Human Subjects in Research

Advances in human health and welfare ultimately depend on research with human subjects. Properly controlled studies with human subjects are essential to verify any conclusions about normal physiology, mechanisms of disease, effectiveness of treatment, learning, or behavior. Unfortunately, not all human studies have been justifiable and useful. Human cruelty can be perpetrated in the name of research. Some of the best known examples occurred in Nazi Germany. Investigations following the war uncovered many atrocities, such as studies in which subjects were immersed in very cold water to gauge how long it would take to die of hypothermia. The discoveries of these abuses were the basis for the Nuremberg trials and development of the Nuremberg Code (1949), the first international codification of minimal expectations for the conduct of research involving human subjects. Some of the most important provisions of the Code were that experiments with human subjects should occur only in the context of a clear scientific rationale and only with subjects who have freely chosen to participate.

Harm to unwilling subjects under the guise of research has not been unique to the Nazis. During World War II, the U.S. conducted medical experiments on people not competent to consent and on subjects without their knowledge (Vanderpool, 1996). In 1932, prior to the start of World War II, 400 African American males with syphilis had been entered into a study at Tuskegee, Alabama with the intended purpose of documenting the natural course of their disease (Rivers et al., 1953; Jones, 1993). Although treatments of some presumed efficacy were available, these were withheld while the study participants were led to believe that experimental procedures (such as spinal taps to examine cerebrospinal fluid) were for the purpose of therapy. By the 1950's, penicillin was available and known to be highly effective against syphilis, but it also was withheld. The surviving participants were only given treatment in 1972, after the nature of the study became publicly known, 23 years after publication of the Nuremberg Code. Recognition of problematic studies published in the medical and social science literature resulted in the appointment of a federal commission to identify fundamental principles that should govern human subjects studies. The final product of this commission was the Belmont Report (1979). It defined the three ethical principles that now guide studies with human subjects in the U.S.​

Research that involves humans is subject to regulation. No procedure or study should be performed that is not explicitly exempted or a part of an approved protocol. Applicable regulations include requirements for adherence to IRB-approved research protocols, maintenance of documentation and records, obtaining approval prior to initiation of changes, and reporting of adverse events. Investigators are responsible for identifying all applicable regulations and complying with them.

Responsible conduct of research involving human subjects requires much more than complying with regulations. The spirit of the regulations and of good science both require that researchers critically review what is known and give thoughtful consideration to what defines an acceptable study. This consideration is necessarily an ongoing process. Factors to be considered include changes in our best understanding of the science, of the risks and potential benefits, of alternative methods for study, and so on. The decision to conduct a study with human subjects carries both ethical and regulatory responsibilities to protect the welfare and interests of those subjects, to design the study so as to minimize risks to subjects, and to obtain adequate training for protecting the interests and welfare of the research subjects.

A prerequisite for the responsible research involving humans is a realistic examination of the probability and magnitude of both the risks and the benefits of the research. Investigators must assess whether the risks are reasonable in relationship to the benefits to the individual subjects and the knowledge to be gained.

It is not enough that a proposed line of work is found to be justifiable; it is also necessary to consider whether alternative methods would be preferable. Any study involving human subjects is likely to involve at least minimal inconvenience and risks; other studies may carry more or less significant physical, social, psychological, or financial risks. Can the same information be obtained with less cost or risk by a less invasive study, by the use of fewer subjects, or by studies of other species?

Investigators conducting a research study with human subjects have an absolute responsibility to ensure that consent to participate has been given freely and is based on an understanding of the risks and benefits. The Belmont principle of respect for persons requires that researchers avoid invading privacy, maintain confidentiality of data, and obtain informed consent. Federal regulations outline numerous requirements for informed consent, including general requirements, basic and additional elements, criteria for waiving informed consent, and documentation for informed consent. The basic assumption underlying the regulations is that subjects need certain information so they can exercise self determination. Informed consent is often needed even for studies in the social sciences that impose little or no inconvenience, but still present the risk of a loss of privacy or confidentiality. Although some costs or risks may be more injurious than others, it must be up to the potential research subject, not the research investigator, to decide whether such costs or risks are outweighed by the benefits of participation.

