HISTORY 135F

Infectious and Epidemic Disease in History

Department of History
University of California, Irvine
 Instructor:    Dr. Barbara J. Becker

Week 5.  Carnalities The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects of Research (April 19, 1979) by The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research

Scientific research has produced substantial social benefits.  It has also posed some troubling ethical questions.  Public attention was drawn to these questions by reported abuses of human subjects in biomedical experiments, especially during the Second World War.  During the Nuremberg War Crime Trials, the Nuremberg Code was drafted as a set of standards for judging physicians and scientists who had conducted biomedical experiments on concentration camp prisoners.  This code became the prototype of many later codes intended to assure that research involving human subjects would be carried out in an ethical manner. [Since 1945, various codes for the proper and responsible conduct of human experimentation in medical research have been adopted by different organizations.  The best known of these codes are the Nuremberg Code of 1947, the Helsinki Declaration of 1964 (revised in 1975), and the 1971 Guidelines (codified into Federal Regulations in 1974) issued by the U.S.  Department of Health, Education, and Welfare Codes for the conduct of social and behavioral research have also been adopted, the best known being that of the American Psychological Association, published in 1973.] The codes consist of rules, some general, others specific, that guide the investigators or the reviewers of research in their work.  Such rules often are inadequate to cover complex situations; at times they come into conflict, and they are frequently difficult to interpret or apply.  Broader ethical principles will provide a basis on which specific rules may be formulated, criticized and interpreted. Three principles, or general prescriptive judgments, that are relevant to research involving human subjects are identified in this statement ... to provide an analytical framework that will guide the resolution of ethical problems arising from research involving human subjects.... A.  Boundaries Between Practice and Research It is important to distinguish between biomedical and behavioral research, on the one hand, and the practice of accepted therapy on the other, in order to know what activities ought to undergo review for the protection of human subjects of research.... For the most part, the term "practice" refers to interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success.... By contrast, the term "research" designates an activity designed to test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge (expressed, for example, in theories, principles, and statements of relationships).... Research and practice may be carried on together when research is designed to evaluate the safety and efficacy of a therapy.  This need not cause any confusion regarding whether or not the activity requires review; the general rule is that if there is any element of research in an activity, that activity should undergo review for the protection of human subjects. B.  Basic Ethical Principles The expression "basic ethical principles" refers to those general judgments that serve as a basic justification for the many particular ethical prescriptions and evaluations of human actions.... 1.  Respect for Persons.--Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.... To show lack of respect for an autonomous agent is to-- repudiate that person's considered judgments, deny an individual the freedom to act on those considered judgments, or withhold information necessary to make a considered judgment, when there are no compelling reasons to do so.... Respect for the immature and the incapacitated may require protecting them as they mature or while they are incapacitated. Some persons are in need of extensive protection, even to the point of excluding them from activities which may harm them; other persons require little protection beyond making sure they undertake activities freely and with awareness of possible adverse consequence. The extent of protection afforded should depend upon the risk of harm and the likelihood of benefit.  The judgment that any individual lacks autonomy should be periodically reevaluated and will vary in different situations. In most cases of research involving human subjects, respect for persons demands that subjects enter into the research voluntarily and with adequate information.... 2.  Beneficence.--Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being.... Two general rules have been formulated as complementary expressions of beneficent actions in this sense: (1) do not harm and (2) maximize possible benefits and minimize possible harms. The Hippocratic maxim "do no harm" has long been a fundamental principle of medical ethics.  Claude Bernard extended it to the realm of research, saying that one should not injure one person regardless of the benefits that might come to others.  However, even avoiding harm requires learning what is harmful; and, in the process of obtaining this information, persons may be exposed to risk of harm.  Further, the Hippocratic Oath requires physicians to benefit their patients "according to their best judgment."  Learning what will in fact benefit may require exposing persons to risk.  The problem posed by these imperatives is to decide when it is justifiable to seek certain benefits despite the risks involved, and when the benefits should be foregone because of the risks.... 3.  Justice.