Within the context of scientific research involving humans, ethical protections of subjects is a relatively recent thing. For most of human history, the systematic investigation of some question involving humans has taken the attitude that the answer being sought was of the utmost importance. The well-being of the people being experimented upon was secondary, if it was thought of at all. Compounding matters was the dehumanizing view that certain populations were viewed in the same way that we tend to view animals: chattel to be exploited. Criminals, the mentally incompetent, even women and children in some cases, were viewed as a means to an end.
So, what changed?
The beginnings of establishing rules and guidelines to protect people used as subjects in research can be traced back, in large part, to World War II. At the end of the war, the Allied forces held a series of military tribunals to try Axis leaders for various war crimes. Among these was the Doctors' Trial. This trial brought 20 Nazi physicians up on charges of war crimes and crimes against humanity. Their acts went beyond the usual level of unethical behavior toward human subjects and, I think, shone a light on just how bad things can become when there is no sort of ethical oversight. Among the charges were committing "murders, brutalities, cruelties, tortures, atrocities and other inhuman acts" in the course of experiments performed on POWs and civilians without the subjects' consent. It was out of this trial that a 10-point document was developed for the ethical conduct of medical research: the Nuremberg Code.
The Nuremberg Code
During the Doctors' Trial, American physician Dr. Leo Alexander submitted to the Counsel for War Crimes six points that could be used to define legitimate medical research. The tribunal added an additional four points. This list, though lacking legal force, became the basis for ethical reforms in human subjects research. It introduced a number of concepts such as:
- Voluntary informed consent;
- Benefit to society that cannot be obtained any other way;
- Based on previous animal research and prior history of disease/problem;
- Avoidance of unnecessary harm or injury;
- Death or disabling injury should not be a suspect outcome of the experiment;
- Risk should not outweigh benefit of solution to humanity;
- Subject should be protected against possibility of injury, disability or death;
- Conducted only by scientifically qualified persons;
- Subject can end participation at any time; and
- Researcher in charge can end subject participation for the well-being of the subject
These ten concepts form the significant basis for the ethical conduct of research involving human subjects. However, the World Medical Association expanded on it, relaxing some points and adding others.
Declaration of Helsinki
The World Medical Association adopted the Declaration of Helsinki in June 1964. It has been amended six times, growing from an initial 11 points (10 from the Nuremberg Code and an additional one tying it to the Declaration of Geneva) to 35 paragraphs, as of the 2008 revision. Like the Nuremberg Code, the Declaration of Helsinki is not a legally binding document, but rather an international code of ethics for the treatment of human subjects and conduct of research. In addition to the concepts of informed consent, avoidance of undue harm and basic scientific qualifications, the Declaration of Helsinki adds several important points. For example, it requires that research protocols not only address the ethical considerations of the study, but also that protocols be submitted for review by an independent ethics committee. And where the Nuremberg Code restricted allowable subjects to only those who are capable of giving free and informed consent, the Declaration of Helsinki allows for consent by an authorized representative where the subject is unable to give consent.
That expansion of consent is an important consideration in a vaccinated vs. unvaccinated study as proposed in my previous post. Clearly, infants are unable to give consent. The Declaration of Helsinki, therefore, allows for a parent or legal guardian to give consent on behalf of the infants. This easing of obtaining consent, however, comes with the addition of numerous additional protections. Vulnerable populations (e.g., infants) may only be involved in research, for example, when the issues under study are likely to benefit the vulnerable population and where the question cannot be studied in a competent population.
Despite efforts like the Nuremberg Code and Declaration of Helsinki to provide ethical guidance to medical researchers, significant ethical lapses still occurred, such as in the Tuskegee Syphilis Study. From 1932 to 1972 in Tuskegee, AL, the U.S. Public Health Service conducted a study of the natural progression of untreated syphilis in impoverished black men. The subjects were given free medical exams, meals and burial insurance. The researchers did not inform the subjects that they had syphilis, nor did they inform the subjects about or provide penicillin when it was validated in 1940 as an effective cure for the disease. The actions of the researchers led to the needless deaths of those infected, transmission of syphilis to the wives of the subjects and children born with congenital syphilis.
