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生命倫理学の歴史と原則、そしてルール作りへ／The History and Principles of Bioethics, and the Development of Its Rules_HSR [TEXT]
English Modules
Drafted date: 2016.3.31
Last update: 2016.6.22
Last update: 2016.6.22
The History and Principles of
Bioethics, and the Development of Its Rules
Bioethics, and the Development of Its Rules
< Material provided by >
APRIN, Association for the Promotion of Research Integrity
APRIN, Association for the Promotion of Research Integrity
Contents
- Introduction
- Why Ethics is Important
- The Definition of “Benefit”
- The Definition of “Risk”
- Weighing Potential Benefits and Risks
- The History of Human Subjects Research and the Dawn of Research Ethics
- Human Subjects Research in the 18th and 19th Centuries
- Human Subjects Research and the Establishment of Research Ethics in the 20th Century
- Ethical Standards for Research That Guide Us Today
- The Distinction between Medical Care and Research
- The Three Principles of the Belmont Report
- Ethics and Regulations of Human Subjects Research
- Other Considerations
- Recent Developments in Japan and the Creation of Rules
- Ethically Questionable Studies
- The Development of Ethical Guidelines by Japanese Administrative Authorities
The History and Principles of Bioethics, and the Development of Its Rules
Introduction
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“It is not cruel to inflict on a few criminals sufferings which may benefit multitudes of innocent people through all centuries,” said the 1st century physician Celsus 
as he justified experiments on condemned criminals in Egypt. This wording became a classic defense for hazardous experiments carried out on humans.
Both the ethics and regulations regarding human subjects research have changed considerably since Celsus’s time. In this module, you will learn how basic principles of research ethics were created and have evolved, and the impact these changes have had on research involving human subjects (hereinafter, “Human Subjects Research”).
Learning Objectives in this section are for the reader to be able to:
as he justified experiments on condemned criminals in Egypt. This wording became a classic defense for hazardous experiments carried out on humans. Both the ethics and regulations regarding human subjects research have changed considerably since Celsus’s time. In this module, you will learn how basic principles of research ethics were created and have evolved, and the impact these changes have had on research involving human subjects (hereinafter, “Human Subjects Research”).
Learning Objectives in this section are for the reader to be able to:
- Discuss why ethical considerations are necessary when conducting Human Subjects Research.
- Describe the major historical events that have influenced the ethics of conducting Human Subjects Research.
- Identify problems with past studies that have violated ethical standards.
- Describe the Belmont Principles.
- Discuss the ethical standards for research that guide practices today.
The History and Principles of Bioethics, and the Development of Its Rules
Why Ethics is Important
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This module will discuss normative ethics. Questions concerning normative ethics include:
- What should morality require?
- What is morally required?
- How should researchers behave?
- How should researchers not behave? What should researchers avoid doing?
- What character traits should researchers cultivate as virtues?
- And, what character traits should researchers try to shun? What character traits are detrimental in research?
- It provides us with a structure for analysis and decisionmaking that enables us to evaluate whether the ongoing research is carried out appropriately from an ethical point of view and to determine an appropriate method.
- It reminds us of the importance of protecting human subjects in Human Subjects Research and encourages us to act accordingly.
- It provides guidelines for evaluating and weighing the benefits and risks of our studies.
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The Definition of “Benefit”
A “benefit” of a research study is the positive value or advantage generated by the study. It might be a concrete benefit for an individual subject, such as a significantly increased chance of having a good therapeutic outcome. It might be more general, such as a social benefit brought about by an outcome of medical research. For example, studies designed to test a new drug on humans (such as clinical trials) might provide an immediate benefit for the patients who receive the drug and achieve positive therapeutic outcomes. Such studies might also provide a good for future patients who suffer from the same disease. Other studies designed to understand the underlying neurobiological causes of or socioeconomic contributions to disorders or behaviors, such as those examining factors related to increasing smoking rates among young people in Japan, might not provide immediate benefits for the study participants. However, these studies might lead to the development of new treatments or to a policy change that benefits the public at large.The History and Principles of Bioethics, and the Development of Its Rules
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The Definition of “Risk”
It is important to consider the following two aspects when evaluating risks: the probability and the magnitude of any harm that might occur as a result. For example, an evaluation should be made whether the risk will occur in almost all subjects or in only one of 10,000 subjects, and whether the harm consists of something like minor itchiness or potential death in some subjects. In the clinical studies setting, we tend to focus on physical risks, but risks may also be social, legal, economic or psychological in nature. Physical risks may also take the form of the worsening of symptoms or deterioration of health as a result of participating in clinical research. There may be psychological distress or damage to the legal or economic status of a subject from accidental disclosure of personal information that is financial, medical or genetic. In addition, risks may apply to individual subjects or to a broader segment of society. We must consider them from many different perspectives.
