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Ethics, Revised Edition
Medical Research

Definition: The application of bioethical principles to investigations whose goal is generalizable knowledge rather than individualized treatment

Date: Fifth century B.C.E. to present

Type of Ethics: Bioethics

Significance: Ethical medical research attempts to ensure that human subjects understand risks, while minimizing harm to them and distributing the benefits of research equitably within the context of social morality; it also promotes the humane treatment of animals.

Medical research, like other types of scientific inquiry, seeks either to discover patterns or test proposed solutions (hypotheses) to problems. Broadly, the research entails observation and experimentation in accordance with the scientific method. Observation may be entirely passive--for example, an epidemiological study that tracks the spread of a disease through a population. Experiments depend upon intervention, that is, introducing some variable, such as a new drug or surgical procedure, in order to define that variable's effect on a disease. Whether involving animal or human subjects, research poses complex ethical problems. In the case of human subjects, both the individual subject and the physician-researcher may face dilemmas if the social benefit of increased knowledge comes at the expense of the subject's health or societal moral principles. The trend in contemporary medicine has been to limit or eliminate ethical conflicts through defined principles, governmental regulation, and oversight panels.

Every time physicians treat patients, some experimentation is involved, since however well tested a medicine or procedure may be, its use on the unique physiology of an individual patient amounts to a new test and carries some risk. In daily practice, however, physicians intend treatments to improve only the individual patient's health. By contrast, researchers hope to acquire generalized knowledge either to increase the basic understanding of the human psyche and soma or to treat all people who have a given disease. Accordingly, research has even broader social and scientific implications than does treatment.

The social implications of medical research become particularly important when such research contravenes a basic moral conviction held by the public in general or by a particular group. Beginning in the 1990's, advances in genetic engineering, stem cell research, and mammalian cloning provoked objections from diverse religious and humanitarian groups in the United States and prompted legislation by state and federal governments. To receive government funding and to protect their research from political pressures, scientists increasingly must accommodate research to extra-scientific moral issues.

History
In Western medicine, the Epidemics, traditionally attributed to Hippocrates (approximately 460-377 B.C.E.), presented the first preserved general guidelines for physicians; its dictum to help patients or at least not harm them acquired pervasive moral authority. (Similar strictures appear in early Hindu and Chinese medical treatises.) The Hippocratic method stressed that physicians should observe patients and their surroundings and assist nature in restoring their health. The method was not innately experimental in the scientific sense.

Although Hippocrates' prestige was great, many early physicians approved of experimental procedures, and so the conflict between research and preserving patients from harm began early. The third century B.C.E. Alexandrian physicians Herophilus and Erasistratus believed that understanding the body's structures must precede effective treatment of diseases. Accordingly, they practiced vivisection on condemned prisoners to study anatomy, reasoning that the pain inflicted on them could lead to knowledge that would benefit humanity in general, which to them justified the vivisection. Later classical writers often disagreed. Celsus and the Christian philosopher Tertullian, for example, considered vivisection to be murder.

During the European Middle Ages, the teachings of the second century Greek physician Galen dominated medicine. Galen taught that nature does nothing without a purpose and that the physician simply must discover that purpose. Medicine was primarily the application of the four-humors theory to specific cases, a method that was congenial to medieval Christian philosophy. Empirical experimentation was considered unnecessary and immoral.

After the Renaissance, when physicians began to abandon the humors theory and investigated the pathology of disease, biochemistry, and anatomy, the impetus to experiment grew. Little research was rigorous, and most of it involved experiments on patients, sometimes resulting in a public outcry. Such was the case in Boston during the smallpox epidemic of 1721-1722. Learning from England that small amounts of infected material stimulated immunity to the disease, Cotton Mather and Zebdeil Boylston inoculated 250 healthy Bostonians; 2 percent died, while 15 percent of plague victims died among the general population. However, the immunization experiment was decried. Not only did the procedure meddle with the workings of God, opponents claimed, but the 2 percent who died might not have contracted smallpox otherwise.

