Two years ago, the Journal of Law, Medicine & Ethics published volume 28, number 4, devoted to a symposium entitled Human Subjects Research and the Role of Institutional Review Boards - Conflicts and Challenges. I had the good fortune to be asked to serve as editor of that issue. In her introduction to the symposium, the then editor-in-chief of the journal, Ellen Wright Clayton, observed that the country is currently undergoing a major reexamination of how biomedical research is conducted. While that reexamination has continued in the interim, some very recent events raise questions about the extent to which this will continue, at least in the short run, with equal vigor. The intervening years have witnessed a variety of new directions and events. The federal Office of Human Research Protections (OHRP), directed by Dr. Greg Koski, who wrote a brief commentary for the last symposium,L has taken a new direction, strongly stressing the need for institutions and their institutional review boards ORBS) to engage in extensive educational and quality improvement efforts with both researchers and their own member.

Thank you very much, Ladies and Gentleman. I am very honored by the invitation to give a keynote address at this very informative, national meeting, before such a distinguished audience.

If you made a list of the hundreds of different activities that go on during the day in a major medical center and tried to rank order them in terms of degree of difficulty, or judgment required, or risk of error, or damage that can result from an error of omission or an error of commission, at the top of the list one might consider the teaching of a surgical resident at the operating table by a senior experienced surgeon, hours on end, often emotionally draining.

An issue of ongoing concern to clinical investigators, medical ethicists, and institutional review board (IRB) members is the problem of obtaining informed consent in research that involves people with mental illness as research participants. Although the presence of a mental disorder per se does not render a person incapable of giving informed consent, some individuals afflicted with significant cognitive impairment, formal thought disorder, substantial anxiety or depression, or a variety of other symptoms may be impaired in their capacity to comprehend consent disclosures and therefore to exercise consent to research participation in a competent manner.

The stakes surrounding this informed consent issue are significant. On the one hand, the inclusion in research of participants who are not capable of giving informed consent may result in their exposure to unwarranted risks and significant harm. These concerns may be exacerbated in certain clinical trials in which patients are required to discontinue their medications during “washout periods” at the onset of a study, or are randomly assigned to a placebo treatment and remain off medication for (potentially) extended periods.

Clinical research employing the randomized clinical trial has, traditionally, been understood to pose an ethical dilemma. On the one hand, each patient ought to get the treatment that best meets her needs, as judged by the patient in consultation with her doctor. On the other hand, the method most helpful to advancing our understanding about what treatments are indeed best able to meet patient needs is the randomized trial, which necessitates that each patient's care is decided not by physician judgment or patient choice but instead by random assignment. The tension can be described as a conflict between the interests of individual patients who are sick today, and the interests of the group of people who will become sick in the future and would benefit from advances in medical understanding. How one ought to balance these important and often competing interests is an important ethical question that resists easy resolution.

Clinical gene transfer research (GTR) has both a unique history and a complex and layered system of research oversight, featuring a unique review body, the Recombinant DNA Advisory Committee (RAC). This paper briefly describes the process of decision-making about clinical GTR, considers whether the questions, problems, and issues raised in clinical GTR are unique, and concludes by examining whether the RAC's oversight is a useful model that should be reproduced for other similar areas of clinical research.

Clinical GTR is governed by the same oversight system as most clinical trials, with a significant addition: the RAC. Like other research with human subjects, GTR, if it is affiliated with a federally funded institution, must be approved by an institutional review board (IRB) whose activities are governed by the common rule, that is, the federal regulations for protection of human subjects in research. Like other research intended to produce a drug, device, or biologic to be marketed in the United States, GTR is also overseen by the Food and Drug Administration (FDA).

In both academic literature and the media, financial conflicts of interest in human subjects research have come center-stage. The cover of a recent edition of Time magazine features a research subject in a cage with the caption human guinea pigs, signifying perhaps that human research subjects are no more protected from research abuses than are laboratory animals. That magazine issue highlights three well-publicized cases of human subjects research violations that occurred at the University of Oklahoma, the University of Pennsylvania, and Johns Hopkins University.

At St. John Medical Center in Tulsa, Oklahoma, a study that was co-sponsored by the University of Oklahoma Health Sciences Center investigated an experimental vaccine for malignant melanoma. In that case, the chair of the university's institutional review board (IRB) — the committee within each medical institution charged with ethics review of human research projects undertaken at that institution — and the dean of the University's College of Medicine allegedly concealed from both the IRB and the United States Food and Drug Administration (FDA) a report by an outside consulting firm that had found severe deficiencies with the melanoma vaccine study being conducted at the medical center.

