Lizbeth A. Adams, PhD, CIP (2013) with contributions by Timothy Callahan, PhD (1998)
The atrocities committed by Nazi physicians on Jewish prisoners during World War II prompted an international tribunal, convened in the city of Nuremberg, Germany between 1945-1946, to elaborate 10 principles, called the Nuremberg Code, by which research involving human subjects should be governed. Publication of the Nuremburg Code in 1947 ushered in the modern era of research ethics, which mandated balancing the advancement of science with the rights and welfare of humans who serve as research subjects.
Since Nuremburg, a multitude of regulations and policy statements have been developed by domestic and international bodies. These regulatory guidance documents, including the World Medical Association Declaration of Helskinki (World Medical Association); the Belmont Report and the Federal Regulations at 45 CFR 46 and 21 CFR 50 share a common purpose: to protect the autonomy, safety, privacy, and welfare of human research subjects. Within institutions where clinical research is conducted, responsibility for the interpretation and application of these ethical principles and regulations rests with committees comprised of scientist and non-scientists, called Institutional Review Boards for the Protection of Human Subjects (IRBs).
General ethical principles applied to research with human subjects.
The Belmont Report, which provides the ethical foundation for research regulations and guides IRB deliberations, was generated by a federally commissioned group of scientists, physicians, ethicists, and philosophers and published in 1979. The three primary ethical principles cited in Belmont are: autonomy, beneficence, and justice.
- Autonomy refers to the right of an individual to determine what activities they will or will not participate in. Implicitly, full autonomy requires that an individual be able to understand what they are being asked to do, make a reasoned judgment about the effect participation will have on them, and make a choice to participate free from coercive influence. The cornerstone of protecting autonomy is the informed consent process, whereby an investigator provides a potential research participant with full disclosure about the nature of the study, the risks, benefits and alternatives, and an extended opportunity to ask questions before deciding whether or not to participate. Populations presumed to have diminished autonomy, by virtue of impaired cognition (for example, children, cognitively-impaired elderly, or mentally ill subjects) or of circumstance (for example prisoners or seriously ill people) are considered to be vulnerable populations. In some of these cases (children and prisoners) special safeguards to protect their autonomy are required by regulation.
- Beneficence refers to the obligation on the part of the investigator to maximize benefits for the individual participant and/or society, while minimizing risk of harm to the individual. Maximizing potential benefits is predicated on sound experimental design, thus research proposals must undergo rigorous scientific review before proceeding to the IRB for ethical review. An honest enumeration of reasonably anticipated risks must be followed by a thorough risk/benefit calculation.
- Justice demands equitable selection of participants, i.e., avoiding participant populations that may be unfairly coerced into participating, such as prisoners and institutionalized children. The principle of justice requires that those who undertake the burdens of research must be likely to benefit from the research, and is a principle often violated by the export of clinical trials to underdeveloped countries.
Designing ethical research studies.
- The primary concern of the investigator should be the safety of the research participant. Protecting subject safety requires the investigator to use all available information to identify potential risks to the subject, to establish means of minimizing those risks, and to continually monitor the ongoing research for adverse events experienced by subjects. The investigator must be prepared to stop the study if serious unanticipated risks are manifest.
- The scientific investigator must obtain informed consent from each research participant. This should be obtained in writing (although oral consents are sometimes acceptable) after the participant has had the opportunity to carefully consider the risks and benefits and to ask any pertinent questions. Informed consent should be seen as an ongoing process, not a single event or a mere formality. There are regulations and guidance documents that govern exceptions to the requirement to obtain informed consent, for example in cases of emergency or if the subject is unconscious and thereby unable to give consent.
- The investigator must protect the subjects’ privacy and confidentiality. Researchers must have mechanisms in place to prevent the disclosure of, or unauthorized access to, data that can be linked to a subject’s individual identity.
- The investigator must consider how adverse events will be handled. In particular, it must be established a priori who will provide care for a participant injured in a study and who will pay for that care.
- The investigator must strive for clinical equipoise. A true null hypothesis should exist at the onset regarding the outcome of the trial, that is, if a new intervention is being tested against the currently accepted treatment, the investigator should be genuinely uncertain which approach is superior.
Components of ethically valid informed consent for research.
Given the appreciation that informed consent is at the crux of human subjects protection, it is not surprising that the regulations reflect extensively upon the necessary elements of the consent document itself as well as on the informed consent process. For an informed consent to be ethically valid, the following components must be present:
- Disclosure: The informed consent document must make clear that the study is a research study, and not clinical therapy. The potential participant must be informed as fully as possible of the nature and purpose of the research, the procedures to be used, the expected benefits to the participant and/or society, the potential of reasonably foreseeable risks, stresses, and discomforts, and alternatives to participating in the research. There should also be a statement that describes procedures in place to ensure the confidentiality of data and anonymity of the participant. The informed consent document must also disclose what compensation and medical treatment are available in the case of a research-related injury. The document should make it clear whom to contact with questions about the research study, research subjects' rights, and in case of injury.