The debate over the welfare of patients and the need for validated medical knowledge began to assume its modern shape during the second half of the nineteenth century. In 1865 Claude Bernard, a French physician, published his Introduction to Experimental Medicine, a fundamentally influential treatise. In it he argued that researchers must force nature to reveal itself; since experimental trials and procedures, including vivisection, are the surest means to produce verifiable knowledge, the physician has a duty to employ them. He added, however, that all research must benefit the test subjects. Those experiments that do only harm must be forbidden.

Bernard's book appeared as an antivivisection movement was spreading, intent upon exposing the cruelty of medical experiments on both animals and humans. Antivivisectionists criticized researchers for looking upon research subjects as objects rather than living, individual beings and for using subjects for the researchers' own ambitions with careless disregard of the pain and injury they may inflict. Such attitudes, according to the argument, are immoral because they conflict with the Christian principle of benevolence and the physicians' Hippocratic oath.

Efforts to codify ethical principles increased following World War II, mainly in reaction to grisly experiments performed in concentration camps by Nazi doctors. The Nuremberg Code (1947-1948) sought to prohibit experiments upon humans against their will or when death is the likely outcome; most subsequent codes were modeled upon it. The World Medical Association's Declaration of Helsinki (1964; revised 1975) suggested methods of protecting human subjects and urged researchers to respect animals' welfare and be cautious about the effect of experiments on the environment. In the United States, various federal agencies published regulations for experiments financed by public funds, especially the Food and Drug Administration (1981) and the Department of Health and Human Services (1983), which required that institutional review boards (IRBs) approve research proposals before projects begin and monitor their execution.

In 1978, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research released The Belmont Report, which proposed broad ethical principles to guide researchers in designing ethical studies. While widely influential, this brief document provided only a framework. Upon researchers and IRBs falls the task of interpreting and applying the principles to resolve ethical problems, sometimes in unprecedented contexts. For example, subsequent epidemics, such as acquired immunodeficiency syndrome (AIDS), challenged the ethics of clinical trials and research funding and raised concerns about public safety.

By 2000, IRBs in their traditional form were increasingly considered inadequate to handle ethical problems. With an estimated two million to twenty million people enrolled in clinical research projects, sometimes tens of thousands in a single drug trial, the case load for monitoring experiments threatened to be overwhelming. Additionally, the complexity of modern experiments and the potential effects on test subjects require understanding a broad range of research protocols and extensive scientific and technical expertise, difficult requirements for many local review boards to meet. At the same time, there was a trend for researchers or their academic institutions to seek profits in the research outcome, especially in patenting and licensing the applications of therapeutic innovations produced by genetic engineering. For these reasons, the Institute of Medicine recommended that IRBs be reconstituted to enhance protection of subjects, rigorously to exclude potential conflicts of interest, and to increase training in the ethics of human studies for board members and researchers.

Furthermore, although some government agencies regulate animal experiments, animal rights advocates condemn tests that harm animals for the benefit of humans, and groups such as the People for the Ethical Treatment of Animals (PETA) have sought legislative and judicial intervention to restrict the practice.

Ethical Principles
The Belmont Report draws from assumptions about equity and autonomy that are common in modern cultures: Each human is to be treated as an individual, rather than as a component of a group; no individual is inherently superior; and no individual can be used primarily as the means to an end. The report's three prima facie principles--respect for persons, beneficence, and justice--assert these values' primacy when they conflict with the central value of scientific research, the acquisition of knowledge.

Respect for persons, also called autonomy, rests upon ensuring the self-determination of research subjects. Prospective subjects must not be enrolled in a study through coercion or deceit. Investigators must explain the nature of their study and its potential to harm subjects; then the subjects' formal, written consent must be obtained. For those subjects incapable of informed consent, such as children, the mentally impaired, and the brain dead, responsible guardians must consent to the enrollment. During the course of a study, researchers must protect the well-being and rights of subjects and permit them to end their participation at any time. In effect, researchers are to treat subjects as partners and collaborators, not as objects.

Beneficence obligates researchers to design a study protocol (the plans and rules for a study) so that the risk of harm to subjects is minimized and the potentiality for benefits is maximized. (Some ethicists divide this principle into beneficence, which assures the well-being of subjects, and nonmaleficence, which requires avoidance of harm. The division, they argue, reduces confusion and emphasizes the tenet in the Hippocratic oath against harming patients.) The Department of Health and Human Services has defined minimal risk as the risk one runs in daily life or during routine physical or psychological tests. Beneficence entails a dual perspective: Not only should each subject expect benefits to health to be greater than harms, but there should also be a reasonable expectation that the study's findings will benefit society.

