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