Drazen JM, Koski G. To protect those who serve. N Eng J Med. 2000;343:1646-1649.
Jeffrey M. Drazen, M.D.
Editor-in-Chief, New England Journal of Medicine
Greg Koski, Ph.D., M.D.
Office for Human Research Protections,
Department of Health and Human Services
Rockville, MD 20852
Any clinical investigator will tell you that the success of a clinical trial is limited by the ability to recruit patients to become research subjects. Altruism aside, many patients who make this transition reach a conscious and informed decision to forgo standard care or even forgo treatment altogether for the chance, but only a chance, that they may benefit from an as yet unproved drug, device, or procedure. The decision takes special courage, and medical science is grateful to the people who display this courage.
The investigational treatment received under a research protocol may be no better than the standard treatment or may be less effective or have more adverse effects. Experienced investigators know that after all the pros and cons have been considered, patients usually base their decision on whether they trust the investigator. It is, after all, the investigator who is responsible for the subject's welfare during the trial, and it is the investigator who must always act in the subject's best interests. The investigator must protect the subject while he or she is participating in the research.
We are both physician-scientists who have recently taken new career paths that afford a fresh perspective on these issues. Our concern is that some clinical investigators may be putting their patients in a position that results in the loss of their trust because of the perception, and in a growing number of cases the reality, of conflicts between the interests of investigators and those of the subjects enrolled in their research trials.
Although there are many opportunities for conflicts of interest to arise, (1) the one that we believe is most troubling is the conflict that results when a clinical investigator has a financial stake in the outcome of a trial while at the same time being responsible for the safety of subjects. If a judgment call needed to be made in a complicated case, it would be uncertain whether the interests of the patient or the interests of the investigator were driving the decision. This is not a new problem. The potential for this type of conflict has led some, but not all, medical institutions engaged in clinical research to prohibit investigators from owning stock (or stock options) in a company whose device or drug they are testing. Equity interests are perhaps the most obvious source of conflict, but any financial arrangement that creates a situation in which a clinical investigator might have to choose between what is best for a subject and what is best for the investigator is troublesome.
It is important to distinguish ownership of equity in a company sponsoring a trial from grants made to institutions for the support of clinical research. Good clinical research is expensive. Many skilled people are required to ensure that the research is properly conducted, documented, and monitored so that the well-being of the subjects is closely guarded. If we want the best and brightest of our academic physicians to participate in clinical research, we need to be sure that their activities are fairly compensated in a manner that does not override the primary motivation for engaging in research -- the desire to apply science to the betterment of the human condition.
In two Special Articles in this issue of the Journal, Lo et al. (2) and McCrary et al. (3) catalogue the differences among academic medical centers in their policies governing financial arrangements between sponsors of clinical research and investigators. These policies have also been studied by others. (4,5) There are no uniform policies, nor is there currently any uniform national guidance, on the disclosure of investigators' financial interests to subjects participating in clinical trials. If subjects want to know whether the person responsible for their safety and well-being during a trial has a conflicting financial interest, they may need to ask the investigator, who may also be their personal physician. Many patients are too intimidated by the circumstances of their participation and their relationship with the investigator to do so. Since there is no consensus on this and many related issues, activities that are prohibited at some institutions are allowed at others. Sadly, but not surprisingly, these differences in policies create the potential for an uneven playing field among academic medical centers, which could have profound implications for the conduct of clinical and basic research.
To maintain the public trust, a number of research groups have recognized the need for rules to prevent even the appearance of conflicts between the interests of research subjects and those of clinical investigators. For example, investigators in the Post Coronary Artery Bypass Graft (Post-CABG) trial and the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial agreed that persons involved in the conduct of these studies would not hold equity in the sponsoring companies. (6,7) The American Society of Gene Therapy recently issued a policy statement stipulating that "all investigators and team members directly responsible for patient selection, the informed consent process and/or clinical management in a trial must not have equity, stock options or comparable arrangements in companies sponsoring the trial." (8) We believe these are good policies that should be widely adopted.
Similar policies have been in effect at some medical schools for over a decade. In a Sounding Board article in this issue of the Journal, Martin and Kasper (9) provide their thoughts on conflicts of interest. They call for medical schools to adopt uniform policies on the ownership of equity among clinical and basic investigators. We support the call for uniform policies.
We recognize that widespread adoption of such policies may involve sacrifice on the part of some clinical investigators, but this will not squelch clinical research. Similar policies have been in place at a number of medical schools where clinical research is flourishing. The extra measure of trust that patients and research subjects will have in the research process as a result of widespread acceptance of such policies may actually encourage patients to enroll in clinical trials.
Conflicts of interest in research are not going to go away. Clinical investigators must be primarily interested in protecting the welfare of the brave and unselfish persons who agree to serve as the subjects of our research. We welcome your thoughts on this important issue.
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