Research Ethics

• History of Human Subjects in Research
  • Examples: Tuskegee Study, WWII/Nazi Experiments
  • Nuremberg Code
  • Belmont Report
• Ethical Principles
• Institutional Review Boards
• Informed Consent

Objectives:

1. Describe historical aspects that led to the creation of various codes of ethics.
2. Define key ethical principles in research.
3. Describe an Institutional Review Board’s key goals
4. Identify procedures to adhere to ethical principles and protect study participants

Historical Aspects of Research Ethics and Key Ethical Principles in Research

We learn from history. Hopefully, atrocities in history teach us to do better and not make the same mistakes. However, we must not forget history and this is especially true in research. Unfortunately, violations of ethical principles and the moral code have occurred as recent as the last few centuries.

Let’s learn about some key history events that have resulted in harm to humans and some ethical codes that have resulted from these events.

World War II/Nazi Experiments: Between 1939 and 1945, at least seventy medical research projects involving cruel and often lethal experimentation on human subjects were conducted in Nazi concentration camps. More than seven thousand victims of such medical experiments have been documented. Victims include Jews, Poles, Roma (Gypsies), political prisoners, Soviet prisoners of war, homosexuals, and Catholic priests.

Nazi physicians organized trials of antibiotic and homoeopathic treatments in the concentration camps at Dachau and Ravensbrück. Healthy prisoners were given injections from the festering tissues of other inmates who had wound infections. In some people, small pieces of wood and glass were placed in open wounds, in order to mimic war injuries more realistically. The victims were then treated with homoeopathic preparations or various applications of sulfonamides; some received no therapy at all. About a third of the victims died. All these experiments followed a scientific logic that was outdated at the time, and which took no account whatever of the wellbeing of those involved in research. The surviving victims had irreversible physical damage and severe psychological trauma (Roelcke, 2004).

Experiments in the context of aviation medicine were aimed at finding methods to help pilots survive after their planes had been hit at very high altitudes, or after an emergency landing at sea. The experiments, carried out in the Dachau concentration camp, focused on physiological questions, such as the effects on the human body of low pressure at high altitude, or of drinking salt water. For the high-altitude experiments, about 200 people were chosen from the camp prisoners, at least 70 of whom died during the experiments in a specially designed low-pressure cabin, or were killed afterwards to study the pathological changes in their brains. Judged strictly on scientific terms, the methods and results of some of these experiments were apparently innovative and useful. The US Air Force continued some of this research after the war and published the results in cooperation with a number of German physicians involved in the original experiments.

The existing evidence illustrates an inherent logic of these research endeavors: the urge to establish new knowledge superseded any respect for the people who suffered in these experiments. Faced with the challenge of a given medical question, researchers sought opportunities to carry out the experiments required to solve it. It was in concentration camps, asylums, and hospitals in the occupied territories that they found these opportunities because existing legal regulations and sanctions did not apply there (Roelcke, 2004).

The list goes on… freezing/hypothermia experiments, twin children experiments, radiation exposure experiments… all with a common theme: The victims had no choice whether or not to participate. Even after the Nuremberg Code resulted from these experiments, with the first principle of “Informed Consent”, the next atrocity happened years later: The Tuskegee Syphilis Study. Had we not learned?

Tuskegee Syphilis Study: The U.S Public Health Service (USPHS) Syphilis Study at Tuskegee was a clinical study conducted between 1932 and 1972. The study was intended to observe the natural history of untreated syphilis. As part of the study, researchers did not collect informed consent from participants and they did not offer treatment, even after it was widely available. The study ended in 1972 on the recommendation of an Ad Hoc Advisory Panel, convened by the Assistant Secretary for Health and Scientific Affairs, following publication of news articles about the study. In 1997, President Clinton issued a formal Presidential Apology, in which he announced an investment to establish what would become The National Center for Bioethics in Research and Health Care at Tuskegee University. Many records can be found in the National Archives.

