Our discussion begins by answering the question: “What are the basic ethical principles?” These four principles, now mainstream, were first championed by Beauchamp and Childress in their book Principles of Biomedical Ethics [8]. They proposed an analytical framework composed of: (1) autonomy, (2) beneficence, (3) non-maleficence, and (4) justice. Autonomy refers to the rights that a competent and mature patient has in making decisions regarding their health care. Beneficence outlines how clinicians and researchers should make decisions that maximize the benefit for a patient, specific for their situation. Non-maleficence is the idea that harm should be avoided whenever possible and risks reduced at all costs. Justice refers to the equal distribution of health resources, void of discrimination. We will now go into a detailed discussion of each ethical pillar.

Autonomy directly opposes the obsolete perspective that the physician is the ultimate authority. It is a concept that enables the patient to share, alongside medical providers, in his or her own care. Autonomy is particularly important to participants in research trials because their enrolment is not only optional, but they may actually receive little benefit from enrolling. And because physicians are in a fiduciary relationship with their patients, they are susceptible to intimidation and coercion. Autonomy therefore stresses the importance of protecting patients’ personal and best interests. Allowing patients the opportunity to drop out of a study at any point in a study is one of many ways to protect patient autonomy.

Allen Hornblum’s book Acres of Skin [9] showcases how one American dermatologist exploited prison inmates, ultimately compromising patient autonomy. The book, based on real government documents, inquiries, and interviews, reveals some concerning research that took place in Philadelphia’s Holmesburg Prison [9]. The lead investigator behind the experiments, Dr. Albert Kligman, was a prolific dermatologist and researcher renowned for developing Retin-A^® and the concept of cosmeceuticals, among many other discoveries. He bridged the gap and blurred the lines between cosmetics and medicine. Funded in part by the University of Pennsylvania, prisoners were paid for each experiment they enrolled in. The amount of money they received for experiments ranged from $10 to $300 per experiment [9] and was disproportionately higher than the money they would receive from more laborious jobs in prison. The lure of money was enough for prisoners to undergo sometimes uncomfortable testing, and it was thought that the vast majority of these prisoners decided to enroll. Many of them were fearful of the experiments, but carried through with it regardless.

Superficially speaking, one could argue that the prisoners did have some patient autonomy. They did have a choice regarding whether to enroll in the research program, and what type of experiment they preferred. Still, this argument is inherently flawed because prisoners are in a vulnerable position in which their autonomy and personal liberties are already restricted. Monetary incentives were used to take advantage of their position, and represent a means of stripping away their autonomy. The prisoners were not given a large amount of money; but, given their bleak environment, they were compelled to carry through with it even if they were fearful of the experiments. With very few other options, enrolling in these experiments was a way for the inmates in Holmesburg prison to make a moderate income compared to working elsewhere. Owing to this incident, hundreds of Philadelphia inmates filed a lawsuit against the researchers, industries, and institutions involved [10]. Unfortunately, the lawsuit was unsuccessful because it took place beyond the statute of limitations [11]. University of Pennsylvania later released an apology for the Holmesburg experimentation [12], which ended as a consequence of regulations put in place that prevented coercion and restricted the use of prisoners as test subjects. The National Research Act of 1974 was established to restrict the use of prisoners as test subjects, and to put in place ethical review boards within research institutions [12]. These regulations were enacted in part as a consequence of the Tuskegee Syphillis study and later became the Belmont Report. We will discuss the Tuskegee study later on in this chapter.

What would have been the ethical thing to do? Admittedly, there are advantages to using prisoners as research subjects, both from a scientific perspective as well as from the prisoner’s point of view. Inmates are human beings like anyone else, and will have medical conditions that would benefit from new drug trials. Certain diseases are more prevalent in prison systems, and it would be beneficial for researchers to have access to this environment so as to learn more about how to prevent disease in prisons. Inmates may also gain intrinsic reward by gaining a sense that they are helping the greater community by volunteering [13]. They also benefit from the attention given to them by “outsiders”, which instills in them a sense of societal importance. In light of all of this, physicians should be extra cautious, not only to respect autonomy, but to protect it among an otherwise compromised population. The higher prevalence of mental illness adds to the need to protect autonomy for those that may lack capacity.

One review article outlines several recommendations that address the use of prisoners as research subjects [13]. First, material incentives such as disproportionate sums of money or food should not be used. Payment, if any at all, should be proportional to wages earned in other areas of the prison. Doing so will allow inmates the option to pursue “equivalent” opportunities rather than become lured into something they do not want to do for external gains. Second, only therapeutic research should be performed. Non-therapeutic studies garner no benefit for participants, and have low yield in terms of the benefit-risk ratio. They mainly cause unnecessary risk exposure. In the case of Dr. Kligman’s experiments, many of the studies were non-therapeutic and driven by industry, money, or curiosity. The final recommendation is that external reviewers should be employed to provide an unbiased authority over the experiments and institutions involved in the research.

Clearly there needs to be a careful balance between promoting useful research and protecting prisoners. Our viewpoint on research with prisoners is in line with guidelines outlined in the Belmont Report. We feel that research involving prisoners is ethical on the assumption that there be [14]:

The line “I will come for the benefit of the sick” from the Hippocratic Oath is a fitting reminder for physicians to always try and help others. Beneficence pertains to the idea that physicians should act to help others. They should promote the best treatment for that patient and minimize harm as much as possible. The Belmont Report suggests two general rules with beneficence: (1) do not harm, and (2) maximize benefit while minimizing harm [14]. Especially true when conducting clinical trials, scientists should not put their research subjects in harm’s way and should act in the best interest of their patients (Table 8.2).

A dilemma with randomized control trials is the paradox between beneficence and randomization. In an ideal scientific setting, researchers should genuinely have no idea about what treatment is the more effective one. However, most physicians do have an inclination about which treatment might work better [15]. Or, they may gain insight as the study progresses based on preliminary data. Given these assumptions, how can a physician continue to randomize patients if they already have an idea about what treatment is more effective? One explanation that some have proposed is the notion of “community equipoise” [16] outlined by Gifford. The idea is that an individual researcher may have formed an opinion about the treatments, but because there is uncertainty among the greater scientific community, the researcher can continue randomizing patients ethically. Another way around this dilemma is to ensure that preliminary results are not disclosed to the physicians involved. Doing so will prevent them from having a preference for treatment. That said, one could argue that the physician is not providing the best care for the patient if he knows that there is data out there which may help him provide better care. Gifford’s paper argues that defending randomization using “community equipoise” is insufficient. In order to justify randomized control trials, the therapeutic duty needs to be relaxed and informed consent more comprehensive.

Another dilemma faced with clinical trials is whether or not the use of placebos is ethical. Placebo controls are attractive because they strengthen statistical significance and establish a baseline as to whether the drug is better than no treatment. But their use remains controversial. Hothman suggests that placebos deny patients from receiving the best available treatment. Additionally, he argues that the informed consent process should not allow patients to agree to a lesser treatment. More ethically sound are clinical trials that compare an experimental group with an established drug. This approach is less controversial because, at the very least, the participants are receiving treatment, which may sometimes be the gold standard, with proven benefit.

Stopping a clinical trial early because of demonstrated benefit is becoming an increasingly common practice [17

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