Biomedical research is currently guided by ethical standards that have evolved over many centuries. Historical and political events, social and legal considerations, and continuous medical and technological advances have led to the prevailing research ethics and practice. Currently, patients and research subjects have complete autonomy while under medical care or when volunteering as research subjects. Enrolling volunteers in human subjects research includes a detailed and meaningful informed consent process that follows the cardinal principles of ethics: autonomy, beneficence, nonmaleficence, and justice. These principles were gradually adopted after World War II, primarily in response to the unethical behavior of German physicians and scientists during the Third Reich. This review emphasizes the importance of historical milestones and the essential role that ethics has in contemporary medical research. Research protocols should achieve maximum benefits for the society, have clinical and scientific value, be subject to independent review, respect human dignity, and follow the principles of informed consent, and most importantly, subjects should have complete autonomy. However, current principles and regulations cannot cover every conceivable situation, particularly in view of the new advances in science and technology. New and evolving medical technology, genetic research, therapeutic interventions, and innovations challenge society to maintain the highest moral and ethical principles.
Highlights
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Brief historical review of the background and evolution of ethical principles in research.
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Review of the significance of the Nuremberg Trials in relation to ethics in research.
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Description of contemporary ethical principles and guidelines for the conduct of research.
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Review of ethical challenges in relation to new evolving technologies and diseases.
Introduction and historical perspectives
Medical ethics and ethical principles have been practiced and debated for centuries in the Hippocratic tradition, but ethical human research standards, protection principles, laws, regulations, and guidelines were gradually introduced and slowly adopted or updated only in the last few decades, primarily as a result of historical events and atrocities committed in the name of research. In recent years, the focus of contemporary medical research ethics has shifted to the protection of the individual patient or volunteer when enrolling as a research subject. Patients are now better informed and aware of their rights and options, especially their right of refusal. The informed consent process has evolved with an emphasis on the subject’s autonomy and choice and the adoption of protective procedures for patients who are less than fully autonomous, including the unborn fetus.
Eugenics had a significant influence on the direction of medical research. In the 1880s, Francis Galton in England coined the term “eugenics,” a so-called “scientific” concept with the aim of purportedly improving racial quality through abortions and sterilization of races deemed “less desirable”; moreover, he introduced forms of population control. He promoted procreation and medical care for the superior races and discouraged procreation and medical care for the inferior races. Eugenics was quickly adopted by many prominent academic and research institutions around the Western world. Eugenics ultimately provided a rationale for initiating and pursuing some of the most unethical human research projects ever undertaken, such as compulsory sterilization, forced abortions, involuntary euthanasia, and mass murder . In Germany, physicians and bioscientists promoted eugenic ideas for three decades before the rise of Hitler, who incorporated them into his public health policy of “applied biology.” American eugenicists, arguably the world’s leaders in eugenics, provided moral, legal, and philanthropic support to the German eugenics movement. The unethical behavior by many scientists who adopted eugenics was driven by moral and racial attitudes that promoted state over individual rights, biologic determinism, and concern over medical expenses for patients with chronic diseases and disabilities.
Eugenics medical and scientific research was by and large poorly defined and unregulated. In the US, prior to 1906, there were no regulations regarding ethics for human subjects in research, no regulatory agencies, no Food and Drug Administration, no Common Rule, and no Institutional Review Boards (IRBs). In 1906, the Pure Food and Act was passed and included the first research regulations in the US with a focus on manufacturing . Other countries permitted human research while ignoring the basic principles of ethics: autonomy, beneficence, nonmaleficence (“first, do no harm”), and justice. In addition to these principles, the benefits derived from the research intervention should significantly exceed their risks.
The concept and the process of informed consent for medical/surgical interventions or research (willing and uncoerced acceptance of medical procedures after disclosure of risks, benefits, and alternatives) was either not recognized or simply disregarded. Among the most publicized unethical research studies in the US. was the Tuskegee Syphilis Study that was initiated by the US Public Health Service in 1932. Despite the availability of effective treatment, the researchers withheld it from 400 poor African American men diagnosed with syphilis. The “research study” resulted in severe complications and many deaths. As disreputable as this research was, it pales in comparison to the unprecedented scale of unethical experiments conducted by Nazi physicians and scientists during the Third Reich. Physicians and their allied scientists during the Nazi regime totally ignored the most basic principles of ethics and were unprecedented in its scale.