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Weighing Potential Benefits and Risks
Risks to a subject or society must be weighed against potential benefits. We must evaluate the probability and magnitude of “benefits” and the probability and magnitude of “harm,” in other words, the relative magnitude of “risks,” as accurately as possible. One of the most difficult tasks for researchers and Research Ethics Review Boards is to determine whether the potential benefits from the research (their outcomes) outweigh the potential risks from conducting it. This is difficult for the following reasons:
- Neither the potential benefits nor risks can be known ahead of time; and
- In many cases, the risks are assumed by individuals, while the benefits may accrue to society at large rather than to individuals.
Research Ethics Review Boards
A Research Ethics Review Board is a committee established in research and other institutions in order to determine whether or not Human Subjects Research studies may be conducted at the respective institutions. In our training materials, we call a committee that reviews research protocols for the protection of human subjects a Research Ethics Review Board. However, it is important to note that committees responsible for this function may be called different names depending on the country. In the United States, partly because of the 1974 National Research Act, the group is called the Institutional Review Board (IRB). In the U. K., it is called a Research Ethics Committee (REC), and in France a Comité de Protection des Personnes (CPP). There is no uniform name for such committees, even in international guidelines. In the 1975 edition of the Declaration of Helsinki, it was initially called as a specially appointed independent committee.
In Japan, committees that serve the function of a Research Ethics Review Board are classified into two categories: an “Institutional Review Board” (customarily called an IRB) stipulated in the GCP Ministerial Ordinance based on the Pharmaceutical Affairs Act and an “Ethical Review Committee,” a voluntary organization often established in a research institution (which may be called something else depending on the institution). The former normally reviews clinical trials, and the latter reviews other types of clinical or human subjects research.
The History and Principles of Bioethics, and the Development of Its Rules
The History of Human Subjects Research and the Dawn of Research Ethics
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Human Subjects Research in the 18th and 19th Centuries
There are several well-known studies involving human subjects in the history of the development of medical science: 
(1) Smallpox vaccine experiments by Jenner:
Edward Jenner (1749-1856) first tested his smallpox vaccines produced from bovines on his son and neighborhood children, which was later proven to be an important discovery.
Edward Jenner (1749-1856) first tested his smallpox vaccines produced from bovines on his son and neighborhood children, which was later proven to be an important discovery.
(2) Rabies vaccination by Pasteur:
Louis Pasteur (1822-1895) discovered that inoculation with attenuated bacteria led to immune responses against rabies in animals. The inoculation with rabies vaccines in humans was done experimentally but helped save children in the village in the end.
Louis Pasteur (1822-1895) discovered that inoculation with attenuated bacteria led to immune responses against rabies in animals. The inoculation with rabies vaccines in humans was done experimentally but helped save children in the village in the end.
(3) Anesthesia and breast cancer operation by Seishu Hanaoka:
Seishu Hanaoka (1760-1835) developed a general anesthetic agent from the extracts of datura and other plants. In the course of developing it, he tested the agent on his mother and wife, killing the former and causing the latter to lose her eyesight. He was, however, successful in conducting the world’s first breast cancer surgery using his general anesthetic technique.
Seishu Hanaoka (1760-1835) developed a general anesthetic agent from the extracts of datura and other plants. In the course of developing it, he tested the agent on his mother and wife, killing the former and causing the latter to lose her eyesight. He was, however, successful in conducting the world’s first breast cancer surgery using his general anesthetic technique.
These events happened in modern medicine’s beginnings in the 18th and 19th centuries and have been cited in many instances as important contributions to the development of medical science. However, there are numerous ethical concerns with these studies: Such concerns would problematize these studies were they conducted today.
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Human Subjects Research and the Establishment of Research Ethics in the 20th Century
Even in the 20th century, various studies and experiments that violated basic human rights or caused considerable harm were conducted in the name of “progress.” Based on the painful lessons from these examples in inhumanity, research ethics have evolved gradually. Some examples are discussed below. (1) The Nuremberg Code
During World War II, doctors for Nazi Germany conducted various kinds of experiments including toxic gas experiments
on Jewish people in concentration camps. During the same period, inhumane experiments were conducted in Japan mainly by Manchukuo Unit 731 of the Japanese Imperial Army.
Human experiments by Nazi Germany were prosecuted before the Nuremberg Military Tribunals, and the court included in the legal judgment ten points describing required elements for conducting research with humans, known as the Nuremberg Code). The Nuremberg Code presents important ethical principles such as mandated informed consent and weighing benefits and risks. However, there were also a number of problems with the Nuremberg Code. It did not have the strength of law, and was created post hoc and applied retroactively. The most serious problem was that it applied only to nontherapeutic Human Subjects Research.
During World War II, doctors for Nazi Germany conducted various kinds of experiments including toxic gas experiments
on Jewish people in concentration camps. During the same period, inhumane experiments were conducted in Japan mainly by Manchukuo Unit 731 of the Japanese Imperial Army. Human experiments by Nazi Germany were prosecuted before the Nuremberg Military Tribunals, and the court included in the legal judgment ten points describing required elements for conducting research with humans, known as the Nuremberg Code). The Nuremberg Code presents important ethical principles such as mandated informed consent and weighing benefits and risks. However, there were also a number of problems with the Nuremberg Code. It did not have the strength of law, and was created post hoc and applied retroactively. The most serious problem was that it applied only to nontherapeutic Human Subjects Research.