After the study, sweeping changes to standard research practices were made. Efforts to promote the highest ethical standards in research are ongoing today (CDC, 2022).

Nuremberg Code

In response to the Nazi experiments, a trial of war criminals resulted. The main trial at Nuremberg after World War II was conducted by the International Military Tribunal. The tribunal was made up of judges from the four allied powers (the United States, Britain, France, and the former Soviet Union) and was charged with trying Germany’s major war criminals. After this first-of-its-kind international trial, the United States conducted 12 additional trials of representative Nazis from various sectors of the Third Reich, including law, finance, ministry, and manufacturing, before American Military Tribunals, also at Nuremberg. The first of these trials, the Doctors’ Trial, involved 23 defendants, all but 3 of whom were physicians accused of murder and torture in the conduct of medical experiments on concentration-camp inmates.

The resulting Nuremberg Code has the following principles:

1. The voluntary consent of the human subject is absolutely essential.
2. The experiment should be such as to yield fruitful results for the good of society, unprocurable by other methods or means of study, and not random and unnecessary in nature.
3. The experiment should be so designed and based on the results of animal experimentation and a knowledge of the natural history of the disease or other problem under study that the anticipated results will justify the performance of the experiment.
4. The experiment should be so conducted as to avoid all unnecessary physical and mental suffering and injury.
5. No experiment should be conducted where there is an a priori reason to believe that death or disabling injury will occur; except, perhaps, in those experiments where the experimental physicians also serve as subjects.
6. The degree of risk to be taken should never exceed that determined by the humanitarian importance of the problem to be solved by the experiment.
7. Proper preparations should be made and adequate facilities provided to protect the experimental subject against even remote possibilities of injury, disability, or death.
8. The experiment should be conducted only by scientifically qualified persons. The highest degree of skill and care should be required through all stages of the experiment of those who conduct or engage in the experiment.
9. During the course of the experiment the human subject should be at liberty to bring the experiment to an end if he has reached the physical or mental state where continuation of the experiment seems to him to be impossible.
10. During the course of the experiment the scientist in charge must be prepared to terminate the experiment at any stage, if he has probable cause to believe, in the exercise of the good faith, superior skill, and careful judgment required of him, that a continuation of the experiment is likely to result in injury, disability, or death to the experimental subject.

Belmont Report

Due to ongoing atrocities, The Belmont Report was written by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. The Commission, created as a result of the National Research Act of 1974, was charged with identifying the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and developing guidelines to assure that such research is conducted in accordance with those principles. Informed by monthly discussions that spanned nearly four years and an intensive four days of deliberation in 1976, the Commission published the Belmont Report, which identifies basic ethical principles and guidelines that address ethical issues arising from the conduct of research with human subjects.

The basic ethical principles of the Belmont Report include:

1. 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. The principle of respect for persons thus divides into two separate moral requirements: the requirement to acknowledge autonomy and the requirement to protect those with diminished autonomy.

2. Beneficence.

Persons are treated in an ethical manner not only by respecting their decisions and protecting them from harm, but also by making efforts to secure their well-being. Such treatment falls under the principle of beneficence. The term “beneficence” is often understood to cover acts of kindness or charity that go beyond strict obligation. 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.

3. Justice.

Who ought to receive the benefits of research and bear its burdens? This is a question of justice, in the sense of “fairness in distribution” or “what is deserved.” An injustice occurs when some benefit to which a person is entitled is denied without good reason or when some burden is imposed unduly. Another way of conceiving the principle of justice is that equals ought to be treated equally. However, this statement requires explication. Who is equal and who is unequal? What considerations justify departure from equal distribution? Almost all commentators allow that distinctions based on experience, age, deprivation, competence, merit and position do sometimes constitute criteria justifying differential treatment for certain purposes. It is necessary, then, to explain in what respects people should be treated equally. There are several widely accepted formulations of just ways to distribute burdens and benefits. Each formulation mentions some relevant property on the basis of which burdens and benefits should be distributed. These formulations are (1) to each person an equal share, (2) to each person according to individual need, (3) to each person according to individual effort, (4) to each person according to societal contribution, and (5) to each person according to merit.

