Lesson 9 - Research with Human Participants
Overview
Introduction
Welcome to this lesson. There is no question that the advance of medical knowledge is an essential front in the ongoing battle against old and new diseases, and that improved techniques, treatment plans, and drugs are necessary to continue to improve lives and alleviate suffering. Although much can be learned through laboratory experiments and computer modeling, researchers frequently require that testing be performed with human subjects, and this introduces an entire array of ethical implications.
Looking Ahead
Medical research involving humans
Competent adult test subjects
Incompetent patients or children
History of medical research’s dark side
Past ethical failures
In this lesson, we’ll be exploring some of the issues that arise with medical research involving humans, first in terms of competent adult test subjects, and then in terms of incompetent patients or children. Medical research has given us miraculous knowledge and uncountable life-saving interventions, but like the history of genetics, the history of medical research also has a dark side, and many of the contemporary concerns about consent and responsible practice are directly related to past ethical failures. Let’s begin by discussing a brief account of this history.
Overview
In some ways, medical experimentation is part and parcel of all medical practice. From the beginning, physicians would try out different possible solutions on a “trial-by-error” approach, without much available theory or science behind the process. When something seemed to work, it would become part of the techniques to be applied in the future. Thus, even in “traditional” approaches to medicine, the results of ad hoc experimentation would be incorporated into the training of the next generation of practitioners.
When scientific knowledge developed to the level of understanding the primary processes in the human body, medical experimentation shifted from unscientific trial and error to something closer to our current understanding of scientifically valid research, which is verifiable and double-blind. But just because experimentation has become scientific, it does not ensure that it is ethical. Indeed, there are numerous horrific examples that could be pointed to in terms of the history of human experimentation, with some of the most atrocious of course being conducted by highly unethical and inhumane methods in Nazi Germany.
Similar experiences were conducted in Manchuria by Japanese researchers during the Second World War. But by no means are the examples limited to these places. Examples of highly unethical practice can be found in the United States, Canada, and elsewhere. The inquiries into the Nazi experiments led to the Nuremberg Code of 1948, which was refined into the Declaration of Helsinki when it was adopted by the World Medical Association a few years later. This code is a set of guidelines that medical research must respect in order to be considered ethically justifiable, and it serves as the foundation also for many national codes of research ethics, including Canada’s Tri-Council Statement.
Randomized, Placebo-Controlled, Double-Blind Research
What does Good Scientific Research Consist of?
Good scientific research has a number of conditions that must be met, including that it be randomized, placebo-controlled, and double-blind.
Randomization
A random set of participants is essential to ensure that local conditions do not skew the results.
Placebo Controls
A placebo is the name for a harmless and therapeutically neutral substance administered to the patient as if it were the real drug. That is, the placebo will have no physiological effect upon the patient or their condition (though sometimes it has a strong psychological effect, since patients come to believe they are being treated). A placebo-controlled group is essential to ensure that the researchers can identify the actual impact of the drug.
Double Blinding
Double-blind is the term used to indicate that the subjects and the researchers are not given information (such as which group has the placebo!) until after the experiment is complete. This is essential to ensure that knowledge of the experiment’s parameters and implementation does not alter the behavior of the participants (on both sides), which could skew the results.
A Good Example
That is, if the experimenter knows patient X has the actual drug and not the placebo, then they may be more likely to “perceive” indication of a cure even if it is not there. Randomized, placebo-controlled, double-blind trials are studies in which research participants are randomly assigned to either an experimental treatment or a placebo and neither they nor the researchers know what they are receiving; these types of trials are meant to provide the gold standard for scientific knowledge.
Some Common Questions
Of course, you should notice some issues arising here! If it is randomized, then what about the persons who might benefit from this treatment who are not randomly selected? Does not beneficence indicate that they should be given access? Or again, is the “placebo” control group essentially being lied to, and if that is the case then how can there be an informed consent? Or again, what if initial tests suggest the drug has negative effects? Don’t the experimenters need to know who is taking the drug and who has the placebo in order to intervene and adjust or stop the experiment? All of these and other considerations should help you to observe that good science and sound ethics do not necessarily come out to the same thing. Thus, the presence and good practice of hospital, university, and governmental groups that approve and supervise medical experimentation has become essential, commonly known as Research Ethics Boards.
Dr. Ewen Cameron
“Dr. Ewen Cameron” By Colin A. Ross
Let us now move to the required reading about Dr. Ewen Cameron who performed mind control experiments at the Allen Memorial Institute in Montreal, one of many leading psychiatrists performing mind control experimentation on unwitting patients with mental illness, prisoners, and even regular citizens.
This Central Intelligence Agency (CIA)-funded research is known to have taken places at top academic universities such as Yale, Harvard, McGill, and others. The subjects of these experiments were not informed of the CIA funding or the mind control purposes of the experiments, never gave informed consent, and never received follow-up assessments. Cameron was, as Ross reports, even part of the American team at the Nuremberg trials performing psychiatric assessments of German war criminals. He must have heard much detail of the Nazi experiments and, in fact, arguably brought these techniques into his work at McGill when he incorporated lysergic acid diethylamide (LSD) into his experiments.
At the time, the brainwashing and re-programing possibilities were actually hailed not as torture, but as a great step forward for psychiatry. Yet clearly, such experiments violated the Nuremberg Code and the Helsinki Declaration
Ross also goes to some length to detail the fact that the funding for the McGill psychiatry department came from military or CIA sources, and the breaches of ethical codes and the significant harm done to patients that resulted.