Main contents of the Nuremberg Code:
- That voluntary informed consent is essential.
- Research involving humans should only be conducted after thorough pre-clinical experimentation using animals.
- Risks involved in research should be justified by the anticipated benefits.
- Only qualified scientists must conduct research.
- Physical and mental suffering must be avoided.
- Research in which death or disabling injury is expected should not be conducted.
(2) The Declaration of Helsinki
In 1964, the World Medical Association developed a code of research ethics that reinterpreted the Nuremberg Code, with a focus on medical research with therapeutic intent. The legal force of what came to be known as the Declaration of Helsinki was not established under international law, but the document has provided authoritative guidelines and influenced the development of laws and regulations in many countries. Many subsequent research ethics guidelines are based on this Declaration, and following its development, journal editors require that research be performed in accordance with it. This document also set the stage for the implementation of the Research Ethics Review Boards. The present text of the Declaration of Helsinki reflects nine revisions to the original document, including additions and amendments.
In 1964, the World Medical Association developed a code of research ethics that reinterpreted the Nuremberg Code, with a focus on medical research with therapeutic intent. The legal force of what came to be known as the Declaration of Helsinki was not established under international law, but the document has provided authoritative guidelines and influenced the development of laws and regulations in many countries. Many subsequent research ethics guidelines are based on this Declaration, and following its development, journal editors require that research be performed in accordance with it. This document also set the stage for the implementation of the Research Ethics Review Boards. The present text of the Declaration of Helsinki reflects nine revisions to the original document, including additions and amendments.
(3) Beecher Article
In 1966, Henry K. Beecher, an anesthesiologist at a hospital affiliated with Harvard University, published an article titled, “Ethics and Clinical Research,” in the New England Journal of Medicine condemning unethical clinical research studies. He described 22 examples of research studies with controversial ethics all of which had been conducted by reputable researchers and published in major journals. These included the Willowbrook Hepatitis Study conducted in the United States in the 1950s and the 1960s, in which children with intellectual disabilities were deliberately infected with a hepatitis virus. He also described the Jewish Chronic Disease Hospital Study, in which live cancer cells were injected into elderly patients with dementia. In his article Beecher wrote that whereas “American medicine is sound, and most progress is soundly attained,” if such unethical research was left uninhibited, the consequences would be destructive to medicine as “unethical or questionably ethical procedures are not uncommon.”
The Beecher Article played a very important role in heightening the awareness of researchers, the public, and the press to the problem of unethical Human Subjects Research. Robert J. Levine, a medical ethicist, said, “Until this article we assumed that unethical research could only occur in a depraved regime like the Nazis.” In 1966, responding to Beecher’s report, the US National Institutes of Health (NIH) published ethical guidelines for Human Subjects Research sponsored by federal funding. These guidelines were groundbreaking because the document sought the establishment of a Research Ethics Review Board for the first time anywhere in the world.
In 1966, Henry K. Beecher, an anesthesiologist at a hospital affiliated with Harvard University, published an article titled, “Ethics and Clinical Research,” in the New England Journal of Medicine condemning unethical clinical research studies. He described 22 examples of research studies with controversial ethics all of which had been conducted by reputable researchers and published in major journals. These included the Willowbrook Hepatitis Study conducted in the United States in the 1950s and the 1960s, in which children with intellectual disabilities were deliberately infected with a hepatitis virus. He also described the Jewish Chronic Disease Hospital Study, in which live cancer cells were injected into elderly patients with dementia. In his article Beecher wrote that whereas “American medicine is sound, and most progress is soundly attained,” if such unethical research was left uninhibited, the consequences would be destructive to medicine as “unethical or questionably ethical procedures are not uncommon.”
The Beecher Article played a very important role in heightening the awareness of researchers, the public, and the press to the problem of unethical Human Subjects Research. Robert J. Levine, a medical ethicist, said, “Until this article we assumed that unethical research could only occur in a depraved regime like the Nazis.” In 1966, responding to Beecher’s report, the US National Institutes of Health (NIH) published ethical guidelines for Human Subjects Research sponsored by federal funding. These guidelines were groundbreaking because the document sought the establishment of a Research Ethics Review Board for the first time anywhere in the world.
(4) Ethical Problems With Past Studies
The following problems were identified in these examples of unethical human studies:
The following problems were identified in these examples of unethical human studies:
- Lack of informed consent
- Coercion or undue pressure on volunteers or on parents to volunteer their children
- Use of vulnerable populations
- Exploitation of vulnerable populations
- Withholding information
- Withholding available treatment
- Withholding information about risks
- Putting subjects at risk
- Risks to subjects outweighing benefits
- Deception
- Violation of rights
It has been reported that, in the 1950s and 1960s, there were also questionable experiments and research studies in Japan. Common to all these was the use of “vulnerable populations” including infants, psychiatric patients, employees of the pharmaceutical industry and personnel of the Self-Defense Forces.