Declaration of Helsinki

In 1964, the World Medical Association adopted what is known as the Declaration of Helsinki, in Helskini, Finland. They developed the declaration as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data.

The General Principles:

1. The Declaration binds the physician with the words, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall act in the patient’s best interest when providing medical care.”
2. It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, including those who are involved in medical research. The physician’s knowledge and conscience are dedicated to the fulfilment of this duty.
3. Medical progress is based on research that ultimately must include studies involving human subjects.
4. The primary purpose of medical research involving human subjects is to understand the causes, development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, procedures and treatments). Even the best proven interventions must be evaluated continually through research for their safety, effectiveness, efficiency, accessibility and quality.
5. Medical research is subject to ethical standards that promote and ensure respect for all human subjects and protect their health and rights.
6. While the primary purpose of medical research is to generate new knowledge, this goal can never take precedence over the rights and interests of individual research subjects.
7. It is the duty of physicians who are involved in medical research to protect the life, health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. The responsibility for the protection of research subjects must always rest with the physician or other health care professionals and never with the research subjects, even though they have given consent.
8. Physicians must consider the ethical, legal and regulatory norms and standards for research involving human subjects in their own countries as well as applicable international norms and standards. No national or international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research subjects set forth in this Declaration.
9. Medical research should be conducted in a manner that minimizes possible harm to the environment.
10. Medical research involving human subjects must be conducted only by individuals with the appropriate ethics and scientific education, training and qualifications. Research on patients or healthy volunteers requires the supervision of a competent and appropriately qualified physician or other health care professional.
11. Groups that are underrepresented in medical research should be provided appropriate access to participation in research.
12. Physicians who combine medical research with medical care should involve their patients in research only to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician has good reason to believe that participation in the research study will not adversely affect the health of the patients who serve as research subjects.
13. Appropriate compensation and treatment for subjects who are harmed as a result of participating in research must be ensured.

The declaration goes on to cover principles of:

Risks, Burdens, and Benefits: Medical research involving human subjects may only be conducted if the importance of the objective outweighs the risks and burdens to the research subjects.

Vulnerable Groups and Individuals: All vulnerable groups and individuals should receive specifically considered protection.

Scientific Requirements and Research Protocols: Medical research involving human subjects must conform to generally accepted scientific principles, be based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be respected.

Research Ethics Committees: The research protocol must be submitted for consideration, comment, guidance and approval to the concerned research ethics committee before the study begins. This committee must be transparent in its functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly qualified. It must take into consideration the laws and regulations of the country or countries in which the research is to be performed as well as applicable international norms and standards but these must not be allowed to reduce or eliminate any of the protections for research subjects set forth in this Declaration.

The committee must have the right to monitor ongoing studies. The researcher must provide monitoring information to the committee, especially information about any serious adverse events. No amendment to the protocol may be made without consideration and approval by the committee. After the end of the study, the researchers must submit a final report to the committee containing a summary of the study’s findings and conclusions.

Privacy and Confidentiality: Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their personal information.

Informed Consent: Participation by individuals capable of giving informed consent as subjects in medical research must be voluntary. Although it may be appropriate to consult family members or community leaders, no individual capable of giving informed consent may be enrolled in a research study unless he or she freely agrees.

Use of Placebo: The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s), except in the following circumstances:

Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention.

Extreme care must be taken to avoid abuse of this option.

Institutional Review Board

An Institutional Review Board (IRB) approves and provides oversight of research studies and projects that involve human subjects. The primary mission of an IRB is to ensure the protection of the rights and welfare of all human participants in research. Under FDA regulations, an Institutional Review Board is group that has been formally designated to review and monitor biomedical research involving human subjects. In accordance with FDA regulations, an IRB has the authority to approve, require modifications in (to secure approval), or disapprove research.

