Ethics on trial

When a new treatment is administered to a patient and an improvement in her condition is observed, the possibility of drawing a conclusion from the fact is hindered by the absence of a counterfactual: possibly the patient would have recovered anyways if left untreated, or maybe a different treatment would have been more effective.

For the concept to work as intended, though, the administration of the experimental treatment should be the sole difference between the experimental and the control group. In actual trials, this is clearly an idealisation: internal variability of groups and contingent differences between groups will introduce confounding factors that affect the possibility to draw conclusions from a trial.

Several aspects of the scientific design of trials have precisely the objective of minimising this kind of interferences on the results. One of the most notorious such aspects is randomised allocation of subjects, typically associated with blindfolding of participants and possibly also of investigators. Patients entering a trial are assigned to either the experimental or the control group following a non-predictable, chance-based procedure, and neither they nor the investigators and the participating physicians know to which arm they have been assigned.

This procedure has the primary objective of removing subjective interferences, for instance, the possibility that investigators assign healthier patients to one arm of the study to begin with [ 6 ]. Because of its scientific credentials, the RCT methodology is currently considered the gold standard in treatment evaluation.

Over the past several decades, RCTs prevailed over clinical judgement, case report, and observational studies as evidential standards in medicine, largely due the effort of the movement known as evidence-based medicine [ 8 ].

Nowadays, clinical trials are large and tightly regulated enterprises that have to comply with ethical requirements while at the same time maintaining high epistemic standards, in a balance that becomes increasingly difficult as the research questions become more sophisticated. The general problem with the ethics of clinical trials stems from the fact that those who stand to gain from the trial results are not the same that bear the risk and burden of trial participation.

Participation in a clinical trial entails an increased level of risk with respect to ordinary clinical care, particularly due to the potential for exposure to unexpected effects of a new treatment. These risks are actually not offset by a prospective clinical benefit, since the primary end of the trial is not that of treating trial participants but rather that of producing generalisable medical knowledge.

In the following, we will see that this ethical tension has several facets, according to which aspect of the RCT is put in the spotlight. For each of the problematic aspects that will be examined—informed consent, use of placebo, randomisation, and protection of participants—the author will provide a brief introduction, then present the ethical principles and concepts that come into play, and finally discuss the most relevant issues that are still open on the subject.

The past history of medical research features several episodes in which the burdens of research participation were placed disproportionally on trial participants, either by deceiving them with the promise of a cure or by deliberately concealing that they were taking part in research.

In our modern ethical conception, this is no longer considered acceptable, and all research conducted on human subjects must be pre-emptively accepted by the subject themselves through the procedure known as informed consent. One of the most important ethical constructs of modern biomedical ethics, informed consent is nowadays an essential condition both for therapy and research. Written authorisation forms were occasionally submitted to participants also in the early times of medical experimentation.

In the modern conception, consent to a therapy or a research protocol must possess three features in order to be valid. It should be voluntarily expressed, it should be the expression of a competent subject, and the subject should be adequately informed. Even though all the three components of informed consent have problematic aspects in their empirical application, the notion of informed consent is most often put to question because of the difficulty in specifying what is an adequate level of information for the consent to be valid [ 9 ].

Information that makes consent valid is generally thought to include the understanding of the risks and benefits of the treatment s that patients may receive, understanding of the procedures that the participant may undergo, including, in the case of RCTs, also blinding and randomisation, understanding that participation in research is voluntary, and finally understanding of the purpose of the research.

What counts as an adequate level of information at each of these stages is notably difficult to define. In part, this issue presents itself also in the context of medical care, where informed consent of the treated subject is necessary for performing any diagnostic or therapeutic intervention.

This means that the patient should have an understanding of the diagnostic or therapeutic procedure, its risks and prospective benefits; something which is clearly challenging for the MD to provide in case of complex procedures [ 10 ]. In medical research, however, the issue has an additional twist due to the fact that the aim of research is not the direct benefit of research participants. Despite the chance that participating patients might receive a therapeutic benefit while enrolled in a trial, this is not the primary end of the trial.

Participants may fail to recognise that the purpose of the study is not to find the best therapy for them , thus falling in what is called the therapeutic misconception [ 11 ]. According to the said authors, this attitude is misguided and it is potentially conducive to the exploitation of participants.