[The Tuskegee Syphilis Experiment: Syphilis human experiments initiated by the US Public Health Service (1932-1972)]
Six hundred African-American men with and without syphilis were enrolled into a study designed to document the natural history of syphilis in Tuskegee, Alabama. They were denied appropriate medical treatment for a pre- and postwar period of 40 years.
The men were recruited without true informed consent and were deliberately misinformed about some of the procedures. Even after penicillin was found to be a safe and effective treatment for syphilis in the 1940s, the men were denied treatment with it. This cruel research continued to track these men until 1972 when the first public accounts of the study by Jean Heller appeared in the Associated Press.
The men were recruited without true informed consent and were deliberately misinformed about some of the procedures. Even after penicillin was found to be a safe and effective treatment for syphilis in the 1940s, the men were denied treatment with it. This cruel research continued to track these men until 1972 when the first public accounts of the study by Jean Heller appeared in the Associated Press.
The History and Principles of Bioethics, and the Development of Its Rules
Ethical Standards for Research That Guide Us Today
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Responding to the media reports about the Tuskegee Syphilis Experiment (see above), the US Congress formed an ad hoc panel which determined that the experiment needed be stopped immediately. The panel recommended that federal regulations for Human Subjects Research be developed, and as a result in 1974, federal regulations were enacted including the National Research Act which set forth general oversight of medical research with humans.
At the same time as the passage of the National Research Act, Congress also authorized the formation of the “National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research,” charging it to identify the basic ethical principles that underlie the conduct of human research. A report published in 1979 by the National Committee is the internationally-renowned Belmont Report*(the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research). The Report should be required reading for anyone involved in Human Subjects Research.
At the same time as the passage of the National Research Act, Congress also authorized the formation of the “National Commission for the Protection of Human Subjects in Biomedical and Behavioral Research,” charging it to identify the basic ethical principles that underlie the conduct of human research. A report published in 1979 by the National Committee is the internationally-renowned Belmont Report*(the Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research). The Report should be required reading for anyone involved in Human Subjects Research.
*The title of the Belmont Report was taken from the Belmont Conference Center in Elkridge, Maryland, where the Commission adopted the text.
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The Distinction between Medical Care and Research
The emphasis of the Belmont Report is to protect human research subjects, especially vulnerable ones, and seeks to prevent researchers from using humans as means to an end. It first makes a clear distinction between medical care and research. “Medical care” is an act of intervention carried out only for the purpose of increasing the welfare of a patient through diagnosis, prevention and/or treatment. On the other hand, “research” is an activity carried out based on a protocol to validate a hypothesis in order to draw a scientific conclusion. Including observational studies, all activities encompassing an element of “research” are subject to ethical review in the view of protecting human research subjects.The History and Principles of Bioethics, and the Development of Its Rules
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The Three Principles of the Belmont Report
The Belmont Report identifies basic ethical principles that underlie all Human Subjects Research: “Respect for persons,” “Beneficence” and “Justice.” 
(1) Respect for Persons
A principle found in the writings of philosopher Immanuel Kant, it requires us to treat individuals as autonomous human beings and to recognize their rights as such. Its emphasis is to ensure that each person is able to make his or her own decisions. Respecting autonomy means to respect the views and decisions made by each person after careful consideration of the information provided and respect for their right to exercise their freedom to volunteer for or withdraw from research without coercion or undue influence from others. In addition, people with limited autonomy, such as children, adolescents and individuals with limited cognitive abilities, should be provided with extra protection around this issue. The idea is that we must not use people as a means to an end and allow them to make decisions for themselves, and to provide extra protection to those with limited autonomy.
Elements of autonomy include:
A principle found in the writings of philosopher Immanuel Kant, it requires us to treat individuals as autonomous human beings and to recognize their rights as such. Its emphasis is to ensure that each person is able to make his or her own decisions. Respecting autonomy means to respect the views and decisions made by each person after careful consideration of the information provided and respect for their right to exercise their freedom to volunteer for or withdraw from research without coercion or undue influence from others. In addition, people with limited autonomy, such as children, adolescents and individuals with limited cognitive abilities, should be provided with extra protection around this issue. The idea is that we must not use people as a means to an end and allow them to make decisions for themselves, and to provide extra protection to those with limited autonomy.
Elements of autonomy include:
- Mental capacity: the ability to understand and process information
- Voluntariness: freedom from the control or influence of others
Rules derived from the principle of “Respect for Persons” include the requirement to obtain informed consent and to respect the privacy of human subjects.
(2) Beneficence
The principle of “Beneficence” helps ensure the well-being of human subjects, by reminding us that we should (i) intend no harm and (ii) minimize any possible harm
and maximize the potential benefits within the constraints of sound research protocol.
Rules derived from the principle of “beneficence” include:
1) The prohibition of research if the risks it poses outweighs the possible benefits,
2) Whenever consistent with sound research design, the requirement to use procedures that increase benefits and decrease harm and
3) Mandating that researchers are able to perform the procedures and manage the risks.