The most visible indication of 'informed consent' is a document to be signed by the research subject. This document is important because it provides a consistent body of information that the investigator and the IRB have agreed is necessary for individuals to provide their informed consent. Unfortunately, subjects may sign such forms without understanding them. Differences in language, levels of comprehension, or retention of what has been read can make subjects fail to appreciate what they have agreed to. Also, the risks of participating in a research project may be overlooked because of the perception that physician scientists, and other health professionals, are clinical caregivers and not researchers. For these reasons, informed consent typically requires a dialogue with the potential subject to ensure that the content of the document is understood. Similarly, circumstances may change during the course of an ongoing study. If those circumstances might have an impact on subjects' willingness to continue with participation, then the investigator has an obligation to provide that new information. Informed consent is not a single event, but an ongoing process.

Not all subjects are able to give true informed consent. In some cases, it is difficult to ensure that consent is given freely, such as in prison populations. In other cases, it may be difficult to convey the necessary information or to verify an understanding in people with reduced decision making capacity-- such as subjects with some developmental disabilities, some psychiatric disorders, or advanced dementia. For all subject populations in which autonomy is diminished, research investigators are responsible for meeting ethical and regulatory obligations to protect the right for self-determination of any prospective or current research subject.

Children also require special consideration. Parents can give permission for their child's participation in research; depending on age and maturity level of the child, however, it may also be appropriate to obtain 'assent' from the child.

Eight basic elements:

  1. a statement that the study involves research
  2. a description of risks or discomforts
  3. a description of benefits to the subject or others
  4. a disclosure of alternatives
  5. a statement concerning confidentiality of records
  6. description of compensation, if any, and availability of medical treatment in the case of injury
  7. contacts for questions concerning the research, research related injury, or research subjects' rights
  8. a statement that participation is voluntary

Six additional elements when appropriate:

  1. presence of unforeseeable risks
  2. circumstances under which a subject's participation may be terminated
  3. possible additional costs to the subject
  4. consequences of decision to withdraw
  5. assurance that new findings that might affect the subjects decision to participate will be communicated to the subject
  6. approximate number of subjects involved in the study

 

The three principles listed below are from the Belmont report (1979). At least three important premises underlie these principles. The first is that studies with human subjects are necessary for improvements in health and welfare. Second, to conduct such research is a privilege, not a right, extended to researchers by society, institutions, and the research subjects themselves. Finally, neither the risks nor the costs of any research study should outweigh the likely benefits.

Respect for persons

'Respect for persons incorporates at least two ethical convictions: first, that individuals should be treated as autonomous agents, and second, that persons with diminished autonomy are entitled to protection.'

Beneficence

'Two general rules have been formulated as complementary expressions of beneficent actions in this sense: (1) do not harm and (2) maximize possible benefits and minimize possible harms.'

Justice

'An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly... For example, the selection of research subjects needs to be scrutinized in order to determine whether some classes (e.g., welfare patients, particular racial and ethnic minorities, or persons confined to institutions) are being systematically selected simply because of their easy availability, their compromised position, or their manipulability, rather than for reasons directly related to the problem being studied. Finally, whenever research supported by public funds leads to the development of therapeutic devices and procedures, justice demands both that these not provide advantages only to those who can afford them and that such research should not unduly involve persons from groups unlikely to be among the beneficiaries of subsequent applications of the research.'

Seventeen federal agencies have regulations governing the conduct of research involving human subjects. Examples of agencies with human subject requirements include the Department of Health and Human Services (DHHS), the Food and Drug Administration (FDA), the National Science Foundation, and the Departments of Defense, Education, Justice, and Veterans Affairs.

Recent concerns about protection of human subjects have resulted in new federal requirements for researchers to receive instruction in the responsible conduct of research (RCR). In June of 2000, the Department of Health and Human Services announced a requirement calling for education of all key personnel working on PHS-funded studies with human subjects (NIH, 2000). In December of 2000, the Office of Research Integrity (ORI) announced a new PHS policy extending the requirement for instruction in RCR to all staff with substantive involvement in PHS-funded research or training (PHS, 2000). Although now suspended (ORI, 2001), this requirement is likely to be re-introduced.

Different agencies define 'human subject' in different ways, but it includes (at minimum) any living person who is involved in research either as an experimental subject or as a control. The scope of activities included under the definition of  'research' is quite broad. One federal regulation defines research as any 'systematic investigation, including research development, testing and evaluation, designed to develop or contribute to generalizable knowledge. Activities which meet this definition constitute research for purposes of this policy, whether or not they are conducted or supported under a program which is considered research for other purposes. For example, some demonstration and service programs may include research activities.' (Code of Federal Regulations for Department of Health and Human Services 45CFR46.102(d)).

