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Q J Med 2002; 95: 713-715
© 2002 Association of Physicians
Editorial |
Conflicts of interest
University of California, and Veterans Medical Research Foundation, San Diego, USA, e-mail: rengler@ucsd.edu
For more than 1500 years, the writings of Hippocrates of Cos have served as the ethical guide of the medical profession. At graduation, I pledged, ‘I will prescribe regimen for the good of my patients according to my ability and my judgment and never do harm to anyone ... I will preserve the purity of my life and my art. In every house where I come I will enter only for the good of my patients.’ The oath states that the physician will always be beneficent, and that all actions will be in the best interest of the patient. Recent developments in clinical research and in the business of clinical medicine in the US suggest that many physicians are no longer able to honour this commitment.
The National Commission for the Protection of Human Subjects was formed in 1979, following an unethical research project sponsored by the National Institutes of Health involving the long-term follow-up of Black men with untreated syphilis. The Belmont Report, issued by the Commission, applied the Hippocratic principles to human research. The Report stated three main principles in human subjects research—respect for persons, beneficence and justice—and adherence to these principles, as elaborated in the report, is a federal requirement in the US. Thus a patient who consults a physician, in either a clinical research or clinical care setting, should be able to trust that all information will be given with their best interests considered, and that the physician will respect their right to be fully informed. Implicit trust that does not have to be earned is a wonderful gift. The patient can assume that every physician who follows the code will be beneficent; conversely the physician enjoys the esteem, respect and trust accorded to doers of good deeds. The Belmont Report extends this principle to physician investigators, allowing patients to enjoy the benefits of clinical research without fear of deception. To ensure this trust, physicians' business concerns should not conflict with their relationship with their patient. While this tenet may be problematic today, it remains an ideal goal.
Recently, two areas of medical practice in America seem to have abandoned the principles of the Hippocratic oath. An example of the first came to public attention from gene therapy research. Researchers at the University of Pennsylvania and a research team at Tufts University in Boston were among the nation's leading pioneers in applying gene transfer as medical therapy. Following the tragic death of an 18-year-old patient in a gene therapy research trial at the University of Pennsylvania, the Food and Drug Administration (FDA), the agency responsible for overseeing clinical trials and drug approval in the US, found that the principal investigator was both sponsor of the research and an investigator. The FDA cited the sponsor with 16 violations of the Code of Federal Regulations including: ‘failed to incorporate agreed upon protocol changes into the protocol ... failed to immediately report the occurrence of adverse reactions ... failed to notify FDA ... of the finding from tests in laboratory animals that suggest a significant risk for human subjects ... failed to ensure that only eligible subjects were enrolled ... failed to ensure that the protocol was followed.’
Gene therapy research at the University of Pennsylvania's Institute for Human Gene Therapy was halted. In halting the gene therapy research at Tufts following a patient death, the FDA found that investigators ‘violated regulations governing the proper conduct of clinical studies ... (including) failure to protect the welfare of subjects under investigator's care.’
While it is easy to point the finger at the FDA, deficiencies in regulation are not the root causes of these problems. Regulatory agencies cannot accompany physicians on every visit to ensure that their actions are in the best interest of their patients, and that their purpose is beneficent. At both institutions, there was no boundary between sponsor and principal investigator. The principal scientists at both institutions were founders and major stockholders in biotechnology companies that stand to gain enormous wealth in the race to develop gene therapy products. While co-investigators may not have had a financial conflict of interest, can patients trust that their physician investigator, or collaborators who work directly for them, are truly informing their consent process and acting ‘only for the good of my patients' in circumstances where fortunes are to be made? Some of the physician researchers in these cases had a major conflict of interest between their duty as physicians and their financial affairs as sponsors of the clinical trials. Furthermore, the FDA's stringent requirements for oversight are foreign to the academic culture.
Traditionally, sponsors of clinical research trials, usually pharmaceutical companies and their salaried employees, are paid professionals whose job it is to ensure good clinical practice (as defined by FDA guidelines); they are not usually the physician investigators dealing with the patients. Physician investigators are generally paid usual and reasonable fees by sponsors for conducting clinical trials. In an ideal world, even these monetary considerations (which should never be excessive ‘per patient’ enrolment bonuses), should be disclosed. Only then can the physician investigator act without conflict of interest. Profound conflicts of interest and lack of professional regulatory experience were probably the root causes of misconduct in these two gene therapy trials, not lack of regulatory oversight or monitoring.
One proposal is to establish fines for violation of regulatory policy, but in a race to make millions, a fine may be a small price to pay. Attacking the problem at its roots by instigating national policy, regulations, and penalties that aim to mitigate significant financial conflict with the Hippocratic oath should be more successful. Academic-based investigations of new drugs may need special scrutiny when investigators lack training in regulatory requirements.
