The Participation of Impoverished Peoples in Placebo-Controlled Pharmaceutical Trials: Scientific Innovation or Neocolonial Exploitation?

Image Credit: Zixin “Harry” Wang

Madison E. Pelletier

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Royal Navy Doctor James Lind is credited with conducting one of the first known placebo-controlled trials. In 1572, he divided a group of his scurvy-ridden sailors into six sections, each receiving a different treatment, ranging from citrus fruits to seawater. Two treatments were proven effective; the remaining four were fatal (Lemoine 1). Thus began a long and controversial discourse. A placebo treatment, in this case seawater, is described as a substance with “no specific therapeutic effect on a patient’s condition, but believed by the patient to be therapeutic” (OED). The randomized, double-blind placebo-controlled trial, wherein neither patients nor doctors know whether the administered treatment is inert, is considered the paragon of research methodology. Ethically, however, physicians seem to stand in violation of their Hippocratic duty to “do no harm” by randomizing their patients to placebo, particularly if those patients are harmed by their lack of treatment––if they die of scurvy, for example (Tyson). Despite the modern prevalence of placebo-controlled trials, it was not until 2008 that their official allowance was written into the Declaration of Helsinki, the foremost governing document for medical and research professionals. Article II.3 of the Declaration, in its most current form, declares, “In any medical study, every patient—including those of a control group, if any—should be assured of the best proven diagnostic and therapeutic methods” (World Medical Association). The debate has thus arisen: is it possible to simultaneously possess a control group and provide the “best proven diagnostic and therapeutic methods,” or has the West simply grown complacent in the face of immorality, because the trials are no longer conducted on its soil? When we examine placebo trials through the lens of Kantian moral philosophy and historical medical ethics, it becomes apparent that the speed of scientific progress has outstripped the development of societal values, both individually and internationally.

The utilitarian case for placebo-controlled trials is clear cut: if lessening the quality of treatment for a minority of test-subjects increases the likelihood of advancing medical knowledge, thus helping the majority, it is permissible. Furthermore, if a drug cannot be proven to be more effective than a placebo within a clinical trial, then it ought not be sold. Some supporters go so far as to suggest that, given the primary role of the physician as an alleviator of patients’ suffering, it does not matter whether a person is receiving a proven drug or an inert substance; a treatment is morally permissible so long as it improves the comfort of the patient (Specter). Opponents of the practice, however, point to studies proving that even when suffering is reduced under administration of a placebo, the patient’s physical health does not improve (Wechsler 124). This contradicts the assumption that the placebo effect can stand in place of a proven treatment. Internationally, the debate hinges on what is possibly humanity’s most enduring moral dilemma: ethics versus economy. By hosting trials in developing nations, pharmaceutical companies assert that they are able to both keep costs low and provide medicine to underprivileged regions. Opponents point out that Western standards of informed consent are all but impossible to uphold in such trials (Miller). Critics also cite countless failed experiments as evidence that corporations cannot be trusted with the lives of the world’s vulnerable populations. Public moralists and developing nations fear the worst, envisioning an unstoppable era of pharmaceutical neocolonialism.

The core principles of Kantian morals and medical ethics have long been intertwined. At the heart of each philosophy rest the concepts of autonomy and beneficence. Kant bases his autonomy on the fundamental belief that every human is a rational being deserving of dignity and respect from others. Because this reason is what gives value to all other things, it is, in and of itself, invaluable. This principle lays the groundwork for the Formula of Humanity as an End, which dictates that a human being “is not a thing and hence not something that can be used merely as a means” (Kant 4:430). Within a Kantian framework, a decision does not possess moral worth unless it is made autonomously, meaning that it is based only upon the rationality of its maker. If coerced by another, the decision-maker is rendered merely a means to achieve that other person’s end. Kant goes on to further qualify this principle, noting the difference between choices made autonomously and those made “heteronomously” (Kant 4:434). Heteronomous choices are influenced by outside forces, be they base, physical need or the coercion of another (Kant 4:435). A decision founded upon fear for one’s safety, need of money, or misinformation cannot be autonomous, as each of these requires the suppression of reason in favor of some other physical or mental faculty. Within medical ethics, Kantian autonomy is honed into the concept of informed consent. This requirement is written into the Declaration of Helsinki, which states, “After ensuring that the potential subject has understood the information, the physician or another appropriately qualified individual must then seek the potential subject’s freely-given informed consent, preferably in writing” (WMA). Within both frameworks, ends reached through the coercion or deception of another are categorically impermissible.