Because research risks the health of a few subjects, even if volunteers, in order to improve medicine for everyone, an innate inequity exists. The principle of justice seeks to moderate this inequity. No class of people, as defined by poverty, race, nationality, mentality, or condition of health, is to be exploited as research subjects so that they assume a disproportionate burden. The subjects are to be treated fairly; that is, their general human rights must be guarded. The benefits of research must be distributed equally among all groups in the society.

Ethical Norms
Six norms, or standards, are widely used to verify that a study adheres to the principles of respect for persons, beneficence, and justice.

First, the design of the study should be rigorously defined and based upon the null hypothesis (also called equipoise). The null hypothesis assumes that none of the treatments involved in a study is known to be superior when the study begins; likewise, if a placebo (inert drug or innocuous procedure) is used, there must be no persuasive evidence beforehand that the treatment is superior to the placebo. This norm protects subjects, especially those with disease, from receiving treatments known to be inferior, and it helps physician-researchers overcome their central dilemma in medical research: withholding the best available treatment in order to test new treatments. Thereby, good research design supports respect for persons and beneficence.

Second, researchers must be competent, possessing adequate scientific knowledge and skill to conduct the study and to give subjects proper medical care. This norm also supports respect for persons and beneficence.

Third, the study should either balance possible benefits with harms or expect more benefits. Furthermore, if in the course of the study one treatment proves to be superior to another or to the placebo, researchers must terminate or modify the study so that all its subjects receive the better treatment. This norm incorporates all three ethical principles.

Fourth, researchers must obtain documented informed consent from each subject before a study begins, which assures respect for persons.

Fifth, to affirm the justice of a study, the selection of subjects must be equitable, drawing at random from the eligible population.

Sixth, again for the sake of justice, researchers should compensate subjects for any injuries incurred because of a study.

Ethical Issues
The most common form of medical research is the three-phase clinical trial, which usually tests new drugs. To eliminate possible biases toward the data and to provide equal treatment of subjects, researchers may incorporate one or more of the following four techniques. First, randomization assigns subjects by a lottery system, rather than on the basis of health, group affiliation, or economic condition. Second, one group of subjects receives the treatment under study, while a second, the control group, receives a placebo. When the first group reacts favorably to the treatment and there is no change to the control group, the researchers can conclude that the treatment causes the reaction, and it is not just an accident. Third, studies are blinded, which means that either the researchers, the subjects, or both (double-blinded) do not have access to documents recording which subjects are receiving treatment and which placebos. Fourth, the groups can exchange roles (crossover); that is, the first group changes from treatment to placebo and the second group from placebo to treatment. A study employing all these techniques is usually called a randomized, double-blinded, placebo-controlled clinical trial with crossover.

Ethical issues trouble every step of such studies. For example, government regulation requires that a new drug be tested on animals before humans try it, and animal rights advocates have long denounced this procedure as cruel and exploitative. A phase I study determines the toxicity, side effects, and safe dosage of a drug on a small group of people in good health. Since an experimental drug can confer no health benefit on these "normals," the study lacks beneficence; however, the trend has been to conduct phase I tests on subjects who have a disease for which a drug or procedure is a potential treatment, which obviates the ethical objection.

Phase II studies are controlled clinical trials on a small number of patients to determine whether a drug has a beneficial effect and is safe. Phase III trials, either with or without a control group, compare the effect of the new treatment with that of the standard treatment on a large group of subjects, while defining the medicinal properties and adverse effects as precisely as possible. When patients in a clinical trial are desperately ill, they may grasp at any new treatment with hope, so the use of randomization, blinded dispensation of treatment, and placebos can seem a deprivation of well-being. Such was the case in the 1980's when azidothymidine (AZT) was tested on subjects carrying the human immunodeficiency virus (HIV) associated with AIDS; the phase I trial showed clinical improvements in some patients. Federal regulations called for a placebo-controlled phase II follow-up, yet scientists were sharply divided over the morality of withholding AZT from HIV-infected persons, because AIDS, once fully developed, was then thought to be universally fatal. A controlled study would be selective and would involve rationing of the drug, which they argued was unjust. Other scientists contended that only a thorough, controlled study could determine whether AZT had side effects more debilitating than the disease itself, and therefore the beneficence of the experimental treatment would remain in doubt.

