<br><h3> Chapter One </h3> <b>Research Ethics, Developing Countries, and Exploitation: A Primer</b> <p> JENNIFER S. HAWKINS <p> <p> As the AZT trials demonstrated, questions about the ethical conduct of clinical research in developing countries are anything but simple. Informed judgments about the cases in this book, and about future directions for policy, require familiarity with both the details of clinical research and significant moral distinctions. This chapter aims to provide some background material relevant to understanding the complexities of the current debates. <p> The first section provides a basic overview of the fundamental concepts of research ethics as they relate to developing country research—informed consent, randomized controlled trials (RCTs), standard of care, and clinical equipoise. It is intended for readers who are familiar with ethical theory but less familiar with the peculiar concerns of clinical research. It aims to familiarize them with the concepts and clearly articulate the disputed questions currently relevant for the discussions of international research that follow. <p> The second section provides an overview of the concept of exploitation to help orient those less familiar with philosophy to the ways in which philosophers have approached the topic. Exploitation is commonly associated with Marxism, but there is, in addition to the Marxist tradition, a robust tradition of non-Marxist accounts of exploitation of which the essays in this book are representative. This section will briefly introduce readers to both the Marxist and the non-Marxist understandings of the concept, and set out the central questions about exploitation that remain open for debate. <p> <p> <b>Brief Background to Clinical Research Ethics</b> <p> Medical research aims to generate knowledge that will hopefully, in turn, lead to improvements in medical practice. It is a long process. Often there is an initial phase of basic scientific research conducted in laboratories. Animal studies are then usually conducted before new agents are tried out in a human body. "Clinical research" refers to the later phases of medical research, when human bodies enter the equation. Even here there are multiple stages. "Phase I" is the name traditionally given to the first studies of an agent in humans. Such studies are usually very small, and hence cannot reveal anything general about how effective an agent is at curbing disease. Instead, the aim is to first learn about "toxicity, metabolism, and other drug dynamics." Many such studies are carried out on healthy volunteers, though research on new cancer drugs is an exception. <p> Phase II and Phase III studies are generally randomized controlled trials where the new agent is compared with something else. Unlike Phase I trials, they are usually conducted on subjects with the illness for which an improvement in treatment is being sought. Phase II studies are generally much smaller than Phase III, and still largely concerned with gaining understanding about safety and side effects. It is the large Phase III clinical trials that enroll hundreds and sometimes thousands of human subjects that aim to determine whether a new agent will indeed prove to be a useful general treatment for the illness in question. The controversies described here are all related to the conduct of Phase III trials. <p> <p> <i>Informed Consent</i> <p> Informed consent is almost universally recognized as a requirement for the ethical conduct of clinical research. Indeed, the more common danger in discussions of research ethics is for people to reduce all moral concerns about research to concerns about consent. While consent is important, it is only one of the key components of ethical research. <p> Valid informed consent has four requirements. First, only those potential subjects who pass the requirements for decision-making competence should be asked to give consent. When it is necessary to enroll incompetent subjects, consent must be obtained from an appropriate surrogate. Three additional requirements must be satisfied with respect to either the competent subject or the incompetent subject's surrogate. There must be full disclosure of all the relevant information, the subject or surrogate must understand the information, and he or she must then consent freely or voluntarily. Force, coercion, and undue inducement are all recognized as undermining the voluntariness, and hence the validity, of informed consent. <p> In the context of research in developing countries, a number of distinct and sometimes contradictory concerns have been raised about informed consent. Most recent discussion has emphasized the difficulties of obtaining genuine informed consent in developing countries. Another, older concern is that informed consent may not be culturally appropriate in all parts of the world. Whereas the first group is concerned that consent is not being obtained often enough, the second thinks that consent may not even be necessary. Let us consider first the concerns of those who think genuine consent is not obtained often enough. <p> Some of the concerns that arise here are concerns about <i>understanding</i>. In 1997, for example, a <i>New York Times</i> article that focused specifically on one of the controversial AZT trials in Côte d'Ivoire sponsored by the National Institutes of Health (NIH) and the Centers for Disease Control (CDC) raised worries about the true level of subject understanding. One subject singled out by the reporter clearly did not understand the concept of a