International Catholic University
The topic of this lecture is the ethics of research involving human subjects. Research is an important component for the advancement of science and for the advancement of medicine. The press to do research arises out of the eros -- the drive -- to know and the press to advance medicine arises out of the desire to heal. The drive to know and the desire to heal are to be acknowledged as gifts of God so that human beings, who are created in God's image and likeness, may exercise creative stewardship, in the created world. Both the desire to know and the drive to heal are to be appropriately directed to human flourishing as the proper end of each. The means to accomplish the end must also be instances of human flourishing. Hence, research, which requires the participation of human subjects, must respect the dignity of the human subject -- a dignity which has its source in the fact that human beings have been created in the image and likeness of God and in the acknowledgement that human beings are ends in themselves.
This lecture will address the issue of research ethics involving human subjects (1) by indicating the sources of danger inherent in research projects, (2) by citing two concrete historical instances of abuse, (3) by presenting some of the efforts to provide guidelines for researchers, (4) by examining an example of the ongoing efforts in the United States to guide and regulate research, and (5) by reflecting on the underlying principles operative in ongoing medical research in order to present some conclusions.
The acknowledgment of the good of the advancement of science and the good of the advancement of medicine does not mean that the pursuit of these goods is unproblematic. A significant problem is present in the tendency of scientists and physician scientists to press and to defend their research as a value-free pursuit -- a pure pursuit of knowledge without the presence of any bias. The study of the history of research involving human subjects, however, reveals that the value-free claim cannot stand and that there have been instances of egregious abuses of human subjects. It has often enough been the case that the research imperative and the healing imperative are so strong that they drive the scientist researcher and the physician researcher past the appropriate limits of research and it is often the case that the cultural bias under which the researcher operates is so distorted that evil rather than good is the result. This lecture will present some examples of the abuse of human subjects in research. The examples will be drawn from the United States and from Nazi Germany. It will then present the efforts to regulate the work of the scientific and research communities through the creation of codes to inform and guide their practices.
The first example of research abuse to be examined, because it appears chronologically earlier than the Nazi research projects, is the Tuskegee Syphilis Study. The syphilis study was begun in 1932 as a project of the United States Public Health Service. It is important to note that at the time the study was begun the United States . . . and the rest of the world as well . . . had articulated no formal position on human experimentation. The scientific purpose of the project was to study the natural course of syphilis in its progression from onset of symptoms through latency to death in black males. The social purpose of the study was to observe how the disease affected the lives of the men. The site of the study was Macon County, Alabama. There were six hundred men involved initially in the study. Four hundred of the men had been diagnosed with syphilis; the other two hundred men were uninfected and they were to serve as controls. The men who were involved in the research were not informed that they were participants in a research project. They were told that they were ill and that the public health services would give them care and that the public health services would even provide for their funeral expenses. They were, as a matter of fact, given no effective medication. In 1936, the first results of the study were published. Publication of the results of the study continued regularly ever four -- six years through the sixties. In 1969, the Center for Disease Control, through one of its committees, made the decision to continue the studies. And the experimental study continued until 1972 when the national press published accounts of the study. Only then, in the midst of a public outcry, did the Department of Health Education and Welfare order the experiment halted.
There are two significant occurrences in the forty years from the commencement of the study until it was stopped. One is the discovery of the effectiveness of penicillin in the treatment of syphilis and its ready availability after World War II. The other is the framing and publication of the Nuremberg Code in 1946 at the trial of physicians. The American Justice, Robert H. Jackson, who presided over the military tribunal, prepared the Nuremberg Code. Two American physicians, Dr. Andrew Ivy and Dr. Leo Alexander, assisted in the preparation of the Code. (Although there is some disagreement between the two physicians regarding the role of each in the drafting of the code, there is enough independent corroborating evidence to show that each made a significant contribution.) In the immediate wake of the trial, the House of Delegates of the American Medical Association formally approved and adopted the principles of the Nuremberg Code. And in 1953, when the National Institutes of Health opened the Institute's clinic, it put into place a policy requiring the voluntary agreement, based on informed understanding, for all its research subjects.
Neither the discovery of penicillin nor the articulation of principles of the Nuremberg Code nor the adoption of the principles of the Code by various regulating bodies in medicine and science was sufficient to stop the experiment and to treat the infected men. The men in the Tuskegee Study were denied, in an explicit decision, penicillin; the application of the principles of the Code never became an issue. The cultural bias, which was fed by social Darwinism, supported by anthropologists, ethnologists, and biologists, viewed the American Negro as a primitive race doomed to disease, vice, crime, and inevitable early extinction. This assessment combined with the research imperative to press for the completion of the study which required post-mortem examination.