The principle of “Beneficence” helps ensure the well-being of human subjects, by reminding us that we should (i) intend no harm and (ii) minimize any possible harm
and maximize the potential benefits within the constraints of sound research protocol. Rules derived from the principle of “beneficence” include:
1) The prohibition of research if the risks it poses outweighs the possible benefits,
2) Whenever consistent with sound research design, the requirement to use procedures that increase benefits and decrease harm and
3) Mandating that researchers are able to perform the procedures and manage the risks.
(3) Justice
Who gains benefits from the research and who bears its burdens? This is when research becomes a question of justice, in terms of “equal distribution” of benefits and risks. The principle of justice requires us to treat people fairly and to design research so that its burdens and benefits are shared as evenly as possible. It is unfair and inappropriate to selected human subjects because they can be easily exploited, are in subservient positions or are obedient for whatever reason, or to exclude individuals belonging to certain groups from participating in research without sound scientific reasons.
Derived rules from the principle of “justice” include:
1) The requirement to select subjects equitably, and
2) The requirement to avoid the exploitation of vulnerable populations or populations of convenience.
Who gains benefits from the research and who bears its burdens? This is when research becomes a question of justice, in terms of “equal distribution” of benefits and risks. The principle of justice requires us to treat people fairly and to design research so that its burdens and benefits are shared as evenly as possible. It is unfair and inappropriate to selected human subjects because they can be easily exploited, are in subservient positions or are obedient for whatever reason, or to exclude individuals belonging to certain groups from participating in research without sound scientific reasons.
Derived rules from the principle of “justice” include:
1) The requirement to select subjects equitably, and
2) The requirement to avoid the exploitation of vulnerable populations or populations of convenience.
(4) Balancing the three principles:
Although each of the three principles of the Belmont Report should have equal moral weight, in some situations, the three principles might conflict with one another. For example, we might derive from the principle of “Respect for Persons” that we should limit the involvement of children in research because children are unable to truly choose for themselves. But, we might derive from the principle of “Justice” that we must involve them in studies so that children as a group will have the opportunity to benefit from the research. The philosophy of the Belmont Report is that one principle does not always outweigh another. That is, when we determine whether a specific research study is ethical, we are required to consider each case separately on its own merits in view of all three principles.
Although each of the three principles of the Belmont Report should have equal moral weight, in some situations, the three principles might conflict with one another. For example, we might derive from the principle of “Respect for Persons” that we should limit the involvement of children in research because children are unable to truly choose for themselves. But, we might derive from the principle of “Justice” that we must involve them in studies so that children as a group will have the opportunity to benefit from the research. The philosophy of the Belmont Report is that one principle does not always outweigh another. That is, when we determine whether a specific research study is ethical, we are required to consider each case separately on its own merits in view of all three principles.
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Ethics and Regulations of Human Subjects Research
In the U.S., federal regulations have been developed based on the basic ethical principles of the Belmont Report, known as the “Common Rule.” These federal regulations provide three basic protections to human subjects:
- Institutional assurances
- Review by a Research Ethics Review Board (an Institutional Review Board (IRB) in the U.S.)
- Informed consent (discussed in a separate module)
(1) Institutional Assurances
Institutional assurances are used as a mechanism to apply federal regulations to all Human Subjects Research within the U.S. When an institution signs assurances in their contracts with the federal government, they may also elect to apply the Department of Health and Human Services (DHHS) regulations and terms of the assurance to all research of the institution, regardless of the source of funding.
Through this system, all clinical research institutions in the U.S., including university hospitals, are required to establish an IRB, register it with the DHHS, and provide opportunities for ethics training to those who engage in clinical research. When Japanese researchers carry out collaborative research with researchers in the U.S., their research institutions (universities and research centers), are required to obtain authorization via the federal assurance from the US government agency. Therefore, such institutions are required to provide ethics training for their researchers in Japan, similar to that found in institutions in the U.S.
Institutional assurances are used as a mechanism to apply federal regulations to all Human Subjects Research within the U.S. When an institution signs assurances in their contracts with the federal government, they may also elect to apply the Department of Health and Human Services (DHHS) regulations and terms of the assurance to all research of the institution, regardless of the source of funding.
Through this system, all clinical research institutions in the U.S., including university hospitals, are required to establish an IRB, register it with the DHHS, and provide opportunities for ethics training to those who engage in clinical research. When Japanese researchers carry out collaborative research with researchers in the U.S., their research institutions (universities and research centers), are required to obtain authorization via the federal assurance from the US government agency. Therefore, such institutions are required to provide ethics training for their researchers in Japan, similar to that found in institutions in the U.S.
(2) A Review by a Research Ethics Review Board (Institutional Review Board)
A review by a Research Ethics Review Board (or an IRB in the U.S.) is the glue that holds the process of evaluating various aspects of a research study together. An IRB review (described in detail in another module) is guided by the ethical principles described in the Belmont Report and asks the following questions:
1. Respect for Persons
A review by a Research Ethics Review Board (or an IRB in the U.S.) is the glue that holds the process of evaluating various aspects of a research study together. An IRB review (described in detail in another module) is guided by the ethical principles described in the Belmont Report and asks the following questions:
1. Respect for Persons
- Does the consent process minimize the possibility of coercion or undue influence to ensure maximum autonomy?
