1932–1972: Tuskegee Syphilis Study: This research used disadvantaged, rural black men to study the course of an untreated disease. The men were offered free examinations and medical care but were not informed of their disease, that they were participating in research, or that the research would not benefit them. Further, in order not to interrupt the project, participants were deprived of demonstrably effective treatment long after such treatment was discovered and had become generally available. (Racism and Research: The Case of Tuskegee Syphilis Study. Hastings Center Report, December 1978. p. 22-29).
1939–1945: Nazi Experiments During World War II: Prisoners in Nazi concentration camps were forced to undergo experiments that included exposing them to extreme temperatures, mutilating surgery, and lethal pathogens. The gruesome experiments that maimed and killed helpless prisoners outraged the world and resulted in criminal indictments against senior Nazi doctors, as well as calls for international regulation of medical experiments.
1944–1974: Human Radiation Experiments: The U.S. Government sponsored several thousand human radiation experiments. In the majority of cases, the experiments were conducted to advance biomedical science. Some experiments were conducted to advance national interests in defense or space exploration, and some served both biomedical and defense or space exploration purposes. Most of these studies involved radioactive tracers administered in amounts not likely to cause physical harm. However, during this period, little attention was given to issues of fairness in the selection of participants. Further, research was conducted on participants without their awareness or consent and on participants not likely to derive direct medical benefit.
1946: Nuremberg Doctors’ Trial: The individuals who conducted Nazi experiments during WWII were tried separately from other war criminals because of their professional status as physicians and the horrendous and unique nature of their crimes. They were found guilty of murder, torture, and other atrocities.
1947: Nuremberg Code: During the trial at Nuremberg, the judges codified fundamental ethical principles for the conduct of research. The Nuremberg Code set forth ten conditions to be met before research could be deemed ethically permissible. The Nuremberg Code became the first international standard for the conduct of research and introduced the modern era of protection for human research participants.
1948: The Universal Declaration of Human Rights was adopted by the United Nations. The Universal Declaration asserted the principle that each human being was entitled to certain rights and freedoms. The Declaration was inspired by atrocities committed during World War II and the conviction that human rights needed to be preserved at the international level.
1953: The Clinical Center of the NIH produced the first U.S. Federal policy for the protection of human participants. This policy provided a mechanism for prospective review of research by individuals who had no direct involvement or intellectual investment in the research. This system served as the precedent for the IRB system.
1963: Jewish Chronic Disease Hospital Study: Studies were undertaken at the Jewish Chronic Disease Hospital to develop information about the human transplant rejection process. Live cancer cells were injected into chronically ill and debilitated patients who had been told they were receiving a skin test. The patients were given information about the test, but consent was not documented or signed. The researchers were eventually prosecuted and found guilty of fraud, deceit, and unprofessional conduct.
1963: The Willowbrook Study: From 1963 to 1966, studies were carried out at Willowbrook State School, a New York institution for “mentally defective persons.” These studies were designed to gain an understanding of the natural history of infectious hepatitis and, subsequently, to test the effects of gamma globulin in preventing or ameliorating the disease. The participants, all children, were deliberately infected with the hepatitis virus. Early participants were fed the stools of infected persons. Later, subjects received injections of more-purified virus preparations. Researchers defended the deliberate injection of these children by noting that the majority would acquire the disease anyway while at Willowbrook, adding that perhaps it would be better for them to be infected under controlled research conditions. During the course of these studies, Willowbrook closed its doors to new inmates, claiming overcrowded conditions. However, the hepatitis program was able to continue to admit new patients because it occupied its own space at the institution. Thus, in some cases, parents found they were unable to admit their children to Willowbrook unless they agreed to their participation in the studies.
1964: Declaration of Helsinki: A landmark international agreement adopted by the World Medical Association recommending ethical standards in medical research. A fifth revision of the document, approved in October 2000, addresses issues raised as a result of rapid expansion of biomedical research and international research activities. The revised Declaration of Helsinki can be found on the WMA Web site, http://www.wma.net/.
1972: Exposé of Tuskegee Study: The discovery of the involvement of the U.S. Public Health Service in violating the rights of research subjects in the Tuskegee Study caused outrage among the public and the study participants. Despite the Government’s attempts to make amends to study victims and their families, reverberations from the study and public mistrust in research continue.
1974: Federal legal protection for human research participants begins. After the Tuskegee Syphilis Study was exposed, the Senate Committee on Labor and Human Resources held hearings on this study and other alleged health care abuses. The outcomes of these hearings were: 1) the enactment of the National Research Act of 1974 requiring the Department of Health, Education, and Welfare to codify its policy for the protection of human subjects into Federal regulations; and 2) the formation of the National Commission for the Protections of Human Subjects of Biomedical and Behavioral Research, which would draft the Belmont Report.