placebo despite repeated explanations and questionings. She is quoted as saying: <p> They gave me a bunch of pills to take, and told me how to take them. Some were for malaria, some were for fevers, and some were supposed to be for the virus. I knew that there were different kinds, but I figured that if one of them didn't work against AIDS, then one of the other ones would. <p> <p> Although there is no evidence to suggest that this woman's poor level of understanding is a widespread phenomenon, such anecdotal evidence is understandably troubling to those who see full understanding among subjects as a central requirement for ethical research. No doubt the challenges of obtaining informed consent among poor, uneducated populations can be daunting. There are often significant language barriers. Not only must the information be translated, but many languages lack words for important medical-scientific concepts. It can be extremely difficult to find a way to explain randomization or the concept of a placebo. In authoritarian cultures, it may also be difficult to get subjects to appreciate that they really are free not to participate, and that their health care will not be jeopardized if they refuse. Then there is the problem—familiar from developed world settings as well—of the therapeutic misconception. This is the tendency of some patients to believe, despite being told otherwise, that the research has a therapeutic purpose. <p> Perhaps the most pressing theoretical question with relation to informed consent and understanding is that of <i>how much</i> understanding must be achieved if research is to go forward while remaining ethical. For this reason, the requirement of understanding is one of the more worrisome, and hence contentious, aspects of the traditional analysis. At one extreme is the view that understanding is not actually necessary for consent to be valid. At the other end is the equally extreme view that complete understanding of all details is required. Taken literally, this view would lead to the conclusion that much clinical research—not just clinical research conducted in developing countries—is unethical, because what evidence we have suggests that full understanding is rarely achieved in <i>any</i> setting. Most theorists appear to accept a view somewhere in the middle. But where to draw an appropriate line remains troubling. <p> Another set of extremely common concerns are those about <i>voluntariness</i>. For example, in a newspaper article detailing some of the worries about consent to research in developing countries, the law professor and bioethicist George Annas is quoted as saying: <p> I'd argue you can't do studies ethically in a country where there is no basic health care. You can tell a person there that this is research, but they hear they have a chance to get care or else refuse their only good chance at care. How can you put them in that position and then say they are giving informed consent? <p> <p> Although Annas does not say precisely what it is that undermines informed consent in these cases, his reference to the <i>choice</i> subjects face suggests that he is worried about voluntariness. He also suggests not just that obtaining informed consent is difficult but that, because of the circumstances in developing countries, it is actually <i>impossible</i>. This suggests, in turn, that he must either believe that all offers made in such circumstances are necessarily coercive, or that all such offers necessarily count as undue inducement. However, neither claim has any merit. <p> Unfortunately, it is not uncommon for theorists to assume that whenever a person facing a grim set of alternatives makes a choice—even if she chooses what under the circumstances is clearly in her best interests—it must be coerced. Such misconceptions are further ingrained because we often speak loosely of the "force" of circumstances. However, the identification of coercion proper requires that we consider two features: the choice set of the agent (B), and the actions (if any) of other parties (A) that have unfairly created that choice set. The first requirement for coercion is that B's set of options be altered unfavorably in the sense of being narrowed. This much is common to many cases of being "forced by circumstances." The second, equally important requirement for coercion, however, is that some agent A (the coercer) must have deliberately brought about the narrowing of the set so as to get B to do what he wants. This may come about as a result of A forcibly eliminating options from B's set. Alternatively (and much more commonly), it involves A threatening to make B worse off if B does not do as A wishes. (Here the <i>threat</i> serves to narrow the set of "good" options B has by altering the payoffs associated with them.) It is this second crucial condition that distinguishes coercion from mere harsh choice situations. <p> Once we abandon the simplistic equation of coercion with harsh choice situations, there is no reason to suppose that the offers researchers extend to potential subjects in developing countries are <i>necessarily</i> coercive as Annas suggests. There is simply no evidence to suggest that researchers routinely force or threaten subjects. They simply make them offers that are, in the sad context where subjects have few options for good health care, extremely attractive. <p> Those who think genuine informed consent is impossible in impoverished settings might, alternatively, be worried that all such transactions—made against a backdrop of poverty and