- Does this study have additional protections for members of vulnerable populations to protect their rights and their welfare?
- Does this study adequately maintain the privacy of the subjects and protect the confidentiality of personal information?
2. Beneficence
- What are the risks? Have they been minimized?
- Does the research design adequately minimize potential risks and maximize potential benefits? Is there room for improvement to minimize risk?
- Are the risks to the subjects reasonable when compared with the anticipated benefits (if any) to subjects and the importance of the knowledge gain expected as an outcome of the research?
3. Justice
- Does the study’s recruitment process target the population that will benefit from the research?
- Does the recruitment process unfairly target a population?
- Are the criteria for inclusion or exclusion fair?
In the U.S., ethical principles and federal regulations provide a framework for IRBs to evaluate research involving human subjects. However, the uniqueness of each study still makes a comprehensive IRB review, a complex process.
[Recent Examples of Ethically Questionable Research]
In the last several years reports of unethical studies in areas such as gene transfer, cancer and psychiatric research have heightened the public’s awareness of these issues. The followings are well-known examples from the U.S.:
1. The Death of a Normal Volunteer
On March 31, 1996, a 19-year-old Asian American student at one university responded to an advertisement for research subjects to undergo bronchoscopy for the harvest of alveolar macrophages. The bronchoscopy in this student was difficult and required numerous doses of topical lidocaine. The investigators repeatedly asked the subject if she wanted to continue and the subject nodded her head “yes.” The study was completed, but the subject returned to the hospital in cardiac arrest from an overdose of lidocaine and died on April 2, 1996.
An investigation into the death revealed that the study protocol did not limit lidocaine doses, that the doses were not documented, that the concentrations of lidocaine were increased without IRB approval, and that the subject was not observed after the bronchoscopy.
An investigation into the death revealed that the study protocol did not limit lidocaine doses, that the doses were not documented, that the concentrations of lidocaine were increased without IRB approval, and that the subject was not observed after the bronchoscopy.
2. A Death in a Gene Therapy Trial
In the fall of 1999, 18-year-old Jesse Gelsinger died as a result of his participation in a gene transfer trial at another university. He had a rare metabolic disorder, ornithine transcarbamylase deficiency syndrome (OTC) that was being controlled by medication and diet. Researchers were testing an innovative technique using adenovirus gene transfer. Shortly after treatment Gelsinger experienced multiple organ failure and subsequently died.
Many issues were identified later in the investigation, including that Gelsinger was admitted into the study despite the fact that his blood ammonia level met the study’s exclusion criteria, two past adverse events as a result of the gene therapy were not reported by the university, and the information that a multiple number of baboons died during preclinical tests was not provided to potential subjects during the informed consent process. The investigator and the university also had a conflict of interest having to do with financial benefits associated with carrying out the study. This case resulted in the instigation of deliberations on controversies in clinical research at the national level, having raised the suspicion of the public.
The Gelsinger case provided a contemporary illustration of continued doubts about the ethical integrity of research with human subjects.
In order to deal with the situation, a new requirement to attest to having received ethics training was imposed in October 2000 on all applicants for NIH research grants with research involving human subjects. In Japan, the “Ethical Guidelines for Medical and Health Research Involving Human Subjects” set forth a similar obligation to complete an ethics training program to investigators and related personnel.
Many issues were identified later in the investigation, including that Gelsinger was admitted into the study despite the fact that his blood ammonia level met the study’s exclusion criteria, two past adverse events as a result of the gene therapy were not reported by the university, and the information that a multiple number of baboons died during preclinical tests was not provided to potential subjects during the informed consent process. The investigator and the university also had a conflict of interest having to do with financial benefits associated with carrying out the study. This case resulted in the instigation of deliberations on controversies in clinical research at the national level, having raised the suspicion of the public.
The Gelsinger case provided a contemporary illustration of continued doubts about the ethical integrity of research with human subjects.
In order to deal with the situation, a new requirement to attest to having received ethics training was imposed in October 2000 on all applicants for NIH research grants with research involving human subjects. In Japan, the “Ethical Guidelines for Medical and Health Research Involving Human Subjects” set forth a similar obligation to complete an ethics training program to investigators and related personnel.
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Other Considerations
Additional considerations in research ethics include the following: (1) The Principal Investigator’s (PI’s) Relationship with Staff
A responsible PI will:
A responsible PI will:
- Obtain and demonstrate team management skills.
- Encourage questions from colleagues and staff.
- Listen to the concerns of the research staff, as they may be the first to notice problems with the protocol and with compliance.
- Build consensus with members of the research team.
- Deal with intimidation by anyone in a supervisory position.
Relationships of authority are not limited to ones between the PI and the staff, but can also include that of the authority of the sponsor over the PI, the PI’s authority over the subject, and the authority of the study protocol over the PI.
(2) Investigator–Subject Relationship
The investigator must place the subject’s rights, welfare and safety above all scientific and even personal concerns. The relationship between researcher and subject is similar to a physician–patient relationship, but is distinctly different in the following ways:
･ Informed consent is required for participation in research.