The research efforts in Nazi Germany have been chronicled since the end of World War II. The accounting of the violations of human dignity in research and medical research appeared as early as 1949 with the publication by Dr. Leo Alexander of his observations of the Nuremberg Trial of Physicians. His paper, Medical Science under Dictatorship, appeared in the prestigious New England Journal of Medicine. A more recent and more expansive account by Robert Jay Lifton appears in his book, The Nazi Doctors: Medical Killing and the Psychology of Genocide, which was published in 1986. While the mass extermination projects that were executed by the Nazi between 1939 and 1945 are comparatively well known, less well known are the research projects undertaken for the advancement of science and the advancement of medicine. The following are two examples of the research imperative. Dr. Julius Hallervorden, renowned German neuropathologist, who was engaged in the study of diseases of the brain, was the glad recipient of materials -- the brains of those who had been killed in the camps -- for the advancement of his studies. He reported to Dr. Alexander that "There was wonderful material among those brains, beautiful mental defectives, malformations and early infantile diseases. I accepted those brains of course. Where they came from and how they came to me was really none of my business" (A, 40). Dr. August Hirt, professor of anatomy at the University of Strassburg, enlisted the help of the camp officials in the procurement of specimens for the development of a collection of skeletons. He preserved them and used them in his anthropological work.
The medical therapeutic imperative in the Nazi era was tied to the risks encountered by the military and efforts to ameliorate those harms. Two examples will suffice. In attempts to develop coagulants to stem hemorrhage on the battlefield, experimental coagulants were tested on live and conscious prisoners whose limbs were amputated in order to measure differences in coagulation time. The concern for the risk of shock from exposure to the cold by pilots who suffered immersion in the North Sea, prompted a team of physicians headed by Dr. Sigmund Rascher to subject prisoners to exposure to brutal cold, sometimes in ice vats, in order to measure the effects of the cold.
In reaction to the atrocities revealed at the Nuremberg Trial, The Nuremberg Code was developed. The Code lists ten principles to guide research involving human subjects. The most important elements in the Code are the following. The Code requires the voluntary consent of the research subject. The Code explicitly defines what it means by voluntary consent. It says, "the person involved should have legal capacity to give consent; should be so situated as to be able to exercise free power of choice, without the intervention of any element of force, fraud, deceit, duress, overreaching, or other ulterior form of constraint or coercion; and should have sufficient knowledge and comprehension of the elements of the subject matter involved as to enable him to make an understanding and enlightened decision" (Code, Article 1). The three elements of informed consent -- freedom, voluntariness, and knowledge -- are present here. Among the other significant components of the Code are that it is the duty of the researcher to make certain that the appropriate consent is in place and, furthermore, it is not a duty that the researcher may delegate to anyone else (ibid.). The research is required to have as its goal "fruitful results for the good of society, unprocurable by other methods or means of study" (Code, Article 2). The research must be necessary and it cannot be random in its design. The design of the research, in order to increase the probability of useful results and in order to protect human subjects, requires that it be "based on the results of animal studies and a knowledge of the natural history of the disease or other problem under study" (Code, Article 3). A most important ratio of degree of harm to degree of knowledge of the research subject is found in the requirement that, "No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects" (Code, Article 5). And if the continuation of the experiment is likely to bring harm to the research subject, the experiment must be terminated (Code, Article 10).
The Nuremberg Code is not law and does not have the power of law. Nonetheless, it exercises powerful influence as an ideal. The limitations of the Nuremberg Code became evident to the scientific and medical research community. There is no distinction between research for the sake of the advancement of knowledge and medical research combined with medical care, that is, research to advance therapy for a patient. The Nuremberg Code attends the researcher-subject relationship, but not the physician-patient relationship. In 1964, the World Medical Association published The Declaration of Helsinki to provide the needed expansion. Of particular interest in the Declaration is its affirmation of the good of the individual over the interests of society in research. The Declaration says, "In medical research on human subjects, considerations related to the well-being of the human subject should take precedence over the interests of science and society" (Article 5). The Declaration is particularly sensitive to vulnerable populations and lists some of those for whom special care should be taken in any research situation. Among the vulnerable populations are "the economically and medically disadvantaged" . . . those who are incapable of consent, those whose consent may be the result of duress, . . . "those who will not benefit personally from the research, and . . . those for whom research is combined with care" (Article 8). The Declaration moves away from the strict informed consent requirements of The Nuremberg Code. It allows the participation or use of research subjects who are incapable of informed consent, such as those who are legally incompetent, whether physically or mentally, and legally incompetent minors. The Declaration substitutes for the informed consent of the participants, the informed consent of the legal representative of the incompetent, with the added limitation that the "research . . . [must be] . . . necessary to promote the health of the population represented and this research cannot be performed on legally competent persons" (Article 24). Another significant development is the addition of an assent requirement on the part of children and other incompetent persons for participation in any research project. The assent requirement carries with it an appropriate understanding and an expressed willingness that does not reach the high standard of informed consent (Article 25). Assent is understood to be an active agreement which takes into account the experience and level of understanding of the legally incompetent person. In articulating the principles for medical research combined with medical care, the Declaration begins with the requirement that the protocol have potential value -- therapeutic or diagnostic or prophylactic -- for the patient (Article 28) and then progresses to the permissibility, within the scope of the other relevant guidelines, for the use of new and unproven procedures for patients for whom proven procedures are ineffective (32).