- Understanding: The participant must understand what has been explained and must be given the opportunity to ask questions and have them answered by someone fully conversant in the study particulars. The informed consent document must be written in lay language, avoiding any technical jargon. The potential participant must be able to read and/or understand the language in which the consent form is written. Consent forms for multinational research must be translated into the respective language for each participating country and back-translated to verify accuracy.
- Voluntariness: The participant's consent to participate in the research must be voluntary, free of any coercion or inflated promise of benefits from participation. Care should be taken that the consent form is administered by someone who does not hold authority over the participant. Ideally, the potential participant is given the opportunity to discuss their participation in the study with family, trusted friends, or their physician before reaching a decision.
- Competence: The participant must be competent to give consent. If the participant is not competent due to mental status, disease, or emergency, a designated surrogate may provide consent if it is in the participant's best interest to participate. In certain emergency cases, consent may be waived due to the lack of competence of the participant and absence of an appropriate surrogate. In the event that there is a question about competence, mental status exams may be administered.
- Consent: The potential human subject must authorize his/her participation in the research study, preferably in writing. If there is no need to collect personally identifiable information, and a signature on the consent form would be the only thing linking the subject to the study, an oral or implicit consent may be more appropriate. Children who cannot read or write should still signal their willingness to participate by an affirmative act (for example, nodding their head). Consent by minors is referred to as assent.
- Exculpatory language: No informed consent may contain any exculpatory language by which the participant waives any legal rights or releases the investigator or sponsor from liability for negligence.
Regulatory requirement to administer informed consent.
According to the regulations at 45 CFR 46.116: "no investigator may involve a human being as a subject in research covered by this policy unless the investigator has obtained the legally effective informed consent of the subject or the subject's legally authorized representative."
IRB review of research: full-board, expedited, and exempt reviews.
- Full board: Clinical trials that expose subjects to more than minimal risk must be reviewed by the IRB at a convened meeting of the full Board. Minimal risk is defined as those risks and discomforts to which a person is commonly exposed in the ordinary course of daily life, including routine visits to physicians. It is important to remember that loss of privacy, i.e unauthorized disclosure of personal information, is considered to be a risk of research. As technology and social media strip away more and more of our privacy, ethicists debate what constitutes a reasonable expectation of privacy (for more information, please see Haigh & Jones, 2005).
- Expedited: Studies that qualify for expedited review are those that present no more than minimal risk to subjects, and involve only procedures commonly done in clinical settings, such as taking hair, saliva, excreta or small amounts of blood. A study that qualifies for expedited review is held to the same ethical standards of autonomy, beneficence and justice that are used in full board review, but the approval process may take less time.
- Exempt: Some research with humans can be designated as exempt from IRB review. Research that is part of a routine educational experience, or in which participants will be anonymous or effectively de-identified falls into this category and may be granted a certificate of exemption. The proposal must still be reviewed by a member of the IRB to assign exempt status, but the application process may be considerably shorter.
Contact the University IRB if you have questions about the category under which your study falls.
Is deception of subjects allowed when doing research?
As a general rule, deception is not acceptable when doing research with humans. Using deception jeopardizes the integrity of the informed consent process and could harm participants, as well as eroding trust between the public and researchers. In some instances deception is necessary to conduct the research: for example, a study of how the decision-making practices of physicians affect their practice of medicine might be presented as a study of "communication behaviors.” The IRB will carefully review any proposal that suggests using deception or misrepresentation. They will require an in-depth justification of why deception is necessary for the study and the steps that will be taken to safeguard participants, including a plan to debrief subjects at the end of the research.
A form of deception of subjects can occur if the terms of the informed consent are violated by the investigator or other scientists. For example, if a subject consents to have their blood sample evaluated for markers of diabetes and the investigator or other scientists use the blood sample for purposes unrelated to diabetes research, the subject has effectively been deceived about the nature of their research participation and they have been denied autonomous agency over their own actions. The recent court case involving Arizona State University v. the Havasupai tribe illustrates the ethical pitfalls and legal consequences of biological sample sharing without explicit prior consent (Drabiak-Syed, 2010).
Core clerkship material: ISMS Project
Lizbeth A. Adams, PhD, CIP
Director, Office of Research Integrity at Bastyr University
Timothy C. Callahan, PhD
Associate VP of Academics & Research