･ Withdrawal from a study is at the discretion of the subject.
･ Investigators should be sensitive to power relationships.
･ The investigator has a moral fiduciary relationship with the subject.
The investigator must place the subject’s rights, welfare and safety above all scientific and even personal concerns. The relationship between researcher and subject is similar to a physician–patient relationship, but is distinctly different in the following ways:
･ Informed consent is required for participation in research.
Example: Let us suppose that a patient insists that she does not want to hear about the risks, benefits and alternatives of a proposed medical procedure. She insists that the physician decide for her. Many would say that it is ethical for the physician to go ahead with the treatment, provided that he or she is convinced that “the physician’s decision is in the best interest of the patient.”
In research the issue is more complex and the relationship is more formal. If a potential research subject is given a consent form, and the subject does not want to read the document and simply asks, “Where do I sign?” the investigator must insist that the subject listen to the investigator’s description of the study and other important information and that the potential subject read and understand the consent document. If the subject refuses to read the consent or hear a full disclosure of the information about the research, then the investigator has an ethical obligation to prohibit their enrollment.
In research the issue is more complex and the relationship is more formal. If a potential research subject is given a consent form, and the subject does not want to read the document and simply asks, “Where do I sign?” the investigator must insist that the subject listen to the investigator’s description of the study and other important information and that the potential subject read and understand the consent document. If the subject refuses to read the consent or hear a full disclosure of the information about the research, then the investigator has an ethical obligation to prohibit their enrollment.
･ Withdrawal from a study is at the discretion of the subject.
Example: A healthy research subject enrolls in a pharmacokinetic study of a drug that is known to cause anxiety and feelings of distrust. After receiving two doses, the subject declares he no longer trusts the researchers and says he will leave. The investigator says, “It’s the drug talking” and tries to continue the procedure.
An ethical researcher will permit subjects to withdraw for whatever reason or for no reason. Of course, a researcher must do what is needed for subject safety; in this last example, the investigator should also ensure the subject’s emotional equilibrium returns to normal before releasing him or her.
An ethical researcher will permit subjects to withdraw for whatever reason or for no reason. Of course, a researcher must do what is needed for subject safety; in this last example, the investigator should also ensure the subject’s emotional equilibrium returns to normal before releasing him or her.
･ Investigators should be sensitive to power relationships.
Example: It is common in basic science laboratories to obtain blood from normal volunteers, usually staff members in the research lab. Some blood donors have difficult veins and may need to be stuck several times to obtain blood. Despite the increased pain of multiple sticks, staff members in an investigator’s lab may feel obliged to endure, saying, “Stick me. I don’t care. I don’t mind needles.”
Responsible investigators should recognize the problem and remove such a person from the study. The investigator should say something to the effect of “You are experiencing more harm than the average subject. I will find someone else to enter the study who will not experience as much harm from the procedure.”
Responsible investigators should recognize the problem and remove such a person from the study. The investigator should say something to the effect of “You are experiencing more harm than the average subject. I will find someone else to enter the study who will not experience as much harm from the procedure.”
･ The investigator has a moral fiduciary relationship with the subject.
Example: There are conflicts of interest* that are so great that even a moral investigator would have a difficult time making the right decision. If doing what is right for the subject means losing $10 million, many of us could be susceptible to making the wrong decision. It is up to the IRB to detect and minimize these conflicts of interest. However, it is also up to the investigator to avoid entering into these untenable conflicts.
*Conflict of interest means “a situation in which financial or other personal considerations have the potential to compromise or bias professional judgment and objectivity.” For details, see CITI Japan training materials entitled “Conflict of Interest” in “Responsible Conduct of Research: Fundamentals.”
The History and Principles of Bioethics, and the Development of Its Rules
Recent Development in Japan and the Creation of Rules
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In recent years, ethically questionable studies, in several research fields, have been identified in Japan. This has led administrative authorities and academic societies to formulate guidelines.
Ethically Questionable Studies
(1) Analysis of genetic information without donors’ consent
From 1999 to 2000, a series of cases involving genetic analysis using donated blood without the consent of the blood donors were reported. In several research institutions, blood sampled from local people, who received general health examinations, were analyzed for genetic research studies on lifestyle diseases without their consent. Subsequently, the universities and research institutions involved have taken measures to prevent such a situation from reoccurring.
From 1999 to 2000, a series of cases involving genetic analysis using donated blood without the consent of the blood donors were reported. In several research institutions, blood sampled from local people, who received general health examinations, were analyzed for genetic research studies on lifestyle diseases without their consent. Subsequently, the universities and research institutions involved have taken measures to prevent such a situation from reoccurring.
(2) Registration for clinical trials without the patient’s consent
A university registered a patient as a human subject for a clinical trial of a new treatment for cervical cancer and conducted chemotherapy on them without obtaining their consent. A high court granted the patient’s damages claim for mental suffering recognizing the university’s lack of accountability, due to the absence of explanation regarding the patient’s registration as a human subject. The university’s appeal to the Supreme Court was dismissed in 2006.