The horrible conduct in the Tuskegee study prompted the United States Congress to enact the National Research Act of 1974, creating the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. One charge for the Commission was to
identify the basic ethical principles that should underlie the conduct of biomedical and behavioral research involving human subjects and to develop guidelines which should be followed to assure that such research is conducted in accordance with those principles.
The Belmont Report
In February 1976, the Commission met over four days at the Belmont Conference Center in Elkridge, MD. Over the next three years, the Commission consulted experts and specialists and, on April 18, 1979, published their findings as "Ethical Principles and Guidelines for the Protection of Human Subjects of Research," more commonly known as The Belmont Report.
The Commission found that while the Nuremberg Code and subsequent codes of conduct, including the Declaration of Helsinki, provided both general and specific rules, they sometimes conflict, are often hard to understand and may be inadequate to apply to complex situations. Their goal, therefore, was to provide a broader ethical construct on which to base more specific rules for the conduct of human subjects research, while also clarifying the distinction between research (activities taken to "test an hypothesis, permit conclusions to be drawn, and thereby to develop or contribute to generalizable knowledge") and practice ("interventions...designed solely to enhance the well-being of an individual patient...and that have a reasonable expectation of success"). The Belmont Report enumerates three basic ethical principles that should apply to all research involving human subjects: respect for persons; beneficence; and justice.
Respect for persons encompasses both autonomy, or the right of an individual to decide for themselves whether or not to participate in research, and protection for those with diminished autonomy. The example used by the Commission to illustrate the complexity of this issue is research involving prisoners. As adults capable of self-determination, they should be allowed to volunteer for research, if they choose. At the same time, however, the prison environment may lead to the prisoners being coerced or unduly influenced to participate, potentially against their best interests.
Beneficence, as applied in the Report, establishes an obligation on the part of the researcher to not only respect the autonomy of the individual, but also to protect the subjects. This involves two concepts. First, do not harm. Second, maximize the possible benefits and minimize the possible harms. Like respect for persons, this principle can often carry some conflict. In order to provide benefit may require that the subject be exposed to some harm. The Report provides an example that is very pertinent to the vaccinated-unvaccinated question:
A difficult ethical problem remains, for example, about research that presents more than minimal risk without immediate prospect of direct benefit to the children involved. Some have argued that such research is inadmissible, while others have pointed out that this limit would rule out much research promising great benefit to children in the future.
Finally, the principle of justice involves who receives the benefits of the research and who bears the burdens. In practice, this means that research subjects (or the populations they represent) should not be denied their fair share of the benefits nor should they unduly bear a greater share of the risks or other burdens of research. As an example, the Tuskegee Syphilis Study that sparked the creation of the Belmont Report used exclusively rural black men to study the untreated course of syphilis, even though the disease is not unique to that population and even after an effective treatment was developed.
The Belmont Report also discusses how the principles of respect, beneficence and justice apply to informed consent, risk/benefit assessment and subject selection.
These three documents provide the context in which to view human subjects research and the regulations governing human research (45 CFR 46 in the U.S., and of particular note for research involving children, Subpart B and Subpart D). Orac, at Respectful Insolence, has a recent post going a bit more in depth about ethics and medical research that is well worth reading. In my next post, I will examine some of the ethical issues of a prospective, RCT vaccinated vs. unvaccinated study in view of the principles presented above and referring to Federal regulations. The full series of posts can be found here.
Vaccinated vs. Unvaccinated Part 1 - An RCT Overview
Vaccinated vs. Unvaccinated Part 3 - Ethical Evaluation
Vaccinated vs. Unvaccinated Part 4 - The Legal Perspective
Complete Vaccinated vs. Unvaccinated Series