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NEJM
In 1963, before the advent of institutional review boards (IRBs), I was a young academic physician studying the regulation of sodium excretion by the kidneys. I paid medical students approximately $50 to serve as subjects for experiments involving only saline infusions and the collection of blood and spontaneously voided urine samples. I do not remember exactly what I told the students about the risks of the experiments but am quite certain that I characterized them as nominal. In one subject, severe phlebitis developed at the site of an intravenous infusion and required extensive therapy. The research project was funded by the National Institutes of Health. I had no possibility of financial gain from it. My primary motive was academic � the desire to advance knowledge about an important physiological mechanism with a bearing on clinical conditions such as edema. A potent secondary motive was to advance my career by publishing the results of the research and maintaining grant support � academic currency that buys prestige and promotion. These dual motives, advancement of medical science and personal benefits from publications and acquisition of grants, have not changed over the past 40 years as clinical research has burgeoned. Presumably, they have been and still are universal motives among academic investigators. They are reinforced by the interest of institutions in enhancing their reputations as research centers. This institutional goal influences the attitude not only of individual investigators but also of IRBs, which for the past three decades have been responsible for weighing the benefits and risks of research involving human subjects. The personal interest of an investigator in advancing knowledge coincides with the altruistic desire of many subjects to participate in research because it is of potential benefit to humanity. The interests of subjects and investigators may also be aligned if the subjects have reason to hope that they may benefit medically themselves. However, an investigator's interest in career advancement, although entirely ethical and appropriate in itself, may conflict, or appear to conflict, with the interest of subjects in minimizing the risk of psychological harm, physical injury, or death. Conflicts of Interest and the Safety of Research Subjects During the past decade, increasing attention has been paid to financial conflicts of interest in research. The dramatic growth of relations between investigators and industry has raised justifiable concern about the influence of financial rewards on the conduct, interpretation, and reporting of research. Academic organizations have published guidelines for avoiding or managing financial conflicts of interest, and federal regulations for this purpose are expected soon. A critical event that accelerated efforts to address the influence of financial conflicts of interest on the safety of research subjects was the death in 1999 of a subject enrolled in a study in which both the principal investigator and the institutional sponsor had substantial financial interests.1 However, the deaths of three other research subjects that have been reported publicly in the past six years apparently did not involve financial conflicts of interest.2,3,4 A broad spectrum of problems has been identified in these cases, involving both individual researchers and IRBs. The problems include the excessive zeal of an investigator in trying to complete a study, the failure of a researcher to report an adverse event in a previous subject to the IRB, an inadequate search of the literature on the toxicity of a drug, use of poorly trained personnel to measure the dose of a substance administered to a subject, the potential vulnerability of employees and students to pressure to serve as research subjects, and the influence of payments to subjects. These deaths all occurred at prominent research institutions. Since all the subjects were healthy volunteers, I do not think there is any doubt that the deaths were caused by the research procedures. I was unable to identify a comprehensive list of deaths of normal volunteers in the United States. The Office of Human Research Protections is not aware of such a comprehensive data set. The Food and Drug Administration requires reports of deaths during clinical trials of investigational drugs, but the information is not made public. There is some general information in the medical literature about deaths and other adverse events among normal volunteers. According to a 1976 survey of American investigators who had conducted "nontherapeutic" research involving more than 93,000 human subjects, temporarily disabling injuries occurred in 37 subjects, and permanent disability in 1; no deaths were reported.5 A 1978 report on more than 29,000 normal volunteers participating in a phase 1 testing program stated that there were 58 drug reactions, with complete recovery in every case.6 In addition, there were five "complications" that were not drug reactions, one of which led to prolonged hip damage. One subject died, although the relation between the death and the study was considered to be uncertain. A 1986 British survey of 27,000 subject-exposures involving the administration of drugs to normal volunteers reported 13 "serious reactions" and 1 death.7 I was not able to find more recent surveys of serious adverse events in research involving healthy volunteers. Deaths and serious injuries, although apparently rare, do occur, even in research involving volunteers who have no underlying diseases. There is no reason to believe that such adverse events occur only in studies in which there are financial conflicts of interest. In the past, the potential for conflict between the rights of subjects and their safety, on the one hand, and the desire of institutions and investigators to maintain and expand research programs, on the other, was not emphasized. In my own experience in the early 1960s, the institutional culture and academic mentors stressed the importance of success in research for the academic career of a faculty member. The risks to subjects was an implicit, not an explicit, issue. The establishment of IRBs a decade later reflected, in part, a recognition that the safety of research subjects demands an explicit acknowledgment that nonfinancial conflicts are inevitable in research and that, since they cannot be eliminated, they must be