A university registered a patient as a human subject for a clinical trial of a new treatment for cervical cancer and conducted chemotherapy on them without obtaining their consent. A high court granted the patient’s damages claim for mental suffering recognizing the university’s lack of accountability, due to the absence of explanation regarding the patient’s registration as a human subject. The university’s appeal to the Supreme Court was dismissed in 2006.
(3) Pathological diagnosis and use of specimens
Pathological diagnosis is an investigation of a patient’s disease based on specimens such as tissues and cells collected from the patient. According to a survey conducted by the Japanese Society of Pathology in 2001, among hospitals that use specimens that are originally taken to make diagnoses for research or educational purposes, approximately only 30% obtained actual written consent from their patients. In general, specimens are kept for at least 5 years after a diagnosis in case of disease recurrence. University hospitals customarily also use these specimens for research or teaching. The Japanese Society of Pathology held meetings to discuss regulations for using specimens and obtaining informed consent, and, in 2005, produced the “Guidelines for Handling Patients’ Pathology Specimens (Biopsy, Cytodiagnosis, Surgical Specimens) (published by the Council of Surgical Academic Societies, or Geka Kanren Gakkai Kyougikai)” for the handling of pathology specimens and for voluntary consent in academic and research settings.
Pathological diagnosis is an investigation of a patient’s disease based on specimens such as tissues and cells collected from the patient. According to a survey conducted by the Japanese Society of Pathology in 2001, among hospitals that use specimens that are originally taken to make diagnoses for research or educational purposes, approximately only 30% obtained actual written consent from their patients. In general, specimens are kept for at least 5 years after a diagnosis in case of disease recurrence. University hospitals customarily also use these specimens for research or teaching. The Japanese Society of Pathology held meetings to discuss regulations for using specimens and obtaining informed consent, and, in 2005, produced the “Guidelines for Handling Patients’ Pathology Specimens (Biopsy, Cytodiagnosis, Surgical Specimens) (published by the Council of Surgical Academic Societies, or Geka Kanren Gakkai Kyougikai)” for the handling of pathology specimens and for voluntary consent in academic and research settings.The History and Principles of Bioethics, and the Development of Its Rules
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The Development of Ethical Guidelines by Japanese Administrative Authorities
In Japan, discussions on research ethics were far behind those in Western countries. The rules for clinical trials “Good Clinical Research Practice” (GCP Ministerial Ordinance) were formulated in 1989 as a ministerial regulation of the Ministry of Health and Welfare, currently called the “Ministry of Health, Labour and Welfare” (or the MHLW), and as an instrument of the Pharmaceutical Affairs Act. However, the focus of this document was to ensure the general quality of clinical trials, not to promote ethical practices and protect human subjects. In an attempt to reduce ethically questionable studies involving genetic analysis without donors’ consent, MHLW published the “Guidelines for Properly Responding to Ethical Problems, Etc. Associated with Gene Analysis Research” in 2000. These set of rules subsequently led to the development of other guidelines including the “Ethical Guidelines for Human Genome/Gene Analysis Research” in 2001 by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the MHLW and the Ministry of Economy, Trade and Industry (METI), the “Ethical Guidelines for Epidemiological Studies” in 2002 by the MEXT and the MHLW, the “Ethical Guidelines for Clinical Studies” in 2003 by the MHLW. In 2015, the last two guidelines are integrated into “Ethical Guidelines for Medical and Health Research Involving Human Subjects.”
As in the above case, ethical guidelines for Human Subjects Research in Japan are published by administrative authorities and have been revised with additions and amendments every few years (see the diagram below). These guidelines by administrative authorities incorporate the basic principles of bioethics outlined in the Belmont Report and the Declaration of Helsinki. Each guideline has a specific scope of application.
Ethical guidelines published by administrative authorities are not instruments of statutes. They are not enforceable by law, unlike rules established for clinical trials based on the Pharmaceutical Affairs Act and the guidelines for using some specified embryos established by the Cloning Techniques Regulation Act. Therefore, an act violating the guidelines does not result in criminal penalties or even administrative sanctions. However, those violating the guidelines will be subject to social sanctions such as the suspension of grants qualification and the disclosure of their names. Thus, everyone who engages in research activities is required to fully understand the contents of these guidelines and comply with them.
It is important for those who engage in Human Subjects Research to know which guidelines apply or do not apply to their specific studies. CITI Japan’s on-screen e-learning program provides not only an overview of the guidelines but also an understanding of what underlies them and certain characteristics of Japanese regulations. If you click the flowchart at right, the image will enlarge to allow you to confirm the guidelines which are likely to apply to your research.
The History and Principles of Bioethics, and the Development of Its Rules
This module is adapted for the APRIN research community from “History and Ethical Principle” (Authors: Elizabeth Bankert and Jeffrey A. Cooper) kindly offered by the CITI Program of BRANY (Biomedical Research Alliance of New York). Adaption was carried out by the APRIN supporting experts in accordance with the various pertinent laws and guidelines, whose names are listed elsewhere.