Ethics, Nazi human experiments, and historical background
“Ethics became nazified, as justifying a researcher’s duty to undertake coercive research … It was not that Nazi research conducted on human subjects had no ethics, but rather that ethical formulations were shaped by distinctive Nazi priorities” .
Soon after the Nazi government came into power in 1934, they passed the Law for the Prevention of Genetically Diseased Offspring or the Sterilization Law. The Nazis found support for their involuntary sterilization law in the US and other Western countries. The first involuntary sterilization law in the world was passed in Indiana in 1907. Twenty-eight American states had involuntary sterilization laws at the time of the 1928 Buck v. Bell Supreme Court decision that declared that involuntary sterilization was constitutional and did not require informed consent . At least 12 countries had approved involuntary sterilization laws before Nazi Germany.
A substantial portion of Nazi medical research focused on racial selection with research projects in genetics, virology, and hormonal applications, with the ultimate goal of achieving racial superiority. The sick, the disabled, healthy Jews, and Roma subjects were the first experimental research victims of the opportunistic researchers at the Kaiser Wilhelm Institute in Germany (the equivalent of the US National Institutes of Health) supported by the German Research Fund. The researchers at the Kaiser Wilhelm Institute pursued eugenic research in anthropology, psychiatry, and “racial improvement” including involuntary sterilization methodology (such as surgical castration and irradiation), which were frequently lethal. One of the objectives was to maintain a sterile work force. Research subjects also included pregnant subjects and their fetuses .
Anthropologists and racial researchers developed policies and algorithms for the implementation of “racial cleansing” including euthanasia. The “researchers” hypothesized that there was a link between psychiatric conditions, “inferior races,” and brain abnormalities. An opportunistic “research” program was attached to the nationwide “euthanasia” program to harvest and study brain tissue obtained from adult and children victims .
After the outbreak of World War II, the Nazis undertook lethal military experiments to test human tolerance to extreme physiological or adverse conditions, including torture, for the benefit of the Nazi military and their agenda . Needless to mention, informed consents were never considered ( Table 1 ). In addition to the “scientists,” many medical students witnessed and participated in these experiments and chose to use the criminally obtained data for their M.D. theses, which led to their indoctrination in Nazi medicine values very early in their careers. Many of these students became indoctrinated in the Nazi medicine values very early into their careers. Published records documented 30 research projects and experiments performed on concentration camp prisoners, most of them Jewish victims, during World War II . The experiments are listed in Table 1 .
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Years later, medical ethicists and scientists questioned the scientific validity of the data obtained in such an unethical manner from these many lethal “experiments” and concluded that they should not to be used or published .
At the conclusion of the Nazi Doctors’ Trial in 1947, the justices issued The Nuremberg Code, the first international code of human subjects research ethics with a primary concern for voluntary consent . For the purpose of the trial procedures, the judges developed principles to be used in human experimentation. The Code’s 10 principles include human subjects are necessary, voluntary consent and withdrawal should be obtained, minimal research risks should be present, the research should be terminated if research subjects could or get injured or harmed, the research should benefit society, research must be based on preclinical animal studies, and most importantly, the research subjects have the right to end participation in the study.
Ironically, it has been argued that the Nuremberg Code was based upon the German Guidelines for Human Experimentation or the Berlin Code, previously drafted in 1931 but suppressed and never implemented .
Soon after the Nazi Doctors’ Trial in 1948, the Universal Declaration of Human Rights was adopted by the General Assembly of the United Nations . In 1964, the World Medical Association issued the Helsinki Declaration on Ethical Principles for Medical Research involving Human Subjects that have been updated and clarified nine times since then .