--Who ought to receive the benefits of research and bear its burdens?  This is a question of justice, in the sense of "fairness in distribution" or "what is deserved."  An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly.  Another way of conceiving the principle of justice is that equals ought to be treated equally.... It is necessary, then, to explain in what respects people should be treated equally.  There are several widely accepted formulations of just ways to distribute burdens and benefits....  These formulations are-- (1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit. Questions of justice have long been associated with social practices such as punishment, taxation and political representation.  Until recently these questions have not generally been associated with scientific research.  However, they are foreshadowed even in the earliest reflections on the ethics of research involving human subjects.  For example, during the 19th and early 20th centuries the burdens of serving as research subjects fell largely upon poor ward patients, while the benefits of improved medical care flowed primarily to private patients.  Subsequently, the exploitation of unwilling prisoners as research subjects in Nazi concentration camps was condemned as a particularly flagrant injustice.  In this country, in the 1940s, the Tuskegee syphilis study used disadvantaged, rural black men to study the untreated course of a disease that is by no means confined to that population.  These subjects were deprived of demonstrably effective treatment in order not to interrupt the project, long after such treatment became generally available. Against this historical background, it can be seen how conceptions of justice are relevant to research involving human subjects.  For example, the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied. Finally, whenever research supported by public funds leads to the development of therapeutic devices and procedures, justice demands both that these not provide advantages only to those who can afford them and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research. C.  Applications Applications of the general principles to the conduct of research leads to consideration of the following requirements:  informed consent, risk/benefit assessment, and the selection of subjects of research. 1.  Informed Consent.--Respect for persons requires that subjects, to the degree that they are capable, be given the opportunity to choose what shall or shall not happen to them.  This opportunity is provided when adequate standards for informed consent are satisfied.... INFORMATION.  Most codes of research establish specific items for disclosure intended to assure that subjects are given sufficient information about...-- the research procedure, their purposes, risks and anticipated benefits, alternative procedures (where therapy is involved), and a statement offering the subject the opportunity to ask questions and to withdraw at any time from the research.... It may be that a standard of "the reasonable volunteer" should be proposed:  the extent and nature of information should be such that persons, knowing that the procedure is neither necessary for their care nor perhaps fully understood, can decide whether they wish to participate in the furthering of knowledge.  Even when some direct benefit to them is anticipated, the subjects should understand clearly the range of risk and the voluntary nature of participation. A special problem of consent arises where informing subjects of some pertinent aspect of the research is likely to impair the validity of the research....  In all cases of research involving incomplete disclosure, such research is justified only if it is clear that-- incomplete disclosure is truly necessary to accomplish the goals of the research, there are no undisclosed risks to subjects that are more than minimal, and there is an adequate plan for debriefing subjects, when appropriate, and for dissemination of research results to them. Information about risks should never be withheld for the purpose of eliciting the cooperation of subjects, and truthful answers should always be given to direct questions about the research.... COMPREHENSION.  The manner and context in which information is conveyed is as important as the information itself.  For example, presenting information in a disorganized and rapid fashion, allowing too little time for consideration or curtailing opportunities for questioning, all may adversely affect a subject's ability to make an informed choice. Because the subject's ability to understand is a function of intelligence, rationality, maturity and language, it is necessary to adapt the presentation of the information to the subject's capacities.  Investigators are responsible for ascertaining that the subject has comprehended the information. While there is always an obligation to ascertain that the information about risk to subjects is complete and adequately comprehended, when the risks are more serious, that obligation increases.  On occasion, it may be suitable to give some oral or written tests of comprehension. Special provision may need to be made when comprehension is severely limited--for example, by conditions of immaturity or mental disability.  Each class of subjects that one might consider as incompetent (e.g., infants and young children, mentally disable patients, the terminally ill and the comatose) should be considered on its own terms. Even for these persons, however, respect requires giving them the opportunity to choose to the extent they are able, whether or not to participate in research.  