Personal expectations about treatment entertained by both patients and investigators may play an unexpectedly large role on the progress of a therapy. For this reason, the scientific test of a new intervention may require that patients in the control group receive a placebo. Placebos are interventions that lack the active principle of the experimental treatment but that are otherwise indistinguishable from it. A first issue concerning the use of placebos concerns the problem of deception.

Patients on the placebo arm of a clinical trial must be made to believe they are receiving a working treatment, even though they are not, for the placebo effect to play a role at all. Despite the appearances, however, it is contentious that placebo-controlled trials PCTs are inherently deceptive towards participants.

This is because participants are actually informed, as they consent to the study, that they will not be told whether they are receiving active medication or placebo [ 13 ]. There is, however, a most serious issue with the use of placebo, i. For many conditions, not receiving an active treatment exposes the patients to higher levels of pain, an aggravation of their conditions, or even the risk of death.

In such situations, clearly, the use of placebos is downright unethical, because the patients on the placebo would be harmed for the sole benefit of third parties—namely for the scientific achievement of the trial completion. In some such cases, the traditional placebo-controlled design can be modified so to use the same population of patients to study both the placebo response and the response to the active treatment, thus avoiding that some in-trial patients are left untreated.

This kind of trial is called a crossover trial because patients in the trial cross over at predetermined time points from the placebo to the treatment arm and vice versa [ 14 ]. However, these non-conventional design options are not applicable in all situations; more importantly, in some cases, measuring the effectiveness of the new treatment as compared with placebo is less relevant than confronting the new treatment, within a clinical setting, with the established standard treatment for the illness under study.

In such cases, there is the possibility to conduct an active-controlled trial ACT. Even though it might appear that there is a clear ethical and scientific rationale to the use of active controls in place of placebo controls, the conduct of ACTs is nonetheless controversial. This issue, known as the problem of assay sensitivity , is a subject of critical discussion [ 16 , 17 ].

In most of the ethical regulations and research guidelines, the use of placebo controls is subjected to a delicate tradeoff between the stringency of the scientific rationale for using it, and the possibility of harm for participating patients. RCTs involve, by definition, randomisation and often blindfolding of participants.

These two epistemic devices are needed in order to rule out the most obvious perturbations of the trial result due to the interference from the investigators or the patients themselves. However, randomisation and blinding may come to conflict with the individual interests of those participating in the trial. A first reason for this conflict is that, when randomisation and blinding are in place, patients cannot enjoy individualised treatment decisions responding to their condition [ 18 ].

This, however, is something patients explicitly consent to when they endorse trial participation. Randomisation between the two arms of the study does, however, raise a further ethical concern that is not so easily dismissed.

By entering an active-controlled RCT, participating patients stand a chance of receiving the treatment that will eventually turn out to be inferior. This is especially problematic if the experimental treatment proves to be worse than the standard that was available outside of trial, since it is a recognised ethical principle that patients should receive the best proven standard of care whenever feasible see [ 3 ].

Apparently, then, randomisation harms trial participants that, by entering the trial, may be denied the best standard of care available. The view that is currently prevalent in the ethical literature is that equipoise , denoting an epistemic state of indifference between two treatments, can relieve this ethical tension. Notwithstanding its success as an ethical paradigm, however, equipoise has critics. A first problem is that of identifying under which conditions equipoise is present given a particular clinical question [ 21 ].

Furthermore, an all but obvious point is whose equipoise or indifference should be morally relevant. While the currently predominant notion, based upon considering the state of knowledge of the scientific community, appears as the most reasonable choice, other options may have a sound rationale as well. For instance, at least for some conditions, equipoise of the participating patients should be just as relevant, since we can hardly expect a patient to be indifferent between, say, an invasive surgical procedure and a therapy based on oral drug administration [ 22 ].

Despite the problems just mentioned, however, equipoise remains a workable ethical paradigm for adjudicating the ethics of clinical trials, routinely used by ethical boards in research hospitals in taking decisions about the approval of new studies.

