she argues, raises ethical and privacy concerns, she says. Bero asks, should researchers who study same-sex transmission of diseases be required to disclose their sexual orientation? Many nonfinancial interests are a matter of public record, through interviews, academic achievements, and theoretical positions. “These interests document a researcher’s intellectual legacy; they are not conflicts of interest,” she says. Although some financial COIs can be managed by eliminating the conflict, nonfinancial conflicts cannot be removed from the researcher.
They also should not be the basis for exclusion from research, Bero says. Not only would this decrease the “diversity of thought brought to a scientific question,” it could favor the participation of “financially conflicted individuals” whose interests uniformly align with a single position. The exclusion would be unfair and impractical because it assumes that the researchers who remain in the study do not have interests that could affect the research, when in reality, they simply have different ones, she says.
Research can be enriched by the diversity and varied interests of the individual researchers, Bero concludes. Focusing on eliminating the nonfinancial interests that make researchers who they are can distract from the process of dealing with the bias relating to financial COI. “The diversity of viewpoints, motivations, and methodological approaches of researchers will advance science, while the narrowing of interests to financial ones will limit it to questions, methods, and reporting that favor the financial interest.”
Add external groups
One JAMA author argues that including groups external to the research and development group can add additional and objectivity to the research. “Many companies have oversight mechanisms involving peer review, senior leadership, or both protocols and clinical development plans to ensure these are rigorous, of high quality, and patient-centered,” says Joanne Waldstreicher, chief medical officer for Johnson & Johnson, New Brunswick, New Jersey, in her article “Managing conflicts of interest in industry-sponsored clinical research: More physician engagement is required.”3
In addition, companies may have a separate safety group that is independent of executives with commercial responsibility and, in some cases, even from the clinical trial research physicians and scientists. Many companies also have internal independent healthcare compliance, audit, and quality assurance staff who audit and monitor for adherence to rules and regulations and work with business partners to remediate identified issues.
Multiple stakeholders independent to the sponsor also may be added to assist with drug or device development. This can include independent external steering committee members or an academic research organization that focuses on the protocol design, ongoing conduct, and interpretation and publication of the results, Waldstreicher says. To avoid the introduction of bias, an independent data and safety monitoring board may be used to review and make recommendations on trial conduct and continuation. In addition, an external independent statistical group could conduct data analysis, while providing access and sharing data with trial investigators and coauthors. And after publication, there should be a process for outside researchers to request access to summary and participant-level clinical trial data for verification and analysis, she says. An independent group can look at the requests to remove any real or suspected subjectivity in their evaluation.
Potential COIs—financial and nonfinancial, conscious and unconscious—will always exist, she concludes. “Continued identification and constructive efforts to work together to address these conflicts in a transparent and collaborative manner will enhance the collective ability of industry, biomedical researchers, and physicians to serve patients and develop new products.”
Financial ties of PIs
Researchers may disavow any bias due to financial ties to a pharmaceutical company. A study published on January 17, 2017, in the BMJ challenged that statement; could a principal investigator’s financial ties to the manufacturer of the study drug affect the outcome of the clinical trial? To provide some answers, the authors of this study looked at 190 papers describing 195 studies published in “core clinical” journals in 2013.4 “We specifically focused on RCTs [randomized controlled trials] that examined the efficacy of drugs, because these studies have a high impact on both clinical practice and healthcare costs. We hypothesized that principal investigators’ financial ties with industry would be independently associated with positive study outcomes,” the authors say.
The results did find an association. Financial ties between principal investigators and the pharmaceutical industry were present in 132 of the 195 studies. Of 397 principal investigators (seven studies had multiple first or senior authors and one study had a single author), 231 had financial ties and 166 did not, the BMJ authors say. Of the principal investigators, 156 reported advisor/consultancy payments, 81 reported speakers’ fees, 81 reported unspecified financial ties, 52 reported honorariums, 52 reported employee relationships, 52 reported travel fees, 41 reported stock ownership, and 20 reported having a patent related to the study drug. The prevalence of financial ties of principal investigators was 76% among positive studies and 49% among negative studies.
In unadjusted analyses, the presence of a financial tie was associated with a positive study outcome. In the primary multivariate analysis, a financial tie was significantly associated with positive RCT outcome after adjustment for
the study-funding source. The secondary analysis controlled for additional RCT characteristics such as study phase, sample size, country of first authors, specialty, trial registration, study design, type of analysis, comparator, and outcome measure. These characteristics, however, did not appreciably affect the relation between financial ties and study outcomes.
Publication bias may be one reason why the presence of financial ties for investigators is associated with positive study outcomes, but the distribution of financial ties among unpublished papers is unknown, the authors say. If the financial ties affect study design and analytic approach, “[t]ransparency alone is not enough to regulate the effect that financial ties have on the evidence base, and disclosure may compromise it further by affecting a principal investigator’s judgment through moral licensing, which is described as ‘the unconscious feeling that biased evidence is justifiable because the advisee has been warned.’”4
One step to consider for reducing bias may be an independent statistical analysis of major RCTs, especially for studies that may have an effect on clinical practice or have financial implications for health systems, the authors say. Another step may be to require the publishing of datasets at the analytic stage. “The requirement to release the dataset to be reviewed later if necessary may discourage some forms of analytical bias,” they say. Finally, authors should be required to include and discuss any deviations from the original protocol. “This may help to prevent changes in the specified outcome at the analytic stage.”
The authors stress that they found an association, not a cause and effect. “Given the importance of industry and academic collaboration in advancing the development of new treatments, more thought needs to be given to the roles that investigators, policy makers, and journal editors can play in ensuring the credibility of the evidence base.”
An accompanying editorial says that interpreting the study’s findings can be “complicated.” First, the study grouped company-run trials with independent academic trials that also received industry funding in its definition. Second, the study did not examine the association of funding source and outcomes, and confidence intervals were wide. Third, previous studies that also controlled for both funding and financial ties had results that differed from this study. Finally, financial ties often are unreported. “Although [the authors] did make efforts to identify undisclosed financial ties, the databases available for such purposes are still limited,” says Andreas Lundh of the Center for Evidence-based Medicine of the University of Southern Denmark and Lisa Bero, one of the JAMA COI authors.5 “The role of companies in the design, conduct, or publication of the research should be transparent. Trials with industry funding or authors with financial ties should be interpreted with caution until all relevant information is fully disclosed and easily accessible.”
- Fineberg HV. Conflict of interest: Why does it matter? JAMA 2017;317:1717-1718.
- Bero L. Addressing bias and conflict of interest among biomedical researchers. JAMA 2017;317:1723-1724.
- Waldstreicher J. Managing conflicts of interest in industry-sponsored clinical research: More physician engagement is required. JAMA 2017;317:1751-1752.
- Ahn R, Woodbridge A, Abraham A, et al. Financial ties of principal investigators and randomized controlled trial outcomes: Cross sectional study. BMJ 2017;356:i6770.
- Lundh A, Bero L. The ties that bind. BMJ 2017;356:j176.
By Sue Coons, MA
This article was reprinted from Research Practitioner, Volume 18, Number 3, July-August 2017. Subscribe >>