1979: Belmont Report: The National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research wrote the report entitled Ethical Principles and Guidelines for the Protection of Human Subjects of Research. This is the cornerstone document of ethical principles and Federal regulations for the protection of research participants based on respect for persons, beneficence, and justice.
1980: The Food and Drug Administration establishes regulations for clinical research. These can be found in the Code of Federal Regulations, Title 21, Part 50.
1982: CIOMS Guidelines: The Council for the International Organization of Medical Sciences (CIOMS) published the International Ethics Guidelines for Biomedical Research Involving Human Subjects (CIOMS Guidelines). These are designed to guide researchers from more technologically advanced countries in conducting research in developing countries.
1991: The Common Rule. The Federal Policy for the Protection of Human Subjects was adopted in 1991, covering research supported by the Departments of Agriculture, Energy, Commerce, HUD, Justice, Defense, Education, Veterans Affairs, Transportation, and HHS, as well as the NSF, NASA, EPA, AID, Social Security Administration, CIA, and the Consumer Product Safety Commission. The provisions are identical to DHHS Regulations (45 CFR 46, Subpart A).
1993: Human radiation experiments are revealed.
1994: President Clinton creates the Advisory Committee on Human Radiation Experiments to investigate human radiation experiments during the period 1944 to 1974; examine cases in which radiation was intentionally released into the environment for research purposes; identify ethical and scientific standards for evaluating these events; and make recommendations to ensure that past wrongdoings will not be repeated.
1995: The National Bioethics Advisory Commission (NBAC) is established to promote the protection of the rights and welfare of human participants in research, identify bioethical issues arising from research on human biology and behavior, and make recommendations to governmental entities regarding their application. The NBAC ended its term in 2001.
2000: Increased Focus on Protection of Human Research Participation. The Office of Human Research Protections (OHRP) was established within the U.S. Department of Health and Human Services. This both elevated and replaced the NIH Office for Protection From Research Risks (OPRR). The OHRP provides leadership for all 17 Federal agencies that carry out research involving humans under the Common Rule regulations. The Office focuses entirely on protection of human participants in research and supervision of Institutional Review Boards.
The Nuremberg Code
The Nuremberg Code served as the first set of principles outlining professional ethics for medical researchers. The ten points included the statement that “voluntary consent of the human subject is absolutely essential.” The Code also established that animal experimentation should precede human experimentation; all unnecessary physical and mental suffering and injury should be avoided; the degree of risk to participants should never exceed the “humanitarian importance of the problem” and should be minimized through “proper preparations”; and that participants should always be at liberty to withdraw from experiments. This set of points established the basic principles that must be observed in order to satisfy moral, ethical, and legal concepts in the conduct of human participant research. The Code has been the model for many professional and governmental codes since the 1950s and has, in effect, served as the first international standard for the conduct of research.
Declaration of Helsinki
The Declaration of Helsinki was developed by the World Medical Association for use by the medical community following dissemination of the Nuremberg Code. The Declaration considers the conduct of clinical research and makes an important distinction between therapeutic and nontherapeutic research. However, this distinction was eliminated in later versions of the Declaration. Like the Nuremberg Code, the Declaration made informed consent a central requirement for ethical research while allowing for surrogate consent when the research participant is incompetent, physically or mentally incapable of giving consent, or a minor. The Declaration also states that research with these groups should be conducted only when the research is necessary to promote the health of the population represented and when this research cannot be performed on legally competent persons. It further states that when the subject is legally incompetent but able to give assent to decisions about participation in research, assent must be obtained in addition to the consent of the legally authorized representative. Further information about the Declaration of Helsinki, in addition to translations of the Declaration into languages other than English, can be found at: http://www.wma.net/
The Declaration has been revised five times, most recently in October 2000, and includes in its 32 principles the statement that “the benefits, risks, burdens, and effectiveness of a new method should be tested against those of the best current prophylactic, diagnostic, and therapeutic methods.” Although it says that this does not exclude the use of placebo or no treatment, in studies where no proven prophylactic, diagnostic, or therapeutic method exists, this stipulation is very controversial, since some interpret it to mean that a placebo should never be used when effective therapy is available, regardless of the seriousness of the condition being studied.
The Declaration is important in the history of research ethics as the first significant effort of the medical community to regulate itself.
The Council for International Organizations of Medical Sciences (CIOMS) is an international, nongovernmental, not-for-profit organization established jointly by WHO and UNESCO in 1949.