regulated. However, the subsequent deaths of research subjects and no doubt other serious adverse events that were not reported publicly indicate the need for continued institutional emphasis on the education of new investigators about the potential hazards of research, even in the absence of financial conflicts of interest. Management of Nonfinancial Conflicts of Interest Financial conflicts of interest on the part of investigators are readily defined in relatively objective, quantitative terms � for example, ownership of equity in the company sponsoring a clinical trial of one of its products. Whatever level of financial interest institutions or government regulations define as a potential conflict of interest can then be the basis for eliminating it. The potential nonfinancial conflict between the personal interests of investigators and those of subjects is inherent in all research involving human subjects, including that in which there is also a financial conflict of interest. The conflict cannot be prevented or eliminated, but its existence must be recognized if the risk to research subjects is to be minimized. To acknowledge the conflict is not to criticize research institutions, investigators, or IRBs. The question is how to deal with such conflicts, not how to punish those who have them, since nonfinancial conflicts of interest are ubiquitous in research involving human subjects, whether the subjects are patients with a disease or healthy volunteers. The first step in managing nonfinancial conflicts of interest is for the leaders of research institutions to acknowledge that these conflicts are intrinsic to research that involves human subjects, whether or not there are financial conflicts of interest. Each institution must promote the expectation that researchers and IRB members will act with that conflict firmly in mind. Institutional documents about conflicts of interest should address nonfinancial as well as financial conflicts, as should institutionally based educational programs on research ethics. Mentors of research trainees should be expected to emphasize the importance of protecting the rights and safety of research subjects, both explicitly and implicitly in their actions as role models. An institutional emphasis on this category of conflict of interest will help IRBs in their difficult task of balancing the safety of subjects and the value of important research. However, the great majority of IRB members are themselves researchers, as well as employees of the research institution and colleagues of the investigators who submit research protocols for review. These IRB members are themselves subject to the influence of a nonfinancial conflict of interest (i.e., the conflict between their responsibility for protecting subjects and their responsibility not to undermine a valuable research program of the institution for which they work). The National Bioethics Advisory Commission has recommended that persons who represent the perspectives of subjects, who are not researchers, and who are not affiliated with the institution should collectively make up at least one quarter of IRB membership.8 I believe that this would be an important step in dealing with nonfinancial conflicts of interest. A second step would be to expand audits of ongoing research involving human subjects. Analysis of the problems leading to recent deaths of volunteers indicates that excessive zeal in trying to complete a project and failure to report a prior adverse event were critical factors in two cases. Periodic audits of studies in progress may identify such problems before a catastrophe occurs. High-risk protocols should be routinely audited, with the initial audit performed soon after the first few subjects have been studied or treated. A review of these audits should be a major responsibility of IRBs. Systematic analysis of serious adverse events, especially in research involving normal volunteer subjects in whom the events cannot be attributed to a disease, would be valuable in determining the effect of nonfinancial conflicts of interest on the safety of subjects. Regrettably, such an analysis is not possible, because there is no effective national reporting system of serious adverse events.9 Although there are formidable barriers to be overcome, the development of a comprehensive national reporting system that can provide adequate data for analysis of the frequency and root causes of adverse events should be a priority. Ultimately, nonfinancial self-interest on the part of investigators cannot be prohibited or eliminated, nor should it be. Academic self-interest is a legitimate part of the motivation to conduct research. Appropriate management of this type of conflict of interest depends on the ethical standards and moral sensitivity of individual investigators, research mentors, IRBs, and institutional leaders. All those involved in the conduct or institutional oversight of research must explicitly recognize the potential conflict between some of the interests of an investigator and a research institution and some of the interests of a research subject. Pellegrino10 has proposed that investigators are parties to a covenant both with society, which grants the privilege to perform research involving human subjects by a social consensus, and with subjects, who depend on the investigator's implied promise to "judiciously balance the patient's interests and those of the scientific protocol." I would add that institutions that sponsor or are the sites of research are also parties to this covenant. Investigators and institutions not only must balance the interests of the subject and the potential benefits of the research but must also explicitly give priority to the former. Financial conflicts of interest are now widely recognized. They can be defined clearly and quantitatively and can be managed by explicit institutional rules and national regulations. Nonfinancial conflicts of interest are more subtle yet more pervasive and cannot be eliminated. They require continuous attention if they are to be managed successfully. IRBs, institutional leaders, research mentors, and the federal government all have key roles in this process. Ultimately, however, the covenant with research subjects and with society relies on the ethical attitudes of individual investigators, with the support of standards set by institutional leaders and by government.
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