When federal regulations made AZT the control drug for all further studies, concerns about confidentiality were raised. By selecting subjects for AIDS-related trials, researchers exposed the fact that these subjects were infected, and many subjects worried that they would face discrimination. Furthermore, the large amount of public funds devoted to AIDS research in the late 1980's brought complaints from scientists that other projects were left underfunded as a consequence. Some of these issues apply to studies of other widespread, deadly diseases, such as cancer and heart disease.

Ethical issues literally arise before subjects' births and continue after their deaths. For example, using the bodies of the brain-dead persons, even if legal wills explicitly grant permission, is potentially unethical if the family members object. Some right-to-life advocates, whose convictions demand that all human life is sacred, object to the use of fetuses or fetal tissue in research. Their beliefs come into direct conflict with stem cell research, one of the most promising lines of investigation at the beginning of the twenty-first century. Stem cells possess the capacity to self-renew and to differentiate into more than one type of cell. There are differing types of stems cells with disparate capacities, but the best for research and therapy are those human stem cells with the ability to become all types of cells, called pluripotent stem cells. They are harvested only from the embryo in an early stage of development. Such cells can be cultured indefinitely and hold great promise in testing pharmaceutical products, regenerating damaged organs, treating cancer, and investigating birth defects and fertility problems.

Because many religions accord full human status to embryos, harvesting embryonic cells following abortion is judged abhorrent, and the abortion itself is regarded as murder. Even the use of excess embryos from in vitro fertilization raises troubling questions about the moral and legal status of the human embryo to many observers. In 2001 President George W. Bush ordered that federal funding be restricted to embryonic stem cell research involving the cells lines already developed from sixty-four embryos.

Research into transgenic organ transplantation, genetic engineering and the possibility of cloning humans raise even more basic ethical and moral questions that does embryonic stem cell research. By altering a basic natural process in some way, each challenges the nature of human identity and uniqueness. For example, scientists succeeded in introducing specially designed fragments of DNA into patients to treat genetic disorders. Transplanting a baboon's heart into a human baby can keep the child alive until a human organ can be found. Thus, cloning--making copies of embryos--promises to help elucidate basic cellular processes, simplify the testing of pharmaceuticals, create rejuvenation therapy, and provide treatments for infertility, genetic syndromes, and cancer.

Few dispute the potential benefits of such modern technologies. However, theologians, ethicists, and some scientists object to them for three basic reasons. The first is often characterized as the "playing god" accusation. Some religions find that the genetic engineering of novel DNA and cloning (should it occur) are impious human attempts to replace the natural processes created by God and accordingly efface the complicated natural chain of events that makes each human unique. Scientists similarly worry that human-manufactured novelties, untested by the slow process of evolution through natural selection, may introduce counterproductive, even deadly, features into the human genome and accidentally eliminate some that are needed. The second objection comes from a general unease concerning the misuses of technology. The therapeutic effects, the argument runs, are admirable, but the power to intervene could escalate little by little into the power to dominate and change, a form of "technotyranny." So, genetic engineering and cloning, critics contend, might eventual produce designer children, eliminate politically unpopular traits, end diversity, and even create a new subspecies of Homo sapiens. This argument is sometimes called the "slippery slope" thesis. The third objection concerns matters of choice and justice. If it is possible to eliminate or replace human traits, who should decide which traits and on what basis? Moreover, since the technology involved is very expensive, there is the risk it will remain available only to limited number of privileged persons. Although transgenic transplantation and genetic engineering weathered such critics for the most part, cloning research did not. By 2003, the United States, Great Britain, and many other countries considered partial or outright bans on human cloning.

Purely observational research may also be unethical when it withholds treatment and allows a disease to progress. For example, the Tuskegee Syphilis Study (1932--1972), designed to define the natural history of syphilis, illustrates harm by omission. The study followed four hundred black men with syphilis and about two hundred without it to determine the occurrence of untreated symptoms and mortality. The study continued even after penicillin, an effective treatment, became available during the late 1940's.