The objections of these subjects to involvement should be honored, unless the research entails providing them a therapy unavailable elsewhere. Respect for persons also requires seeking the permission of other parties in order to protect the subjects from harm.  Such persons are thus respected both by acknowledging their own wishes and by the use of third parties to protect them from harm. The third parties chosen should be those who are most likely to understand the incompetent subject's situation and to act in that person's best interest.  The person authorized to act on behalf of the subject should be given an opportunity to observe the research as it proceeds in order to be able to withdraw the subject from the research, if such action appears in the subject's best interest. VOLUNTARINESS.  An agreement to participate in research constitutes a valid consent only if voluntarily given.  This element of informed consent requires conditions free of coercion and undue influence.  Coercion occurs when an overt threat of harm is intentionally presented by one person to another in order to obtain compliance.  Undue influence, by contrast, occurs through an offer of an excessive, unwarranted, inappropriate or improper reward or other overture in order to obtain compliance.  Also, inducements that would ordinarily be acceptable may become undue influences if the subject is especially vulnerable.... 2.  Assessment of Risks and Benefits.--The assessment of risks and benefits requires a careful arrayal of relevant data, including, in some cases, alternative ways of obtaining the benefits sought in the research....  For the investigator, it is a means to examine whether the proposed research is properly designed.  For a review committee, it is a method for determining whether the risks that will be presented to subjects are justified.  For prospective subjects, the assessment will assist the determination whether or not to participate. THE NATURE AND SCOPE OF RISKS AND BENEFITS.  The requirement that research be justified on the basis of a favorable risk/benefit assessment bears a close relation to the principle of beneficence, just as the moral requirement that informed consent be obtained is derived primarily from the principle of respect for persons. The term "risk" refers to a possibility that harm may occur.... The term "benefit" is used in the research context to refer to something of positive value related to health or welfare.... The SYSTEMATIC ASSESSMENT OF RISKS AND BENEFITS.  It is commonly said that benefits and risks must be "balanced" and shown to be "in a favorable ratio."... Finally, assessment of the justifiability of research should reflect at least the following considerations: Brutal or inhumane treatment of human subjects is never morally justified. Risks should be reduced to those necessary to achieve the research objective.  It should be determined whether it is in fact necessary to use human subjects at all.... When research involves significant risk of serious impairment, review committees should be extraordinarily insistent on the justification of the risk.... When vulnerable populations are involved in research, the appropriateness of involving them should itself be demonstrated.... Relevant risks and benefits must be thoroughly arrayed in documents and procedures used in the informed consent process. 3.  Selection of Subjects.--...the principle of justice gives rise to moral requirements that there be fair procedures and outcomes in the selection of research subjects. Justice is relevant to the selection of subjects of research at two levels:... Individual justice in the selection of subjects would require that researchers exhibit fairness:  thus, they should not offer potentially beneficial research only to some patients who are in their favor or select only "undesirable" persons for risky research. Social justice requires that distinction be drawn between classes of subjects that ought, and ought not, to participate in any particular kind of research, based on the ability of members of that class to bear burdens and on the appropriateness of placing further burdens on already burdened persons.... Injustice ... arises from social, racial, sexual and cultural biases institutionalized in society.... Some populations, especially institutionalized ones, are already burdened in many ways by their infirmities and environments.  When research is proposed that involves risks and does not include a therapeutic component, other less burdened classes of persons should be called upon first to accept these risks of research, except where the research is directly related to the specific conditions of the class involved.  Also, even though public funds for research may often flow in the same directions as public funds for health care, it seems unfair that populations dependent on public health care constitute a pool of preferred research subjects if more advantaged populations are likely to be the recipients of the benefits. One special instance of injustice results from the involvement of vulnerable subjects.  Certain groups, such as racial minorities, the economically disadvantaged, the very sick, and the institutionalized may continually be sought as research subjects, owing to their ready availability in settings where research is conducted.  Given their dependent status and their frequently compromised capacity for free consent, they should be protected against the danger of being involved in research solely for administrative convenience, or because they are easy to manipulate as a result of their illness or socioeconomic condition.