The US Congress established a milestone in human subjects research in 1974 with the National Research Act . In 1979, the Department of Health, Education, and Welfare issued the Belmont Report , which emphasized three ethical principles :
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Respect for persons: the ability to control his/her own actions and requirements to obtain informed consent.
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Beneficence: minimizing harms and risks and maximizing benefits from study participation.
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Justice: equitable distribution of benefits and risks/harms and equitable subject selection (to avoid social inequalities and disparities in subjects’ selection).
The National Research Act and the Belmont Report stimulated and directed the creation of informed consent principles and policies that remain in use today.
In 2002, the Council for International Organizations of Medical Sciences affirmed and adopted the International Ethical Guidelines for Biomedical Research , which include the following :
Ethical justification of the research , Scientific validity , Review and approval by ethics committee , Informed consent , Inducements to participate , Risks and benefits , Research in low-resource populations , Choice of control groups in clinical trials , Research including vulnerable subjects , Confidentiality , Compensation for injury as a result of research, and Ethical obligation to provide health services as needed. These guidelines are periodically updated and also modified to conform to local regulatory ethical rules. The guidelines also define the roles of sponsors, investigators, monitors, and research associates.
In 2012, 65 years after the issuance of the Nuremberg Code for research on human subjects, the German Medical Assembly issued the “Nuremberg Declaration” acknowledging the initiation by, and participation of, the scientific and medical community in Germany and Austria in the most unethical and inhumane “research experiments” on concentration camp prisoners .
Notwithstanding this belated admission after many years of unregulated and unethical research ( Table 2 ), the International Ethical Guideline for Biomedical Research of 2002 were gradually adopted and affirmed by the scientific community.
| 1796 Edward Jenner in the UK conducted smallpox vaccine experiments on his son and neighborhood children without their knowledge or understanding of risks. |
| 1932–72 Tuskegee Syphilis Study. Researchers withheld treatment from subjects. |
| 1939–45 Research by German and Austrian scientists on concentration camp prisoners and by Japanese scientists on Chinese prisoners of war. |
| 1946–47 Researchers at the University of Rochester injected uranium-234 into human subjects to study human body tolerance. |
| 1947 Nuremberg Code for Research on human subjects adopted. |
| 1940–80 The US government sponsored research on the effects of radiation on uninformed or consented human subjects (cancer patients, pregnant women, and military personnel). |
| 1950–63 The US mind control research, including the administration of LSD to unwitting subjects. |
| 1960 Patients, without informed consent, at the Jewish Chronic Hospital in Brooklyn were injected with live cancer cells by Chester Southam to investigate how human bodies “fight invasion of cancer cells.” |
| 1956–80 S. Krugman and J. Giles hepatitis experiments on mentally disabled children (Experiments approved by the New York Department of Health). |
| 1964 World Medical Association, Helsinki Declaration on Ethical Principles for Medical Research involving Human Subjects. |
| 1960–85 Policies on Humane Care and Use of Laboratory Animals. |
| 1974 Congress passes the National Research Act, federal agencies authorized to develop human research regulations. |
| 1979 The National Commission releases the Belmont Report, principles of ethical research on human subjects. |
| 1981 The US Department of Health, Education, and Welfare (now Department of Health and Human Services) conducts major revisions of the federal human research regulations on human subjects research. |
| 1989 The NIH requires that all graduate students on training grants receive education in responsible conduct of research. |
| 1990 The US launches the Human Genome Project. |
| 1991 All US government agencies, except the Environmental Protection Agency, accept one basic regulatory framework for human research known as “the Common Rule.” |
| 1993 Fertility researchers successfully clone human embryos. |
| 1994 The Clinton Administration declassifies information on radiation experiments and issues an apology. |
| 1998 Scientists perfect methods for growing human embryonic stem cells. Some countries ban the research, others promote it. |
| 1999-present: The NIH and the Office for Human Research Protections provide leadership and directions for the protection, rights, welfare, and wellbeing of human subjects involved in research conducted or supported by the US government. The directives require all individuals conducting or overseeing human research to have training in research ethics. |
| 2002 International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences and World Health Organization). |
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