Conflict of Interest

After the Gelsinger case at the University of Pennsylvania and multiple cases at Fred Hutchinson Cancer Center, much attention has been focused on the financial conflicts of interest of clinical researchers in general and of oncology researchers in particular.96,97 This controversy raises five fundamental questions: What is a conflict of interest? How frequently do researchers have a financial interest in their own clinical research? Do financial interests distort the design, conduct, or dissemination of research data or compromise patient safety and well-being? How should they be regulated? How well do the safeguards work?

What is a conflict of interest? All professionals have primary interests that define and orient their professional activities. Teachers' primary interest is to educate their students. Judges' primary interest is to ensure justice is served for plaintiffs and defendants. Physicians' primary interests are to promote patient well-being and to teach medical students. The primary interests of clinical researchers are to produce and disseminate generalizable knowledge that will improve health care for future patients and to ensure the health and well-being of their research participants. In addition to these primary interests, professionals also have secondary interests. For a researcher, these could include publishing, gaining recognition and fame, spending time with his or her family, and obtaining a good income. These secondary interests are not in themselves illegitimate or nefarious; in fact, secondary interests can often be praiseworthy. What makes them problematic is their ability to unduly influence decisions about an individual's primary interest.98

A conflict of interest occurs when a secondary interest distorts or appears to distort a judgment related to a primary interest. In other words, a conflict of interest occurs when a reasonable person could "believe that professional judgment has been improperly influenced, whether or not it has."98 Mere suspicion by a reasonable person that a professional judgment is biased or unduly influenced is sufficient reason for a conflict of interest to exist, regardless of whether an undue influence has actually occurred. Conflict of interest rules are meant both to ensure objectivity in professional judgments by minimizing the likelihood such judgments will be compromised and to minimize any harms that might result from the bias if it does exist. Thus, the aim of conflict of interest regulations is not to prevent secondary interests altogether, but to prevent the secondary interest from influencing or appearing to influence judgments concerning the primary interest.98

How frequently do researchers have financial interest in their own clinical research? With the passage of the Bayh-Dole Act in 1980, which granted universities and medical schools the exclusive licensing rights to intellectual property developed through federally funded research conducted at their institutions, industry support of research grew significantly.99 In 1986, 46% of all biotechnology firms supported research at universities; by 1996, the proportion had doubled to 92%. As a result, universities' share of new gene patents increased from 53% to 73% between 1990 and 1999, and at least 2,900 companies have been formed around an innovation licensed from researchers at an academic institution since 1980.100,101 Consequently, from 1991 to 2000, the income to universities from licensing grew from $121 million to $997 million per year.99 Similarly, the fraction of clinical research supported by industry grew from 32% in 1980 to approximately 62% in 2000 while the federal government's share fell.102 This expansion by industry has many positive effects for research and researchers, including providing access to industrial facilities and databases, increased financial support for research, and use of industrial expertise.103 However, this increase in industry support and involvement in research has also resulted in further opportunities for financial conflicts of interest in clinical research.

Financial relationships between industry and researchers are common; studies suggest that between 23% and 28% of academic investigators in biomedical research receive funding from industry.104,105 Probably the most well documented rates of researcher-industry relations are those of the UCSF faculty, which consists of 900 PIs (principal investigators) in an institution with $374 million in National Institutes of Health (NIH) grants, placing it in the top five institutions receiving NIH funding.106 In 1999, 7.6% of the faculty reported having personal financial ties to their research sponsors.106 Of these, 34% had occasional speaking engagements, 33% had paid consultancy arrangements, 32% served on boards of directors or scientific advisory boards, and 14% had equity in a company, with the mean value of the equity being $100,000. Thus, although the prevalence of faculty with financial ties to industry was relatively low, those with financial interests often had multiple ties, some of which involved substantial sums.

Do financial interests distort the design, conduct, or dissemination of research data or compromise patient safety and well-being? In one bone marrow protocol at the Fred Hutchinson Cancer Center, 80 of 82 enrolled research subjects died and the study investigators had $294 million of holdings in a drug company sponsoring part of the research.97 Importantly, this does not prove that the patients' well-being was compromised by the potential conflict of interest, but it does raise questions. In fact, the researchers were cleared of conflict of interest allegations in a lawsuit that was brought against them and Fred Hutchinson Cancer Research Center by the patient's families.107,108 Unfortunately, there are no data substantiating whether the financial interests of investigators compromise the safety of research subjects. This conjecture is difficult to establish, especially as there are no data on the overall safety of clinical research.

Regarding the link between financial interests and research design, the data indicate that industry-sponsored research is certainly no worse methodologically than clinical research sponsored by nonprofit organizations, such as the NIH.109-112 Indeed, the data indicate that industry-sponsored research studies may well be more methodologically rigor-ous.18,113 In one study, industry-sponsored trials were more likely to be double blind than trials with other sources of funding.114 In another study that used a 100-point scale to evaluate five criteria for methodological rigor—randomization, outcome, inclusion/exclusion criteria, statistical analysis, and report of the interventions—industry-sponsored trials scored 73.1 while nonindustry-sponsored studies averaged 53.4 (P < 0.0001).115 Recently, Lexchin et al. comprehensively reviewed studies that assessed sponsorship, design, and conduct of research.116 They found that "none of the 13 [assessments in the literatures] reported that industry funded studies had poorer methodological quality ... Of nine [out of 13 assessments] that provided statistical analyses, four found that drug company sponsored research had better quality scores." Thus, it appears that financial interests do not compromise research design.

Financial interests may, however, adversely affect data collection and interpretation. Many studies have reported that research funded by industry is more likely to be favorable to the industry's experimental interventions than if the research was funded by a nonindustry source. Of 11 meta-analyses, 9 reported that industry-sponsored trials were significantly more likely to give pro-industry results.102 Indeed, when all studies were aggregated, having industry sponsorship was associated with an odds ratio of 3.60 (95% CI, 2.63-4.91) for having a pro-industry conclusion. For instance, Als-Nielsen et al. reported that among studies funded by forprofit entities, 51% reported results favorable to industry, whereas only 16% of studies funded by nonprofits generated results favorable to industry.117 Furthermore, one report summarizing a number of randomized studies conducted in multiple myeloma, found that 74% of industry-sponsored trials produced results favorable to the industry's new treatment, whereas only 53% of trials funded by nonprofit entities generated results favorable to the experimental treatments.18 Specifically regarding oncology studies, Friedberg et al. reported that drug company-sponsored studies were much less likely to report unfavorable qualitative outcomes than studies funded by nonprofit sources (5% versus 38%).118

Importantly, such data do not necessarily demonstrate bias or compromised studies. The fact that industry-sponsored studies generate pro-industry results may reflect a "pipeline" issue; that is, because conducting large research trials is very expensive, industry tends to only undertake drug trial studies when it is reasonably sure the results will be positive. Experimental interventions that are more uncertain or may not generate huge profits may be terminated before large randomized studies because of industry's caution about expending resources. This decision may ultimately deprive society of important new interventions, but it does not constitute a financial conflict of interest that might compromise the integrity of the research design or the data collection and interpretation. However, none of the reported studies links industry funding to biased scientific judgments, which, in turn, produce too many study outcomes favorable to the funding industry. Just showing that industry-sponsored studies generate pro-industry conclusions is insufficient to demonstrate that financial conflicts of interest actually bias the conduct of studies.

Nevertheless, there are data suggesting that industry financial support does distort the judgment of researchers. Stelfox and colleagues analyzed all published studies in 1995-1996 regarding the safety of calcium channel blockers

TABLE 9.6. Support of calcium channel antagonists and financial interest.119
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