It is worth mentioning, in closing the section, that medical investigators and biostatisticians in the past have strived for finding a methodological solution in order to minimise the chance that patients are exposed to the less effective treatment. Techniques such as unequal randomisation—i. However, such methodological solutions pose more ethical problems than they solve, given the difficulty of justifying the ethics of enrolling in the trial the patients that end up in the non-preferred arm.

As discussed in opening the section, in clinical research, there exists a gap between those who are exposed to the risk of a medical intervention—the trial participants—and those who are the intended beneficiaries of the trial results—future patients and society at large.

The existence of this gap has informed the conception of most ethical guidelines that are currently in use, which were created with a keen eye to protecting participants from the risks and the burdens of research. Mostly, two considerations speak against it.

The first point is the observation that the sole effect of such strict regulation in developed countries has been that of encouraging the outsourcing of trials conduct to countries where standards for the protection of participants are lower. This is clearly an issue, also due to the fact that both the national states involved and the prospective participants individually often find themselves in a situation of economic vulnerability and captivity towards the large pharmaceutical groups that are running the trial see [ 24 ] and [ 25 ].

Thus, strong protection norms prove ultimately ineffective in warranting high levels of protection to participants in a globalised setting, appearing on the contrary to foster new forms of exploitation. Negotiating the adequate level of protection that can be set as a global standard for medical research has proven challenging, as testified by the continuing effort in revising of the Helsinki Declaration [ 26 ].

A second argument that has been raised against the current paradigm concerns the issue of paternalism [ 27 ], i. A patient participating in a trial might wish to take a higher level of risk for the sake of an individually gauged perceived benefit, for instance, by taking a chance with an innovative and promising treatment.

Or, more controversially, a patient might wish to take part in a research from which she knowingly stands no chance of receiving any benefit, for the sake of benefiting other patients or posterity. The issues discussed in this review stem from general features of clinical research and the RCT methodology, such as the need to subject patients to blindfolding and random allocation between treatment arms, or the point that medical research and practice respond to different ethical standards.

In closing this review, the author will examine the context of oncological research more specifically. As a consequence, most of the ethical issues we discussed through this chapter—for instance, the legitimacy of the use of placebo or the risk of therapeutic misconception—arise in the context of testing anticancer drugs to a preeminent point. Surgical procedures will not be considered in the following discussion, even though they represent the front-line intervention against several tumours, due to the fact that they are not typically evaluated through RCTs [ 30 ].

In addition to the questions already explored through the review, however, oncological research presents a whole new family of ethical issues as the field goes through the so-called genomic revolution. The completion of the Human Genome Project has brought about the potential for a profound transformation of the understanding and managing of non-infective diseases.

The offshoot is personalised or precision medicine, or the idea of proceeding from the genetic and molecular hallmarks of common diseases in order to design and administer situationally the least harmful and most effective treatment [ 31 ]. We will cover inappropriate contact with jurors, fist fighting judges, lying attorneys, inappropriate romantic interludes with clients, substance abuse, and much more. Well, no more. There are presumptions, assumptions and stereotypes that influence decisions.

Sometimes, these presumptions are good. But sometimes, they can work to discriminate against people based on race and sex. This class examines how implicit bias works, and how it can impact clients. Please be sure you know what time this is in your time zone. Comedian of Law cannot issue refunds for webinars for those that do not log in to Zoom at the proper time.

Laws that made homosexuality a criminal offence, and others that allowed racial and sexual discrimination, are examples that have existed in my lifetime. Our current health system, and the laws that maintain it as a self-regulated monopoly, is supported by a vociferous minority of physicians who are often not in clinical practice. In their enthusiasm to uphold the status quo, they have made pronouncements that illustrate a lack of insight and sensitivity into the plight of patients, and an arrogant disregard for the rights of individuals to exercise control over their own bodily health.

But the complexities of the waiting list issue suggest careful study and planning before we try to solve a problem that may be much smaller than we imagine. As for urgent patients in pain, the public system will decide when their pain requires care. These are societal decisions. The individual is not able to decide rationally.

Quebec decision to legalize private insurance in Quebec. Patients should not have to sue for access. We hope to persuade the court that Canadians should not be forced to suffer, and even die while they wait for care. Such an approach is not only unethical but, in our view, also illegal. Clarke J. Royal College of Physicians and Surgeons of Canada. Accessed 2 March