CIOMS serves the scientific interests of the international biomedical community in general and has been active in promulgating guidelines for the ethical conduct of research, among other activities. CIOMS promulgated guidelines in 1993 entitled International Ethical Guidelines for Biomedical Research Involving Human Subjects. These 15 guidelines address issues including informed consent, standards for external review, recruitment of participants, and more. The Guidelines are general instructions and principles of ethical biomedical research. CIOMS is in the process of revising the Guidelines to address emerging issues in genetic research, commercial research, and research in developing countries. For further information about CIOMS and the Guidelines, refer to http://www.cioms.ch/
In the 1950s and 1960s, Federal funding for biomedical research increased dramatically. Along with increased interest and funding, there was heightened public concern about research abuses such as the Tuskegee Study and other reported biomedical abuses. In response to this public outcry, in 1974, Congress established the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research to make recommendations for the conduct of research involving humans. The primary task of the National Commission was to identify the ethical principles that would guide all research involving humans. In 1979, the National Commission wrote the Belmont Report, Ethical Principles and Guidelines for the Protection of Human Subjects, which serves as the cornerstone of ethical principles upon which Federal regulations for the protection of human research participants are based. The Belmont Report can be found at the following site: http://www.hhs.gov/ohrp//humansubjects/guidance/belmont.html
In 1979, the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research wrote the report entitled Ethical Principles and Guidelines for the Protection of Human Subjects of Research, commonly called the “Belmont Report.” In this report, the Commission identified and described the basic ethical principles that underlie research. The Commission considered the boundaries between biomedical and behavioral research and the accepted and routine practice of medicine in order to “know what activities ought to undergo review for the protection of human subjects of research.” The report also describes the assessment of risk/benefit criteria in the determination of appropriateness of research on participants, appropriate guidelines for this assessment, and the nature and definition of informed consent. The three fundamental ethical principles that guide the ethical conduct of research involving human participants are: 1. Respect for Persons (autonomy) 2. Beneficence 3.Justice Respect for Persons
The principle of respect for persons incorporates at least two ethical standards:
1. Individuals should be treated as autonomous agents. “An autonomous person is an individual capable of deliberation about personal goals and of acting under such deliberation. To respect autonomy is to give weight to the autonomous person’s considered opinions and choices while refraining from obstructing his or her actions ….” (Belmont Report). Prospective research participants must be given the information they need to determine whether or not to participate in a study. There should be no pressure to participate and ample time to decide. Respect for persons demands that participants enter into the research voluntarily and with adequate information. This is called informed consent.
2. Persons with diminished autonomy may need additional protections. Special provision may need to be made when comprehension is severely limited or when a class of participants is considered incapable of informed decision making (such as with children or people with severe developmental disorders or dementias). 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 activities. In some cases, respect for persons may require seeking the permission of other parties, such as a parent or legal guardian. The judgment that someone lacks autonomy should be periodically reevaluated and may vary in different situations.
Human participants are treated in an ethical manner not only by respecting their decision and protecting them from harm, but also by making efforts to secure their well-being. The principle of beneficence obligates the researcher to maximize possible benefits and minimize possible harm.
The problem posed by these imperatives is to decide when it is justifiable to seek certain benefits despite inherent harms or risks. Balancing risks and benefits is an important consideration. The goal of much research is societal benefit; however, in the interest of securing societal benefits; no individual shall be intentionally injured.
The ethical considerations of risks versus benefits leads to the question of justice. This principle requires that participants be treated fairly and involves questions such as: Who should bear the risks of research, and who should receive its benefits?
Justice is a difficult and complex ethical issue. Attempts must be made at all times in a study to distribute the risks and benefits fairly and without bias. Also, unless there is clear justification, research should not involve persons from groups that are unlikely to benefit from subsequent applications of the research. The concept of justice may be questioned when deciding who will be given an opportunity to participate, who will be excluded, and the reasons for exclusion. When making such decisions, the researcher must ask: Are some classes of persons being selected simply because of their availability, their compromised position, or their vulnerability—rather than for reasons directly related to the problem being studied?
The Statutory Framework
In addition to ethical considerations, the Federal Government mandates certain legal standards for protection of humans in research. These standards are set forth in the Code of Federal Regulations, Title 45 CFR Part 46 (see http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.html). Subpart A, the basic policy for protection of human research subjects, is referred to as the “Common Rule.” The regulations were enacted in 1991 and apply to all federally funded human research. Once a research activity is deemed human subject research, the Department of Health and Human Services requires review by Institutional Review Boards and imposition of certain standards for informed consent.
Other standards apply for research submitted to the Food and Drug Administration for review and approval. (See https://www.fda.gov and http://www.fda.gov/oc/gcp/guidance.html for information regarding good clinical practice for research studies involving human participants in FDA-regulated products.)