To return to the United States and its efforts to guide research: in 1973, after the public outcry to the revelation of the Tuskegee Study, the United States Department of Health, Education and Welfare (now the United States Department of Health and Human Services) proposed its first set of regulations to protect human subjects in behavioral and biomedical research. These guidelines were published in May of 1974 as the Code of Federal Regulations, Title 45 Public Welfare and Part 46 Protection of Human Subjects (45 CFR 46). In 1979, the Belmont Report was published. The Belmont Report sets out an ethical framework as the basis for regulation. The framework lists as important principles: respect for persons, beneficence and non-maleficence, and distributive justice. It provides guidelines for informed consent, assessment of risks and benefits, and the selection of subjects. In 1983, the Code of Federal Regulations specifically addressed the issue of research with children and added a section to protect the interests of children.
The progression of science and medicine combined with the need for testing the products of its research, and the occasional revelation of yet more abuses and missteps, requires regular oversight of research by regulatory agencies and refinement of the principles and regulations. (Of course no set of regulations are needed for the reputable responsible scientist and no set of regulations are sufficient for the unscrupulous scientist.) The Council for International Organizations of Medical Science (CIOMS) has taken up the task of speaking for and to the international community. The progression in its documents may be seen in the development of guidelines for research involving subjects in underdeveloped communities and countries. In the United States, the Department of Health and Human Services under the direction of its secretary has the responsibility for the maintenance and development of its regulations. The power of the DHHS derives mainly from the funding it provides or refuses.
The consideration of the current set of regulations in the Code of Federal Regulations for research projects that involve children is illustrative of the advances since The Nuremberg Code. There are four guidelines, §46.404, §46.405, §46.406, and §46.407, which require, as the research progresses from decreasing benefit to the child, an increasing degree of regulation. Regulation 404 addresses research not involving greater than minimal risk to the patient and a direct benefit to the patient. Regulation 405 addresses research involving greater than minimal risk to the patient and a direct benefit to the patient. Regulation 406 addresses research that is likely to yield generalizable knowledge about the patient's condition or disorder, but does not directly benefit the patient. Regulation 407 addresses research "not otherwise approvable which presents an opportunity to understand, prevent or alleviate a serious problem affecting the health or welfare of children." Regulations 404 and 405 are considered therapeutic research because there is direct benefit to the child with, respectively, either minimal risk or a favorable benefit/risk ratio; regulations 406 and 407 are considered non-therapeutic because, while they offer the possibility of an increase in knowledge or an increase in the understanding of disease, they offer no direct benefit to the child. To be in compliance with the federal code, all four types of research require review and approval by the institutional review board and all four require the assent of the child and the consent of a parent. Regulation 406 and 407 require consent by both parents if two parents are available. Regulation 407 requires approval by the Secretary of the Department of Health and Human Services who is required to consult with a panel of representative experts and who is required, furthermore, to provide the opportunity for public review. In addition, regulation 407 requires that the research be in accord with sound ethical principles.
The participation of human beings in research that benefits either themselves or others or that advances knowledge or understanding of human development or human illness is a morally permissible good, provided that respect for human dignity and respect for the gift of life are maintained. Participation in research that benefits oneself is in accord with the Natural Law precept to preserve human life. Participation in research which benefits others is a sign of one's membership in the human community and a sign of one's solidarity with that community. Participation in research which advances knowledge is in itself a contribution to the progression of science. Participation in research is justified but limited by the application of the principle of totality, which allows the use of the part for the good of the whole. The principle requires the distinction between a physical organism and a moral organism with a consequent limitation on activities. The individual person may consent to participate in research which serves to benefit the personal life even to the degree that the research may require the use of a part -- or if the part is diseased the destruction of the part -- that is not required for the good of the whole person. The individual person may participate in research which benefits the community, but only to a limited degree, that is the relationship of the person to the community as part to whole is limited to the use of the activities, not the use of the life, of the person. Respect for human dignity requires careful attendance to the provisions for informed consent. The greater the risks attendant on the research and the more diminished the benefits for the patient subject, the more stringent are the requirements for informed consent -- knowledge, voluntariness, and freedom. There is of course a limit which cannot be traversed. The following minimal conclusions are: (1) under no circumstance may the life of a human being be sacrificed for the good of research and (2) under no circumstance may research be carried out on any human subject without the assent and consent provisions in place.