Biomedical Conflicts of Interest and Therapeutic Misconception
“Biomedical Conflicts of Interest” By Arthur Schafer
Another important factor is funding. A major concern in the contemporary situation is the relationship between academic research institutions and powerful corporations that fund much of the research.
Two famous Canadian cases are outlined in the reading by Arthur Schafer, namely the cases of Nancy Olivieri and David Healy, both who revealed unfavorable results and potential dangers to patients related to the drugs being tested. In both cases, the drug companies funding the research were also large donors to the institution (the University of Toronto), and in both cases the “whistleblowing” physicians found themselves fired, discredited, or subject to damaging accusations.
Therapeutic Misconception
We will now be discussing the role of consent in research in cases where the research subjects have a diminished ability to give informed consent. We explored the notion of informed consent earlier in relation to medical decisionmaking and here, it is important to keep in mind a distinction; health care versus health research.
While both aim to improve human health, health research — such as the testing of new therapies and collection of observational health data — does not directly benefit the participant’s care. They aim to benefit the general understanding and advance the knowledge of human health; they aim to benefit future patients.
Patients who participate in health research frequently commit this therapeutic misconception in thinking that they will be directly benefited in the study. This misconception leads to underestimated risks and overestimated prospects of direct personal benefits. Researchers can sometimes fall prey to therapeutic misconception too because many researchers are also health care providers (HCPs) and may see research as an extension of clinical care. This conception can subtly affect how the researchers design their studies. For instance, think back to the HCP-patient relationships that we discussed earlier in the course. In the therapeutic relationship, we suggested that a good model was the family-centered model by which trust and respect governed the relationship.
But in the case of a pure research setting, the subject is not being treated by a physician with an interest in the patient’s health, but rather is being tested by a researcher with an interest in the experiment’s results and ultimate success. Many argue that this means the informed consent process must be even more stringent, since the patient indeed stands to receive no direct benefit for participation. Any benefit, that is, is indirectly through a vague “benefit to human beings in general.”
Consent in Health Research
What Does Consent Entail in Health Research?
Now let’s discuss informed consent in the health research setting. We discussed informed consent in clinical health care in earlier lessons. Unlike in clinical health care, health research does not directly benefit the subject involved in the research. Since there is no direct benefit to the subject in health research, consent must be rigorously enforced because it can never be assumed or overridden for the “well-being” of the subject. Also, some argue that this requires a much more detailed disclosure of what is being done, what is being sought, and what the risks are of the experiment or study.
That is, rather than trusting a physician to disclose to a patient the necessary information based on a relationship of trust, some argue that a researcher must disclose everything to a potential research subject, even if the subject doesn’t ask to know specifics. The standard of what should be disclosed in a research setting then is more extensive than what should be disclosed in a therapeutic setting, since a “reasonable person” would want different levels of information in each setting.
Halushka v. University of Saskatchewan
This difference is in fact established in Canadian law through the case of Halushka v. University of Saskatchewan (Chapter 9, Case 2). Walter Halushka, a student at the University of Saskatchewan in 1961, volunteered for a research experiment for a new drug. The researchers presented the test as “perfectly safe,” and he was only partially informed about the procedures that would be necessary to monitor the effects of the new anesthetic drug. He was not informed that there was a low, but quantifiable, degree of serious risk such as cardiac arrest.
During the testing, the worst happened, and Mr. Halushka’s life was saved only through a procedure in which his chest was opened up and his heart massaged manually. He was unconscious for four days, and suffered brain damage and other significant side effects.
The courts upheld Mr. Halushka’s lawsuit for trespass and negligence, primarily because he was told it was perfectly safe, not told the drug was new, and not told about a catheter which would be inserted directly into his heart (he was told it would be in an arm vein). In the decision, Justice Hall emphasized that the reasonable person standard requires more disclosure in the research setting since there is no counterweight of the patient’s well-being to justify for withholding information.
Jesse Gelsinger Case
Another relevant case is Jesse Gelsinger (Chapter 9, Case 4); we mentioned this case in the lesson discussing genetic choices and genetic information. Gelsinger died after accepting an injection of corrected genes as apart of a clinical trial at the University of Pennsylvania. The U.S. Food and Drug Administration (FDA) investigation concluded that the scientists involved broke several rules of conduct, including failure to disclose important information such as the side effects of the therapy on patients as well as the deaths of monkeys receiving similar therapy. In addition, the scientists also failed to disclose two patients had experienced serious side effects from the gene therapy; and lastly, they failed to disclose a possible conflict of interest—both the university and the primary researcher had financial stakes in the research.
Wrap-Up
In this lesson, we discussed a number of topics. We started with the past ethical failures in health research, the traditional “trial-by-error” approach. Then we moved on to the scientifically supported modern health research. We discussed randomized, placebo-controlled, double-blind research and why we need them in science.
We discussed the ethical complication that comes with randomized, placebo-controlled, double-blind research. We then turned to the case of Dr. Ewen Cameron who conducted notorious mind control experiments in Montreal.
We also talked about the relationship between academic research institutions and powerful corporations that fund research. Importantly, we visited the distinction between health care and health research, and the very relevant concept of therapeutic misconception. This distinction leads us to understand the difference between consent in a therapeutic setting (health care) and consent in a non-therapeutic setting (health research). It helps us to understand why consent in health research needs to be more stringent than in health care.