Before undertaking a study, researchers must submit research plans to an IRB and must also undergo any training that the IRB has established at a given facility or institution. We have an IRB here at Utah University, and all faculty, staff, and students must submit an IRB application if they are planning on conducting systematic research with human subjects.

With particular focus in ethical protection of human subjects is the rights of special vulnerable groups. These include:

• Children: Children do not have the competence to given informed consent, so the children’s parents or guardians must give consent. However, the children must give assent (affirmative agreement)as well.
• Mentally or emotionally disabled people: Individuals whose disability makes it impossible or difficult to obtain informed consent must have legal guardian consent.
• Severely ill or physically disabled people: For these individuals, it might be necessary to assess their ability to make reasoned decisions about study participation.
• The terminally ill: These individuals can seldom expect to personally benefit from research, so the risk/benefit ration needs to be very carefully assessed.
• Institutionalized people: These individuals may be coerced to participate with fear of jeopardizing their care or parole status. Voluntary nature of the research needs to be emphasized.
• Pregnant women: The U.S. government has issued additional requirements governing research with pregnant women and fetuses.

Ethical Principles and Protecting Study Participants

In addition to applying to an IRB, the researcher must also have procedures in place to protect human subjects from risk of harm.

One strategy that helps to minimize this risk is to do a risk/benefit assessment. With this assessment, researchers evaluate whether the benefits of participating in a study are in line with the costs.

View the Risk-Benefit Assessment from UCLA research administration: https://ohrpp.research.ucla.edu/assessing-risks/ 

Another important method for safeguarding research participants is to obtain an informed consent. In an informed consent, the study is explained in simple terms, with explanations of their power of free choice. The consent contains information about the study purpose, specific expectations of the participation, potential costs, any benefits, the voluntary nature, and who to contact for more information, if needed.

In some situations, consent is implied. For example, if a nursing instructor were to walk into a classroom and explain that they are conducting a survey for research, and then hand the survey out to whomever wants it, it is implied consent if you proceed to fill the survey out.

Study participants also have the right to keep their information private and in strict confidence. A participant’s right to privacy is protected.

Anonymity is the most secure means of protecting confidentiality. This occurs when the researchers cannot link the data to the individual. For example, if in the above example, you filled out the survey and it did not contain your name, it would be anonymous. The researcher would not know who filled out each survey.

Sometimes there is confidentiality in the absence of anonymity. A promise of confidentiality is given to the participant that even though the researcher may have some private information about them (e.g. birth data, name, etc.), the information will be secured in locked files, substituting identification numbers for names, and reporting only on aggregate data for groups of participants.

Finally, an important concept to also note is debriefing. Debriefing sessions are sometimes advisable to have following data collection so that participants can ask questions or share concerns. It is up to the researchers to whether they decide to share study findings with the participants after data has been analyzed, but this is a good practice to have if reasonable to do so.

In summary, it is vital for nurses and healthcare providers to be knowledgeable about research ethics. Be alert to vulnerable patients and that their rights are upheld. It is everyone’s position and role to advocate for ethical rights of all people.

EBP Poster Application! Appraise the ethical components of the studies you are reviewing. Anything pop out to you? How many studies have stated that they had IRB approval? Were research participants adequately protected? Discuss any obvious issues in your Discussion section and make notes in your Synthesis of Evidence Table.

References & Attribution

“Green check mark” by rawpixel licensed CC0.

“Magnifying glass” by rawpixel licensed CC0

Centers for Disease Control and Prevention. (2022). The U.S. Public Health Service Syphilis Study at Tuskegee. https://www.cdc.gov/tuskegee/index.html

Roelcke, V. (2004). Nazi medicine and research on human beings. The Lancet, 364, 6-7.