The concept of medical beneficence, though not as clearly outlined, is equally indivisible from Kantian morals. This principle stands at the heart of medical ethics; the Declaration of Geneva of the World Medical Association declares on behalf of physicians, “The health of my patient will be my first consideration,” and the International Code of Medical Ethics dictates that “a physician shall act in the patient’s best interest when providing medical care” (WMA). It is the fundamental role of doctors to care for their patients, and it is this role that links the principle of beneficence to Kant’s categorical imperative. Within the imperative, each citizen is ordered to act only upon a maxim which she would will to become universal law. If the universalization of the maxim would result in its own invalidation, the maxim is impermissible (Kant 4:423). When examined against this formula of universal law, the necessity of beneficence stands. Citizens place both their trust and their bodies in the hands of physicians, who are expected to “promote and safeguard the health, well-being, and rights of patients” (WMA). If it were to become universal law that these so-called caregivers acted against the best interest of their patients, the people would no longer employ their care, and the profession itself would cease to exist. It is with these two core values that each question within the bioethical discourse must be considered, and the debate surrounding placebo-controlled trials is no exception. By administering an inert substance in place of a proven therapy, physicians may be advancing medical knowledge, but by doing so, they render their patients as mere means to scientific discovery, as opposed to  rational beings deserving of care in their own right.

To begin discussion of the moral application of the placebo effect, one key misunderstanding must first be addressed. The placebo effect is the phenomenon observed when patients given inert substances, such as sugar or saline, report the same lessening of symptoms as their counterparts receiving the trial’s active drug. It is generally accepted that the placebo effect is a part of the body’s natural response to medication––when the brain believes it will soon receive a painkiller, for example, endorphin production begins independently in order to prepare for the effects of the medicine (Specter). Where public perception falls short of fact, however, is in equating subjective relief to objective medical benefit. In a groundbreaking study published in the New England Journal of Medicine, researchers found that placebo treatments were highly effective in the reduction of symptoms, yet showed no ability to cure the underlying medical issue causing those symptoms. This study was performed on participants with mild to severe asthma. Of the four trial arms, one received no treatment of any kind, one was given placebo acupuncture, one a placebo inhaler, and one group received an inhaler with active Albuterol, the most common treatment for asthma patients in the United States. Though both placebo groups reported roughly the same comfort-level as those given Albuterol, their lung function––measured by their performance on an FEV exhalation test––was not improved (Wechsler 123). This study highlights an important fallacy within the debate: that a patient’s increased comfort level necessarily means that they are healing. Proponents of placebo-usage argue that the health of a patient in the control group is improved by the placebo effect, thus absolving themselves of the moral responsibility to treat illness. The effect is not a miracle cure, however, and a saline injection will not treat hypertension any more than a sham inhaler improves asthmatic lungs. The doctors who administer these treatments cannot claim to fulfill their duty of beneficence, as a placebo group is not receiving the best care available. With this in mind, the debate becomes one of scientific detachment versus medical responsibility.

Western pharmaceutical corporations have, by and large, shipped their trials overseas, where both the cost and risks are lower. Corporate officials claim that Western standards of informed consent are upheld within the trials, but critics point out the sheer improbability of that statement. In a recent interview, Dr. Arthur Kaplan, director of the University of Pennsylvania’s Center for Bioethics, noted that pharmaceutical trials can no longer find sufficient participation for trials held in the West, because citizens simply “don’t want to be randomized to placebo” (Miller). Despite the unwillingness of their Western counterparts, pharmaceutical companies claim that each of their trial participants has given their own fair consent, with full knowledge of the trial’s methodology and potential treatment plans. Dr. Arand Rai, who was fired from his job at a hospital in Indore, India for raising ethical concerns, contests this statement. According to Rai, the doctors at his hospital specifically chose “poor, illiterate people who do not understand the meaning of clinical drug trials” to participate (Lloyd-Roberts). When a person in a developing nation is offered the opportunity to participate in a Western drug trial, it may very well be their only way to receive treatment for their condition. These people do not have the choice between participating in a potentially high-risk, experimental trial or going to their local doctor to purchase a proven treatment. They are at the mercy of the trial. Dr. Kaplan poses the question: “are [the participants] really giving you informed consent or will they sign up for anything that you show up with because they are desperate and have an overwhelming faith in anybody in a white coat?” (Miller). Again, consent that is gained through coercion and misinformation fundamentally cannot be autonomous; these patients, most of whom are poor, ailing, and scared, are acting upon their heteronomous, physical needs, and the abuse of such a situation is morally impermissible. Proponents of these trials have offered many solutions to this methodological failing, going so far as to propose a system of “community consent” wherein local leaders are tasked with both informing and consenting for their community (Weijer). This system, however, which seems to put poor women at disproportionate risk within male-dominated developing nations, would not increase the subjects’ autonomy, but detract from it. In her review of the oft-criticized maternal-fetal HIV transmission trials of the 1990s, researcher Paquita de Zulueta of Imperial College London notes the failings of such a system, and argues that “if individuals’ competence is vitiated by a lack of understanding, they should be afforded greater protection, not less” (304). If a patient’s ability to exercise their autonomy is compromised, it is the duty of the physician to bridge the ethical divide by acting beneficently on behalf of the patient, not the corporation.

