By Ben A. Rich, J.D., Ph.D., UC Davis School of Medicine Bioethics Endowed Professor
The Historical Perspective
Viewed through the ethical "retrospectroscope," human-subjects research has a checkered history. The horrors inflicted by the Nazi doctors on purported research subjects during Hitler's Third Reich led to the Doctors' Trial at Nuremberg and the promulgation of the Nuremberg Code that set minimal standards for the use of human-subjects in research, beginning with informed consent as the first principle.
The fact that the foundational pronouncement on the ethics of human-subjects research was a reaction to one category of atrocity perpetrated by the Nazi regime actually may have limited its impact. Those medical researchers seeking to advance the scientific foundations of medical care were presumed to be inherently virtuous and above the need for any ethical scrutiny of their research enterprise.
Then, nearly 20 years after the Nuremberg Code, the validity of that presumption was shattered when a study by Henry Beecher, an endowed professor and chair of Anesthesiology at Harvard Medical School, was published in the New England Journal of Medicine. He described over 20 research protocols undertaken by mainstream investigators in the previous 20 years that endangered the lives of the subjects without either their knowledge or approval.
It was not until after Beecher's rigorous expose that the infamous Tuskegee study of untreated syphilis in the black male population of Macon County, Alabama, came to light and prompted a public and political demand for rigorous oversight of medical research.
Contemporary Issues in Clinical Research
While there is no longer any dispute as to whether ethical principles apply to medical research involving human subjects, there has been an ongoing discussion in the clinical and bioethics literature as to whether, and, if so, in what ways, the ethical responsibilities of clinical investigators to research subjects are materially different than a physician's responsibilities to patients.
The argument for such a distinction between the two was prominently set forth in a 1979 publication by the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research, known as the "Belmont Report." The report characterizes the distinction in these terms: "The purpose of medical or behavioral practice is to provide diagnosis, preventive treatment or therapy particular to individuals...Research designates an activity designed to test a hypothesis, permit conclusions to be drawn and thereby develop or contribute to generalizable knowledge."
The report goes on to note that innovative departures from recognized (usual and customary) practice by clinicians do not necessarily constitute research (or, for that matter, a departure from the standard of care). Indeed, clinical practice can vary widely even within the same state and patient category.
For example, in one locality in Maine, 20 percent of women will have undergone a hysterectomy by the time they reach 70 years of age, whereas in another part of the state the percentage is as high as 70. The exercise of sound clinical judgment in pursuit of the best outcome for a particular patient may require therapeutic innovation, which is neither experimentation nor research.
Wearing Two Hats
The most challenging situations are those in which physicians who provide patient care also conduct clinical research in their clinical specialty. When some of their patients are recruited into clinical trials, the risk of the therapeutic misconception is at its peak.
The concept was originally articulated in the early 1980s to describe a propensity of persons enrolled in clinical trials to see themselves not as research subjects potentially contributing to the advancement of medical science and the development of treatments that might benefit future patients, but rather as extremely fortunate patients who by virtue of enrollment in the clinical trial were receiving "tomorrow's care today."
The therapeutic misconception is most ethically concerning when it manifests itself, as it occasionally does, among participants in Phase I cancer clinical trials. Participants in these trials are patients with advanced cancer who have failed all currently accepted therapies, and the purpose of the trial is to assess the maximum tolerable dose of an investigational drug. To enroll in a clinical trial, particularly of this nature, with the misunderstanding that it is a form of personal medical care, is inconsistent with the fundamental doctrine of informed consent required in both patient care and the conduct of human subjects research.
Those who are most concerned about the therapeutic misconception have gone farther than the data support, suggesting that by enrolling in clinical trials, patients are actually depriving themselves (unknowingly) of beneficial care. What the data actually show are that clinical-trial participants have outcomes that are as good as, and in some instances, superior to comparable non-participants who simply continue to receive standard interventions.
It is also important to realize that physician investigators do not deprive patients of currently available and effective therapies in the process of enrolling them in clinical trials, at least so long as in doing so they adhere to another fundamental principle that applies in these circumstances, that of "clinical equipoise."
If there currently exists a genuine disagreement among qualified medical professionals concerning the preferred treatment, then a clinician investigator may ethically enroll a patient as a research subject in a trial that seeks to increase our knowledge about the best treatment for a malady. If the malady has no currently recognized treatment, randomizing the subjects between an investigational and a placebo arm of the study is generally acceptable. The use of placebos becomes much more controversial, even with fully informed consent, when there is an effective treatment available and randomization to a placebo may pose risks to those subjects.
Institutional Oversight of Clinical Research
The primary responsibility for thoroughly and objectively assessing the scientific merits and the full range of ethical implications of clinical research has been placed with institutional review boards (IRB).
This oversight is mandatory for all federally funded research (with certain narrow exceptions) involving human subjects prior to approval and so long as the protocol is ongoing.
An important goal underlying the recent development of and federal support for clinical and translational science centers in leading academic institutions, including UC Davis, is to expedite the development and implementation of new treatments. Ethics education and analysis are integral components of this new initiative.