The motivation of physician scientists has been of interest to philosophers for some time, and depends partly on their environment. In commercial biotechnology and the pharmaceutical industry, filing patents, developing pharmaceuticals and making money is paramount. Being first to the discovery and first to market can produce enormous financial rewards. Volunteer patients have been insulated from these self-serving motives by Institutional Review Boards and by physician investigators, historically separate from the sponsor, who judge whether the entry criteria for a trial have been met, insure informed consent, and monitor patient safety.
In academia, credit for the discovery of truth is the Golden Fleece. It is critically important to be correct, or at least to have interpreted the data correctly. Subsequent research will be based on important discovered truths, and scientists who make mistakes through motivations other than the rigorous pursuit of truth can be ruined. In academic clinical science, we want personal motivations and incentives to emphasize fame, academic promotion, and altruistic rewards. While these incentives have inevitable conflicts of interest, they are well recognized and fairly well managed.
When the boundary between commercial and academic environments is blurred, motivations become mixed, and there is an inherent conflict of interest. If academic physicians want to develop their own discoveries, they should turn over at least the patient recruitment and informed consent aspect of any clinical trial to others who are without such conflicts. As a co-founder of two successful biotechnology companies, I know the impatience and frustration that can occur when others test your ideas in the clinic. However, I have come to realize that clinical trials conducted by neutral parties are the best and most convincing way to prove the efficacy and usefulness of new clinical discoveries. It also avoids the bias of enthusiasm for one's own ideas. The FDA and US Department of Health and Human Services policies should be rewritten to exclude physicians with significant financial or academic conflict of interest from all aspects of the informed consent process, although when uniquely skilled physicians are critical to the procedure or device application, their participation in treatment (but not the consent process) may be reasonable.
The second area of concern arises from the financial pressure that managers of health care systems place upon physicians delivering medical care. Until recently, physicians were paid either set salaries or standard cost rates that were ‘usual and reasonable’, by third parties. My father, who grew up during the Depression, advised me to go into medicine because I would always make a good living. As a patient, I want my doctor to have an assured, comfortable income that does not depend on decisions about my evaluation and treatment. I want my doctor to be motivated primarily by humanitarian motives and the satisfaction of practicing medicine, and to be free to follow the Hippocratic oath.
In previous decades in the US, fee-for-service medicine certainly tied physician income to services, but nearly unlimited third party payments erred on the side of too much medical care rather than too little, where the potential for harm was arguably less. However, following the increase in US medical care expenditure to over 14% of GNP, the business of medical care delivery was recently restructured. A number of financial models developed, such as Health Maintenance Organizations (HMOs), preferred providers, and managed care; nearly three-quarters of these are now for-profit enterprises, on the principle that profit motivation will control costs. Practicing cost-effective medicine is certainly a worthy goal, and savings can be made when physicians review resource utilization and consider results of Health Services Research regarding best practices. However, in many care models, individual physicians are given personal financial incentives (profit sharing, bonuses, etc.) for reducing the cost to the medical care enterprise by, for example, ordering fewer tests or avoiding hospital admissions. In some systems, physicians receive a set fee for taking care of a patient, including the costs of any tests they order. How do they decide if the money goes to care for the patient or into their pocket? Further, the US Supreme Court recently affirmed a law blocking HMO patients from suing the HMO, even though their physician's diagnostic and treatment prescriptions might have been motivated by avarice. The Court would not allow a remedy when a patient apparently suffered harm because a diagnostic test was not ordered, purportedly to save money. The US Congress is currently considering a patient's bill of rights, something the Founding Fathers did not foresee in drafting the first 10 amendments to the US Constitution. For-profit health care may easily conflict with the principles of Hippocrates; does the physician work for the patient's benefit or the stockholders?
To conclude, it seems to me that physician clinical investigators should not stand to gain wealth from the success of their research. Likewise, physicians in clinical practice should not be enticed to subjugate their duties to their patients to financial motives set by profit-seeking managers and stockholders. Doing so violates the inherent trust given by their patients and abandons the great gift of Hippocrates. When potentially lucrative intellectual property being tested belongs to universities and/or discovery scientists, we need new models that allow continued creative participation and motivation of investigators, while maintaining the veracity of results and managing the conflicts. Salary components for the investigator in the clinical research budget should be subject to institutional review to ensure that they are commensurate with effort. In health-care, salary incentives to physicians linked to cost savings should not be allowed. Physicians should perform quality assurance audits of their colleagues for the best practice of evidence-based medicine, including cost-effectiveness, as they are now required to do for quality of care delivered. Making physicians responsible for cost-effective medicine is mandatory, but structuring salary so that personal financial incentive conflicts with acting in the patient's best interest is nefarious and unethical. The Hippocratic ethic of medical practice inherently conflicts with for-profit health care. It is time for American medicine to revisit its roots in ancient Greece to address these ethical problems in the research and delivery of medical care.
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