Pharmaceutical companies may be in the business of saving lives, but they prioritize the success of that business above all else. It is failingly idealistic to expect that a multibillion dollar corporation will act according to the well-being of their trial participants when it is opposed to their pocketbooks; providing healthcare to the poor, though noble, is not inexpensive. The fifth version of the Declaration of Helsinki, released by the World Medical Association in 2005, had even expressly “prohibited the use of placebos in situations of local scarcity if the ‘best current method’ exists elsewhere” (de Zulueta 307). Since the Declaration’s revision in 2008, however, the use of placebo-controls has skyrocketed, and supporters argue that their obligation rests only in providing “the highest standard of care practically attainable in the country in which the research is being carried out” (Perinatal HIV Intervention Research). By this measure, the responsibility to provide care for participants in some of the world’s poorest regions is all but nonexistent. Vindicated by this line of thinking, administrators of pharmaceutical trials feel no responsibility to care for a community that is no longer profitable. De Zulueta notes the prevalence of HIV trials that, upon completion, leave their participants ostracized without treatment, without prospects, and without a cure (de Zulueta 290). Once these participants have served their purpose, they are worthless. In 2003, a trial of the mania drug Risperdal came under fire for its abuse of international health standards. The trial, conducted on poor citizens of Gujarat, India, took psychiatric patients off of their existing medicine, placing them into groups receiving either risperidone or a placebo drug. The placebo arm of the trial possessed 145 patients (Weyzig and Schipper). Given the high instances of acute and long-term morbidity associated with untreated mania, sources, such as the British Journal of Psychology, have called the trial “unethical and inhumane,” suggesting, “All future trials concerning the efficacy of a medication for acute mania should use an arm with one of the proven medications as a comparator and not include a placebo arm” (Basil). A similar trial was conducted, with joint sponsorship from the UK Medical Research Council (MRC), Rockefeller Foundation, DfID (Uganda), GlaxoSmithKline, Gilead, and Boehringer-Ingelheim, in Uganda, Zimbabwe, and Côte d’Ivoire from 2003 to 2005. The trial, which tested Anti-Retroviral Therapy––used to slow the progress of the HIV virus––forced a group of patients off of their medication in order to test the effects of intermittent treatment. Though concerns were raised during the trial, attempts to re-administer ART drugs failed, and several members of the interruption group died (Weyzig and Schipper).

Trials such as these––and unfortunately these are only two of many examples––breed distrust of foreign entities abroad, making the work of truly beneficent groups all the more difficult. When administrators of these trials deny patients their life-saving medicine in order to satisfy the curiosity of Western scientists, the Hippocratic principle of nonmaleficence is all but disregarded and human lives are treated as nothing more than a means to medical discovery and financial gain (Tyson). This is not because corporations actively wish to do harm, but rather because they can afford to not do good. For every settlement a corporation must pay, such as the $175,000 payout Pfizer recently made to four of the eleven families whose children they killed in a clinical drug trial in Nigeria (“Pfizer: Nigeria Drug Trial Victims Get Compensation”), they stand to gain millions from the development of a successful new drug. It is clear that pharmaceutical corporations cannot be relied upon to “do no harm” (Tyson) to the more vulnerable patients they test. With this in mind, it is of the utmost importance that regulatory bodies, be they federal or non-governmental, take a stand against the abuse of vulnerable populations and force these corporations to incorporate beneficence into the caregiving process once more.

It is impossible to host a placebo-controlled trial abroad without violating the core ethical values of autonomy and beneficence. The Declaration of Helsinki’s “best proven diagnostic and therapeutic methods” are never given, and often even standard, local medical care is denied to participants. The myth of informed consent is little more than the abuse of a people who hold “the implicit assumption that health care professionals will always protect patient’s best interests, and provide effective treatment” (de Zulueta 310). These people are not in a position to make autonomous decisions; instead, their rationality is suppressed and their physical health exploited to ensure their enrollment in potentially dangerous medical experiments. Not only do the trials take advantage of this assumption of beneficence, but they fail to deliver even the most basic care inherent in that duty. Multinational pharmaceutical corporations have been caught time and again disregarding the health, safety, and dignity of their patients in order to maximize their profit margins. Within the framework of both classic Kantian morals and the modern medical ethic, it is clear that the use of placebo-controlled trials in the developing world is an impermissible abuse of vulnerable populations. The lives of the world’s poorest citizens cannot to be used merely as a means to provide a product for their Western counterparts. They are humans, and they deserve better than what has been forced upon them.

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