There’s been a pretty fierce debate in public health circles over a pressing question, when testing drugs to treat Ebola virus or vaccines that might prevent infection. Ebola treatments carried out in makeshift emergency hospitals by researcher in the middle of a deadly epidemic, will be some of the most unusual drug trials ever done. And they also raise major ethical and practical questions, some of which were intensely debated at a World Health Organization (WHO) meeting in Geneva, Switzerland, on 11 and 12 November.
The ethical tension has several facets, according to which aspect of the RCT is put in the spotlight. 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.
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. For instance, according to the Declaration of Helsinki in its most recent formulation, the use of placebo is acceptable under the condition that no proven treatment exists, but also ‘where for compelling and scientifically sound methodological reasons, [it] is necessary to determine the efficacy or safety of an intervention’, provided that ‘the patients who receive placebo or no treatment will not be subjected to any risk of serious or irreversible harm.
The term ‘human experimentation’ still evokes, in many, the ghastly impression of the infamous experiments conducted on war prisoners during World War II. Such episodes, taking place in democratic and civilised countries, were the proof that war atrocities were not the only threat to the condition of human research subjects: the conception of research ethics had to be recast as a whole. Indeed, until as recently as the 1970s, the medical investigator was considered the sole authority that could adjudicate the legitimacy of a study protocol.
At the same time, 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 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. The endeavour of medical research actually confronts physicians with an ethical dilemma. On the one hand, the doctor is bound by her professional ethics to do all that is in her power to benefit her current patient. On the other hand, though, the doctor has also an obligation to forward medical science to the benefit of future patients. The necessity of a framework for critically discussing and evaluating human experimentation arises because the tools of medical ethics alone are insufficient to direct a course of action in the face of such a dilemma.
A physician who is personally more inclined towards scientific progress may feel that her duty falls more on the side of pursuing research and thus eventually establishing better therapeutic options, while her colleague may instead feel bound to care for her current patients regardless of medical progress. Furthermore, in such a framework, there is no place for considerations that we do instead value in other contexts in our society, such as the right of patients to decide whether they want to take part in research or not.
In essence, 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.
Whatever the cause of the interest research involving human subjects has anything but a glorious legacy and it’s effects are clear. There is of course a glaring irony in the fact that, in some extreme cases at least, it was premeditated murder that facilitated a supply of corpses to the medical profession that, in turn, led to the advancement of medical science and ultimately to the saving of lives. It goes to show that the history of medicine needed not just heroes but a few villains along the way to give us the knowledge and intricate understanding of the human body that we have today. It also demonstrates that this knowledge must never be taken for granted, and asks those of us who feel uneasy about donating our bodies or bits of our bodies to medical science to perhaps think again about how valuable our contribution may be to society as a whole.
Knowledge of the internal structure of the human body was already considerable by the eighteenth century – thanks in part to the illegal acquisition of human corpses by the medical profession – as this superbly detailed drawing from 1748 of the head and neck by anatomist Jaques-Fabien Gautier shows – advances in medical science that took place before the time of the Anatomy Act could not have come about without the practice of body snatching. However, how simple or crude the practice of medicine and surgery back then may seem to us, it was still treating people and still saving lives, and the doctors owed their extensive knowledge and skills at least in part to the resurrection men.
Our modern concept of research with human subjects is inspired by three influential documents, conceived in the aftermath of the episodes of research misdemeanour. First is, The Nuremberg Code: a legal and ethical code promulgated by the U.S. judges at the trial of the Nazi doctors at Nuremberg after World War II.
Many consider it as the most authoritative legal reference on the subject of human experimentation.
It is based on universal principles of natural law and human rights, and it establishes the basic principle that the participation in research requires the free, informed consent of the participating subject.
Second, The Declaration of Helsinki: arguably the most widely known and influential guideline in medical research worldwide. It is an official policy of the World Medical Association (WMA), which was adopted for the first time in 1964 and has since undergone a number of revisions. The Declaration can be regarded as the expression of the WMA’s effort in balancing the need to generate sound medical knowledge with the need to protect the health and interests of research participants.
And third, Randomised controlled trials (RCTs)
Over the past decades, randomised controlled trials (RCTs) have prevailed over clinical judgement, case reports, and observational studies and became the gold evidential standard in medicine. Furthermore, during the same time frame, RCTs became a crucial part of the regulatory process whereby a new therapeutic can gain access to the drug market. 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.
For many clinical indications there will often be several possible interventions. The evidence base consists of a set of pair-wise comparisons of interventions
–Placebo comparisons of limited use to the practitioner or policy-maker who wants to know the ‘best’ treatment to recommend/ prescribe.
Health care decisions should be based on ‘best available’ evidence from systematic reviews & meta-analysis of RCTs.
So far, investigational Ebola drugs have generally been used in the few patients —that received experimental intervention treatment in the United States or Europe. Given the accelerated development of Ebola drugs (which involves, for example, proceeding on the basis of only limited phase 1 data and little or no traditional phase 2 data) and preliminary data suggesting potential for adverse effects, such drugs need to be evaluated in RCTs with an appropriate control group so that any harm can be detected.
Do the treatments of Ebola work?
Researcher will soon begin trials in West Africa to find a solid answer to the question. Perhaps the most important question: a disease as deadly as Ebola: Is it right to do randomized controlled trials in which some people don´t get the novel intervention? From the epistemic point of view, the idea behind the RCT is that of the counterfactual analysis. When a new treatment is administered to a patient and an improvement in her condition is observed. Otherwise, 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. In an RCT, participants are divided into two groups, one that receives the experimental treatment and another that acts like a control, providing the answer to the ‘what if’ counterfactual question.
Properly designed RCTs that give reliable answers are critical to identifying urgently needed treatments for responding to the ongoing Ebola crisis and any future outbreaks. “RCTs is the sole means of obtaining knowledge about efficient treatments” — The Case for RCTs. The argument is made in the New England Journal of Medicine by three FDA officials: Edward Cox, M.D., M.P.H., Luciana Borio, M.D., and Robert Temple, M.D. Evaluating Ebola Therapies. Randomized, placebo-controlled trials are necessary, they write, and, in fact, the speediest way of actually getting vaccines that might control the outbreak and treatments that might save patients’ lives into broad use.