Regulation
Scientists applying for public funding and pharmaceutical companies seeking FDA approval of a new drug must comply with federal regulations, many of which are designed to satisfy the ethical principles enunciated in The Belmont Report. The initial responsibility for compliance belongs to IRBs, which act on behalf of their parent institutions (mainly hospitals and universities), not as agents of the government. Composition of IRBs varies, but all must have doctors and scientists capable of reviewing the scientific merit of a proposed study; clergy, nurses, administrators, ethicists, and members of the public may also participate to safeguard the rights, well-being, and privacy of subjects. Even institutions that do not rely on public funds routinely convene IRBs to review research proposals.

Since federal agencies lack the resources to scrutinize every research project, medical research is largely self-regulated from a project's beginning, through IRBs, to its final product: publication. Medical journal standards call for editors to reject articles written by researchers who have not adhered to The Belmont Report's principles, although some editors do publish such articles but follow them with editorials calling attention to ethical problems.

In the United States, the courts have also begun to provide ad hoc review of medical research as a result of litigation. Both individual and class-action civil suits seek redress, usually monetary awards, for injury sustained in research, but there have also been allegations of fraud or deception, which can involve punitive judgments as well. Researchers, institutions, and IRBs have been named as plaintiffs. As a result, research designers and IRBs must anticipate possible legal liabilities as part of their analysis of ethical issues.

Roger Smith

Bibliography
Beauchamp, Tom L., and James F. Childress. Principles of Biomedical Ethics. 5th ed. New York: Oxford University Press, 2001. General philosophical treatment of medical ethics, of which research ethics forms an appreciable part, and one of the most frequently cited investigations of the subject. Attempts to educe the ethical theory that best serves American health care.

Cohen, Carl. "The Case for the Use of Animals in Biomedical Research." New England Journal of Medicine 315 (October 2, 1986): 865-870. Argues that animal experimentation reduces risks to human subjects while accumulating much knowledge that is beneficial to human and veterinary medicine; urges also that animals be used humanely. While sympathetic to research, Cohen provides a good introduction to the animal rights controversy.

Espejo, Roman, ed. Biomedical Ethics: Opposing Viewpoints. Farmington Hills, Miss.: Greenhaven Press, 2003. The book offers reprinted articles that debate the ethics of human cloning, organ donations, reproductive technologies, and genetic research. It is well suited for readers unfamiliar with medical or bioethical terminology.

Holland, Suzanne, Karen Lebacqz, and Laurie Zoloth, eds. The Human Embryonic Stem Cell Debate: Science, Ethics, and Public Policy. Cambridge, Mass.: MIT Press, 2001. The reprinted and original articles in this collection provide sophisticated considerations of stem cell research in four parts. The first explains the science and its potential benefits to medicine. The second summarizes basic ethic issues. The third offers secular and religious perspectives on the controversy. The fourth discusses the role of public policy in the research. With a helpful glossary.

Kass, Leon R., ed. Human Cloning and Human Dignity: The Report of the President's Council on Bioethics. New York: Public Affairs, 2002. The President's Council on Bioethics provides this committee-generated report as an introduction to the moral significance of cloning and the ethical and policy questions raised by it in order to clarify its recommendations to President George W. Bush. It also supplies an explanation and history of cloning and a glossary.

Levine, Robert J. Ethics and Regulation of Clinical Research. 2d ed. Baltimore: Urban & Schwarzenberg, 1986. Levine, a consultant to the National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research, interprets and expands upon the principals enunciated in The Belmont Report, drawing also upon such documents as the Nuremberg Code and the Declaration of Helsinki. A valuable, thorough discussion of specific issues as well as theory.

National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Belmont Report. Washington, D.C.: Government Printing Office, 1978. Brief document that has widely influenced research ethics in the United States. Far from exhaustive, it nevertheless describes the basic principles that underlie most subsequent discussions.

See Also
American Medical Association; Animal research; Bioethics; Biotechnology; Experimentation, ethics of; Genetic engineering; Genetic testing; Medical Bills of Rights; Medical ethics; Nazi science; "Playing God"; Science, ethics of; Stem cell research.