Studies in several developing countries for treatmen to prevent HIV-transmission from mother to child generated considerable controversy in 1997. Critics of the studies argued that basic principles of research ethics were violated. According to the critics, researchers subjected women in developing countries to studies that would have been unethical in the United States (and other developed countries) and that the researchers were therefore engaged in unethical exploitation ofcitizens of the developing countries in which the studies were conducted.

While the critics agreed that unethical exploitation had occurred, they differed on the exact nature of the exploitation. Some observers condemned the researchers for employing a double standard — because the researchers were applying a standard of care that would have been unacceptable in their own country. In the view of these critics, researchers should have been comparing the experimental treatment to established therapy rather than to placebo, as would have been required in the United States or other developed countries.

Over the past decade, the number of clinical trials registered with the Food and Drug Administration (FDA) has increased dramatically. The business of clinical research has become more diverse, involving academic institutions, clinician-researchers in community settings, pharmaceutical companies, and contract research organizations. This growth has been accompanied by increasing concerns about the ethical conduct of research. Much of this concern has been directed to procedural issues including institutional review board (IRB) review, data monitoring, and informed consent forms. However, the protection of human subjects cannot be achieved by relying solely on procedural safeguards. There are more nuanced issues related to recruitment and retention of subjects, and to the process of informed consent, that are generated during the interaction between study staff and subjects. It is only through an examination of these relationships that one can more fully define and understand the challenges of protecting subjects in research.

As the public profile of bioethics rises, and as litigation about issues ranging from assisted reproduction to gene therapy multiplies, the presence of bioethics experts in a litigation context has become more common. Dozens of appellate opinions refer to bioethics testimony in the lower courts. Today's technical advisory services for attorneys advertise bioethics experts along with experts in scientific fields. A single bioethicist has served as an expert in more than fifty cases. In all likelihood, opportunities for bioethicists to fill the role of testifying expert will grow as medicine and biotechnology become more complex. Bioethics experts have also been involved in several other kinds of litigation-related activities, including investigation, consultation with attorneys, preparing reports that express expert opinions, and explaining and defending these opinions by deposition.

Despite the growth of these activities by bioethicists, they have never been free of controversy, have recently been received with little enthusiasm by the judiciary, and could become highly problematic in the future.

In August 2000, Arthur Matas and his colleagues de scribed a protocol in which their institution began to accept as potential donors, individuals who came to the University of Minnesota hospital offering to donate a kidney to any patient on the waiting list. Matas and his colleagues refer to these donors as nondirected donors by which is meant that the donors are altruistic and that they give their organs to an unspecified pool of recipients with whom they have no emotional relationship. This paper represents an ethical and policy critique of the nondirected donation protocol that was implemented at the University of Minnesota in August 1999. Specifically, I address the ethical questions: Whether altruistic living solid organ donations by strangers (nondirected donations) should be permitted? And if so, What are appropriate ethical guidelines for such donations?

Lainie Ross, in her article in this issue, criticizes on ethical grounds a number of factors in the University of Minnesota program that allows unrelated strangers to donate kidneys for transplant. I have to admit that when the transplant center at the University proposed allowing the practice of what came to be called nondirected donation, I was skeptical about a number of the same issues that trouble Dr. Ross. But as my colleagues and I examined and discussed the ethics of such a plan, along with the risks to prospective donors, their possible motivations, and the logistics of performing the surgeries under conditions of anonymity between donor and recipient, among other factors, we came to believe that such donations can be ethically acceptable. As a product of frequent meetings over the course of a year in advance of the first nondirected donation, we set out to craft a process that would first and foremost meet the test of an ethical approach to organ donation and transplant, the description of which was published in the New England Journal of Medicine in August 2000.

Jeffrey Kahn and I agree that organ donation by altruistic strangers is acceptable, and that the organ procured this way ought to be allocated equitably. Our agreement in principle, however, is challenged in the details of its application. Specifically, I want to focus on three issues raised by Kahn that merit further discussion: whether relationships matter; how kidneys should be allocated; and the ethical acceptability of the expanded donor pool.

Biomedical advances of the past 20 years have stimulated a renewed interest in medical ethics. Transplantation of multiple human organs, implantation of artificial devices, advances in genetics, and stem cell research are a few of the medical procedures and discoveries that have awakened in both professionals and the public an awareness that medical discoveries often raise important ethical and societal issues. Today, members of the medical profession face issues that did not seem so pressing to their predecessors, and physician conduct in response to many of these issues involves decision-making based on ethical principles. Issues of informed consent, gifts from pharmaceutical companies, and patient rights to privacy were not of great concern to most physicians a generation ago. However, these and other topics that involve a physician's ethical conduct have become increasingly pertinent to the practice of medicine.

A renewed emphasis on ethics has been voiced by leaders in the field of medicine.