Federal Regulation and the “Common Rule”
By 1981, the Department of Health and Human Services and the Food and Drug Administration published regulations based on the Belmont principles, establishing rules for research involving human subjects. In 1991, 17 Federal departments and agencies agreed to harmonize their policies on protection of human participants in research and adopt a single standard. This standard policy for federally funded research is set forth in Title 45, Code of Federal Regulations, Part 46.
This policy covers research funded by the Departments of Agriculture, Energy, Commerce, HUD, Justice, Defense, Education, Veterans Affairs, Transportation, and Health and Human Services (DHHS), as well as the National Science Foundation (NSF), NASA, Environmental Protection Agency (EPA), Agency for International Development (AID), Social Security Administration, Central Intelligence Agency (CIA), and Consumer Product Safety Commission.
Subpart A of the Regulation is the DHHS Policy for the Protection of Human Research Subjects. This DHHS policy is referred to as the “Common Rule.”
Subpart B of the Regulations addresses additional protections extended to research involving fetuses, pregnant women, and human in vitro fertilization. Subpart C pertains to protection of prisoners who are participants in human subject research. Subpart D addressed protections for children who participate in research.
Food and Drug Administration Guidelines
The FDA regulates research involving products regulated by the FDA, including research and marketing permits for drugs, biological products, and medical devices for human use, etc. whether or not Federal funds are used.
The FDA guidelines for informed consent and protection of human subjects are found at: http://www.access.gpo.gov/nara/cfr/waisidx_00/21cfr50_00.html
The most notorious example in the United States of prolonged and knowing violations of the rights of a vulnerable group of research participants was the long-term study of black males conducted at Tuskegee by the United States Public Health Service. This study was initiated in the 1930s as an examination of the natural history of untreated syphilis; it continued until 1972.
More than 400 black men with syphilis participated, and about 200 men without syphilis served as controls. The men were recruited without informed consent and, in fact, were misinformed that some of the procedures done in the interest of research (e.g., spinal taps) were actually “special free treatment.”
By 1936, it was apparent that many more infected men than controls had developed complications, and 10 years later, a report of the study indicated that the death rate among those with syphilis was about twice as high as it was among the controls. In the 1940s, penicillin was found to be effective in the treatment of syphilis. The study continued, however, and the men were neither informed nor treated with the antibiotic. The first accounts of this study appeared in the national press in 1972. The resulting public outrage led to the appointment of an ad hoc advisory panel by the Department of Health, Education and Welfare to review the study and advise on how to ensure that such experiments would never again be conducted. Among the recommendations was the request that Congress establish a “permanent body with the authority to regulate, at least, all federally supported research involving human subjects.”
In acknowledgement of its responsibility, the Government continues to compensate surviving participants and the families of deceased participants.
In 1963, studies were undertaken at New York’s Jewish Chronic Disease Hospital to understand whether the body’s inability to reject cancer cells was due to cancer or debilitation. Previous studies had indicated that healthy persons reject cancer cells promptly, and the researchers allegedly believed that the debilitated patients would also reject the cancers but at a substantially slower rate when compared to healthy participants.
These studies involved the injection of foreign, live cancer cells into patients who were hospitalized with various chronic debilitating diseases. Consent had been given orally, but did not include a discussion on the injection of cancer cells, and consent was not documented. The researchers felt that documentation was unnecessary because it was customary to undertake much more dangerous medical procedures without the use of consent forms.
Further, patients were not told that they would receive cancer cells, because the researchers felt it would unnecessarily frighten them. Researchers defended this view with the assertion that they had good cause to predict that the cancer cells were going to be rejected.
In subsequent review proceedings conducted by the Board of Regents of the State University of New York, it was found that the study had not been presented to the hospital’s research committee and that the physicians responsible for the patients’ care had not been consulted. The researchers were found guilty of fraud, deceit, and unprofessional conduct.
The vulnerability of children, especially institutionalized children, as participants in research is demonstrated in a series of studies conducted from 1963 through 1966 at the Willowbrook State School, a New York institution for “mentally defective” children. In order to gain an understanding of the natural history of infectious hepatitis under controlled circumstances, newly admitted children were deliberately infected with the hepatitis virus. Researchers defended the deliberate injection of these children by pointing out that the vast majority of them would acquire the infection anyway while at Willowbrook, given the crowded and unsanitary conditions, and because only children whose parents had given consent were included.
During the course of these studies, Willowbrook closed its doors to new patients, claiming overcrowded conditions. However, the hepatitis program, because it occupied its own space at the institution, was able to continue to admit new patients. Thus, in some cases, parents found they were unable to admit their children to Willowbrook unless they agreed to their participation in the studies.
This controversial case raised important questions about the adequacy and freedom of consent, inadequate disclosure of the child’s risk of later developing chronic liver disease, and the lack of information given to parents about access to doses of gamma globulin for their children.