Human subject protections are a shared responsibility of principal investigators, other personnel involved in studies with human subjects, and the Institutional Review Board (IRB). Although most institutions are concerned primarily with regulations of DHHS and FDA, investigators are obligated to identify any special regulations or guidelines implicated by the project funding source or by the institution in which the study is performed.

The IRB is a primary mechanism for institutional protection of human subjects. An IRB is designed to be an advocate for potential and actual research subjects. Under both DHHS and FDA regulations, the IRB has responsibility to approve or disapprove all covered research activity, requiring for instance that subjects are given enough information to be able to provide informed consent. The IRB must conduct periodic reviews of research to ensure continued protection of the welfare of human subjects and compliance with relevant regulations.

The membership of an IRB is defined to include at least five members. The membership must include at least one person whose concerns are primarily scientific, one with nonscientific concerns, and one person who is both unaffiliated with the institution and unrelated to anyone from the institution. As appropriate, the IRB should also seek out special expertise for the review of projects presenting unusual ethical, legal, social, or scientific considerations. The IRB membership cannot consist of members from only one profession or gender. Additionally, any member with conflicting interest should be excluded from the review process. The diverse membership of the IRB is designed to protect the interests and welfare of human research subjects.

ÃÛÌÒÓ°Ïñ Policies

All ÃÛÌÒÓ°Ïñ researchers must be familiar with the following ÃÛÌÒÓ°Ïñ Policy governing human subjects research: Protection of Human Research Participants.

Protocol Review

All research involving human subjects must be approved by the IRB. The key here is - Is it research? If it is not research, it is not in the purview of the IRB. Questions about whether or not an activity is human subjects research are most common in projects that involve program assessment. The IRB has a guidance document (WORD) to help you make this determination. Research in some disciplines (i.e. oral history or linguistics) may or may not fit the definition of human subjects research even though it involves working with living people. If you have questions regarding whether or not your project requires IRB review contact the ORI for a determination BEFORE completing the IRB Protocol application.

When reviewing a protocol the IRB applies three basic ethical principles: respect for persons, beneficence and justice. One of the most important parts of any human subjects protocol is the informed consent process. In most cases, consent forms should read at no more than an 8th grade reading level. A great litmus test for the informed consent process is to ask someone unfamiliar with your research to read the consent documents; if they don't easily understand what you are doing and what their options are then it isn't ready to submit to the IRB!

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  • DHHS (2000):
  • Jones JH (1993): Bad Blood: The Tuskegee Syphilis Experiment. Free Press, New York.
  • NIH (2000): Required education in the protection of human research participants.
  • ORI (2001): Notice of suspension of PHS Policy on Instruction in the Responsible Conduct of Research.
  • PHS (2000):
  • Rivers E, Schumann SH, Simpson L, Olansky S (1953): Twenty years of follow-up experience in a long-range medical study. Public Health Reports 68(4): 391-395.
  • Vanderpool HY (1996): The Ethics of Research Involving Human Subjects: Facing the 21st Century. University Publishing Group, Frederick, Maryland, 531 pp.

Guidelines for Research with Human Subjects

  • Helsinki declaration (1964-2002) The World Medical Association's statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects.
  • Shuster E (1997): Fifty years later: The significance of the Nuremberg Code. New England J Med 20(337): 1436-1440.

Human Subjects Research Regulations and Oversight

  • FDA (2000):
  • FDA (2000):
  • (1993): Protecting Human Research Subjects: Institutional Review Board Guidebook. US Government Printing Office, Washington, DC.

Ethics and Human Research

  • Beecher HK (1966): Ethics and clinical research. New England J Med 274: 1354-1360.
  • Brieger GH (1978): Human Experimentation: History. In: Encyclopedia of Bioethics, Macmillan, New York, pp. 684-692.
  • Emanuel EJ, Wendler D, Grady C (2000): What Makes Clinical Research Ethical? Journal of the American Medical Association 283(20): 2701-2711.
  • Levine RJ (1988): Ethics and Regulation of Clinical Research. 2nd Edition, Yale University Press, New Haven, CT.
  • Milgram S (1983): Obedience to Authority. Harper Collins, New York.
  • Rothman DJ (1995): Research, Human: Historical Aspects. In: Encyclopedia of Bioethics, Simon & Schuster Macmillan, New York, revised edition, pp. 2248-2258.
  • Sieber JE (1993): Ethical considerations in planning and conducting research on human subjects. Academic Medicine 68(9)(suppl.): S9-S1.