desperation—constitute <i>undue inducement</i>. For example, in a recent policy brief, Lindegger and Bull note that "economic factors" may undermine voluntary consent. In particular, if subjects have few other options for health care, these authors worry that research may be too <i>attractive</i>. They give as an example the following statement from a Thai subject who claimed: <p> The study staff gives good advice and when this project is over I hope I can enroll in another study. For that matter, I hope there will be new studies for me to participate in all the time. If there would be no more studies, I don't know if I would have the strength to go on, as I would not know where to get drugs outside of clinical trials. <p> <p> The idea behind undue inducement is that some offers are excessive and hence irresistible in a way that is morally problematic. But how are we to understand this more precisely? While it is sometimes claimed that an offer is excessive whenever it leads a person to choose something she would not otherwise choose, this is a highly implausible account of the badness of undue inducement. That would suggest that every case of accepting a job for a good salary would count as undue inducement. A better account of what is morally problematic with undue inducement is that certain highly attractive offers may lead individuals to make choices that are not in their long-term interests, by, for example, leading them to accept risks that are not really worth it. However, if that is correct, it is hard to see how the offers made in developing world research necessarily induce in a bad way. For in the cases that concern us, the sad fact is that, by participating in research, subjects really are choosing something that does—given their current options—serve their long-term interests. As Annas admits in the quotation from earlier, it may be their only chance for effective care. <p> In short, since there is no reason to believe that either coercion or undue inducement is a <i>necessary</i> feature of offers made to subjects in developing countries, there is no reason to think that voluntary informed consent is impossible to obtain. <p> Let us now consider briefly the claims of those who think that informed consent in developing countries may not be ethically required and may even be culturally inappropriate. In the years prior to the dispute about the AZT transmission trials, a number of commentators argued that, for cultural reasons, individual informed consent might not be a necessary ethical requirement of research in developing countries. The claim was that informed consent is a uniquely Western ideal, one grounded in the peculiarly Western fascination with personal autonomy understood generally as individual decision making. Where this value is not shared, it was argued, it may be inappropriate to impose such practices. This does not seem to be a widely held view, and it has been explicitly challenged. But it does reflect genuine concerns people have had about how to approach informed consent in cultures where the practice does not neatly fit with local norms. Without being able to settle the issues here, it is worth making a few points about the general weakness of such arguments. The problem derives from placing too much emphasis on the autonomy-based justification for informed consent, as if that were the <i>only</i> reason to obtain informed consent. However, there are other justifications for the practice besides that one. <p> First, <i>even if</i> informed consent is a Western practice reflecting Western values, it is worth remembering that RCTs are also a Western practice that reflect Western values. Assuming that people are interested in importing the practice of RCTs, it may not be inappropriate to insist that informed consent be imported along with RCTs. At any rate, we should not take the mere fact that individuals in other places find the practice odd or cumbersome to be reason for giving it up. Their puzzlement may simply reflect their unfamiliarity with the realities of research as opposed to treatment. Informed consent is part of the apparatus developed in the West for safeguarding participants in a particular type of Western practice that strongly resembles but nonetheless differs from the practice of medicine. If it makes sense to think that ethical practices develop in accordance with the prevailing nonethical context, it would not be surprising to discover that a community with no tradition of research will have had no prior need to develop a practice of individual consent. But it would be too hasty to assume that it would not benefit from having a practice such as informed consent in place when it begins to participate in research. <p> Second, such arguments assume that the only ethical considerations that speak in favor of informed consent are considerations pertaining to decision making. In essence, the claim is that if individuals in a particular community do not value the opportunity to make decisions for themselves, then there is no need to obtain individual informed consent. This argument assumes that informed consent is merely a vehicle for allowing people to exercise decision-making power. <p> <i>(Continues...)</i> <p> <p> <!-- copyright notice --> <br></pre> <blockquote><hr noshade size='1'><font size='-2'> Excerpted from <b>Exploitation and Developing Countries</b> Copyright © 2008 by Princeton University Press. Excerpted by permission of Princeton University Press. All rights reserved. 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